Investigative ophthalmology & visual science最新文献

Purpose: The purpose of this study was to assess associations of intraocular pressure (IOP) readings.

Methods: This was a population-based studies conducted in Russia, China, and India. The project included the population-based investigations of the Beijing Eye Study (BES; n = 3139 participants, age = 40+ years), Ural Eye and Medical Study (UEMS; n = 5514, age = 40+ years), Ural Very Old Study (UVOS; n = 522, age = 85+ years), and Ural Children Eye Study (UCES; n = 4294, age = 6+ years), and Central India Eye and Medical Study (CIEMS; n = 4508, age = 30+ years). Pneumo-tonometry or applanation tonometry were performed.

Results: The study included 35,199 eyes (17,977 individuals, mean age = 46.9 ± 23.2 years, range = 6-100 years, axial length = 23.2 ± 1.0 mm, range = 18.22-34.20 mm). In the test group (BES, UVOS, and UCES), higher IOP-readings were associated (r2 = 0.37) with younger age, female sex, rural habitation region, higher prevalence of diabetes mellitus, higher systolic blood pressure, thicker central corneal thickness (CCT) and smaller corneal curvature radius (i.e. steeper cornea), longer axial length, lower prevalence of cataract surgery, and higher prevalence of pseudoexfoliation. IOP values, corrected for these associations, correlated with the IOP readings in the external validation groups of UEMS (r2 = 0.85) and CIEMS (r2 = 0.80). In Bland-Altman analysis, the mean bias was 0.80 millimeters of mercury (mm Hg; 95% confidence interval [CI] = 0.76-0.84 or 5.8%, 95% CI = 5.5-6.1) and 1.51 mm Hg (95% CI = 1.47-1.56 or 10.2%, 95% CI = 9.9-10.5), in the UEMS and CIEMS, respectively. The corrected IOP compared to the measured IOP was 8.1 mm Hg lower and 10.0 mm Hg higher, respectively, in 2 clinical examples. A real IOP value of 21 mm Hg corresponded to a measured IOP readings ranging from 29.1 mm Hg to 11.0 mm Hg.

Conclusions: Among numerous ocular and systemic factors influencing IOP readings (with a relative low correlation coefficient), corneal curvature radius was one of the main ocular determinants. Correction of measured IOP readings led to a large interindividual variation in the upper limit of the "normal" IOP range.

Purpose: Glaucoma is a leading cause of irreversible blindness, yet the circulating proteins and metabolic pathways that causally contribute to different glaucoma subtypes remain poorly defined.

Methods: We analyzed baseline plasma proteomics in 1485 glaucoma cases (447 primary open‑angle glaucoma [POAG], 177 primary angle-closure glaucoma [PACG], 120 normal-tension glaucoma [NTG]) in the UK Biobank using Cox models with graded adjustment. We then integrated five independent protein quantitative trait loci resources with FINLAND R12 genome-wide association study data to perform two‑sample Mendelian randomization (MR) and cross‑cohort meta‑analysis for overall glaucoma and each subtype. To prioritize effector genes and pathways, we conducted summary-data-based Mendelian randomization (SMR) using eQTLGen and two‑step mediation MR using metabolite quantitative trait loci data for ∼1400 plasma metabolites from the Canadian Longitudinal Study on Aging cohort.

Results: In fully adjusted Cox models, 484 proteins were associated with incident glaucoma, 135 with NTG, 59 with POAG, and 1 with PACG (false discovery rate <0.05). Multicohort MR and meta‑analysis identified eight proteins with robust causal effects: NRP2, TSPAN1, and HAVCR2 for overall glaucoma; NRXN3 for PACG; MANSC4 for NTG; and LTBP2, CD69, and SMAD1 for POAG. SMR supported NRP2 (overall glaucoma) and SMAD1 (POAG) as causal genes. Mediation MR revealed that sphingomyelins, acylcarnitines, and bile acid-related metabolites partially mediated the effects of several proteins, defining shared (e.g., sphingolipid) and subtype‑specific metabolic pathways.

