Royal Victoria Eye and Ear Hospital

Weighted gene coexpression network analysis (WGCNA) is a powerful 'guilt-by-association'-based method to extract coexpressed groups of genes from large heterogeneous messenger RNA expression data sets. We have utilized WGCNA to identify 11 coregulated gene clusters across 2342 breast cancer samples from 13 microarray-based gene expression studies. A number of these transcriptional modules were found to be correlated to clinicopathological variables (e.g. tumor grade), survival endpoints for breast cancer as a whole (disease-free survival, distant disease-free survival and overall survival) and also its molecular subtypes (luminal A, luminal B, HER2+ and basal-like). Examples of findings arising from this work include the identification of a cluster of proliferation-related genes that when upregulated correlated to increased tumor grade and were associated with poor survival in general. The prognostic potential of novel genes, for example, ubiquitin-conjugating enzyme E2S (UBE2S) within this group was confirmed in an independent data set. In addition, gene clusters were also associated with survival for breast cancer molecular subtypes including a cluster of genes that was found to correlate with prognosis exclusively for basal-like breast cancer. The upregulation of several single genes within this coexpression cluster, for example, the potassium channel, subfamily K, member 5 (KCNK5) was associated with poor outcome for the basal-like molecular subtype. We have developed an online database to allow user-friendly access to the coexpression patterns and the survival analysis outputs uncovered in this study (available at http://glados.ucd.ie/Coexpression/).

In March 2008, the European Registry of Quality Outcomes for Cataract and Refractive Surgery (EUREQUO) commenced. This 3-year project was cofunded by the European Union (EU) and the European Society of Cataract & Refractive Surgeons (ESCRS). The ESCRS became the lead partner in the project with 11 national societies as associated partners. The aims of the project were to improve treatment and standards of care for cataract and refractive surgery and to develop evidence-based guidelines for cataract and refractive surgery across Europe. Surgeons from all participating societies contributed to the database, which contained data on 820,000 cataract surgeries in November 2011. The present guidelines are based on data entered from January 1, 2009, to August 28, 2011 (523,921 cataract extractions). The guidelines include only those steps in the cataract surgery process that can be analyzed by the database.

INTRODUCTION: Cigarette smoking is the strongest modifiable risk factor for developing thyroid-associated ophthalmopathy (TAO), and the severity of TAO is related to the current number of cigarettes smoked per day. We aimed to establish the effects of cigarette smoke extract (CSE) on an in vitro model of TAO. METHODS: Orbital tissue was taken during surgery from 10 patients with TAO and nine control subjects. Orbital fibroblasts were cultured and exposed to CSE, and intercellular adhesion molecule 1 (ICAM1) expression was measured by flow cytometry. Glycosaminoglycan production was measured by hyaluronic acid ELISA. Orbital fibroblasts were grown in adipogenic media with or without CSE and/or IL-1, and the degree of adipogenesis was quantified. RESULTS: Fibroblasts from patients with TAO and controls showed similar responses. ICAM1 expression was not affected by CSE. Hyaluronic acid production was stimulated by CSE in a dose-dependent manner (correlation coefficient, 0.978; P = 0.022), with 5% CSE causing an increase of 44% (P = 0.001). CSE increased adipogenesis in a dose-related manner, as did IL-1. The effects of CSE and IL-1 on adipogenesis were synergistic, with the degree of adipogenesis in the well containing both 5% CSE and 0.1 ng/ml IL-1 being double the magnitude of the sum of the values obtained from either stimulus alone (P < 0.001). Addition of an anti-IL-1 antibody to the well containing both 5% CSE and 0.1 ng/ml IL-1 reduced the degree of adipogenesis by 82% (P < 0.001). CONCLUSION: These findings may help explain how cigarette smoking has a detrimental effect in TAO and suggests that IL-1 may be an attractive therapeutic target in TAO.

