[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.

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.

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.

[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.

[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.

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.

Trauma of the globe: State of art in global and in China.

Current states of traumatic eye injury are reviewed in terms of epidemiology in the developing countries and developed countries, causes of the trauma, eye injury types, traumatic eye injury diagnostic methods and treatments. Trauma-caused vision-threatening conditions such as open global injury, traumatic optic neuropathy and proliferative vitreoretinopathy are particularly discussed. Also the most updated clinic research in China as Eye Injury Vitrectomy Study is discussed. At the end, the current achievements and research in traumatic eye injury in the world are summerized.

[Proliferative vitreoretinopathy: modern view on etiology and pathogenesis].

Studies on etiology and pathogenesis of proliferative vitreoretinopathy are necessitated by the absence of a unified theory, which would provide a clear understanding of causes and mechanisms of the disease. The results of recent investigations allow to consider proliferative vitreoretinopathy as an uncontrollable plastic process caused by certain changes in the retina aimed at survival of its cells under oxidative stress. This approach enables preclinical indication of the process and development of new therapies.

Microphthalmia-associated transcription factor (MITF) promotes differentiation of human retinal pigment epithelium (RPE) by regulating microRNAs-204/211 expression.

The retinal pigment epithelium (RPE) plays a fundamental role in maintaining visual function and dedifferentiation of RPE contributes to the pathophysiology of several ocular diseases. To identify microRNAs (miRNAs) that may be involved in RPE differentiation, we compared the miRNA expression profiles of differentiated primary human fetal RPE (hfRPE) cells to dedifferentiated hfRPE cells. We found that miR-204/211, the two most highly expressed miRNAs in the RPE, were significantly down-regulated in dedifferentiated hfRPE cells. Importantly, transfection of pre-miR-204/211 into hfRPE cells promoted differentiation whereas adding miR-204/211 inhibitors led to their dedifferentiation. Microphthalmia-associated transcription factor (MITF) is a key regulator of RPE differentiation that was also down-regulated in dedifferentiated hfRPE cells. MITF knockdown decreased miR-204/211 expression and caused hfRPE dedifferentiation. Significantly, co-transfection of MITF siRNA with pre-miR-204/211 rescued RPE phenotype. Collectively, our data show that miR-204/211 promote RPE differentiation, suggesting that miR-204/211-based therapeutics may be effective treatments for diseases that involve RPE dedifferentiation such as proliferative vitreoretinopathy.

Diabetic retinopathy: pathogenesis, clinical grading, management and future developments.

Decades of research into the pathophysiology and management of diabetic retinopathy have revolutionized our understanding of the disease process. Diabetic retinopathy is now more accurately defined as a neurovascular rather than a microvascular disease as neurodegenerative disease precedes and coexists with microvascular changes. However, the complexities of the pathways involved in different stages of disease severity continue to remain a challenging issue for drug discovery. Currently, laser photocoagulation is the mainstay of treatment for proliferative diabetic retinopathy, but is gradually being superseded for diabetic macular oedema. However, it is destructive and at best results in a gradual but modest improvement in vision in the long term. So, diabetic retinopathy remains the most prevalent cause of visual impairment in the working-age population despite established screening programmes, early diagnosis and treatment of the condition. The recent discovery of inhibitors of vascular endothelial growth factor is revolutionizing the management of diabetic retinopathy, particularly diabetic macular oedema. However, not all patients respond to anti-vascular endothelial growth factor agents, reinforcing the fact that diabetic retinopathy is a multifactorial disease. Studies are still required to improve our understanding of how retinal structure correlates with visual function. It is hoped that these will lead to better characterization of the disease phenotype based on treatment responses to different agents and allow an algorithm to be developed that will guide the management of diabetic retinopathy and diabetic macular oedema at different stages of severity.

A novel approach to attenuate proliferative vitreoretinopathy using ultrasound-targeted microbubble destruction and recombinant adeno-associated virus-mediated RNA interference targeting transforming growth factor-ß2 and platelet-derived growth factor-B.

