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Sachdeva MM, Jakobiec FA, Stagner AM, Papakostas A, Eliott D. Clinical and Ultrastructural Studies of Epiretinal Pigmentary Deposits after Retinectomy with Silicone Oil. Ophthalmology 2016;123(12):2595-2602.Abstract

PURPOSE: Large relaxing retinectomies have become increasingly used in the repair of retinal detachment related to proliferative vitreoretinopathy (PVR). Retinectomies expose the retinal pigment epithelium (RPE) to the vitreous cavity; the direct effects of silicone oil on the RPE are only beginning to be understood. DESIGN: Retrospective case series. PARTICIPANTS: Twelve patients noted to develop pigmented epiretinal deposits at regularly scheduled follow-up visits after repair of complex retinal detachments using silicone oil tamponade and retinectomy. METHODS: Epiretinal pigment deposits were characterized clinically by wide-field color photography, fundus autofluorescence imaging, and spectral-domain optical coherence tomography (SD OCT). At the time of silicone oil removal, the pigmented membranes were preserved in fixative and analyzed by light microscopy/immunostaining or electron microscopy for histologic characterization. MAIN OUTCOME MEASURES: Not applicable. RESULTS: We describe the development of diffuse preretinal pigmentary deposits in 12 eyes after surgery for complicated PVR detachments using retinectomies with oil, with an average onset of 3.2 months postoperatively. These pigment clumps produced a striking leopard-spot pattern on fundus autofluorescence imaging. Histopathologic and ultrastructural analysis of these epiretinal proliferations peeled at the time of silicone oil removal revealed RPE cells with intracellular silicone oil droplets, singly dispersed membrane-bound melanin granules, glial tissue (1 case), and a fibrous stroma. CONCLUSIONS: Although in vitro studies have suggested that RPE cells can phagocytose emulsified oil droplets, this report represents the first in vivo documentation by electron microscopy of this phenomenon in patients. These findings underscore that direct contact with silicone oil may affect the behavior of the RPE, which may be clinically relevant in patients who have undergone large relaxing retinectomies with silicone oil tamponade for PVR-related retinal detachments.

Mittal SK, Omoto M, Amouzegar A, Sahu A, Rezazadeh A, Katikireddy KR, Shah DI, Sahu SK, Chauhan SK. Restoration of Corneal Transparency by Mesenchymal Stem Cells. Stem Cell Reports 2016;7(4):583-590.Abstract

Transparency of the cornea is indispensable for optimal vision. Ocular trauma is a leading cause of corneal opacity, leading to 25 million cases of blindness annually. Recently, mesenchymal stem cells (MSCs) have gained prominence due to their inflammation-suppressing and tissue repair functions. Here, we investigate the potential of MSCs to restore corneal transparency following ocular injury. Using an in vivo mouse model of ocular injury, we report that MSCs have the capacity to restore corneal transparency by secreting high levels of hepatocyte growth factor (HGF). Interestingly, our data also show that HGF alone can restore corneal transparency, an observation that has translational implications for the development of HGF-based therapy.

Katikireddy KR, Schmedt T, Price MO, Price FW, Jurkunas UV. Existence of Neural Crest-Derived Progenitor Cells in Normal and Fuchs Endothelial Dystrophy Corneal Endothelium. Am J Pathol 2016;186(10):2736-50.Abstract

Human corneal endothelial cells are derived from neural crest and because of postmitotic arrest lack competence to repair cell loss from trauma, aging, and degenerative disorders such as Fuchs endothelial corneal dystrophy (FECD). Herein, we identified a rapidly proliferating subpopulation of cells from the corneal endothelium of adult normal and FECD donors that exhibited features of neural crest-derived progenitor (NCDP) cells by showing absence of senescence with passaging, propensity to form spheres, and increased colony forming efficacy compared with the primary cells. The collective expression of stem cell-related genes SOX2, OCT4, LGR5, TP63 (p63), as well as neural crest marker genes PSIP1 (p75(NTR)), PAX3, SOX9, AP2B1 (AP-2β), and NES, generated a phenotypic footprint of endothelial NCDPs. NCDPs displayed multipotency by differentiating into microtubule-associated protein 2, β-III tubulin, and glial fibrillary acidic protein positive neurons and into p75(NTR)-positive human corneal endothelial cells that exhibited transendothelial resistance of functional endothelium. In conclusion, we found that mitotically incompetent ocular tissue cells contain adult NCDPs that exhibit a profile of transcription factors regulating multipotency and neural crest progenitor characteristics. Identification of normal NCDPs in FECD-affected endothelium holds promise for potential autologous cell therapies.

