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This document is a response to a comment on an article titled "Single-Cell Transcriptomics Reveals Novel Role of Microglia in Fibrovascular Membrane of Proliferative Diabetic Retinopathy." The authors address the comment and concerns raised by Corano Scheri and Fawzi. They explain that microglia, a type of myeloid cell, express macrophage-related genes and exhibit heterogeneous disease-associated profiles. The authors acknowledge that further experiments are needed to determine the ontogeny of profibrotic retinal myeloid cells. They also discuss the expression of certain markers in FVM-resident myeloid cells and their similarity to scar-associated macrophages in other fibrotic diseases. The authors emphasize the importance of understanding the immunopathogenic nature of FVM for the development of targeted therapeutic strategies. [Extracted from the article]

Introduction: Fixed-combination bimatoprost 0.03%/timolol 0.5% ophthalmic solution (FCBT; Ganfort®, Allergan, an AbbVie company) effectively reduces intraocular pressure (IOP) via complementary mechanisms of action of the agents, but long-term (> 12 weeks) safety evaluations of FCBT remain limited. FCBT safety is evaluated herein, with particular focus on hyperemia and eyelash growth, at 24 weeks in Chinese patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods: In this multicenter, open-label, noncomparative, phase 4 study conducted in China, patients diagnosed with OAG or OHT having insufficient response to β-blocker- or prostaglandin analogue/prostamide (PGA)-based IOP-lowering monotherapy in one or both eyes were switched from their current IOP-lowering treatment to FCBT (one drop per eye every evening) without prior washout. Assessment visits were scheduled at baseline and weeks 4, 12, and 24 (or study exit). The primary outcome measure was adverse event (AE) incidence through 24 weeks. Results: Of 725 patients enrolled, 632 (87.2%) completed the study; 93 (12.8%) patients discontinued, including 29 (4.0%) due to AEs. Of 1326 FCBT-treated eyes (total), 594 (44.8%) experienced ≥ 1 ocular treatment-related AE during the study. Conjunctival hyperemia (the most common AE overall) and eyelash growth were reported in 269 (20.3%) and 54 (4.1%) FCBT-treated eyes, respectively. The incidence of other known PGA-related AEs (including blepharal pigmentation and erythema of eyelid) was < 10% each. Most conjunctival hyperemia reports were mild in severity (214/259; 82.6%) and only 1/259 (0.4%) was severe. Similarly, most cases of eyelash growth were mild (46/52; 88.5%); none were severe. One (< 0.1%) FCBT-treated eye had a serious ocular AE (OAG) considered FCBT-related. Conclusions: The frequency and severity of FCBT-related AEs, including conjunctival hyperemia and eyelash growth, are consistent with previously published findings. No new safety concerns were raised. This prospective study reaffirms that once-daily FCBT is a safe and well-tolerated therapy for OAG and OHT. ClinicalTrials.gov Identifier: NCT02571712. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy, predictability, stability, safety, and complications of secondary anterior iris fixation of the Artisan iris-fixated intraocular lens (IOL) to correct aphakia in eyes without sufficient capsule support. Setting: Department of Ophthalmology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China. Design: Cohort study. Methods: Eyes having implantation of aphakic iris-fixated IOLs for aphakia correction were followed for 3 years. Results: The study evaluated 72 eyes (72 patients). After 3 years, the uncorrected distance visual acuity improved in all eyes (P<.05); 53 eyes (73.6%) reached 20/40 or better. Two eyes had a postoperative corrected distance visual acuity (CDVA) worse than the preoperative CDVA due to postoperative ischemic optic neuropathy and retinal detachment, respectively. The mean spherical equivalent (SE) decreased from 11.65 diopters (D) ± 1.21 (SD) to −0.58 ± 0.56 D (P<.05); the SE at the last follow-up was within ±1.00 D of the target refraction in 63 eyes (87.5%). The mean endothelial cell loss 3 years postoperatively was 9.78%. There was no significant postoperative intraocular pressure increase throughout the follow-up. Twelve patients (16.7%) reported glare and halos during night driving. Iris pigment precipitates on the IOLs occurred in 4 eyes (5.6%) 3 years postoperatively. No other serious complications occurred. Conclusions: Three-year results indicate that secondary implantation of aphakic IOLs is effective, predictable, and safe for the correction of aphakia in eyes without capsule support. However, longer follow-up with a larger cohort is necessary to confirm these conclusions. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, a combined interior point homotopy method is used to solve constrained nonconvex programming problems. Some results for the homotopy pathway are obtained. It is known that a K–K–T point can be obtained from this homotopy method, and it proves that, when the homotopy map is a regular map, the K–K–T point must be a local minimum point on choosing a proper homotopy equation. [Copyright &y& Elsevier]

This cross-sectional study aims to investigate the prevalence and causes of visual impairment (VI) and blindness in Jiangsu Province, China in 2022 during the COVID-19 pandemic. Participants (n = 13,208, aged 18–93) underwent comprehensive ocular examinations. The prevalence and causes of binocular VI (presenting visual acuity [VA] ≥ 20/400 and < 20/63 in the better eye) and blindness (presenting VA < 20/400 in the better eye) were assessed according to the World Health Organization (WHO) criteria. The estimation of refractive error prevalence was conducted using the following classification: myopia ≤ − 0.50 diopters (D), high myopia ≤ − 6.00 D, hyperopia ≥ 0.50 D, and anisometropia ≥ 1.00 D. The overall prevalence of binocular VI and blindness was 21.04% (95% confidence interval [CI] 20.35–21.74%) and 0.47% (95% CI 0.37–0.60%). The highest prevalence of binocular VI was in the population aged 18–24 years old (46.29%, [95% CI 44.30–48.28%]), those with education at university and above (43.47%, [95% CI 41.93–45.02%]), students (54.96%, [95% CI 52.73–57.17%]). Uncorrected refractive error (URE) was the leading cause of presenting binocular VI (93.40%) and blindness (50.79%). The prevalence of myopia was 54.75% (95% CI 53.90–55.60%). Actions are needed to control URE and myopia within the adult Chinese population, with a particular emphasis on the younger, well-educated demographic. [ABSTRACT FROM AUTHOR]

Abnormal ocular neovascularization, a major pathology of eye diseases, leads to severe visual loss. The role of lens epithelial cell (LEC)‐derived exosomes (Lec‐exo) is largely unknown. Thus, we aimed to investigate whether Lec‐exo can inhibit abnormal ocular neovascularization and explore the possible mechanisms. In our study, we proved the first evidence that exosomes derived from LECs attenuated angiogenesis in both oxygen‐induced retinopathy and laser‐induced choroidal neovascularization mice models. Further in vitro experiments proved that Lec‐exo inhibited proliferation, migration, and tube formation capability of human umbilical vein endothelial cells in high glucose condition. Further high‐throughput miRNAs sequencing analysis detected that miR‐146a‐5p was enriched in Lec‐exo. Mechanistically, exosomal miR‐146a‐5p was delivered to endothelial cells and bound to the NRAS coding sequence, which subsequently inactivated AKT/ERK signaling pathway. We successfully elucidated the function of Lec‐exo in inhibiting abnormal ocular neovascularization, which may offer a promising strategy for treatment of abnormal ocular neovascularization. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is currently one of the common causes of vision loss in working-age adults. It is clinically diagnosed and classified according to the vascular changes in the fundus. However, the activation of immune cells occurs before these vascular changes become detectable. These, together with molecular studies and the positive clinical outcomes of anti-inflammatory treatment, highlight the pivotal involvement of the immune system. The role of innate immunity in DR pathophysiology has been studied in depth, but the contribution of adaptive immunity remains largely elusive. This review aims to summarize our current understanding of the activation mechanism of adaptive immunity in DR microenvironments and to discuss the relationship between adaptive immunity and local vascular units or innate immunity, which opens new avenues for clinical applications in DR treatment. [ABSTRACT FROM AUTHOR]

