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Moustafa GA, Borkar DS, McKay MK, Eton EA, Koulisis N, Lorch AC, Kloek CE, Kloek CE. Outcomes in resident-performed cataract surgeries with iris challenges: Results from the Perioperative Care for Intraocular Lens study. J Cataract Refract Surg 2018;44(12):1469-1477.Abstract
PURPOSE: To assess the outcomes of resident-performed cataract surgeries with iris challenges and to compare these outcomes with similar surgeries performed by attending surgeons. SETTING: Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA. DESIGN: Retrospective chart review. METHODS: All cases of cataract extraction by phacoemulsification with intraocular lens implantation, performed by comprehensive ophthalmologists between January 1 and December 31, 2014, were reviewed. Cases with preoperative or intraoperative miosis, iris prolapse, and intraoperative floppy iris syndrome, were included for analysis. Visual outcomes and the rate of perioperative adverse events were compared between resident and attending surgeon cases. Factors predicting adverse events were also assessed. RESULTS: In total, 1931 eye cases of 1434 patients were reviewed, and 65 resident cases and 168 attending surgeon cases were included. The mean logarithm of the minimum angle of resolution corrected distance visual acuity was better in the resident group 1 month after surgery (0.051 ± 0.10 [SD] versus 0.132 ± 0.30, P = .03); however, the difference was eliminated when controlling for macular disease. The mean operative time was 43.8 ± 26.5 minutes and 30.9 ± 12.6 minutes for cases performed by resident surgeons and attending surgeons, respectively (P  .0001). Residents utilized supplemental pharmacologic dilation or retraction more frequently than attending surgeons (98% versus 87% of cases, P = .008). The overall rate of adverse events was no different between residents and attending surgeons (P = 0.16). Dense nuclear sclerosis predicted adverse events in cataract cases with iris challenges (adjusted odds ratio, 1.86; 95% confidence interval, 1.17-2.94; P = .001). CONCLUSION: Although requiring longer operative times and more surgical manipulation, residents who performed cataract surgeries with iris challenges achieved outcomes comparable to those performed by attending surgeons, and residents should be given the opportunity to operate on these eyes.
Nwanaji-Enwerem JC, Wang W, Nwanaji-Enwerem O, Vokonas P, Baccarelli A, Weisskopf M, Herndon LW, Wiggs JL, Park SK, Schwartz J. Association of Long-term Ambient Black Carbon Exposure and Oxidative Stress Allelic Variants With Intraocular Pressure in Older Men. JAMA Ophthalmol 2018;Abstract
Importance: Elevated intraocular pressure is a major risk factor for glaucoma, a leading cause of irreversible blindness worldwide. Environmental air pollution has been suggested as a potential contributor to elevated intraocular pressure; however, no studies have demonstrated such an association to date. Objective: To investigate the association of long-term ambient black carbon exposure with intraocular pressure in community-dwelling older adults. Design, Setting, and Participants: This population-based analysis, conducted from October 18, 2017, through March 22, 2018, used data from the all-male, New England-based Normative Aging Study of the US Department of Veterans Affairs. The analysis included 419 older men with a total of 911 follow-up study visits between January 1, 2000, and December 30, 2011. Intraocular pressure was measured by Goldmann applanation tonometry during the study visits. Validated spatiotemporal models were used to generate 1-year black carbon exposure levels at the addresses of the participants. Main Outcomes and Measures: An independently developed genetic score approach was used to calculate allelic risk scores for 3 pathways associated with black carbon toxicity: endothelial function, oxidative stress, and metal processing. The associations among black carbon exposure, allelic risk scores, and intraocular pressure were explored using linear mixed-effects models. Results: All 419 participants were men with a mean (SD) age of 75.3 (6.9) years. The mean (SD) 1-year black carbon exposure was 0.51 (0.18) μg/m3, and the mean (SD) intraocular pressure for the left eye was 14.1 (2.8) mm Hg and for the right eye was 14.1 (3.0) mm Hg. Of the 911 visits, 520 (57.1%) had a high endothelial function allelic risk score, 644 (70.7%) had a high metal-processing allelic risk score, and 623 (68.4%) had a high oxidative stress allelic risk score. In fully adjusted linear mixed-effects models, the association of black carbon with intraocular pressure was greater in individuals with a high oxidative stress allelic score (β = 0.36; 95% CI, 0.003-0.73) compared with individuals with a low score (β = -0.35; 95% CI, -0.86 to 0.15). Conclusions and Relevance: Ambient black carbon exposure may be a risk factor for increased intraocular pressure in individuals susceptible to other biological oxidative stressors. If additional studies confirm these results, monitoring ambient black carbon exposure and physiological oxidative stress may prevent the development and progression of intraocular pressure-related disease.
