BACKGROUND: Corneal neovascularization increases the risk of T cell-mediated allograft rejection. Here, we investigate whether T cells promote angiogenesis in transplantation. METHODS: Conventional effector T cells were collected from draining lymph nodes of allogeneic or syngeneic corneal transplanted BALB/c mice. T cells were either cocultured with vascular endothelial cells (VECs) to assess VEC proliferation or used in a mixed lymphocyte reaction assay. Messenger RNA (mRNA) expression of vascular endothelial growth factor (VEGF)-A, -C, and VEGF receptor 2 (VEGF-R2) in VECs was assessed by real-time PCR. VEGF-A protein expression was determined by enzyme-linked immunosorbent assay. Flow cytometry was used to analyze VEGF-R2 expression in corneal CD31 cells, and VEGF-A and IFNγ expression in corneal CD4 T cells. RESULTS: Allogeneic T cells from high-risk (HR) grafted mice induced more VEC proliferation than those from syngeneic transplant recipients (P = 0.03). Vascular endothelial growth factor-A mRNA and protein expression were higher in T cells from draining lymph nodes (P = 0.03 and P = 0.04, respectively) and cornea (protein; P = 0.04) of HR compared with low-risk (LR) grafted hosts. Vascular endothelial growth factor-A, VEGF-C, and VEGF-R2 mRNA expression were increased in VECs when cocultured with T cells from HR transplants compared with LR transplants and naive mice. In addition, IFNγ blockade in T cell/VEC coculture increased VEC proliferation and VEGF-A protein expression, whereas blocking VEGF-A significantly reduced VEC proliferation (P = 0.04). CONCLUSIONS: Allogeneic T cells from corneal transplant hosts promote VEC proliferation, probably via VEGF-A signaling, whereas IFNγ shows an antiangiogenic effect. Our data suggest that T cells are critical mediators of angiogenesis in transplantation.
The brain has a tightly regulated environment that protects neurons and limits inflammation, designated "immune privilege." However, there is not an absolute lack of an immune response. We tested the ability of the brain to initiate an innate immune response to a virus, which was directly injected into the brain parenchyma, and to determine whether this response could limit viral spread. We injected vesicular stomatitis virus (VSV), a transsynaptic tracer, or naturally occurring VSV-derived defective interfering particles (DIPs), into the caudate-putamen (CP) and scored for an innate immune response and inhibition of virus spread. We found that the brain parenchyma has a functional type I interferon (IFN) response that can limit VSV spread at both the inoculation site and among synaptically connected neurons. Furthermore, we characterized the response of microglia to VSV infection and found that infected microglia produced type I IFN and uninfected microglia induced an innate immune response following virus injection.
Endophthalmitis is a severe eye infection that may result in permanent loss of useful vision in the affected eye. Most cases are exogenous and occur as a complication of cataract surgery, an intravitreal injection, or penetrating ocular trauma. Endogenous endophthalmitis results from hematogenous seeding of the eye by bacteria or fungi, but bacteremia or fungemia may be transient and patients may present without symptoms of systemic infection. Nearly all endophthalmitis patients present with decreased vision, and some also have eye pain. Eye examination usually reveals a hypopyon and intraocular inflammation. Diagnosis is clinical, supported by cultures of the vitreous and/or aqueous or by blood cultures in some endogenous cases. Molecular diagnostic techniques have been used in research laboratories for pathogen identification in endophthalmitis and offer the possibility of rapid diagnosis, including in culture-negative cases. Intravitreal injection of antibiotics is the most important component of treatment; some cases also benefit from surgical debridement of the vitreous by a vitrectomy. The visual outcome depends partly on the pathogen: coagulase-negative staphylococcal endophthalmitis has a better prognosis than does streptococcal endophthalmitis, for example. Endophthalmitis is a medical emergency, and prompt diagnosis and treatment are essential for saving vision.
