The impact of primary repair timing on longitudinal visual outcomes after open globe injury.

BACKGROUND: The urgency with which to repair open globe injuries is a debated topic that lacks grounding in longitudinal visual outcomes data. We aim to test the association between primary repair timing and visual recovery potential following OGI. SUBJECTS/METHODS: We performed a retrospective cohort study of medical records from a US academic medical center (7/2017 to 11/2021). We included all patients with a principal diagnosis of OGI, a documented date and time of injury, presentation, repair, and ≥ 3 months of complete follow-up data on visual outcomes. We excluded those with prior OGI in the same eye. We also tested the correlation of injury to repair time (ITR) in hours with best corrected visual acuity (BCVA, in logMAR units) at last follow-up in the general cohort and select subpopulations and the impact of repair delay on visual improvement over the follow-up period. RESULTS: One hundred twenty-nine patients with OGI were analyzed (91 patients with ≥ 3 months of follow-up). The majority were male (105/129, 81%) with a median age of 45 years. Most OGI involved zone 1 (57%), followed by zone 3 (24%), and zone 2 injuries (19%). Median ocular trauma score (OTS) was 60 (IQR 37-70); mean presenting BCVA was logMAR 1.9 (median 2.3, IQR 1.0-2.7). Median ITR was 22 h (IQR 15-30 h, range 5-199 h). ITR time did not significantly correlate with final BCVA (n = 91, ß = - 0.003, 95% CI - 0.009-0.002, P = 0.233), nor did it significantly increase the odds of developing ocular complications or requiring secondary ocular surgeries (OR 0.985, 95% CI 0.967-1.002, P = 0.085). Additionally, the rate of BCVA improvement over subsequent months of follow-up did not significantly differ based on ITR time. Presenting BCVA (R2 = 0.701, P < 0.001) and OTS (R2 = 0.477, P < 0.001) significantly correlated with final BCVA, independent of repair delays. CONCLUSIONS: In this cohort of OGI patients, repair timing does not significantly correlate with final BCVA, and delays beyond 24 h do not significantly correlate with worse visual recovery potential. Repair time alone should be emphasized to a lesser extent as a prognosticator of visual potential, in favor of significant predictors such as the ocular trauma score and presenting visual acuity.

Complement Factor H Mutation W1206R Causes Retinal Thrombosis and Ischemic Retinopathy in Mice.

Single-nucleotide polymorphisms and rare mutations in factor H (FH; official name, CFH) are associated with age-related macular degeneration and atypical hemolytic uremic syndrome, a form of thrombotic microangiopathy. Mice with the FH W1206R mutation (FHR/R) share features with human atypical hemolytic uremic syndrome. Herein, we report that FHR/R mice exhibited retinal vascular occlusion and ischemia. Retinal fluorescein angiography demonstrated delayed perfusion and vascular leakage in FHR/R mice. Optical coherence tomography imaging of FHR/R mice showed retinal degeneration, edema, and detachment. Histologic analysis of FHR/R mice revealed retinal thinning, vessel occlusion, as well as degeneration of photoreceptors and retinal pigment epithelium. Immunofluorescence showed albumin leakage from blood vessels into the neural retina, and electron microscopy demonstrated vascular endothelial cell irregularity with narrowing of retinal and choroidal vessels. Knockout of C6, a component of the membrane attack complex, prevented the aforementioned retinal phenotype in FHR/R mice, consistent with membrane attack complex-mediated pathogenesis. Pharmacologic blockade of C5 also rescued retinas of FHR/R mice. This FHR/R mouse strain represents a model for retinal vascular occlusive disorders and ischemic retinopathy. The results suggest complement dysregulation can contribute to retinal vascular occlusion and that an anti-C5 antibody might be helpful for C5-mediated thrombotic retinal diseases.

Oral administration of the iron chelator deferiprone protects against loss of retinal ganglion cells in a mouse model of glaucoma.

