[Biomechanics of diabetic vitreopapillary traction syndrome]. / Biomekhanika diabeticheskogo vitreopapillyarnogo traktsionnogo sindroma.

Diabetic vitreopapillary traction syndrome (VPT) is a variant of diabetic retinopathy (DR) that can lead to vision loss in advanced stages. This review reports on the biomechanics of the vitreous in the pathogenesis of proliferative DR, in particular diabetic VPT. The article analyzes and summarizes literature data, presents the views of different authors on this problem, and provides the results of Russian and foreign scientific research on this pathology. It is concluded that further research in this area can lead to a significant improvement in the results of therapy, timely diagnosis, and preservation of vision in patients with DR.

CRISPR-Based Genome Editing as a New Therapeutic Tool in Retinal Diseases.

Retinal diseases are the primary reasons for severe visual defects and irreversible blindness. Retinal diseases are also inherited and acquired. Both of them are caused by mutations in genes or disruptions in specific gene expression, which can be treated by gene-editing therapy. Clustered regularly interspaced short palindromic repeats (CRISPR-Cas9) system is a frontier of gene-editing tools with great potential for therapeutic applications in the ophthalmology field to modify abnormal genes and treat the genome or epigenome-related retinal diseases. The CRISPR system is able to edit and trim the gene include deletion, insertion, inhibition, activation, replacing, remodeling, epigenetic alteration, and modify the gene expression. CRISPR-based genome editing techniques have indicated the enormous potential to treat retinal diseases that previous treatment was not available for them. Also, recent CRISPR genome surgery experiments have shown the improvement of patient's vision who suffered from severe visual loss. In this article, we review the applications of the CRISPR-Cas9 system in human or animal models for treating retinal diseases such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), and proliferative vitreoretinopathy (PVR), then we survey limitations of CRISPR system for clinical therapy.

Hirudo (Leech) for proliferative vitreous retinopathy: A protocol for systemic review and meta-analysis.

INTRODUCTION: Proliferative vitreous retinopathy (PVR) is characterized by proliferation of cells and contraction of membranes on either the retinal surface or in the vitreous cavity, which leads to retinal detachment and visual impairment. PVR is commonly seen in patients with rhegmatogenous retinal detachment and diabetic retinopathy, which seriously affects the patient's work and life. Previous studies indicated that Hirudo (Leech) or compound prescription containing Hirudo (Leech) for treatment of PVR would be effective. However, due to the lack of evidence, there are no specific methods or suggestions, so it is necessary to carry out systematic evaluations on Hirudo (Leech) for PVR and provide effective evidence for further research. METHODS AND ANALYSIS: The following 8 databases will be searched: Cochrane Central Register of Controlled Trials, PubMed, MEDLINE, EMBASE, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, VIP Database, and Wanfang Database. All randomized controlled trials in English or Chinese related to Hirudo (Leech) for PVR will be included. Outcomes will include change in Vitreous opacity, Vision changes, production of the anterior macular membrane, and retinal detachment again. The incidence of adverse events will be assessed for safety evaluation. Study inclusion, data extraction and quality assessment will be performed independently by 2 reviewers. Assessment of risk of bias and data synthesis will be performed using Review Manager V.5.3. RESULTS: In this systematic review and meta-analysis, we will synthesize the studies to assess the safety and efficacy of Hirudo (Leech) for PVR. CONCLUSION: The summary of our study will clarify whether Hirudo (Leech) therapy could be an efficient and safe method for PVR, which can further guide the promotion and application of it. OPEN SCIENCE FRAMEWORK OSF REGISTRATION NUMBER: 10.17605/OSF.IO/FP7VG (https://osf.io/fp7vg).

Perioperative anti-vascular endothelial growth factor agents treatment in patients undergoing vitrectomy for complicated proliferative diabetic retinopathy: a network meta-analysis.