Sabel BA, Flammer J, Merabet LB. Residual vision activation and the brain-eye-vascular triad: Dysregulation, plasticity and restoration in low vision and blindness - a review. Restor Neurol Neurosci 2018;Abstract
Vision loss due to ocular diseases such as glaucoma, optic neuropathy, macular degeneration, or diabetic retinopathy, are generally considered an exclusive affair of the retina and/or optic nerve. However, the brain, through multiple indirect influences, has also a major impact on functional visual impairment. Such indirect influences include intracerebral pressure, eye movements, top-down modulation (attention, cognition), and emotionally triggered stress hormone release affecting blood vessel dysregulation. Therefore, vision loss should be viewed as the result of multiple interactions within a "brain-eye-vascular triad", and several eye diseases may also be considered as brain diseases in disguise. While the brain is part of the problem, it can also be part of the solution. Neuronal networks of the brain can "amplify" residual vision through neuroplasticity changes of local and global functional connectivity by activating, modulating and strengthening residual visual signals. The activation of residual vision can be achieved by different means such as vision restoration training, non-invasive brain stimulation, or blood flow enhancing medications. Modulating brain functional networks and improving vascular regulation may offer new opportunities to recover or restore low vision by increasing visual field size, visual acuity and overall functional vision. Hence, neuroscience offers new insights to better understand vision loss, and modulating brain and vascular function is a promising source for new opportunities to activate residual vision to achieve restoration and recovery to improve quality of live in patients suffering from vision loss.
Tellefsen S, Morthen MK, Richards SM, Lieberman SM, Rahimi Darabad R, Kam WR, Sullivan DA. Sex Effects on Gene Expression in Lacrimal Glands of Mouse Models of Sjögren Syndrome. Invest Ophthalmol Vis Sci 2018;59(13):5599-5614.Abstract
Purpose: Sjögren syndrome is an autoimmune disease that occurs primarily in women, and is associated with lacrimal gland inflammation and aqueous-deficient dry eye. We hypothesize that sex-associated differences in lacrimal gland gene expression are very important in promoting lymphocyte accumulation in this tissue and contribute to the onset, progression, and/or severity of the inflammatory disease process. To test our hypothesis, we explored the nature and extent of sex-related differences in gene expression in autoimmune lacrimal glands. Methods: Lacrimal glands were collected from age-matched, adult, male and female MRL/MpJ-Tnfrsf6lpr (MRL/lpr) and nonobese diabetic/LtJ (NOD) mice. Glands were processed for the analysis of differentially expressed mRNAs by using CodeLink Bioarrays and Affymetrix GeneChips. Data were evaluated with bioinformatics and statistical software. Results: Our results show that sex significantly influences the expression of thousands of genes in lacrimal glands of MRL/lpr and NOD mice. The immune nature of this glandular response is very dependent on the Sjögren syndrome model. Lacrimal glands of female, as compared with male, MRL/lpr mice contain a significant increase in the expression of genes related to inflammatory responses, antigen processing, and chemokine pathways. In contrast, it is the lacrimal tissue of NOD males, and not females, that presents with a significantly greater expression of immune-related genes. Conclusions: These data support our hypothesis that sex-related differences in gene expression contribute to lacrimal gland disease in Sjögren syndrome. Our findings also suggest that factors in the lacrimal gland microenvironment are critically important in mediating these sex-associated immune effects.
Dobyns WB, Aldinger KA, Ishak GE, Mirzaa GM, Timms AE, Grout ME, Dremmen MHG, Schot R, Vandervore L, van Slegtenhorst MA, Wilke M, Kasteleijn E, Lee AS, Barry BJ, Chao KR, Szczałuba K, Kobori J, Hanson-Kahn A, Bernstein JA, Carr L, D'Arco F, Miyana K, Okazaki T, Saito Y, Sasaki M, Das S, Wheeler MM, Bamshad MJ, Nickerson DA, of for Genomics UWCM, for at the of and Harvard CMGBIMIT, Engle EC, Verheijen FW, Doherty D, Mancini GMS. MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance. Am J Hum Genet 2018;103(6):1009-1021.Abstract
To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.