Glaucoma is a progressive neurodegenerative process affecting the retinal ganglion cells (RGCs) and the optic nerve. Oxidative stress has been implicated in glaucoma pathogenesis, and iron is a potent generator of oxidative stress. The oral iron chelator deferiprone (DFP) is protective against retinal degenerations associated with oxidative stress. To test whether DFP could be protective in glaucoma, we used microbead injections to induce elevated intraocular pressure (IOP) in a cohort of 3-month old C57BL/6J mice. One eye of each animal was injected with magnetic microbeads resulting in ocular hypertension for >7 weeks while the fellow eye was injected with saline and served as a normotensive internal control. While half of the cohort received oral DFP (1 mg/ml in the drinking water), the other half did not and served as controls. After 8 weeks, Brn3a immunolabeling of flat-mounted retinas was used for manual RGC quantification. Axon counts were obtained from thin sections of optic nerves using the AxonJ plugin for ImageJ. DFP administration was protective against RGC and optic nerve loss in the setting of elevated IOP. These results suggest that iron chelation by DFP may provide glaucoma neuroprotection.

Dietary Methionine Restriction Regulates Liver Protein Synthesis and Gene Expression Independently of Eukaryotic Initiation Factor 2 Phosphorylation in Mice.

Background: The phosphorylation of eukaryotic initiation factor 2 (p-eIF2) during dietary amino acid insufficiency reduces protein synthesis and alters gene expression via the integrated stress response (ISR).Objective: We explored whether a Met-restricted (MR) diet activates the ISR to reduce body fat and regulate protein balance.Methods: Male and female mice aged 3-6 mo with either whole-body deletion of general control nonderepressible 2 (Gcn2) or liver-specific deletion of protein kinase R-like endoplasmic reticulum kinase (Perk) alongside wild-type or floxed control mice were fed an obesogenic diet sufficient in Met (0.86%) or an MR (0.12% Met) diet for ≤5 wk. Ala enrichment with deuterium was measured to calculate protein synthesis rates. The guanine nucleotide exchange factor activity of eIF2B was measured alongside p-eIF2 and hepatic mRNA expression levels at 2 d and 5 wk. Metabolic phenotyping was conducted at 4 wk, and body composition was measured throughout. Results were evaluated with the use of ANOVA (P < 0.05).Results: Feeding an MR diet for 2 d did not increase hepatic p-eIF2 or reduce eIF2B activity in wild-type or Gcn2-/- mice, yet many genes transcriptionally regulated by the ISR were altered in both strains in the same direction and amplitude. Feeding an MR diet for 5 wk increased p-eIF2 and reduced eIF2B activity in wild-type but not Gcn2-/- mice, yet ISR-regulated genes altered in both strains similarly. Furthermore, the MR diet reduced mixed and cytosolic but not mitochondrial protein synthesis in both the liver and skeletal muscle regardless of Gcn2 status. Despite the similarities between strains, the MR diet did not increase energy expenditure or reduce body fat in Gcn2-/- mice. Finally, feeding the MR diet to mice with Perk deleted in the liver increased hepatic p-eIF2 and altered body composition similar to floxed controls.Conclusions: Hepatic activation of the ISR resulting from an MR diet does not require p-eIF2. Gcn2 status influences body fat loss but not protein balance when Met is restricted.

Trabecular Microbypass Stent and Phacoemulsification in African American Patients With Open-angle Glaucoma: Outcomes and Effect of Prior Laser Trabeculoplasty.

PRECIS: In African American patients with glaucoma, iStent/phacoemulsification lowered intraocular pressure and reduced glaucoma medication usage for up to 1 year, even in patients with prior selective laser trabeculoplasty (SLT). PURPOSE: Currently, no studies have examined the outcomes of a trabecular microbypass stent and phacoemulsification in African American patients. Here, the authors investigate whether iStent/phacoemulsification decreases intraocular pressure (IOP) and/or medication usage in African American patients with glaucoma. They are also interested in whether prior SLT would affect outcomes of iStent/phacoemulsification. PATIENTS AND METHODS: A multicenter, retrospective case series of eyes that underwent iStent/phacoemulsification between 2013 and 2017 with up to 1-year follow-up. Eyes with a confirmed diagnosis of glaucoma in African American patients were included. Eyes with neovascular glaucoma or closed angle glaucoma and eyes that underwent previous incisional glaucoma surgery were excluded. RESULTS: Eighty-nine eyes were included in the study and data for 66 eyes were available at postoperative year 1 (POY1). IOP decreased from 18.3±5.7 mm Hg to 15.9±4.6 (P<0.001) and glaucoma medication usage decreased from 1.9±1.1 to 1.1±1.1 (P<0.001) at POY1. Eyes that underwent prior SLT experienced less of a decrease in IOP when compared with eyes without prior SLT, but IOP at POY1 was not significantly different between these groups. Both groups had a similar reduction in medication usage. The most common complications were IOP spikes on postoperative day 1 and microhyphemas. CONCLUSIONS: In this cohort, there was a significant decrease in IOP and medication usage 1 year after iStent/phacoemulsification. iStent/phacoemulsification is an effective and safe treatment option in African American patients with glaucoma.

