Using Advanced Bioinformatics Tools to Identify Novel Therapeutic Candidates for Proliferative Vitreoretinopathy.

Purpose: Proliferative vitreoretinopathy (PVR) is the dreaded cause of failure following retinal detachment repair; however, no cures or preventative therapies exist to date. The purpose of this study was to use bioinformatics tools to identify drugs or compounds that interact with biomarkers and pathways involved in PVR pathogenesis that could be eligible for further testing for the prevention and treatment of PVR. Methods: We queried PubMed to compile a comprehensive list of genes described in PVR to date from human studies, animal models, and genomic studies found in the National Center for Biotechnology Information database. Gene enrichment analysis was performed using ToppGene on PVR-related genes against drug-gene interaction databases to construct a pharmacome and estimate the statistical significance of overrepresented compounds. Compounds with no clinical indications were filtered out from the resulting drug lists. Results: Our query identified 34 unique genes associated with PVR. Out of 77,146 candidate drugs or compounds in the drug databases, our analysis revealed multiple drugs and compounds that have significant interactions with genes involved in PVR, including antiproliferatives, corticosteroids, cardiovascular agents, antioxidants, statins, and micronutrients. Top compounds, including curcumin, statins, and cardiovascular agents such as carvedilol and enalapril, have well-established safety profiles and potentially could be readily repurposed for PVR. Other significant compounds such as prednisone and methotrexate have shown promising results in ongoing clinical trials for PVR. Conclusions: This bioinformatics approach of studying drug-gene interactions can identify drugs that may affect genes and pathways implicated in PVR. Predicted bioinformatics studies require further validation by preclinical or clinical studies; however, this unbiased approach could identify potential candidates among existing drugs and compounds that could be repurposed for PVR and guide future investigations. Translational Relevance: Novel repurposable drug therapies for PVR can be found using advanced bioinformatics models.

[Advantages of corticosteroids in managing acute bacterial postoperative endophthalmitis]. / Intérêt des corticoïdes dans la prise en charge de l'endophtalmie postopératoire aiguë bactérienne.

Most studies show a trend toward a beneficial or at least neutral effect of associating corticosteroids and antibiotics. However, caution must be taken, with various factors considered: the type, virulence, and size of the inoculum, and the treatment chosen. Early intravitreal administration of 400 microg of dexamethasone seems to be beneficial in treating postoperative Staphylococcus epidermidis-related endophthalmitis. However, a large-scale prospective, randomized, controlled study is mandatory to gain evidence supporting steroid therapy in postoperative endophthalmitis.

Técnica para injeção intravítrea de drogas no tratamento de doenças vítreorretinianas / Technique of intravitreal drug injection for therapy of vitreoretinal diseases

A injeção intravítrea é atualmente a técnica mais utilizada no tratamento de várias doenças vítreorretinianas. Neste artigo serão discutidas a técnica e complicações da injeção intravítrea de drogas no tratamento de doenças vítreorretinianas. Em resumo, a técnica envolve várias etapas. Inicialmente dias antes da injeção pode-se realizar aplicação de antibióticos e acetazolamida para prevenção de infecção e redução da pressão intra-ocular. Antes do procedimento deve-se dilatar a pupila e executar anestesia tópica com colírios ou gel anestésico. A antissepsia pré-operatória envolve aplicação de colírios de iodo-povidona 5 por cento no fundo de saco conjuntival ao menos 10 minutos antes do procedimento. A injeção deve ser realizada no centro cirúrgico com uso de luvas estéreis e máscara pelo cirurgião. O olho deve ser exposto com blefarostato estéril, e proteção com "sterile-drape" para evitar contato entre a agulha e pálpebras/cílios. A agulha deve ser posicionada no momento da injeção a 3,5 - 4 mm do limbo, e leve mobilização da conjuntiva com um cotonete estéril ou uma pinça facilitam a penetração da agulha através da conjuntiva e esclera. A agulha deve ser inserida gentilmente para dentro da cavidade vítrea até 6 mm de profundidade. Imediatamente após a injeção o paciente deve ser examinado por técnica de oftalmoscopia binocular indireta. Caso a acuidade visual seja ausência de percepção luminosa ou oclusão vascular arterial retiniana seja observada, terapias para diminuição da pressão como paracentese na camada anterior ou massagem por oculopressão diretamente sobre o globo ocular devem ser imediatamente tomadas. A alta ambulatorial deve ser realizada quando o cirurgião estiver ciente da ausência de complicações intra-operatórias; o paciente deverá sair do centro cirúrgico com curativo oclusivo. O paciente deve ser submetido a exame oftalmológico completo no primeiro dia pós-operatório quando associação de antibióticos com corticosteróides...