• MiRNA sequencing for exosomes. • Some selective exosomal miRNAs from retinal pigment epithelial cells expressed by oxidative stress. • Potential functions and targets of the differentially expressed exosomal miRNAs. The function of exosomal miRNAs (miRs) in retinal degeneration is largely unclear. We were aimed to investigate the functions of exosomes as well as their miRs derived from retinal pigment epithelial (RPE) cells following exposure to oxidative stress (OS). After the OS by lipopolysaccharide and rotenone on RPE cells, interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α) were upregulated, along with the decreased mitochondrial membrane potential and upregulated oxidative damage marker 8-OH-dG in RPE cells. RPE-derived exosomes were then isolated, identified, injected into the subretinal space in mice. After subretinal injection, RPE-exosomes after OS not only induced higher ROS level and apoptotic retinal cells, but also elevated IL-1β, IL-6 alongside TNF-α expressions among retina/RPE/choroidal complex. Next, miRs inside the exosomes were sequenced by the next generation sequencing (NGS) technology. NGS revealed that certain miRs were abundant in exosomes, while others were selectively kept by RPE cells. Further, downregulated miRs, like miR-125b-5p, miR-125a-5p, alongside miR-128-3p, and upregulated miR, such as miR-7-5p were validated byRT-qPCR. Finally, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to find the possible target genes of those selective exosomal miRs. Our results proved that the RPE-derived exosomes after OS selectively express certain miRs, providing novel insights into the pathogenesis of age-related macular degeneration (AMD) in future. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR), a most common microangiopathy of diabetes, causes vision loss and even blindness. The mechanisms of exosomal lncRNA remain unclear in the development of DR. Here, we first identifed the pro-angiogenic effect of exosomes derived from vitreous humor of proliferative diabetic retinopathy patients, where lncRNA-MIAT was enriched inside. Secondly, lncRNA-MIAT was demonstrated significantly increased in exosomes from high glucose induced human retinal vascular endothelial cell, and can regulate tube formation, migration and proliferation ability to promote angiogenesis in vitro and in vivo. Mechanistically, the pro-angiogenic effect of lncRNA-MIAT was via the lncRNA-MIAT/miR-133a-3p/MMP-X1 axis. The reduced level of lncRNA-MIAT in this axis mitigated the generation of retinal neovascular in mouse model of oxygen-induced retinopathy (OIR), providing crucial evidence for lncRNA-MIAT as a potential clinical target. These findings enhance our understanding of the role of exosomal lncRNA-MIAT in retinal angiogenesis, and propose a promising therapeutic strategy against diabetic retinopathy. [Display omitted] • LncRNAs may serve as interventional targets in management of DR. • The exosomes from vitreous humor (VH) of PDR patients (exo-PDR) exhibited a pro-angiogenic property. • LncRNA-MIAT modulated MMP-X1 expression through sponging miR-133a-3p. • The role of exosomal lncRNA-MIAT in retinal angiogenesis may propose a promising therapeutic strategy against DR. [ABSTRACT FROM AUTHOR]

Objectives: Stem cell‐derived photoreceptor replacement therapy is a promising strategy for the treatment of retinal degenerative disease. The development of 3D retinal organoids has permitted the production of photoreceptors. However, there is no strategy to enrich a specific photoreceptor subtype due to inadequate knowledge of the molecular mechanism underlying the photoreceptor fate determination. Hence, our aim is to explore the uncharacterized function of somatostatin signalling in human pluripotent stem cell‐derived photoreceptor differentiation. Materials and Methods: 3D retinal organoids were achieved from human embryonic stem cell. The published single‐cell RNA‐sequencing datasets of human retinal development were utilized to further investigate the transcriptional regulation of photoreceptor differentiation. The assays of immunofluorescence staining, lentivirus transfection, real‐time quantitative polymerase chain reaction and western blotting were performed. Results: We identified that the somatostatin receptor 2 (SSTR2)‐mediated signalling was essential for rod photoreceptor differentiation at the precursor stage. The addition of the cognate ligand somatostatin in human 3D retinal organoids promoted rod photoreceptor differentiation and inhibited cone photoreceptor production. Furthermore, we found that the genesis of rod photoreceptors was modulated by endogenous somatostatin specifically secreted by developing retinal ganglion cells. Conclusions: Our study identified SSTR2 signalling as a novel extrinsic regulator for rod photoreceptor fate determination in photoreceptor precursors, which expands the repertoire of functional signalling pathways in photoreceptor development and sheds light on the optimization of the photoreceptor enrichment strategy. [ABSTRACT FROM AUTHOR]

Purpose: To monitor the intraocular proangiogenic and profibrotic cytokine profiles within 7 days after intravitreous injection of conbercept (IVC) for patients with proliferative diabetic retinopathy (PDR). Methods: This prospective, randomized controlled, consecutive, comparative study included 157 eyes with PDR. Participant eyes underwent sham IVC or IVC and subsequent vitrectomy at days 2, 3, 4, 5, 6, 7 postinjection. The intraocular cytokines profiles were measured using beaded assay methods. Results: After IVC, the vascular endothelial growth factor (VEGF)‐A level in PDR vitreous decreased rapidly by approximately 10 times at day 2 (p = 0.00001) and kept at a low level at days 3, 4, 5, 6, 7 (p < 0.001, each compared with IVC‐sham group). Similar tendency of the change in VEGF‐A was observed in aqueous humour. The level of placenta growth factor (PIGF) in aqueous humour decreased 2 days after IVC whereas returned to baseline level after 5 days. The vitreous profibrotic cytokines, tissue growth factor (TGF)‐β1, TGF‐β2, TGF‐β3 and connective tissue growth factor did not increase after IVC in each group. Conclusion: We observed a remarkable and rapid decrease in intraocular VEGF‐A, temporal decrease in PIGF from day 2 to day 4, increase in VEGF‐C and VEGF‐D from day 2 onwards, but no profibrotic switch in PDR eyes after IVC. The findings might suggest that ideal vitrectomy timing might be around 3 days after IVC. [ABSTRACT FROM AUTHOR]

Vitreous fibrovascular membranes (FVMs), the hallmark of proliferative diabetic retinopathy (PDR), cause retinal hemorrhage, detachment, and eventually blindness. However, little is known about the pathophysiology of FVM. In this study, we used single-cell RNA sequencing on surgically harvested PDR-FVMs and generated a comprehensive cell atlas of FVM. Eight cellular compositions were identified, with microglia as the major cell population. We identified a GPNMB+ subpopulation of microglia, which presented both profibrotic and fibrogenic properties. Pseudotime analysis further revealed the profibrotic microglia was uniquely differentiated from retina-resident microglia and expanded in the PDR setting. Ligand-receptor interactions between the profibrotic microglia and cytokines upregulated in PDR vitreous implicated the involvement of several pathways, including CCR5, IFNGR1, and CD44 signaling, in the microglial activation within the PDR microenvironment. Collectively, our description of the novel microglia phenotypes in PDR-FVM may offer new insight into the cellular and molecular mechanism underlying the pathogenesis of DR, as well as potential signaling pathways amenable to disease-specific intervention. [ABSTRACT FROM AUTHOR]

Highlights: [•] We established the pNCHS4 Rho–NLS–cre plasmid that containing human rhodopsin promoter. [•] Rho–Cre transgenic mice were generated by vector construction and pronuclear microinjection. [•] Retina-specific expression of Rho–Cre mRNA was determined by RT-PCR. [•] Cre expression and activity were obtained in rod photoreceptors when crossed with Rosa26R mice by X-gel staining. [ABSTRACT FROM AUTHOR]