PURPOSE: To determine the incidence of retinal redetachment due to proliferative vitreoretinopathy after open-globe trauma in smokers and nonsmokers. METHODS: A total of 892 patients comprising 893 open-globe injuries, in whom 255 eyes were diagnosed with a retinal detachment, and 138 underwent surgical repair were analyzed in a retrospective case-control study. Time to redetachment was examined using the Kaplan-Meier method and analysis of risk factors was analyzed using Cox proportional hazards modeling. RESULTS: Within one year after retinal detachment surgery, 47% (95% CI, 39-56%) of all 138 repaired retinas redetached because of proliferative vitreoretinopathy. Being a smoker was associated with a higher rate of detachment (adjusted hazard ratio 1.96, P = 0.01). As shown in previous studies, the presence of proliferative vitreoretinopathy at the time of surgery was also an independent risk factor for failure (adjusted hazard ratio 2.13, P = 0.005). Treatment with vitrectomy-buckle compared favorably to vitrectomy alone (adjusted hazard ratio 0.58, P = 0.04). Only 8% of eyes that redetached achieved a best-corrected visual acuity of 20/200 or better, in comparison to 44% of eyes that did not redetach (P < 0.001). CONCLUSION: Proliferative vitreoretinopathy is a common complication after the repair of retinal detachment associated with open-globe trauma, and being a smoker is a risk factor for redetachment. Further study is needed to understand the pathophysiologic mechanisms underlying this correlation.
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.
Corneal cross-linking was approved by United States Food and Drug Administration for the treatment of progressive keratoconus in April 2016. As this approach becomes more widely used for the treatment of keratoconus and post-laser in situ keratomileusis (LASIK) ectasia, the medical community is becoming more familiar with potential complications associated with this procedure. This article aims to review the reported complications of collagen cross-linking for the treatment of keratoconus and post-LASIK ectasia.
PURPOSE: To compare the diagnostic capability of 3-dimensional (3D) neuroretinal rim parameters with existing 2-dimensional (2D) neuroretinal and retinal nerve fiber layer (RNFL) thickness rim parameters using spectral domain optical coherence tomography (SD-OCT) volume scans. MATERIALS AND METHODS: Design: Institutional prospective pilot study. STUDY POPULATION: 65 subjects (35 open-angle glaucoma patients, 30 normal patients). OBSERVATION PROCEDURES: One eye of each subject was included. SD-OCT was used to obtain 2D RNFL thickness values and 5 neuroretinal rim parameters [ie, 3D minimum distance band (MDB) thickness, 3D Bruch's membrane opening-minimum rim width (BMO-MRW), 3D rim volume, 2D rim area, and 2D rim thickness]. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve values, sensitivity, and specificity. RESULTS: Comparing all 3D with all 2D parameters, 3D rim parameters (MDB, BMO-MRW, rim volume) generally had higher area under the receiver operating characteristic curve values (range, 0.770 to 0.946) compared with 2D parameters (RNFL thickness, rim area, rim thickness; range, 0.678 to 0.911). For global region analyses, all 3D rim parameters (BMO-MRW, rim volume, MDB) were equal to or better than 2D parameters (RNFL thickness, rim area, rim thickness; P-values from 0.023 to 1.0). Among the three 3D rim parameters (MDB, BMO-MRW, and rim volume), there were no significant differences in diagnostic capability (false discovery rate >0.05 at 95% specificity). CONCLUSIONS: 3D neuroretinal rim parameters (MDB, BMO-MRW, and rim volume) demonstrated better diagnostic capability for primary and secondary open-angle glaucomas compared with 2D neuroretinal parameters (rim area, rim thickness). Compared with 2D RNFL thickness, 3D neuroretinal rim parameters have the same or better diagnostic capability.
