2017

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Abdelaziz M, Dohlman CH, Sayegh RR. Measuring Forward Light Scatter by the Boston Keratoprosthesis in Various Configurations. Cornea 2017;36(6):732-735.Abstract
PURPOSE: Light scatter results in degradation of visual function. An optical bench model was used to identify the origins of scatter in the setting of a Boston keratoprosthesis (KPro). The effect of various modifications in the device design and light-blocking configurations was explored. METHODS: A KPro was mounted on a contact lens holder on a bench, and forward light scatter was recorded with a camera attached to a rotating goniometer arm. Scattered light was recorded at different angles for different KPro modifications, and the point-spread function (PSF) curves were recorded. The area under the curve (AUC) was calculated for each PSF curve. RESULTS: The isolated KPro optical cylinder in a totally blackened holding lens had a tight PSF (AUC = 3.3). Additional blackening of the walls of the KPro stem did not further diminish forward scatter significantly. If the holding lens is made translucent by sandblasting (to simulate an in vivo carrier cornea) and the KPro is inserted without a backplate, forward scatter is substantial (AUC = 11.3). If a standard backplate (with holes) is added, light scatter is considerably reduced regardless of whether the backplate is made of polymethyl methacrylate or titanium (AUC = 5.3 and 4.4, respectively). Addition of an acrylic intraocular lens behind the KPro (the pseudophakic KPro setup) did not increase scatter. CONCLUSIONS: Most of the scattered light in eyes implanted with a KPro originates from the surrounding hazy corneal graft. The standard addition of a backplate reduces light scatter. There was no difference in forward light scatter between the aphakic and the pseudophakic KPro.
AbdelRazek MA, Chwalisz B, Oaklander AL, Venna N. Evidence of small-fiber neuropathy (SFN) in two patients with unexplained genital sensory loss and sensory urinary cystopathy. J Neurol Sci 2017;380:82-84.
Adini A, Adini I, Chi Z-L, Derda R, Birsner AE, Matthews BD, D'Amato RJ. A novel strategy to enhance angiogenesis in vivo using the small VEGF-binding peptide PR1P. Angiogenesis 2017;20(3):399-408.Abstract
Therapeutic angiogenesis is an experimental frontier in vascular biology that seeks to deliver angiogenic growth factors to ischemic or injured tissues to promote targeted formation of new blood vessels as an alternative approach to surgical revascularization procedures. Vascular endothelial growth factor (VEGF) is a potent angiogenic signal protein that is locally upregulated at sites of tissue injury. However, therapies aimed at increasing VEGF levels experimentally by injecting VEGF gene or protein failed to improve outcomes in human trials in part due to its short half-life and systemic toxicity. We recently designed a novel 12-amino acid peptide (PR1P) whose sequence was derived from an extracellular VEGF-binding domain of the pro-angiogenic glycoprotein prominin-1. In this study, we characterized the molecular binding properties of this novel potential therapeutic for targeted angiogenesis and provided the foundation for its use as an angiogenic molecule that can potentiate endogenous VEGF. We showed that PR1P bound VEGF directly and enhanced VEGF binding to endothelial cells and to VEGF receptors VEGFR2 and neuropilin-1. PR1P increased angiogenesis in the murine corneal micropocket assay when combined with VEGF, but had no activity without added VEGF. In addition, PR1P also enhanced angiogenesis in murine choroidal neovascularization and wound-healing models and augmented reperfusion in a murine hind-limb ischemia model. Together our data suggest that PR1P enhanced angiogenesis by potentiating the activity of endogenous VEGF. In so doing, this novel therapy takes advantage of endogenous VEGF gradients generated in injured tissues and may improve the efficacy of and avoid systemic toxicity seen with previous VEGF therapies.
