Role of Gpr124 in the Migration and Proliferation of Retinal Microvascular Endothelial Cells and Microangiopathies in Diabetic Retinopathy.

Retinal microangiopathies, such as neovascularization and preretinal and vitreous hemorrhages, are the primary pathological features of diabetic retinopathy (DR). These conditions can worsen visual impairment and may result in blindness. Furthermore, multiple metabolic pathways are associated with microangiopathy in DR. However, the specific underlying pathological mechanisms remain unclear. Several studies have demonstrated the important role of G protein-coupled receptor 124 (Gpr124) in cerebral vascular endothelial cells, but its effect on the retinal endothelium has not been elucidated. In this study, we found that Gpr124 is expressed in both pathological retinal fibrous vascular membranes of DR patients and retinal blood vessels of mice, with elevated protein expression specifically observed in the retinas of DR model mice. Furthermore, Gpr124 expression was elevated after high-glucose treatment of human retinal microvascular endothelial cells (HRMECs). Inhibition of Gpr124 expression affected the high glucose-induced proliferation, migration, and tube-forming ability of HRMECs. We concluded that Gpr124 expression was upregulated in DR and promoted HRMECs angiogenesis in a high-glucose environment. This finding may help to elucidate the pathogenesis of DR and provide a critical research basis for identifying effective treatments.

Patterns of Structural Changes in the Fundus Measured by Optical Coherence Tomography Angiography as Potential Markers of Acute Mountain Sickness.

Purpose: To use optical coherence tomography angiography (OCTA) to assess the pattern of changes in retinal and choroidal blood flow and structure in healthy volunteers who quickly went from sea level to a plateau and to determine the parameters associated with acute mountain sickness (AMS). Methods: Forty-five individuals (89 eyes) were examined by OCTA and filled out the AMS questionnaire. One baseline examination was performed on the plain, followed by examinations at days 1, 3, and 5 after entering the plateau. Parameters were self-controlled to explore patterns of change, analyzed for correlation with AMS score, and modeled as a nomogram of AMS risk. Results: On the plateau compared to the plain, vascular morphology showed dilated superficial macular retinal vessels and constricted deeper layers with increased vessel length density and fractal dimension; vessel density increased in all retinal strata and decreased in the choroidal macrovascular layer; and thickness increased except for a decrease in mean retinal thickness in the central macular sulcus. The rate of increase in retinal nerve fiber layer (RNFL) thickness in the inner and outer macular rings correlated with AMS score (r = -0.211). The nomogram showed moderate accuracy (AUC = 0.672) and consistency (C-index = 0.659) in assessing AMS risk. Conclusions: In high-altitude hypoxia, retinal vessels dilate and distort, resulting in increased blood flow density and thickness. Increased RNFL thickness in the paracentral macula may be a marker of low AMS risk. Translational Relevance: The changes in the retinal structure of the fundus can be used to assess the risk of developing AMS.

Central retinal artery occlusion without cherry-red spots.

BACKGROUND: Cherry-red spots are a very important sign for the clinical diagnosis of central retinal artery occlusion (CRAO). We retrospectively summarized the clinical manifestations of CRAO and analysed the causes and characteristics of CRAO without cherry-red spots. In this study, we explored a diagnostic method for CRAO without cherry red spots. METHODS: Seventy patients (70 eyes) with CRAO were examined retrospectively. Corrected distance visual acuity, fundus photos, FA and OCT images were collected at the first outpatient visit. The causes of CRAO without cherry-red spots were analysed through fundus photos. The incidence of increased hyperreflectivity of the inner retina, central macular thickness (CMT) and arteriovenous transit time in patients with and without cherry-red spots were compared. RESULTS: Fundus examination showed posterior retinal whitening in 57 cases (81.43%) and cherry-red spots in 39 cases (55.71%). Thirty-one patients presented at the first outpatient visit without cherry-red spots. The reasons for the absence of cherry-red spots included leopard fundus (32.26%), retinal vein occlusion (25.81%), no obvious inner retinal coagulative necrosis (19.35%), ciliary retinal artery sparing (12.90%), high macular oedema (9.68%) and cherry-red spot enlargement (3.23%). OCT revealed increased hyperreflectivity of the inner retina in 67 CRAO patients (95.71%). All 3 patients without increased hyperreflectivity of the inner retina did not present with cherry-red spots at the first visit. The median CMT in patients without cherry-red spots was 166.00 µm, while the median MCT in patients with cherry-red spots was 180.00 µm; there was no significant difference between these two groups (P = 0.467). FA showed delayed arteriovenous transit time > 23 s in 20 patients (28.57%), > 15 s in 43 patients (61.43%) and no delay in 27 patients (30.77%). The median arteriovenous transit time in patients without cherry-red spots was 19.00 s, while it was 18.00 s in patients with cherry-red spots; there was no significant difference between these two groups (P = 0.727). CONCLUSIONS: There are multiple factors that could cause the absence of cherry-red spots in CRAO. The use of OCT to observe increased hyperreflectivity of the inner retina is the most effective imaging method for the early diagnosis of CRAO without cherry-red spots.