Human corneal transplantation (keratoplasty) is typically considered to have superior short- and long-term outcomes and lower requirement for immunosuppression compared to solid organ transplants because of the inherent immune privilege and tolerogenic mechanisms associated with the anterior segment of the eye. However, in a substantial proportion of corneal transplants, the rates of acute rejection and/or graft failure are comparable to or greater than those of the commonly transplanted solid organs. Critically, while registry data and observational studies have helped to identify factors that are associated with increased risk of corneal transplant failure, the extent to which these risk factors operate through enhancing immune-mediated rejection is less clear. In this overview, we summarize a range of important recent clinical and basic insights related to high-risk corneal transplantation, the factors associated with graft failure, and the immunological basis of corneal allograft rejection. We highlight critical research areas from which continued progress is likely to drive improvements in the long-term survival of high-risk corneal transplants. These include further development and clinical testing of predictive risk scores and assays; greater use of multicenter clinical trials to optimize immunosuppressive therapy in high-risk recipients and robust clinical translation of novel, mechanistically-targeted immunomodulatory and regenerative therapies that are emerging from basic science laboratories. We also emphasize the relative lack of knowledge regarding transplant outcomes for infection-related corneal diseases that are common in the developing world and the potential for greater cross-pollination and synergy between corneal and solid organ transplant research communities.

PURPOSE: To assess the risk factors for endothelial cell loss after phacoemulsification cataract surgery performed by a junior resident. SETTING: Ophthalmic teaching hospital, Dublin, Ireland. METHODS: This prospective study included 40 eyes having divide-and-conquer phacoemulsification cataract surgery by a junior resident under the supervision of an experienced surgeon. Nine variables were examined to assess the risk for corneal endothelial cell loss postoperatively. RESULTS: The mean overall endothelial cell loss was 11.6%. Longer surgery time, longer absolute and effective phaco time, higher mean ultrasound power, and higher cataract density were significantly associated with endothelial cell loss on univariate analysis. Multivariate analysis identified a grade 3 nucleus (severely dense) and long absolute phaco time as independent predictors for endothelial cell loss, with longer absolute phaco time the stronger predictor. CONCLUSIONS: Divide-and-conquer phacoemulsification cataract surgery was a safe technique in the hands of an ophthalmic trainee. This study supports advice to junior surgeons to choose cases with less dense cataracts as this will help reduce the absolute phaco time and thus minimize endothelial cell loss.

PURPOSE: To analyze the visual outcome after cataract surgery. SETTING: Cataract surgery clinics in 15 European countries. DESIGN: Database study. METHODS: Data were drawn from case series of cataract extractions reported to the European Registry of Quality Outcomes for Cataract and Refractive Surgery database. These data were entered into the database via the Web by surgeons or by transfer from existing national registries or electronic medical record systems. The database contains individual anonymous data on preoperative, intraoperative, and postoperative measurements. RESULTS: Data on 368,256 cataract extractions were available for analysis. The best visual outcome was achieved in age groups 40 to 74 years, and men showed a higher percentage of excellent vision (1.0 [20/20] or better) than women. A corrected distance visual acuity (CDVA) of 0.5 (20/40) or better and of 1.0 (20/20) or better was achieved in 94.3% and 61.3% of cases, respectively. Ocular comorbidity and postoperative complications were the strongest influences on the visual outcome; however, surgical complications and ocular changes requiring complex surgery also had a negative influence. Deterioration of visual acuity after the surgery (n= 6112 [1.7% of all cases]) was most common in patients with a good preoperative visual acuity. CONCLUSIONS: The visual outcomes of cataract surgery were excellent, with 61.3% of patients achieving a corrected distance visual acuity of 1.0 (20/20) or better. Age and sex influenced the visual outcomes, but the greatest influences were short-term postoperative complications, ocular comorbidity, surgical complications, and complex surgery. A weakness of the study could be that some of the data is self-reported to the registry.