PURPOSE: To provide current estimates of the prevalence of diagnosed dry eye disease (DED) and associated demographics among US adults aged ≥18 years. DESIGN: Cross-sectional, population-based survey. METHODS: Data were analyzed from 75,000 participants in the 2013 National Health and Wellness Survey to estimate prevalence/risk of diagnosed DED overall, and by age, sex, insurance, and other demographic factors. We weighted the observed DED prevalence to project estimates to the US adult population and examined associations between demographic factors and DED using multivariable logistic regression. RESULTS: Based on weighted estimates, 6.8% of the US adult population was projected to have diagnosed DED (∼16.4 million people). Prevalence increased with age (18-34 years: 2.7%; ≥75 years: 18.6%) and was higher among women (8.8%; ∼11.1 million) than men (4.5%; ∼5.3 million). After adjustment, there were no substantial differences in prevalence/risk of diagnosed DED by race, education, or US census region. However, there was higher risk of diagnosed DED among those aged 45-54 years (odds ratio [OR]: 1.95; 95% confidence interval [CI]: 1.74-2.20) and ≥75 years (OR: 4.95; 95% CI: 4.26-5.74), vs those aged 18-34 years. Risk was also higher among women vs men (OR: 2.00; 95% CI: 1.88-2.13) and insured vs uninsured participants (OR: 2.12; 95% CI: 1.85-2.43 for those on government and private insurance vs none). CONCLUSIONS: We estimate that >16 million US adults have diagnosed DED. Prevalence is higher among women than men, increases with age, and is notable among those aged 18-34 years.
Current treatments for choroidal neovascularization, a major cause of blindness for patients with age-related macular degeneration, treat symptoms but not the underlying causes of the disease. Inflammation has been strongly implicated in the pathogenesis of choroidal neovascularization. We examined the inflammatory role of Toll-like receptor 2 (TLR2) in age-related macular degeneration. TLR2 was robustly expressed by the retinal pigment epithelium in mouse and human eyes, both normal and with macular degeneration/choroidal neovascularization. Nuclear localization of NF-κB, a major downstream target of TLR2 signaling, was detected in the retinal pigment epithelium of human eyes, particularly in eyes with advanced stages of age-related macular degeneration. TLR2 antagonism effectively suppressed initiation and growth of spontaneous choroidal neovascularization in a mouse model, and the combination of anti-TLR2 and antivascular endothelial growth factor receptor 2 yielded an additive therapeutic effect on both area and number of spontaneous choroidal neovascularization lesions. Finally, in primary human fetal retinal pigment epithelium cells, ligand binding to TLR2 induced robust expression of proinflammatory cytokines, and end products of lipid oxidation had a synergistic effect on TLR2 activation. Our data illustrate a functional role for TLR2 in the pathogenesis of choroidal neovascularization, likely by promoting inflammation of the retinal pigment epithelium, and validate TLR2 as a novel therapeutic target for reducing choroidal neovascularization.
Investigating the impact of early visual deprivation on evaluations related to social trust has received little attention to date. This is despite consistent evidence suggesting that early onset blindness may interfere with the normal development of social skills. In this study, we investigated whether early blindness affects judgments of trustworthiness regarding the actions of an agent, with trustworthiness representing the fundamental dimension in the social evaluation. Specifically, we compared performance between a group of early blind individuals with that of sighted controls in their evaluation of trustworthiness of an agent after hearing a pair of two positive or two negative social behaviors (impression formation). Participants then repeated the same evaluation following the presentation of a third (consistent or inconsistent) behavior regarding the same agent (impression updating). Overall, blind individuals tended to give similar evaluations compared to their sighted counterparts. However, they also valued positive behaviors significantly more than sighted controls when forming their impression of an agent's trustworthiness. Moreover, when inconsistent information was provided, blind individuals were more prone to revise their initial evaluation compared to controls. These results suggest that early visual deprivation may have a dramatic effect on the evaluation of social factors such as trustworthiness.
PURPOSE: To determine incidence of new-onset diplopia, resolution of preexisting diplopia, and impact on proptosis resulting from endoscopic orbital decompression with and without preservation of the inferomedial orbital strut for thyroid orbitopathy. METHODS: Retrospective review of all patients undergoing endoscopic 2- or 3-wall decompression with or without preservation of the strut for thyroid orbitopathy from January 2012 to June 2015. RESULTS: Twenty-six patients (45 orbits) were included and divided into 4 primary categories: 2-wall decompression with strut preservation (4 orbits, 8%), 2-wall decompression with strut removal (7 orbits, 16%), 3-wall decompression with strut preservation (27 orbits, 60%), and 3-wall decompression with strut removal (7 orbits, 16%). The incidence of new-onset diplopia was 20% (2/10 patients without preoperative diplopia) overall and 16% in the strut preservation group (1/6 patients without preoperative diplopia). Resolution of diplopia occurred in 4 of 16 patients (25%) with preoperative diplopia, and all 4 had been treated with a 3-wall decompression with strut preservation. Resolution of diplopia in the group treated with strut preservation was 36% (4/11 patients with preoperative diplopia), and 0% of the 5 diplopic patients treated without strut preservation. Reduction in proptosis was statistically greater in those treated with strut removal (p = 0.003). CONCLUSIONS: This study demonstrates that endoscopic orbital decompression with preservation of the inferomedial bone strut results in a comparable to lower rate of new-onset diplopia compared with other reported techniques. When combined with 3-wall balanced decompression, this technique demonstrates a high rate of resolution of preexisting diplopia.
