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High intraocular pressure (IOP) is one of the early complications after pars plana vitrectomy (PPV), which may cause glaucoma and poor visual prognosis secondary to surgery. Proliferative vitreoretinopathy (PVR) is one of the complications of retinal detachment (RD) and is the main reason for the poor prognosis, which is related to different kinds of cytokines. It's essential for the basic mechanism to analyze the relative aqueous humor cytokine profiles with IOP after PPV for RD. In this study, we have collected the aqueous humor of 16 patients and qualified 27 cytokines using Luminex and compared biomarkers with the high IOP group and the normal group. As a result, the concentrations of VEGF, IL-6, FGF2, and G-CSF upregulated significantly (P < 0.05), while VEGFR2 downregulated significantly (P < 0.05) in the high IOP group. IL-6 was positively correlated with high IOP (r = 0.561, P = 0.041). Meanwhile, the concentrations of IL-6 (r = 0.543, P = 0.03), IL-5 (r = 0.576, P = 0.019), IL-15 (r = 0.614, P = 0.011), IL-4 (r = 0.517, P = 0.04), ICAM-1 (r = 0.611, P = 0.012), and G-CSF (r = 0.636, P = 0.008) were significantly associated with preoperative PVR classification, and the aqueous humor levels of IL-4 (r = 0.567, P = 0.022), HGF (r = 0.701, P = 0.005), and MCP-1 (r = 0.565, P = 0.035) are significant relative to laser points. Hence, cytokines might potentially be the therapeutic target of high IOP after PPV., (© 2024. The Author(s).)

Background: The aim of this study was to identify inflammatory biomarkers in traumatic proliferative vitreoretinopathy (TPVR) patients and further validate the expression curve of particular biomarkers in the rabbit TPVR model., Methods: The Olink Inflammation Panel was used to compare the differentially expressed proteins (DEPs) in the vitreous of TPVR patients 7-14 days after open globe injury (OGI) ( N = 19) and macular hole patients ( N = 22), followed by correlation analysis between DEPs and clinical signs, protein-protein interaction (PPI) analysis, area under the receiver operating characteristic curve (AUC) analysis, and function enrichment analysis. A TPVR rabbit model was established and expression levels of candidate interleukin family members (IL-6, IL-7, and IL-33) were measured by enzyme-linked immunosorbent assay (ELISA) at 0, 1, 3, 7, 10, 14, and 28 days after OGI., Results: Forty-eight DEPs were detected between the two groups. Correlation analysis showed that CXCL5, EN-RAGE, IL-7, ADA, CD5, CCL25, CASP8, TWEAK, and IL-33 were significantly correlated with clinical signs including ocular wound characteristics, PVR scoring, PVR recurrence, and final visual acuity ( R = 0.467-0.699, p < 0.05), and all with optimal AUC values (0.7344-1). Correlations between DEP analysis and PPI analysis further verified that IL-6, IL-7, IL-8, IL-33, HGF, and CXCL5 were highly interactive (combined score: 0.669-0.983). These DEPs were enriched in novel pathways such as cancer signaling pathway ( N = 14, p < 0.000). Vitreous levels of IL-6, IL-7, and IL-33 in the rabbit TPVR model displayed consistency with the trend in Olink data, all exhibiting marked differential expression 1 day following the OGI., Conclusion: IL-7, IL-33, EN-RAGE, TWEAK, CXCL5, and CD5 may be potential biomarkers for TPVR pathogenesis and prognosis, and early post-injury may be an ideal time for TPVR intervention targeting interleukin family biomarkers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Guo, Wang, Yu, Shi, Liang, Chen, He and Yan.)

Purpose: Proliferative vitreoretinopathy (PVR) is the most common cause of failure of surgically repaired rhegmatogenous retinal detachment (RRD). Chemically induced and cell injection PVR models do not fully simulate the clinical characteristics of PVR in the post-RRD context. There is an unmet need for translational models in which to study mechanisms and treatments specific to RRD-PVR., Methods: RRD was induced in adult Dutch Belted rabbits. Posterior segments were fixed or processed for RNA sequencing at 6 hours and 2, 7, 14, and 35 days after induction. Histochemical staining and immunolabeling for glial fibrillary acidic protein, alpha smooth muscle actin, vascular endothelial growth factor receptor 2, CD68, and RPE 65 kDa protein were performed, and labeling intensity was scored. Single cell RNA sequencing was performed., Results: Acute histopathological changes included intravitreal and intraretinal hemorrhage, leukocytic vitritis, chorioretinitis, and retinal rarefaction. Chronic lesions showed retinal atrophy, gliosis, fibrotic subretinal membranes, and epiretinal fibrovascular proliferation. Fibrillar collagen was present in the fibrocellular and fibrovascular membranes in chronic lesions. Moderate to strong labeling of glia and vasculature was detected in chronic lesions. At day 14, most cells profiled by single cell sequencing were identified as Mϋller glia and microglia, consistent with immunolabeling. Expression of several fibrillar collagen genes was upregulated in chronic lesions., Conclusions: Histological and transcriptional features of this rabbit model simulate important features of human RRD-PVR, including the transition to chronic intraretinal and periretinal fibrosis. This animal model of RRD with features of PVR will enable further research on targeted treatment interventions.

Background: Eyes sustaining open globe trauma are at high risk of severe visual impairment. Proliferative vitreoretinopathy is the most common cause of retinal detachment and visual loss in eyes with open globe trauma. There is evidence from experimental studies and pilot clinical trials that the use of adjunctive steroid medication triamcinolone acetonide can reduce the incidence of proliferative vitreoretinopathy and improve outcomes of surgery for open globe trauma., Objective: The Adjunctive Steroid Combination in Ocular Trauma or ASCOT study aimed to investigate the clinical effectiveness of adjunctive triamcinolone acetonide given at the time of vitreoretinal surgery for open globe trauma., Design: A phase 3 multicentre double-masked randomised controlled trial randomising patients undergoing vitrectomy following open globe trauma to either adjunctive triamcinolone acetonide or standard care., Setting: Hospital vitreoretinal surgical services dealing with open globe trauma., Participants: Patients undergoing vitrectomy surgery who had sustained open globe trauma., Interventions: Triamcinolone acetonide 4 mg/0.1 ml into the vitreous cavity and 40 mg/1 ml sub-Tenon's or standard vitreoretinal surgery and postoperative care., Main Outcome Measures: The primary outcome was the proportion of patients with at least 10 letters of improvement in corrected visual acuity at six months. Secondary outcomes included retinal detachment secondary to proliferative vitreoretinopathy, retinal reattachment, macula reattachment, tractional retinal detachment, number of operations, hypotony, elevated intraocular pressure and quality of life. Health-related quality of life was assessed using the EuroQol Five Domain and Visual Function Questionnaire 25 questionnaires., Results: A total of 280 patients were randomised; 129 were analysed from the control group and 130 from the treatment group. The treatment group appeared, by chance, to have more severe pathology on presentation. The primary outcome (improvement in visual acuity) and principal secondary outcome (change in visual acuity) did not demonstrate any treatment benefit for triamcinolone acetonide. The proportion of patients with improvement in visual acuity was 47% for triamcinolone acetonide and 43% for standard care (odds ratio 1.03, 95% confidence interval 0.61 to 1.75, p = 0.908); the baseline adjusted mean difference in the six-month change in visual acuity was -2.65 (95% confidence interval -9.22 to 3.92, p = 0.430) for triamcinolone acetonide relative to control. Similarly, the secondary outcome measures failed to show any treatment benefit. For two of the secondary outcome measures, stable complete retinal reattachment and stable macular retinal reattachment, outcomes for the treatment group were significantly worse for triamcinolone acetonide at the 5% level (respectively, odds ratio 0.59, 95% confidence interval 0.36 to 0.99, p = 0.044 and odds ratio 0.59, 95% confidence interval 0.35 to 0.98, p = 0.041) compared with control in favour of control. The cost of the intervention was £132 per patient. Health economics outcome measures (Early Treatment Diabetic Retinopathy Study, Visual Function Questionnaire 25 and EuroQol Five Dimensions) did not demonstrate any significant difference in quality-adjusted life-years., Conclusions: The use of combined intraocular and sub-Tenon's capsule triamcinolone acetonide is not recommended as an adjunct to vitrectomy surgery for intraocular trauma. Secondary outcome measures are suggestive of a negative effect of the adjunct, although the treatment group appeared to have more severe pathology on presentation., Future Work: The use of alternative adjunctive medications in cases undergoing surgery for open globe trauma should be investigated. Refinement of clinical grading and case selection will enable better trail design for future studies., Trial Registration: This trial is registered as ISRCTN 30012492, EudraCT number 2014-002193-37, REC 14/LNO/1428, IRAS 156358, Local R&D registration CHAD 1031., Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (12/35/64) and will be published in full in Health Technology Assessment ; Vol. 27, No. 12. See the NIHR Journals Library website for further project information.