The lens is an avascular tissue, where epithelial cells (LECs) are the primary living cells. The role of LECs-derived exosomes (LEC-exos) is largely unknown. In our study, we determined the anti-angiogenic role of LEC-exos, manifested as regressed retinal neovascularization (NV) using the oxygen-induced retinopathy (OIR), and reduced choroidal NV size and pathological vascular leakage using the laser-induced choroidal neovascularization (laser-induced CNV). Furthermore, the activation and accumulation of microglia were also restricted by LEC-exos. Based on Luminex multiplex assays, the expressions of chemokines such as SCYB16/CXCL16, MCP-1/CCL2, I-TAC/CXCL11, and MIP 3beta/CCL19 were decreased after treatment with LEC-exos. Transwell assays showed that LEC-exos restricted the migration of the mouse microglia cell line (BV2 cells). After incubation with LEC-exos-treated BV2 cells, human umbilical vein endothelial cells (hUVECs) were collected for further evaluation using tube formation, Transwell assays, and 5-ethynyl-2′-deoxyuridine (EDU) assays. Using in vitro experiments, the pro-angiogenic effect of microglia was restricted by LEC-exos. Hence, it was investigated that LEC-exos attenuated ocular NV, which might attribute to the inhibition of microglial activation and accumulation. • LEC-exos play a pivotal role in the non-vascularized state of the lens. • Microglia stimulated with hypoxia or inflammation promote the ocular angiogenesis. • LEC-exos suppressed the activation and accumulation of microglia. • After pretreated with LEC-exos, BV2 cells display less pro-angiogenic effect. [ABSTRACT FROM AUTHOR]

Optical coherence tomography angiography (OCTA) is a novel imaging modality that has been widely utilized in ophthalmology and neuroscience studies to observe retinal vessels and microvascular systems. However, publicly available OCTA datasets remain scarce. In this paper, we introduce the largest and most comprehensive OCTA dataset dubbed OCTA-500, which contains OCTA imaging under two fields of view (FOVs) from 500 subjects. The dataset provides rich images and annotations including two modalities (OCT/OCTA volumes), six types of projections, four types of text labels (age/gender/eye/disease) and seven types of segmentation labels (large vessel/capillary/artery/vein/2D FAZ/3D FAZ/retinal layers). Then, we propose a multi-object segmentation task called CAVF, which integrates capillary segmentation, artery segmentation, vein segmentation, and FAZ segmentation under a unified framework. In addition, we optimize the 3D-to-2D image projection network (IPN) to IPN-V2 to serve as one of the segmentation baselines. Experimental results demonstrate that IPN-V2 achieves an about 10% mIoU improvement over IPN on CAVF task. Finally, we further study the impact of several dataset characteristics: the training set size, the model input (OCT/OCTA, 3D volume/2D projection), the baseline networks, and the diseases. The dataset and code are publicly available at: https://ieee-dataport.org/open-access/octa-500. • Proposed OCTA-500, which is the largest and comprehensive OCTA dataset. • The OCTA-500 includes OCTA imaging from 500 subjects and rich annotation information. • Proposed a CAVF task, which integrates multiple key segmentation tasks. • Optimized the IPN to IPN-V2 to serve as one of the competitive baselines. • The OCTA-500 dataset has great potential to promote other researches in OCTA. [ABSTRACT FROM AUTHOR]

Purpose: To robustly segment retinal layers that are affected by complex variety of retinal diseases for optical coherence tomography angiography (OCTA) en face projection generation. Methods: In this paper, we propose a robust retinal layer segmentation model to reduce the impact of multifarious abnormalities on model performance. OCTA vascular distribution that is regarded as the supplements of spectral domain optical coherence tomography (SD‐OCT) structural information is introduced to improve the robustness of layer region encoding. To further reduce the sensitivity of region encoding to retinal abnormalities, we propose a multitask layer‐wise refinement (MLR) module that can refine the initial layer region segmentation results layer‐by‐layer. Finally, we design a region‐to‐surface transformation (RtST) module without additional training parameters to convert the encoding layer regions to their corresponding layer surfaces. This transformation from layer regions to layer surfaces can remove the inaccurate segmentation regions, and the layer surfaces are easier to be used to protect the retinal layer natures than layer regions. Results: Experimental data includes 273 eyes, where 95 eyes are normal and 178 eyes contain complex retinal diseases, including age‐related macular degeneration (AMD), diabetic retinopathy (DR), central serous chorioretinopathy (CSC), choroidal neovascularization (CNV), and so forth. The dice similarity coefficient (DSC: %) of superficial, deep and outer retina achieves 98.92, 97.48, and 98.87 on normal eyes and 98.35, 95.33, and 98.17 on abnormal eyes. Compared with other commonly used layer segmentation models, our model achieves the state‐of‐the‐art layer segmentation performance. Conclusions: The final results prove that our proposed model obtains outstanding performance and has enough ability to resist retinal abnormalities. Besides, OCTA modality is helpful for retinal layer segmentation. [ABSTRACT FROM AUTHOR]

Aims: To investigate the association between diabetic retinopathy (DR) in type 2 diabetes mellitus and three polymorphisms of the receptor for advanced glycation end products (RAGE) gene, -429T/C, -374T/A and Gly82Ser. Methods: A literature search was conducted through PubMed and Web of Science (up to August 31, 2011). Pooled odds ratios (ORs) were estimated using fixed-effects (FE) and random-effects (RE) models in co-dominant, recessive and dominant models. A sensitivity analysis was performed by excluding invalid studies. Results: Six articles investigated the -429T/C polymorphism, 7 publications were associated with the -374T/A polymorphism and 5 studies were associated with Gly82Ser in DR. For the -429T/C variant, we found no significant difference between DR patients and those with diabetes without retinopathy. A significant association of allele A with DR was found in the recessive model for the -374T/A variant (RE OR = 0.64, 95% CI = 0.42-0.99, p = 0.05, p heterogeneity = 0.55). In the recessive and co-dominant models for the Gly82Ser polymorphism, the pooled ORs were positive in the fixed-effects model (FE OR = 2.89, 95% CI = 1.49-5.60, p = 0.002, p heterogeneity = 0.20; and FE OR = 3.45, 95% CI = 1.76-6.67, p = 0.0003, p heterogeneity = 0.07, respectively), but in the random-effects model the results were negative. Conclusions: Our research confirmed an association between the RAGE -374T/A polymorphism and retinopathy in subjects with type 2 diabetes and the -374AA allele was found to be a protective factor for type 2 diabetes. Otherwise, the RAGE Gly82Ser polymorphism might be considered a significant risk for DR in Asian populations. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The performance of supervised deep learning significantly relies on the volume of training samples. However, the vast majority of medical images lacks manual expert annotations. Compared to natural image annotation, the cost of medical image annotation is more expensive as it requires professional medical knowledge guidance. To tackle the predicament, semi-supervised learning and self-supervised learning are very effective technologies. In this paper, we present a twin self-supervision based semi-supervised learning (TS-SSL) approach that embeds two types of self-supervised strategies (namely generative self-supervised learning and discriminative self-supervised learning) into semi-supervised framework to simultaneously learn from few-shot labeled images and vast unlabeled images. TS-SSL is an end-to-end classification model, in which semi-supervision and self-supervision can be jointly trained. The proposed TS-SSL is applied to perform retinal anomaly classification based on spectral-domain optical coherence tomography (SD-OCT) images. The experiments demonstrate that TS-SSL yields the good classification performance on one public SD-OCT dataset and two private SD-OCT datasets with only 10% labels. We also claim that TS-SSL can be transferred to other medical imaging modalities. The code is available at https://github.com/ZhangYH0502/TS-SSL. [ABSTRACT FROM AUTHOR]

Objectives. Idiopathic epiretinal membrane (iERM) or idiopathic macular hole (iMH) is frequently used as a "healthy" control in comparison of vitreous cytokines with other vitreoretinal diseases. This study aimed to investigate if there is a difference in vitreal cytokines expression between patients with iERM and iMH. Methods. In this prospective study, all subjects received standard pars plana vitrectomy surgery, and 0.5 ml of native vitreous sample was extracted during the vitrectomy. Luminex technology and enzyme-linked immunosorbent assay were used to profile the concentration of 52 classic angiogenic, inflammatory, and profibrotic cytokines and chemokines. Statistical analyses were performed by the Mann–Whitney U test, followed by multiple comparisons by the Bonferroni correction. Results. Vitreal samples from 13 iERM and 24 iMH were studied. Of the 52 tested cytokines, 41 were similar in expression, and 5 were under the detection limit, while 6 cytokines (MMP-8, Eotaxin, MIP-1a, RANTES, TGF-β2, and IL-4) were differently expressed between two groups (p < 0.05). Nevertheless, these significances disappeared after the adjustment of Bonferroni correction. Conclusion. The tested cytokines showed similar expression between iERM and iMH patients. This indicates that eyes with iERM or iMH can be together served as "healthy" controls. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the changes in vessel density in patients with unilateral congenital cataract after cataract extraction. Materials and Methods: Children with unilateral congenital cataract were enrolled in our study. All of the patients underwent congenital cataract extraction and intraocular lens (IOL) implantation successfully. Optical coherence tomography angiography (OCTA) was performed to image the retinal vasculature in the macular and optic disc areas before and after surgery. The differences in vessel density and retinal thickness between groups were compared. Results: We found that the best corrected visual acuity (BCVA) was significantly improved one month after surgery compared with that before surgery (t=5.179, p< 0.001). The axial length was also changed one month after surgery (t=5.350, p< 0.001). The vessel density in the macular and optic disc areas of the affected eyes was significantly lower than that in the normal eyes, while the vessel density at the posterior pole was significantly improved one month after cataract extraction. Conclusion: The decrease in vessel density in the macular and optic disc areas might be a consequence of the congenital cataract. Cataract extraction can relieve the form deprivation of the affected eye and increase the vessel density at the posterior pole of the affected eye significantly. [ABSTRACT FROM AUTHOR]