Gupta M, Jardeleza MSR, Kim I, Durand ML, Kim L, Lobo A-M. Varicella Zoster Virus Necrotizing Retinitis in Two Patients with Idiopathic CD4 Lymphocytopenia. Ocul Immunol Inflamm 2016;24(5):544-8.Abstract

PURPOSE: Progressive outer retinal necrosis (PORN) associated with varicella zoster virus (VZV) is usually diagnosed in HIV positive or immunosuppressed patients. We report two cases of immunocompetent patients with necrotizing viral retinitis found to have idiopathic CD4 lymphocytopenia. METHODS: Clinical presentation, examination, imaging, and laboratory testing of two patients with VZV retinitis are presented. RESULTS: An HIV negative patient with history of herpes zoster presented with rapid loss of vision and examination consistent with PORN. PCR testing confirmed VZV. Lymphocytopenia was noted with a CD4 count of 25/mm(3). A second HIV negative patient presented with blurred vision and lid swelling and was found to have peripheral VZV retinitis confirmed by PCR. Laboratory workup revealed lymphocytopenia with a CD4 count of 133/mm(3). CONCLUSIONS: VZV necrotizing retinitis classic for PORN can occur in HIV negative patients. Idiopathic CD4 lymphocytopenia should be considered healthy patients who develop ocular infections seen in the immunocompromised.

Davoudi S, Ahmadi T, Papavasilieou E, Leskov I, Sobrin L. Phage Immunoprecipitation Sequencing of Autoantigens in Autoimmune Retinopathy. Ocul Immunol Inflamm 2016;:1-8.Abstract

PURPOSE: To identify autoantigens in autoimmune retinopathy patients by phage immunoprecipitation sequencing (PhIP-Seq), a new technique for autoantigen discovery. METHODS: PhIP-Seq was used to sequence putative autoantibodies in plasma from 11 patients with autoimmune retinopathy and eight controls. We compared the autoantibodies' molecular weights with those of proteins detected by Western blot. RESULTS: Several autoantigens were found in cases and not detected in the controls. Autoantigens RTN3, PRPF6, TRPC6, and B3GNT8, four proteins expressed in the retina, were detected in plasma as autoantibodies from one patient each and no controls. Only one patient had an autoantibody, B3GNT8 (43.4 kDa), within a similar weight range as that detected by antiretinal antibody Western blot (42 kDa). Autoantibody POLR3A, which has a well-characterized role in scleroderma, was detected in two cases and no controls. CONCLUSION: PhIP-Seq detected autoantigens that are expressed in the retina as well as scleroderma-related autoantigens in autoimmune retinopathy patients.

Tsikata E, Lee R, Shieh E, Simavli H, Que CJ, Guo R, Khoueir Z, de Boer J, Chen TC. Comprehensive Three-Dimensional Analysis of the Neuroretinal Rim in Glaucoma Using High-Density Spectral-Domain Optical Coherence Tomography Volume Scans. Invest Ophthalmol Vis Sci 2016;57(13):5498-5508.Abstract

Purpose: To describe spectral-domain optical coherence tomography (OCT) methods for quantifying neuroretinal rim tissue in glaucoma and to compare these methods to the traditional retinal nerve fiber layer thickness diagnostic parameter. Methods: Neuroretinal rim parameters derived from three-dimensional (3D) volume scans were compared with the two-dimensional (2D) Spectralis retinal nerve fiber layer (RNFL) thickness scans for diagnostic capability. This study analyzed one eye per patient of 104 glaucoma patients and 58 healthy subjects. The shortest distances between the cup surface and the OCT-based disc margin were automatically calculated to determine the thickness and area of the minimum distance band (MDB) neuroretinal rim parameter. Traditional 150-μm reference surface-based rim parameters (volume, area, and thickness) were also calculated. The diagnostic capabilities of these five parameters were compared with RNFL thickness using the area under the receiver operating characteristic (AUROC) curves. Results: The MDB thickness had significantly higher diagnostic capability than the RNFL thickness in the nasal (0.913 vs. 0.818, P = 0.004) and temporal (0.922 vs. 0.858, P = 0.026) quadrants and the inferonasal (0.950 vs. 0.897, P = 0.011) and superonasal (0.933 vs. 0.868, P = 0.012) sectors. The MDB area and the three neuroretinal rim parameters based on the 150-μm reference surface had diagnostic capabilities similar to RNFL thickness. Conclusions: The 3D MDB thickness had a high diagnostic capability for glaucoma and may be of significant clinical utility. It had higher diagnostic capability than the RNFL thickness in the nasal and temporal quadrants and the inferonasal and superonasal sectors.