Purpose: We previously hypothesized a causal relationship between vitreoschisis-induced vitreous cortex remnants (VCR) and the development of proliferative vitreoretinopathy (PVR). This study aims to substantiate this association through histopathological analysis of surgical specimens in support of strategies to improve therapeutic outcomes., Methods: A descriptive, prospective, non-consecutive case series. Histopathological and immunohistochemical analyses were performed on membranes removed from the peripheral retinal surface during initial vitrectomy for primary rhegmatogenous retinal detachment (RRD) (n = 11) or recurrent retinal detachment (n = 12). The clinical aspect of the membranes ranged from loose-meshed membranes visualized with triamcinolone to more fibrotic membranes stained with trypan blue., Results: Consistent with the clinical presentation, histopathological analysis revealed membranes with different area characteristics. Paucicellular lamellar collagen-rich areas, suggestive of VCR, appeared to transition to areas of increased cellularity and eventually more fibrotic areas of low cellularity. Five different area characteristics could be identified that seemed to correspond to five histopathological stages in PVR formation, with lamellar VCR collagen acting as an essential precondition: 1. Lamellar collagen, low cellularity (hyalocytes). 2. Lamellar collagen, increased cellularity (hyalocytes, glial cells). 3. Lamellar collagen, high cellularity (macrophages, glial cells, RPE-cells). 4. Early fibrosis, decreased cellularity (myofibroblasts). 5. Fibrosis, low cellularity (myofibroblasts)., Conclusion: These findings confirm the role of VCR in preretinal PVR formation posterior to the vitreous base. We propose that the presence of VCR over the retinal surface should be qualified as a risk factor for PVR formation. Detection and adequate removal of VCR may improve the success rate of vitreoretinal surgeries., (© 2022 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

The specific changes linked to de novo development of postoperative PVR have remained elusive and were the object of the underlying study. Vitreous fluid (VF) was obtained at the beginning of vitrectomy from 65 eyes that underwent vitrectomy for primary rhegmatogenous retinal detachment (RRD) without preoperative PVR. Eyes developing postoperative PVR within 6 months after re-attachment surgery were compared to those which did not regarding the preoperative concentrations of 43 cytokines and chemokines in the VF, using multiplex beads analysis. For all comparisons Holm's correction was applied in order to control for multiple comparisons. Twelve out of 65 eyes (18.5%) developed PVR postoperatively. While 12 of the chemokines and cytokines presented concentration differences on a statistical level of p < 0.05 (CXCL5, CCL11, CCL24, CCL26, GM-CSF, IFN-γ, CCL8, CCL7, MIF, MIG/CXCL9, CCL19, and CCL25), CXCL5 was the only cytokine with sufficiently robust difference in its VF concentrations to achieve significance in eyes developing postoperative PVR compared to eyes without PVR. CXCL5 may represent a potent biomarker for the de novo development of postoperative PVR. In line with its pathophysiological role in the development of PVR, it might serve as a basis for the development of urgently needed preventive options., (© 2021. The Author(s).)

This study was aim to investigate whether the progression of proliferative vitreoretinopathy (PVR) depended on the activation of Yes-associated protein (YAP) and the subsequent epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cell. The effect of YAP activation on retinal fibrosis in a PVR mouse model and in human ARPE-19 cells in vitro was studied. After treated with transforming growth factor-β2(TGF-β2), the expressions of fibrogenic molecules, YAP activation and the TGF-β2-Smad signalling pathway in ARPE-19 cells were detected by Western blot and immunocytochemical analyses. The effect of YAP on change in fibrosis and EMT was tested by knockdown experiment using verteporfin (YAP inhibitor). YAP was upregulated in the PVR mouse model and during TGF-β2-induced RPE cell EMT. In an in vivo study, verteporfin attenuated PVR progression in a mouse model. Additionally, YAP knockdown retained phenotype of RPE cells and ameliorated TGF-β2-induced migration, gel contraction and EMT in vitro. YAP knockdown inhibited the TGF-β2-induced upregulation of connective tissue growth factor (CTGF), smooth muscle actin (SMA-α) and fibronectin. YAP was essential for the TGF-β2-induced nuclear translocation and phosphorylation of Smad2/3. Our work provides direct evidence that YAP is an essential regulator of EMT and profibrotic responses in PVR and indicates that YAP inhibition could be a potential target in PVR therapeutic intervention., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Purpose: Uncontrolled coagulation reactions contribute to pathological fibroproliferation in several organs, and yet their role in proliferative vitreoretinopathy (PVR) remains to be elucidated. In this study, we evaluated the profibrotic effects of FXa in RPE cells and in a mouse model of PVR., Methods: FXa levels in the eyes of traumatic PVR patients and rabbit models of mechanical ocular trauma was measured by ELISA and immunohistochemistry. FXa-induced RPE EMT was assessed by examining cell proliferation, migration, tight junction changes, and expression of fibrotic markers. For in vivo study, FXa was injected into dispase-injured eyes, then intraocular fibrosis was evaluated by histological analysis and Western blotting. The therapeutic effect of FXa inhibitor was also examined in PVR mouse models., Results: Vitreous FXa were higher in patients with traumatic PVR compared to patients with macular hole. Moreover, expressions of FXa and PAR1 were found in the epiretinal membranes from traumatic PVR patients. Vitreous FXa were markedly increased after mechanical ocular trauma in rabbits. In vitro, FXa stimulated RPE EMT characterized as ZO-1 disruption, compromised cell polarity, and increased fibronectin expressions. Co-injection of FXa and dispase in mice induced more severely damaged retinal structures, and increased α-SMA expressions than FXa or dispase treatment alone. Oral FXa or thrombin inhibitors significantly blocked intraocular fibrosis in PVR mouse models. FXa promoted phospho-activation of p38 in ARPE19 cells, which was dependent on PAR1. Moreover, TGF-βR inhibitor also significantly alleviated FXa-induced intraocular fibrosis in mice., Conclusions: FXa promotes intraocular fibrosis in mice via mechanisms involving RPE activation.

We aimed to assess the feasibility of machine learning (ML) algorithm design to predict proliferative vitreoretinopathy (PVR) by ophthalmologists without coding experience using automated ML (AutoML). The study was a retrospective cohort study of 506 eyes who underwent pars plana vitrectomy for rhegmatogenous retinal detachment (RRD) by a single surgeon at a tertiary-care hospital between 2012 and 2019. Two ophthalmologists without coding experience used an interactive application in MATLAB to build and evaluate ML algorithms for the prediction of postoperative PVR using clinical data from the electronic health records. The clinical features associated with postoperative PVR were determined by univariate feature selection. The area under the curve (AUC) for predicting postoperative PVR was better for models that included pre-existing PVR as an input. The quadratic support vector machine (SVM) model built using all selected clinical features had an AUC of 0.90, a sensitivity of 63.0%, and a specificity of 97.8%. An optimized Naïve Bayes algorithm that did not include pre-existing PVR as an input feature had an AUC of 0.81, a sensitivity of 54.3%, and a specificity of 92.4%. In conclusion, the development of ML models for the prediction of PVR by ophthalmologists without coding experience is feasible. Input from a data scientist might still be needed to tackle class imbalance-a common challenge in ML classification using real-world clinical data.