Background: Abnormally expressed long noncoding RNA (lncRNA) high expression in hepatocellular carcinoma (HEIH) has been implicated in many types of human cancer, and plays crucial roles in tumor development and progression. However, little is known about its function in retinoblastoma. Methods: qRT-PCR was used to determine the expression levels of HEIH, miR-194-5p and WEE1 in retinoblastoma tissues and cell lines. The trypan blue exclusion method, colony formation assay, wound-healing assay and transwell invasion assay were performed to evaluate the effects of HEIH, miR-194-5p and WEE1 on cell proliferation, migration and invasion. Bioinformatics analysis, dual-luciferase reporter assay and Western blot were employed to investigate the regulatory relationship among HEIH, miR-194-5p and WEE1. Results: We found that HEIH was up-regulated in retinoblastoma tissues and cell lines. Furthermore, high level of HEIH was associated with TNM stage, optic nerve invasion and choroidal invasion of patients with retinoblastoma. Functional studies showed that HEIH knockdown significantly suppressed retinoblastoma cell proliferation, migration and invasion. Mechanistically, HEIH promoted retinoblastoma progression by serving as a sponge of miR-194-5p to regulate WEE1 expression. Conclusion: Our work suggests that HEIH acts as an oncogenic lncRNA to promote retinoblastoma proliferation and metastasis, providing a new insight into the retinoblastoma treatment. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the vision-related quality of life of vitrectomy combined with autologous internal limiting membrane (ILM) transplantation for refractory macular holes (MHs). Methods: There were 40 eyes with refractory MHs included, and all eyes received 23 G vitrectomy and ILM peeling with autologous ILM transplantation. Preoperative and postoperative basic conditions were recorded. The Chinese version of the vision-related quality-of-life scale was used to evaluate patients after operation. Quality of life, postoperative visual acuity, and size of MHs before operation were assessed with Spearman rank correlations. Results: All patients were followed up for 3 months after surgery. Mean postoperative best-corrected visual acuity had significantly improved after surgery. Vision-related quality of life of patients after surgery was closely related to the MH index, but negatively correlated with best-corrected visual acuity before and after surgery. Conclusion: The anatomical structure of refractory MHs with ILM peeling combined with autologous ILM transplantation was largely reduced, and the visual acuity of patients improved significantly. [ABSTRACT FROM AUTHOR]

On the basis of Robinson's normal equation and smoothing projection operator, a homotopy method for solving mathematical programs with box-constrained variational inequalities (MPBVI) is presented. In which, the Chen–Harker–Kanzow–Smale smooth function is used to transform MPBVI into a smooth optimization problem. Under some mild assumptions, the existence and global convergence of a smooth path from almost any initial point to the GKKT point of the approximate problems is proven. And, the convergence of the GKKT point to a strong C-stationary point of the original problems is proved. Finally, some numerical results are given to show the effectiveness and feasibility of the homotopy method. [ABSTRACT FROM AUTHOR]

NLRP3, as a crucial inflammasome component, plays important roles in age‐related macular degeneration. Though some activators of NLRP3 have been studied, microRNAs (miRNAs) which potentially regulate NLRP3 messenger RNA (mRNA) have not been fully explored in retinal pigment epithelial (RPE) cells and retinopathy. In this study, by miRNA microarray profiling and bioinformatic analysis, we identified that four miRNAs, miR‐4286, miR‐223‐3p, miR‐365a, miR‐22‐3p, may target NLRP3 mRNA in RPE inflammatory damage in vivo. Further, real‐time polymerase chain reaction verified that only miR‐22‐3p was significantly decreased, which was associated with NLRP3 upregulation in blue‐light‐induced retinopathy. Mechanistically, the dual‐fluorescent reporter suggested miR‐22‐3p directly binds NLRP3 mRNA. Moreover, overexpression of miR‐22‐3p could significantly reduce whereas inhibition miR‐22‐3p could increase the mRNA and protein expressions of NLRP3, Caspase‐1, and mature IL‐1β. Collectively, our results indicate that miR‐22‐3p plays a suppressive role in RPE damage by targeting NLRP3, which provides new insights into the future intervention to retinopathy. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to automatically and accurately segment hyper‐reflective foci (HRF) in spectral domain optical coherence tomography (SD‐OCT) images with diabetic retinopathy (DR) using deep convolutional neural networks. Methods: An automatic HRF segmentation model for SD‐OCT images based on deep networks was constructed. The model segmented small lesions through pixel‐wise predictions based on small image patches. We used an approach for discriminative features extraction for small patches by introducing small kernels and strides in convolutional and pooling layers, which was applied on the state‐of‐the‐art deep classification networks (GoogLeNet and ResNet). The features extracted by the adapted deep networks were fed into a softmax layer to produce the probabilities of HRF. We trained different models on a dataset with 16 HRF eyes by using different sizes of patches, and then, we fused these models to generate optimal results. Results: Experimental results on 18 eyes demonstrated that our method is effective for the HRF segmentation. The dice similarity coefficient (DSC) for the foci area in B‐scan, projection images, and foci amount in B‐scan images reaches 67.81%, 74.09%, and 72.45%, respectively. Conclusions: The proposed segmentation model can accurately segment HRF in SD‐OCT images with DR and outperforms traditional methods. Our model may provide reliable segmentations for small lesions in SD‐OCT images and may be helpful in the clinical diagnosis of diseases. [ABSTRACT FROM AUTHOR]

Purpose: To quantify the preoperative neovascular change pattern on the fibrovascular membrane (FVM) within 7 days after intravitreal injection of conbercept (IVC) using optical coherence tomography angiography (OCTA) in proliferative diabetic retinopathy (PDR). Methods: Prospective, observational study of PDR patients with visible FVM receiving or not receiving IVC. Neovascular changes were assessed by OCTA pre-IVC and 1, 3, 5, and 7 days post-IVC. Vessel skeleton density (SD) and vessel density (VD) were quantified by an intensity-based optical microangiography algorithm. The interclass correlation coefficient (ICC) was calculated to assess the agreement between measurements. The SD and VD were compared between follow-ups using repeated-measures analysis in the IVC group. Results: The ICC was 0.992 (95% confidence interval [CI]: 0.982–0.996) for SD and 0.926 (95% CI: 0.838–0.912) for VD of neovascularization. The neovascularization on FVM significantly regressed in the IVC group (n = 16) compared with no IVC (n = 8) (p = 0.001 for SD and p < 0.001 for VD). The comparisons between consecutive follow-ups showed a statistically significant reduction in SD and VD at 1 and 3 days post-IVC. However, from day 3 onward, the SD and VD remained unchanged. There was no development or progression of tractional retinal detachment within the 7-day period after IVC. Conclusion: OCTA–based quantification of the neovascularization on FVM in PDR is feasible, with high inter-reader agreement. The regression of neovascularization reaches a plateau 3 days after IVC. Clinical Trial Registration: This trial is registered with the Chinese Clinical Trial Registry (http://www.chictr.org.cn, registration number ChiCTR-IPR-17014160). [ABSTRACT FROM AUTHOR]