The necessity of pretreatment with 0.1% pranoprofen for femtosecond-assisted cataract surgery: A single-center, randomized controlled trial.

Purpose: To explore the effect of the variation of pupil diameter (PD) and intraocular pressure (IOP) induced by femtosecond laser treatment on the subsequent phacoemulsfication and intraocular lens implantation. And whether the application of 0.1% pranoprofen could significantly reduce the miosis and increased IOP caused by femtosecond laser treatment in femtosecond laser-assisted cataract surgery (FLACS). Methods: In this study, patients were pretreated with (trial group) or without (control group) topical 0.1% pranoprofen. The PD and IOP were measured at different time points within 30 â€‹min after the completion of the femtosecond laser treatment. Results: The comparisons of the two groups showed the PD of patients pretreated with 0.1% pranoprofen was significantly larger than that of the control only at 15 â€‹min after FLACS (P â€‹= â€‹0.046), and there was no significant difference in IOP at any time point (P â€‹> â€‹0.05). Neither the ratio of significant miosis (PD â€‹≤ â€‹5 â€‹mm) nor intraocular hypertension (IOP ≥30 â€‹mmHg) was significantly different between the control group (1.72%, 6.67%) and the trial group (1%, 4.17%) (P â€‹> â€‹0.05). Conclusions: The PD and IOP of patients undergoing FLACS showed fluctuations within a small range. The rates of significant miosis and intraocular hypertension are very low, it is safe for surgeons to complete the follow-up procedures within 30 â€‹min after femtosecond laser treatment. Pretreatment with 0.1% pranoprofen exerted a slight, albeit significant prophylactic effect preventing pupil miosis. However, it provided only a limited benefit in patients undergoing FLACS without other complications.

Recent advances in ocular graft-versus-host disease.

Ocular graft-versus-host-disease (GVHD) remains a significant clinical complication after allogeneic hematopoietic stem cell transplantation. Impaired visual function, pain, and other symptoms severely affect affected individuals' quality of life. However, the diagnosis of and therapy for ocular GVHD involve a multidisciplinary approach and remain challenging for both hematologists and ophthalmologists, as there are no unified international criteria. Through an exploration of the complex pathogenesis of ocular GVHD, this review comprehensively summarizes the pathogenic mechanism, related tear biomarkers, and clinical characteristics of this disease. Novel therapies based on the mechanisms are also discussed to provide insights into the ocular GVHD treatment.

Nomogram model predicts the risk of visual impairment in diabetic retinopathy: a retrospective study.