Intravitreal injections are the standard technique applied in the treatment of some vitreoretinal diseases. In this paper the technique and complications of intravitreal injections are presented. In summary, the procedure involves various consecutive steps. Initially, days before the treatment topical antibiotics and acetazolamide may be prescribed for reduction of the ocular flora and intraocular pressure. Before the injection, the pupil should be dilated and topical anesthesia should be achieved. Injection shall be performed in the operating room under sterile conditions, the surgeon should wear surgical gloves and mask. The eye is then exposed with sterile blepharostat and sterile-drape thereby providing protection of the needle against the contact with contaminated lashes and lids. Injection is done 3.5 mm from the limbus through the pars plana. The needle should be inserted up to 6 mm into the vitreous cavity. Immediately after injection the patient must be examined by indirect ophthalmoscopy to verify central artery perfusion and complications as vitreous hemorrhage. Visual acuity better than light perception should be detected right after injection. If persistent central retinal artery occlusion is diagnosed, anterior chamber paracentesis should be performed. The patient may be discharged with an occlusive patch. Examination at the first postoperative day should exclude various complications such as endophthalmitis, and topical steroid and antibiotics should be prescribed for 7 days. Some complications encountered after intravitreal injections include retinal detachment, vitreous hemorrhage, cataract, uveitis, ocular hypertension, or endophthalmitis.

Combined proton beam radiotherapy and transpupillary thermotherapy for large uveal melanomas: a randomized study of 151 patients.

INTRODUCTION: Exudation from the tumour scar and glaucoma can be major problems after proton beam irradiation of uveal melanoma and can sometimes lead to secondary enucleation. We conducted a randomized study to determine whether systematic transpupillary thermotherapy (TTT) after proton beam radiotherapy could have a beneficial effect. PATIENTS AND METHOD: Between February 1999 and April 2003, all the patients treated by proton beam radiotherapy for uveal melanomas >/=7 mm thick or >/=15 mm in diameter were included in this study after giving their informed consent. One half of the patients received proton beam radiotherapy alone (60 Gy in 4 fractions) and the other half received the same dose of proton beam radiotherapy followed by TTT at 1, 6 and 12 months. All the information concerning the initial tumour parameters, treatments and follow-up was recorded and a statistical analysis was performed. RESULTS: We randomized 151 patients. The median follow-up was 38 months. The 2 groups of patients were similar in terms of age, gender and tumour characteristics. The patients treated with TTT showed a greater reduction of tumour thickness (p = 0.06), less retinal detachment at the latest follow-up (p = 0.14) and a lower secondary enucleation rate (p = 0.02). DISCUSSION: The present study is the first randomized analysis to demonstrate a significant decrease in the secondary enucleation rate in patients treated with TTT after proton beam radiotherapy. Further studies should be performed to determine whether TTT could be beneficial to smaller tumours and to define its optimal dose.

[Progressing myopia in children: does it need treatment or not?].

The purpose of the case study was to evaluate the remote consequences of a complex of laser and repeated surgical sclerorestorative procedures made in progressing myopia and its complications. Three hundred and forty-six children, aged 8-10, with rapidly progressing uncomplicated myopia of 4.25 to 9.5 D were shared between 2 groups. Two hundred and forty patients of the experimental group were made sclerorestorative procedures and transscleral low-energy laser stimulation of the ciliary muscle by means of infrared laser MACDEL-09. No such treatment was applied to patients of the control group. When indicated, preventive laser coagulation of the retina was made in both groups. The dynamic 10-year follow-up over the status of refraction and eye bottom showed that the complex scheme of repeated sclerorestorative procedures and low-energy laser treatment combined with preventive peripheral laser coagulation of the retina cut the rate of progressing myopia and prevented peripheral vitreoretinal dystrophy and retinal detachment in children and teenagers with progressing myopia.