Currently, controversies regarding the optimal time-point of anti-vascular endothelial growth factor (VEGF) pretreatment before pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR) still exist. To clarify this, we conducted a network meta-analysis, 26 randomized controlled trials including 1806 PDR patients were included. Compared with the sham group, performing anti-VEGF injection at preoperative (Pre-Op) 6 to 14 days could significantly improve post-operative best-corrected visual acuity (BCVA) and decrease the incidence of recurrent vitreous hemorrhage (VH). Meanwhile, it could significantly reduce the duration of surgery. Performing anti-VEGF injection at Pre-Op more than 14 days, 6 to 14 days or 1 to 5 days could significantly reduce the incidence of intra-operative bleeding, while no significant benefit existed at the end of PPV (P > 0.05). No significant difference existed between all those strategies and sham group in reducing the rate of silicone oil tamponade. Based on currently available evidence, performing the anti-VEGF pretreatment at pre-operative 6 to 14 days showed best efficacy in improving post-operative BCVA, reducing the duration of surgery and incidence of recurrent VH, it also achieves satisfactory effect in reducing the incidence of intra-operative bleeding.

Intra-silicone Oil Injection of Methotrexate in Retinal Reattachment Surgery for Proliferative Vitreoretinopathy.

Purpose: To evaluate the role of intrasilicone oil injection of methotrexate (MTX) at the end of vitrectomy surgery for rhegmatogenous retinal detachment (RRD) associated with proliferative vitreoretinopathy (PVR).Methods: In this prospective comparative study, pars plana vitrectomy and retinal reattachment were performed for eyes with RRD with grade C PVR. In the MTX group, 250 µg MTX was injected into the silicone oil at the end of surgery. The rate of retinal redetachment associated with PVR was assessed.Results: In total, 44 eyes of 44 patients (22 in the MTX group and 22 controls) were included. Baseline characteristics were similar between the two groups. Retinal redetachment occurred in one eye (4.5%) in the MTX group and five eyes (22.7%) in the control group (p = 0.18). The change in visual acuity was similar between the two groups at final visit (p = 0.15).Conclusion: The rate of redetachment associated with PVR was lower after intrasilicone injection of MTX at the end of vitrectomy for RRD with severe PVR compared to control group; however, the difference was not statistically significant.

Proliferative vitreoretinopathy: revised concepts of pathogenesis and adjunctive treatment.

Proliferative vitreoretinopathy (PVR) remains a significant challenge for vitreoretinal surgeons. Its incidence, as a complication of retinal detachment, does not appear to have altered despite improvement in surgical techniques. Extensive laboratory research has been undertaken to investigate the pathogenesis of PVR and the use of adjunctive mediations to modify the disease process. To date these studies have not resulted in improved clinical management of PVR. Previous concepts of the pathogenesis of PVR, focussing on a central role for RPE cells, may be flawed and could potentially have contributed to the lack of clinical advances. Revised clinical classifications and novel approaches to adjunctive treatment may in the future result in improved surgical outcomes.

Blockade of MDM2 with inactive Cas9 prevents epithelial to mesenchymal transition in retinal pigment epithelial cells.

Epithelial to mesenchymal transition (EMT) plays an important role in the pathogenesis of proliferative vitreoretinopathy (PVR). We aimed to demonstrate the role of mouse double minute 2 (MDM2) in transforming growth factor-beta 2 (TGF-ß2)-induced EMT in human retinal pigment epithelial cells (RPEs). Immunofluorescence was used to assess MDM2 expression in epiretinal membranes (ERMs) from patients with PVR. A single guide (sg)RNA targeting the second promoter of MDM2 was cloned into a mutant lentiviral Clustered Regularly Interspaced Short Palindromic Repeats (lentiCRISPR) v2 (D10A and H840A) vector for expressing nuclease dead Cas9 (dCas9)/MDM2-sgRNA in RPEs. In addition, MDM2-sgRNA was also cloned into a pLV-sgRNA-dCas9-Kruppel associated box (KRAB) vector for expressing dCas9 fused with a transcriptional repressor KRAB/MDM2-sgRNA. TGF-ß2-induced expression of MDM2 and EMT biomarkers were assessed by quantitative polymerase chain reaction (q-PCR), western blot, or immunofluorescence. Wound-healing and proliferation assays were used to evaluate the role of MDM2 in TGF-ß2-induced responses in RPEs. As a result, we found that MDM2 was expressed obviously in ERMs, and that TGF-ß2-induced expression of MDM2 and EMT biomarkers Fibronectin, N-cadherin and Vimentin in RPEs. Importantly, we discovered that the dCas9/MDM2-sgRNA blocked TGF-ß2-induced expression of MDM2 and the EMT biomarkers without affecting their basal expression, whereas the dCas9-KRAB/MDM2-sgRNA suppressed basal MDM2 expression in RPEs. These cells could not be maintained continuously because their viability was greatly reduced. Next, we found that Nutlin-3, a small molecule blocking the interaction of MDM2 with p53, inhibited TGF-ß2-induced expression of Fibronectin and N-cadherin but not Vimentin in RPEs, indicating that MDM2 functions in both p53-dependent and -independent pathways. Finally, our experimental data demonstrated that dCas9/MDM2-sgRNA suppressed TGF-ß2-dependent cell proliferation and migration without disturbing the unstimulated basal activity. In conclusion, the CRISPR/dCas9 capability for blocking TGF-ß2-induced expression of MDM2 and EMT biomarkers can be exploited for a therapeutic approach to PVR.