Proliferative vitreoretinopathy (PVR) is a blinding eye disease. Epithelial-mesenchymal transition (EMT) of RPE cells plays an important role in the pathogenesis of PVR. In the current study, we sought to investigate the role of the methyl-CpG-binding protein 2 (MeCP2), especially P-MeCP2-421 in the pathogenesis of PVR. The expressions of P-MeCP2-421, P-MeCP2-80, PPAR-γ and the double labelling of P-MeCP2-421 with α-SMA, cytokeratin, TGF-β and PPAR-γ in human PVR membranes were analysed by immunohistochemistry. The effect of knocking down MeCP2 using siRNA on the expressions of α-SMA, phospho-Smad2/3, collagen I, fibronectin and PPAR-γ; the expression of α-SMA stimulated by recombinant MeCP2 in ARPE-19; and the effect of TGF-β and 5-AZA treatment on PPAR-γ expression were analysed by Western blot. Chromatin immunoprecipitation was used to determine the binding of MeCP2 to TGF-β. Our results showed that P-MeCP2-421 was highly expressed in PVR membranes and was double labelled with α-SMA, cytokeratin and TGF-β, knocking down MeCP2 inhibited the activation of Smad2/3 and the expression of collagen I and fibronectin induced by TGF-β. TGF-β inhibited the expression of PPAR-γ, silence of MeCP2 by siRNA or using MeCP2 inhibitor (5-AZA) increased the expression of PPAR-γ. α-SMA was up-regulated by the treatment of recombinant MeCP2. Importantly, we found that MeCP2 bound to TGF-β as demonstrated by Chip assay. The results suggest that MeCP2 especially P-MeCP2-421 may play a significant role in the pathogenesis of PVR and targeting MeCP2 may be a potential therapeutic approach for the treatment of PVR., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

To describe the 25-year surgical trends, long-term outcomes and risk factors affecting the outcomes of giant retinal tear-related rhegmatogenous retinal detachments (GRT-RRD). Patients' demographics, pre-operative characteristics, risk factors, operative procedures and post-operative outcomes were collected and divided into three groups - Group A: 1991 to 2015 (overall); Group B: 1991 to 2005, and Group C: 2006 to 2015. Functional and anatomical successes were monitored over a 5-year period. Multivariate logistic regression analysis was performed to identify the risk factors related to functional and anatomical success.127 eyes of 127 patients were included in the study. At 5 th year, 69.4% patients had visual acuity (VA) < logMAR 1.0 with 87.5% primary anatomical success rate. While the functional outcome remained the same between group B and C, there was an increase in the anatomical success from 89.7% to 100%, albeit not statistically significant. Patients with worse presenting VA, 150 degrees or more of giant retina tear, macula-detached status and presence of PVR were associated with VA of> logMAR 1.0 (all p < 0.05). The types of surgery (TPPV vs combined SB/TPPV), number of breaks, lens extraction and additional cryotherapy were not associated with the functional or anatomical success. In conclusion, the GRT-RRD functional and structural outcomes were comparable between 1991-2005 and 2006-2015, albeit a statistically insignificant improvement of anatomical outcome over the past 25 years. Worse presenting VA, 150 degrees or more of giant retinal tear, detached macula and presence of PVR were associated with poorer visual outcome.

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.

Purpose: To investigate the clinical characteristics and visual outcomes of patients with work-related open globe injuries (OGIs) and compare them with patients with non-work-related OGIs., Design: Retrospective, observational, multicentre, case-control study., Methods: A total of 374 patients with work-related OGIs and 170 patients with non-work-related OGIs who presented to hospitals that belong to the Japan-Clinical Research of Study group from 2005 to 2015 were included in this study. Clinical data including age, sex, initial and final visual acuity, type of open globe injury, lens status, zone of injury, wound length, and presence of proliferative vitreoretinopathy, retinal detachment, expulsive haemorrhage, and endophthalmitis were recorded., Main Outcome Measures: Visual acuity. Results Work-related OGIs were associated with younger age, male sex, better initial and final visual acuity, more laceration, smaller wounds, presence of retinal detachment, and expulsive haemorrhage, compared with non-work-related OGIs. Multiple regression analysis revealed that final visual acuity is significantly associated with initial visual acuity, wound length, and the presence of proliferative vitreoretinopathy in work-related OGIs., Conclusions: Work-related OGIs showed better visual outcomes than other OGIs. Initial visual acuity, wound length, and the presence of proliferative vitreoretinopathy are predictors of visual outcomes in patients with work-related OGIs.

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-β2)-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-β2-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-β2-induced responses in RPEs. As a result, we found that MDM2 was expressed obviously in ERMs, and that TGF-β2-induced expression of MDM2 and EMT biomarkers Fibronectin, N-cadherin and Vimentin in RPEs. Importantly, we discovered that the dCas9/MDM2-sgRNA blocked TGF-β2-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-β2-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-β2-dependent cell proliferation and migration without disturbing the unstimulated basal activity. In conclusion, the CRISPR/dCas9 capability for blocking TGF-β2-induced expression of MDM2 and EMT biomarkers can be exploited for a therapeutic approach to PVR.

Aim: To assess the long-term anatomical and functional outcomes in addition to complications of a new surgical technique of localized intraocular application of mitomycin C (MMC) to prevent proliferative vitreoretinopathy (PVR) in eyes with open globe trauma., Methods: Prospective non-comparative interventional case series of 16 consecutive eyes with perforating and deep choroidal impact foreign body injuries presenting over a 2-year period. Patients underwent vitrectomy with intraocular application of MMC at the site of the chorioretinal injury and were followed-up for 1 year. The primary outcome measure was the rate of postoperative PVR. Secondary outcome measures were number of vitreoretinal surgeries (VRS) required, best corrected visual acuity (BCVA), final anatomical success rate and globe survival rate (GSR)., Results: Patients underwent VRS at a mean time of 8.5 ± 4.6 days after the injury. Postoperative PVR developed in 2 (13 %) eyes and required only one additional VRS each. One other eye underwent further peeling of an epimacular membrane. BCVA improved from mean LogMAR 3.08 ± 0.72 preoperatively to 0.66 ± 0.79 at 1 year. All 10 eyes without a macular injury had a final BCVA of LogMAR 0.40 or better. The final anatomical success rate was 94% and GSR rate was 100%. There were no complications related to the intraocular use of MMC., Conclusions: Vitrectomy and intraocular application of Mitomycin C may have a potential role in reducing the rate of post traumatic PVR and improving anatomical and functional outcomes in eyes with perforating and deep choroidal impact foreign body injuries.

Background: To compare the abundance of vitreous proteins between the patients with proliferative diabetic retinopathy (PDR) and idiopathic macular hole (IMH)., Methods: In this study, we performed mass spectrometry-based label-free quantitative proteomics analysis of vitreous samples from type 2 diabetic patients with PDR (n = 9) and IMH subjects (n = 9) and identified the abundance of 610 proteins., Results: Out of 610 proteins, 64 proteins (Group A) were unique to PDR patients, while 212 proteins (Group B) could be identified in IMH vitreous only. Among the other 334 proteins that could be detected in both PDR and IMH eyes, 62 proteins differed significantly (p < 0.05, fold change > 2), which included 52 proteins (Group C) and 10 proteins (Group D) over- and under-expressed in PDR vitreous compared with the control. All proteins in these four groups were counted as significant proteins in our study., Conclusions: We identified and quantified 610 proteins in total, which included 338 significant proteins in our study. Protein distribution analysis demonstrated a clear separation of protein expression in PDR and IMH. The protein function analysis illustrated that immunity and transport related proteins might be associated with PDR.

Purpose: As some surgical procedures have been shown to increase postoperative flare values and thus contribute to blood-ocular barrier breakdown, retinal reattachment surgery might influence the risk of developing proliferative vitreoretinopathy (PVR). Therefore, we investigated whether postoperative aqueous flare values are a surrogate marker for the development of postoperative PVR., Methods: We prospectively included 195 patients with primary rhegmatogenous retinal detachment (RRD) and measured aqueous laser flare preoperatively, and at 2 and 6 weeks postoperatively. Postoperative PVR was defined as reoperation for redetachment due to PVR membranes, within 6 months of initial surgery. Logistic regression and receiver operating characteristic (ROC) analysis determined whether higher postoperative flare values were associated with an increased risk of developing PVR later on., Results: Reoperation for postoperative PVR was needed in 12 (6.2%) patients; in 18 (9.2%), reoperation was not related to PVR. The median flare value for patients who would develop PVR was significantly higher than that of patients who would not develop PVR, both at 2 weeks (p = 0.001) and 6 weeks (p < 0.001) postoperatively. Logistic regression analyses showed that a higher flare value significantly increased the odds of developing PVR, either at 2 weeks [odds ratio (OR) 1.027; 95% CI: 1.010-1.044] or 6 weeks (OR 1.076; 95% CI: 1.038-1.115)., Conclusion: Flare values both at 2 and 6 weeks postoperatively seem a good surrogate marker in terms of sensitivity and specificity for the development of postoperative PVR but have only a modest positive predictive value. The 2-week value would be more useful in terms of early recognition of high-risk patients and hence give the possibility to better study effects of treatment methods., (© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: Tissue inhibitors of metalloproteinases (TIMPs) block the catalysis by matrix metalloproteinases (MMPs) and have additional biologic activities, including regulation of cell growth and differentiation, apoptosis, angiogenesis and oncogenesis. We investigated the expression levels of all the four human TIMPs and correlated these levels with those of MMP-9 and vascular endothelial growth factor (VEGF) in proliferative diabetic retinopathy (PDR)., Methods: Vitreous samples from 38 PDR and 21 nondiabetic control patients and epiretinal membranes from 14 patients with PDR and 10 patients with proliferative vitreoretinopathy (PVR) were studied by enzyme-linked immunosorbent assay, Western blot analysis and immunohistochemistry., Results: Tissue inhibitor of metalloproteinases-1, TIMP-4, MMP-9 and VEGF levels were significantly higher in vitreous samples from PDR patients than in nondiabetic controls (p < 0.0001 for all comparisons), whereas TIMP-2 and TIMP-3 levels did not differ significantly. TIMP-1, TIMP-4, MMP-9 and VEGF levels in PDR with active neovascularization were significantly higher than those in inactive PDR (p < 0.0001, 0.001, 0.013, 0.004, respectively). Significant positive correlations existed between levels of TIMP-1 and levels of TIMP-4 (r = 0.37; p = 0.004), MMP-9 (r = 0.65; p < 0.0001) and VEGF (r = 0.59; p < 0.0001), between levels of TIMP-4 and levels of MMP-9 (r = 0.61; p < 0.0001) and VEGF (r = 0.62; p < 0.0001) and between levels of MMP-9 and VEGF (r = 0.62; p < 0.0001). TIMP-1 and TIMP-3 were expressed in vascular endothelial cells in PDR epiretinal membranes and in myofibroblasts and leucocytes in PDR and PVR epiretinal membranes., Conclusion: The differential expression of TIMPs in PDR suggests that among the 4 TIMPs, TIMP-1 and TIMP-4 may be possible biomarkers of disease activity., (© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