Does vitreoretinal surgery under local anaesthesia result in missed fellow eye pathology?

PURPOSE: There has been a significant increase in the number of vitreoretinal procedures being performed under local anaesthesia over the past few years. This trend is expected to continue. This study was performed to investigate whether by undertaking retinal detachment surgery under local anaesthesia fellow eye examination was compromised. DESIGN: This was a prospective, consecutive, blind, observational study. SETTING: This study was performed at a tertiary referral vitreoretinal unit in a teaching hospital. STUDY POPULATION: In all, 108 consecutive patients undergoing retinal detachment surgery under general anaesthesia were included. OBSERVATION PROCEDURES: Patients were examined independently by different retinal surgeons pre- and intraoperatively. MAIN OUTCOME MEASURES: The findings of the two examiners were compared and differences were analysed. RESULTS: There were 108 patients in this study, 57 of these were males and 51 females. The mean age was 59.01 years (range 16-91). Of these 108 eyes, 48/108 (49.08%) the preoperative examination was regarded as unsatisfactory by the examiner. Over 34% of eyes had fellow eye pathology when examined preoperatively but there were nine (8.33%) eyes in which additional lesions were found intraoperatively. CONCLUSION: General anaesthesia should be considered for patients in whom preoperative fellow eye examination is unsatisfactory.

Prophylactic treatment of the fellow eye of patients with retinal detachment: a retrospective study.

BACKGROUND: Controversy exists over the prophylactic treatment of predisposing lesions to prevent retinal detachment. METHODS: Seven hundred sixty consecutive phakic fellow eyes with rhegmatogenous retinal detachment in the first eye were examined by the same vitreoretinal surgeon before detachment surgery and for a follow-up period ranging from 1 to 72 months, with a mean of 36 months. During this period, in 305 fellow eyes (40.1%) predisposing retinal lesions were present and prophylactic treatments (photocoagulation, cryotherapy or scleral buckle) were performed independently of vitreous status. The results were then compared with the incidence of bilateral RD without prophylaxis reported in Folk and Burton's study of 1982; the two study's data were well matched and showed no significant difference in regards to age, sex, incidence myopia > or =-2.5 and incidence of lattice degeneration. The objective was to investigate whether or not prophylactic treatment is able to avert retinal detachment in the fellow eye. RESULTS: The age of the patients with peripheral retinal lesions was correlated inversely with the presence of myopia. Nine eyes out of 305 eyes treated (2.9%) developed a retinal detachment, reducing the rate of bilateral retinal detachment to 1.2% (9 eyes out of 760). CONCLUSIONS: This incidence of bilaterality (1.2%) was lower than the incidence of retinal detachment in fellow eyes not prophylactically treated as reported in the literature, and there exists a highly statistically significant difference between this study's data of 1.2% after prophylaxis and a 13.4% rate of bilaterality as reported by Folk without prophylaxis (P=0.0000).

Is prophylactic 360-degree laser retinopexy protective? Risk factors for retinal redetachment after removal of silicone oil.

OBJECTIVES: To identify risk factors for retinal redetachment after removal of silicone oil. To determine the effectiveness of prophylactic laser in preventing retinal redetachment after removal of silicone oil. DESIGN: A nonrandomized retrospective comparative interventional trial. PARTICIPANTS: Three hundred seventy-six patients undergoing vitrectomy with silicone oil tamponade for rhegmatogenous retinal detachment at one institution over a 4-year period. Two hundred eighty-seven patients with fully attached retinas subsequently underwent removal of silicone oil. One hundred thirty-eight cases had undergone prophylactic 360 degrees laser retinopexy before removal of silicone oil, either at the time of their final retinal reattachment procedure (n = 36) or as a separate supplementary procedure (n = 102). METHODS: A retrospective case note review was performed to identify clinical and demographic factors associated with increased or reduced odds of retinal redetachment after removal of silicone oil. Both univariate and multiple variable analysis were used to identify significant risk factors. MAIN OUTCOME MEASURES: Incidence of retinal redetachment after removal of silicone oil. RESULTS: Median follow-up after removal of silicone oil was 272 days. Three hundred sixty-degree prophylactic laser retinopexy was associated with a reduction from 26% to 14% in the incidence of redetachment after removal of silicone oil (adjusted odds ratio, 0.42; 95% confidence interval, 0.22-0.78; P = 0.006). Patients requiring further retinal reattachment surgery after their first oil procedure were at twice the odds of re-detachment after oil removal (adjusted odds ratio, 2.10; 95% confidence interval, 1.03-4.26; P = 0.04). CONCLUSIONS: The need for retinal reattachment surgery subsequent to a first silicone oil procedure was associated with twice the odds of retinal redetachment after removal of silicone oil. Prophylactic laser retinopexy may halve the incidence of retinal redetachment after removal of silicone oil.