Abstract Retinitis pigmentosa (RP), the most common form of inherited retinal dystrophies, exhibits significant genetic heterogeneity. The crumbs homolog 2 (CRB2) protein, together with CRB1 and CRB3, belongs to the Crumbs family. Given that CRB1 mutations account for 4% of RP cases, the role of CRB2 mutations in RP etiology has long been hypothesized but never confirmed. Herein, we report the identification of CRB2 as a novel RP causative gene in a Chinese consanguineous family and have analyzed its pathogenic effects. Comprehensive ophthalmic and systemic evaluations confirmed the clinical diagnosis of the two patients in this family as RP. WES revealed a homozygous missense mutation, CRB2 p.R1249G, to segregate the RP phenotype, which was highly conserved among multiple species. In vitro cellular study revealed that this mutation not only interrupted the stability of the transcribed CRB2 mRNA and the encoded CRB2 protein, but also interfered with the wild type CRB2 mRNA/protein and decreased their expression. This mutation was also shown to trigger epithelial-mesenchymal transition (EMT) in retinal pigment epithelium (RPE) cells, thus impairing regular RPE phagocytosis and induce RPE degeneration and apoptosis. Thus, we conclude that CRB2 p.R1249G mutation causes RP via accelerating EMT, dysfunction and loss of RPE cells, and establish CRB2 as a novel Crumbs family member associated with non-syndromic RP. We provide important hints for understanding of CRB2 defects and retinopathy, and for the involvement of EMT of RPE cells in RP pathogenesis. Highlights • CRB2 is a novel causative gene for non-syndromic retinitis pigmentosa. • CRB2 p.R1249G interrupts stability of the transcribed mRNA and the encoded protein. • CRB2 p.R1249G induce degeneration and apoptosis of retinal pigment epithelium. • Epithelial-mesenchymal transition is involved in retinitis pigmentosa pathogenesis. • p.R1249G triggers epithelial-mesenchymal transition of retinal pigment epithelium. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a multifactorial disease resulting in the gradual loss of retinal pigment epithelium (RPE) and the permanent visual damage. Various risk factors, including oxidative stress, form a complex network at the confluence of inflammation. Mesenchymal stem cell (MSC) is a well-studied population of adult stem cell with strong neuroprotective and immunoregulatory properties. Here, we reported the protective effect of MSC on sodium iodate (NaIO3)-triggered RPE degeneration. Sodium iodate (NaIO3)-induced RPE cell death was remarkably reduced when cocultured with MSC. Inhibition of several cell death pathways mediated by mitochondrial instability and its subsequent caspase-1/3/8 activation was implicated in this process. In addition, NLRP3 inflammasome, the upstream of caspase-1 activation, was also found downregulated via suppressing its priming signal NF-κB pathway. Taken together, MSC protected against NaIO3-triggered RPE death via deactivating NF-κB-mediated NLRP3 inflammasome and maintaining mitochondrial integrity. This study highlights the significant role of MSC in modulating the proinflammatory environment of AMD, and suggests the clinical value of MSC in treating AMD as well as RPE replacement therapy. [ABSTRACT FROM AUTHOR]

Background and Objective The measurement of choroidal volume is more related with eye diseases than choroidal thickness, because the choroidal volume can reflect the diseases comprehensively. The purpose is to automatically segment choroid for three-dimensional (3D) spectral domain optical coherence tomography (SD-OCT) images. Methods We present a novel choroid segmentation strategy for SD-OCT images by incorporating the enhanced depth imaging OCT (EDI-OCT) images. The down boundary of the choroid, namely choroid-sclera junction (CSJ), is almost invisible in SD-OCT images, while visible in EDI-OCT images. During the SD-OCT imaging, the EDI-OCT images can be generated for the same eye. Thus, we present an EDI-OCT-driven choroid segmentation method for SD-OCT images, where the choroid segmentation results of the EDI-OCT images are used to estimate the average choroidal thickness and to improve the construction of the CSJ feature space of the SD-OCT images. We also present a whole registration method between EDI-OCT and SD-OCT images based on retinal thickness and Bruch's Membrane (BM) position. The CSJ surface is obtained with a 3D graph search in the CSJ feature space. Results Experimental results with 768 images (6 cubes, 128 B-scan images for each cube) from 2 healthy persons, 2 age-related macular degeneration (AMD) and 2 diabetic retinopathy (DR) patients, and 210 B-scan images from other 8 healthy persons and 21 patients demonstrate that our method can achieve high segmentation accuracy. The mean choroid volume difference and overlap ratio for 6 cubes between our proposed method and outlines drawn by experts were −1.96µm3 and 88.56%, respectively. Conclusions Our method is effective for the 3D choroid segmentation of SD-OCT images because the segmentation accuracy and stability are compared with the manual segmentation. [ABSTRACT FROM AUTHOR]

Aims Proliferative diabetic retinopathy (PDR), characterized by angiogenesis, can cause serve vision loss and even blindness. Recent studies have suggested a pivotal role of vasohibin-2 (VASH2) in the promotion of angiogenesis in tumor tissues. Here we further investigated the role of VASH2 in the proliferation and migration of retinal endothelial cells. Main methods The expression of VASH2 in vascular endothelial cells of epiretinal fibrovascular membranes (FVMs) from PDR patients were detected by immunofluorescence. VASH2 gene interfering lentiviral vectors ( VASH2 -shRNA) and miR-200b/c were constructed for the evaluation of the VASH2 effect on high glucose induced human retinal microvascular endothelial cell line (HRMECs). Cell proliferation, cell cycle and cell migration were carried out subsequently. The relationship between VASH2 and miR-200b/c was determined by luciferase reporter gene assays. Key findings A positive expression of VASH2 was identified in vascular endothelial cells of FVMs from PDR patients. In HRMECs, cells transfected with shRNA or miR-200b/c mimics showed a significantly reduced VASH2 expression compared with negative control group by real time-polymerase chain reaction and western-blot analysis. Inhibition of VASH2 was demonstrated to suppress cell proliferation and migration from Day 2 to Day 4. The luciferase reporter gene assays confirmed the post-transcriptional regulation of VASH2 by miR-200b/c in HRMECs. Significance The present study suggests a protective effect of miR-200b/c on high glucose induced HRMECs dysfunction by inhibiting VASH2. It could be a potential therapeutic strategy to inhibit angiogenesis for the treatment of retinal vascular disease. [ABSTRACT FROM AUTHOR]

In this study we described a new model of subretinal edema induced by single intraocular injection of DL-alpha-aminoadipic acid (DLAAA) that can be employed to study the mechanism of retinal edema and test the efficacy or potential toxicity of treatments. The progression of subretinal edema was evaluated by fundus photography, fluorescein angiography and optical coherence tomography for up to 4 weeks following DLAAA injection. The VEGF, IL-6, TNF-α, Occludin, ZO-1, AQP4, Kir4.1, GFAP and GS levels were examined in DLAAA models by immunostaining, immumohistochemical staining and Western blot. Additionally, bulk RNA-seq was used to detect the mechanism involved in DLAAA-induced retinal Müller cellular injuries. In vivo and vitro assays were further conducted to confirm the sequencing results. Subretinal edema was successfully induced by DLAAA in New Zealand White rabbits (1.29 mg/eye) and C57BL/6 mice (50 or 100 μg/eye). Our results demonstrated that the disruption of blood-retinal-barrier, including vascular hyperpermeability, inflammation, and Müller cell dysfunction of fluid clearance, was involved in subretinal edema formation in the model. Bulk RNA-seq and in vitro studies indicated the activation of p38 MAPK signaling pathway in DLAAA models. This DLAAA-induced subretinal edema model can be used for mechanistic studies or drug screening. [Display omitted] • The first report of a novel model of subretinal edema induced by DL-alpha aminoadipic acid (DLAAA) • The disruption of blood-retinal-barrier, including vascular hyperpermeability, inflammation, and Müller cell dysfunction of fluid clearance, was involved in subretinal edema formation in DLAAA models • DLAAA-induced dysfunction of Müller cells is partly via the activation of p38 MAPK signaling pathway [ABSTRACT FROM AUTHOR]