Chun BY, Cestari DM. Myelin oligodendrocyte glycoprotein-IgG-associated optic neuritis. Curr Opin Ophthalmol 2018;29(6):508-513.Abstract
PURPOSE OF REVIEW: Myelin oligodendrocyte glycoprotein (MOG)-IgG-associated optic neuritis has been established as a new entity of optic neuropathy. We will review recent advances in pathophysiology, diagnosis, and clinical manifestations of MOG-IgG-associated optic neuritis to better understand its distinctive characteristics. RECENT FINDINGS: MOG is expressed on the surface of myelin sheaths and oligodendrocytes. MOG is highly immunogenic and is a potential target of inflammatory demyelinating disease. MOG-IgG activate immune responses and cause demyelination without astrocytopathy. MOG-IgG are measured by cell-based assays, which have higher sensitivity and specificity than ELISA. Patients with MOG-IgG-associated optic neuritis present with initially severe vision loss, are more likely to have optic disc edema, but have favorable visual outcomes. Furthermore, patients with MOG-IgG-associated optic neuritis have higher rates of recurrence compared with MOG-IgG seronegative patients. MOG-IgG-associated optic neuritis responds well to steroid treatment, however, close monitoring for signs of relapse and long-term immunosuppression may be necessary. SUMMARY: MOG-IgG associated optic neuritis demonstrates distinctive pathophysiological and clinical characteristics from optic neuritis in aquaporin4-IgG seropositive or multiple sclerosis patients. Measurements of MOG-IgG titers by cell-based assays will be helpful for the diagnosis and treatment of optic neuritis.
Jurkunas UV. Fuchs Endothelial Corneal Dystrophy Through the Prism of Oxidative Stress. Cornea 2018;37 Suppl 1:S50-S54.Abstract
The corneal endothelium (CE) is vital for maintaining the water balance and clarity of the cornea. The CE is a cell layer that is particularly susceptible to aging because of its postmitotic arrest, high metabolic activity involving pumping of ions, and lifelong exposure to ultraviolet light. Despite gradual age-related cell loss, a sufficient number of CE cells are preserved during the lifespan of an individual. However, in conditions such as Fuchs endothelial corneal dystrophy (FECD), permanent loss of CE cells leads to corneal edema and loss of vision requiring corneal transplantation. FECD is a genetic and oxidative stress disorder manifested by abnormal cell-matrix interactions and expedited cellular aging culminating in cellular death. Because the endothelium has minimal replicative capacity in vivo and an inability to replace its genome, it is particularly prone to cumulative DNA damage acquired throughout life. In FECD, the underlying genetic defects make the CE genome even more vulnerable to this damage, to the point of causing mitochondrial dysfunction, mitochondrial membrane potential loss, and excessive mitophagy activation. Endogenous and exogenous intracellular stressors alter the synthetic footprint of CE cells, leading to endothelial-mesenchymal transition and secretion of aberrant extracellular matrix (in the form of guttae), resembling scar formation in other organs. In turn, the guttae or endothelial scars contribute to a vicious cycle of FECD pathogenesis and, by further inducing endothelial-mesenchymal transition and oxidant-antioxidant imbalance, perpetuate the molecular changes of the degenerating endothelium.
Galli J, Ambrosi C, Micheletti S, Merabet LB, Pinardi C, Gasparotti R, Fazzi E. White matter changes associated with cognitive visual dysfunctions in children with cerebral palsy: A diffusion tensor imaging study. J Neurosci Res 2018;96(11):1766-1774.Abstract
Children with cerebral palsy often present with cognitive-visual dysfunctions characterized by visuo-perceptual and/or visuo-spatial deficits associated with a malfunctioning of visual-associative areas. The neurofunctional model of this condition remains poorly understood due to the lack of a clear correlation between cognitive-visual deficit and morphological brain anomalies. The aim of our study was to quantify the pattern of white matter abnormalities within the whole brain in children with cerebral palsy, and to identify white matter tracts sub-serving cognitive-visual functions, in order to better understand the basis of cognitive-visual processing. Nine subjects (three males, mean age 8 years 9 months) with cerebral palsy underwent a visual and cognitive-visual evaluation. Conventional brain MRI and diffusion tensor imaging were performed. The fractional anisotropy maps were calculated for every child and compared with data from 13 (four males, mean age 10 years 7 months) healthy children. Children with cerebral palsy showed decreased fractional anisotropy (a marker of white matter integrity) in corticospinal tract bilaterally, left superior longitudinal fasciculus and bilateral hippocampus. Focusing on the superior longitudinal fasciculus, the mean fractional anisotropy values were significantly lower in children affected by cerebral palsy with cognitive-visual deficits than in those without cognitive-visual deficits. Our findings reveal an association between cognitive-visual profile and the superior longitudinal fasciculus integrity in children with cerebral palsy, supporting the hypothesis that visuo-associative deficits are related to changes in fibers connecting the occipital cortex with the parietal-frontal cortices. Decreased fractional anisotropy within the superior longitudinal fasciculus could be considered a biomarker for cognitive-visual dysfunctions.