Limiting the proliferation and reactivity of retinal Müller cells during experimental retinal detachment: the value of oxygen supplementation.

PURPOSE: To assess the role of hypoxia in inducing the proliferation, hypertrophy, and dysfunction of Muller cells in detached retina and the effectiveness of supplemental oxygen in limiting these reactions. METHODS: Retinal detachments were produced in the right eye of each of 13 cats; the cats survived surgery for 3 days, during which six were kept in normoxia (room air, 21%) and seven in hyperoxia (70% oxygen). Retinas were labeled for proliferation with an antibody (MIB-1) to a cell cycle protein (Ki-67), for evidence of hypertrophy employing antibodies to the intermediate filament protein glial fibrillary acidic protein (GFAP) and to beta-tubulin and for disturbance of glutamate neurochemistry employing antibodies to glutamate to a glutamate receptor (GluR-2) and to glutamine synthetase. RESULTS: Results from the two animals kept in normoxia after retinal detachment confirmed previous reports that detachment caused the proliferation of Muller cells, the hypertrophy of Muller cell processes, and the disruption of glutamate recycling by Muller cells. Oxygen supplementation during detachment reduced Muller cell proliferation and hypertrophy and reduced the abnormalities in the distributions of glutamate, GluR-2, and glutamine synthetase. CONCLUSIONS: Oxygen supplementation reduced the reaction of retinal Muller cells to retinal detachment, limiting their proliferation and helping to maintain their normal structure and function. In the clinical setting, oxygen supplementation between diagnosis and reattachment surgery may reduce the incidence and severity of glial-based complications, such as proliferative vitreoretinopathy.

Inhibition of preretinal proliferation by free radical scavengers in an experimental model of tractional retinal detachment.

An original model of experimental proliferative vitreoretinopathy consisting of an intravitreal injection of 10(7) human platelets and 1 IU of hyaluronidase was developed in pigmented rabbits. One group of 11 eyes served as non-treated controls. Two other groups of 11 eyes each received Ginkgo Biloba extracts which are known free radical scavengers (EGb761, Ipsen, France), given orally in two doses, 50 mg kg-1 day-1 and 100 mg kg-1 day-1 respectively, from the day after the platelet injection to the end of the first month. The fourth group (11 eyes) was intravenously injected with a unique dose of 15000 U kg-1 of superoxide dismutase the day after platelet injection. All animals were ophthalmoscopically examined in a masked fashion twice a week for 1 month and killed at the end of the experiment for histological analysis. Vitreoretinal proliferation was graded according to a six-stage classification. The non-treated eyes showed a high rate of retinal detachment (11/11 eyes), with a mean final score of 3.91 +/- 0.94. Histologic examinations consistently showed retinal retraction by fibrocellular preretinal membranes spreading to both surfaces of the retina as well as preretinal neovascularization. Many cells positively reacted with anti-cytokeratin or anti-vimentin monoclonal antibodies. All three groups of treated eyes showed significantly lower scores of vitreoretinal proliferation at almost each time point of examination. At the end of the study, five retinal detachments were found in the EGb761 group at 50 mg kg-1 day-1 (mean final score 2.45 +/- 1.37), only one in the group receiving 100 mg kg-1 day-1 (mean score 1.64 +/- 1.03), and one in the SOD treated eyes. The lowest mean score found at day 28 was observed in the group receiving SOD (1.36 +/- 1.43), although this group presented during the first 3 weeks with an intense vitreous and sometimes anterior chamber inflammation. Statistical comparison between treatments did not show significant differences at most time points of the study. These results demonstrate that antioxidants may efficiently prevent preretinal proliferation, in clinicopathological entities where free radicals had not yet been shown to play a direct pathogenetic role. They are also among the first attempts for inhibiting preretinal proliferations with non-cytotoxic agents and using a non-ocular route.