Activating PI3K/AKT/mTOR signaling pathway via deleting phosphatase and tensin homolog (PTEN) has been confirmed to enhance intrinsic growth capacity of neurons to facilitate the axons regeneration of central nervous system after injury. Considering conditional gene deletion is currently not available in clinical practice, we exploited capsid residue tyrosine 444 to phenylalanine mutated single-stranded adeno-associated virus serotype 2 (AAV2) as a vector delivering short hairpin RNA to silence PTEN to promote retinal ganglion cells (RGCs) survival and axons regeneration in adult rat optic nerve axotomy paradigm. We found that mutant AAV2 displayed higher infection efficiency to RGCs and Müller cells by intravitreal injection, mediated PTEN suppression, resulted in much more RGCs survival and more robust axons regeneration compared with wild type AAV2, due to the different extent of the mTOR complex-1 activation and glutamate aspartate transporter (GLAST) regulation. These results suggest that high efficiency AAV2-mediated PTEN knockdown represents a practicable therapeutic strategy for optic neuropathy. [ABSTRACT FROM AUTHOR]

For years, branch retinal vein occlusion is still a controversial disease in many aspects. An increasing amount of data is available regarding classification, pathogenesis, risk factors, natural history, and therapy of branch retinal vein occlusion. Some of the conclusions may even change our impression of branch retinal vein occlusion. It will be beneficial for our doctors to get a deeper understanding of this disease and improve the treatment skills. The aims of this review is to collect the information above and report new ideas especially from the past a few years. [ABSTRACT FROM AUTHOR]

Purpose: The retinal vessel visualization from spectral-domain optical coherence tomography (SDOCT) images is important for ocular disease diagnosis and multimodal retinal image processing. The purpose is to display the retinal vessel in a single projection image from 3D SD-OCT images by using the light absorption and shadow characteristics of the retinal vessel. Methods: The authors present a novel retinal vessel projection method for SD-OCT images, which utilizes the light absorption and shadow characteristics of the retinal vessel, called high-low reflectivity enhancement (HLRE) method. The reflectivity of the retinal vessel increases between the internal limiting membrane and inner nuclear layer-outer plexiform layer (INL-OPL) layers because of the light absorption, and the reflectivity below the retinal vessel decreases because of the influence of the retinal vessel shadow. A retinal vessel mask image generated based on the reflectivity characteristics of the retinal vessel is used to enhance the subvolume projection image restricted between the INL-OPL and Bruch's membrane layers. Results: Experimental results with 22 SD-OCT cubes from 12 patients and 10 normal persons demonstrate that the authors' method is more effective in displaying the retinal vessel than the summed-voxel projection and other five region restriction based projection methods. The average of the mean difference between the retinal vessel and background regions based on their HLRE method is 0.1921. Conclusions: The proposed HLRE method was more effective for the visualization of the retinal vessels than the state-of-art methods because it provides higher contrast and distinction. [ABSTRACT FROM AUTHOR]

Corneal endothelial cells (CECs) are a monolayer of cells covering the inner-side of cornea, playing a pivotal role in keeping the cornea transparent. Because adult CECs have no proliferative capacity, the loss of CECs during aging or under pathological conditions would lead to corneal edema, eventually leading to the blindness. Clinically, donated CECs have been successfully transplanted to treat the diseases of CEC deficiency; however, the source of CEC donation is very limited. As an alternative cell source for CEC transplantation, CEC-like cells can be obtained via in vitro differentiation of human pluripotent stem cells. In this study, we introduced a modified two-stage differentiation method to convert H9 human embryonic stem cells (hESCs) to neural crest cells (NCCs), then further into CEC-like cells. The CEC-like cells treated with bovine CEC conditional medium morphologically best resembled primary CECs among all the culture conditions. By whole transcriptome analysis, we found that the typical markers of CECs, such as Na+-K+-ATPase, AQP1, Col8a and ZO-1, are highly expressed in hESC-derived CEC-like cells. By comparing RNA transcriptome of hESC-derived CEC-like cells with human primary fetal and adult CECs, we further identified shared molecular markers such as TRIT1, HSPB11, CRY1 that can be used to quality control CEC derivatives from hESCs. Our study paves the way for the quality-control and future application of hESC-derived CECs in the treatment of CEC deficiency disorders. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the impact of postoperative posturing with or without face-down on the anatomical and functional outcomes of macular hole surgery. Methods A literature-based meta-analysis was conducted to identify studies relevant to posturing following macular hole surgery ( MHS). PubMed and Web of Science databases were used to retrieve articles up to 1 June 2015. The primary measures included MH closure and ideal vision acuity improvement. Pooled odds ratios ( ORs) and 95% confidence intervals ( CIs) were estimated in Review Manager. Results Four randomized control trials ( RCTs) comprising 251 cases were included in the final meta-analysis. No face-down posturing ( FDP) after MHS revealed lower anatomic success rate compared to face-down posturing ( OR = 0.33, 95% CI [0.13, 0.81], p = 0.02). For holes smaller than 400 μm in size, the subgroup meta-analysis indicated no significant effect of FDP on successful hole closure ( OR = 0.29, 95% CI [0.01, 7.34], p = 0.45). However, when holes were larger than 400 μm, it seemed less effective on MH closure following surgery in no FDP group ( OR = 0.23, 95% CI [0.07, 0.71]), and this was statistically significant (p = 0.01). Conclusions Our work found that no FDP was not inferior to its face-down counterpart for the success of MHS when macular holes were smaller than 400 μm in size. For macular holes larger than 400 μm, statistical analysis proved that FDP might be necessary. More well-conducted randomized control trials are needed to verify our findings. [ABSTRACT FROM AUTHOR]

Recent studies were mainly focus on the cytidine deaminase family genes, which contained a lot of members that varied on the function of catalytic deamination in RNA or DNA and were involved in the process of growth maintenance, host immunity, retroviral infection, tumorigenesis, and drug resistance with a feature of C-U deamination. In this study, we identified a new member of cytidine deaminase family, NYD-SP15. Previous work showed that the deduced structure of the protein contained two dCMP_cyt_deam domains, which were involved in zinc ion binding. NYD-SP15 was expressed variably in a wide range of tissues, indicating its worthy biological function and creative significances. Sequence analysis, RT-PCR, western blot, flow cytometry, direct-site mutation and GST pull-down assay were performed to analyze the construction and function of NYD-SP15. The results in our studies showed that NYD-SP15 was closely related to deoxycytidylate deaminase and cytidine deaminase, with authentic cytidine deaminase activity in vivo and vitro as well as homo dimerization effects. NYD-SP15 contained nuclear localization sequence (NLS) and nuclear export-signal (NES) and could dynamically shuttle between the nucleus and cytoplasm. Furthermore, NYD-SP15 gene over-expression reduced the cells growth and blocked G1 to S phase, which implied a potential inhibition effect on cell growth. [ABSTRACT FROM AUTHOR]

Purpose: In clinical research, it is important to measure choroidal thickness when eyes are affected by various diseases. The main purpose is to automatically segment choroid for enhanced depth imagingoptical coherence tomography (EDI-OCT) images with five B-scans averaging. Methods: The authors present an automated choroid segmentation method based on choroidal vasculature characteristics for EDI-OCT images with five B-scans averaging. By considering the large vascular of the Haller's layer neighbor with the choroid-sclera junction (CSJ), the authors measured the intensity ascending distance and a maximum intensity image in the axial direction from a smoothed and normalized EDI-OCT image. Then, based on generated choroidal vessel image, the authors constructed the CSJ cost and constrain the CSJ search neighborhood. Finally, graph search with smooth constraints was utilized to obtain the CSJ boundary. Results: Experimental results with 49 images from 10 eyes in 8 normal persons and 270 images from 57 eyes in 44 patients with several stages of diabetic retinopathy and age-related macular degeneration demonstrate that the proposed method can accurately segment the choroid of EDI-OCT images with five B-scans averaging. The mean choroid thickness difference and overlap ratio between the authors' proposed method and manual segmentation drawn by experts were -11.43 µm and 86.29%, respectively. Conclusions: Good performance was achieved for normal and pathologic eyes, which proves that the authors' method is effective for the automated choroid segmentation of the EDI-OCT images with five B-scans averaging. [ABSTRACT FROM AUTHOR]

