Epigenetic regulation in the commitment of progenitor cells during retinal development and regeneration.

Retinal development is initiated by multipotent retinal progenitor cells, which undergo several rounds of cell divisions and subsequently terminal differentiation. Retinal regeneration is usually considered as the recapitulation of retinal development, which share common mechanisms underlying the cell cycle re-entry of adult retinal stem cells and the differentiation of retinal neurons. However, how proliferative retinal progenitor cells perform a precise transition to postmitotic retinal cell types during the process of development and regeneration remains elusive. It is proposed that both the intrinsic and extrinsic programming are involved in the transcriptional regulation of the spatio-temporal fate commitment. Epigenetic modifications and the regulatory mechanisms at both DNA and chromatin levels are also postulated to play an important role in the timing of differentiation of specific retinal cells. In the present review, we have summarized recent knowledge of epigenetic regulation that underlies the commitment of retinal progenitor cells in the settings of retinal development and regeneration.

A novel model of subretinal edema induced by DL-alpha aminoadipic acid.

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.

JP1, a polypeptide specifically targeting integrin αVß3, ameliorates choroidal neovascularization and diabetic retinopathy in mice.

Anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular eye diseases, but responses are incomplete in some patients. Recent evidence shows that integrins are involved in the pathogenesis of neovascular age-related macular degeneration and diabetic retinopathy. JP1, derived from an optimized seven-amino-acid fragment of JWA protein, is a polypeptide specifically targeting integrin αVß3. In this study we evaluated the efficacy of JP1 on laser-induced choroidal neovascularization (CNV) and retinal vascular leakage. CNV mice received a single intravitreal (IVT) injection of JP1 (10, 20, 40 µg) or ranibizumab (RBZ, 10 µg). We showed that JP1 injection dose-dependently inhibited laser-induced CNV; the effect of RBZ was comparable to that of 20 µg JP1; a combined IVT injection of JP1 (20 µg) and RBZ (5 µg) exerted a synergistic effect on CNV. In the 3rd month after streptozotocin injection, diabetic mice receiving IVT injection of JP1 (40 µg) or RBZ (10 µg) once a week for 4 weeks showed significantly suppressed retinal vascular leakage. In both in vivo and in vitro experiments, JP1 counteracted oxidative stress and inflammation via inhibiting ROS/NF-κB signaling in microglial cells, and angiogenesis via modulating MEK1/2-SP1-integrin αVß3 and TRIM25-SP1-MMP2 axes in vascular endothelial cells. In addition, intraperitoneal injection of JP1 (1, 5 or 10 mg) once every other day for 3 times also dose-dependently inhibited CNV. After intraperitoneal injection of FITC-labeled JP1 (FITC-JP1) or FITC in laser-induced CNV mice, the fluorescence intensity in the CNV lesion was markedly increased in FITC-JP1 group, compared with that in FITC group, confirming that JP1 could penetrate the blood-retinal barrier to target CNV lesion. We conclude that JP1 can be used to design novel CNV-targeting therapeutic agents that may replace current invasive intraocular injections.

TRANSSCLERAL INCISION FOR PEELING SUBRETINAL PROLIFERATION TISSUE IN GRADE C PROLIFERATIVE VITREORETINOPATHY.

PURPOSE: The purpose of this study was to investigate the clinical outcomes of an optimized method to clearly remove the subretinal proliferative tissue by transscleral puncture into the subretinal space in patients with grade C proliferative vitreoretinopathy without inducing retinal injury. METHODS: This was a prospective clinical observation study. Eight consecutive patients who had undergone optimized vitrectomy surgery for retinal detachment complicated by grade C proliferative vitreoretinopathy were investigated. Subretinal proliferation was cleared by adding one additional scleral 23-gauge trocar under the detached retina at 9 mm to 10 mm from the limbus. After the sclera is pierced, the puncture knife changed its direction without touching the retina. 23-G intraocular forceps were used to remove the proliferation strand or membrane through the puncture channel. RESULTS: Retinal reattachment was achieved in each case without a retinotomy. The mean best-corrected visual acuity was improved within the first 1 month ( P = 0.039) and remained stable at the following phase. There were no postoperative complications, such as reoccurrence of retinal detachment or proliferative vitreoretinopathy. No postoperative hemorrhage or hypotension was observed. CONCLUSION: The satisfying results demonstrated the feasibility of this cost-effective, easy-to-follow, transscleral vitrectomy method in treating retinal detachment with grade C proliferative vitreoretinopathy.