Conclusions: By integrating epidemiologic, proteomic, genetic, and metabolomic data, we identify convergent systemic protein and metabolic signatures associated with glaucoma susceptibility and its clinical subtypes. These findings nominate NRP2, SMAD1, and related pathways as promising biomarkers and therapeutic targets and support a systems‑level view of glaucoma pathogenesis beyond intraocular pressure alone.

Purpose: To determine whether topical naltrexone (NTX) treatment can decrease the elevated reactive oxygen species pathways and select proinflammatory cytokines in the rat cornea and lacrimal glands that are elevated in diabetic dry eye.

Methods: Type 1 diabetic male and female Sprague-Dawley rats were rendered hyperglycemic for 6-8 weeks and then treated topically with NTX eyedrops twice daily for 15 days. Corneal epithelium and lacrimal glands were evaluated for expression of dihydroethidium, C/EBP homologous protein, and NADPH oxidase -2 (NOX-2) as well as the proinflammatory cytokines interleukin (IL) -1β, IL-6, and tumor necrosis factor alpha (TNF-α) to identify pathways targeted in the mitigation of diabetic dry eye.

Results: Type 1 diabetes resulted in dry eye and corneal surface insensitivity, accompanied by increased levels of oxidative stress and inflammation mediators in both corneal epithelium and lacrimal glands. Topical NTX treatment restored tear volume and corneal surface sensitivity, and significantly reduced expression of dihydroethidium, C/EBP homologous protein, and NOX-2, as well as proinflammatory cytokines IL-1β, IL-6, and TNF-α in male and female diabetic rats.

Conclusions: Blockade of the opioid growth factor (OGF)-OGF receptor system with topical NTX rapidly reversed diabetic dry eye and restored corneal surface sensitivity. The mechanism involved downregulating oxidative stress and decreasing proinflammatory cytokines to levels at or below those of nondiabetic rats of the same sex. These findings support a mechanistic role for OGF receptor blockade in the reversal of diabetic dry eye.

Purpose: Glaucoma is a multifactorial disease, where metabolic and mitochondrial dysfunction may play a major role in the progressive loss of retinal ganglion cells that characterize the disease. Currently, treatment strategies consist of IOP-lowering approaches with no available neuroprotective agent. In epidemiological studies and models of glaucoma, GLP-1 receptor agonists (GLP-1RAs) reduce the risk of glaucoma and provide protection against the loss of retinal ganglion cells.

Methods: In this study, we explored the potential of semaglutide (SEM), a known GLP-1RA, to protect retinal ganglion cells from rotenone-induced metabolic dysfunction. We pretreated C57BL/6 mice subcutaneously with either SEM (5 mg/kg) or saline solution for one week. After one week, the mice received intravitreal injections of rotenone (10 mM) or dimethylsulfoxide (1%) and were euthanized 24 hours later.

Results: We demonstrated that rotenone caused a significant loss of retinal ganglion cells, which was prevented by SEM pretreatment. Metabolic analyses revealed that SEM enhanced glucose metabolism, which suggested the enhancement of glucose homeostasis/alternative pathways possibly supporting metabolic flexibility of retinal ganglion cells.

Conclusions: SEM may help preserve retinal ganglion cells under conditions of mitochondrial Complex I inhibition, suggesting a potential therapeutic role in glaucoma management; however, further studies are required to confirm metabolic changes observed in this study.

Purpose: The purpose of this study was to evaluate motor skill impairments in children with intermittent exotropia (IXT), and to investigate associations between clinical visual parameters and motor deficits.

Methods: In this cross-sectional study, motor proficiency in children with basic-type IXT and age-matched controls was evaluated using the Movement Assessment Battery for Children, Second Edition (MABC-2). All participants had normal best-corrected visual acuity (BCVA). This yielded scores for Total Motor Score, manual dexterity, aiming and catching, and balance. Within the IXT cohort, key ophthalmic characteristics, including deviation control, stereoacuity, and suppression, were documented. Group differences were analyzed, and relationships between visual features and MABC-2 scores in the IXT group were assessed using Spearman's correlation and multivariable regression models. Sensitivity analyses were performed to confirm the robustness of findings.