Lamont RE, Tan W-H, Innes MA, Parboosingh JS, Schneidman-Duhovny D, Rajkovic A, Pappas J, Altschwager P, DeWard S, Fulton A, Gray KJ, Krall M, Mehta L, Rodan LH, Saller DN, Steele D, Stein D, Yatsenko SA, Bernier FP, Slavotinek AM. Expansion of phenotype and genotypic data in CRB2-related syndrome. Eur J Hum Genet 2016;24(10):1436-44.Abstract

Sequence variants in CRB2 cause a syndrome with greatly elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein levels, cerebral ventriculomegaly and renal findings similar to Finnish congenital nephrosis. All reported patients have been homozygotes or compound heterozygotes for sequence variants in the Crumbs, Drosophila, Homolog of, 2 (CRB2) genes. Variants affecting CRB2 function have also been identified in four families with steroid resistant nephrotic syndrome, but without any other known systemic findings. We ascertained five, previously unreported individuals with biallelic variants in CRB2 that were predicted to affect function. We compiled the clinical features of reported cases and reviewed available literature for cases with features suggestive of CRB2-related syndrome in order to better understand the phenotypic and genotypic manifestations. Phenotypic analyses showed that ventriculomegaly was a common clinical manifestation (9/11 confirmed cases), in contrast to the original reports, in which patients were ascertained due to renal disease. Two children had minor eye findings and one was diagnosed with a B-cell lymphoma. Further genetic analysis identified one family with two affected siblings who were both heterozygous for a variant in NPHS2 predicted to affect function and separate families with sequence variants in NPHS4 and BBS7 in addition to the CRB2 variants. Our report expands the clinical phenotype of CRB2-related syndrome and establishes ventriculomegaly and hydrocephalus as frequent manifestations. We found additional sequence variants in genes involved in kidney development and ciliopathies in patients with CRB2-related syndrome, suggesting that these variants may modify the phenotype.

Besner S, Scarcelli G, Pineda R, Yun S-H. In Vivo Brillouin Analysis of the Aging Crystalline Lens. Invest Ophthalmol Vis Sci 2016;57(13):5093-5100.Abstract

Purpose: To analyze the age dependence of the longitudinal modulus of the crystalline lens in vivo using Brillouin scattering data in healthy subjects. Methods: Brillouin scans were performed along the crystalline lens in 56 eyes from 30 healthy subjects aged from 19 to 63 years. Longitudinal elastic modulus was acquired along the sagittal axis of the lens with a transverse and axial resolution of 4 and 60 μm, respectively. The relative lens stiffness was computed, and correlations with age were analyzed. Results: Brillouin axial profiles revealed nonuniform longitudinal modulus within the lens, increasing from a softer periphery toward a stiffer central plateau at all ages. The longitudinal modulus at the central plateau showed no age dependence in a range of 19 to 45 years and a slight decrease with age from 45 to 63 years. A significant intersubject variability was observed in an age-matched analysis. Importantly, the extent of the central stiff plateau region increased steadily over age from 19 to 63 years. The slope of change in Brillouin modulus in the peripheral regions were nearly age-invariant. Conclusions: The adult human lens showed no measurable age-related increase in the peak longitudinal modulus. The expansion of the stiff central region of the lens is likely to be the major contributing factor to age-related lens stiffening. Brillouin microscopy may be useful in characterizing the crystalline lens for the optimization of surgical or pharmacological treatments aimed at restoring accommodative power.

