ENDOGENOUS ENDOPHTHALMITIS ASSOCIATED WITH INJECTION DRUG USE COMPARED WITH OTHER ETIOLOGIES.

PURPOSE: To compare features of endogenous endophthalmitis associated with injection drug use (IDU) to endogenous endophthalmitis from other etiologies. METHODS: The authors retrospectively collected data on patients with endogenous endophthalmitis due to IDU or other causes from three academic tertiary care centers over a six-year period. Differences in presenting characteristics, culture results, treatment, and visual acuity were compared between groups. RESULTS: Thirty-eight patients (34%) had IDU-associated endogenous endophthalmitis while 75 patients (67%) had endogenous endophthalmitis from other causes. Compared with patients in the non-IDU group, IDU patients were significantly younger, more frequently male, had longer duration of symptoms at diagnosis, and were less likely to have bilateral disease ( P < 0.05 for all). Injection drug use patients were less likely to have a systemic infection source identified (29% vs. 71%, P < 0.001) or have positive cultures (47% vs. 80%, P < 0.001). The IDU group was less likely to be admitted to the hospital (71% vs. 92%, P = 0.005) and less likely to receive treatment with intravenous antimicrobials (55% vs. 83%, P = 0.003). Visual acuity did not significantly differ between groups. CONCLUSION: Endophthalmitis related to IDU presents in younger patients with less comorbidities and frequently without positive cultures or an identifiable systemic source; therefore, a high index of suspicion is needed to identify this disease.

The effect of select systemic medications on outcomes in diabetics with central retinal vein occlusion.

BACKGROUND: Diabetes mellitus is a risk factor for central retinal vein occlusion (CRVO); however, it is unclear whether certain commonly used medications among diabetics or glycemic control impact visual outcomes in diabetic eyes with CRVO. PURPOSE: To evaluate the effect of select systemic medications and glycemic control on presenting features, treatment burden, and outcomes in patients with diabetes who develop a central retinal vein occlusion (CRVO). METHODS: Retrospective longitudinal cohort study at a single tertiary academic referral center from 2009-2017 investigating eyes of patients being treated for diabetes mellitus at CRVO onset. Eyes with a prior history of anti-vascular endothelial growth factor (anti-VEGF) therapy or laser treatment within the year prior to CRVO onset were excluded. Main outcomes and measures were visual acuity (VA), central subfield thickness (CST), cystoid macular edema (CME), and number of intravitreal injections and laser treatment throughout follow-up. RESULTS: We identified 138 eyes of 138 participants who were diabetic at CRVO onset. Of these, 49% had an ischemic CRVO. Median follow-up time was 25.5 months. Fifty-five eyes (40%) had a HbA1c within 6 months of CRVO presentation. HbA1c was positively correlated with both presenting CST (p = 0.04) and presence of CME (p < 0.01). In all 138 eyes, mean presenting VA was 20/246, and mean final VA was 20/364. Better-presenting VA was significantly associated with aspirin 325 mg use (p = 0.04). Lower CST at presentation was significantly associated with metformin use (p = 0.02). Sitagliptin use at CRVO onset was associated with a lower prevalence of CME at final follow-up (p < 0.01). Lower final CST was significantly associated with glipizide use at CRVO onset (p = 0.01). There were no significant associations between systemic medications or HbA1c and treatment burden or final VA (p > 0.05). CONCLUSION: Although aspirin 325 mg, metformin, sitagliptin, and glipizide were associated with better-presenting VA, lower-presenting CST, lower prevalence of macular edema at final visit, and lower final CST, respectively, none of these systemic agents or glycemic control were associated with decreased treatment burden or improved visual outcomes in diabetics with CRVO.

Central Retinal Vein Occlusion: The Effect of Antiplatelet and Anticoagulant Agents.

Purpose: This work evaluates the effect of antiplatelet and anticoagulant agents on clinical outcomes, optical coherence tomography (OCT) parameters, and macular ischemia in eyes with central retinal vein occlusion (CRVO). Methods: A retrospective longitudinal cohort study was performed to evaluate patients with CRVO. Demographics, OCT parameters before and after treatment, macular ischemia on fluorescein angiography, and clinical outcomes including the number of injections received were analyzed. Results: A total of 365 patients with CRVO were identified. The average follow-up was 36 months. Antiplatelet or anticoagulant agent use was not associated with a significant difference in visual acuity (VA), prevalence of macular edema, or central subfield thickness on OCT at presentation or final visit. The use of 81-mg aspirin alone was associated with an increased prevalence of foveal hemorrhage at presentation. Patients who were taking an antiplatelet agent, an anticoagulation agent, or both and had an ischemic CRVO with logMAR VA of less than 1.0 experienced improved VA at the final study visit. Patients given antiplatelet or anticoagulant agents had a similar incidence of neovascular sequelae compared with patients not administered these agents. Conclusions: In eyes with CRVO, the use of antiplatelet or anticoagulant agents at CRVO onset was not associated with significantly different functional outcomes, except in ischemic CRVO eyes with VA of less than 20/200. The use of 81-mg aspirin was associated with foveal hemorrhage at CRVO presentation. Otherwise, the use of any antiplatelet agent or anticoagulation was not associated with any CRVO structural outcomes.