BACKGROUND: To date, with the exception of surgery, there are no satisfactory treatments available for proliferative vitreoretinopathy (PVR). Ultrasound-targeted microbubble destruction (UTMD) represents a new approach for the gene therapy of eye diseases. The present study aimed to investigate the feasibility of the attenuation of PVR by a combinatorial use of UTMD and recombinant adeno-associated virus (rAAV)-mediated RNA interference (RNAi) targeting transforming growth factor (TGF)-ß2 and platelet-derived growth factor (PDGF)-B. METHODS: One hundred and eighty rats of the PVR model were averagely divided into six groups (G). The left eyes, respectively, received an intravitreal injection as follows: normal saline (G1), rAAV2-control small interfering RNA (siRNA) (G2), rAAV2-TGF-ß2-siRNA (G3), rAAV2-PDGF-B-siRNA (G4), rAAV2-TGF-ß2-siRNA and rAAV2-PDGF-B-siRNA (G5, G6) on day 3 after PVR induction. In G6, a condition of UTMD was used additionally. On days 14 and 28, pathological changes of eye fundus were assessed by ophthalmoscopic and histopathologic examination, and the protein and mRNA levels of TGF-ß2 and PDGF-B expression were tested using enzyme-linked immunosorbent assay and a reverse transcriptase-polymerase chain reaction, respectively. RESULTS: The average grade scales of proliferation and the protein and mRNA expression levels of TGF-ß2 and PDGF-B in G6 were all lower than that in G5 on day 28 (p<0.05, unpaired t-test). They were all lower in G5 and G6 than in G1, G2, G3 and G4 on day 28 (p<0.05, one-way analysis of variance), although the protein and mRNA expression levels of PDGF-B in G6 did not differ from that in G1, G2, G3, G4 and G5 on day 14. CONCLUSIONS: The combinatorial use of UTMD and rAAV2-mediated RNAi targeting TGF-ß2 and PDGF-B can serve as a novel approach to attenuate PVR.

[Heavy tamponade in complicated inferior retinal detachment]. / Schwere Tamponade bei komplizierten inferioren Netzhautablösungen.

BACKGROUND: Retinal detachment with inferior proliferative vitreoretinopathy is a difficult to treat problem. The aim of our study was to assess the safety and efficacy of Densiron in the clinical management of complicated retinal detachment. HISTORY AND SIGNS: 6 eyes of 6 consecutive patients presenting with a retinal detachment with inferior proliferative vitreoretinopathy grade 3 were treated with pars plana vitrectomy and injection of Densiron. The mean age of the patients was 61 years. 3 patients had a previous unsuccessful vitreoretinal surgery and 3 patients had Densiron as a first procedure. The extent of detachment was at least 2 or more quadrants with macular involvement in 3 cases. Preoperatively the mean visual acuity was 29.2 letters with ETDRS. THERAPY AND OUTCOME: Densiron was removed after an average of 58 days. 5 patients achieved retinal re-attachment without further tamponade, and 1 patient after additional injection of conventional silicon oil. 4 - 6 weeks after removal of Densiron the mean visual acuity was 50.2 letters with ETDRS. The most common complication was an elevated intraocular pressure during endotamponade, which resolved following removal of the agent. CONCLUSIONS: Densiron improves inferior tamponade, and in clinical practice may be considered to increase the anatomic success rate in selected cases of complicated retinal detachment with inferior proliferative vitreoretinopathy.

[Genetic implications and therapeutic possibilities in the course of hereditary macular pathology and vitreoretinopathies]. / Implicatii genetice si posibilitati terapeutice în heredoipatii maculare evolutive si vitreoretinopati.

There are many hereditary diseases in ophthalmology including retinal dystrophies--diseases of great heterogeneity requiring genetic determination, individual or in entire family.

Midterm results of low-dose intravitreal triamcinolone as adjunctive treatment for proliferative vitreoretinopathy.

PURPOSE: To evaluate the midterm anatomical and functional outcomes of intravitreal injection of low-dose triamcinolone acetonide in silicone oil-filled eyes as an adjunctive treatment for proliferative vitreoretinopathy. METHODS: This is a retrospective interventional case series. Patients with proliferative vitreoretinopathy grade C or D received pars plana vitrectomy combined with silicone oil tamponade and intravitreal injection of 2 mg of triamcinolone acetonide in the first stage and silicone oil removal in the second stage. Primary outcome measures were retinal reattachment rate and best-corrected visual acuity. RESULTS: In all, 37 eyes from 37 patients were included in this study. The mean follow-up duration was 22.9 ± 9.6 months. Retina was reattached in 36 (97.3%) eyes at the last visit. The mean best-corrected visual acuity was 1.76 ± 0.56 logMAR at baseline, which improved to 0.87 ± 0.60 logMAR at the last visit (P < 0.001). Best-corrected visual acuity increased in 31 (83.8%) eyes, remained unchanged in 5 (13.5%) eyes, and decreased in 1 (2.7%) eye at last visit compared with baseline. CONCLUSION: Low-dose (2 mg) triamcinolone acetonide intravitreal injection as an adjunct to vitrectomy and silicone oil tamponade in treating proliferative vitreoretinopathy (grade C or D) appears to be effective and safe.

Patomechanisms in proliferative vitreoretinopathy.

Proliferative vitreoretinopathy (PVR) remains the most common cause of recurrent retinal detachment following retinal detachment surgery. The development of PVR is a complex process involving humoral and cellular factors. Surgical treatment of PVR, which consists of removal of the fibrous membranes and restoration of physiological anatomic ocular conditions is often unsuccessful. Therefore the surgery should by backed up by local medication to inhibit new formation of proliferative lesions. Unfortunately, there is no satisfactory antiproliferative treatment available so far. Proliferative vitreoretinopathy remains a therapeutic challenge.

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).