Successful Proof-of-Concept for Topical Delivery of Novel Peptide ALM201 with Potential Usefulness for Treating Neovascular Eye Disorders.

Purpose: To evaluate the therapeutic benefit of a novel peptide, ALM201, in ocular pathologic vascularization. Design: Experimental study in mouse, rat, and rabbit animal models. Participants: Ten-week-old Lister Hooded male rats, 8-week-old Brown Norway male rats, 9-day-old C57BL/6J mice, and 12-month-old New Zealand male rabbits. Methods: Corneal vascularization was scored for vessel density and vessel distance to suture in a rat corneal suture model. Ocular penetration and biodistribution were evaluated by matrix-assisted laser desorption/ionization mass spectrometry imaging after topical ALM201 application to rabbit eyes. A mouse choroidal sprouting assay, with aflibercept as positive control, was used to evaluate choroidal neovascularization (CNV) in the posterior segment tissue. Efficacy of topical ALM201 was assessed using a rat laser CNV model of neovascular age-related macular degeneration. Main Outcome Measures: Clinical scoring and histologic analysis of vascularized corneas, sprouting area, lesion size, and vessel leakiness in posterior segments. Results: Assessment of ALM201 treatment in the rat corneal suture model showed a significant decrease in vessel density (P = 0.0065) and vessel distance to suture (P = 0.021) compared with vehicle control (phosphate-buffered saline [PBS]). Infiltration of inflammatory cells into the corneal stroma also was reduced significantly compared with PBS (724.5 ± 122 cells/mm2 vs. 1837 ± 195.9 cells/mm2, respectively; P = 0.0029). Biodistribution in rabbit eyes confirmed ALM201 bioavailability in anterior and posterior ocular segments 1 hour after topical instillation. ALM201 treatment significantly suppressed choroid vessel sprouting when compared with PBS treatment (44.5 ± 14.31 pixels vs. 120.9 ± 33.37 pixels, respectively; P = 0.04) and was not inferior to aflibercept (65.63 ± 11.86 pixels; P = 0.7459). Furthermore, topical ALM201 significantly improved vessel leakiness (leakage scores: 2.1 ± 0.7 vs. 2.9 ± 0.1; P = 0.0274) and lesion size (144,729 ± 33,239 µm3 vs. 187,923 ± 28,575 µm3; P = 0.03) in the rat laser CNV model when compared with topical PBS vehicle. Conclusions: ALM201 is a promising novel molecule with anti-inflammatory and antivascularization activity and is a strong candidate to meet the clinical need of a new, topically delivered therapeutic agent for treating inflammation and pathologic vascularization in the anterior and posterior segments of the eye.

Outcome of primary rhegmatogenous retinal detachment surgery in a tertiary referral centre in Northern Ireland - A regional study.

PURPOSE: To report the primary and final success, functional outcome and complication rates of patients with primary rhegmatogenous retinal detachment (RRD) who underwent retinal detachment surgery in a tertiary referral centre in Northern Ireland. VENUE: Vitreoretinal service, Royal Victoria Hospital, Belfast, Northern Ireland. METHODS: This is a retrospective case series of all patients who underwent primary RRD repair between 1st of January 2013 and 31st of December 2013. Charts were reviewed. Patients' demographics, overall primary and final success, functional outcome, complication rates were identified and recorded. Subgroup analysis according to lens status and foveal attachment was also performed. RESULTS: A total of 212 cases of primary RRD were included. Mean age at time of surgery was 56.6 years (range 9-90 years); 175(82.5%) had pars plana vitrectomy (PPV), 27 (12.5%), scleral buckle (SB) repair and 10 (5%) pneumatic retinopexy (PR). Overall primary and final success rate were 86% and 95.6% respectively. Overall mean visual acuity improved from 1.1 to 0.4 LogMAR postoperatively after a mean follow-up of 9 months. There was no significant difference in the primary success rate in relation to the baseline lens status (χ2 = 3.4, P = 0.2) and to the baseline macular status (χ2 = 0.6, P = 0.7). Presence of proliferative vitreoretinopathy (PVR) negatively affected the primary success rate (χ2=7.2, P = 0.03). Poor prognostic factors for success were PVR at presentation, inferior breaks and increasing number of detached quadrants. CONCLUSIONS: This study demonstrates a success rate comparable with other centres with a low rate of final failure. Despite sub-specialism and the great advances in VR surgery, the biology of RRD dictates a failure rate. New therapies may improve results in the future.