BACKGROUND/AIMS: A moderately elevated plasma concentration of the sulphur amino acid homocysteine is an independent risk factor for atherosclerotic vascular disease. Many of the risk factors associated with coronary, cerebral, and peripheral atherosclerotic vascular disease are common to retinal vascular occlusive disease but it is unclear whether elevated plasma concentrations of homocysteine are also associated with such disease. This study assessed the relation between retinal vascular occlusive disease and elevated levels of plasma total homocysteine (tHcy). METHODS: A retrospective case-control study involving hospital based controls and cases with retinal artery, central retinal vein (including hemiretinal vein), and branch retinal vein occlusions was performed. The relation between elevated tHcy, defined as a level greater than or equal to 12 micromol/l and risk of retinal vascular occlusive disease was examined. RESULTS: 87 cases of retinal vascular occlusive disease including 26 cases of retinal artery occlusion, 40 cases with central retinal vein occlusion, and 21 cases of branch retinal vein occlusion were compared with 87 age matched controls. Mean tHcy levels were higher in all disease groups and this difference was significant in patients with retinal artery occlusions (p= 0.032) and patients with central retinal vein occlusion (p=0.0001). When adjusted for known cardiovascular risk factors, tHcy was an independent risk factor for retinal vascular occlusive disease (OR 2.85 (95% CI 1.43-5.68)). CONCLUSIONS: Elevated tHcy is an independent risk factor for retinal vascular occlusive disease. Assessment of tHcy may be important in the investigation and management of patients with retinal vascular occlusive disease.

AIM: To determine the potential role of basic fibroblast growth factor (bFGF) and platelet derived growth factor (PDGF) in the pathogenesis of proliferative vitreoretinopathy (PVR). METHODS: An enzyme linked immunosorbent assay technique was used to determine the quantities of bFGF and PDGF in 38 vitreous samples taken from patients undergoing trans pars plana vitrectomy (PPV) for a variety of vitreoretinal disorders. RESULTS: bFGF levels ranged from undetectable to 318.7 pg/ml. The mean concentration was 27.57 pg/ml. PDGF levels ranged from undetectable to 160 pg/ml, the mean concentration being 40.06 pg/ml. Eight of 13 patients with clinical evidence of retinal detachment (RD) and PVR had significantly elevated bFGF concentrations, whereas only one of 11 patients with RD and no PVR had detectable bFGF; seven of eight patients with RD and PVR had elevated PDGF concentrations in the vitreous, whereas all 10 patients with RD and no PVR had no detectable vitreous PDGF. Eight patients with vitreous haemorrhage had raised PDGF concentrations, and the levels were particularly high (> 120 pg/ml) in those two patients with active neovascularisation. Two out of nine patients with vitreous haemorrhage had raised bFGF levels. CONCLUSIONS: bFGF and PDGF concentrations are elevated in PVR even in the absence of vitreous haemorrhage, and not in patients with RD uncomplicated by PVR. This observation suggests that both cytokines may be involved in the pathogenesis of PVR.

Mutational heterogeneity represents one of the greatest barriers impeding the progress toward the clinic of gene therapies for many dominantly inherited disorders. A general strategy of gene suppression in conjunction with replacement has been proposed to overcome this mutational heterogeneity. In the current study, various aspects of this strategy are explored for a dominant form of the retinal degeneration, retinitis pigmentosa (RP), caused by mutations in the rhodopsin gene (RHO-adRP). While > 200 mutations have been identified in rhodopsin (RHO), in principle, suppression and replacement may be employed to provide a single mutation-independent therapeutic for this form of the disorder. In the study we demonstrate in a transgenic mouse simulating human RHO-adRP that RNA interference-based suppression, together with gene replacement utilizing the endogenous mouse gene as the replacement, provides significant benefit as evaluated by electroretinography (ERG). Moreover, this is mirrored histologically by preservation of photoreceptors. AAV-based vectors were utilized for in vivo delivery of the therapy to the target cell type, the photoreceptors. The results demonstrate that RNAi-based mutation-independent suppression and replacement can provide benefit for RHO-adRP and promote the therapeutic approach as potentially beneficial for other autosomal dominantly inherited disorders.

Age-related macular degeneration (AMD) is the most common form of central retinal blindness globally. Distinct processes of the innate immune system, specifically activation of the NLRP3 inflammasome, have been shown to play a central role in the development of both "dry" and neovascular ("wet") forms of the disease. We show that the inflammatory cytokine interleukin-18 (IL-18) can regulate choroidal neovascularization formation in mice. We observed that exogenous administration of mature recombinant IL-18 has no effect on retinal pigment epithelial (RPE) cell viability, but that overexpression of pro-IL-18 or pro-IL-1β alone can cause RPE cell swelling and subsequent atrophy, a process that can be inhibited by the promotion of autophagy. A direct comparison of local and systemic administration of mature recombinant IL-18 with current anti-VEGF (vascular endothelial growth factor)-based therapeutic strategies shows that IL-18 treatment works effectively alone and more effectively in combination with anti-VEGF therapy and represents a novel therapeutic strategy for the treatment of wet AMD.