Aggarwal S, Yamaguchi T, Dana R, Hamrah P. Exophiala phaeomuriformis Fungal Keratitis: Case Report and In Vivo Confocal Microscopy Findings. Eye Contact Lens 2017;43(2):e4-e6.Abstract

PURPOSE: Corneal infections, particularly fungal keratitis due to rare fungal species, pose a diagnostic and therapeutic challenge because of difficulty in identification and varying susceptibility profiles. In this study, we report the first case of fungal keratitis because of Exophiala phaeomuriformis. METHODS: We report the clinical findings and microbial identification techniques of a case of fungal keratitis due to E. phaeomuriformis. An 84-year-old woman presented with redness, pain, and itching in the left eye for 2 weeks. Slit-lamp biomicroscopy revealed one broken suture from previous penetrating keratoplasty (PKP), black infiltrates at the 4-o'clock position, without an overlying epithelial defect and hypopyon. Microbial identification was based cultures on Sabouraud dextrose agar and DNA sequencing and correlations to laser in vivo confocal microscopy (IVCM; Heidelberg Retinal Tomograph 3/Rostock Cornea Module, Heidelberg Engineering) and multiphoton microscopy (Ultima Microscope; Prairie Technologies) images. RESULTS: Slit-lamp biomicroscopy revealed one broken suture from previous PKP, black infiltrates at the 4-o'clock position, without an overlying epithelial defect and hypopyon. Based on a clinical suspicion of fungal keratitis, antifungals and fortified antibiotics were started. However, the patient did not respond to therapy and required urgent PKP. After surgery, the patient was maintained on topical and systemic voriconazole and also topical 2% cyclosporine for 5 months because of possibility of scleral involvement noticed during surgery. At the end of the treatment period, her vision improved from hand motion to 20/40, with no recurrence observed in a follow-up period of 1 year. Results of diagnostic tests were supported by fungal elements in stroma on IVCM. Culture from the infiltrate grew black yeast. DNA sequencing led to the diagnosis of E. phaeomuriformis keratitis. Antifungal susceptibility testing revealed sensitivity to voriconazole. CONCLUSION: This is, to our knowledge, the first reported case of E. phaeomuriformis fungal keratitis. Diagnostic testing included slit-lamp biomicroscopy, which revealed pigmented infiltrates, culture plates grew black yeast, microscopy showed branched fungal hyphae with budding conidia, and physiological features showed tolerance to high temperatures, nitrate assimilation, and ribosomal DNA sequencing. Collectively, these tests demonstrate unique features seen for this microorganism. High suspicion should be kept with pigmented infiltrates and with dark yeast on culture plates. Prompt and aggressive medical management with voriconazole or therapeutic PKP in nonresponsive cases is essential to prevent irreversible loss of vision.

Agyemang AA, Sveinsdóttir K, Vallius S, Sveinsdóttir S, Bruschettini M, Romantsik O, Hellström A, Smith LEH, Ohlsson L, Holmqvist B, Gram M, Ley D. Cerebellar Exposure to Cell-Free Hemoglobin Following Preterm Intraventricular Hemorrhage: Causal in Cerebellar Damage?. Transl Stroke Res 2017;Abstract
Decreased cerebellar volume is associated with intraventricular hemorrhage (IVH) in very preterm infants and may be a principal component in neurodevelopmental impairment. Cerebellar deposition of blood products from the subarachnoid space has been suggested as a causal mechanism in cerebellar underdevelopment following IVH. Using the preterm rabbit pup IVH model, we evaluated the effects of IVH induced at E29 (3 days prior to term) on cerebellar development at term-equivalent postnatal day 0 (P0), term-equivalent postnatal day 2 (P2), and term-equivalent postnatal day 5 (P5). Furthermore, the presence of cell-free hemoglobin (Hb) in cerebellar tissue was characterized, and cell-free Hb was evaluated as a causal factor in the development of cerebellar damage following preterm IVH. IVH was associated with a decreased proliferative (Ki67-positive) portion of the external granular layer (EGL), delayed Purkinje cell maturation, and activated microglia in the cerebellar white matter. In pups with IVH, immunolabeling of the cerebellum at P0 demonstrated a widespread presence of cell-free Hb, primarily distributed in the white matter and the molecular layer. Intraventricular injection of the Hb scavenger haptoglobin (Hp) resulted in a corresponding distribution of immunolabeled Hp in the cerebellum and a partial reversal of the damaging effects observed following IVH. The results suggest that cell-free Hb is causally involved in cerebellar damage following IVH and that blocking cell-free Hb may have protective effects.