BACKGROUND: To develop a model for predicting the risk of visual impairment in diabetic retinopathy (DR) by a nomogram. METHODS: Patients with DR who underwent both optical coherence tomography angiography (OCTA) and fundus fluorescein angiography (FFA) were retrospectively enrolled. FFA was conducted for DR staging, swept-source optical coherence tomography (SS-OCT) of the macula and 3*3-mm blood flow imaging by OCTA to observe retinal structure and blood flow parameters. We defined a logarithm of the minimum angle of resolution visual acuity (LogMAR VA) ≥0.5 as visual impairment, and the characteristics correlated with VA were screened using binary logistic regression. The selected factors were then entered into a multivariate binary stepwise regression, and a nomogram was developed to predict visual impairment risk. Finally, the model was validated using the area under the receiver operating characteristic (ROC) curve (AUC), calibration plots, decision curve analysis (DCA), and clinical impact curve (CIC). RESULTS: A total of 29 parameters were included in the analysis, and 13 characteristics were used to develop a nomogram model. Finally, diabetic macular ischaemia (DMI) grading, disorganization of the retinal inner layers (DRIL), outer layer disruption, and the vessel density of choriocapillaris layer inferior (SubVD) were found to be statistically significant (P < 0.05). The model was found to have good accuracy based on the ROC (AUC = 0.931) and calibration curves (C-index = 0.930). The DCA showed that risk threshold probabilities in the (3-91%) interval models can be used to guide clinical practice, and the proportion of people at risk at each threshold probability is illustrated by the CIC. CONCLUSION: The nomogram model for predicting visual impairment in DR patients demonstrated good accuracy and utility, and it can be used to guide clinical practice. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2200059835. Registered 12 May 2022, https://www.chictr.org.cn/edit.aspx?pid=169290&htm=4.

Proteomics and phosphoproteomics analysis of vitreous in idiopathic epiretinal membrane patients.

PURPOSE: The purpose of the present study was to characterize the idiopathic epiretinal membrane (iERM) through proteomics and phosphoproteomics analysis to facilitate the diagnosis and treatment of iERM. EXPERIMENTAL DESIGN: The vitreous of 25 patients with an iERM and 15 patients with an idiopathic macular hole were analyzed by proteomic and phosphoproteomic analysis based on tandem mass tag. PRM was used to verify the differential proteins. RESULTS: Proteomic analysis identified a total of 878 proteins, including 50 differential proteins. Tenascin-C, galectin-3-binding protein, glucose-6-phosphate isomerase, neuroserpin, collagen alpha-1(XI) chain, and collagen alpha-1(II) chain were verified to be upregulated in iERM by PRM. Phosphoproteomic analysis identified a total of 401 phosphorylation sites on 213 proteins, including 27 differential phosphorylation sites on 24 proteins. Mitogen-activated protein kinase-activated protein kinase (MAPKAPK)3 and MAPKAPK5 were predicted as the major kinases in the vitreous of iERM. Twenty-six of the differential proteins and phosphorylated proteins may be closely related to fibrosis in iERM. CONCLUSION AND CLINICAL RELEVANCE: Our results indicated the potential biomarkers or therapeutic targets for iERM, provided key kinases that may be involved in iERM. Fibrosis plays an essential role in iERM, and further exploration of related differential proteins has important clinical significance.

Effects of aerobic exercise on tear secretion and tear film stability in dry eye patients.

BACKGROUND: To study the effects of aerobic exercise (AE) on tear secretion and tear film stability in dry eye patients. METHODS: This study consisted of two parts, each part included 3 groups, namely dry eye without AE group, dry eye with AE group and pre-clinical dry eye with AE group. In part 1, we studied the variations of Schirmer I test and six tear compositions before and after AE (34 eyes in each group). In part 2, we studied the variations of tear meniscus height, first and average non-invasive tear breakup time (F-NITBUT and A-NITBUT), lipid layer thickness, number of incomplete and complete blinks, partial blink rate (PBR) and visual acuity before and after AE (30 eyes in each group). RESULTS: In dry eye with AE group, Schirmer I test at 0 min after AE increased significantly compared to baseline (P < 0.001), the oxidative stress marker 8-hydroxy-2'-deoxyguanosine after AE decreased significantly compared to baseline (P = 0.035, P = 0.045), F-NITBUT and A-NITBUT after AE prolonged significantly compared to baseline (P < 0.001, P = 0.007, P = 0.036; P < 0.001, P = 0.001, P = 0.044), number of incomplete blinks and PBR at 10 min after AE decreased significantly compared to baseline (P < 0.001; P < 0.001) while number of complete blinks increased significantly (P < 0.001). Besides, significant differences were also found between dry eye with AE group and dry eye without AE group at all above corresponding time point (P < 0.05). CONCLUSION: AE promotes tear secretion and improves tear film stability in dry eye patients. AE may be a potential treatment for dry eye. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000038673 . Registered 27 September 2020.