Purpose: Diabetes mellitus is an increasingly common systemic disease. Many diabetic patients seek cataract surgery for a better visual acuity. Unlike in the general population, the influence of cataract surgery on tear film function in diabetic patients remains elusive. The aim of this study was to evaluate the tear function in diabetic and nondiabetic patients following cataract surgery. Methods: In this prospective, interventional case series, 174 diabetic patients without dry eye syndrome (DES) and 474 age-matched nondiabetic patients as control who underwent phacoemulsification were enrolled at two different eye centers between January 2011 and January 2013. Patients were followed up at baseline and at 7 days, 1 month, and 3 months postoperatively. Ocular symptom scores (Ocular Surface Disease Index, OSDI) and tear film function including tear film stability (tear film break-up time, TBUT), corneal epithelium integrity (corneal fluorescein staining, CFS), and tear secretion (Schirmer’s I test, SIT) were evaluated. Results: In total, 83.9% of the diabetic patients (146 cases with 185 eyes) and 89.0% of the nondiabetic patients (422 cases with 463 eyes) completed all check-ups after the interventions (P = 0.095). The incidence of DES was 17.1% in the diabetic patients and 8.1% in the nondiabetic patients at 7 days after cataract surgery. In the diabetic patients, the incidence of DES remained 4.8% at 1 month postoperatively and decreased to zero at 3 months after surgery. No DES was diagnosed in nondiabetic patients at either the 1-month or 3-month follow-up. Compared with the baseline, the diabetic patients had worse symptom scores and lower TBUT values at 7 days and 1 month but not at 3 months postoperatively. In the nondiabetic patients, symptom scores and TBUT values had returned to preoperative levels at 1-month check-up. CFS scores and SIT values did not change significantly postoperatively in either group (P = 0.916 and P = 0.964, respectively). Conclusions: Diabetic patients undergoing cataract surgery are prone to DES. Ocular symptoms and tear film stability are transiently worsened in diabetic patients and are restored more slowly than those in nondiabetic patients. [ABSTRACT FROM AUTHOR]

Purpose. To describe both the functional and pathological alternations in neurosensory retina in a murine model of spontaneous type 2 diabetes (db/db mouse). Methods. db/db (BKS/DB−/−) mice and heterozygous littermates (as control group) at various ages (12, 16, 20, 24, and 28 weeks) were inspected with pattern electroretinogram (PERG), fundus fluorescein angiography (FFA), and optical coherence tomography (OCT). Histological markers of neuroinflammation (IBA-1 and F4/80) were evaluated by immunohistochemistry. In addition, levels of retinal ganglion cell death were measured by terminal dUTP nick-end labeling (TUNEL). Results. Significant alternations of PERG responses and increased retinal ganglion cells (RGCs) apoptosis were observed in diabetic db/db mice for 20-week period when compared with control group. IBA-1 and F4/80 expression in microglia/macrophages became evidently for 24-week period, thus supporting the PERG findings. Furthermore, obvious thinning of nasal and dorsal retina in 28-week-old db/db mice was also revealed by OCT. No visible retinal microvascular changes were detected by FFA throughout the experiments on db/db mice. Conclusions. Diabetic retina underwent neurodegenerative changes in db/db mice, which happened at retinal ganglion cell layer and inner nuclear layer. But there was no obvious abnormality in retinal vasculature on db/db mice. [ABSTRACT FROM AUTHOR]

Background: Diabetic retinopathy (DR) is a retinopathy resulting from diabetes mellitus (DM) which was classified into non-proliferative DR (NPDR) and proliferative DR (PDR). Without an early screening and effective diagnosis, patients with PDR will develop serious complications. Therefore, we sought to identify special serum microRNAs (miRNAs) that can serve as a novel non-invasive screening signature of PDR and test its specificity and sensitivity in the early diagnosis of PDR. Methods: In total, we obtained serum samples from 90 PDR cases, 90 matched NPDR patients and 20 controls. An initial screening of miRNA expression was performed through TaqMan Low Density Array (TLDA). The candidate miRNAs were validated by individual reverse transcription quantitative real-time PCR (RT-qPCR) arranged in an initial and a two-stage validation sets. Moreover, additional double-blind testing was performed in 20 patients clinically suspected of having DR to evaluate the diagnostic value and accuracy of the serum miRNA profiling system in predicting PDR. Results: Three miRNAs were significantly increased in patients with PDR compared with NPDR after the multiple stages. The areas under the receiver operating characteristic (ROC) curves of the validated three-serum miRNAs signature were 0.830, 0.803 and 0.873 in the initial and two validation sets, respectively. Combination of miR-21, miR-181c, and miR-1179 possessed a moderate ability to discrimination between PDR and NPDR with an area under ROC value of 0.89. The accuracy rate of the three-miRNA profile as PDR signature was 82.6%. Conclusions: These data provide evidence that serum miRNAs have the potential to be sensitive, cost-effective biomarkers for the early detection of PDR. These biomarkers could serve as a dynamic monitoring factor for detecting the progression of PDR from NPDR. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: Diabetic retinopathy (DR) is a common diabetic eye disease which is well-known as the result of microvascular retinal changes. Although the potential biological functions of astragaloside IV (AS IV) have long been described in traditional system of medicine, its protective effect on DR remains unclear. This study aims to investigate the function and mechanism of AS IV on type 2 diabetic db/db mice. Methods: Db/db mice were treated with AS IV (4.5 mg/kg or 9 mg/kg) or physiological saline by oral gavage for 20 weeks along with db/m mice. In each group, retinal ganglion cell (RGC) function was measured by pattern electroretinogram (ERG) and apoptosis was determined by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Blood and retina aldose reductase (AR) activity were quantified by chemiluminescence analysis. The expressions of phosporylated-ERK1/2, NF-κB were determined by Western blot analysis. Furthermore, the expression of related downstream proteins were quantified by Label-based Mouse Antibody Array. Results: Administration of AS IV significantly improved the amplitude in pattern ERG and reduced the apoptosis of RGCs.in db/db mice. Furthermore, downregulation of AR activity, ERK1/2 phosphorylation, NF-κB and related cytokine were observed in AS IV treatment group. Conclusions: Our study indicated that AS IV, as an inhibitor of AR, could prevent the activation of ERK1/2 phosporylation and NF-kB and further relieve the RGCs disfunction in db/db mice with DR. It has provided a basis for investigating the clinical efficacy of AR inhibitors in preventing DR. [ABSTRACT FROM AUTHOR]

Objective: To construct a life-sized eye model using the three-dimensional (3D) printing technology for fundus viewing study of the viewing system. Methods: We devised our schematic model eye based on Navarro's eye and redesigned some parameters because of the change of the corneal material and the implantation of intraocular lenses (IOLs). Optical performance of our schematic model eye was compared with Navarro's schematic eye and other two reported physical model eyes using the ZEMAX optical design software. With computer aided design (CAD) software, we designed the 3D digital model of the main structure of the physical model eye, which was used for three-dimensional (3D) printing. Together with the main printed structure, polymethyl methacrylate(PMMA) aspherical cornea, variable iris, and IOLs were assembled to a physical eye model. Angle scale bars were glued from posterior to periphery of the retina. Then we fabricated other three physical models with different states of ammetropia. Optical parameters of these physical eye models were measured to verify the 3D printing accuracy. Results: In on-axis calculations, our schematic model eye possessed similar size of spot diagram compared with Navarro's and Bakaraju's model eye, much smaller than Arianpour's model eye. Moreover, the spherical aberration of our schematic eye was much less than other three model eyes. While in off- axis simulation, it possessed a bit higher coma and similar astigmatism, field curvature and distortion. The MTF curves showed that all the model eyes diminished in resolution with increasing field of view, and the diminished tendency of resolution of our physical eye model was similar to the Navarro's eye. The measured parameters of our eye models with different status of ametropia were in line with the theoretical value. Conclusions: The schematic eye model we designed can well simulate the optical performance of the human eye, and the fabricated physical one can be used as a tool in fundus range viewing research. [ABSTRACT FROM AUTHOR]