Results: Children with IXT demonstrated significantly lower Total Motor Score than controls (P < 0.001), with specific deficits in manual dexterity (P < 0.001) and balance (P < 0.001), aiming and catching scores were comparable between groups (P = 0.332). Within the IXT cohort, poorer manual dexterity was significantly associated with reduced stereoacuity. Furthermore, aiming and catching performance was associated with the presence of sensory suppression.

Conclusions: Childhood IXT, despite its intermittent nature, is associated with broad motor deficits extending beyond the ocular motor system. These functional impairments are related to the condition's underlying sensory adaptations. Our findings reveal the widespread implications of disordered binocular vision and underscore the necessity of monitoring motor development in these patients.

Purpose: The Vglut2-Cre;ndufs4loxP/loxP mouse strain with retinal ganglion cell (RGC)-specific mitochondrial complex I dysfunction develops severe RGC degeneration by postnatal day 90 (P90), with accompanying retinal mononuclear phagocyte (MNP) accumulation. We have reported that continuous exposure to hypoxia partially rescues RGC death in these mice, with minimal effect on MNP abundance. We hypothesized that pharmacological depletion of MNPs with the colony-stimulating factor-1 receptor inhibitor pexidartinib would enhance RGC neuroprotection by hypoxia.

Methods: Iba1+ retinal MNP depletion was assessed in C57Bl/6J mice fed control or pexidartinib-infused chow beginning at P25. Subsequently, Vglut2-Cre;ndufs4loxP/loxP mice and control littermates were raised under normoxia or hypoxia and fed control or pexidartinib chow from P25 to P90. The neuroprotective effect of pexidartinib and hypoxia alone and in combination was assessed by quantifying RGC soma and axon survival in retinal flat mounts and optic nerve cross-sections.

Results: Pexidartinib completely depleted retinal MNPs within 1 week of treatment. Untreated Vglut2-Cre;ndufs4loxP/loxP mice exhibited the expected approximately 50% reduction of RGC soma and axon survival at P90 (P < 0.0001 for both). Hypoxia or pexidartinib monotherapy each reduced RGC degeneration by more than one-half, whereas their combination resulted in complete RGC neuroprotection (P < 0.01 for all 3 treatments). Normal myelination patterns were restored in mice receiving dual therapy.

Conclusions: Pexidartinib effectively depletes retinal MNPs and is neuroprotective in the setting of severe RGC mitochondrial dysfunction. This therapeutic effect is additive to that of hypoxia. Combating retinal neuro-inflammation may therefore be a useful adjunct therapy in mitochondrial optic neuropathies like Leber hereditary optic neuropathy (LHON).

Purpose: X-linked retinoschisis (XLRS), caused by RS1 pathogenic variants, leads to macular dystrophy. Patients with XLRS show diurnal changes in optical coherence tomography (OCT), with more schisis in the morning. We studied diurnal variation in Rs1-knockout (KO) mice retinal structure and electrical function.

Methods: Rs1-KO mice 2.5 to 4 months old (MO) had electroretinogram (ERG), OCT, and intraocular pressure (IOP) measurements collected at 5 AM and 5 PM on different days and under different experimental conditions. Mice were maintained under standard 12-hour light/dark cycle, reversed 12-hour light/dark cycle, continuous light, or continuous darkness. At study endpoint, eyes were collected and fixed for immunohistochemistry or harvested for Western blot analysis.

Results: Extended light exposure resolved cysts completely and improved ERG b-wave amplitudes, whereas darkness worsened schisis and ERG function. Synaptic staining confirmed disrupted photoreceptor-bipolar connections in dark-exposed retinas and reorganization after light exposure, without changes in synaptic protein expression or rhodopsin localization. IOP still followed a diurnal pattern under constant light or dark, whereas cyst fluctuation correlated with lighting rather than time of day.

