PURPOSE: To compare effectiveness of fornix- and limbal-based conjunctival flaps in trabeculectomy surgery. DESIGN: Systematic review. METHODS: Setting: CENTRAL, MEDLINE, LILACS, ISRCTN registry, ClinicalTrials.gov, WHO, and ICTRP were searched to identify eligible randomized controlled trials (RCTs). STUDY POPULATION: RCTs in which benefits and complications of fornix- vs limbal-based trabeculectomy for glaucoma were compared in adult glaucoma patients. OBSERVATION PROCEDURE: We followed Cochrane methodology for data extraction. MAIN OUTCOME MEASURES: Proportion of failed trabeculectomies at 24 months, defined as the need for repeat surgery or uncontrolled intraocular pressure (IOP) >22 mm Hg, despite topical/systemic medications. RESULTS: The review included 6 trials with a total of 361 participants, showing no difference in effectiveness between fornix-based vs limbal-based trabeculectomy surgery, although with a high level of uncertainty owing to low event rates. In the fornix-based and limbal-based surgery, mean IOP at 12 months was similar, with ranges of 12.5-15.5 mm Hg and 11.7-15.1 mm Hg, respectively. Mean difference was 0.44 mm Hg (95% CI -0.45 to 1.33) and 0.86 mm Hg (95% CI -0.52 to 2.24) at 12 and 24 months of follow-up, respectively. Mean number of postoperative glaucoma medications was similar between the 2 groups. Mean difference was 0.02 (95% CI -0.15 to 0.19) at 12 months. As far as postoperative complications, an increased risk of shallow anterior chamber was observed in the limbal-based group. CONCLUSION: Similar efficacy of trabeculectomy surgery with respect to bleb failure or IOP control was observed in both types of conjunctival flap incisions. A significant difference was detected in the risk of postoperative shallow anterior chamber, which was increased in the limbal-based group.
Th17 cells are principal mediators of many autoimmune conditions. Recently, memory Th17 cells have been revealed as crucial in mediating the chronicity of various refractory autoimmune disorders; however, the underlying mechanisms maintaining memory Th17 cells have remained elusive. Here, using a preclinical model of ocular autoimmune disease we show that both IL-7 and IL-15 are critical for maintaining pathogenic memory Th17 cells. Neutralization of these cytokines leads to substantial reduction of memory Th17 cells; both IL-7 and IL-15 provide survival signals via activating STAT5, and IL-15 provides additional proliferation signals via activating both STAT5 and Akt. Topical neutralization of ocular IL-7 or IL-15 effectively reduces memory Th17 cells at the inflammatory site and draining lymphoid tissues, while topical neutralization of IL-17 alone, the major pathogenic cytokine secreted by Th17 cells, does not diminish memory Th17 cells at the draining lymphoid tissues. Our results suggest that the effective removal of pathogenic memory Th17 cells via abolishing environmental IL-7 or IL-15 is likely to be a novel strategy in the treatment of autoimmune diseases.
Specialized pro-resolving mediators (SPM), e.g. Resolvin D1, Protectin D1, Lipoxin A₄, and Resolvin E1 have each shown to be active in ocular models reducing inflammation. In general, SPMs have specific agonist functions that stimulate resolution of infection and inflammation in animal disease models. The presence and quantity of SPM in human emotional tears is of interest. Here, utilizing a targeted LC-MS-MS metabololipidomics based approach we document the identification of pro-inflammatory (Prostaglandins and Leukotriene B₄) and pro-resolving lipid mediators (D-series Resolvins, Protectin D1, and Lipoxin A₄) in human emotional tears from 12 healthy individuals. SPMs from the Maresin family (Maresin 1 and Maresin 2) were not present in these samples. Principal Component Analysis (PCA) revealed gender differences in the production of specific mediators within these tear samples as the SPMs were essentially absent in these female donors. These results indicate that specific SPM signatures are present in human emotional tears at concentrations known to be bioactive. Moreover, they will help to further appreciate the mechanisms of production and action of SPMs in the eye, as well as their physiologic roles in human ocular disease resolution.
