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Park JH, Tanaka Y, Arango NA, Zhang L, Benedict AL, Roh M, Donahoe PK, Teixeira JM. Induction of WNT inhibitory factor 1 expression by Müllerian inhibiting substance/antiMullerian hormone in the Müllerian duct mesenchyme is linked to Müllerian duct regression. Dev Biol 2014;386(1):227-36.Abstract
A key event during mammalian sexual development is regression of the Müllerian ducts (MDs) in the bipotential urogenital ridges (UGRs) of fetal males, which is caused by the expression of Müllerian inhibiting substance (MIS) in the Sertoli cells of the differentiating testes. The paracrine signaling mechanisms involved in MD regression are not completely understood, particularly since the receptor for MIS, MISR2, is expressed in the mesenchyme surrounding the MD, but regression occurs in both the epithelium and mesenchyme. Microarray analysis comparing MIS signaling competent and Misr2 knockout embryonic UGRs was performed to identify secreted factors that might be important for MIS-mediated regression of the MD. A seven-fold increase in the expression of Wif1, an inhibitor of WNT/β-catenin signaling, was observed in the Misr2-expressing UGRs. Whole mount in situ hybridization of Wif1 revealed a spatial and temporal pattern of expression consistent with Misr2 during the window of MD regression in the mesenchyme surrounding the MD epithelium that was absent in both female UGRs and UGRs knocked out for Misr2. Knockdown of Wif1 expression in male UGRs by Wif1-specific siRNAs beginning on embryonic day 13.5 resulted in MD retention in an organ culture assay, and exposure of female UGRs to added recombinant human MIS induced Wif1 expression in the MD mesenchyme. Knockdown of Wif1 led to increased expression of β-catenin and its downstream targets TCF1/LEF1 in the MD mesenchyme and to decreased apoptosis, resulting in partial to complete retention of the MD. These results strongly suggest that WIF1 secretion by the MD mesenchyme plays a role in MD regression in fetal males.
Karamichos D, Funderburgh ML, Hutcheon AEK, Zieske JD, Du Y, Wu J, Funderburgh JL. A role for topographic cues in the organization of collagenous matrix by corneal fibroblasts and stem cells. PLoS One 2014;9(1):e86260.Abstract
Human corneal fibroblasts (HCF) and corneal stromal stem cells (CSSC) each secrete and organize a thick stroma-like extracellular matrix in response to different substrata, but neither cell type organizes matrix on tissue-culture polystyrene. This study compared cell differentiation and extracellular matrix secreted by these two cell types when they were cultured on identical substrata, polycarbonate Transwell filters. After 4 weeks in culture, both cell types upregulated expression of genes marking differentiated keratocytes (KERA, CHST6, AQP1, B3GNT7). Absolute expression levels of these genes and secretion of keratan sulfate proteoglycans were significantly greater in CSSC than HCF. Both cultures produced extensive extracellular matrix of aligned collagen fibrils types I and V, exhibiting cornea-like lamellar structure. Unlike HCF, CSSC produced little matrix in the presence of serum. Construct thickness and collagen organization was enhanced by TGF-ß3. Scanning electron microscopic examination of the polycarbonate membrane revealed shallow parallel grooves with spacing of 200-300 nm, similar to the topography of aligned nanofiber substratum which we previously showed to induce matrix organization by CSSC. These results demonstrate that both corneal fibroblasts and stromal stem cells respond to a specific pattern of topographical cues by secreting highly organized extracellular matrix typical of corneal stroma. The data also suggest that the potential for matrix secretion and organization may not be directly related to the expression of molecular markers used to identify differentiated keratocytes.