GLP-1 Receptor Agonist NLY01 Reduces Retinal Inflammation and Neuron Death Secondary to Ocular Hypertension.

Glaucoma is the leading cause of irreversible blindness and is characterized by the death of retinal ganglion cells (RGCs). Recent studies have implicated pro-inflammatory microglia, macrophages, and A1 astrocytes in the pathogenesis of neurodegenerative diseases. The role of pro-inflammatory, neurotoxic A1 astrocytes in glaucoma is just beginning to be explored. Using a mouse model of glaucoma, we demonstrate that ocular hypertension is sufficient to trigger production of C1q, interleukin-1α (IL-1α), and tumor necrosis factor α (TNF-α), three cytokines necessary and sufficient to drive the formation of A1 astrocytes. Upregulation of these cytokines occurs first in CD11b+ CD11c+ cells followed by CD11b+ CD11c- cells. Ablation of this pathway, by either genetic deletions of C1qa, IL-1α, and TNF-α, or treatment with glucagon-like peptide-1 receptor agonist NLY01, reduces A1 astrocyte transformation and RGC death. Together, these results highlight a neuroinflammatory mechanism of glaucomatous neurodegeneration that can be therapeutically targeted by NLY01 administration.

Outcomes of Complex Cataract Surgery in Patients with Primary Open-angle Glaucoma.

AIM: Whether pupillary expansion during phacoemulsification causes a change in postoperative intraocular pressure (IOP) is currently unknown. However, a growing proportion of patients can present with concurrent glaucoma and cataracts, which poses an increased risk of having small pupils and makes finding the answer to this question imperative for treating physicians. MATERIALS AND METHODS: This was a retrospective, observational cohort study which utilized data from 2008 to 2016 from the University Hospital, Newark, New Jersey, USA. All patients with primary open-angle glaucoma (POAG) who underwent phacoemulsification with pupillary expansion were considered for inclusion. Cases were subsequently excluded if they had prior incisional glaucoma surgery, if phacoemulsification was combined with another surgery, or if they had any incisional surgery in the eye 1 year preoperatively or postoperatively. The control group was made up of patients without POAG. The primary outcome was IOP. RESULTS: Thirty-seven eyes from 31 glaucoma patients and 29 eyes from 28 control patients met inclusion criteria. The mean IOP in the POAG group increased from 15.0 ± 4.6 mm Hg to 15.9 ± 3.5 mm Hg after 1 year, whereas the control group decreased from 14.1 ± 3.6 mm Hg to 11.9 ± 3.9 mm Hg. Multivariate analysis showed that glaucoma was associated with a 5.56 mm Hg increase in IOP at 12 months postoperatively. The average number of glaucoma medications decreased significantly from 1.7 ± 1.4 at the baseline to 1.3 ± 1.3 after 1 year. CONCLUSION: In contrast with non-POAG patients, no significant drop in the mean IOP was noted after complex cataract surgery for this cohort of glaucoma patients, although medication burden significantly decreased and VA improved significantly. CLINICAL SIGNIFICANCE: Phacoemulsification with intraoperative pupillary expansion in POAG patients may not decrease IOP after 12 months but it can decrease the number of anti-glaucoma medications they take. HOW TO CITE THIS ARTICLE: Bargoud AR, Parikh H, et al. Outcomes of Complex Cataract Surgery in Patients with Primary Open-angle Glaucoma. J Curr Glaucoma Pract 2019;13(2):62-67.

Evaluating the effect of 20-hydroxyecdysone (20HE) on mechanistic target of rapamycin complex 1 (mTORC1) signaling in the skeletal muscle and liver of rats.

Phytoecdysteroids such as 20-hydroxyecdysone (20HE) are nutritional supplements marketed as enhancers of lean body mass. In this study the impact of 20HE ingestion on protein kinase B/Akt-mechanistic target of rapamycin complex 1 signaling in the skeletal muscle and liver of male rats was found to be limited. Bioavailability of 20HE, whether consumed alone or with leucine, also remained low at all doses ingested. Additional work is necessary to clarify 20HE mechanism of action in vivo.