Ocular toxocariasis in humans is typically a unilateral disease caused by second-stage larvae of the Toxocara species. Serological evidence of widespread infection in humans provides little information on clinical disease. There is only a single previous estimate of the prevalence of ocular toxocariasis (from Alabama). The present survey examined the extent of consultant-diagnosed toxocaral eye disease among a population of schoolchildren. More than 120,000 participants were surveyed by questionnaire and follow-up. Two sets of control subjects from the same school and from the same county were compared with persons who had ocular toxocariasis. The prevalence of consultant-diagnosed toxocaral eye disease was 6.6 cases per 100,000 persons when only cases regarded as definite by the consultant ophthalmologist were included. This increased to 9.7 cases per 100,000 persons when both definite and strongly suspected cases were included. Geophagia and a history of convulsion were associated with toxocaral eye disease in both of the case-control studies.

PURPOSE OF REVIEW: Radiation maculopathy is a sight-limiting consequence of radiotherapy in the management of uveal melanoma and other intraocular tumors. In this review, we consider clinical, fluorescein angiographic and optical coherence tomographic findings, propose a classification for radiation maculopathy and discuss the management of this condition. RECENT FINDINGS: Radiation macular edema (RME) can be classified by optical coherence tomography into noncystoid or cystoid edema, with foveolar or extrafoveolar involvement. Optical coherence tomographic grading of RME has been found to correlate with visual acuity. Focal argon laser might have some limited benefit in the treatment of RME. Intravitreal triamcinolone and intravitreal antivascular endothelial growth factor agents can be of short-term benefit in the treatment of RME. In a randomized controlled trial, periocular triamcinolone significantly reduced rates of RME and vision loss up to 18 months following plaque radiotherapy for uveal melanoma. SUMMARY: Currently, there is no proven treatment for established RME, though periocular triamcinolone has been shown to have a preventive benefit. An accepted classification system for radiation maculopathy would be of benefit in planning and comparing future treatment trials.

The results of a randomised double-blind clinical trial of 3% acyclovir and 0.5% idoxuridine (IDU) ophthalmic ointments in 60 patients with corneal dendritic ulceration are presented. Ulcers in all 30 patients treated with acyclovir healed compared with 22 (76%) of 29 patients treated with IDU (P < 0.01). Patients treated with acyclovir healed more rapidly (average 4.4 days) than those who received IDU (average 9.2 days) (P < 0.01). No serious side effects were observed, though transient stinging was recorded in 8 patients receiving acyclovir and in 2 patients receiving IDU. Other side effects in the IDU treated group were watering in 2 patients and superficial punctate erosions in 6 patients.

PURPOSE: Orbital myositis occurs in typical and atypical forms. This review summarizes and updates the current state of knowledge of all forms of inflammation affecting extraocular muscle, excluding thyroid-associated orbitopathy. METHODS: A comprehensive literature review of orbital myositis was performed. RESULTS: Orbital myositis typically occurs in an idiopathic acute form, with painful diplopia due to inflammation in 1 or more extraocular muscles of young adult females, which usually responds to a course of oral corticosteroids. Atypical forms include idiopathic chronic or recurrent orbital myositis, and myositis related to systemic autoimmune, inflammatory, and infective conditions. The commonest associated autoimmune condition is inflammatory bowel disease. Immunoglobulin G4-related ophthalmic disease often affects extraocular muscle. Drug reactions and rarely paraneoplastic disease may also cause extraocular muscle inflammation. CONCLUSIONS: Orbital myositis occurs in a typical acute steroid responsive form, but atypical forms related to specific autoimmune and inflammatory conditions are increasingly recognized. Orbital myositis has many similarities to uveitis and would benefit from a systematic approach to nomenclature, diagnosis, and treatment.

