Panigrahy D, Adini I, Mamluk R, Levonyak N, Bruns CJ, D'Amore PA, Klagsbrun M, Bielenberg DR. Regulation of soluble neuropilin 1, an endogenous angiogenesis inhibitor, in liver development and regeneration. Pathology 2014;46(5):416-23.Abstract

Neuropilin-1 (NRP1) is a receptor for vascular endothelial growth factor (VEGF). A soluble isoform of Nrp1 (sNrp1) has not been described in the mouse. Our goal was to examine the expression of mouse sNrp1 during liver development and regeneration.sNrp1 was cloned from mouse liver. The expression of sNrp1 and VEGF was examined in mouse liver during post-natal development and regeneration using northern blot, western blot, in situ hybridisation, and immunohistochemical analyses. HGF/NRP1 binding was examined in vitro.A novel 588-amino acid sNrp1 isoform was found to contain the ligand binding regions of Nrp1. The adult liver expressed more sNrp1 than full-length Nrp1. In vivo, hepatocytes constitutively expressed VEGF and sNrp1 in the quiescent state. sNrp1 was highly up-regulated at P20, a time point coinciding with a plateau in liver and body weights. Following hepatectomy, endogenous levels of sNrp1 decreased during the rapid growth phase, and VEGF levels were highest just prior to and during the angiogenic phase. sNrp1 levels again rose 5-10 days post-hepatectomy, presumably to control regeneration. HGF protein bound NRP1 and binding was competed with sNRP1.We cloned a novel mouse sNrp1 isoform from liver and provide evidence that this endogenous angiogenesis inhibitor may regulate VEGF or HGF bioavailability during normal physiological growth and development as well as during liver regeneration.

Papakostas TD, Jakobiec FA, Mantagos J, Rashid A, Fay A, Vavvas DG. Idiopathic dacryoadenitis mimicking a primary intraocular tumour in a young girl. Clin Experiment Ophthalmol 2014;42(8):785-8.
Papakostas TD, Kohanim S, Skondra D, Lo K, Chodosh J. Medical management of Alternaria keratitis with endophthalmitis in a patient with a corneal graft. Clin Exp Ophthalmol 2014;42(5):496-7.
Paramasivam S, Fay A, Fifi J, Berenstein A. O-015 image guided bleomycin sclerotherapy for orbital lymphatic malformation. J Neurointerv Surg 2014;6 Suppl 1:A8-9.Abstract

INTRODUCTION: Orbital lymphatic malformations (OLMs) are a unique subset of head and neck low flow vascular malformations, located either in the periorbital region or in the closed orbital cavity. We discuss our experience of minimally invasive strategies of treatment using advanced imaging and Bleomycin sclerotherapy to effectively treat these malformations. MATERIALS AND METHODS: Between 2008 and 2013, we have treated 54 cases of orbital low flow vascular malformations including 22 cases of OLMs of which 16 were treated using Bleomycin. This retrospective analysis was performed from patient charts, operative reports, operative images, pre-operative, and post-operative MR imaging. Bleomycin was used for sclerotherapy in all the cases with a maximum dose per session of treatment limited to 15 mgs. DIRECT PUNCTURE SCLEROTHERAPY TECHNIQUE: OLMs target was determined using pre-procedure MR imaging and direct puncture either per-cutaneous or per-conjunctival was achieved using ultrasound or i-guide guidance. In most lymphatic fluid was drained else the position confirmed with constrast injection under fluoroscopy. Bleomycin was used either undiluted or in various concentrations mixed with saline, or contrast material and recently we favor the use of Bleofoam mixed with 25% Human albumin and air. Microcystic LMs, were treated using gravity technique, the needle track was sealed with Surgiflo or Floseal. In cases of intra cystic or intra ocular haemorrhage with elevated orbital pressure, lateral canthotomy was performed to prevent permanent damage to vision and the contents of the orbit. Postoperatively, the patients recover in ICU and monitored for vision and orbital swelling. Bleomycin skin precautions were followed for 72 h in order to avoid skin hyperpigmentation. Optimal results were obtained at 6 to 8 weeks and assessed using follow-up MRI and ophthalmologic evaluation. RESULTS: The patient's age ranged from 1 to 45 years, with equal male to female ratio. Most cases (13/16) (80%) presented non acutely while three patients (20%) presented acutely with proptosis, visual disturbance and double vision due to haemorrhage within the malformation. Treatment completed in 14, one lost to follow up and the other is yet to be followed. The follow up period ranged from 6weeks to 6 months. 65% (9/14) needed less than three procedures while the remaining five patients needed between 3-5 procedures. All patients had improvement in proptosis; vision either remained stable or improved; volume reduction of more than 80% was noted in 57% (8/14), while the remaining patients 43% had volume reduction of 50-79%. One patient had transient mydriasis post procedure that completely recovered at three months. Another developed haemorrhage within the malformation immediate post sclerotherapy requiring lateral canthotomy, drainage and redo sclerotherapy. None of our patients developed skin pigmentation or pulmonary complication related to bleomycin usage. CONCLUSION: Bleomycin sclerotherapy combined with appropriate image guidance for precise target localization is an effective and safe treatment for OLMs. Bleomycin is a preferred sclerosant as it induces minimal inflammation and post procedure swelling. Standard precautions must be instituted to prevent cutaneous pigmentation and pulmonary fibrosis. DISCLOSURES: S. Paramasivam: None. A. Fay: None. J. Fifi: None. A. Berenstein: None.