Ahmed AH, Foster SC, Shields CL. Association of Disease Location and Treatment With Survival in Diffuse Large B-Cell Lymphoma of the Eye and Ocular Adnexal Region. JAMA Ophthalmol 2017;135(10):1062-1068.Abstract
Importance: Primary diffuse large B-cell lymphoma (DLBCL) of the ocular region is rare, and the utility of surgery and radiation therapy remains unresolved. Objective: To explore the clinical characteristics and determine factors associated with overall survival in primary vitreoretinal lymphoma (PVRL) and ocular adnexal (OA)-uveal DLBCL. Design, Setting, and Participants: This retrospective analysis included 396 patients with ophthalmic DLBCL from January 1, 1973, through December 31, 2014, using the Surveillance, Epidemiology, and End Results database. The median follow-up was 39.0 months (interquartile range, 5.1-72.9 months). All patients diagnosed with primary DLBCL of the eye or retina (PVRL) or the eyelid, conjunctiva, choroid, ciliary body, lacrimal gland, or orbit (OA-uveal lymphoma) were included. Patients diagnosed at autopsy or with additional neoplastic disease were excluded. Main Outcomes and Measures: Patient demographic characteristics, disease location, treatment modalities, and overall survival. Results: Forty-seven patients with PVRL (24 women [51.1%] and 23 men [48.9%]) and 349 with OA-uveal DLBCL (192 women [55.0%] and 157 men [45.0%]) had a similar mean (SD) age at diagnosis (69.6 [12.3] vs 66.1 [17.7] years). No difference in the use of surgery or radiation therapy by location was found. For all PVRL and OA-uveal DLBCL, a Cox proportional hazards regression model affirmed that age older than 60 years was associated with increased risk for death (hazard ratio [HR], 2.7; 95% CI, 1.9-4.0; P < .001). Gross total resection was associated with a decreased risk for death (HR, 0.5; 95% CI, 0.3-0.9; P = .04), whereas radiation therapy was not. The 5-year overall survival among patients with PVRL was 41.4% (SE, 8.6%); among those with OA-uveal DLBCL, 59.1% (SE, 2.8%; Mantel-Cox test, P = .007). Median overall survival was lower in PVRL (38.0 months; 95% CI, 14.2-61.8 months) than in OA-uveal DLBCL (96.0 months; 95% CI, 67.3-124.7 months; Mantel-Cox test, P = .007). In addition, median overall survival in ophthalmic-only disease was higher (84.0 months; 95% CI, 63.2-104.8 months) than that in primary DLBCL that occurred outside the central nervous system and ophthalmic regions (46.0 months; 95% CI, 44.4-47.6 months; Mantel-Cox test, P < .001). Conclusions and Relevance: The 5-year survival in PVRL vs OA-uveal DLBCL differed by 17.7%, and overall survival was greater in ophthalmic DLBCL than in DLBCL located outside the central nervous system and ophthalmic regions. Younger age (≤60 years) and gross total resection were associated with increased survival.