While individually classed as rare diseases, hereditary retinal degenerations (IRDs) are the major cause of registered visual handicap in the developed world. Given their hereditary nature, some degree of intergenic heterogeneity was expected, with genes segregating in autosomal dominant, recessive, X-linked recessive, and more rarely in digenic or mitochondrial modes. Today, it is recognized that IRDs, as a group, represent one of the most genetically diverse of hereditary conditions - at least 260 genes having been implicated, with 70 genes identified in the most common IRD, retinitis pigmentosa (RP). However, targeted sequencing studies of exons from known IRD genes have resulted in the identification of candidate mutations in only approximately 60% of IRD cases. Given recent advances in the development of gene-based medicines, characterization of IRD patient cohorts for known IRD genes and elucidation of the molecular pathologies of disease in those remaining unresolved cases has become an endeavor of the highest priority. Here, we provide an outline of progress in this area.

BACKGROUND: Drainage after routine thyroid and parathyroid surgery remains controversial. However, there is increasing evidence from a number of randomized clinical trials (RCTs) suggesting no benefit from the use of drains. METHODS: A systematic review and meta-analysis was performed according to PRISMA guidelines. A literature search was carried out, and RCTs comparing the use of drains versus no drains in patients who underwent thyroid or parathyroid surgery were included. Trials including patients who underwent lateral neck dissection were excluded. Methodological quality was graded and data were extracted by independent reviewers. Risk ratio (RR) or mean difference (MD) with 95 per cent confidence interval (c.i.) was calculated and heterogeneity was assessed. RESULTS: Twenty-five RCTs were included in the meta-analysis comprising 2939 patients. There was no significant difference between the two groups in rate of reoperation for neck haematoma (RR 1·90, 95 per cent c.i. 0·87 to 4·14), ultrasound-assessed fluid volume on day 1 after surgery (MD 2·30 (95 per cent c.i. -0·73 to 5·34) ml), wound collection requiring intervention (RR 0·64, 0·38 to 1·09) or not (RR 0·93, 0·66 to 1·30), transient voice change (RR 2·33, 0·91 to 5·96) and persistent recurrent laryngeal nerve palsy (RR 1·67, 0·22 to 12·51). Length of hospital stay was significantly greater in the drain group (MD 1·25 (0·83 to 1·68) days), as were wound infection rates (RR 2·53, 1·23 to 5·21) and pain score measure using a visual analogue scale from 1 to 10 on day 1 after surgery (MD 1·46 (0·67 to 2·26) units). CONCLUSION: The results indicate that drain use after routine thyroid surgery does not confer a benefit to patients.

BACKGROUND: Unilateral peripheral vestibular loss results in gait and balance impairment, dizziness and oscillopsia. Vestibular rehabilitation benefits patients but optimal treatment remains unknown. Virtual reality is an emerging tool in rehabilitation and provides opportunities to improve both outcomes and patient satisfaction with treatment. The Nintendo Wii Fit Plus® (NWFP) is a low cost virtual reality system that challenges balance and provides visual and auditory feedback. It may augment the motor learning that is required to improve balance and gait, but no trials to date have investigated efficacy. METHODS/DESIGN: In a single (assessor) blind, two centre randomised controlled superiority trial, 80 patients with unilateral peripheral vestibular loss will be randomised to either conventional or virtual reality based (NWFP) vestibular rehabilitation for 6 weeks. The primary outcome measure is gait speed (measured with three dimensional gait analysis). Secondary outcomes include computerised posturography, dynamic visual acuity, and validated questionnaires on dizziness, confidence and anxiety/depression. Outcome will be assessed post treatment (8 weeks) and at 6 months. DISCUSSION: Advances in the gaming industry have allowed mass production of highly sophisticated low cost virtual reality systems that incorporate technology previously not accessible to most therapists and patients. Importantly, they are not confined to rehabilitation departments, can be used at home and provide an accurate record of adherence to exercise. The benefits of providing augmented feedback, increasing intensity of exercise and accurately measuring adherence may improve conventional vestibular rehabilitation but efficacy must first be demonstrated. TRIAL REGISTRATION: Clinical trials.gov identifier: NCT01442623.