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.
Paschalis EI, Eliott D, Vavvas DG. Removal of Silicone Oil From Intraocular Lens Using Novel Surgical Materials. Transl Vis Sci Technol 2014;3(5):4.Abstract

PURPOSE: To design, fabricate, and evaluate novel materials to remove silicone oil (SiO) droplets from intraocular lenses (IOL) during vitreoretinal surgery. METHODS: Three different designs were fabricated using soft lithography of polydimethylsiloxane (PDMS), three-dimensional (3D) inverse PDMS fabrication using water dissolvable particles, and atomic layer deposition (ALD) of alumina (Al2O3) on surgical cellulose fibers. Laboratory tests included static and dynamic contact angle (CA) measurements with water and SiO, nondestructive x-ray microcomputer tomography (micro-CT), and microscopy. SiO removal was performed in vitro and ex vivo using implantable IOLs and explanted porcine eyes. RESULTS: All designs exhibited enhanced hydrophobicity and oleophilicity. Static CA measurements with water ranged from 131° to 160° and with SiO CA approximately 0° in 120 seconds following exposure. Nondestructive x-ray analysis of the 3D PDMS showed presence of interconnected polydispersed porosity of 100 to 300 μm in diameter. SiO removal from IOLs was achieved in vitro and ex vivo using standard 20-G vitrectomy instrumentation. CONCLUSION: Removal of SiO from IOLs can be achieved using materials with lower surface energy than that of the IOLs. This can be achieved using appropriate surface chemistry and surface topography. Three designs, with enhanced hydrophobic properties, were fabricated and tested in vitro and ex vivo. All materials remove SiO within an aqueous environment. Preliminary ex vivo results were very promising, opening new possibilities for SiO removal in vitreoretinal surgeries. TRANSLATIONAL RELEVANCE: This is the first report of an instrument that can lead to successful removal of SiO from the surface of IOL. In addition to the use of this instrument/material in medicine it can also be used in the industry, for example, retrieval of oil spills from bodies of water.