Pathological neovascularization, a leading cause of blindness, is seen in retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Using a mouse model of hypoxia-driven retinal neovascularization, we find that fibroblast growth factor 21 (FGF21) administration suppresses, and FGF21 deficiency worsens, retinal neovessel growth. The protective effect of FGF21 against neovessel growth was abolished in adiponectin (APN)-deficient mice. FGF21 administration also decreased neovascular lesions in two models of neovascular age-related macular degeneration: very-low-density lipoprotein-receptor-deficient mice with retinal angiomatous proliferation and laser-induced choroidal neovascularization. FGF21 inhibited tumor necrosis α (TNF-α) expression but did not alter Vegfa expression in neovascular eyes. These data suggest that FGF21 may be a therapeutic target for pathologic vessel growth in patients with neovascular eye diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration.
Specific factors from the corneal epithelium underlying the stimulation of stromal fibrosis and myofibroblast formation in corneal wound healing have not been fully elucidated. Given that exosomes are known to transfer bioactive molecules among cells and play crucial roles in wound healing, angiogenesis, and cancer, we hypothesized that corneal epithelial cell-derived exosomes may gain access to the underlying stromal fibroblasts upon disruption of the epithelial basement membrane and that they induce signaling events essential for corneal wound healing. In the present study, exosome-like vesicles were observed between corneal epithelial cells and the stroma during wound healing after corneal epithelial debridement. These vesicles were also found in the stroma following anterior stromal keratectomy, in which surgical removal of the epithelium, basement membrane, and anterior stroma was performed. Exosomes secreted by mouse corneal epithelial cells were found to fuse to keratocytes in vitro and to induce myofibroblast transformation. In addition, epithelial cell-derived exosomes induced endothelial cell proliferation and ex vivo aortic ring sprouting. Our results indicate that epithelial cell-derived exosomes mediate communication between corneal epithelial cells and corneal keratocytes as well as vascular endothelial cells. These findings demonstrate that epithelial-derived exosomes may be involved in corneal wound healing and neovascularization, and thus, may serve as targets for potential therapeutic interventions.
IMPORTANCE: To describe presenting patterns of breast cancer metastases to the orbit and eyelids BACKGROUND: To provide clinical, radiographic, and pathologic correlations of breast metastases to the orbit or eyelids and evaluate radiographic volumetric orbital changes DESIGN: Retrospective review in an academic center PARTICIPANTS: Ten female patients with periocular metastatic breast carcinoma who were seen at the Massachusetts Eye and Ear Infirmary Oculoplastics Clinic METHODS: Retrospective review of patient records, imaging and pathology findings. MAIN OUTCOME MEASURES: Presenting clinical characteristics, radiographic findings, and histopathological features were assessed and correlated to discover distinctive presenting patterns. Volumetric measurements of the tumors and orbital soft tissue structures were made on magnetic resonance imaging studies. RESULTS: The breast metastases included 9 orbital and 1 eyelid lesions. Two distinct clinical presentations were observed. The first consisted of seven patients who had either enophthalmos or euphthalmos in the setting of a retrobulbar lesion, a radiographically indistinct lesion, and a classic microscopic invasive lobular breast carcinoma (ILBC) with a prominent fibrotic stroma. The second group consisted of two proptotic patients with mass lesions on imaging and an atypical ILBC pathological subtype (pleomorphic or alveolar). One patient had diffusely indurated eyelid fullness. Volumetric analyses demonstrated variable tumor sizes with an inconsistent impact on the orbital volume and fat. CONCLUSIONS AND RELEVANCE: This correlative study provides the clinical-radiographic-histopathologic basis for separating two overarching phenotypic presentations of metastatic breast carcinoma to the orbit. Previously postulated mechanisms for the distinctive finding of tumor-induced enophthalmos are re-examined in the light of the foregoing conclusions.