Repeated Injection of Methotrexate into Silicone Oil-Filled Eyes for Grade C Proliferative Vitreoretinopathy: A Pilot Study.

PURPOSE: To evaluate the effects of repeated intra-silicone oil (SO) injections of methotrexate (MTX) on the outcomes of surgery for rhegmatogenous retinal detachment (RRD) with grade C proliferative vitreoretinopathy (PVR-C). METHODS: In this prospective pilot case series, eyes with RRD and PVR-C underwent pars plana vitrectomy and intraocular injection of SO. At the conclusion of the procedure, 250 µg of MTX was injected into the SO-filled vitreous cavity. Intra-SO injection was repeated at weeks 3 and 6; the minimum follow-up period was 6 months. The main outcome measure was retinal reattachment rate. RESULTS: Eleven eyes of 11 patients (mean age, 52.73 ± 18.01 years) were included. The mean follow-up period was 9 ± 3 months (range, 6-15 months). Total retinal detachment with anterior and/or posterior PVR-C was present in all eyes before surgery. Mean preoperative best-corrected visual acuity (BCVA) was 2.62 ± 0.04 logMAR. All operated eyes exhibited retinal reattachment posterior to the equator during the follow-up period. Mean postoperative BCVA was significantly improved to 1.02 ± 0.51 logMAR (p = 0.003). No ocular or systemic side effects were observed. CONCLUSION: Repeated intra-SO injection of MTX as an adjunctive therapy for RRD complicated by PVR showed promising results and was not associated with adverse effects. Further studies are needed to confirm its possible beneficial effects on the final anatomic and functional outcomes in these cases.

Adiponectin: A potential candidate for treating fibrosis in posterior segment of the eye.

Fibrosis in ocular tissues causes severe visual deterioration and blindness in patients with glaucoma, cataract, age related macular degeneration (AMD) and diabetic retinopathy (DR). Currently available anti-fibrotic agents exhibit undesirous cytotoxic effects and thus prove ineffective to treat post-surgical fibrosis. Accordingly, there is a need to develop efficient and novel anti-fibrotic agents. Adiponectin (APN), an adipokine from adipocytes is increased in the aqueous and vitreous humor of the patients with micro-angiopathy and chronic inflammation. Furthermore, it is reported to be elevated in the subretinal fluid, vitreous and epiretinal membrane of patients with AMD, proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR) respectively. Since APN has anti-angiogenic activity and reduces VEGF levels, we hypothesize that APN might regulate the angio-fibrotic switch and drive the formation of fibrovascular membrane at advanced stages of AMD, PVR and PDR. Intriguingly, APN is shown to inhibit liver, cardiac and pulmonary fibrosis, yet it accelerates renal fibrosis. Therefore, the factors such as tissue and cell type, disease specific pathological milieu and the choice of APN receptor interaction could determine the pro- or anti-fibrotic nature of APN. We speculate that APN could play a profibrotic role in the posterior segment of the eye.

Periostin in vitreoretinal diseases.