BACKGROUND: Contemporary data for causes of vision impairment and blindness form an important basis of recommendations in public health policies. Refreshment of the Global Vision Database with recently published data sources permitted modelling of cause of vision loss data from 1990 to 2015, further disaggregation by cause, and forecasts to 2020. METHODS: In this systematic review and meta-analysis, we analysed published and unpublished population-based data for the causes of vision impairment and blindness from 1980 to 2014. We identified population-based studies published before July 8, 2014, by searching online databases with no language restrictions (MEDLINE from Jan 1, 1946, and Embase from Jan 1, 1974, and the WHO Library Database). We fitted a series of regression models to estimate the proportion of moderate or severe vision impairment (defined as presenting visual acuity of <6/18 but ≥3/60 in the better eye) and blindness (presenting visual acuity of <3/60 in the better eye) by cause, age, region, and year. FINDINGS: We identified 288 studies of 3 983 541 participants contributing data from 98 countries. Among the global population with moderate or severe vision impairment in 2015 (216·6 million [80% uncertainty interval 98·5 million to 359·1 million]), the leading causes were uncorrected refractive error (116·3 million [49·4 million to 202·1 million]), cataract (52·6 million [18·2 million to 109·6 million]), age-related macular degeneration (8·4 million [0·9 million to 29·5 million]), glaucoma (4·0 million [0·6 million to 13·3 million]), and diabetic retinopathy (2·6 million [0·2 million to 9·9 million]). Among the global population who were blind in 2015 (36·0 million [12·9 million to 65·4 million]), the leading causes were cataract (12·6 million [3·4 million to 28·7 million]), uncorrected refractive error (7·4 million [2·4 million to 14·8 million]), and glaucoma (2·9 million [0·4 million to 9·9 million]). By 2020, among the global population with moderate or severe vision impairment (237·1 million [101·5 million to 399·0 million]), the number of people affected by uncorrected refractive error is anticipated to rise to 127·7 million (51·0 million to 225·3 million), by cataract to 57·1 million (17·9 million to 124·1 million), by age-related macular degeneration to 8·8 million (0·8 million to 32·1 million), by glaucoma to 4·5 million (0·5 million to 15·4 million), and by diabetic retinopathy to 3·2 million (0·2 million to 12·9 million). By 2020, among the global population who are blind (38·5 million [13·2 million to 70·9 million]), the number of patients blind because of cataract is anticipated to rise to 13·4 million (3·3 million to 31·6 million), because of uncorrected refractive error to 8·0 million (2·5 million to 16·3 million), and because of glaucoma to 3·2 million (0·4 million to 11·0 million). Cataract and uncorrected refractive error combined contributed to 55% of blindness and 77% of vision impairment in adults aged 50 years and older in 2015. World regions varied markedly in the causes of blindness and vision impairment in this age group, with a low prevalence of cataract (<22% for blindness and 14·1-15·9% for vision impairment) and a high prevalence of age-related macular degeneration (>14% of blindness) as causes in the high-income subregions. Blindness and vision impairment at all ages in 2015 due to diabetic retinopathy (odds ratio 2·52 [1·48-3·73]) and cataract (1·21 [1·17-1·25]) were more common among women than among men, whereas blindness and vision impairment due to glaucoma (0·71 [0·57-0·86]) and corneal opacity (0·54 [0·43-0·66]) were more common among men than among women, with no sex difference related to age-related macular degeneration (0·91 [0·70-1·14]). INTERPRETATION: The number of people affected by the common causes of vision loss has increased substantially as the population increases and ages. Preventable vision loss due to cataract (reversible with surgery) and refractive error (reversible with spectacle correction) continue to cause most cases of blindness and moderate or severe vision impairment in adults aged 50 years and older. A large scale-up of eye care provision to cope with the increasing numbers is needed to address avoidable vision loss. FUNDING: Brien Holden Vision Institute.