Purpose: Vascular endothelial growth factor receptor 2 (VEGFR2) plays a key role in VEGF-induced angiogenesis. The goal of this project was to test the hypothesis that editing genomic VEGFR2 loci using the technology of clustered regularly interspaced palindromic repeats (CRISPR)-associated DNA endonuclease (Cas)9 in Streptococcus pyogenes (SpCas9) was able to block VEGF-induced activation of Akt and tube formation. Methods: Four 20 nucleotides for synthesizing single-guide RNAs based on human genomic VEGFR2 exon 3 loci were selected and cloned into a lentiCRISPR v2 vector, respectively. The DNA fragments from the genomic VEGFR2 exon 3 of transduced primary human retinal microvascular endothelial cells (HRECs) were analyzed by Sanger DNA sequencing, surveyor nuclease assay, and next-generation sequencing (NGS). In the transduced cells, expression of VEGFR2 and VEGF-stimulated signaling events (e.g., Akt phosphorylation) were determined by Western blot analyses; VEGF-induced cellular responses (proliferation, migration, and tube formation) were examined. Results: In the VEGFR2-sgRNA/SpCas9-transduced HRECs, Sanger DNA sequencing indicated that there were mutations, and NGS demonstrated that there were 83.57% insertion and deletions in the genomic VEGFR2 locus; expression of VEGFR2 was depleted in the VEGFR2-sgRNA/SpCas9-transduced HRECs. In addition, there were lower levels of Akt phosphorylation in HRECs with VEGFR2-sgRNA/SpCas9 than those with LacZ-sgRNA/SpCas9, and there was less VEGF-stimulated Akt activation, proliferation, migration, or tube formation in the VEGFR2-depleted HRECs than those treated with aflibercept or ranibizumab. Conclusions: The CRISPR-SpCas9 technology is a potential novel approach to prevention of pathologic angiogenesis.
PURPOSE: To investigate the association between sleep duration and diabetic retinopathy (DR). METHODS: A population-based cross-sectional study using a nation-wide, systemically stratified, multistage, clustered sampling method included a total of 1670 subjects aged ≥40 years with diabetes who participated in the Korean National Health and Nutrition Examination Survey during 2008-2012. All participants performed standardized interviews, including self-reported sleep duration, and comprehensive ophthalmic examinations. Seven standard retinal fundus photographs were obtained from both eyes after pupil dilatation. Diabetic retinopathy (DR) was graded and classified as any DR and vision-threatening DR. Participants were stratified into men and women. RESULTS: The mean sleep duration was 6.71 hr/day. In men, adjusted OR of any DR was 1.88 [95% confidence interval (OR), 1.01-3.59] in those with ≤5 hr sleep, and 2.19 (95% CI, 1.01-4.89) in those with ≥9 hr sleep, compared to in subjects with 6-8 hr sleep, after adjusting for potential confounders including age, body mass index (BMI), diabetes duration, fasting glucose level, haemoglobin A1c levels and hypertension. In women, however, no significant association between sleep duration and DR was found. The vision-threatening DR was not significantly associated with sleep duration in either men or women. CONCLUSIONS: Short and long sleep was associated with high prevalence of DR in men. Sleep deprivation may be involved in the pathogenesis of DR development.