Jakobiec FA, Stacy RC, Mendoza PR, Chodosh J. Hyperplastic corneal pannus: an immunohistochemical analysis and review. Surv Ophthalmol 2014;59(4):448-53.Abstract
An exuberant corneal pannus usually develops in adults with a history of surgery or trauma in the anterior central stroma and appears as a glistening, vascularized, moderately elevated, well circumscribed white nodule. We describe a 78-year-old woman with such a pannus, which in the past has typically been referred to as keloidal or hypertrophic. The involved eye had only light perception, and she underwent a penetrating keratoplasty that improved her vision to 20/100. Histopathologic and immunohistochemical evaluations of a the specimen disclosed a reactive spindle cell stromal proliferation of myofibroblasts that were smooth muscle actin positive with a low Ki67 proliferation index. Desmin, caldesmon, and calponin were negative, in keeping with the incomplete myofilamentary differentiation of a myofibroblast. There was a generous admixture of CD68/163-positive histiocytes and dispersed C3/5-positive T-lymphocytes. An absence of CD138- and IgG4-positive plasma cells ruled out an IgG4-related disease. For a lesion to be keloidal, the collagen must have a thick hyaline character, sharp edges, and a sparsity of intervening cells and vessels. A hypertrophic pannus would be composed of large swollen cells not necessarily increased in number. We therefore recommend adoption of the term hyperplastic for lesions like that described here because of the obvious increase in cellularity from proliferating myofibroblasts and the lack of true keloidal collagen.
Huang R, Baranov P, Lai K, Zhang X, Ge J, Young MJ. Functional and morphological analysis of the subretinal injection of human retinal progenitor cells under Cyclosporin A treatment. Mol Vis 2014;20:1271-80.Abstract
PURPOSE: The purpose of this study is to evaluate the functional and morphological changes in subretinal xenografts of human retinal progenitor cells (hRPCs) in B6 mice treated with Cyclosporin A (CsA; 210 mg/l in drinking water). METHODS: The hRPCs from human fetal eyes were isolated and expanded for transplantation. These cells, with green fluorescent protein (GFP) at 11 passages, were transplanted into the subretinal space in B6 mice. A combination of invasive and noninvasive approaches was used to analyze the structural and functional consequences of the subretinal injection of the hRPCs. The process of change was monitored using spectral domain optical coherence tomography (SDOCT), histology, and electroretinography (ERG) at 3 days, 1 week, and 3 weeks after transplantation. Cell counts were used to evaluate the survival rate with a confocal microscope. ERGs were performed to evaluate the physiologic changes, and the structural changes were evaluated using SDOCT and histological examination. RESULTS: The results of the histological examination showed that the hRPCs gained a better survival rate in the mice treated with CsA. The SDOCT showed that the bleb size of the retinal detachment was significantly decreased, and the retinal reattachment was nearly complete by 3 weeks. The ERG response amplitudes in the CsA group were less decreased after the injection, when compared with the control group, in the dark-adapted and light-adapted conditions. However, the cone-mediated function in both groups was less affected by the transplantation after 3 weeks than the rod-mediated function. CONCLUSIONS: Although significant functional and structural recovery was observed after the subretinal injection of the hRPCs, the effectiveness of CsA in xenotransplantation may be a novel and potential approach for increasing retinal progenitor cell survival.
Heidary G, Calderwood L, Cox GF, Robson CD, Teot LA, Mullon J, Anselm I. Optic atrophy and a Leigh-like syndrome due to mutations in the c12orf65 gene: report of a novel mutation and review of the literature. J Neuroophthalmol 2014;34(1):39-43.Abstract
Combined oxidative phosphorylation deficiency type 7 (COXPD7) is a rare disorder of mitochondrial metabolism that results in optic atrophy and Leigh syndrome-like disease. We describe 2 siblings with compound heterozygous mutations in the recently identified C12orf65 gene who presented with optic atrophy and mild developmental delays and subsequently developed bilateral, symmetric lesions in the brainstem reminiscent of Leigh syndrome. Repeat neuroimaging demonstrated reversibility of the findings in 1 sibling and persistent metabolic stroke in the other. This article highlights the phenotypic manifestations from a novel mutation in the C12orf65 gene and reviews the clinical presentation of the 5 other individuals reported to date who carry mutations in this gene.