More than 100 mutations within the rhodopsin gene have been found to be responsible for some forms of retinitis pigmentosa, a progressive retinal degeneration characterized by night blindness and subsequent disturbance of day vision that may eventually result in total blindness. Congenital stationary night blindness (CSNB) is an uncommon inherited retinal dysfunction in which patients complain of night vision difficulties of a nonprogressive nature only and in which generally there is no involvement of day vision. We report the results of molecular genetic analysis of an Irish family segregating an autosomal dominant form of CSNB in which a previously unreported threonine-to-isoleucine substitution at codon 94 in the rhodopsin gene was found to segregate with the disease. Computer modeling suggests that constitutive activation of transducin by the altered rhodopsin protein may be a mechanism for disease causation in this family. Only two mutations within the rhodopsin gene have been previously reported in patients with congenital stationary night blindness, constitutive activation also having been proposed as a possible disease mechanism.

AIMS: To correlate histological features of ocular adnexal lymphoma using the revised European American lymphoma classification (REAL), with stage of disease at presentation, treatment modalities, and patient outcome. MALT lymphoma defines an extranodal marginal zone B cell lymphoma as outlined in the REAL classification. Comparison groups of patients included those with primary ocular adnexal MALT lymphoma versus primary ocular adnexal lymphomas of other types, MALT lymphoma versus non-MALT lymphomas (primary and secondary), and primary ocular adnexal lymphoma (MALT lymphomas and other types) versus secondary ocular adnexal lymphomas. METHODS: A retrospective review of the National Ophthalmic Pathology Laboratory records identified 20 cases of ocular adnexal lymphoma over a 10 year period which were reclassified using appropriate immunohistochemical stains. Patients' medical records were examined for data including stage of the disease at presentation, mode of treatment, and patient outcome. RESULTS: Among the 20 cases identified 14 had primary ocular adnexal lymphomas. 10 of the primary lymphomas had histological features of MALT lymphoma. One case was a primary ocular adnexal T cell lymphoma, one a follicular centre, follicular B cell lymphoma, and two were large cell B cell lymphomas. Six cases had systemic disease, four large B cell, one follicular centre, follicular B cell, and one mantle cell. A significantly higher proportion of patients with MALT lymphomas had early disease (p = 0.005), initially required local treatment (p = 0.005) and were alive at last follow up (p = 0.001) than those without. Two patients with MALT lymphoma had recurrence of lymphoma which responded to further treatment. CONCLUSIONS: Patients with primary ocular adnexal MALT lymphomas present with localised disease requiring local treatment and have a better outcome compared with patients with other types. As a small percentage of these tumours recur, patients should be followed up indefinitely.

AIM: To identify the risk factors for, and to report the microbiological findings and clinical outcomes of, severe microbial keratitis (MK). METHODS: This was a retrospective study of all cases of presumed MK admitted to a tertiary referral center over a 2-year period (September 2001 to August 2003). Data recorded included demographic data, details relating to possible risk factors, results of microbiological studies, clinical findings at presentation, and clinical and visual outcomes. RESULTS: Ninety patients were admitted with a diagnosis of presumed MK during the study period. The mean age of patients was 45 +/- 32 years, and the male to female ratio was 47:43 (52.2%:47.7%). Predisposing risk factors for MK included contact lens wear (37; 41.1%), anterior segment disease (19; 21.1%), ocular trauma (13; 14.4%), systemic disease (5; 5.6%), and previous ocular surgery (1; 1.1%). Cultured organisms included gram-negative bacteria (17; 51.5%), gram-positive bacteria (11, 33.3%), acanthamoeba (2; 6.1%), and fungi (1; 3%). Visual acuity improved significantly after treatment [mean best-corrected visual acuity (+/-standard deviation) at presentation: 0.76 (+/-0.11); mean best-corrected visual acuity at last follow-up: 0.24 (+/-0.07); P < 0.001]. Secondary surgical procedures were required in 18 (20%) cases, and these included punctal cautery (1; 1.1%), tissue glue repair of corneal perforation (2; 2.2%), tarsorrhaphy (9; 9.9%), Botulinum toxin-induced ptosis (1; 1.1%), penetrating keratoplasty (3; 3.3%), and evisceration (2; 2.2%). CONCLUSIONS: Contact lens wear remains a significant risk factor for severe MK. MK remains a threat to vision and to the eye, but the majority of cases respond to prompt and appropriate antimicrobial therapy.