PURPOSE: To evaluate changes in corneal endothelial cell density over time in patients with dry eye disease (DED) and to correlate endothelial cell loss with corneal subbasal nerve density. METHODS: This retrospective study included 40 eyes of 20 patients with DED. Laser in vivo confocal microscopy had been performed in the central cornea of both eyes at an initial visit and repeated after a mean follow-up of 33.2 ± 10.2 months. The densities of corneal endothelial cells and subbasal nerves were measured in both visits and compared with 13 eyes of 13 normal age-matched controls. RESULTS: At the initial visit, the DED group had lower densities of corneal endothelial cells (2620 ± 386 cells/mm) and subbasal nerves (17.8 ± 7.5 mm/mm) compared with the control group (2861 ± 292 cells/mm and 22.8 ± 3.0 mm/mm, with P = 0.08 and P = 0.01, respectively). At the end of follow-up, although there was no significant change in subbasal nerve density (16.7 ± 7.2 mm/mm, P = 0.43), the mean corneal endothelial cell density significantly decreased to 2465 ± 391 cells/mm (P = 0.01), with a mean corneal endothelial cell loss of 2.1 ± 3.6% per year. The endothelial cell loss showed a statistically significant negative correlation with the initial subbasal nerve density (Rs = -0.55, P = 0.02). CONCLUSIONS: Patients with DED have an accelerated corneal endothelial cell loss compared with that reported in the literature for normal aging. Those with lower subbasal nerve density, in particular, are at a higher risk for endothelial cell loss over time.
Purpose: To screen for and characterize compounds that protect corneal endothelial cells against unfolded protein response (UPR) and oxidative stress. Methods: Bovine corneal endothelial cells (BCECs) were treated for 48 hours with 640 compounds from a Food and Drug Administration (FDA)-approved drug library and then challenged with thapsigargin or H2O2 to induce UPR or oxidative stress, respectively. Cell viability was measured using the CellTiter-Glo survival assay. Selected "hits" were subjected to further dose-response testing, and their ability to modulate expression of UPR and oxidative stress markers was assessed by RT-PCR, Western blot, and measurement of protein carbonyl and 8-hydroxydeoxyguanosine (8-OHdG) adducts in immortalized human corneal endothelial cells (iHCECs). Results: Forty-one drugs at 20 μM and 55 drugs at 100 μM increased survival of H2O2-challenged cells, and 8 drugs at 20 μM and 2 drugs at 100 μM increased survival of thapsigargin-challenged cells, compared with untreated control cells. Nicergoline, ergothioneine, nimesulide, oxotremorine, and mefenamic acid increased survival of both H2O2- and thapsigargin-challenged cells. Oxotremorine altered DNA damage inducible 3 (CHOP) gene expression, glucose-regulated protein 78 kDa (GRP78) and activating transcription factor 4 (ATF4) protein expression, and protein carbonyl and 8-OHdG levels. Mefenamic acid altered GRP78 protein expression and protein carbonyl and 8-OHdG levels. Conclusions: Oxotremorine and mefenamic acid are potential survival factors for corneal endothelial cells under UPR and oxidative stress. The described assay can be further expanded to screen additional drugs for potential therapeutic effect in corneal endothelial diseases such as Fuchs' endothelial corneal dystrophy.
PURPOSE: To assess long-term effectiveness of rituximab therapy for refractory noninfectious uveitis affecting the posterior segment. METHODS: Retrospective case series. Patients diagnosed with recalcitrant noninfectious posterior uveitis who were treated with rituximab intravenous infusions between 2010 and 2015 were included. Patients underwent best-corrected visual acuity testing and fluorescein angiography evidence of disk or vascular staining at 6, 12, 18, and 24 months. Patients had at least 24 months of follow-up. RESULTS: Eleven patients (21 eyes) with refractory posterior uveitis treated with intravenous rituximab were included. Nine (81.8%) patients were female. Mean follow-up was 29.3 ± 7.8 months. rituximab was administered as complementary therapy because of previous inefficacy of other therapies in 7 (63.7%) patients, and it was the only treatment in four (36.3%) patients who did not tolerate other drugs. Inflammation signs by fluorescein angiography were controlled in nine (81.8%) patients at the end of follow-up. Baseline best-corrected visual acuity was 20/80 (logarithm of the minimal angle of resolution 0.6 ± 0.4), and final best-corrected visual acuity was 20/40 (0.3 ± 0.5) (P = 0.005). No significant side effects were reported. CONCLUSION: Rituximab therapy was associated with stability and remission of recalcitrant noninfectious posterior uveitis in patients who did not tolerate or did not respond to other therapies.