Pasquale LR, Jiwani AZ, Zehavi-Dorin T, Majd A, Rhee DJ, Chen T, Turalba A, Shen L, Brauner S, Grosskreutz C, Gardiner M, Chen S, Borboli-Gerogiannis S, Greenstein SH, Chang K, Ritch R, Loomis S, Kang JH, Wiggs JL, Levkovitch-Verbin H. Solar exposure and residential geographic history in relation to exfoliation syndrome in the United States and Israel. JAMA Ophthalmol 2014;132(12):1439-45.Abstract
IMPORTANCE: Residential (geographic) history and extent of solar exposure may be important risk factors for exfoliation syndrome (XFS) but, to our knowledge, detailed lifetime solar exposure has not been previously evaluated in XFS. OBJECTIVE: To assess the relation between residential history, solar exposure, and XFS. DESIGN, SETTING, AND PARTICIPANTS: This clinic-based case-control study was conducted in the United States and Israel. It involved XFS cases and control individuals (all ≥60-year-old white individuals) enrolled from 2010 to 2012 (United States: 118 cases and 106 control participants; Israel: 67 cases and 72 control participants). MAIN OUTCOMES AND MEASURES: Weighted lifetime average latitude of residence and average number of hours per week spent outdoors as determined by validated questionnaires. RESULTS: In multivariable analyses, each degree of weighted lifetime average residential latitude away from the equator was associated with 11% increased odds of XFS (pooled odds ratio [OR], 1.11; 95% CI, 1.05-1.17; P < .001). Furthermore, every hour per week spent outdoors during the summer, averaged over a lifetime, was associated with 4% increased odds of XFS (pooled OR, 1.04; 95% CI, 1.00-1.07; P = .03). For every 1% of average lifetime summer time between 10 am and 4 pm that sunglasses were worn, the odds of XFS decreased by 2% (OR, 0.98; 95% CI, 0.97-0.99; P < .001) in the United States but not in Israel (OR, 1.00; 95% CI, 0.99-1.01; P = .92; P for heterogeneity = .005). In the United States, after controlling for important environmental covariates, history of work over water or snow was associated with increased odds of XFS (OR, 3.86; 95% CI, 1.36-10.9); in Israel, there were too few people with such history for analysis. We did not identify an association between brimmed hat wear and XFS (P > .57). CONCLUSIONS AND RELEVANCE: Lifetime outdoor activities may contribute to XFS. The association with work over snow or water and the lack of association with brimmed hat wear suggests that ocular exposure to light from reflective surfaces may be an important type of exposure in XFS etiology.
Pasquale LR, Kang JH, Wiggs JL. Prospects for gene-environment interactions in exfoliation syndrome. J Glaucoma 2014;:S64-7.Abstract

Complex traits can be triggered by environmental factors in genetically predisposed individuals. The lysyl oxidase-like 1 gene (LOXL1) variants associated with exfoliation syndrome (XFS) are detected in >90% of cases that have been genotyped from sites around the world. Remarkably, roughly 80% of people without XFS also possess these same variants in all populations that have been tested. Nonetheless, the prevalence of XFS varies from ≤0.4% to >20%. These data suggest that other genetic variants, epigenetic modifications, or environmental factors also contribute to XFS. Furthermore, it is possible that environmental factors modify the association between LOXL1 and XFS. Interactions between LOXL1 variants and environmental factors could explain the varying prevalence of XFS seen throughout the world. At the very least, the discovery of the association between LOXL1 variants and XFS has opened the door to the discovery of environmental risk factors for this condition. Candidate gene-environment interactions in XFS will be discussed.

Patel M, Vavvas DG. Spontaneous resolution of a postvitrectomy macular hole retinal detachment. Retin Cases Brief Rep 2014;8(3):161-3.Abstract

PURPOSE: The purpose of this report was to describe a case of spontaneous resolution of a large postvitrectomy macular hole retinal detachment. METHODS: Case report and optical coherence tomography imaging. RESULTS: A 64-year-old man with history of macula-off retinal detachment and 4 previous vitrectomies in the left eye developed a macular hole and associated retinal detachment 3 months after his last vitreoretinal surgery. Two months later, examination revealed that the macular hole had spontaneously closed, and the retinal detachment had resolved. CONCLUSION: Spontaneous resolution of macular hole-associated retinal detachment in a previously vitrectomized eye has not been reported previously. Changes in tangential traction by the associated epiretinal membrane, improvement of the cystoid changes noted at the edge of the macular hole, and/or proliferation of glial tissue to bridge the hole, along with the absorption of the subretinal fluid by the retinal pigment epithelium pump contributed to this rare event have been hyphothesized.