Axon regeneration after optic nerve injury in rats can be improved via PirB knockdown in the retina.

BACKGROUND: In the central nervous system (CNS), three types of myelin-associated inhibitors (MAIs) exert major inhibitory effects on nerve regeneration: Nogo-A, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp). MAIs have two co-receptors, Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PirB). Existing studies confirm that inhibiting NgR only exerted a modest disinhibitory effect in CNS. However, the inhibitory effects of PirB on nerve regeneration after binding to MAIs are controversial too. We aimed to further investigate the effect of PirB knockdown on the neuroprotection and axonal regeneration of retinal ganglion cells (RGCs) after optic nerve injury in rats. METHODS: The differential expression of PirB in the retina was observed via immunofluorescence and western blotting after 1, 3, and 7 days of optic nerve injury (ONI). The retina was locally transfected with adeno-associated virus (AAV) PirB shRNA, then, the distribution of virus in tissues and cells was observed 21 days after AAV transfection to confirm the efficiency of PirB knockdown. Level of P-Stat3 and expressions of ciliary neurotrophic factor (CNTF) were detected via western blotting. RGCs were directly labeled with cholera toxin subunit B (CTB). The new axons of the optic nerve were specifically labeled with growth associated protein-43 (GAP43) via immunofluorescence. Flash visual evoked potential (FVEP) was used to detect the P1 and N1 latency, as well as N1-P1, P1-N2 amplitude to confirm visual function. RESULTS: PirB expression in the retina was significantly increased after ONI. PirB knockdown was successful and significantly promoted P-Stat3 level and CNTF expression in the retina. PirB knockdown promoted the regeneration of optic nerve axons and improved the visual function indexes such as N1-P1 and P1-N2 amplitude. CONCLUSIONS: PirB is one of the key molecules that inhibit the regeneration of the optic nerve, and inhibition of PirB has an excellent effect on promoting nerve regeneration, which allows the use of PirB as a target molecule to promote functional recovery after ONI.

The Relationship between Anterior Chamber Angle and Intraocular Pressure Early after V4c Implantable Collamer Lens Implantation.

PURPOSE: To confirm the relationship between anterior chamber angle (ACA) and intraocular pressure (IOP) early after V4c implantable collamer lens (ICL) implantation. METHODS: Patients were assigned to two groups: (1) right eyes (control group) and (2) left eyes (experimental group), with miosis conducted immediately after ICL implantation in the left eyes. IOP, angle opening distance (AOD), trabecular-iris angle (TIA), and pupil diameter (PD) were compared between two groups at postoperative hours 1, 2, and 24. The relationship between ACA, PD, and IOP was analyzed by multiple linear regression. RESULT: Thirty-six eyes of 18 patients were enrolled. The prevalence of ocular hypertension (OHT, defined as IOP ≥ 21 mmHg) was 61.11% and 16.67% in the right and left eyes, respectively, (χ 2 = 7.481, p=0.006). At postoperative hours 1 and 2, IOP and PD were significantly higher (p < 0.001) in the right eyes, and TIA and AOD were significantly lower (p < 0.05) in the right eyes than in the left eyes. There was no significant difference at 24 h postoperative in these parameters. After the right eye ICL implantation, the changes of AOD 500 and PD were both linearly correlated with postoperative IOP change (ß = -23.707 and 1.731, respectively; p = 0.013 and 0.002, respectively). CONCLUSION: The ACA was significantly narrowed immediately after V4c ICL implantation. There was a negative linear correlation between ACA and early IOP and a positive linear correlation between PD and early IOP. We recommend the use of intracameral miotics immediately after V4c ICL implantation to reduce the incidence of IOP spikes.