Al-Haddad CE, Abdulaal M, Al-Moujahed A, Ervin A-M, Ismail K. Fornix-Based Versus Limbal-Based Conjunctival Trabeculectomy Flaps for Glaucoma: Findings From a Cochrane Systematic Review. Am J Ophthalmol 2017;174:33-41.Abstract

PURPOSE: To compare effectiveness of fornix- and limbal-based conjunctival flaps in trabeculectomy surgery. DESIGN: Systematic review. METHODS: Setting: CENTRAL, MEDLINE, LILACS, ISRCTN registry, ClinicalTrials.gov, WHO, and ICTRP were searched to identify eligible randomized controlled trials (RCTs). STUDY POPULATION: RCTs in which benefits and complications of fornix- vs limbal-based trabeculectomy for glaucoma were compared in adult glaucoma patients. OBSERVATION PROCEDURE: We followed Cochrane methodology for data extraction. MAIN OUTCOME MEASURES: Proportion of failed trabeculectomies at 24 months, defined as the need for repeat surgery or uncontrolled intraocular pressure (IOP) >22 mm Hg, despite topical/systemic medications. RESULTS: The review included 6 trials with a total of 361 participants, showing no difference in effectiveness between fornix-based vs limbal-based trabeculectomy surgery, although with a high level of uncertainty owing to low event rates. In the fornix-based and limbal-based surgery, mean IOP at 12 months was similar, with ranges of 12.5-15.5 mm Hg and 11.7-15.1 mm Hg, respectively. Mean difference was 0.44 mm Hg (95% CI -0.45 to 1.33) and 0.86 mm Hg (95% CI -0.52 to 2.24) at 12 and 24 months of follow-up, respectively. Mean number of postoperative glaucoma medications was similar between the 2 groups. Mean difference was 0.02 (95% CI -0.15 to 0.19) at 12 months. As far as postoperative complications, an increased risk of shallow anterior chamber was observed in the limbal-based group. CONCLUSION: Similar efficacy of trabeculectomy surgery with respect to bleb failure or IOP control was observed in both types of conjunctival flap incisions. A significant difference was detected in the risk of postoperative shallow anterior chamber, which was increased in the limbal-based group.

Al-Moujahed A, Brodowska K, Stryjewski TP, Efstathiou NE, Vasilikos I, Cichy J, Miller JW, Gragoudas E, Vavvas DG. Verteporfin inhibits growth of human glioma in vitro without light activation. Sci Rep 2017;7(1):7602.Abstract
Verteporfin (VP), a light-activated drug used in photodynamic therapy for the treatment of choroidal neovascular membranes, has also been shown to be an effective inhibitor of malignant cells. Recently, studies have demonstrated that, even without photo-activation, VP may still inhibit certain tumor cell lines, including ovarian cancer, hepatocarcinoma and retinoblastoma, through the inhibition of the YAP-TEAD complex. In this study, we examined the effects of VP without light activation on human glioma cell lines (LN229 and SNB19). Through western blot analysis, we identified that human glioma cells that were exposed to VP without light activation demonstrated a downregulation of YAP-TEAD-associated downstream signaling molecules, including c-myc, axl, CTGF, cyr61 and survivin and upregulation of the tumor growth inhibitor molecule p38 MAPK. In addition, we observed that expression of VEGFA and the pluripotent marker Oct-4 were also decreased. Verteporfin did not alter the Akt survival pathway or the mTor pathway but there was a modest increase in LC3-IIB, a marker of autophagosome biogenesis. This study suggests that verteporfin should be further explored as an adjuvant therapy for the treatment of glioblastoma.
Alkharashi M, Fulton AB. Available Evidence on Leber Congenital Amaurosis and Gene Therapy. Semin Ophthalmol 2017;32(1):14-21.Abstract

Leber congenital amaurosis (LCA) is a group of severe inherited retinal dystrophies that lead to early childhood blindness. In the last decade, interest in LCA has increased as advances in genetics have been applied to better identify, classify, and treat LCA. To date, 23 LCA genes have been identified. Gene replacement in the RPE65 form of LCA represents a major advance in treatment, although limitations have been recognized. In this article, we review the clinical and genetic features of LCA and evaluate the evidence available for gene therapy in RPE65 disease.