Lammer J, Karst SG, Lin MM, Cheney M, Silva PS, Burns SA, Aiello LP, Sun JK. Association of Microaneurysms on Adaptive Optics Scanning Laser Ophthalmoscopy With Surrounding Neuroretinal Pathology and Visual Function in Diabetes. Invest Ophthalmol Vis Sci 2018;59(13):5633-5640.Abstract
Purpose: We evaluate diabetic microaneurysm (MA) features on high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) and their correlations with visual acuity (VA) and local retinal pathology on spectral domain optical coherence tomography (SDOCT). Methods: Diabetic participants underwent VA testing and AOSLO and SDOCT imaging of MAs. AOSLO images were graded for MA dimension, wall hyperreflectivity (WH), intraluminal hyperreflectivity (IH), and perfusion pattern. SDOCTs centered on each MA were graded for disorganization of the retinal inner layers (DRIL) and other neuroretinal pathology. Results: We imaged 109 MAs (30 eyes). Multivariate modeling, including statistically significant covariates from bivariate analyses, associated WH with greater MA size (P = 0.001) and DRIL (P = 0.04). IH was associated with perfusion (P = 0.003) and MA visibility on photographs (P = 0.0001), and larger MA size with partial perfusion (P = 0.03), MA ring signs (P = 0.0002), and photographic visibility (P = 0.01). Multivariate modeling revealed an association of WH and VA with DRIL. Conclusions: AOSLO imaging demonstrates associations of hyperreflective MA walls with MA size and adjacent DRIL, as well as the presence of DRIL with lower VA. This study identifies a correlation between vascular and neural pathology associated with VA decline. Further studies of MA structure and neuroretinal disorganization may enable novel approaches to assess anatomic and functional outcomes in the diabetic eye.
Hark LA, Myers JS, Rahmatnejad K, Wang Q, Zhan T, Hegarty SE, Leiby BE, Udyaver S, Waisbourd M, Leite S, Henderer JD, Pasquale LR, Lee PP, Haller JA, Katz JL. Philadelphia Telemedicine Glaucoma Detection and Follow-up Study: Analysis of Unreadable Fundus Images. J Glaucoma 2018;27(11):999-1008.Abstract
PURPOSE: The purpose of this study was to ascertain determinants of unreadable fundus images for participants enrolled in the Philadelphia Telemedicine Glaucoma Detection and Follow-up Study. METHODS: Individuals were screened for glaucoma at 7 primary care practices and 4 Federally Qualified Health Centers using telemedicine. Screening (visit 1) included fundus photography, assessing family history of glaucoma, and intraocular pressure (IOP) measurements. Participants with an unreadable image in at least one eye were deemed unreadable and invited to return for a confirmatory eye examination (visit 2). RESULTS: A total of 906 participants completed the visit 1 eye screening and 17.1% (n=155/906) were "unreadable." In the multivariable logistic regression analysis, older age, male sex, smoking, and worse visual acuity were significantly associated with an unreadable fundus image finding at the eye screening (P<0.05). Of the 89 participants who were invited for the confirmatory eye examination solely for unreadable images and attended visit 2, 58 (65.2%) were diagnosed with at least one ocular pathology. The most frequent diagnoses were cataracts (n=71; 15 visually significant, 56 nonvisually significant), glaucoma suspects (n=27), and anatomical narrow angle (n=10). CONCLUSIONS: Understanding the causes of unreadable fundus images will foster improvements in telemedicine techniques to optimize the predictive accuracy, efficiency, and cost in ophthalmology. A high proportion of participants with unreadable images (65.2%) in our study were diagnosed with some ocular pathology, indicating that the finding of an unreadable fundus image warrants a referral for a comprehensive follow-up eye examination.