PurposeThe purpose of the study was to evaluate the efficacy and safety of intravitreal pirfenidone for inhibition of proliferative vitreoretinopathy (PVR) in a model of penetrating ocular injury.Patients and methodsPenetrating trauma was induced on the retina of rabbit and treated either with 0.1 ml of phosphate-buffered saline (PBS) or 0.1 ml of 0.5% pirfenidone, and development of PVR was evaluated clinically and graded after 1 month. Histopathology and immunohistochemistry with transforming growth factor beta (TGFβ), alpha smooth muscle actin (αSMA), and collagen-1 were performed to assess the fibrotic changes. Expression of cytokines in the vitro-retinal tissues at different time points following pirfenidone and PBS injection was examined by RT-PCR. Availability of pirfenidone in the vitreous of rabbit at various time points was determined by high-performance liquid chromatography following injection of 0.1 ml of 0.5% pirfenidone. In normal rabbit eye, 0.1 ml of 0.5% pirfenidone was injected to evaluate any toxic effect.ResultsClinical assessment and grading revealed prevention of PVR formation in pirfenidone-treated animals, gross histology, and histopathology confirmed the observation. Immunohistochemistry showed prevention in the expression of collagen-I, αSMA, and TGFβ in the pirfenidone-treated eyes compared to the PBS-treated eyes. Pirfenidone inhibited increased gene expression of cytokines observed in control eyes. Pirfenidone could be detected up to 48 h in the vitreous of rabbit eye following single intravitreal injection. Pirfenidone did not show any adverse effect following intravitreal injection; eyes were devoid of any abnormal clinical sign, intraocular pressure, and electroretinography did not show any significant change and histology of retina remained unchanged.ConclusionThis animal study shows that pirfenidone might be a potential therapy for PVR. Further clinical study will be useful to evaluate the clinical application of pirfenidone.

Purpose: The purpose of this study was to develop a method for isolating, culturing, and characterizing cells from patient-derived membranes in proliferative vitreoretinopathy (PVR) to be used for drug testing., Methods: PVR membranes were obtained from six patients with grade C PVR. Membrane fragments were analyzed by gross evaluation, fixed for immunohistologic studies to establish cell identity, or digested with collagenase II to obtain single cell suspensions for culture. PVR-derived primary cultures were used to examine the effects of methotrexate (MTX) on proliferation, migration, and cell death., Results: Gross analysis of PVR membranes showed presence of pigmented cells, indicative of retinal pigment epithelial cells. Immunohistochemistry identified cells expressing α-smooth muscle actin, glial fibrillary acidic protein, Bestrophin-1, and F4/80, suggesting the presence of multiple cell types in PVR. Robust PVR primary cultures (C-PVR) were successfully obtained from human membranes, and these cells retained the expression of cell identity markers in culture. C-PVR cultures formed membranes and band-like structures in culture reminiscent of the human condition. MTX significantly reduced the proliferation and band formation of C-PVR, whereas it had no significant effect on cell migration. MTX also induced regulated cell death within C-PVR as assessed by increased expression of caspase-3/7., Conclusions: PVR cells obtained from human membranes can be successfully isolated, cultured, and profiled in vitro. Using these primary cultures, we identified MTX as capable of significantly reducing growth and inducing cell death of PVR cells in vitro.

Purpose: To investigate aqueous flare as a preoperative predictor for later proliferative vitreoretinopathy (PVR) development in patients with rhegmatogenous retinal detachment (RD) and to determine the validity of this measurement in patients at low clinical risk for postoperative PVR., Methods: This study included 100 eyes of 100 patients who underwent surgery for primary RD. Aqueous flare was determined preoperatively with a laser flare-cell meter (Kowa FM-500, Kowa Company Ltd, Tokyo, Japan). Patients were followed for at least 6 months postoperatively. Failures related to PVR were recorded for statistical analysis., Results: Twenty eyes (20%) developed PVR postoperatively. Preoperative flare values in these eyes were significantly higher than in eyes with no redetachment (48.12 ± 61.24 versus 17.74 ± 29.63 photon counts per millisecond (pc/ms), p = 0.002). The odds ratio for PVR development with flare values >15 pc/ms was 12.3 (p < 0.0001, 95% confidence interval, 3.54-42.59). Of 54 eyes at low clinical risk for postoperative PVR, five developed PVR postoperatively. Flare values were significantly higher in these eyes (25.30 ± 7.10 pc/ms) than in eyes with no redetachment (12.44 ± 10.16 pc/ms, p = 0.008). Using logistic regression, the odds ratio of PVR redetachment risk increased by the factor 1.078 per 1 pc/ms of flare value (95% CI, 1.01-1.15)., Conclusion: Preoperative aqueous flare is a strong predictive factor for PVR redetachment. The laser flare-cell meter provides a fast and safe tool to accurately identify patients at risk for postoperative PVR, especially when clinical examination did not predict this risk., (© 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Proliferative vitreoretinopathy (PVR) is mediated by proliferation and epithelial mesenchymal transition (EMT) of retinal pigment epithelium (RPE). Because heavy chain-hyaluronic acid/pentraxin 3 (HC-HA/PTX3) purified from human amniotic membrane exerts anti-inflammatory and anti-scarring actions, we hypothesized that HC-HA/PTX3 could inhibit these PVR-related processes in vitro. In this study, we first optimized an ARPE-19 cell culture model to mimic PVR by defining cell density, growth factors, and cultivation time. Using this low cell density culture model and HA as a control, we tested effects of HC-HA/PTX3 on the cell viability (cytotoxicity), proliferation (EGF + FGF-2) and EMT (TGF-β1). Furthermore, we determined effects of HC-HA/PTX3 on cell migration (EGF + FGF-2 + TGF-β1) and collagen gel contraction (TGF-β1). We found both HA and HC-HA/PTX3 were not toxic to unstimulated RPE cells. Only HC-HA/PTX3 dose-dependently inhibited proliferation and EMT of stimulated RPE cells by down-regulating Wnt (β-catenin, LEF1) and TGF-β (Smad2/3, collagen type I, α-SMA) signaling, respectively. Additionally, HA and HC-HA/PTX3 inhibited migration but only HC-HA/PTX3 inhibited collagen gel contraction. These results suggest HC-HA/PTX3 is a non-toxic, potent inhibitor of proliferation and EMT of RPE in vitro, and HC-HA/PTX3's ability to inhibit PVR formation warrants evaluation in an animal model.