Alkharashi M, Hunter DG. Reduced surgical success rate of rectus muscle plication compared to resection. J AAPOS 2017;Abstract
PURPOSE: To evaluate the surgical success of rectus muscle plication compared to resection and to compare the short- and long-term changes in ocular alignment after both procedures. METHODS: The medical records of all patients who underwent a rectus muscle tightening procedure (resection or plication) at a single institution over a 5-year period by a single surgeon were reviewed retrospectively. Binocular alignment was recorded before and immediately after surgery and again at 6-12 weeks and final follow-up visit. Primary outcome was surgical success rate, defined as distance alignment of ≤10(Δ) for horizontal and ≤6(Δ) for vertical strabismus. Secondary outcomes were reoperation rate and postoperative alignment drift. RESULTS: A total of 72 surgeries were identified for inclusion: 48 resections and 24 plications. Surgical success was significantly higher in the resection group than in the plication group (89% vs 58%; P = 0.005) at both 6-12 weeks' follow-up (P = 0.005) and at mean final follow-up of 19 ± 13 months (range, 3-56 months [n = 48]; P = 0.03). Reoperations were performed in 3 patients in the plication group (12.5%), all for undercorrection; there were no reoperations in the resection group (P = 0.03). CONCLUSIONS: Rectus muscle plication has many potential advantages over resection, including sparing of the ciliary circulation. In our experience, however, patients treated with plication had lower surgical success rates and a higher reoperation rate. Surgeons should monitor their long-term results before considering plication as their procedure of choice over resection.
Alkharashi M, Dagi AF, Dagi LR. Pericardial patch graft repair of severe localized scleral thinning encountered during strabismus surgery. J AAPOS 2017;21(2):156-156.e1.Abstract

This article presents a surgical technique using a pericardial patch for the permanent repair of severe scleral thinning encountered during strabismus surgery. In the present case scleral thinning resulted from buckle removal. Familiarity with this technique may prove important for the strabismus surgeon treating patients with a history of surface ocular hardware or disease-induced scleral thinning. This video article may be viewed atjaapos.org.

Altschwager P, Moskowitz A, Fulton AB, Hansen RM. Multifocal ERG Responses in Subjects With a History of Preterm Birth. Invest Ophthalmol Vis Sci 2017;58(5):2603-2608.Abstract
Purpose: The purpose of this study is to assess cone-mediated central retinal function in children with a history of preterm birth, including subjects with and without retinopathy of prematurity (ROP). The multifocal electroretinogram (mfERG) records activity of the postreceptor retinal circuitry. Methods: mfERG responses were recorded to an array of 103 hexagonal elements that subtended 43° around a central fixation target. The amplitude and latency of the first negative (N1) and first positive (P1) response were evaluated in six concentric rings centered on the fovea. Responses were recorded from 40 subjects with a history of preterm birth (severe ROP, mild ROP, no ROP) and 19 term-born control subjects. Results: The amplitude of N1 and P1 varied significantly with eccentricity and ROP severity. For all four groups, these amplitudes were largest in the center and decreased with eccentricity. At all eccentricities, N1 amplitude was significantly smaller in severe ROP and did not differ significantly among the other three groups (mild ROP, no ROP, term-born controls). P1 amplitude in all preterm groups was significantly smaller than in controls; P1 amplitude was similar in no ROP and mild ROP and significantly smaller in severe ROP. Conclusions: These results provide evidence that premature birth alone affects cone-mediated central retinal function and that the magnitude of the effect varies with severity of the antecedent ROP. The lack of difference in mfERG amplitude between the mild and no ROP groups is evidence that the effect of ROP on the neurosensory retina may not depend solely on appearance of abnormal retinal vasculature.
