Intraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Here, we used RNA-sequencing and metabolomics to examine ...early glaucoma in DBA/2J mice. We demonstrate gene expression changes that significantly impact pathways mediating the metabolism and transport of glucose and pyruvate. Subsequent metabolic studies characterized an intraocular pressure (IOP)-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Remarkably, retinal glucose levels were elevated 50-fold, consistent with decreased glycolysis but possibly including glycogen mobilization and other metabolic changes. Oral supplementation of the glycolytic product pyruvate strongly protected from neurodegeneration in both rat and mouse models of glaucoma. Investigating further, we detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration, supporting a damaging role for IOP-induced mTOR activation in perturbing metabolism and promoting glaucoma. Together, these findings support the use of treatments that limit metabolic disturbances and provide bioenergetic support. Such treatments provide a readily translatable strategy that warrants investigation in clinical trials.
Neovascular age-related macular degeneration, also known as exudative or wet age-related macular degeneration, is the leading cause of blindness in the developed world. Photobiomodulation has the ...potential to target the up-stream hypoxic and pro-inflammatory drivers of choroidal neovascularization. This study investigated whether photobiomodulation attenuates characteristic pathological features of choroidal neovascularization in a rodent model.
Experimental choroidal neovascularization was induced in Brown Norway rats with laser photocoagulation. A custom-designed, slit-lamp-mounted, 670 nm laser was used to administer retinal photobiomodulation every 3 days, beginning 6 days prior to choroidal neovascularization induction and continuing until the animals were killed 14 days later. The effect of photobiomodulation on the size of choroidal neovascular membranes was determined using isolectin-B4 immunohistochemistry and spectral domain-optical coherence tomography. Vascular leakage was determined with fluorescein angiography. The effect of treatment on levels of vascular endothelial growth factor expression was quantified with enzyme-linked immunosorbent assay.
Treatment with photobiomodulation was associated with choroidal neovascular membranes that were smaller, had less fluorescein leakage, and a diminished presence of inflammatory cells as compared to sham eyes. These effects were not associated with a statistically significant difference in the level of vascular endothelial growth factor when compared to sham eyes.
The data shown herein indicate that photobiomodulation attenuates pathological features of choroidal neovascularization in a rodent model by mechanisms that may be independent of vascular endothelial growth factor.
•Photobiomodulation does not induce choroidal neovascularization.•Photobiomodulation promotes regression of choroidal neovascularization.•Photobiomodulation promotes normalization of outer blood retinal barrier function.•Vascular endothelial growth factor expression is not modulated by photobiomodulation.•Photobiomodulation reduces retinal inflammation in choroidal neovascularization.
IMPORTANCE: Irreversible vision loss from primary open-angle glaucoma (POAG) can be prevented through timely diagnosis and treatment, although definitive diagnosis can be difficult in early-stage ...disease. As a consequence, large numbers of individuals with suspected glaucoma require regular monitoring, even though many of these may never develop disease and other high-risk individuals with suspected glaucoma may have delayed or inadequate treatment. POAG is one of the most heritable common diseases, and this provides an opportunity to use genetic instruments in risk-stratified screening, diagnosis, and treatment of early glaucoma. OBJECTIVE: To assess the association of glaucoma polygenic risk with glaucoma progression in early-stage disease. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used clinical and genetic data obtained from a longitudinal cohort study, Progression Risk of Glaucoma: Relevant SNPs With Significant Association (PROGRESSA). Participants of European ancestry with characteristic optic nerve head changes suggestive of glaucoma were included. Data were collected between February 2012 and June 2020. Analysis took place between July 2020 and April 2022. MAIN OUTCOMES AND MEASURES: The association of a glaucoma polygenic risk score (PRS) (2673 uncorrelated variants) with rate of peripapillary retinal nerve fiber layer thinning on optical coherence tomography and progression of visual field loss on 24-2 Humphrey visual fields. RESULTS: A total of 1777 eyes from 896 individuals had sufficient data for structural progression analyses and 1563 eyes from 808 individuals for functional progression analyses. The mean (SD) age was 62.1 (9.9) years, 488 (44%) were male, and 1087 of 1103 individuals (98.5%) had European ancestry. An ancestrally matched normative population cohort (n = 17 642) was used for PRS reference. Individuals in the top 5% PRS risk group were at a higher risk of visual field progression compared with the remaining 95% after 5 years (hazard ratio, 1.5; 95% CI, 1.13-1.97; P = .005). Conversely, those in the bottom 20% PRS risk group were at a lower risk of visual field progression compared with an intermediate risk group over 3 years (hazard ratio, 0.52; 95% CI, 0.28-0.96; P = .04). CONCLUSIONS AND RELEVANCE: In this study, high polygenic risk was associated with more rapid structural and functional progression in early POAG, despite more intensive treatment. A PRS may serve as a valuable adjunct to identify individuals who stand to benefit the most from more frequent surveillance and earlier or more intensive treatment.