Purpose: Retinal vascular occlusions in sickle cell anemia patients cause tissue ischemia and the release of angiogenic mediators that promote the development of retinal neovascularization, initiating proliferative sickle retinopathy (PSR). Laser photocoagulation (LPC) has emerged as the most common treatment for PSR. Nonetheless, only two randomized controlled clinical trials have evaluated the use of LPC for PSR, and both failed to definitively demonstrate efficacy of this approach. This may be due to a lack of knowledge regarding the appropriate location for placement of laser coagulations in PSR eyes. To help address this question, we examined the expression of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) in PSR eyes., Methods: The expression pattern of HIF-1α and VEGF in PSR (n = 5) and control (n = 3) eyes was examined by immunohistochemistry in different retinal regions defined by the presence or absence of retinal vessels., Results: Hypoxia-inducible factor 1α and VEGF were expressed in the inner retina of 5/5 untreated PSR eyes adjacent to retinal neovascularization; expression of HIF-1α was not detected (and VEGF only lightly detected) in normal retinal and choroidal vasculature of 3/3 control eyes. Hypoxia-inducible factor 1α and VEGF were strongly expressed in retinal cells within avascular (nonperfused) retina, anterior to the boundary between perfused and nonperfused retina, as well as in posterior ischemic retina in the presence or absence of neovascular sea fans., Conclusions: If the goal of LPC in PSR is to quench the expression of HIF-1-driven angiogenic mediators, our results support broad application of peripheral laser for its treatment.

Bronchopulmonary dysplasia (BPD) is a major cause of neonatal morbidity in premature infants, occurring as a result of arrested lung development combined with multiple postnatal insults. Infants with BPD exposed to supplemental oxygen are at risk of retinopathy of prematurity as well. Thus, we studied the effects of hyperoxia on the retinal vasculature in a murine model of BPD. The retinal phenotype of this model, which we termed hyperoxia-induced proliferative retinopathy (HIPR), shows severe disruption of retinal vasculature and loss of vascular patterning, disorganized intra-retinal angiogenesis, inflammation and retinal detachment. Neonatal mice were subjected to 75% oxygen exposure from postnatal day (P)0 to P14 to model BPD, then allowed to recover in room air for 1 (P15), 7 (P21), or 14 days (P28). We quantified retinal thickness, protein levels of HIF-1α, NOX2, and VEGF, and examined the cellular locations of these proteins by immunohistochemistry. We examined the retinal blood vessel integrity and inflammatory markers, including macrophages (F4/80) and lymphocytes (CD45R). Compared to controls, normal retinal vascular development was severely disrupted and replaced by a disorganized sheet of intra-retinal angiogenesis in the HIPR mice. At all time-points, HIPR showed persistent hyaloidal vasculature and a significantly thinner central retina compared to controls. HIF-1α protein levels were increased at P15, while VEGF levels continued to increase until P21. Intra-retinal fibrinogen was observed at P21 followed by sub-retinal deposition in at P28. Inflammatory lymphocytes and macrophages were observed at P21 and P28, respectively. This model presents a severe phenotype of disrupted retinal vascular development, intra-retinal angiogenesis inflammation and retinal detachment., Competing Interests: The authors have declared that no competing interests exist.

Background: Eyes sustaining open globe trauma are at high risk of severe visual impairment. Ocular injuries which result in visual loss invariably affect the posterior segment of the eye, and prevention of visual loss involves posterior segment (vitreoretinal) surgery. Despite improvements in vitreoretinal surgical techniques, outcomes in these patients remain unsatisfactory, and development of the intraocular scarring response proliferative vitreoretinopathy is the leading cause. Proliferative vitreoretinopathy is the most common cause of recurrent retinal detachment in these eyes; it is reported to occur in up to 45 % of cases., Methods/design: The Adjunctive Steroid Combination in Ocular Trauma (ASCOT) trial is a multi-centre, double-masked, parallel-arm randomised controlled trial with an internal pilot designed to investigate the effectiveness and cost-effectiveness of using intravitreal and sub-Tenon's triamcinolone acetonide peri-operatively in patients undergoing vitrectomy following open globe trauma. In total, 300 eyes of 300 patients will be recruited and randomly allocated to one of two treatment groups. Both groups will receive standard surgical treatment and routine pre-operative and post-operative treatment and care. The treatment group will receive an adjunctive peri-operative steroid combination (triamcinolone acetonide) consisting of 4 mg/0.1 ml into the vitreous cavity and 40 mg/1 ml into the sub-Tenon's space. The trial incorporates a two-stage internal pilot to examine projected recruitment and retention rates. Progression criteria from the internal pilot study will enable us to determine whether to undertake the main trial. Patients and primary outcome assessors will be masked to treatment allocation. The primary outcome will be an improvement from baseline to 6 months of at least 10 on the corrected visual acuity as measured by ETDRS letter score. Secondary outcomes will be development of scarring, retinal detachment, intraocular pressure abnormalities, quality of life and public sector service use., Discussion: This is the first powered, controlled clinical trial to investigate the use of adjunctive triamcinolone in patients undergoing vitrectomy following open globe trauma., Trial Registration: EudraCT2014-002193-37 . Registered on 5 September 2014. ISRCTN30012492 . Registered on 5 September 2014.

Background: Proliferative vitreoretinopathy (PVR) is a known complication of retinal detachment surgery. It has been postulated that the establishment of PVR involves inflammatory and ischaemic processes. Surgical and clinical risk factors contribute to making certain patients more vulnerable to developing PVR. The objective of this systematic review is to identify and appraise the evidence on clinical and surgical risk factors and their utility in predicting the occurrence or worsening of PVR post-surgery., Methods: Electronic databases and grey literature will be searched dating from 1980. Studies will be eligible if they include patients that underwent retinal reattachment surgery for rhegmatogenous retinal detachment (RRD), with and without PVR, and where risk factors were measured before or during surgery. Screening, data extraction and quality assessment will be performed independently by two reviewers using pre-defined criteria. Should any models be identified, we will liaise with the Cochrane prognostic group to help define the most appropriate quality assessment criteria based on the PROBLAST tool which is in development. All findings will be tabulated and narratively synthesised. Studies presenting models or adjusted data will likely be more informative than studies reporting unadjusted results for a single risk factor. When clinically and methodologically appropriate, random effects meta-analysis will be performed., Discussion: This review will systematically and comprehensively retrieve evidence to evaluate the clinical and surgical risk factors associated with PVR. The identified evidence may aid standardisation of clinical practice and more effective management for improving patient outcomes following RRD surgery and will provide a clear reference point for vitreoretinal surgeons., Systematic Review Registration: PROSPERO CRD42016035848.

Purpose: Previous studies have shown that vitreous stimulates degradation of the tumor suppressor protein p53 and that knockdown of phosphatidylinositol 5-phosphate 4-kinases (PI5P4Kα and -β) abrogates proliferation of p53-deficient cells. The purpose of this study was to determine whether vitreous stimulated expression of PI5P4Kα and -β and whether suppression of PI5P4Kα and -β would inhibit vitreous-induced cellular responses and experimental proliferative vitreoretinopathy (PVR)., Methods: PI5P4Kα and -β encoded by PIP4K2A and 2B, respectively, in human ARPE-19 cells were knocked down by stably expressing short hairpin (sh)RNA directed at human PIP4K2A and -2B. In addition, we rescued expression of PI5P4Kα and -β by re-expressing mouse PIP4K2A and -2B in the PI5P4Kα and -β knocked-down ARPE-19 cells. Expression of PI5P4Kα and -β was determined by Western blot and immunofluorescence. The following cellular responses were monitored: cell proliferation, survival, migration, and contraction. Moreover, the cell potential of inducing PVR was examined in a rabbit model of PVR effected by intravitreal cell injection., Results: We found that vitreous enhanced expression of PI5P4Kα and -β in RPE cells and that knocking down PI5P4Kα and -β abrogated vitreous-stimulated cell proliferation, survival, migration, and contraction. Re-expression of mouse PIP4Kα and -β in the human PI5P4Kα and -β knocked-down cells recovered the loss of vitreous-induced cell contraction. Importantly, suppression of PI5P4Kα and -β abrogated the pathogenesis of PVR induced by intravitreal cell injection in rabbits. Moreover, we revealed that expression of PI5P4Kα and -β was abundant in epiretinal membranes from PVR grade C patients., Conclusions: The findings from this study indicate that PI5P4Kα and -β could be novel therapeutic targets for the treatment of PVR.