Amarnani D, Machuca-Parra AI, Wong LL, Marko CK, Stefater JA, Stryjewski TP, Eliott D, Arboleda-Velasquez JF, Kim LA. Effect of Methotrexate on an In Vitro Patient-Derived Model of Proliferative Vitreoretinopathy. Invest Ophthalmol Vis Sci 2017;58(10):3940-3949.Abstract
Purpose: The purpose of this study was to develop a method for isolating, culturing, and characterizing cells from patient-derived membranes in proliferative vitreoretinopathy (PVR) to be used for drug testing. Methods: PVR membranes were obtained from six patients with grade C PVR. Membrane fragments were analyzed by gross evaluation, fixed for immunohistologic studies to establish cell identity, or digested with collagenase II to obtain single cell suspensions for culture. PVR-derived primary cultures were used to examine the effects of methotrexate (MTX) on proliferation, migration, and cell death. Results: Gross analysis of PVR membranes showed presence of pigmented cells, indicative of retinal pigment epithelial cells. Immunohistochemistry identified cells expressing α-smooth muscle actin, glial fibrillary acidic protein, Bestrophin-1, and F4/80, suggesting the presence of multiple cell types in PVR. Robust PVR primary cultures (C-PVR) were successfully obtained from human membranes, and these cells retained the expression of cell identity markers in culture. C-PVR cultures formed membranes and band-like structures in culture reminiscent of the human condition. MTX significantly reduced the proliferation and band formation of C-PVR, whereas it had no significant effect on cell migration. MTX also induced regulated cell death within C-PVR as assessed by increased expression of caspase-3/7. Conclusions: PVR cells obtained from human membranes can be successfully isolated, cultured, and profiled in vitro. Using these primary cultures, we identified MTX as capable of significantly reducing growth and inducing cell death of PVR cells in vitro.
Amouzegar A, Mittal SK, Sahu A, Sahu SK, Chauhan SK. Mesenchymal Stem Cells Modulate Differentiation of Myeloid Progenitor Cells During Inflammation. Stem Cells 2017;35(6):1532-1541.Abstract
Mesenchymal stem cells (MSCs) possess distinct immunomodulatory properties and have tremendous potential for use in therapeutic applications in various inflammatory diseases. MSCs have been shown to regulate pathogenic functions of mature myeloid inflammatory cells, such as macrophages and neutrophils. Intriguingly, the capacity of MSCs to modulate differentiation of myeloid progenitors (MPs) to mature inflammatory cells remains unknown to date. Here, we report the novel finding that MSCs inhibit the expression of differentiation markers on MPs under inflammatory conditions. We demonstrate that the inhibitory effect of MSCs is dependent on direct cell-cell contact and that this intercellular contact is mediated through interaction of CD200 expressed by MSCs and CD200R1 expressed by MPs. Furthermore, using an injury model of sterile inflammation, we show that MSCs promote MP frequencies and suppress infiltration of inflammatory cells in the inflamed tissue. We also find that downregulation of CD200 in MSCs correlates with abrogation of their immunoregulatory function. Collectively, our study provides unequivocal evidence that MSCs inhibit differentiation of MPs in the inflammatory environment via CD200-CD200R1 interaction. Stem Cells 2017;35:1532-1541.