Vitamin C- and Valproic Acid-Induced Fetal RPE Stem-like Cells Recover Retinal Degeneration via Regulating SOX2.

Retinal pigment epithelial (RPE) cell replacement therapy has provided promising outcomes in the treatment of retinal degenerative diseases (RDDs), but the resulting limited visual improvement has raised questions about graft survival and differentiation. Through combined treatment with vitamin C and valproic acid (together, VV), we activated human fetal RPE (fRPE) cells to become highly proliferative fetal RPE stem-like cells (fRPESCs). In this study, we report that SOX2 (SRY-box 2) activation contributed to mesenchymal-epithelial transition and elevated the retinal progenitor and mesenchymal stromal markers expressions of fRPESCs. These fRPESCs could differentiate into RPE cells, rod photoreceptors, and mesenchymal lineage progenies under defined conditions. Finally, fRPESCs were transplanted into the subretinal space of an RDD mouse model, and a photoreceptor rescue benefit was demonstrated. The RPE and rod photoreceptor differentiation of transplanted fRPESCs may account for the neural retinal recovery. This study establishes fRPESCs as a highly proliferative, multi-lineage differentiation potential (including RPE, rod photoreceptor, and mesenchymal lineage differentiation), mesenchymal-to-epithelial-transitioned retinal stem-like cell source for cell-based therapy of RDDs.

Identification of a novel GPR143 mutation in a large Chinese family with isolated foveal hypoplasia.

BACKGROUND: Pathogenic variants of G-protein coupled receptor 143 (GPR143) gene often leads to ocular albinism type I (OA1) characterized by nystagmus, iris and fundus hypopigmentation, and foveal hypoplasia. In this study, we identified a novel hemizygous nonsense mutation in GPR143 that caused an atypical manifestation of OA1. CASE PRESENTATION: We reported a large Chinese family in which all affected individuals are afflicted with poor visual acuity and foveal hypoplasia without signs of nystagmus. Fundus examination of patients showed an absent foveal reflex and mild hypopigmentation. The fourth grade of foveal hypoplasia and the reduced area of blocked fluorescence at foveal region was detected in OCT. OCTA imaging showed the absence of foveal avascular zone. In addition, the amplitude of multifocal ERG was reduced in the central ring. Gene sequencing results revealed a novel hemizygous mutation (c.939G > A) in GPR143 gene, which triggered p.W313X. However, no iris depigmentation and nystagmus were observed among both patients and carriers. CONCLUSIONS: In this study, we reported a novel nonsense mutation of GPR143 in a large family with poor visual acuity and isolated foveal hypoplasia without nystagmus, which further expanded the genetic mutation spectrum of GPR143.

Optimization of Contact Lenses for Corneal Protection During Vitreoretinal Surgery.

OBJECTIVES: To optimize parameters of contact lenses (CLs) and evaluate their ability to protect the cornea during vitreoretinal surgery. METHODS: We compared the protective effects of balanced saline solution, viscoelastic agent, and CLs on rabbit corneas under conditions simulating vitreoretinal surgery. We evaluated CLs of different thicknesses and compared the protective effects of polymethyl methacrylate (PMMA) and gas-permeable fluorosilicone acrylate (XO) lenses on the corneas of rabbits and patients with severe proliferative diabetic retinopathy (PDR). The corneal fluorescein staining score (FSS) was measured to compare the protective effects of CLs. RESULTS: The FSS was significantly lower in the PMMA group than in the balanced saline solution and viscoelastic agent groups. The thickness of the PMMA lenses had no significant effect on the FSS. The FSS was significantly higher in the PMMA group than in the XO group. In patients with PDR, on day 1 after vitreoretinal surgery, the FSS was significantly higher in the PMMA group than in the XO group, although no significant difference was observed on postoperative day 7. CONCLUSION: The XO lens offers better corneal protection during noncontact wide-angle vitreoretinal surgery and protects the corneal epithelium more efficiently during vitrectomy in patients with PDR, irrespective of its thickness.

RetFluidNet: Retinal Fluid Segmentation for SD-OCT Images Using Convolutional Neural Network.

Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness and is characterized by fluid-related accumulations such as intra-retinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED). Spectral-domain optical coherence tomography (SD-OCT) is the primary modality used to diagnose AMD, yet it does not have algorithms that directly detect and quantify the fluid. This work presents an improved convolutional neural network (CNN)-based architecture called RetFluidNet to segment three types of fluid abnormalities from SD-OCT images. The model assimilates different skip-connect operations and atrous spatial pyramid pooling (ASPP) to integrate multi-scale contextual information; thus, achieving the best performance. This work also investigates between consequential and comparatively inconsequential hyperparameters and skip-connect techniques for fluid segmentation from the SD-OCT image to indicate the starting choice for future related researches. RetFluidNet was trained and tested on SD-OCT images from 124 patients and achieved an accuracy of 80.05%, 92.74%, and 95.53% for IRF, PED, and SRF, respectively. RetFluidNet showed significant improvement over competitive works to be clinically applicable in reasonable accuracy and time efficiency. RetFluidNet is a fully automated method that can support early detection and follow-up of AMD.

Gremlin-1: An endogenous BMP antagonist induces epithelial-mesenchymal transition and interferes with redifferentiation in fetal RPE cells with repeated wounds.

Purpose: To investigate the role of Gremlin-1, which is an endogenous antagonist of the bone morphogenetic protein (BMP) signaling pathway, in inducing epithelium-mesenchymal transition (EMT) in fetal RPE cells after repeated wounds. Methods: Subconfluent repetitive passages in fetal RPE cells were regarded as a model of repeated wounds. A phase contrast microscope was used to observe the morphology and pigment formation in cells. The expression of GREM1 (Gene ID: 26585; OMIM 603054) and EMT- or RPE-related genes in cells was evaluated with quantitative PCR (qPCR). Recombinant human protein Gremlin-1 (0.1 µg/ml) was added every day to investigate the molecular effects of Gremlin-1 on fetal RPE cells. The cell migration rate was investigated using a cell wound scratch assay, and western blotting was used to analyze the representative proteins (P-cadherin, ZO-1, vimentin, Smad4, and phosphorylated-Smads). In addition, transfection of siRNA was used to explore the rescue effects on EMT cells through the downregulation of GREM1. Finally, LDN193189, which is a type of pan-inhibitor of BMP receptors, was used to verify whether complete blocking of the BMP pathway interferes with the redifferentiation in low-passage fetal cells, even if the cells were treated with transforming growth factor beta 1 (TGF-ß) inhibitors. Results: In fetal RPE cells, the expression of GREM1 were gradually upregulated with repetitive passages, and at the same time, the function-specific genes in fetal RPE cells (TJP1, PMEL, BEST1, RPE65, and MERTK) were downregulated while the EMT-specific genes were upregulated. In addition, GREM1 had a similar expression pattern as SNAI1, which is a key transcription factor to trigger EMT. Recombinant human Gremlin-1 promoted EMT with the upregulation of SNAI1 and elevated the cell migration rate in a cell scratch assay, as well as decreased the expression of two key transcription factors of RPE embryonic development (MITF and OTX2) and the RPE marker, RPE65. Furthermore, the EMT marker, vimentin, and the TGF-ß pathway downstream transcription factor phosphorylated-Smad2 (p-Smad2) increased, but the epithelial marker, ZO-1, was reduced. Additionally, Smad4, which plays a role as a Snail1 cooperator by binding Smad3, was also increased. In contrast, GREM1 silencing increased the expression of MITF and OTX2, which means there was better redifferentiation in subconfluent fetal RPE cells, but it had little influence on p-Smad2 compared to the negative control group. Finally, by adding LDN193189, the BMP signaling pathway was blocked, and this block led to poor redifferentiation in low-passage cells, although the cells were treated with TGF-ß inhibitors. In addition, as positive feedback to block the BMP pathway, GREM1 was subsequently upregulated. Conclusions: In fetal RPE cells, Gremlin-1 induces EMT and inhibits redifferentiation by promoting the TGF-ß pathway and inhibiting the BMP pathway. GREM1 silencing alleviates EMT and increases the redifferentiation of cells by relieving the blockade of the BMP pathway. However, GREM1 silencing has no effects on the TGF-ß pathway. Thus, Gremlin-1 may serve as a novel target to treat proliferative vitreoretinopathy (PVR) and inhibit subretinal fibrosis, which is a risk factor for influencing the therapeutic effects of anti-vascular endothelial growth factor (anti-VEGF) on neovascular age-related macular degeneration (nAMD).