Purpose: To investigate the effect of thrombin on the proliferation of human Müller glial cells (MCs) and define the possible signaling mechanisms involved in this process., Methods: Protease-activated receptor (PARs 1-4) expression was analyzed using RT-PCR and Western blot in the MIO-M1 Müller cell line (MC). Müller cell proliferation was assessed by the MTS reduction method. Wound healing and immunoreactivity to Ki67 antigen were used to dissociate proliferation and migration. Cell migration was examined using transwell migration assays. The involvement of extracellular signal-regulated kinase (ERK1/2) phosphorylation/activation in thrombin-induced human MC proliferation was determined by Western blot. Intracellular pathways involved in ERK1/2 activation were analyzed by pharmacologic inhibition., Results: We first demonstrated that human MCs express PARs 1 to 4. Our results show that thrombin dose-dependently stimulates MC proliferation by 44%, with a calculated Ec50 of 0.86 nM. Müller cell maximal proliferation required sustained thrombin treatment for 72 hours, in contrast to our previous findings in RPE cells showing maximal thrombin-induced proliferation at 24-hour stimulation. We demonstrate that thrombin induces MC cell proliferation through the Ras-independent activation of the Raf/MEK/ERK cascade, under the control of protein kinase C (PKC)-ζ., Conclusions: The breakdown of blood-retina barrier (BRB) exposes MCs to thrombin contained in serum. Our findings further strengthen the critical involvement of thrombin in the development of proliferative retinopathies and may provide pharmacologic targets for the prevention or treatment of these diseases.

Proliferative vitreoretinopathy (PVR) is the major cause of failure in patients undergoing surgery for rhegmatogenous retinal detachment (RRD). Characterized by the formation of an abnormal contractile membrane within the eye, PVR can cause tractional retinal redetachment. Epithelial-to-mesenchymal transition (EMT), in which epithelial cells morphologically and phenotypically transdifferentiate into mesenchymal cells, is the major pathological process implicated in PVR. Among the various cell types involved in the process, retinal pigment epithelium cells are primary contributors although, after decades of research, the mechanisms underlying EMT have remained elusive. Recently, signaling pathways, some involving growth factors, have been demonstrated to contribute to EMT. In this article, we review research to date about the roles of such signaling, including including transforming growth factor-beta-, hepatocyte growth factor-, platelet-derived growth factor-, and Notch-, Wnt/β-catenin-, and Hippo-signaling pathways, in the EMT of PVR.

The aim of this study was to evaluate the use of different fixatives on the reliability of histopathological changes in a rabbit model of proliferative vitreoretinopathy (PVR). Twenty eyes from 10 rabbits were divided into four groups. The right eyes were used in two experimental groups (each n = 5), and the left, in two control groups (each n = 5). Using a newly developed scleral incision marker, an oblique scleral incision was standardized in the experimental groups, followed by intravitreal injection of 0.4 ml autologous blood and the left for wound repair for four weeks. Eyes were enucleated at four weeks. The groups differed in the type of used fixative solution (formaldehyde 4% vs. 1% buffered formaldehyde and 1.25% glutaraldehyde). The eyes were evaluated for the development of fibrosis, retinal detachment (RD), and processed for histopathology. Fibrous ingrowth of a variable degree was present in the experimental groups originating from the trauma site. Experimental eyes fixed with formaldehyde 4% had RD extension that was greater than that fixed in formaldehyde/glutaraldehyde mixture; however, the difference did not reach statistical significance (P = 0.15). This difference was not fully explained by the fibrosis which developed. In addition, in control groups, formaldehyde 4% induced a fixative-dependent retinal separation that was absent in eyes fixed with formaldehyde/glutaraldehyde mixture (P = 0.03). In conclusion, a mixture of buffered formaldehyde 1% and glutaraldehyde 1.25% combined with standardized scleral incision resulted in consistent pathological changes. A reliable PVR model is a condition sine qua non to evaluate antifibrotic treatment strategies., (© 2015 The Authors. International Journal of Experimental Pathology © 2015 International Journal of Experimental Pathology.)

Proliferative vitreoretinopathy (PVR) is the most important complication of rhegmatogenous retinal detachment (RRD) and the main cause of RRD surgery failure. This is a review of recent literature data, which concerns PVR pathogeny and risk factors. The occurrence of pre- and subretinal membranes is a consequence of retinal pigment epithelial cells activation and migration, with concomitant participation of inflammatory cells. The newly synthesized extracellular matrix interacts with cells promoting membrane contraction. Photoreceptor apoptosis limits functional recovery--but there is ongoing research for neuroprotective mechanisms. A lot of evidence has been accumulated about the role of growth factors (PDGF, VEGF, HGF, EGF, TGF α and β, G-CSF, FGF, IGF-1,CTGF), cytokines (interleukins IL-1, -6, -8, -10 and interferon γ), matrix metalloproteinases and chemokines, by measuring their concentrations in the vitreous or the subretinal fluid of PVR patients. A list of risk factors (common or more controversial) may help the surgeon make the best approach for the management of individual cases. Adjuvant therapies tested for PVR prevention (steroids, heparin, 5 fluorouracil, daunomycin, colchicine and 13-cis retinoic acid) did not enter current practice, but there are numerous research directions currently being developed.

The retinopathy in association with malaria fever described so far includes retinal hemorrhages, vessel changes, retinal discoloration/whitening and papilledema. Malaria retinopathy has been mostly described in severe cases, associated with Plasmodium falciparum, correlating the patho-physiology of retinal and cerebral manifestations. We report an unusual case of proliferative retinopathy as a manifestation of malaria fever, caused by P. falciparum with no cerebral involvement. The patient had features of unilateral retinal vascular occlusion with proliferative changes and vitreous hemorrhage. To the best of our knowledge, such a case has never been reported so far in the literature. This report highlights the possible occurrence of severe proliferative changes associated with malaria fever, which if diagnosed early can prevent possible blindness.

Objective: Carotid atherosclerotic lesions have been described more frequently in patients with diabetes and microvascular disease than in those with uncomplicated diabetes. In this study, we investigated the role of blood pressure as a risk factor of diabetic retinopathy in normotensive patients with type 2 diabetes. We also assessed the correlation of carotid intima-media thickness with both blood pressure and diabetic retinopathy., Methods: The study group consisted of 140 normotensive patients (68 males and 72 females) with type 2 diabetes and diabetic retinopathy. Carotid intima-media thickness was evaluated using high-resolution B-mode ultrasonography. Diabetic retinopathy was assessed and graded, using colored fundus photography and fundus fluorescein angiography, as either non-proliferative or proliferative., Results: Patients with proliferative diabetic retinopathy showed a higher systolic and diastolic blood pressure (p<0.01). Carotid intima-media thickness was higher in patients with proliferative than non-proliferative diabetic retinopathy ones (1.094 ± 0.142 vs. 0.842 ± 0.134 mm, respectively; p<0.001) Carotid intima-media thickness showed positive correlation with both systolic (p<0.001) and diastolic blood pressures (p<0.01). No significant differences were found between males and females in any of the studied parameters., Conclusion: Our study proves that both systolic and diastolic blood pressures are important risk factors for the progression of retinopathy in normotensive patients with type 2 diabetes. We also demonstrate that carotid intima-media thickness, as a marker of atherosclerosis, is strongly correlated with both blood pressure and diabetic retinopathy in those patients.

Purpose: To determine the roles of interleukin (IL)-1β and IL-10 in the vitreous of proliferative diabetic retinopathy (PDR)., Materials and Methods: Vitreous samples were obtained from 26 eyes of 26 patients with PDR and from eight eyes of eight cases without PDR. The IL-1β and IL-10 concentration in the vitreous was measured by using an enzyme-linked immunosorbent assay (ELISA)., Results: Levels of IL-1β and IL-10 in vitreous were higher in PDR patients compared with control group. And there was significantly negative correlation between IL-1β and IL-10 in control group (r = -0.795; P = 0.032), whereas there was no significant correlation in PDR group (r = 0.176; P = 0.391)., Conclusion: Levels of IL-1β and IL-10 were upregulated in vitreous of PDR patients, and these two cytokines play roles in regulating the development and progression of PDR.