Wang Z, Liu C-H, Sun Y, Gong Y, Favazza TL, Morss PC, Saba NJ, Fredrick TW, He X, Akula JD, Chen J. Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy. Am J Pathol 2016;186(10):2588-600.Abstract

Familial exudative vitreoretinopathy (FEVR) is characterized by delayed retinal vascular development, which promotes hypoxia-induced pathologic vessels. In severe cases FEVR may lead to retinal detachment and visual impairment. Genetic studies linked FEVR with mutations in Wnt signaling ligand or receptors, including low-density lipoprotein receptor-related protein 5 (LRP5) gene. Here, we investigated ocular pathologies in a Lrp5 knockout (Lrp5(-/-)) mouse model of FEVR and explored whether treatment with a pharmacologic Wnt activator lithium could bypass the genetic defects, thereby protecting against eye pathologies. Lrp5(-/-) mice displayed significantly delayed retinal vascular development, absence of deep layer retinal vessels, leading to increased levels of vascular endothelial growth factor and subsequent pathologic glomeruloid vessels, as well as decreased inner retinal visual function. Lithium treatment in Lrp5(-/-) mice significantly restored the delayed development of retinal vasculature and the intralaminar capillary networks, suppressed formation of pathologic glomeruloid structures, and promoted hyaloid vessel regression. Moreover, lithium treatment partially rescued inner-retinal visual function and increased retinal thickness. These protective effects of lithium were largely mediated through restoration of canonical Wnt signaling in Lrp5(-/-) retina. Lithium treatment also substantially increased vascular tubular formation in LRP5-deficient endothelial cells. These findings suggest that pharmacologic activation of Wnt signaling may help treat ocular pathologies in FEVR and potentially other defective Wnt signaling-related diseases.

Maleki A, Cao JH, Silpa-Archa S, Foster SC. VISUAL OUTCOME AND POOR PROGNOSTIC FACTORS IN ISOLATED IDIOPATHIC RETINAL VASCULITIS. Retina 2016;36(10):1979-85.Abstract

PURPOSE: To describe the clinical course, visual outcome, and prognosis of isolated, idiopathic retinal vasculitis. METHODS: Eighty patients (150 eyes) with isolated, idiopathic retinal vasculitis were included. Demographic data, clinical data, complications at the initial visit and during follow-up, fluorescein angiography, and optical coherence tomography findings were collected from the Massachusetts Eye Research and Surgery Institution (MERSI) database from September 2005 to February 2015. RESULTS: Seventy-five (93.7%) patients required treatment with immunomodulatory therapy. Of those 75 patients, 60 (75%) patients were able to achieve durable remission. Factors which were independently significant predictive of poor visual outcome were lower initial visual acuity (OR: 3.78; 95% CI: 1.75-8.16; P = 0.001), cystoid macular edema (OR: 5.54; 95% CI: 1.81-16.99; P = 0.003), and macular ischemia (OR: 5.12; 95% CI: 1.12-23.04; P = 0.036). CONCLUSION: The majority (67.25%) of our patients enjoyed a good visual outcome (most recent visit best-corrected visual acuity equal to or better than 20/40 and within one line or better from the baseline) with immunomodulatory therapy. We found that cystoid macular edema, macular ischemia, and lower best-corrected visual acuity during the first consultation visit were significant independent risk factors for poor visual outcome.

Baniasadi N, Paschalis EI, Haghzadeh M, Ojha P, Elze T, Mahd M, Chen TC. Patterns of Retinal Nerve Fiber Layer Loss in Different Subtypes of Open Angle Glaucoma Using Spectral Domain Optical Coherence Tomography. J Glaucoma 2016;25(10):865-872.Abstract

PURPOSE OF THE STUDY: The purpose of the study was to determine whether there are different patterns of retinal nerve fiber layer (RNFL) thinning as measured by spectral domain optical coherence tomography (SD-OCT) for 4 subtypes of open angle glaucoma (OAG): primary OAG (POAG), normal tension glaucoma (NTG), pseudoexfoliation glaucoma (PXG), and pigmentary glaucoma (PDG) and to compare them with normal controls. MATERIALS AND METHODS: SD-OCT RNFL thickness values were measured for 4 quadrants and for 4 sectors (ie, superior-nasal, superior-temporal, inferior-nasal, and inferior-temporal). Differences in RNFL thickness values between groups were analyzed using analysis of variance. Paired t tests were used for quadrant comparisons. RESULTS: Two hundred eighty-five participants (102 POAG patients, 33 with NTG, 48 with PXG, 13 with PDG, and 89 normal patients) were included in this study. All 4 subtypes of OAG showed significant RNFL thinning in the superior, inferior, and nasal quadrants as well as the superior-temporal and inferior-temporal sectors (all P-values <0.0001) compared with normals. POAG and NTG patients had greater RNFL thinning inferiorly and inferior-temporally than superiorly (P-values: 0.002 to 0.018 and 0.006, respectively) compared with PXG patients. In contrast, PDG patients had greater RNFL thinning superiorly and superior-nasally than inferiorly compared with other OAG subtypes (ie, POAG, NTG, PXG groups, with P-values: 0.009, 0.003, 0.009, respectively). Of the 4 OAG subtypes, PXG patients exhibited the greatest degree of inter-eye RNFL asymmetry. CONCLUSIONS: This study suggests that SD-OCT may be able to detect significant differences in patterns of RNFL thinning for different subtypes of OAG.