[Homoharringtonine on traumatic vitreous proliferation].

Rabbit models of intraocular proliferation were made by intravitreal injection of cultured homologous conjunctival fibroblasts. 0.025 mg of homoharringtonine, a Chinese herbal drug that potently inhibited rabbit fibroblast proliferation in vitro, or distilled water, as control, was injected into the vitreous immediately after the cell transplantation. On days 1, 3, 7, 10 after the injection, the homoharringtonine eyes were given same doses of the agent subconjunctivally. After 21 days, these eyes developed significantly less intravitreal proliferation than the control eyes, and no retinal detachment occurred while 54.5% of the control eyes did. Light microscopy and TEM revealed no toxic effect on tissues in the medicated eyes. Hence, homoharringtonine may be of clinical value in the treatment of post-traumatic proliferation in the eye.

Improvement in efficacy of corticosteroid therapy in an animal model of proliferative vitreoretinopathy by pretreatment.

Intraocular injection of the corticosteroid triamcinolone acetonide reduces the incidence of retinal detachment in rabbit eyes injected with tissue-cultured fibroblasts. When the steroid was injected simultaneously with the cells, a reduction of retinal detachment from 93% (control) to 75% (treated) was achieved on day 28. When the steroid was injected 24 h preceding cell injection, the reduction of retinal detachment was from 85% (control) to 43% (treated). The development of retinal detachment is caused by proliferation of injected fibroblasts. Reduction of this proliferation is probably achieved partially through direct inhibition of mitosis, but more important may be the reduction of the reactive inflammatory process.

Localized retinectomy indications in the treatment and prevention of retinal detachment.

Retinectomy can be helpful in several cases: retinal inversion and giant tears when the edges are rolled up, and when vitreous strands are implanted on to pieces of the tear flaps; the approach to the subretinal area (subretinal glial strands, subretinal fluid drainage, subretinal foreign bodies); nondissectable areas of retinal retraction (retinal incarceration, vitreo-retinal proliferation, etc.). Most of these retinectomies have to be supplemented by vitrectomy followed by a silicone oil injection, with peroperatory cryotherapy or argon laser photocoagulation.

Fluorouracil therapy for proliferative vitreoretinopathy after vitrectomy.

Fluorouracil effectively inhibits epiretinal membrane formation and traction retinal detachment after vitrectomy surgery. When 0.5 mg of fluorouracil was administered intraocularly every 24 hours for seven days, traction retinal detachment two weeks after the intraocular injection of 200,000 cultured retinal pigment epithelial cells occurred in 12 of 12 control eyes but in only six of 14 eyes treated with fluorouracil (P less than .001). Four weeks after cell injection, eight of 12 eyes treated with fluorouracil had traction retinal detachments whereas 12 of 12 control eyes did (P less than .001). The height of the traction retinal detachment four weeks after intraocular injection of 200,000 cultured retinal pigment epithelial cells was reduced 50% in eyes treated with 0.5 mg of fluorouracil every 24 hours for seven days compared to control eyes (P less than .001). When the number of injected retinal pigment epithelial cells was increased to 400,000 cells and 1.25 mg of fluorouracil was administered intraocularly every 24 hours for seven days, traction retinal detachment two weeks after injection occurred in 15 of 15 eyes in the control group but in none of ten eyes in the treated group. Four weeks after cell injection, eight of eight eyes in the control group and five of five eyes in the fluorouracil-treated group had detachments and the mean height of the detachments in the two groups was equal. Autoradiography of the epiretinal membranes in eyes injected with 200,000 cultured retinal pigment epithelial cells and labeled for two hours with tritiated thymidine showed that 0.8% of the epiretinal cell nuclei were labeled two weeks after cell injection but that no labeled cells were present in the fluorouracil-treated eyes. Tritiated thymidine labeling of epiretinal cells in the fluorouracil-treated eyes was first noted three weeks after the cell injection. The presence of tritiated thymidine labeling in the fluorouracil-treated eyes correlated with an increase in the number of epiretinal cells and an increase in the incidence of traction retinal detachment.