Iris Flocculi as an ocular marker of ACTA2 mutation in familial thoracic aortic aneurysms and dissections.

Non-syndromic familial thoracic aortic aneurysms and dissections (TAAD) are inherited in an autosomal dominant manner. We report a missense mutation in the smooth muscle α-actin (ACTA2; MIM*102620) gene in a 3 generational family from Northern Ireland in which iris flocculi were an ocular marker of the disease.

VEGF-targeted therapy and beyond: pharmacotherapy and emerging treatments in agerelated macular degeneration.

Treatment of age-related macular degeneration (AMD) has changed dramatically over the last decade. It has evolved from primarily destructive therapies (laser-based treatment strategies) to nondestructive therapies (intravitreal pharmacotherapies that target angiogenesis). Intermittent intravitreal ranibizumab, an inhibitor of VEGF, is currently the gold standard of care for neovascular AMD as it is the only treatment where a significant proportion of treated eyes have been shown to experience improvements in visual acuity. As our understanding of the pathological and molecular mechanisms involved in AMD increases, multiple new treatments are emerging. Distinct therapeutic approaches are being used, including inhibition of oxidative stress, interference with the visual cycle and immunomodulation. Targets within the complex cycle of angiogenesis include upstream pathways, such as mTOR and HIF-α, and downstream targets include integrins, PDGF and receptor tyrosine kinases.

Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism, and risk of retinal vein occlusion: a meta-analysis.

OBJECTIVE: To assess the role of plasma total homocysteine (tHcy) concentrations and homozygosity for the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) C677T gene as risk factors for retinal vascular occlusive disease. DESIGN: Retinal vein occlusion (RVO) is an important cause of vision loss. Early meta-analyses showed that tHcy was associated with an increased risk of RVO, but a significant number of new studies have been published. PARTICIPANTS AND/OR CONTROLS: RVO patients and controls. METHODS: Data sources included MEDLINE, Web of Science, and PubMed searches and searching reference lists of relevant articles and reviews. Reviewers searched the databases, selected the studies, and then extracted data. Results were pooled quantitatively using meta-analytic methods. MAIN OUTCOME MEASURES: tHcy concentrations and MTHFR genotype. RESULTS: There were 25 case-control studies for tHcy (1533 cases and 1708 controls) and 18 case-control studies for MTHFR (1082 cases and 4706 controls). The mean tHcy was on average 2.8 micromol/L (95% confidence interval [CI], 1.8-3.7) greater in the RVO cases compared with controls, but there was evidence of between-study heterogeneity (P<0.001, I(2) = 93%). There was funnel plot asymmetry suggesting publication bias. There was no evidence of association between homozygosity for the MTHFR C677T genotype and RVO (odds ratio [OR] 1.20; 95% CI, 0.84-1.71), but again marked heterogeneity (P = 0.004, I(2) = 53%) was observed. CONCLUSIONS: There was some evidence that elevated tHcy was associated with RVO, but not homozygosity for the MTHFR C677T genotype. Both analyses should be interpreted cautiously because of marked heterogeneity between the study estimates and possible effect of publication bias on the tHcy findings. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

The incidence and rate of rhegmatogenous retinal detachment seven years after cataract surgery in patients with high myopia.

BACKGROUND: Cataract extraction is the most commonly performed surgery in the National Health Service. Myopia increases the risk of postoperative rhegmatogenous retinal detachment (RRD). The aim of this study was to determine the incidence and rate of RRD seven years after cataract extraction in highly myopic eyes. METHODS: Retrospective review was performed of notes of all high myopes (axial length 26.0 mm or more) who underwent cataract extraction during the study period in one centre. RESULTS: 84 eyes met the study criteria. Follow-up time from surgery was 93 to 147 months (median 127 months). The average axial length was 28.72 mm (sd 1.37). Two eyes developed post-operative RRD; the incidence was 2.4% and the rate one RRD per 441.6 person-years. The results of 15 other studies on the incidence of RRD after cataract extraction in high myopia were pooled and combined with our estimate. CONCLUSION: Both patients in our study who developed RRD had risk factors for this complication as well as high myopia. Risk factors are discussed in the light of our results and the pooled estimate. Our follow-up time is longer than most. Future case series should calculate rates to allow meaningful comparison of case series.