Zareian R, Susilo ME, Paten JA, McLean JP, Hollmann J, Karamichos D, Messer CS, Tambe DT, Saeidi N, Zieske JD, Ruberti JW. Human Corneal Fibroblast Pattern Evolution and Matrix Synthesis on Mechanically Biased Substrates. Tissue Eng Part A 2016;22(19-20):1204-1217.Abstract

In a fibroblast colony model of corneal stromal development, we asked how physiological tension influences the patterning dynamics of fibroblasts and the orientation of deposited extracellular matrix (ECM). Using long-term live-cell microscopy, enabled by an optically accessible mechanobioreactor, a primary human corneal fibroblast colony was cultured on three types of substrates: a mechanically biased, loaded, dense, disorganized collagen substrate (LDDCS), a glass coverslip, and an unloaded, dense, disorganized collagen substrate (UDDCS). On LDDCS, fibroblast orientation and migration along a preferred angle developed early, cell orientation was correlated over long distances, and the colony pattern was stable. On glass, fibroblast orientation was poorly correlated, developed more slowly, and colony patterns were metastable. On UDDCS, cell orientation was correlated over shorter distances compared with LDDCS specimens. On all substrates, the ECM pattern reflected the cell pattern. In summary, mechanically biasing the collagen substrate altered the early migration behavior of individual cells, leading to stable emergent cell patterning, which set the template for newly synthesized ECM.

Moran EP, Wang Z, Chen J, Sapieha P, Smith LEH, Ma J-X. Neurovascular cross talk in diabetic retinopathy: Pathophysiological roles and therapeutic implications. Am J Physiol Heart Circ Physiol 2016;311(3):H738-49.Abstract

Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in developed countries, and its prevalence will increase as the global incidence of diabetes grows exponentially. DR begins with an early nonproliferative stage in which retinal blood vessels and neurons degenerate as a consequence of chronic hyperglycemia, resulting in vasoregression and persistent retinal ischemia, metabolic disequilibrium, and inflammation. This is conducive to overcompensatory pathological neovascularization associated with advanced proliferative DR. Although DR is considered a microvascular complication, the retinal microvasculature is intimately associated with and governed by neurons and glia; neurodegeneration, neuroinflammation, and dysregulation of neurovascular cross talk are responsible in part for vascular abnormalities in both early nonproliferative DR and advanced proliferative DR. Neuronal activity directly regulates microvascular dilation and blood flow in the process of neurovascular coupling. Retinal neurons also secrete guidance cues in response to injury, ischemia, or metabolic stress that may either promote or suppress vascular outgrowth, either alleviating or exacerbating DR, contingent on the stage of disease and retinal microenvironment. Neurodegeneration, impaired neurovascular coupling, and dysregulation of neuronal guidance cues are key events in the pathogenesis of DR, and correcting these events may prevent or delay development of advanced DR. The review discusses the mechanisms of neurovascular cross talk and its dysregulation in DR, and their potential therapeutic implications.

Gipson IK. Goblet cells of the conjunctiva: A review of recent findings. Prog Retin Eye Res 2016;54:49-63.Abstract

Goblet cells within the conjunctival epithelium are specialized cells that secrete mucins onto the surface of the eye. Recent research has demonstrated new characteristics of the cells, including factors influencing their differentiation, their gene products and their functions at the ocular surface. The following review summarizes the newly discovered aspects of the role of Spdef, a member of the Ets transcription factor family in conjunctival goblet cell differentiation, the newly discovered goblet cell products including claudin2, the Wnt inhibitor Frzb, and the transmembrane mucin Muc16. The current concepts of conjunctival goblet cell function, including debris removal and immune surveillance are reviewed, as are changes in the goblet cell population in ocular surface diseases. Major remaining questions regarding conjunctival cell biology are discussed.

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