Purpose: HM-3, an RGD-modified endostatin-derived polypeptide, is a potent angiogenesis inhibitor synthesized in our laboratory. This study investigated the HM-3 pharmacokinetics of intravitreally administered in mice eyes as an anti-angiogenesis drug for age-related macular degeneration. Materials and methods: A total of 288 C57BL/6J mice were evaluated and divided into four groups. Each mouse in different groups received single bilateral intravitreal injection with HM-3. The concentrations of HM-3 in choroid/sclera, retina and serum were determined by indirect competitive enzyme-linked immunosorbent assay. Results: After intravitreal administration of doses of 0, 10, 20 and 40 μg/eye HM-3, the observed maximum concentration ( Cmax) was 12.98 ± 1.42, 27.87 ± 3.64 and 55.96 ± 11.94 ng/mg, respectively; and the total area under the curve (AUCtot) was 739.23 ± 190.32, 1171.74 ± 528.75 and 1777.71 ± 511.64 h ng/mg; the elimination half-life ( T1/2) in retina was 104.85 ± 36.90, 107.42 ± 35.25 and 101.12 ± 15.82 h; the mean residence time (MRT) was 172.46 ± 63.80, 164.70 ± 52.72 and 181.32 ± 26.01 h, respectively. In choroid/sclera, the Cmax was 5.29 ± 0.34, 6.29 ± 1.87 and 8.14 ± 0.71 ng/mg, respectively; AUCtot was 579.03 ± 56.50, 762.20 ± 201.09 and 720.91 ±243.87 h ng/mg; T1/2 was 54.04 ± 25.99, 59.33 ± 24.46 and 47.10 ± 10.00 h, respectively; MRT was 139.98 ± 23.93, 155.43 ± 17.81 and 136.45 ± 18.17 h, respectively. But in serum, the Cmax was 482.00 ± 38.97, 493.94 ± 97.64 and 1033.10 ± 276.33 ng/ml, respectively; AUCtot was 21128.55 ± 4683.68, 53444.57 ± 16963.99 and 53164.84 ±1535.06 h ng/ml; T1/2 was 48.39 ± 14.89, 47.96 ± 12.97 and 49.98 ± 30.07 h, respectively; MRT was 108.6 ± 47.17, 159.76 ± 18.82 and 125.33 ± 21.41 h, respectively. Conclusions: The pharmacokinetic profiles of intravitreal administration HM-3 provide the basis for the development of reasonable dosing regimens of clinical choroidal neovascularization (CNV) treatment. However, the vitreous and blood retinal barrier might be barriers to drug distribution and diffusion. In addition, fluid flow for the anterior transport and choroidal blood circulation might play important roles for multiple peaking. Carrying out the research into pharmacokinetics of HM-3 provides the information for laying down drug delivery scheme in mice model of CNV. [ABSTRACT FROM AUTHOR]

Primary open-angle glaucoma (POAG) is one of the leading causes of blindness worldwide. The association between the APOE ε2/ε3/ε4 polymorphism and the risk of POAG has been widely reported, but the results of previous studies remain controversial. To comprehensively evaluate the APOE ɛ2/ɛ3/ε4 polymorphism on the genetic risk for POAG, we performed a systematic review and meta-analysis of previously published studies. The PubMed and Web of Science databases were systematically searched to identify relevant studies. Data were extracted from these studies and odds ratios with corresponding 95% confidence intervals were computed to estimate the strength of the association. Stratified analyses according to ethnicity and sensitivity analyses were also conducted for further confirmation. A total of nine studies were eligible for the meta-analysis, and these studies included data on 1928 POAG cases and 1793 unrelated match controls. The combined results showed that there were no associations between the APOE ε2/ε3/ε4 polymorphism and POAG risk in any of the 10 comparison models. The analysis that was stratified by ethnicity subgroups also failed to reveal a significant association. The sensitivity analysis confirmed the stability and reliability of the findings. There was no risk of publication bias. Our meta-analysis provides strong evidence that the APOE ε2/ε3/ε4 polymorphism is not associated with POAG susceptibility in any populations. [ABSTRACT FROM AUTHOR]

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the clinical treatment of retinal injury. In this study, we investigated the protective effects of edaravone against diabetic retinal damage in the mouse. Diabetic retinopathy in the mouse was induced by injection of streptozotocin. Edaravone was given once-daily and was intraperitoneally (i.p.) treated at a dose of 3 mg/kg from streptozotocin injection to 4 weeks after onset of diabetes. Retinal ganglion cells (RGCs) damage was evaluated by recording the pattern electroretinogram (ERG). RGCs damage was also detected by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and the levels of reactive oxygen species (ROS) were determined fluorometrically. The expressions of phosporylated-ERK1/2, BDNF, and caspase-3 were determined by Western blot analysis. Retinal levels of ROS, phosphorylated ERK1/2, and cleaved caspase-3 were significantly increased, whereas the expression of BDNF was significantly decreased in the retinas of diabetic mice, compared to nondiabetic mice. Administration of edaravone significantly attenuated diabetes induced RGCs death, upregulation of ROS, ERK1/2 phosphorylation, and cleaved caspase-3 and downregulation of BDNF. These findings suggest that oxidative stress plays a pivotal role in diabetic retinal damage and that systemic administration of edaravone may slow the progression of retinal neuropathy induced by diabetes. [ABSTRACT FROM AUTHOR]

Highlights: [•] To describe a novel method for multi-parameter measurements for the mouse retina. [•] To indicate a modified combination of lenses adapted to Zeiss HD-OCT firstly. [•] To quantify the magnification of this OCT system for mouse retinal imaging firstly. [•] To replace the traditional measurement on histological sections by our method. [Copyright &y& Elsevier]

Using the paradigm of in vitro differentiation of hESCs/iPSCs into retinal pigment epithelial (RPE) cells, we have recently profiled mRNA and miRNA transcriptomes to define a set of RPE mRNA and miRNA signature genes implicated in directed RPE differentiation. In this study, in order to understand the role of DNA methylation in RPE differentiation, we profiled genome-scale DNA methylation patterns using the method of reduced representation bisulfite sequencing (RRBS). We found dynamic waves of de novo methylation and demethylation in four stages of RPE differentiation. Integrated analysis of DNA methylation and RPE transcriptomes revealed a reverse-correlation between levels of DNA methylation and expression of a subset of miRNA and mRNA genes that are important for RPE differentiation and function. Gene Ontology (GO) analysis suggested that genes undergoing dynamic methylation changes were related to RPE differentiation and maturation. We further compared methylation patterns among human ESC- and iPSC-derived RPE as well as primary fetal RPE (fRPE) cells, and discovered that specific DNA methylation pattern is useful to classify each of the three types of RPE cells. Our results demonstrate that DNA methylation may serve as biomarkers to characterize the cell differentiation process during the conversion of human pluripotent stem cells into functional RPE cells. [ABSTRACT FROM AUTHOR]

Purpose: To investigate a possible association between gene variants and patient response to treatment with intravitreal ranibizumab for neovascular age-related macular degeneration (AMD). Methods: Visual acuity score (VAS) was recorded at baseline and a subsequent visit at 6 months. Genotypes of 3 polymorphisms in known AMD susceptibility loci (rs1061170 in complement factor H (CFH), rs11200638 in HTRA1 and rs1413711 in VEGF) were determined. Central retinal thickness and maximum thickness of the lesion were also measured. Results: A total of 168 neovascular AMD patients treated with intravitreal ranibizumab were included in our study. For HTRA1 rs11200638, mean VAS changes were 3.5, 9.4 and 10.6 letters for the AA, AG and GG genotypes, respectively (p = 0.022). In contrast, for CFH rs1061170 and VEGF rs1413711, mean VAS changes were not significant. However, there was no significant difference in the changes in central retinal thickness and maximum lesion thickness among the genotypes of the tested single-nucleotide polymorphisms. Conclusions: HTRA1 gene polymorphism may influence patient response to treatment with intravitreal ranibizumab for neovascular AMD. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]