Amparo F, Yin J, Di Zazzo A, Abud T, Jurkunas UV, Hamrah P, Dana R. Evaluating Changes in Ocular Redness Using a Novel Automated Method. Transl Vis Sci Technol 2017;6(4):13.Abstract
PURPOSE: To evaluate interobserver concordance in measured ocular redness among a group of raters using an objective computer-assisted method (ocular redness index [ORI]) and a group of clinicians using an ordinal comparative scale. METHODS: We conducted a prospective study to evaluate ocular redness in clinical photographs of 12 patients undergoing pterygium surgery. Photographs were acquired preoperatively, and at 1 week and 1 month postoperatively. One group of clinicians graded conjunctival redness in the photographs using an image-based comparative scale. A second group applied the ORI to measure redness in the same photographs. We evaluated redness change between time points, level of agreement among raters, and assessed redness score differences among observers within each group. RESULTS: Interobserver agreement using the image-based redness scale was 0.458 (P < 0.001). Interobserver agreement with the ORI was 0.997 (P < 0.001). We observed statistically significant differences among clinicians' measurements obtained with the image-based redness scale (P < 0.001). There were no significant differences among measurements obtained with the ORI (P = 0.27). We observed a significant change in redness between baseline and follow-up visits with all scoring methods. Detailed analysis of redness change was performed only in the ORI group due to availability of continuous scores. CONCLUSION: Our findings suggest that the ORI scores provide higher consistency among raters than ordinal scales, and can discriminate redness changes that clinical observers often can miss. TRANSLATIONAL RELEVANCE: The ORI may be a reliable alternative to measure ocular redness objectively in the clinic and in clinical trials.
Amphornphruet A, Silpa-Archa S, Preble JM, Foster SC. Endogenous Cryptococcal Endophthalmitis in Immunocompetent Host: Case Report and Review of Multimodal Imaging Findings and Treatment. Ocul Immunol Inflamm 2017;:1-5.Abstract

PURPOSE: To describe a case of bilateral endogenous cryptococcal endophthalmitis in an immunocompetent host and to review adjunctive ophthalmic imaging patterns and treatment. METHODS: A retrospective case report. RESULTS: A 45-year-old female patient with two distinct presentations of endogenous cryptococcal endophthalmitis in each eye presented initially with progressive blurred vision in the left eye, beginning more than 10 years after a craniotomy with ventriculoperitoneal shunt. Complete ophthalmic imaging was conducted and compared with data from previous literature. Administration of amphotericin-B had poorly responded; however, consolidation of fluconazole resulted in disease stabilization. CONCLUSIONS: Bilateral intraocular cryptococcal infection can present with two distinct patterns of posterior segment findings. A review of ophthalmic imaging patterns found consistency in some characteristics of A-scan ultrasonogram and fundus fluorescein angiogram. Besides conventional treatment, voriconazole is likely to play an important role in the management of cryptococcal endophthalmitis.

Arafat SN, Robert M-C, Abud T, Spurr-Michaud S, Amparo F, Dohlman CH, Dana R, Gipson IK. Elevated Neutrophil Elastase in Tears of Ocular Graft-Versus-Host Disease Patients. Am J Ophthalmol 2017;176:46-52.Abstract

PURPOSE: To investigate the levels of neutrophil elastase (NE), matrix metalloproteinases (MMPs), and myeloperoxidase (MPO) in tear washes of patients with ocular graft-vs-host disease (oGVHD). DESIGN: Case-control study. METHODS: Based on established criteria, oGVHD patients (n = 14; 28 eyes) and age-/sex-matched healthy controls (n = 14; 28 eyes) were enrolled. Tear washes were collected and analyzed for NE using a single-analyte enzyme-linked immunosorbent assay (ELISA). MMPs (1, 2, 3, 7, 8, 9, 12), MPO, and tissue inhibitor of matrix metalloproteinase (TIMP)-1 were analyzed using multianalyte bead-based ELISA assays. Total MMP activity was measured using a fluorimetric assay. Correlation studies were performed between NE, MMP-8, MMP-9, and MPO within study groups. RESULTS: NE, MMP-8, MMP-9, and MPO levels were elevated in oGVHD tears when compared with controls (P < .0001). NE was the most elevated analyte. MMP activity was higher and TIMP-1 levels were lower in oGVHD than in control (P < .0001). In oGVHD, NE significantly correlated with MMP-8 (r = 0.92), MMP-9 (r = 0.90), and MPO (r = 0.79) (P < .0001). MMP-8 correlated with MMP-9 (r = 0.96, P < .0001), and MPO (r = 0.60, P = .001). MMP-9 correlated with MPO (r = 0.55, P = .002). In controls, NE, MMP-9, and MPO significantly correlated with each other (P < .0001). CONCLUSIONS: The marked increase in NE in oGVHD tears that correlated strongly with elevated MMP-8, MMP-9, and MPO suggests a common neutrophilic source and provides evidence of neutrophil activity on the ocular surface of oGVHD patients.