Multimodal imaging of type 2 acute macular neuroretinopathy in a young woman.

We report a case of type 2 acute macular neuroretinopathy (AMN) that occurred in an otherwise healthy 22-year-old white woman taking oral contraceptives and consuming large quantities of caffeinated coffee. The patient presented with a teardrop-shaped scotoma just inferior to her central vision in her left eye after a recent and significant increase in coffee consumption. A small extrafoveal retinal lesion was present superior to the fovea on pseudocolor fundus photography. Multimodal retinal imaging demonstrated focal disruption of the inner segment-outer segment junction of the photoreceptors with overlying hyperreflectivity at the level of the outer plexiform layer superior to the fovea, consistent with a diagnosis of type 2 AMN. Oral contraceptive use and high caffeine intake may be risk factors for the development of type 2 AMN.

Systemic antiplatelet agents and anticoagulants in eyes with branch retinal vein occlusion.

PURPOSE: The purpose of this study was to investigate the effect of systemic antiplatelet agents and anticoagulants on the structural and functional outcomes of eyes with branch retinal vein occlusion (BRVO). METHODS: A retrospective longitudinal cohort study was performed on BRVO patients evaluated at a single tertiary care referral center between 2009 and 2017. Medical records were reviewed for antiplatelet agent and anticoagulant use including aspirin, clopidogrel, warfarin, rivaroxaban, apixaban, or dabigatran prior to BRVO onset. In addition, optical coherence tomography (OCT) parameters, clinical outcomes, and treatment patterns were also recorded. RESULTS: A total of 354 BRVO eyes were identified with a mean follow-up time of 36 months. Antiplatelet or anticoagulant use was associated with presence of cystoid macular edema (CME) at presentation after controlling for potential confounding variables in a multivariate logistic regression. Multivariate regression also revealed an association between foveal hemorrhage at presentation and use of antiplatelet or anticoagulant medications. There were no significant differences in visual acuity or prevalence of CME at the final visit in those with antiplatelet/anticoagulant use compared to those not on these agents. CONCLUSION: Although the use of systemic antiplatelet or anticoagulant agents was associated with increased prevalence of CME and foveal hemorrhage at presentation of BRVO, the use of these medications was not associated with different visual or structural outcomes at the final visit.

Meibomian gland dysfunction is suppressed via selective inhibition of immune responses by topical LFA-1/ICAM antagonism with lifitegrast in the allergic eye disease (AED) model.

PURPOSE: The etiology of meibomian gland dysfunction (MGD) is incompletely understood, despite being a common ophthalmic condition and an area of unmet medical need. It is characterized by an insufficiency in glandular provision of specialized lipids (meibum) to the tear film and is a major cause of dry eye. Work in the allergic eye disease (AED) mouse model has revealed an immunopathogenic role in MGD causation, now raising interest in the applicability of immunomodulatory therapies. As such, we herein ask whether inhibition of lymphocyte function associated antigen (LFA)-1/intracellular adhesion molecules (ICAM)-1 signaling via topical lifitegrast administration has a therapeutic effect on MGD in AED mice. METHODS: Mice were induced with AED by i.p. injection of ovalbumin (OVA) mixed with alum and pertussis toxin, followed 2 weeks later by once daily topical OVA challenges for 7 days. Mice were treated topically with 5% lifitegrast ophthalmic solution or vehicle (PBS) 30 min prior to challenge. We developed a clinical ranking method to assess MGD severity, and also scored clinical allergy. Conjunctivae and draining lymph nodes were collected for flow cytometry. RESULTS: Topical lifitegrast significantly inhibited clinical MGD severity, which was associated with diminished pathogenic TH17 cell and neutrophil numbers in the conjunctiva. No significant change in conjunctival TH2 cells or eosinophils, and only marginal differences in ocular allergy were observed. CONCLUSIONS: In AED mice, lifitegrast inhibited MGD severity marked by a reduction in select immune populations in the conjunctiva. Our findings warrant future examination of lifitegrast in the treatment of patients with forms of MGD.