Conclusions: Initial findings suggested a diurnal rhythm in cyst size but reversed light cycle experiments showed that light exposure-not time of day-drives retinal changes in Rs1-KO mice. RS1-deficient retinas are vulnerable to darkness, whereas light exposure preserves retinal structure and function. To ensure valid OCT and ERG comparisons in XLRS, measurements should be time- and lighting-stamped. Dark-adapted conditions may best reveal treatment effects. Controlled light exposure may be a therapeutic option for patients with XLRS.

Purpose: Müller glia play dual roles in glaucoma, contributing to retinal homeostasis and neuroinflammation; activation by elevated intraocular pressure through mechanosensitive transient receptor potential vanilloid 4 (TRPV4) promotes a reactive state that drives retinal ganglion cell loss. Lipoxin B4 (LXB4), an endogenous lipid mediator produced by retinal astrocytes, suppresses glial reactivity and protects retinal ganglion cells. This study investigated whether LXB4 modulates TRPV4-driven Müller glial activation and whether Müller glia contribute to the lipoxin pathway.

Methods: Ocular hypertension was induced in mice via a silicone oil model, and reactive Müller glia were isolated by magnetic sorting for transcriptomics. In vitro, Müller glia cultures were treated with a TRPV4 agonist with or without LXB4. Glial reactivity was assessed by flow cytometry, immunostaining, qPCR, and Western blotting. Lipidomics quantified pathway metabolites, and single-cell RNA sequencing examined transcriptional responses to LXB4.

Results: Bulk RNA sequencing and qPCR revealed Müller glia express 5- and 15-lipoxygenase. Lipidomics confirmed a functional pathway, with endogenous LXB4 production, identifying Müller glia as a source of neuroprotective LXB4. TRPV4 activation induced gliosis with increased glial fibrillary acidic protein, IL-6, and signal transducers and activators of transcription 3 (STAT3) expression, and lipoxin production, indicating biomechanical stress triggers reactivity and protective signaling. LXB4 suppressed TRPV4-induced gliosis in vitro by downregulating IL-6 and STAT3 and in vivo by reducing Stat3, Il6, and Tnf-α and attenuating TRPV4 upregulation during ocular hypertension.

Conclusions: Müller glia are a significant source of LXB4 in the retina. This neuroprotective Müller glia pathway is amplified during chronic TRPV4 activation to counter-regulate gliosis. These findings support the targeting of the TRPV4-lipoxin pathway as a potential approach to protect against ocular hypertension-induced neurodegeneration in glaucoma.

Purpose: Investigate retinopathy of prematurity (ROP) notch physiology, using ultra-widefield optical coherence tomography (UWF-OCT), and a computational model.

Methods: From June 2023 to October 2024, infants screened for ROP at the Oregon Health and Science University neonatal intensive care unit were imaged with an investigational 800 kilohertz (kHz), 140-degree, swept-source UWF-OCT. Eyes were included upon developing at least stage 1 ROP in zone I or II, with adequate image quality. Minimum retinal arc-length (min-RAL) to the vascular border were calculated. Then, a computational model simulated a modified-diffusion limited aggregation (DLA) system on a circular grid approximating the retina from ora to ora. Randomly released particles moved via Brownian motion until aggregating with the vascular network originating at the optic disc. An inferred central repulsive force operating by the inverse square law from the fovea was modeled. The simulation was terminated 50 times in zone I, and 50 in mid-zone II. A grader assessed both the simulations and the UWF-OCT images for a temporal notch.

Results: Among 85 eyes (52 patients), notches appeared in 54 eyes (36 infants). Infants with a notch had lower gestational age (25.0 ± 2.0 vs. 27.4 ± 2.1 weeks), lower birthweight (533.6 ± 112 grams vs. 914 ± 359 grams), and shorter min-RAL (10.5 ± 2.6 vs. 12.9 ± 1.8 mm). The modified computational DLA model aligned predicting higher notch incidence in zone I (86% in simulation versus 83% in real eyes) than zone II (48% simulated versus 51% in real eyes).

Conclusions: This computational model introducing a foveal repulsive effect may explain varied retinal vasculogenesis patterns, like notch formation, and supports future predictive models.