Rottlerin acts as a therapeutic in primary open-angle glaucoma by targeting the trabecular meshwork via activation of Rap1 signaling.

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide, and elevated intraocular pressure (IOP) is a major risk factor. While IOP is mainly controlled by adjusting the outflow resistance in the trabecular meshwork (TM), drugs that act directly on the TM are rare. In this study, we discovered a novel compound and pathway that acts on the TM and decreases IOP by genomic, proteomic, and bioinformatic analyses of POAG-derived TMs and experimental validation. Overlapping differentially expressed genes of the TM between patients with POAG and normal controls from two independent gene expression profiles in public databases were analyzed and matched by using the Connectivity Map (CMap). Rottlerin was identified as a potential compound. Subsequent experiments confirmed that rottlerin reversed POAG phenotypes in vitro and that it decreased IOP and actin/extracellular matrix accumulation in vivo with no detectable ocular side effects. SwissTargetPrediction in combination with pathway analysis predicted that the effects of rottlerin may be mediated by activation of the Rap1 pathway. Finally, we confirmed that rottlerin upregulated Rap1 and the downstream PI3K/AKT pathway independent of the MAPK/ERK pathway in a dexamethasone-induced POAG cell model.

Paired Immunoglobulin-like Receptor B Inhibition in Müller Cells Promotes Neurite Regeneration After Retinal Ganglion Cell Injury in vitro.

In the central nervous system (CNS), three types of myelin-associated inhibitors (MAIs) have major inhibitory effects on nerve regeneration. They include Nogo-A, myelin-associated glycoprotein, and oligodendrocyte-myelin glycoprotein. MAIs possess two co-receptors, Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PirB). Previous studies have confirmed that the inhibition of NgR only results in a modest increase in regeneration in the CNS; however, the inhibitory effects of PirB with regard to nerve regeneration after binding to MAIs remain controversial. In this study, we demonstrated that PirB is expressed in primary cultures of retinal ganglion cells (RGCs), and the inhibitory effects of the three MAIs on the growth of RGC neurites are not significantly decreased after direct PirB knockdown using adenovirus PirB shRNA. Interestingly, we found that retinal Müller cells expressed PirB and that its knockdown enhanced the regeneration of co-cultured RGC neurites. PirB knockdown also activated the JAK/Stat3 signaling pathway in Müller cells and upregulated ciliary neurotrophic factor levels. These findings indicate that PirB plays a novel role in retinal Müller cells and that its action in these cells may indirectly affect the growth of RGC neurites. The results also reveal that PirB in Müller cells affects RGC neurite regeneration. Our findings provide a novel basis for the use of PirB as a target molecule to promote nerve regeneration.

A case of bilateral endogenous endophthalmitis misdiagnosed as Purtscher's retinopathy.

BACKGROUND: Purtscher's retinopathy characterized by the appearance of cotton-wool spots and intraretinal hemorrhage at the posterior pole that commonly occurs after severe head and chest trauma. We report a patient who presented with multiple white retinal patches and retinal hemorrhage forty-two days after a severe thoracoabdominal trauma, which was misdiagnosed as Purtscher's retinopathy. CASE PRESENTATION: A middle-aged woman presented to the eye clinic complaining of decreased vision and distortion in the right eye forty-two days after thoracoabdominal trauma. Upon first glance at her fundal appearances with multiple white retinal patches and retinal hemorrhage, we considered it to be bilateral Purtscher's retinopathy. No specific treatment was given to her. Ten days later, the four white retinal patches in the right eye joined together with star-shaped hard exudates and radial folds in the macula. This was not consistent with the characteristics of Purtscher's retinopathy. In retrospect, we found that the onset time, shape, and location of the white retinal patches were not cotton-wool spots. A detailed history revealed that she had Staphylococcus aureus septicaemia due to abdominal incision infection, and she underwent intravenous antibiotic therapy. Fundus fluorescein angiography (FFA) revealed hyperpermeable vasculature and extensive fluorescence leakage in the middle and late stages. Optical coherence tomography (OCT) revealed highly reflective exudates in the neuroepithelium and macular edema in the right eye. Taking her history and the FFA and OCT results into consideration, she was diagnosed with bilateral endogenous endophthalmitis. CONCLUSION: In the present case, multiple white patches and intraretinal hemorrhage at the posterior pole forty-two days after the trauma were not Purtscher's retinopathy. It was bilateral endogenous endophthalmitis. The subretinal abcesses that developed secondary to Staphylococcus aureus infection involved the macula causing decreased vision and distortion in the right eye. We concluded that in the case of multiple white retinal patches at the posterior pole in patients after trauma, especially in patients with infectious disease, Purtscher's retinopathy is not the only possible diagnosis. Correct diagnosis depends on reevaluation of the lesions by FFA and OCT, laboratory investigation and detailed history.