Regulatory T cells (Tregs) are critical modulators of immune homeostasis. Tregs maintain peripheral tolerance to self-antigens, thereby preventing autoimmune disease. Furthermore, Tregs suppress excessive immune responses deleterious to the host. Recent research has deepened our understanding of how Tregs function at the ocular surface. This manuscript describes the classification, the immunosuppressive mechanisms, and the phenotypic plasticity of Tregs. We review the contribution of Tregs to ocular surface autoimmune disease, as well as the function of Tregs in allergy and infection at the ocular surface. Finally, we review the role of Tregs in promoting allotolerance in corneal transplantation.
PURPOSE: To highlight the effect of ascent to high altitude on intraocular pressure (IOP) in a patient with primary open-angle glaucoma, who had previously undergone trabeculectomy in 1 eye. METHODS: Case report. RESULTS: A 66-year-old mountaineer with primary open-angle glaucoma and previous right trabeculectomy performed self-tonometry using a rebound tonometer (Icare HOME) before and during an expedition in the Himalaya. In the nonoperated eye, there was a statistically significant increase in IOP as the patient ascended to 5000 m over 8 days (R=0.790, P=0.001), consistent with recent literature. IOP increased by 1.73 mm Hg with each 1000 m increase in altitude. In the trabeculectomized eye there was no significant increase in IOP (R=0.219, P=0.172). CONCLUSIONS: Filtration surgery may be protective against IOP fluctuations associated with ascent to high altitude. Self-tonometry complements standard glaucoma care by providing opportunities for IOP monitoring outside office hours and in remote locations.
Purpose: Neovascular age-related macular degeneration (AMD) is a major cause of legal blindness in the elderly. Diets with omega3-long-chain-polyunsaturated-fatty-acid (ω3-LCPUFA) correlate with a decreased risk of AMD. Dietary ω3-LCPUFA versus ω6-LCPUFA inhibits mouse ocular neovascularization, but the underlying mechanism needs further exploration. The aim of this study was to investigate if adiponectin (APN) mediated ω3-LCPUFA suppression of neovessels in AMD. Methods: The mouse laser-induced choroidal neovascularization (CNV) model was used to mimic some of the inflammatory aspect of AMD. CNV was compared between wild-type (WT) and Apn-/- mice fed either otherwise matched diets with 2% ω3 or 2% ω6-LCPUFAs. Vldlr-/- mice were used to mimic some of the metabolic aspects of AMD. Choroid assay ex vivo and human retinal microvascular endothelial cell (HRMEC) proliferation assay in vitro was used to investigate the APN pathway in angiogenesis. Western blot for p-AMPKα/AMPKα and qPCR for Apn, Mmps, and IL-10 were used to define mechanism. Results: ω3-LCPUFA intake suppressed laser-induced CNV in WT mice; suppression was abolished with APN deficiency. ω3-LCPUFA, mediated by APN, decreased mouse Mmps expression. APN deficiency decreased AMPKα phosphorylation in vivo and exacerbated choroid-sprouting ex vivo. APN pathway activation inhibited HRMEC proliferation and decreased Mmps. In Vldlr-/- mice, ω3-LCPUFA increased retinal AdipoR1 and inhibited NV. ω3-LCPUFA decreased IL-10 but did not affect Mmps in Vldlr-/- retinas. Conclusions: APN in part mediated ω3-LCPUFA inhibition of neovascularization in two mouse models of AMD. Modulating the APN pathway in conjunction with a ω3-LCPUFA-enriched-diet may augment the beneficial effects of ω3-LCPUFA in AMD patients.