Evaluation of day care versus inpatient cataract surgery performed at a Jiangsu public Tertiary A hospital.

BACKGROUND: High cataract incidence and low cataract surgical rate are serious public health problems in China, despite the fact that efficient day care cataract surgery has been implemented in some public Tertiary A hospitals in China. In this study, we compared not only clinical outcomes, hospitalization time and total costs but also payment manners between day care and inpatient procedures for cataract surgery in a Jiangsu public Tertiary A hospital to put forward several instructional suggestions for the improvement of government medical policies. METHODS: In total, 4151 day care cases and 2509 inpatient cases underwent the same cataract surgery in the day care ward and ordinary ward respectively, and were defined as two groups. General information, complications, postoperative best corrected visual acuity (BCVA), hospitalization time, total costs and especially payment method were analyzed to compare day care versus inpatient. RESULTS: The general data display no significant differences (P > 0.05), and no significant difference between complications and postoperative BCVA were observed between the two groups (P > 0.05). The period of stay in hospital was significantly different (P < 0.001). The total costs were lower for day care than for inpatients (P < 0.001). To avoid sampling error, we analyzed the data of payment manner for each patient among this period. Day care patients tended to pay for the procedure using the Urban Employees Basic Medical Insurance (UEBMI) method, while inpatients tended to use the Out-of-Pocket Medical Treatment (OMT) payment method (P < 0.001). CONCLUSION: Day surgery of cataract is more cost-effective and efficient than inpatient surgery with equivalent clinical outcomes. As an efficient therapeutic regimen, day care surgery should be further promoted and supported by the government policies.

Thin Rigid Contact Lens Used in Vitreous-Retinal Surgery for Corneal Protection: A Randomized Controlled Trial.

PURPOSE: To design a rigid contact lens (CL) to be used in combination with a wide-angle viewing system and analyze its protection for corneal epithelial during vitreous-retinal surgery. METHODS: A thin and lightweight rigid CL was designed and constructed. The impact of the CL on the visualized fundus range was evaluated using a concrete eye model. Patients with severe proliferative diabetic retinopathy (PDR) were randomized to either the CL group, corneal protective agent (CPA) group, or balanced salt solution (BSS) group. All patients underwent phacoemulsification and a standard 23-gauge three-port vitrectomy. Surgery time and corneal fluorescein staining score (FSS) postoperatively were mainly measured. RESULTS: In the eye model, a larger area of fundus was visualized with the use of our CL under 128 D or 60 D Resight lens. The mean surgery time was 51.36±8.06 min, 50.89±8.26 min, and 55.46±9.14 in CL, CPA, and BSS group, respectively (F=2.325, P=0.105). In eight eyes in the BSS group, corneal epithelial layer was peeled off because the dryness of the cornea could not maintain a clear fundus image. The FSS in BSS group was markedly higher than that of CL and BSS group 1 day (P<0.001), 3 days (P<0.001), and 7 days (P=0.002) postoperatively. There was no statistical significance of the FSS between CL and CPA group at each follow-up endpoint. CONCLUSIONS: The CL that we designed can slightly enlarge the visible fundus range and efficiently protect corneal epithelium during vitrectomy for patients with PDR.

Directed differentiation of human embryonic stem cells to corneal endothelial cell-like cells: A transcriptomic analysis.

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.

Automated choroid segmentation based on gradual intensity distance in HD-OCT images.

The choroid is an important structure of the eye and plays a vital role in the pathology of retinal diseases. This paper presents an automated choroid segmentation method for high-definition optical coherence tomography (HD-OCT) images, including Bruch's membrane (BM) segmentation and choroidal-scleral interface (CSI) segmentation. An improved retinal nerve fiber layer (RNFL) complex removal algorithm is presented to segment BM by considering the structure characteristics of retinal layers. By analyzing the characteristics of CSI boundaries, we present a novel algorithm to generate a gradual intensity distance image. Then an improved 2-D graph search method with curve smooth constraints is used to obtain the CSI segmentation. Experimental results with 212 HD-OCT images from 110 eyes in 66 patients demonstrate that the proposed method can achieve high segmentation accuracy. The mean choroid thickness difference and overlap ratio between our proposed method and outlines drawn by experts was 6.72µm and 85.04%, respectively.