Grob S, Yonekawa Y, Eliott D. Multimodal imaging of adult-onset foveomacular vitelliform dystrophy. Saudi J Ophthalmol 2014;28(2):104-10.Abstract
Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a clinically heterogeneous maculopathy that may mimic other conditions and be difficult to diagnose. It is characterized by late onset, slow progression and high variability in morphologic and functional alterations. Diagnostic evaluation should include careful ophthalmoscopy and imaging studies. The typical ophthalmoscopic findings are bilateral, asymmetric, foveal or perifoveal, yellow, solitary, round to oval elevated subretinal lesions, often with central pigmentation. The lesions characteristically demonstrate increased autofluorescence and hypofluorescent lesions surrounded by irregular annular hyperfluorescence on fluorescein angiography. Optical coherence tomography studies demonstrate homogenous or heterogeneous hyperreflective material between the retinal pigment epithelium and the neurosensory retina. The visual prognosis is generally favorable, but visual loss can occur from chorioretinal atrophy and choroidal neovascularization.
Kruger JM, Yonekawa Y, Skidd P, Cestari DM. Ocular flutter as the presenting sign of lung adenocarcinoma. Digit J Ophthalmol 2014;20(1):4-6.Abstract
Ocular flutter is a rare ophthalmic finding that could represent paraneoplastic phenomena. In adults it is most commonly associated with small cell lung cancer (SCLC). Most patients also present with other neurological defects. We report the case of a 75-year-old woman who presented with isolated ocular flutter. The ensuing workup was significant for an early lung adenocarcinoma that would not have been biopsied otherwise due to its small size. To our knowledge, this is the first reported case of isolated ocular flutter as the presenting symptom of non-SCLC.
Kang JH, Wiggs JL, Pasquale LR. Relation between time spent outdoors and exfoliation glaucoma or exfoliation glaucoma suspect. Am J Ophthalmol 2014;158(3):605-14.e1.Abstract
PURPOSE: To evaluate the relation between time spent outdoors at various life periods and risk of exfoliation glaucoma or exfoliation glaucoma suspect. DESIGN: Retrospective cohort study in the United States. METHODS: Participants (49 033 women in the Nurses Health Study and 20 066 men in the Health Professionals Follow-up Study) were 60+ years old, were free of glaucoma and cataract, reported eye examinations, and completed questions about time spent outdoors in direct sunlight at midday at 3 life periods: high school to age 24 years, age 25-35 years, and age 36-59 years (asked in 2006 in women and 2008 in men). Participants were followed biennially with mailed questionnaires from 1980 women/1986 men to 2010. Incident cases (223 women and 38 men) were confirmed with medical records. Cohort-specific multivariable-adjusted rate ratios from Cox proportional hazards models were estimated and pooled with meta-analysis. RESULTS: Although no association was observed with greater time spent outdoors in the ages of 25-35 or ages 36-59 years, the pooled multivariable-adjusted rate ratios for ≥11 hours per week spent outdoors in high school to age 24 years compared with ≤5 hours per week was 2.00 (95% confidence interval = 1.30, 3.08; P for linear trend = .001). In women, this association was stronger in those who resided in the southern geographic tier in young adulthood (P for interaction = .07). CONCLUSIONS: Greater time spent outdoors in young adulthood was associated with risk of exfoliation glaucoma or exfoliation glaucoma suspect, supporting an etiologic role of early exposures to climatic factors.