Proliferative vitreoretinal diseases such as diabetic retinopathy, proliferative vitreoretinopathy (PVR), and age-related macular degeneration are a leading cause of decreased vision and blindness in developed countries. In these diseases, retinal fibro(vascular) membrane (FVM) formation above and beneath the retina plays an important role. Gene expression profiling of human FVMs revealed significant upregulation of periostin. Subsequent analyses demonstrated increased periostin expression in the vitreous of patients with both proliferative diabetic retinopathy and PVR. Immunohistochemical analysis showed co-localization of periostin with α-SMA and M2 macrophage markers in FVMs. In vitro, periostin blockade inhibited migration and adhesion induced by PVR vitreous and transforming growth factor-ß2 (TGF-ß2). In vivo, a novel single-stranded RNAi agent targeting periostin showed the inhibitory effect on experimental retinal and choroidal FVM formation without affecting the viability of retinal cells. These results indicated that periostin is a pivotal molecule for FVM formation and a promising therapeutic target for these proliferative vitreoretinal diseases.

MicroRNA-containing extracellular vesicles released from endothelial colony-forming cells modulate angiogenesis during ischaemic retinopathy.

Endothelial colony-forming cells (ECFCs) are a defined subtype of endothelial progenitors that modulate vascular repair and promote perfusion in ischaemic tissues. Their paracrine activity on resident vasculature is ill-defined, but mediated, at least in part, by the transfer of extracellular vesicles (EVs). To evaluate the potential of isolated EVs to provide an alternative to cell-based therapies, we first performed a physical and molecular characterization of those released by ECFCs. Their effects upon endothelial cells in vitro and angiogenesis in vivo in a model of proliferative retinopathy were assessed. The EVs expressed typical markers CD9 and CD63 and formed a heterogeneous population ranging in size from ~60 to 1500 nm by electron microscopy. ECFC EVs were taken up by endothelial cells and increased cell migration. This was reflected by microarray analyses which showed significant changes in expression of genes associated with angiogenesis. Sequencing of small RNAs in ECFCs and their EVs showed that multiple microRNAs are highly expressed and concentrated in EVs. The functional categories significantly enriched for the predicted target genes of these microRNAs included angiogenesis. Intravitreally delivered ECFC EVs were associated with the vasculature and significantly reduced the avascular area in a mouse oxygen-induced retinopathy model. Our findings confirm the potential of isolated EVs to influence endothelial cell function and act as a therapy to modulate angiogenesis. The functions associated with the specific microRNAs detected in ECFC EVs support a role for microRNA transfer in mediating the observed effects.

Intraocular Dexamethasone Implant as Adjunct to Silicone Oil Tamponade for Proliferative Vitreoretinopathy.

Background Proliferative vitreoretinopathy (PVR) occurs in 10 % of patients with retinal detachment and is characterized by excessive epi-, sub- or intraretinal contraction. Corticosteroids have been shown to counter this contraction. Patients and Methods Retrospective review of 5 patients (3 females, 2 males) with recurrent retinal detachment with stage C PVR. The mean age was 61.2 ± 20.5 years and myopia > - 5.0 dioptres was present in 3 eyes. Patients were treated with 23 g vitrectomy, retinectomy and endolaser, dexamethasone (Ozurdex®) injection under perfluorocarbone and 5500 cs silicone oil tamponade. Results After a total follow-up of 8.8 ± 6.4 months with silicone oil tamponade, the Ozurdex® implant was localised in the macula in 1 case, and in 4 cases behind the iris with a completely attached retina. Preoperative intraocular pressure was 11.0 ± 4.0 mmHg, which remained stable at 7.8 ± 3.5 mmHg at the end of the final follow-up. No localised adverse effects were observed of the implant on the retina or the iris. Conclusions The dexamethasone implant Ozurdex® is well tolerated in conjunction with silicone oil tamponade in eyes with retinal detachment and PVR. The implant may be a potential candidate for the prevention of PVR.

[Ocular Hypotension: How the Retina Surgeon Sees the Causes and Therapeutic Options]. / Okuläre Hypotonie - Ursachen und therapeutische Möglichkeiten aus Sicht des Netzhautchirurgen.