Serum miRNA biomarkers serve as a fingerprint for proliferative diabetic retinopathy.

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.

Multiplex bead array assay of plasma cytokines in type 2 diabetes mellitus with diabetic retinopathy.

PURPOSE: The aim of this study was to assess the roles of plasma cytokines in diabetic retinopathy (DR) and their relationship with the severity of DR. METHODS: This study included 59 diabetic patients and 19 non-diabetic controls. The plasma concentrations of endothelial growth factor (EGF), eotaxin, fibroblast growth factor 2 (FGF-2), Flt-3 ligand (Flt-3L), fractalkine, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), growth-related oncogene (GRO), interferon (IFN)-α2, IFN-γ, interleukin (IL)-1α, IL-1ß, IL-1Ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IFN-inducible protein-10 (IP-10), monocyte chemoattractant protein (MCP)-1, MCP-3, macrophage-derived cytokine (MDC), macrophage inflammatory protein (MIP)-1α, MIP-1ß, sCD40L, sIL-2Rα, transforming growth factor (TGF)-α, tumor necrosis factor (TNF)- α, TNF-ß, and VEGF were measured with Luminex multiplex bead immunoassay. The levels of these cytokines were investigated according to the DR stage. RESULTS: The plasma level of ten cytokines-MCP-1, IL-6, IL-7, IL-9, IL-13, IL-15, IL-17, sCD40L, sIL-2Rα and TNF-ß-increased significantly in the diabetic group compared to the controls. The Flt-3L, IL-1Ra, IL-3, IL-5, and IL-12 (p40) levels were lower in the diabetic group than in the control group. The TNF-α plasma level was significantly elevated in patients with proliferative diabetic retinopathy (PDR) compared with the levels in patients with non-proliferative diabetic retinopathy (NPDR) and patients with no apparent diabetic retinopathy (NDR). CONCLUSIONS: TNF-α might be involved in the progression of DR, especially in the pathogenesis of PDR. TNF-α is a potential cytokine for the prognosis of DR and might act as a therapeutic target in DR.

Maternal germline mosaicism of kinesin family member 21A (KIF21A) mutation causes complex phenotypes in a Chinese family with congenital fibrosis of the extraocular muscles.

PURPOSE: To identify the causative mutation with its possible origin in a Chinese family with congenital fibrosis of extraocular muscles type 1 (CFEOM1) and to characterize the ocular phenotypes and lesions in the corresponding intracranial nerves. METHODS: Three affected siblings and their asymptomatic parents underwent comprehensive ophthalmic examinations and neuropathologic analysis involving magnetic resonance imaging (MRI). KIF21A, PHOX2A, and TUBB3 genes were sequenced on the leukocyte-derived DNA to detect variants. The disease-linked haplotype was analyzed using four microsatellite markers across the KIF21A locus. RESULTS: All three affected individuals displayed typical CFEOM1. MRI revealed complicated but consistent neuromuscular abnormalities in the two patients examined, including hypoplastic oculomotor nerves, complete absence of bilateral superior rectus muscles, and unilateral absence of the abducens nerve with marked atrophy of the corresponding lateral rectus muscle. A heterozygous hotspot mutation KIF21A c.2860C>T was identified in all patients, but it was absent in both parents. Haplotype analysis of the disease locus showed the likely maternal inheritance of the disease-associated haplotype to all three affected offspring, strongly suggesting maternal germline mosaicism of the mutation. CONCLUSIONS: Germline mosaicism of KIF21A c.2860C>T is likely to cause the high occurrence of this mutation in the population. This information may be useful for genetic counseling. KIF21A mutations can affect the abducens nerve and cause complete absence of the bilateral superior rectus muscles. MRI characterization of new CFEOM1 phenotypes would assist clinical management.

Risk Factors and Management of Intraocular Pressure Elevation After Vitrectomy Combined with Silicone Oil Tamponade.

Silicone oil has emerged as the common option for intraocular tamponade during complicated retina vitrectomy. However, the postoperative elevation of intraocular pressure (IOP), influenced by numerous factors, remains a significant and frequently encountered complication that poses a potential threat to vision. Extensive research has been conducted to investigate the risk factors associated with elevated IOP following silicone oil tamponade, including silicone oil viscosity, preoperative high IOP, diabetes, and lens status. This comprehensive review aims to gather and summarize the current research findings regarding the risk factors contributing to IOP elevation following silicone oil tamponade, as well as the optimal management strategies for secondary glaucoma. The analysis includes the physicochemical properties of silicone oil, preoperative and intraoperative risk factors, and the effective management of secondary glaucoma. Enhancing our understanding of the primary factors associated with silicone oil-induced IOP elevation will facilitate the guidance of timely and appropriate interventions.