PURPOSE: To investigate the association between exercise and glaucoma in a South Korean population-based sample. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: A total of 11,246 subjects, 40 years and older who underwent health care assessment as part of the 2008-2011 Korean National Health and Nutrition Examination Survey. METHODS: Variables regarding the duration (total minutes per week), frequency (days per week), and intensity of exercise (vigorous, moderate exercise and walking) as well as glaucoma prevalence were ascertained for 11,246 survey participants. Demographic, comorbidity, and health-related behavior information was obtained via interview. Multivariable logistic regression analyses were performed to determine the association between the exercise-related parameters and odds of a glaucoma diagnosis. MAIN OUTCOME MEASURE(S): Glaucoma defined by International Society for Geographical and Epidemiological Ophthalmology criteria. RESULTS: Overall, 336 (2.7%) subjects met diagnostic criteria for glaucomatous disease. After adjustment for potential confounding variables, subjects engaged in vigorous exercise 7 days per week had higher odds of having glaucoma compared with those exercising 3 days per week (Odds Ratio [OR] 3.33, 95% confidence interval [CI] 1.16-9.54). High intensity of exercise, as categorized by the guidelines of the American College of Sports Medicine (ACSM), was also associated with greater glaucoma prevalence compared with moderate intensity of exercise (OR 1.55, 95% CI 1.03-2.33). There was no association between other exercise parameters including frequency of moderate exercise, walking, muscle strength exercise, flexibility training, or total minutes of exercise per week, and the prevalence of glaucoma. In sub-analyses stratifying by gender, the association between frequency of vigorous exercise 7 days per week and glaucoma diagnosis remained significant in men (OR 6.05, 95% CI 1.67-21.94) but not in women (OR 0.96 95% CI: 0.23-3.97). A U-shaped association between exercise intensity and glaucoma prevalence was noted in men (OR 1.71, 95% CI 1.09-2.69 for low intensity versus moderate intensity; OR 2.19, 95% CI 1.25-3.85 for high intensity versus moderate intensity). CONCLUSION: In a South Korean population sample, daily vigorous exercise was associated with higher glaucoma prevalence. In addition, the intensity of exercise was positively associated with glaucoma diagnosis in men but not women.
OBJECTIVE: Several attributes of female reproductive history, including age at natural menopause (ANM), have been related to primary open-angle glaucoma (POAG). We assembled 18 previously reported common genetic variants that predict ANM to determine their association with ANM or POAG. METHODS: Using data from the Nurses' Health Study (7,143 women), we validated the ANM weighted genetic risk score in relation to self-reported ANM. Subsequently, to assess the relation with POAG, we used data from 2,160 female POAG cases and 29,110 controls in the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD), which consists of 8 datasets with imputed genotypes to 5.6+ million markers. Associations with POAG were assessed in each dataset, and site-specific results were meta-analyzed using the inverse weighted variance method. RESULTS: The genetic risk score was associated with self-reported ANM (P = 2.2 × 10) and predicted 4.8% of the variance in ANM. The ANM genetic risk score was not associated with POAG (Odds Ratio (OR) = 1.002; 95% Confidence Interval (CI): 0.998, 1.007; P = 0.28). No single genetic variant in the panel achieved nominal association with POAG (P ≥0.20). Compared to the middle 80 percent, there was also no association with the lowest 10 percentile or highest 90 percentile of genetic risk score with POAG (OR = 0.75; 95% CI: 0.47, 1.21; P = 0.23 and OR = 1.10; 95% CI: 0.72, 1.69; P = 0.65, respectively). CONCLUSIONS: A genetic risk score predicting 4.8% of ANM variation was not related to POAG; thus, genetic determinants of ANM are unlikely to explain the previously reported association between the two phenotypes.