Purpose: A free autologous retinal pigment epithelium (RPE)-choroid graft can be harvested during transplantation surgery from a 6 or 12 o'clock site in the midperiphery. This study evaluated whether proliferative vitreoretinopathy (PVR) occurs more frequently in patients with an inferior donor site retinotomy, which is not closed by the tamponade and is in contact with the hydrophilic, pro-inflammatory and fibrotic environment, than in patients with a superior donor site retinotomy., Methods: Retrospective analysis of a prospective cohort of 246 patients with exudative age-related macular degeneration treated with an RPE-choroid graft transplantation and a lighter-than-water, 5000 centistoke silicone oil endotamponade. The location of the donor site, the presence or absence of PVR development and the location of PVR were noted. The two-tailed Fisher's exact test was used for statistical analysis., Results: Thirty-nine of 246 (15.9%) patients developed PVR, of whom 35 had a superior donor site and four an inferior donor site. Of the 209 patients without PVR, 155 had a superior donor site and 25 had an inferior one. For 27 patients, no donor site location was explicitly documented in the patient files. We found no difference between the groups with a superior or inferior donor site and the occurrence of PVR (p=0.8)., Conclusion: Shifting the inflammatory aqueous milieu away from the graft donor site does not prevent the occurrence of PVR., (© 2013 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Proliferative vitreoretinopathy (PVR) is the commonest cause of late anatomical failure in rhegmatogenous retinal detachment. Visual and anatomical outcomes remain poor despite advances in vitreoretinal surgical techniques with reported primary failure rates of up to nearly 50%. Numerous adjunctive medications have been evaluated in clinical trials with no agent gaining widespread acceptance and use.This study was designed to investigate the benefits of using a slow-release dexamethasone implant delivered intra-operatively in patients undergoing vitrectomy surgery for retinal detachment with established PVR., Methods/design: For the study, 140 patients requiring vitrectomy surgery with silicone oil for retinal detachment with established PVR will be randomised to receive either standard treatment or study treatment in a 1:1 treatment allocation ratio. Both groups will receive the standard surgical treatment appropriate for their eye condition and routine peri-operative treatment and care, differing only in the addition of the supplementary adjunctive agent in the treatment group. The investigated primary outcome measure is stable retinal reattachment with removal of silicone oil without additional vitreoretinal surgical intervention at 6 months., Discussion: This is the first randomised controlled clinical trial to investigate the use of an adjunctive slow-release dexamethasone implant in patients undergoing vitrectomy surgery for retinal detachments with proliferative vitreoretinopathy., Trial Registration: EudraCT No: 2011-004498-96.

Purpose: To identify inflammatory cytokines significantly elevated and independent of VEGF levels in the vitreous of proliferative diabetic retinopathy (PDR) patients that may serve as novel diagnostic factors or therapeutic targets., Methods: Thirty-nine cytokines and chemokines were measured from the vitreous of 72 patients undergoing vitrectomy (29 controls and 43 PDR) via a magnetic bead-based immunoassay. Patient information, including sex, age, history of smoking, cancer diagnosis and treatment, and presence of diabetes and hypertension were also collected. Univariate and multivariate logistic regression analyses were performed to assess the association of cytokine concentrations and patient demographics with disease., Results: Nineteen cytokines were significantly elevated in the vitreous of PDR patients compared with controls, including five novel cytokines that have not previously been associated with PDR: sCD40L, GM-CSF, IFNα2, IL-12p40, and MCP-3. Sixteen cytokines were found to be statistically independent of VEGF. Of these, 14 show a statistically significant interaction with VEGF, while two do not. With regards to patient demographics, age and hypertension were statistically significant risk factors with the odds of disease decreasing with increasing age and increasing 3-fold for hypertensive patients., Conclusions: This is the first report of a comprehensive multiplex analysis to identify novel VEGF-independent cytokines associated with PDR. Of the 39 inflammatory cytokines tested, 16 are predictive of disease risk, independent of VEGF levels. These PDR-associated cytokines represent potential targets in the treatment of PDR, both in conjunction with anti-VEGF therapy, as well as for patients that are nonresponders to such therapy.

Purpose: To report the outcomes of chorioretinectomy in severe ocular injuries where a foreign body penetrated the choroid or perforated the globe., Methods: The study sample consisted of a retrospective, non-comparative, consecutive interventional case series of 13 perforating or severe intraocular foreign body ocular injuries that were treated at a single institution from March 2008 to March 2010. All the patients were operated with 20-gauge three-port pars plana vitrectomy (PPV) by removing the choroid and/or retina with scar tissue at the perforation site of the foreign body. The reports of patients were examined for best-corrected visual acuity, globe survival, retinal detachment status, and proliferative vitreoretinopathy., Results: A total of 13 eyes of 13 patients with a mean age of 25.8 ± 9.0 years (range, 11-38 years) were followed for a median of 13.8 ± 5.4 months (range, 8-29 months). The mean time period between injury and the vitreoretinal surgery was 13.6 ± 9.3 days. All had an exit/impact site wound, eight of which were located in the posterior pole, which caused choroidal and retinal incarceration in the macular area. PPV together with chorioretinectomy, endolaser applications, silicone oil tamponade, with/without encircling band, and lensectomy surgery was applied to all of them. Final best-corrected visual acuity (BCVA) ≥20/200 occurred in 4 of 13 (30.76%) patients. Globe survival rates were 100% (13 of 13), and final retinal attachment rate was 84.6% (11 of 13). The proliferative vitreoretinopathy rate was 2 of 13 (15.3%)., Conclusion: Chorioretinectomy is a surgical option that may decrease post-traumatic proliferative vitreoretinopathy and tractional retinal detachment rates, thus improving final BCVA and increasing globe survival rates when a foreign body penetrates the choroid and perforates the globe.

Background: Eyes sustaining open globe trauma (OGT) is a group at high risk of severe visual impairment. Proliferative vitreoretinopathy (PVR) is the commonest cause of retinal redetachment in these eyes and is reported to occur in up to 45% of cases. Intensive anti-inflammatory agents have been shown to be effective at modifying experimental PVR and to be well tolerated clinically.The Adjuncts in Ocular Trauma (AOT) Trial was designed to investigate the benefits of using intensive anti-inflammatory agents (intravitreal and sub-Tenon's triamcinolone, oral flurbiprofen and guttae prednisolone 1.0%) perioperatively in patients undergoing vitrectomy surgery following open globe trauma., Methods/design: Patients requiring posterior vitrectomy surgery following open globe trauma will be randomised to receive either standard treatment or study treatment. Both groups will receive the standard surgical treatment appropriate for their eye condition and routine perioperative treatment and care, differing only in the addition of supplementary adjunctive agents in the treatment group. The investigated primary outcome measure is anatomical success at 6 months in the absence of internal tamponade., Discussion: This is the first randomised controlled clinical trial to investigate the use of adjunctive intensive antiinflammatory agents in patients undergoing vitrectomy following open globe trauma. It will provide evidence for the role of these adjuncts in this group of patients, as well as provide data to power a definitive study. EUDRACT NO: 2007/005138/35.

Purpose: To evaluate the effect of adjunctive subtenon injection of triamcinolone acetonide (TA) in gas-filled eyes after vitrectomy for complicated proliferative diabetic retinopathy (PDR)., Methods: This nonrandomized comparative study included 27 patients (27 eyes) who underwent pars plana vitrectomy and gas tamponade for treatment of PDR with tractional or combined tractional-rhegmatogenous retinal detachment and who received subtenon injection of TA (40 mg) at the end of surgery. The study group was compared with the control group (29 eyes), which was matched with the study group for preoperative and intraoperative parameters, but underwent pars plana vitrectomy and gas tamponade without a subtenon injection of TA., Results: Retinal reattachments without reoperation were achieved in 25 eyes (92.6%) and 26 eyes (89.7%) at 6 months (p = 1.000) in the study and control groups, respectively. The study group and the control group did not differ significantly in the frequency of postoperative proliferative vitreoretinopathy, retinal redetachment rate, reoperation rate, macular pucker formation, postoperative vitreous hemorrhage, gain in visual acuity, intraocular pressure, and intraocular inflammation (p > 0.05)., Conclusions: The clinical results of pars plana vitrectomy for complicated PDR are not improved significantly by an adjunctive subtenon TA injection in gas-filled eyes.

Eye injury is a significant disabling worldwide health problem. Proliferative Vitreoretinopathy (PVR) is a common complication that develops in up to 40-60% of patients with an open-globe injury. Our knowledge about the pathogenesis of PVR has improved in the last decades. It seems that the introduction of immune cells into the vitreous, like in penetrating ocular trauma, triggers the production of growth factors and cytokines that come in contact with intra-retinal cells, like Müller cells and RPE cells. Growth factors and cytokines drive the cellular responses leading to PVR's development. Knowledge of the pathobiological and pathophysiological mechanisms involved in posttraumatic PVR is increasing the possibilities of management, and it is hoped that in the future our treatment strategies will evolve, in particular adopting a multidrug approach, and become even more effective in vision recovery. This paper reviews the current literature and clinical trial data on the pathogenesis of PVR and its correlation with ocular trauma and describes the biochemical/molecular events that will be fundamental for the development of novel treatment strategies. This literature review included PubMed articles published from 1979 through 2013. Only studies written in English were included.