Peacock ZS, Boulos T, Miller JB, Gardiner MF, Chuang S-K, Troulis MJ. Orbital fractures and ocular injury: is a postoperative ophthalmology examination necessary?. J Oral Maxillofac Surg 2014;72(8):1533-40.Abstract
PURPOSE: To determine whether formal ophthalmology evaluation is necessary after operative repair of orbital fractures and the association of an ocular injury to the severity of facial injury. PATIENTS AND METHODS: This was a retrospective cohort study of patients with orbital fractures undergoing operative repair from 2005 to 2013. Subjects were included if they had undergone reconstruction of orbital floor fractures and had data from pre- and postoperative examinations by the oral and maxillofacial surgery and ophthalmology services available. The predictor variables included the service performing the ocular examination (oral and maxillofacial surgery or ophthalmology) and the number of fractures present. The outcome variables were the presence of pre- and postoperative ocular injuries. Logistic regression models were used to determine the relationship of the fracture number to ocular injury. RESULTS: A total of 28 subjects had undergone repair of orbital fractures with preoperative and postoperative examinations performed by both services. Preoperative ocular injuries were found in 17 of the 28 subjects. Those detected by oral and maxillofacial surgeons were limited to changes in visual acuity, pupillary response, and extraocular muscle dysfunction in 11 subjects. Two subjects had new postoperative ocular findings that were considered minor and did not alter management. An increasing number of facial fractures was associated with an increased risk of ocular trauma. Those with 3 or more fractures had an odds ratio of 14.625 (95% confidence interval, 2.191 to 97.612, P = .006) for the presence of ocular injury. CONCLUSIONS: Operative repair of orbital fractures did not lead to new ocular injuries that would change the management. Thus, those without preoperative ocular injuries will not require a formal postoperative ophthalmology examination. However, the subjects with more fractures had an increased likelihood of ocular injuries.
Pemp B, Deák G, Prager S, Mitsch C, Lammer J, Schmidinger G, Scholda C, Schmidt-Erfurth U, Bolz M, Bolz M. Distribution of intraretinal exudates in diabetic macular edema during anti-vascular endothelial growth factor therapy observed by spectral domain optical coherence tomography and fundus photography. Retina 2014;34(12):2407-15.Abstract
PURPOSE: To evaluate changes in the distribution and morphology of intraretinal microexudates and hard exudates (HEs) during intravitreal anti-vascular endothelial growth factor therapy in patients with persistent diabetic macular edema. METHODS: Twenty-four patients with persistent diabetic macular edema after photocoagulation were investigated in this prospective cohort study. Each eye was assigned to a loading dose of three anti-vascular endothelial growth factor treatments at monthly intervals. Additional single treatments were performed if diabetic macular edema persisted or recurred. Intraretinal exudates were analyzed over 6 months using spectral domain optical coherence tomography (SD-OCT) and fundus photography. RESULTS: Before treatment, microexudates were detected by SD-OCT as hyperreflective foci in 24 eyes, whereas HEs were seen in 22 eyes. During therapy, HE increased significantly in number and size. This was accompanied by accumulation of microexudates in the outer retina. Enlargement of hyperreflective structures in SD-OCT was accompanied by enlargement of HE at corresponding fundus locations. A rapid reduction in diabetic macular edema was seen in all patients, but to varying degrees. Patients with hemoglobin A1c levels <7% and serum cholesterol <200 mg/dL formed fewer HEs and featured more edema reduction and visual acuity gain. CONCLUSION: Diabetic macular edema reduction during intravitreal anti-vascular endothelial growth factor therapy was accompanied by dynamic rearrangement of intraretinal exudates at corresponding locations in fundus photography and SD-OCT. Intraretinal aggregates of microexudates detectable as hyperreflective foci by SD-OCT may compose and precede HE before they become clinically visible.
Pennock S, Haddock LJ, Mukai S, Kazlauskas A. Vascular Endothelial Growth Factor Acts Primarily via Platelet-Derived Growth Factor Receptor α to Promote Proliferative Vitreoretinopathy. Am J Pathol 2014;Abstract

Proliferative vitreoretinopathy (PVR) is a nonneovascular blinding disease and the leading cause for failure in surgical repair of rhegmatogenous retinal detachments. Once formed, PVR is difficult to treat. Hence, there is an acute interest in developing approaches to prevent PVR. Of the many growth factors and cytokines that accumulate in vitreous as PVR develops, neutralizing vascular endothelial growth factor (VEGF) A has recently been found to prevent PVR in at least one animal model. The goal of this study was to test if Food and Drug Administration-approved agents could protect the eye from PVR in multiple animal models and to further investigate the underlying mechanisms. Neutralizing VEGF with aflibercept (VEGF Trap-Eye) safely and effectively protected rabbits from PVR in multiple models of disease. Furthermore, aflibercept reduced the bioactivity of both experimental and clinical PVR vitreous. Finally, although VEGF could promote some PVR-associated cellular responses via VEGF receptors expressed on the retinal pigment epithelial cells that drive this disease, VEGF's major contribution to vitreal bioactivity occurred via platelet-derived growth factor receptor α. Thus, VEGF promotes PVR by a noncanonical ability to engage platelet-derived growth factor receptor α. These findings indicate that VEGF contributes to nonangiogenic diseases and that anti-VEGF-based therapies may be effective on a wider spectrum of diseases than previously appreciated.