PURPOSE: To review antibiotic resistance associated with S. aureus endophthalmitis and the virulence of S. aureus. METHODS: Review of the current and prospective approaches for treating S. aureus endophthalmitis. RESULTS: Bacterial endophthalmitis remains to be a major threat for vision. S. aureus endophthalmitis specifically, carries a poor visual prognosis making early diagnosis and treatment crucial. Methicillin resistant Staphylococcus aureus (MRSA) endophthalmitis represents a significant number of S. aureus endophthalmitis cases. MRSA with reduced susceptibility to glycopeptide antibiotics such as vancomycin (vancomycin intermediate S. aureus, VISA) have also emerged in the ocular infections, and there has been a rise in S. aureus resistance to new and old generation fluoroquinolones that are commonly used for prophylaxis after intravitreal injections and intraocular surgeries. CONCLUSIONS: With the rise in the number of penetrating procedures in the ophthalmology practice and the parallel rise in antibiotic resistance, prophylaxis and awareness of the antimicrobial resistance profiles remain crucial and the identification of novel antimicrobials is essential.
PURPOSE: Obstructive meibomian gland dysfunction is a leading cause of ocular morbidity and its treatment remains a challenge. Meibomian gland probing was initially described in 2010. Here, the authors describe a modified technique, dynamic intraductal meibomian probing, which offers several advantages over the traditional approach including increased magnification, greater eyelid stabilization, enhanced anesthesia, and easier identification of gland orifices through the expression of meibum. METHODS: The authors conducted a retrospective chart review of 70 eyelids with treatment-resistant obstructive meibomian gland dysfunction undergoing dynamic intraductal meibomian probing between January 2013 and April 2015. RESULTS: Immediately after the procedure, 91.4% of cases experienced symptomatic improvement, and no complications were noted. CONCLUSIONS: Dynamic intraductal meibomian probing is an effective and safe treatment for obstructive meibomian gland dysfunction that is resistant to traditional therapies.
OBJECTIVE: To compare clinical outcomes of cataract surgery in eyes with and without pseudoexfoliation (PXF). DESIGN: Retrospective deidentified data analysis. PARTICIPANTS: A total of 123 PXF and 4776 non-PXF eyes of patients who underwent cataract surgery. METHODS: We compared data on visual acuity, Visual Function Questionnaire (VFQ)-based quality of life, and complications in PXF and non-PXF eyes from the Veterans Affairs (VA) Ophthalmic Surgery Outcomes Data Project across 5 VA medical centres. RESULTS: Pupillary expansion devices were used in 31 (25.2%) PXF cases and 398 (8.4%) non-PXF cases (p < 0.0001). Capsular tension rings were used in 6 (4.9%) PXF cases and 55 (1.2%) non-PXF cases (p < 0.004). The following complications occurred more frequently in PXF cases: zonular dehiscence without vitrectomy (4 [3.3%] PXF cases vs 40 [0.8%] non-PXF cases p = 0.02), persistent inflammation (28 [24.1%] vs 668 [14.5%]; p = 0.007), and persistent intraocular pressure elevation (5 [4.3%] vs 68 [1.5%]; p = 0.03). Best corrected visual acuity (BCVA) improved in both groups after 1 month, but 87 (83.7%) PXF cases achieved postoperative BCVA better than or equal to 20/40 compared to 3991 (93.8%) non-PXF cases (p = 0.0003). There was no significant difference in the postoperative composite VFQ scores between PXF (82.1 ± 16.9) and non-PXF cases (84.2 ± 16.8, p = 0.09). CONCLUSIONS: Several complications occurred more frequently in the PXF group compared to the non-PXF group, and fewer PXF cases achieved BCVA better than or equal to 20/40. Despite this, both groups experienced similar improvement in vision-related quality of life after cataract surgery.