Ocular Toxocariasis Presenting as Endophthalmitis in a Young Adult Intravenous Drug User.

Purpose: This report describes the diagnosis of ocular toxocariasis presenting as endophthalmitis in an adult intravenous drug user. Methods: A case is reported. Results: Fundus imaging showed numerous white opacities obscuring the macula. Toxocara canis serology was reactive with an enzyme immunoassay titer of 1:2 (positive ≥ 1:32). Findings from bacterial and fungal cultures were negative, and vitrectomy cytology revealed no organisms. Postoperatively, serial optical coherence tomography imaging demonstrated a slight decrease in size of an intraretinal hyperreflective lesion in the macula. Conclusions: Owing to a variety of presentations, ocular toxocariasis can be challenging to diagnose. In a patient with a history of intravenous drug use where fungal and bacterial organisms are more common causes of endophthalmitis, it is important to have a wide differential of causative organisms, particularly in the context of negative culture results and a worsening clinical examination.

Positively charged residues within the MYO19 MyMOMA domain are essential for proper localization of MYO19 to the mitochondrial outer membrane.

Myosins are well characterized molecular motors essential for intracellular transport. MYO19 copurifies with mitochondria, and can be released from mitochondrial membranes by high pH buffer, suggesting that positively-charged residues participate in interactions between MYO19 and mitochondria. The MYO19-specific mitochondria outer membrane association (MyMOMA) domain contains approximately 150 amino acids with a pI approximately 9 and is sufficient for localization to the mitochondrial outer membrane. The minimal sequence and specific residues involved in mitochondrial binding have not been identified. To address this, we generated GFP-MyMOMA truncations, establishing the boundaries for truncations based on sequence homology. We identified an 83-amino acid minimal binding region enriched with basic residues (pI ∼ 10.5). We sequentially replaced basic residues in this region with alanine, identifying residues R882 and K883 as essential for mitochondrial localization. Constructs containing the RK882-883AA mutation primarily localized with the endoplasmic reticulum (ER). To determine if ER-associated mutant MyMOMA domain and mitochondria-associated wild type MyMOMA display differences in kinetics of membrane interaction, we paired FRAP analysis with permeabilization activated reduction in fluorescence (PARF) analysis. Mitochondria-bound and ER-bound MYO19 constructs displayed slow dissociation from their target membrane when assayed by PARF; both constructs displayed exchange within their respective organelle networks. However, ER-bound mutant MYO19 displayed more rapid exchange within the ER network than did mitochondria-bound MYO19. Taken together these data indicate that the MyMOMA domain contains strong membrane-binding activity, and membrane targeting is mediated by a specific, basic region of the MYO19 tail with slow dissociation kinetics appropriate for its role(s) in mitochondrial network dynamics. © 2016 Wiley Periodicals, Inc.

Permeabilization activated reduction in fluorescence: A novel method to measure kinetics of protein interactions with intracellular structures.

Understanding kinetic information is fundamental in understanding biological function. Advanced imaging technologies have fostered the development of kinetic analyses in cells. We have developed Permeabilization Activated Reduction in Fluorescence (PARF) analysis for determination of apparent t1/2 and immobile fraction, describing the dissociation of a protein of interest from intracellular structures. To create conditions where dissociation events are observable, cells expressing a fluorescently-tagged protein are permeabilized with digitonin, diluting the unbound protein into the extracellular media. As the media volume is much larger than the cytosolic volume, the concentration of the unbound pool decreases drastically, shifting the system out of equilibrium, favoring dissociation events. Loss of bound protein is observed as loss of fluorescence from intracellular structures and can be fit to an exponential decay. We compared PARF dissociation kinetics with previously published equilibrium kinetics as determined by FRAP. PARF dissociation rates agreed with the equilibrium-based FRAP analysis predictions of the magnitude of those rates. When used to investigate binding kinetics of a panel of cytoskeletal proteins, PARF analysis revealed that filament stabilization resulted in slower fluorescence loss. Additionally, commonly used "general" F-actin labels display differences in kinetic properties, suggesting that not all fluorescently-tagged actin labels interact with the actin network in the same way. We also observed differential dissociation kinetics for GFP-VASP depending on which cellular structure was being labeled. These results demonstrate that PARF analysis of non-equilibrium systems reveals kinetic information without the infrastructure investment required for other quantitative approaches such as FRAP, photoactivation, or in vitro reconstitution assays. © 2016 Wiley Periodicals, Inc.