Prabakaran S, Hemberg M, Chauhan R, Winter D, Tweedie-Cullen RY, Dittrich C, Hong E, Gunawardena J, Steen H, Kreiman G, Steen JA. Quantitative profiling of peptides from RNAs classified as noncoding. Nat Commun 2014;5:5429.Abstract

Only a small fraction of the mammalian genome codes for messenger RNAs destined to be translated into proteins, and it is generally assumed that a large portion of transcribed sequences--including introns and several classes of noncoding RNAs (ncRNAs)--do not give rise to peptide products. A systematic examination of translation and physiological regulation of ncRNAs has not been conducted. Here we use computational methods to identify the products of non-canonical translation in mouse neurons by analysing unannotated transcripts in combination with proteomic data. This study supports the existence of non-canonical translation products from both intragenic and extragenic genomic regions, including peptides derived from antisense transcripts and introns. Moreover, the studied novel translation products exhibit temporal regulation similar to that of proteins known to be involved in neuronal activity processes. These observations highlight a potentially large and complex set of biologically regulated translational events from transcripts formerly thought to lack coding potential.

Qi Q, Kilpeläinen TO, Downer MK, Tanaka T, Smith CE, Sluijs I, Sonestedt E, Chu AY, Renström F, Lin X, Angquist LH, Huang J, Liu Z, Li Y, Asif Ali M, Xu M, Ahluwalia TS, Boer JMA, Chen P, Daimon M, Eriksson J, Perola M, Friedlander Y, Gao Y-T, Heppe DHM, Holloway JW, Houston DK, Kanoni S, Kim Y-M, Laaksonen MA, Jääskeläinen T, Lee NR, Lehtimäki T, Lemaitre RN, Lu W, Luben RN, Manichaikul A, Männistö S, Marques-Vidal P, Monda KL, Ngwa JS, Perusse L, van Rooij FJA, Xiang Y-B, Wen W, Wojczynski MK, Zhu J, Borecki IB, Bouchard C, Cai Q, Cooper C, Dedoussis GV, Deloukas P, Ferrucci L, Forouhi NG, Hansen T, Christiansen L, Hofman A, Johansson I, Jørgensen T, Karasawa S, Khaw K-T, Kim M-K, Kristiansson K, Li H, Lin X, Liu Y, Lohman KK, Long J, Mikkilä V, Mozaffarian D, North K, Pedersen O, Raitakari O, Rissanen H, Tuomilehto J, van der Schouw YT, Uitterlinden AG, Zillikens CM, Franco OH, Shyong Tai E, Ou Shu X, Siscovick DS, Toft U, Verschuren MWM, Vollenweider P, Wareham NJ, Witteman JCM, Zheng W, Ridker PM, Kang JH, Liang L, Jensen MK, Curhan GC, Pasquale LR, Hunter DJ, Mohlke KL, Uusitupa M, Cupples AL, Rankinen T, Orho-Melander M, Wang T, Chasman DI, Franks PW, Sørensen TIA, Hu FB, Loos RJF, Nettleton JA, Qi L. FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals. Hum Mol Genet 2014;23(25):6961-72.Abstract