RNA-sequencing expression profile and functional analysis of retinal pigment epithelium in atrophic age-related macular degeneration.

The retinal pigment epithelium (RPE) is fundamental to sustaining retinal homeostasis. RPE abnormality leads to visual defects and blindness, including age-related macular degeneration (AMD). Although breakthroughs have been made in the treatment of neovascular AMD, effective intervention for atrophic AMD is largely absent. The inadequate knowledge of RPE pathology is hindered by a lack of patient RPE datasets, especially at the single-cell resolution. In this study, we delved into a large-scale single-cell resource of AMD donors in which RPE cells were occupied in a substantial proportion. Bulk RNA-seq datasets of atrophic AMD were integrated to extract molecular characteristics of RPE in the pathogenesis of atrophic AMD. Both in vivo and in vitro models revealed that carboxypeptidase X, M14 family member 2 (CPXM2) was specifically expressed in the RPE cells of atrophic AMD, which might be induced by oxidative stress and involved in the epithelial-mesenchymal transition of RPE cells. Additionally, silencing of CPXM2 inhibited the mesenchymal phenotype of RPE cells in an oxidative stress cell model. Thus, our results demonstrate that CPXM2 plays a crucial role in regulating atrophic AMD and may serve as a potential therapeutic target for atrophic AMD.

Diverse Data Generation for Retinal Layer Segmentation with Potential Structure Modelling.

Accurate retinal layer segmentation on optical coherence tomography (OCT) images is hampered by the challenges of collecting OCT images with diverse pathological characterization and balanced distribution. Current generative models can produce high-realistic images and corresponding labels without quantitative limitations by fitting distributions of real collected data. Nevertheless, the diversity of their generated data is still limited due to the inherent imbalance of training data. To address these issues, we propose an image-label pair generation framework that generates diverse and balanced potential data from imbalanced real samples. Specifically, the framework first generates diverse layer masks, and then generates plausible OCT images corresponding to these layer masks using two customized diffusion probabilistic models respectively. To learn from imbalanced data and facilitate balanced generation, we introduce pathological-related conditions to guide the generation processes. To enhance the diversity of the generated image-label pairs, we propose a potential structure modeling technique that transfers the knowledge of diverse sub-structures from lowly- or non-pathological samples to highly pathological samples. We conducted extensive experiments on two public datasets for retinal layer segmentation. Firstly, our method generates OCT images with higher image quality and diversity compared to other generative methods. Furthermore, based on the extensive training with the generated OCT images, downstream retinal layer segmentation tasks demonstrate improved results. The code is publicly available at: https://github.com/nicetomeetu21/GenPSM.

Exploration on OCT biomarker candidate related to macular edema caused by diabetic retinopathy and retinal vein occlusion in SD-OCT images.

To improve the understanding of potential pathological mechanisms of macular edema (ME), we try to discover biomarker candidates related to ME caused by diabetic retinopathy (DR) and retinal vein occlusion (RVO) in spectral-domain optical coherence tomography images by means of deep learning (DL). 32 eyes of 26 subjects with non-proliferative DR (NPDR), 77 eyes of 61 subjects with proliferative DR (PDR), 120 eyes of 116 subjects with branch RVO (BRVO), and 17 eyes of 15 subjects with central RVO (CRVO) were collected. A DL model was implemented to guide biomarker candidate discovery. The disorganization of the retinal outer layers (DROL), i.e., the gray value of the retinal tissues between the external limiting membrane (ELM) and retinal pigment epithelium (RPE), the disrupted and obscured rate of the ELM, ellipsoid zone (EZ), and RPE, was measured. In addition, the occurrence, number, volume, and projected area of hyperreflective foci (HRF) were recorded. ELM, EZ, and RPE are more likely to be obscured in RVO group and HRFs are observed more frequently in DR group (all P ≤ 0.001). In conclusion, the features of DROL and HRF can be possible biomarkers related to ME caused by DR and RVO in OCT modality.