Argüeso P. Proteolytic activity in the meibomian gland: Implications to health and disease. Exp Eye Res 2017;163:53-57.Abstract
The function of the meibomian gland in the upper and lower eyelids is critical to maintaining homeostasis at the ocular surface. Highly specialized meibocytes within the gland must differentiate and accumulate intracellular lipid droplets that are released into the tear film following rupture of the cell membrane. Proteases and their inhibitors have been recognized as key players in remodeling extracellular matrices and promoting the normal integrity of glandular tissue. They modulate a wide range of biological processes, such as cell proliferation and differentiation, and can contribute to disease when aberrantly expressed. Deciphering the role of proteolytic activity in the meibomian gland offers an opportunity to gain a more comprehensive and fundamental understanding of the developmental, physiological, and pathological processes associated with this gland.
Aschard H, Kang JH, Iglesias AI, Hysi P, Cooke Bailey JN, Khawaja AP, Allingham RR, Ashley-Koch A, Lee RK, Moroi SE, Brilliant MH, Wollstein G, Schuman JS, Fingert JH, Budenz DL, Realini T, Gaasterland T, Scott WK, Singh K, Sit AJ, Igo RP, Song YE, Hark L, Ritch R, Rhee DJ, Gulati V, Haven S, Vollrath D, Zack DJ, Medeiros F, Weinreb RN, Cheng C-Y, Chasman DI, Christen WG, Pericak-Vance MA, Liu Y, Kraft P, Richards JE, Rosner BA, Hauser MA, Hauser MA, Klaver CCW, van Duijn CM, Haines J, Wiggs JL, Pasquale LR. Genetic correlations between intraocular pressure, blood pressure and primary open-angle glaucoma: a multi-cohort analysis. Eur J Hum Genet 2017;25(11):1261-1267.Abstract
Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 × 10-27) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 × 10-5); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.
Au ED, Fernandez-Godino R, Kaczynksi TJ, Sousa ME, Farkas MH. Characterization of lincRNA expression in the human retinal pigment epithelium and differentiated induced pluripotent stem cells. PLoS One 2017;12(8):e0183939.Abstract
Long intervening non-coding RNAs (lincRNAs) are increasingly being implicated as important factors in many aspects of cellular development, function, and disease, but remain poorly understood. In this study, we examine the human retinal pigment epithelium (RPE) lincRNA transcriptome using RNA-Seq data generated from human fetal RPE (fRPE), RPE derived from human induced pluripotent stem cells (iPS-RPE), and undifferentiated iPS (iPS). In addition, we determine the suitability of iPS-RPE, from a transcriptome standpoint, as a model for use in future studies of lincRNA structure and function. A comparison of gene and isoform expression across the whole transcriptome shows only minimal differences between all sample types, though fRPE and iPS-RPE show higher concordance than either shows with iPS. Notably, RPE signature genes show the highest degree of fRPE to iPS-RPE concordance, indicating that iPS-RPE cells provide a suitable model for use in future studies. An analysis of lincRNAs demonstrates high concordance between fRPE and iPS-RPE, but low concordance between either RPE and iPS. While most lincRNAs are expressed at low levels (RPKM < 10), there is a high degree of concordance among replicates within each sample type, suggesting the expression is consistent, even at levels subject to high variability. Finally, we identified and annotated 180 putative novel genes in the fRPE samples, a majority of which are also expressed in the iPS-RPE. Overall, this study represents the first characterization of lincRNA expression in the human RPE, and provides a model for studying the role lincRNAs play in RPE development, function, and disease.

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