Retinal blood vessel-origin yes-associated protein (YAP) governs astrocytic maturation via leukaemia inhibitory factor (LIF).

OBJECTIVES: To testify that endothelial cells (ECs) induce astrocyte maturation by leukaemia inhibitory factor (LIF) secretion. MATERIALS AND METHODS: In vivo experiments, mice bearing floxed alleles of YAP were crossed with mice expressing a Cre recombinase driven by the endothelial Tek promoter (Tek-Cre) to finally obtain the following three genotypes: YAPf/f , Tek-Cre; YAPf/w , Tek-Cre; and YAPf/f . Retinal vascularization and astrocyte network were evaluated by whole-mount fluorescence and Western blotting. In vitro, experiments were performed in an astrocyte and human microvascular endothelial cell (HMEC-1) coculture model to analyse the mechanisms underlying the effect of endothelial YAP on astrocytes. RESULTS: In vivo, YAPf/f ;Tek-Cre mice showed delayed angiogenesis, sparse vessels and decreased glial fibrillary acidic protein (GFAP)+ astrocytes but aberrant growth of endothelial networks and immature astrocytes (platelet-derived growth factor A, PDGFRA+ astrocytes) overgrowth. In vitro, Yap deletion attenuated the LIF release that delayed the maturation of retinal astrocyte which was consistent with the results of HMEC-1-astrocyte coculture. The effect of YAP overexpression on LIF-LIFR axis in HMEC-1 interferes the GFAP expression of astrocyte. In contrast, LIF protein rescues the astrocytic GFAP expression when EC YAP was inhibited by siRNAs. CONCLUSIONS: We show that EC yes-associated protein (YAP) is not only a critical coactivator of Hippo signalling in retinal vessel development but also plays an essential role in retinal astrocyte maturation by regulating LIF production.

Factors affecting pain in patients undergoing bilateral cataract surgery.

PURPOSE: To compare the perceived pain and estimated operative duration among patients undergoing bilateral cataract surgery and to demonstrate correlations with the surgical interval and the demographic and medical characteristics of the patients. METHODS: A total of 466 patients with cataract who underwent ocular surgery were included. The patients estimated the perceived operative duration and pain they felt during the operation at two times, immediately after surgery and on the first postoperative day; pain was scored using a visual analog scale ranging from 0 (no pain) to 10 (unbearable pain). Patients undergoing bilateral surgeries were divided into four subgroups based on the interval between the two operations (1, 2, 4, or 6 weeks). The perceived pain score and the estimated operative duration were the primary outcomes. RESULTS: The pain scores were higher for the second surgery than for the first surgery both immediately after surgery (P = 0.043) and on the first postoperative day (P = 0.002). The estimated operative duration was longer for the second surgery (P = 0.001). Only patients who underwent the second surgery at an interval of 2 weeks perceived more pain both immediately and 1 day postoperatively (P = 0.002, P = 0.022) and a longer operative duration (P < 0.001). Gender, age, and education level might also influence the pain score. CONCLUSIONS: Female patients, patients with a younger age, and patients with higher education level are likely to report more pain. Patients who require bilateral cataract surgery should not undergo the second surgery before an interval of 2 weeks.