Jackson ML, Bex PJ, Ellison JM, Wicks P, Wallis J. Feasibility of a web-based survey of hallucinations and assessment of visual function in patients with Parkinson's disease. Interact J Med Res 2014;3(1):e1.Abstract
BACKGROUND: Patients with Parkinson's disease (PD) experience visual hallucinations, which may be related to decreased contrast sensitivity (ie, the ability to discern shades of grey). OBJECTIVE: The objective of this study was to investigate if an online research platform can be used to survey patients with Parkinson's disease regarding visual hallucinations, and also be used to assess visual contrast perception. METHODS: From the online patient community, PatientsLikeMe, 964 members were invited via email to participate in this study. Participants completed a modified version of the University of Miami Parkinson's disease hallucinations questionnaire and an online vision test. RESULTS: The study was completed by 27.9% (269/964) of those who were invited: 56.9% of this group had PD (153/269) and 43.1% (116/269) were non-Parkinson's controls. Hallucinations were reported by 18.3% (28/153) of the Parkinson's group. Although 10 subjects (9%) in the control group reported experiencing hallucinations, only 2 of them actually described formed hallucinations. Participants with Parkinson's disease with a mean of 1.75 (SD 0.35) and the control group with a mean of 1.85 (SD 0.36) showed relatively good contrast perception as measured with the online letter test (P=.07). People who reported hallucinations showed contrast sensitivity levels that did not differ from levels shown by people without hallucinations (P=.96), although there was a trend towards lower contrast sensitivity in hallucinators. CONCLUSIONS: Although more Parkinson's responders reported visual hallucinations, a significant number of non-Parkinson's control group responders also reported visual hallucinations. The online survey method may have failed to distinguish between formed hallucinations, which are typical in Parkinson's disease, and non-formed hallucinations that have less diagnostic specificity. Multiple questions outlining the nature of the hallucinations are required. In a clinical interview, the specific nature of the hallucination would be further refined to rule out a vague description that does not indicate a true, formed visual hallucination. Contrary to previous literature, both groups showed relatively good contrast sensitivity, perhaps representing a ceiling effect or limitations of online testing conditions that are difficult to standardize. Steps can be taken in future trials to further standardize online visual function testing, to refine control group parameters and to take steps to rule out confounding variables such as comorbid disease that could be associated with hallucinations. Contacting subjects via an online health social network is a novel, cost-effective method of conducting vision research that allows large numbers of individuals to be contacted quickly, and refinement of questionnaires and visual function testing may allow more robust findings in future research.
Hou Y, Lin H, Zhu L, Liu Z, Hu F, Shi J, Yang T, Shi X, Guo H, Tan X, Zhang L, Wang Q, Li Z, Zhao Y. The inhibitory effect of IFN-γ on protease HTRA1 expression in rheumatoid arthritis. J Immunol 2014;193(1):130-8.Abstract
The high temperature requirement A1 (HTRA1) is a potent protease involved in many diseases, including rheumatoid arthritis (RA). However, the regulatory mechanisms that control HTRA1 expression need to be determined. In this study, we demonstrated that IFN-γ significantly inhibited the basal and LPS-induced HTRA1 expression in fibroblasts and macrophages, which are two major cells for HTRA1 production in RA. Importantly, the inhibitory effect of IFN-γ on HTRA1 expression was evidenced in collagen-induced arthritis (CIA) mouse models and in human RA synovial cells. In parallel with the enhanced CIA incidence and pathological changes in IFN-γ-deficient mice, HTRA1 expression in the joint tissues was also increased as determined by real-time PCR and Western blots. IFN-γ deficiency increased the incidence of CIA and the pathological severity in mice. Neutralization of HTRA1 by Ab significantly reversed the enhanced CIA frequency and severity in IFN-γ-deficient mice. Mechanistically, IFN-γ negatively controls HTRA1 expression through activation of p38 MAPK/STAT1 pathway. Dual luciferase reporter assay and chromatin immunoprecipitation analysis showed that STAT1 could directly bind to HTRA1 promoter after IFN-γ stimulation. This study offers new insights into the molecular regulation of HTRA1 expression and its role in RA pathogenesis, which may have significant impact on clinical therapy for RA and possibly other HTRA1-related diseases, including osteoarthritis, age-related macular degeneration, and cancer.
Gupta M, Leskov I, Kruger JM, Cestari DM. Intermittent Horner syndrome in a pediatric patient. J Neuroophthalmol 2014;34(2):149-50.Abstract
Intermittent Horner syndrome is uncommon in both the adult and pediatric population. We describe a case of a pediatric patient with an intermittent Horner syndrome. Infrared photography and videography were used to help establish the diagnosis.