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

Radcliffe NM, Smith SD, Syed ZA, Park SC, Ehrlich JR, De Moraes CG, Liebmann JM, Ritch R. Retinal blood vessel positional shifts and glaucoma progression. Ophthalmology 2014;121(4):842-8.Abstract
PURPOSE: To determine the characteristics and significance of retinal blood vessel (RBV) positional shifts over time in a cohort of patients with progressive glaucoma. DESIGN: Retrospective cohort study. PARTICIPANTS: Baseline and serial stereophotographs from 1 eye of 125 patients with open-angle glaucoma with ≥8 reliable Swedish interactive threshold algorithm standard visual fields (VFs) were included. On the basis of global rates of threshold sensitivity change, patients with glaucoma were divided into groups of minimal (<-0.02 decibels [dB]/year), moderate (-0.02 to -0.65 dB/year), or fast (≥-0.65 dB/year) progression. To determine whether graders' assessments of RBV positional shifts were false-positives, a control group consisting of 33 patients with glaucoma with 2 sets of photographs taken on the same day was included. METHODS: Masked graders reviewed serial photographs aligned with automated alternation flicker (EyeIC, Narbeth, PA) and assessed them for the presence of any discrete RBV positional shifts (2 graders) and for traditional measures of structural progression (2 graders), including neuroretinal rim loss, parapapillary atrophy progression, and disc hemorrhage (DH). MAIN OUTCOME MEASURES: Presence or absence of RBV positional shifts, rates of VF progression, and presence or absence of traditional measures of structural progression. RESULTS: A total of 158 image sets (125 longitudinal and 33 same-day controls) from patients with glaucoma were included. Retinal blood vessel shifts were noted in 33 of 125 (26.4%) longitudinally followed glaucomatous eyes and 2 of 33 (6%) same-day control patients (P = 0.01). Agreement between graders I and II was 90.4% (kappa=0.77; P< 0.001). Eyes with RBV positional change progressed more rapidly than those without (-0.55 vs. -0.29 dB/year; 95% confidence interval [CI], 0.03-0.48); P = 0.03). Retinal blood vessel shift was present in 12.1% of minimal progressors versus 31.5% of moderate and fast progressors (P = 0.04). Rate of VF progression was statistically associated with RBV shift (odds ratio [OR], 2.2; 95% CI, 1.1-4.5; P = 0.03). Other variables significantly associated with RBV shift included neuroretinal rim loss (OR, 21.9; 95% CI, 5.7-83.6; P< 0.001) and DH (OR, 4.6; 95% CI, 1.5-15.5; P< 0.01). A multivariable model revealed that rim loss and DH, but not rate of functional change, were significantly associated with RBV shift. CONCLUSIONS: Retinal blood vessel positional shifts occurred in eyes with functionally progressive glaucoma, neuroretinal rim loss, and DH. This is a novel clinical finding that could help identify glaucoma progression or individuals at higher risk for future progression.
Rahimi Darabad R, Suzuki T, Richards SM, Jakobiec FA, Zakka FR, Barabino S, Sullivan DA. Does estrogen deficiency cause lacrimal gland inflammation and aqueous-deficient dry eye in mice?. Exp Eye Res 2014;127:153-60.Abstract

Researchers have proposed that estrogen deficiency will lead to a Sjögren's syndrome (SjS)-like lacrimal gland inflammation, aqueous tear deficiency and dry eye. The purpose of this study was to determine whether this proposal is correct. Lacrimal glands were obtained from adult, age-matched wild type (WT) and aromatase knockout (ArKO) mice, in which estrogen synthesis is completely eliminated. Tissues were also obtained from autoimmune MRL/Mp-lpr/lpr (MRL/lpr) mice as inflammation controls. Tear volumes in WT and ArKO mice were measured and glands were processed for molecular biological and histological evaluation. Our results demonstrate that estrogen absence does not lead to a SjS-like inflammation in lacrimal tissue or to an aqueous-deficient dry eye. There was no upregulation of genes associated with inflammatory pathways in lacrimal glands of male or female ArKO mice. Such inflammatory activity was prominent in autoimmune MRL/lpr tissues. We also found no evidence of inflammation in lacrimal gland tissue sections of estrogen-deficient mice, and tear volumes of ArKO males were actually increased as compared to those WT controls. Interestingly, our study did show that estrogen absence influences the expression of thousands of lacrimal gland genes, and that this impact is sex- and genotype-specific. Our findings demonstrate that estrogen absence is not a risk factor for the development of SjS-like lacrimal gland inflammation or for aqueous-deficient dry eye in mice.

Rashid A, Lee GN, Jakobiec FA, Freitag SK. Epstein-Barr virus-positive polymorphous lymphoplasmacytic infiltrate of the lacrimal glands in a patient with acute lymphoblastic leukemia. JAMA Ophthalmol 2014;132(7):892-4.
Ratnapriya R, Zhan X, Fariss RN, Branham KE, Zipprer D, Chakarova CF, Sergeev YV, Campos MM, Othman M, Friedman JS, Maminishkis A, Waseem NH, Brooks M, Rajasimha HK, Edwards AO, Lotery A, Klein BE, Truitt BJ, Li B, Schaumberg DA, Morgan DJ, Morrison MA, Souied E, Tsironi EE, Grassmann F, Fishman GA, Silvestri G, Scholl HPN, Kim IK, Ramke J, Tuo J, Merriam JE, Merriam JC, Park KH, Olson LM, Farrer LA, Johnson MP, Peachey NS, Lathrop M, Baron RV, Igo RP, Klein R, Hagstrom SA, Kamatani Y, Martin TM, Jiang Y, Conley Y, Sahel J-A, Zack DJ, Chan C-C, Pericak-Vance MA, Jacobson SG, Gorin MB, Klein ML, Allikmets R, Iyengar SK, Weber BH, Haines JL, Léveillard T, Deangelis MM, Stambolian D, Weeks DE, Bhattacharya SS, Chew EY, Heckenlively JR, Abecasis GR, Swaroop A. Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration. Hum Mol Genet 2014;23(21):5827-37.Abstract

Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch's membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR = 1.10; P-value = 3.79 × 10(-5)). Thus, it appears that rare and common variants in a single gene-FBN2-can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

Rezende FA, Lapalme E, Qian CX, Smith LE, SanGiovanni JP, Sapieha P. Omega-3 supplementation combined with anti-vascular endothelial growth factor lowers vitreal levels of vascular endothelial growth factor in wet age-related macular degeneration. Am J Ophthalmol 2014;158(5):1071-1078.e1.Abstract
PURPOSE: To determine the influence of omega-3 supplementation on vitreous vascular endothelial growth factor A (VEGF-A) levels in patients with exudative age-related macular degeneration (wet AMD) receiving intravitreal anti-VEGF treatment. DESIGN: Prospective, randomized, open-label, single-center, clinical trial, consecutive interventional case series. METHODS: The study included 3 cohorts with wet AMD and a control group with epiretinal membrane or macular hole. Twenty wet AMD patients being treated with anti-VEGF were randomized to daily supplementation of antioxidants, zinc, and carotenoids with omega-3 fatty acids (docosahexaenoic acid and eicosapentaenoic acid; group 1, n = 10) or without omega-3 fatty acids (group 2, n = 10). They were compared with an anti-VEGF treatment-naïve wet AMD group (group 3, n = 10) and an epiretinal membrane or macular hole group (group 4, n = 10). Primary outcome was vitreal VEGF-A levels (at the time of anti-VEGF injection). Secondary outcomes were plasma VEGF-A and central foveal thickness. Patients with new submacular hemorrhage or any other treatment within 3 months were excluded. Final analyses included 9, 6, 7, and 8 patients in groups 1 through 4, respectively. RESULTS: Patients receiving omega-3s (group 1) had significantly lower levels of vitreal VEGF-A (141.11 ± 61.89 pg/mL) when compared with group 2 (626.09 ± 279.27 pg/mL; P = .036) and group 3 (735.48 ± 216.43 pg/mL; P = .013), but similar levels to group 4 (235.81 ± 33.99 pg/mL; P = .215). All groups showed similar values for plasma VEGF-A and central foveal thickness measurements. CONCLUSIONS: This study demonstrated that omega-3 supplementation combined with anti-VEGF treatment is associated with decreased vitreal VEGF-A levels in wet AMD patients.
Ribeiro AG, Rodrigues RAM, Guerreiro AM, Regatieri CVS. A teleophthalmology system for the diagnosis of ocular urgency in remote areas of Brazil. Arq Bras Oftalmol 2014;77(4):214-8.Abstract
PURPOSES: To validate a teleophthalmology mobile system aimed at improving and providing eye urgency screenings in remote and poor area settings in Brazil. The system enables one or more ophthalmologists to remotely examine a patient's condition and submit a decision describing the gravity of the case. If necessary, the patient can be forwarded to a hospital for further consultation. METHODS: A cellphone (Nexus One model, with a 5 megapixel camera) was used to collect data and pictures from 100 randomly selected patients at the Ophthalmology Emergency Room located at the General Hospital of the Federal University of São Paulo (UNIFESP). Data was then sent remotely to an online recording system to be reviewed by an ophthalmologist who provided feedback regarding the state of ocular urgency. RESULTS were then compared to the gold standard diagnosis provided at the hospital. RESULTS: The diagnosis of urgency was given by two ophthalmologists: one in the hospital (gold standard) and one remotely. When we compared both diagnoses we obtained results of 81.94% specificity, 92.85% sensitivity, and 85% accuracy, with a negative predictive value of 96.72%. This work also included a processing time analysis, resulting in an average time of 8.6 min per patient for remote consultations. CONCLUSIONS: This study is the first that has used only a cellphone for diagnosing the urgency of ocular cases. Based on our results, the system can provide a reliable distinction between urgent and non-urgent situations and can offer a viable alternative for the servicing of underprivileged areas. In screening techniques, the most important outcome is to identify urgent cases with a high level of sensitivity and predictive negative value. Thus, our results demonstrate that this tool is robust and we suggest that a major study aimed to verify its efficiency in resource-poor areas should be initiated.