de Boer IH, Zelnick LR, Lin J, Schaumberg D, Wang L, Ruzinski J, Friedenberg G, Duszlak J, Bubes VY, Hoofnagle AN, Thadhani R, Glynn RJ, Buring JE, Sesso HD, Manson JAE. Vitamin D and omega-3 trial to prevent and treat diabetic kidney disease: Rationale, design, and baseline characteristics. Contemp Clin Trials 2018;74:11-17.Abstract
Diabetic kidney disease (DKD), defined as reduced glomerular filtration rate (GFR), elevated urine albumin excretion, or both that is clinically attributable to diabetes, is a common and morbid diabetes complication. Animal-experimental data, observational human studies, and short-term clinical trials suggest that vitamin D and omega-3 fatty acid supplements may be safe and inexpensive interventions to reduce the incidence and progression of DKD. The Vitamin D and Omega-3 Trial to Prevent and Treat DKD (VITAL-DKD) was designed as an ancillary study to the VITAL trial of 25,871 US adults. In a 2 × 2 factorial design, VITAL participants were randomly assigned to vitamin D (cholecalciferol, 2000 IU daily) or placebo and to marine omega-3 fatty acids (eicospentaenoic acid and docosahexaenoic acid, 1 g/d) or placebo. VITAL-DKD enrolled a subset of 1326 VITAL participants with type 2 diabetes at baseline to test the effects of vitamin D and omega-3 fatty acids on changes in estimated GFR and urine albumin excretion. Over five years of follow-up, VITAL-DKD collected blood and urine samples to quantify changes in estimated GFR (the primary study outcome) and urine albumin excretion. At baseline, mean age of VITAL-DKD participants was 67.6 years, 46% were women, 30% were of racial or ethnic minority, and the prevalence of DKD (estimated GFR <60 mL/min/1.73m or urine albumin-creatinine ratio ≥ 30 mg/g) was 17%. In this type 2 diabetes population, VITAL-DKD will test the hypotheses that vitamin D and omega-3 fatty acids help prevent the development and progression of DKD.
Chen TC, Hoguet A, Junk AK, Nouri-Mahdavi K, Radhakrishnan S, Takusagawa HL, Chen PP. Spectral-Domain OCT: Helping the Clinician Diagnose Glaucoma: A Report by the American Academy of Ophthalmology. Ophthalmology 2018;125(11):1817-1827.Abstract
PURPOSE: To review the current published literature on the use of spectral domain (SD) OCT to help detect changes associated with the diagnosis of glaucoma. METHODS: Searches of the peer-reviewed literature were conducted on June 11, 2014, November 7, 2016, August 8, 2017, and April 19, 2018, in the PubMed and Cochrane Library databases and included only articles published since the last glaucoma imaging Ophthalmic Technology Assessment, which included articles up until February 2006. The abstracts of these 708 articles were examined to exclude reviews and non-English articles. After inclusion and exclusion criteria were applied, 74 articles were selected, and the panel methodologist (K.N.-M.) assigned ratings to them according to the level of evidence. Two articles were rated level I, 57 articles were rated level II, and the 15 level III articles were excluded. RESULTS: Spectral-domain OCT is capable of detecting damage to the retinal nerve fiber layer (RNFL), macula, and optic nerve in patients with preperimetric and perimetric glaucoma (level I and II evidence). The most commonly studied single parameter was RNFL thickness. Of note, RNFL thickness measurements are not interchangeable between instruments. Various commercially available SD OCT instruments have similar abilities to distinguish patients with known glaucoma from normal subjects. Despite different software protocols, all SD OCT instruments are able to detect the same typical pattern of glaucomatous RNFL loss that affects primarily the inferior, inferior temporal, superior, and superior temporal regions of the optic nerve (level II evidence). Across many SD OCT instruments, macular imaging also can detect a preferential inferior, inferior temporal, and superior temporal thinning in patients with glaucoma compared with controls. Best disc parameters for detecting glaucomatous nerve damage are global rim area, inferior rim area, and vertical cup-to-disc ratio. Studies suggest that newer reference-plane independent optic nerve parameters may have the same or better detection capability when compared with older reference-plane dependent disc parameters (level II evidence). CONCLUSIONS: Structural glaucomatous damage can be detected by SD OCT. Optic nerve, RNFL, and macular parameters can help the clinician distinguish the anatomic changes that are associated with patients with glaucoma when compared with normal subjects.