The retinal pigment epithelium (RPE) comprises a monolayer of cells located between the neuroretina and the choriocapillaries. The RPE serves several important functions in the eye: formation of the ...blood‐retinal barrier, protection of the retina from oxidative stress, nutrient delivery and waste disposal, ionic homeostasis, phagocytosis of photoreceptor outer segments, synthesis and release of growth factors, reisomerization of all‐trans‐retinal during the visual cycle, and establishment of ocular immune privilege. Age‐related macular degeneration (AMD) is the leading cause of blindness in developed countries. Dysfunction of the RPE has been associated with the pathogenesis of AMD in relation to increased oxidative stress, mitochondrial destabilization and complement dysregulation. Photobiomodulation or near infrared light therapy which refers to non‐invasive irradiation of tissue with light in the far‐red to near‐infrared light spectrum (630–1000 nm), is an intervention that specifically targets key mechanisms of RPE dysfunction that are implicated in AMD pathogenesis. The current evidence for the efficacy of photobiomodulation in AMD is poor but its safety profile and proposed mechanisms of action motivate further research as a novel therapy for AMD.
The transformed RGC-5 retinal ganglion cell line is used widely in glaucoma research. Increased resistance to glutamate was noted in published literature and led to the recharacterization of the ...RGC-5 cell line.
Characterization of the RGC-5 cell line was performed by sequencing of a region of the nuclear Thy1 gene and mitochondrial DNA sequencing of a region of the d-loop and tRNA(Phe) gene. Marker expression was examined in undifferentiated cells, and cells differentiated with 50 microg/mL succinyl concanavalin A (S Con A) for 3 days. Glutamate sensitivity was examined in undifferentiated and S Con A differentiated cells by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay after 24-hours of glutamate treatment.
RGC-5 cells were found to be of mouse (Mus musculus), not rat (Rattus norvegicus), origin by mitochondrial and nuclear DNA analyses. RGC-5 DNA sequenced in a second laboratory was subsequently found to be of M. musculus origin. Cells stained positively for the neuronal markers beta-tubulin and PGP9.5 and for the microtubule-associated protein tau, but not for known markers of ganglion cells such as neurofilaments or Thy1.2, suggesting that they likely represented a lineage of mouse neuronal precursor cells. Differentiation with S Con A did not increase RGC-5 sensitivity to glutamate excitotoxicity or increase the expression of retinal or ganglion cell marker proteins.
Investigators using cells designated as RGC-5 should confirm the species to be of rat origin and retinal-specific marker expression before considering their use as retinal ganglion-like cells.