Gilbert AL, Jakobiec FA, Chodosh J, Eliott D. A comparison of retrokeratoprosthetic membrane and conjunctival inflammatory responses to silicone oil. J Ophthalmic Inflamm Infect 2014;4:15.Abstract
Silicone oil continues to be an important aid in retinal detachment surgery. We report a case in which disparate responses to silicone oil were noted in the conjunctiva and intraocularly. Intraocularly, the oil permeated a fibrous membrane that formed behind a keratoprosthesis, the first example of this phenomenon. We detail the histological response to the oil at this site as well as a distinctly different reaction present to oil in the conjunctiva of the same eye. The divergence of histological responses provides a demonstration of the eye's apparent retained capacity to protect against intraocular inflammation, despite multiple previous surgeries.
Karamichos D, Hutcheon AEK, Rich CB, Trinkaus-Randall V, Asara JM, Zieske JD. In vitro model suggests oxidative stress involved in keratoconus disease. Sci Rep 2014;4:4608.Abstract
Keratoconus (KC) affects 1:2000 people and is a disorder where cornea thins and assumes a conical shape. Advanced KC requires surgery to maintain vision. The role of oxidative stress in KC remains unclear. We aimed to identify oxidative stress levels between human corneal keratocytes (HCKs), fibroblasts (HCFs) and keratoconus cells (HKCs). Cells were cultured in 2D and 3D systems. Vitamin C (VitC) and TGF-β3 (T3) were used for 4 weeks to stimulate self-assembled extracellular matrix (ECM). No T3 used as controls. Samples were analyzed using qRT-PCR and metabolomics. qRT-PCR data showed low levels of collagen I and V, as well as keratocan for HKCs, indicating differentiation to a myofibroblast phenotype. Collagen type III, a marker for fibrosis, was up regulated in HKCs. We robustly detected more than 150 metabolites of the targeted 250 by LC-MS/MS per condition and among those metabolites several were related to oxidative stress. Lactate levels, lactate/malate and lactate/pyruvate ratios were elevated in HKCs, while arginine and glutathione/oxidized glutathione ratio were reduced. Similar patterns found in both 2D and 3D. Our data shows that fibroblasts exhibit enhanced oxidative stress compared to keratocytes. Furthermore the HKC cells exhibit the greatest level suggesting they may have a myofibroblast phenotype.
Jakobiec FA, Werdich XQ, Chodosh J, Freitag SK. An analysis of conjunctival and periocular venous malformations: clinicopathologic and immunohistochemical features with a comparison of racemose and cirsoid lesions. Surv Ophthalmol 2014;59(2):236-44.Abstract
Vascular tumors (in contrast to dilations or ectasias) of the conjunctiva and other adnexal tissues are rare, with no previous convincing example of a congenital, purely venous conjunctival malformation having been described. A 33-year-old man with a previously well-tolerated racemose conjunctival lesion present from birth developed bothersome symptoms when it underwent multifocal thrombosis with papillary endothelial cell hyperplasia as part of the process of thrombotic organization. Conservative subtotal excision with placement of an amniotic graft led to an acceptable cosmetic appearance, abatement of symptoms, and retention of full ocular function. Histopathologically, the lesion was composed of patulous vascular channels with thin walls displaying a negligible and irregular muscularis, diffuse supportive mural fibrosis, and the absence of an elastic lamina. Immunohistochemically the endothelial cells were CD31- and CD34-positive (vascular origin) but D2-40-negative (lymphatic origin). An associated neovascular capillary bed was not detected. Venous (racemose or grape-like) malformations should be distinguished from: arteriovenous (cirsoid or twisted) malformations in which the vessels possess thicker and more uniform muscular walls, some of which are endowed with an elastica; varices (hemorrhoidal dilations typically of a pre-existent vein); and venous angiomas (noncongenital lesions acquired in middle life) composed of regularly structured muscular channels devoid of an elastic lamina. Other conditions not to be confused with congenital venous malformations include hemorrhagic lymphangiectasia (of Leber), hemorrhagic lymphangiomas, and complex lymphaticovenous malformations.

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