Lopez MJ, Seyed-Razavi Y, Jamali A, Harris DL, Hamrah P. The Chemokine Receptor CXCR4 Mediates Recruitment of CD11c+ Conventional Dendritic Cells Into the Inflamed Murine Cornea. Invest Ophthalmol Vis Sci 2018;59(13):5671-5681.Abstract
Purpose: The cornea contains distinct populations of antigen-presenting cells (APCs), including conventional dendritic cells (cDCs). Little is known about the molecular mechanisms involved in cDCs homing and recruitment into the naïve and inflamed cornea. The purpose of this study was to investigate the presence of CXCR4 and its ligand CXCL12 in the murine cornea and its role in cDC migration during corneal inflammation. Methods: The expression of CXCR4 and CXCL12 in naïve and suture-inflamed murine corneas was assessed by whole-mount staining, flow cytometry, and quantitative PCR. The role of CXCR4 in recruitment into inflamed corneas was investigated using adoptive transfer of cDCs blocked with neutralizing antibody against CXCR4. Results: We show the chemokine receptor CXCR4 to be expressed on 51.7% and 64.8% of total corneal CD11c+ cDCs, equating to 98.6 ± 12.5 cells/mm2 in the peripheral and 64.7 ± 10.6 cells/mm2 in the central naïve cornea, respectively. Along with a 4.5-fold increase in CXCL12 expression during inflammation (P < 0.05), infiltrating cDCs also expressed CXCR4 in both the peripheral (222.6 ± 33.3 cells/mm2; P < 0.001) and central cornea (161.9 ± 23.8 cells/mm2; P = 0.001), representing a decrease to 31.0% and 37.3% in the cornea, respectively. Further, ex vivo blockade (390.1 ± 40.1 vs. 612.1 ± 78.3; P = 0.008) and local blockade (263.5 ± 27.1 vs. 807.5 ± 179.5, P < 0.001) with anti-CXCR4 neutralizing antibody resulted in a decrease in cDCs homing into the cornea compared with cells pretreated with isotype controls. Conclusions: Our results demonstrate that corneal CXCL12 plays a direct role in CXCR4+ cDC recruitment into the cornea. The CXCR4/CXCL12 axis is therefore a potential target to modulate corneal inflammatory responses.
Ibrahim AS, Elmasry K, Wan M, Abdulmoneim S, Still A, Khan F, Khalil A, Saul A, Hoda MN, Al-Shabrawey M. A Controlled Impact of Optic Nerve as a New Model of Traumatic Optic Neuropathy in Mouse. Invest Ophthalmol Vis Sci 2018;59(13):5548-5557.Abstract
Purpose: Traumatic optic neuropathy (TON) is the most feared visual consequence of head and ocular trauma in both military and civilian communities, for which standard treatment does not exist. Animal models are critical for the development of novel TON therapies as well as the understanding of TON pathophysiology. However, the models currently used for TON have some limitations regarding consistency and mirroring the exact pathological progression of TON in closed ocular trauma. In this study, we modified the model of controlled cortical impact and adapted it for studying TON. Methods: We defined new standardized procedures to induce TON in mice, wherein the optic nerve is reproducibly exposed to a graded controlled impact of known velocity to produce a graded deficit in retinal ganglion cell (RGC) electrophysiological functions. Results: The key results of validating this newly modified model, "controlled orbital impact (COI)," included (1) the injury parameters (velocity as well as contusion depth and time), which were quantifiable and manageable to generate a wide range of TON severities; (2) a reproducible endpoint of diminished positive scotopic threshold response (pSTR) has been achieved without the interference of surgical variability and destruction of surrounding tissues; (3) the contralateral eyes showed no significant difference to the eyes of naïve mice, allowing them to be used as an internal control to minimize interindividual variability among mice; and (4) the occurrence of injury-associated mortality and/or ocular comorbidity was rare. Conclusions: Taken together, this model overcomes some limitations of prior TON mouse models and provides an innovative platform to identify therapeutic targets for neuroprotection and/or neurorestoration following traumatic ocular injury.

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