Retrobulbar hemorrhage after sub-Tenon's anesthesia.

We present a case of retrobulbar hemorrhage complicating sub-Tenon's anesthesia in a patient receiving oral anticoagulants. To our knowledge, this has been described only once in the literature.

An in vitro study of human lens epithelial cell adhesion to intraocular lenses with and without a fibronectin coating.

PURPOSE: To demonstrate differences in human lens epithelial cell adhesion to different intraocular lens biomaterials in vitro and to determine whether these differences can be influenced by coating the intraocular lens surface with commercially available fibronectin. METHODS: A prospective laboratory-based study comparing human lens epithelial cell adhesion to silicone (n=18), polymethylmethacrylate (PMMA; n=18), and acrylic (n=18) intraocular lenses in vitro. The three types of intraocular lenses were then coated with fibronectin: silicone (n=6), PMMA (n=6), and acrylic (n=6). The main outcome measure was the mean number of lens epithelial cells attached to each lens type after 24 hours of incubation. RESULTS: In the uncoated lens group, there was a significantly higher number of lens epithelial cells attached to the acrylic than to the silicone or PMMA lenses (P<0.001). Coating the lenses with fibronectin caused a significant increase in attachment of lens epithelial cells for all three lens types. CONCLUSIONS: There was a significant difference in the degree of lens epithelial cell attachment to the various types of intraocular lenses in vitro. Cell attachment was more prominent in the acrylic lenses, but the fibronectin coating negated differences in lens type and caused a significant increase in cell attachment across all groups.

Retinal vein occlusion, homocysteine, and methylene tetrahydrofolate reductase genotype.

PURPOSE: The aim of this case-control study was to investigate the relationship between homocysteine (tHcy), 5,10 methylene tetrahydrofolate reductase (MTHFR) C677T genotype, folate and vitamin B12 status, and retinal vein occlusion (RVO). METHODS: Subjects with RVO (n = 106) were recruited from outpatient and inpatient sources. Controls (n = 98) were selected to achieve a similar age and sex distribution. Full ocular examination was performed and medical history was taken for each study participant. Plasma and serum samples were analyzed for tHcy level and folate and vitamin B12 status, and extracted DNA was assessed for the MTHFR C677T genotype. RESULTS: There was no significant difference in plasma tHcy level or thermolabile MTHFR allele frequency between subjects and controls. Similarly, there was no significant difference in folate or vitamin B12 status between subjects and controls. MTHFR genotype did not affect folate or vitamin B12 concentrations in subjects or controls. However, tHcy was significantly higher in thermolabile homozygotes than in nonthermolabile homozygotes (ratio of geometric means, 1.35; 95% confidence interval [CI], 1.04-1.74; P = 0.024). CONCLUSIONS: Hyperhomocysteinemia, the MTHFR C677T mutation, and folate and vitamin B12 status are not important risk factors for RVO in this population.

Suprachoroidal haemorrhage following Nd:YAG laser posterior capsulotomy.

Nd:YAG laser posterior capsulotomy is the commonest procedure for posterior capsule thickening following cataract surgery. Complications following this laser surgery are relatively few, and this is ordinarily a safe and effective procedure. Herein a case is described of suprachoroidal haemorrhage following Nd:YAG laser posterior capsulotomy. To the best of the authors' knowledge, this is the first report of this complication. Patients undergoing this procedure should be warned of this rare but potentially devastating complication.

Presentation of intraocular foreign body 25 years after the event.

Delayed presentation of retained intraocular foreign body is a diagnostic and therapeutic challenge to the ophthalmologist. Herein a case of a man presenting 25 five years after initial injury with a retained metallic foreign body adjacent to the optic disc is described.