Purpose: To determine the prevalence and risk factors for cataracts in the Vientiane Province. Methods: We conducted a population-based study of 1264 participants aged ≥40 years of age from urban and ...rural areas of Vientiane Province. Data collection included demographic information, smoking history, body mass index, blood pressure, history of trauma and dilated lens examination using the World Health Organization WHO Simplified Cataract Grading System. Aphakic and pseudophakic eyes were included as operated cataracts for statistical analysis. Results: The mean age of the 1264 participants was 57.6 years. The prevalence of any cataract including operated eyes was 46.8% (95% CI: 44.1 - 49.6%): 36.9% nuclear, 21.7% cortical and 10.1% posterior subcapsular cataracts. Conclusion: The prevalence of cataract in the Vientiane Eye Study is similar compared to the prevalence reported in other studies from Asian regions; however, the median age in this study was low, reflecting the age group of the population and the rapid urbanisation occurring in the Lao People's Democratic Republic. A significant association for any cataract was found with elevated blood pressure >148mmHg (OR2.48, 95%CI:1.55 - 3.97, P < 0.01), increasing age (OR1.19, 95%CI:1.17 - 1.22, P < 0.001) and rural inhabitants for cortical cataract (OR1.99, 95%CI:1.37 - 2.90, P < 0.001). An inverse relationship between rural inhabitants with any cataract and nuclear cataract was found (OR 0.63, 95%CI: 0.45 - 0.89, P < 0.01 and OR 0.42, 95%CI: 0.31 - 0.59, P < 0.001) respectively. Nevertheless, cataract remains a high prevalence disease in this population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide
. Both IOP and POAG are highly ...heritable
. We report a combined analysis of participants from the UK Biobank (n = 103,914) and previously published data from the International Glaucoma Genetic Consortium (n = 29,578)
that identified 101 statistically independent genome-wide-significant SNPs for IOP, 85 of which have not been previously reported
. We examined these SNPs in 11,018 glaucoma cases and 126,069 controls, and 53 SNPs showed evidence of association. Gene-based tests implicated an additional 22 independent genes associated with IOP. We derived an allele score based on the IOP loci and loci influencing optic nerve head morphology. In 1,734 people with advanced glaucoma and 2,938 controls, participants in the top decile of the allele score were at increased risk (odds ratio (OR) = 5.6; 95% confidence interval (CI): 4.1-7.6) of glaucoma relative to the bottom decile.
To determine normal globe position values, interzygomatic distance (IZD), and globe axial length and width on computed tomography in an Australian cohort.
Retrospective cohort study.
Patients who ...underwent computed tomography of the orbits. Patients with bilateral disease, previous orbital surgery, or poor scan quality were excluded.
An axial slice through the midglobe was used to conduct the globe position measurements. Anterior globe position was defined as the perpendicular distance from the anterior globe margin to the interzygomatic line and posterior globe position as the perpendicular distance from the posterior globe margin to the interzygomatic line.
The normal measurements (mean ± SD) were IZD, 97.4 ± 4.1 mm; anterior globe position, 18.8 ± 2.8 mm; posterior globe position, 6.2 ± 2.9 mm; axial globe length, 24.9 ± 1.1 mm; and axial globe width, 25.9 ± 1.2 mm. A significant positive correlation was seen between the IZD and the anterior globe position (r = 0.15, p = 0.03), axial globe length (r = 0.33, p < 0.01), and axial globe width (r = 0.30, p < 0.01).
This normative globe position data may be used to diagnose radiologic exophthalmos or enophthalmos.
Déterminer par tomodensitométrie les valeurs correspondant à la position normale du globe oculaire, à la distance inter-zygomatique (DIZ) de même qu’à la longueur et à la largeur axiales du globe oculaire au sein d'une cohorte australienne.
Étude de cohorte rétrospective.
Patients qui ont fait l'objet d'une tomodensitométrie orbitaire, excluant ceux qui présentaient une atteinte bilatérale, qui avaient déjà subi une chirurgie orbitaire ou dont les images tomodensitométriques étaient de piètre qualité.
La coupe axiale au milieu du globe a permis de mesurer la position du globe oculaire. La position antérieure du globe se définissait comme la distance perpendiculaire de la marge antérieure du globe à la ligne inter-zygomatique, tandis que la position postérieure du globe se définissait comme la distance perpendiculaire de la marge postérieure du globe à la ligne inter-zygomatique.
Voici les mesures normales (moyenne ± é.-t.) : DIZ, 97,4 ± 4,1 mm; position antérieure du globe, 18,8 ± 2,8 mm; position postérieure du globe, 6,2 ± 2,9 mm; longueur axiale du globe, 24,9 ± 1,1 mm et largeur axiale du globe, 25,9 ± 1,2 mm. On a pu établir une corrélation positive significative entre la DIZ et la position antérieure du globe (r = 0,15; p = 0,03), la longueur axiale du globe (r = 0,33; p < 0,01) et la largeur axiale du globe (r = 0,30; p < 0,01).
Ces données normatives quant à la position du globe oculaire peuvent servir au diagnostic radiologique des exophtalmies ou des énophtalmies.
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