Introduction: Nepal has many mountains including the highest one in the world. People living in high altitude are often involved in climbing mountains., Objective: To explore the pattern of vitreo-retinal disorders at high altitude in Nepal., Materials and Methods: Consecutive patients aged 40 years and older who presented at the micro-surgical eye camp at Lukla of Solukhumbu district (2,860 metres) were included. Detailed ocular and systemic histories and ocular examination including dilated fundus evaluation were done., Results: There were a total 81 patients with the mean age of 56.7 years (S.D 11.15). Females (51.9 %) outnumbered males. Sherpa comprised of 76.5 % followed by Rai (9.8 %). The main occupation was agriculture (51.9 %) followed by mountain trekking (28.4 %). Smokers comprised of 13.5 %. Hypertension was the predominant systemic problem (28 %). The best corrected visual acuity of 6/18 and better was found in 86.4 % of cases and less than 3/ 60 in 3.6 % of cases. Age-related macular degeneration (AMD) was found in 19.6 % of cases with a predominant mild AMD (16 %), hypertensive retinopathy in 12.2 %, with grade I hypertensive change in 8.6 %, retinal vein occlusion (RVO) in 7.1 % of cases and with a branch RVO in 4.9 %. Dilated and tortuous retinal vessels were present in 25.9 % of cases; out of this, 9.8 % of the cases had concurrent AMD and/or hypertensive retinopathy. Other retinal problems were macular hole (2.46 %), solar retinopathy (2.46 %) and choroidal tear (1.2 %)., Conclusion: AMD, hypertensive retinopathy, and RVO are the main vitreo-retinal disorders besides the dilated and tortuous retinal vessels in people living at high altitude in Nepal., (© NEPjOPH.)

The molecular mechanism formation of secondary epiretinal membranes (ERMs) after proliferative diabetic retinopathy (PDR) or primary idiopathic ERMs is still poorly understood. Therefore, the present study focused on the assessment of IGF1, IGF1R, and IGFBP3 mRNA levels in ERMs and PBMCs from patients with PDR. The examined group comprised 6 patients with secondary ERMs after PDR and the control group consisted of 11 patients with idiopathic ERMs. Quantification of IGF1, IGF1R, and IGFBP3 mRNAs was performed by real-time QRT-PCR technique. In ERMs, IGF1 and IGF1R mRNA levels were significantly higher in patients with diabetes compared to control subjects. In PBMCs, there were no statistically significant differences of IGF1, IGF1R, and IGFBP3 expression between diabetic and nondiabetic patients. In conclusion, our study indicated IGF1 and IGF1R differential expression in ERMs, but not in PBMCs, of diabetic and nondiabetic patients, suggesting that these factors can be involved in the pathogenesis or progression of proliferative vitreoretinal disorders. This trial is registered with NCT00841334.

Purpose: To develop a large animal model of proliferative vitreoretinopathy (PVR) in the swine to eventually study disease pathophysiology, as well as novel therapies., Methods: PVR was induced in domestic swine by creation of a posterior vitreous detachment, creation of a retinal detachment by the injection of subretinal fluid, and intravitreal injection of green fluorescent protein-positive retinal pigment epithelial (GFP+ RPE) cells. Control eyes had the same surgical procedures without RPE cell injection. PVR was clinically graded on days 3, 7, and 14. Animals were euthanized on day 14, and enucleated eyes were analyzed by light microscopy and immunohistochemistry., Results: Injection of GFP+ RPE cells into the vitreous cavity produced localized, traction retinal detachments by day 14 in all eyes (14 of 14); in contrast, the retina spontaneously reattached by day 3 and remained attached in all control eyes (10 of 10). Contractile epiretinal membranes on the inner retinal surface that caused the traction retinal detachments consisted predominantly of GFP+ RPE cells. These cells stained positive for cytokeratin, confirming their epithelial origin, and also expressed α-SMA and fibronectin, markers for myofibroblasts and fibrosis, respectively., Conclusions: We established a swine PVR model that recapitulates key clinical features found in humans and, thus, can be used to study the pathophysiology of PVR, as well as new novel therapies. GFP+ RPE cells injected into the vitreous cavity formed contractile membranes on the inner retinal surface and caused localized traction retinal detachments.

Purpose: To document the characteristics, treatments, and anatomical and functional outcomes of patients with ocular trauma from improvised explosive devices (IEDs)., Methods: Retrospective review of ocular injuries caused by IEDs, admitted to our tertiary referral centre., Results: In total, sixty-one eyes of the 39 patients with an average age of 24 years (range, 20-42 years) were included in the study. In total, 49 (80%) eyes of the patients had open-globe and 12 (20%) had closed-globe injury. In eyes with open-globe injury, intraocular foreign body (IOFB) injury was the most frequently encountered type of injury, observed in 76% of eyes. Evisceration or enucleation was required as a primary surgical intervention in 17 (28%) of the eyes. Twenty-two (36%) eyes had no light perception at presentation. Patients were followed up for an average of 6 months (range, 4-34 months). At the last follow-up, 26 (43%) of 61 eyes had no light perception. Postoperative proliferative vitreoretinopathy (PVR) developed in 12 (50%) of the 24 eyes that underwent vitreoretinal surgery, and four of these eyes became phthisical. There were no cases of endophthalmitis. The presence of open-globe injury and presenting visual acuity worse than 5/200 were significantly associated with poor visual outcome (<5/200, P<0.05). In eyes with open-globe injury, the presence of an IOFB was not associated with poor visual outcome (P>0.05)., Conclusion: Ocular injuries from IEDs are highly associated with severe ocular damage requiring extensive surgical repair or evisceration/enucleation. Postoperative PVR is a common cause of poor anatomical and visual outcome.

Purpose: To evaluate the clinical features, and anatomical and visual outcomes in patients with closed-globe contusion injury involving the posterior segment., Methods: Retrospective review of posterior segment contusion injuries admitted to our tertiary referral center., Results: In all, 115 patients (115 eyes) with complete data were reviewed. Surgery had been performed in 79 (69%) patients. The mean follow-up period was 6 months (range, 2-34 months). Retinal detachment, in 31% of eyes, was the most frequently encountered posterior segment pathology. The presence of retinal detachment was associated with poor visual outcome (<20/100), (P<0.001). Coexisting (five patients, 4%) and postoperative proliferative vitreoretinopathy (PVR) (two patients, 2%) was the main cause of failure in these cases. A significant positive correlation was obtained between initial and final visual acuity levels in both the medical treatment group and the surgical treatment group (P<0.05). The presenting visual acuity of <20/400 was associated with poor visual outcome (P<0.05 for both groups). Poor visual outcome in 13 patients with successful repair of retinal detachment was due to the macular lesions and the optic atrophy., Conclusion: Retinal detachment was the most frequently encountered posterior segment pathology subsequent to closed-globe contusion injuries. In addition to macular scarring and optic nerve damage, development of PVR has prognostic significance in these eyes.

Purpose: We investigated the activity of matrix metalloproteinase (MMP)-2 and -9 and their latent pro-forms (proMMP-2, -9), and protein levels of MMP-1, -3, -8 and tissue inhibitor of MMPs (TIMP)-1 in the subretinal fluid (SRF) and vitreous of patients with rhegmatogenous retinal detachment (RRD). Potential correlations with proliferative vitreoretinopathy (PVR) grade were determined., Methods: Thirty-seven SRF and 32 vitreous samples from RRD patients and nine vitreous samples from human organ donors (controls), were collected and assayed for MMP-1, -3, -8/TIMP-1 levels using enzyme-linked immunosorbent assay (ELISA), and for proMMP-2, -9, MMP-2, -9 activity employing gelatine zymography., Results: ProMMP-2, -9, MMP-1, -3, -9, TIMP-1 were significantly higher in the SRF and vitreous of RRD patients compared to the vitreous of organ donors. MMP-8 levels were higher in RRD patients' SRF. Regarding PVR grade, MMPs and TIMP-1 were differentially present in SRF and vitreous. PVR grade correlated significantly with the levels of MMP-2 in SRF, while proMMP-2, MMP-1, -2, -3, -8, -9 and TIMP-1 levels correlated with PVR grade in the vitreous., Conclusion: MMP/TIMP-1 levels are elevated in SRF and vitreous during RRD. Significant correlations between PVR grade and MMP-2 in SRF and proMMP-2, MMP-1, -2, -3, -8, -9 and TIMP-1 levels in vitreous were revealed. Investigation of MMP activity in vitreous may provide more valid conclusions compared to SRF pertaining to the role of the MMPs during RRD. The observations of the present study suggest a possible role for MMPs and TIMP-1 in PVR pathophysiology., (© 2009 The Authors. Journal compilation © 2009 Acta Ophthalmol.)