Ocular hypotension is a result of a lack of production or a loss of intraocular fluid. Intraocular inflammation, drugs, or proliferative vitreoretinopathy (PVR) with overgrowth of the ciliary body can result in reduced secretion of intraocular fluid. Loss of intraocular fluid can result from external loss, such as in fistulating surgery or trauma, or internally, e.g. from cyclodialysis clefts or retinal detachment. In this review, we discuss the causal therapy of ocular hypotension: fixation of the ciliary body, removal of ciliary body membranes, surgery for PVR, choice of tamponade, possibilities and limitations of an iris diaphragm, and pharmacological options.

A phase III, multi-centre, double-masked randomised controlled trial of adjunctive intraocular and peri-ocular steroid (triamcinolone acetonide) versus standard treatment in eyes undergoing vitreoretinal surgery for open globe trauma (ASCOT): statistical analysis plan.

BACKGROUND: Open globe ocular trauma complicated by intraocular scarring (proliferative vitreoretinopathy) is a relatively rare, blinding, but potentially treatable condition for which, at present, surgery is often unsatisfactory and visual results frequently poor. To date, no pharmacological adjuncts to surgery have been proven to be effective. The aim of the Adjunctive Steroid Combination in Ocular Trauma (ASCOT) randomised controlled trial is to determine whether adjunctive steroid (triamcinolone acetonide), given at the time of surgery, can improve the outcome of vitreoretinal surgery in patients with open globe ocular trauma. This article presents the statistical analysis plan for the main publication as approved and signed off by the Trial Steering Committee prior to the first data extraction for the Data Monitoring Committee meeting report. METHODS/DESIGN: ASCOT is a pragmatic, multi-centre, parallel-group, double-masked randomised controlled trial. The aim of the study is to recruit from 20-25 centres in the United Kingdom and randomise 300 eyes (from 300 patients) into two treatment arms. Both groups will receive standard surgical treatment and care; the intervention arm will additionally receive a pre-operative steroid combination (triamcinolone acetonide) into the vitreous cavity consisting of 4 mg/0.1 ml and 40 mg/1 ml sub-Tenon's. Participants will be followed for 6 months post-surgery. The primary outcome is the proportion of patients achieving a clinically meaning improvement in visual acuity in the study eye at 6 months after initial surgery, defined as a 10 letter score improvement in the ETDRS (the standard scale to test visual acuity). TRIAL REGISTRATION: ISRCTN30012492 . Registered on 5 September 2014. EudraCT2014-002193-37 . Registered on 5 September 2014.

[Interpretation of Pathological Changes at the Vitreoretinal Interface]. / Interpretation pathologischer Veränderungen am vitreoretinalen Interface.

For decades there was a general consensus about diagnostic investigations and surgical treatment of symptomatic pathological changes in the vitreomacular interface (VMI). The introduction of SD-OCT imaging helped in the understanding of the pathogenetic processes at this interface and risk factors were defined for the macular traction syndrome, epiretinal membrane (ERM) and macular hole. After approval of ocriplasmin for non-surgical treatment, a new classification based on treatment outcome and new imaging techniques was established. Precise separation of physiological, age-related changes in the VMI and pathological changes was then possible. Clinically relevant aspects in the diagnostic testing and treatment of diseases of the VMI are reported in this literature review.

Development of medical treatment for eye injuries in the mainland of China over the past decade.

In the article, the development of medical treatment for eye injuries in the mainland of China was reviewed. According to the data provided in Eye Injury Vitrectomy Study (EIVS), 27% of 72 eyes with no light perception (NLP) gained recovery in term of antomy and visual function. Vitrectomy initiated at more than 4 weeks after open eye injury is an independent risk factor for developing PVR. Prognosis of anatomy and visual function of the injured eye with PVR is markedly worse than that without PVR. Serious injuries of ciliary body, choroid and retina are three key parts of the eye with NLP. The concept that the treatment of the eye injury gradually focus on the whole globe is embodied. The data from 13575 in patients with traumatic eyes in 14 hospitals revealed that the rate of immediate enucleation was remarkable reduced with comparison of 20 years ago.