Intravitreal slow-release dexamethasone alleviates traumatic proliferative vitreoretinopathy by inhibiting persistent inflammation and Müller cell gliosis in rabbits

AIM:To evaluate the effects of intravitreal slow-release dexamethasone on traumatic proliferative vitreoretinopathy(PVR)and Müller cell gliosis and preliminarily explored the possible inflammatory mechanism in a rabbit model induced by penetrating ocular trauma.METHODS:Traumatic PVR was induced in the right eyes of pigmented rabbits by performing an 8-mm circumferential scleral incision placed 2.5 mm behind the limbus,followed by treatment with a slow-release dexamethasone implant(Ozurdex)or sham injection.Left eyes were used as normal controls.The intraocular pressure(IOP)was monitored using an iCare tonometer.PVR severity was evaluated via anatomical and histopathological examinations every week for 6wk;specific inflammatory cytokine and proliferative marker levels were measured by quantitative real-time polymerase chain reaction,Western blot,protein chip analysis,or immunofluorescence staining.RESULTS:During the observation period,PVR severity gradually increased.Intense Müller cell gliosis was observed in the peripheral retina near the wound and in the whole retina of PVR group.Ozurdex significantly alleviated PVR development and Müller cell gliosis.Post-traumatic inflammation fluctuated and was persistent.The interleukin-1β(IL-1β)mRNA level was significantly upregulated,peaking on day 3 and increasing again on day 21 after injury.The expression of nod-like receptor family pyrin domain containing 3(NLRP3)showed a similar trend that began earlier than that of IL-1βexpression.Ozurdex suppressed the expression of IL-1β,NLRP3,and phosphorylated nuclear factor-kappa B(NF-κB).The average IOP after treatment was within normal limits.CONCLUSION:The present study demonstrates chronic and fluctuating inflammation in a traumatic PVR rabbit model over 6wk.Ozurdex treatment significantly inhibites inflammatory cytokines expression and Müller cell gliosis,and thus alleviates PVR severity.This study highlights the important role of IL-1β,and Ozurdex inhibites inflammation presumably via the NF-κB/NLRP3/IL-1βinflammatory axis.In summary,Ozurdex provides a potential therapeutic option for traumatic PVR.

Nomogram for predicting non-proliferative vitreoretinopathy probability after vitrectomy in eyes with rhegmatogenous retinal detachment

AIM:To identify the risk factors for postoperative proliferative vitreoretinopathy(PVR)in patients with primary rhegmatogenous retinal detachment(RRD)and develop a nomogram for predicting postoperative PVR-free probability.METHODS:A total of 741 patients(741 eyes)diagnosed with primary RRD who underwent first surgery in the same hospital were retrospectively reviewed and randomly assigned with 521 to the training set and 220 to the validation set.Univariate and multivariate logistic regression analyses were performed in the training cohort to determine risk factors to construct a nomogram for predicting the 3-,4-,5-,and 6-month postoperative PVR-free probabilities.Nomogram performance was estimated by the concordance index(C-index),calibration plot,and the area receiver operating characteristic(ROC)curve.RESULTS:A nomogram was constructed based on the preoperative PVR,silicone oil tamponade time(SOTT),photocoagulation energy(PE),retinal tear size(RTS),and hypertension.In the training set,the C-index of the nomogram was 0.896,0.936,0.961,and 0.972 at 3,4,5,and 6mo,respectively.The C-index values in the validation set were 0.860,0.936,0.951,and 0.965 at 3,4,5,and 6mo,respectively.Decision-curve analysis indicated that only the 4-,5-,and 6-month nomograms had significant net benefits over a large threshold probabilities interval.CONCLUSION:Preoperative PVR,SOTT,PE,RTS,and hypertension are significant risk factors for postoperative PVR formation in patients with primary RRD.The proposed nomogram can effectively predict the 4-,5-,and 6-month PVR-free probabilities after surgery and assist in making clinical decisions during follow-up.

Outcomes and predictors of vitrectomy and silicone oil tamponade in retinal detachments complicated by proliferative vitreoretinopathy

AIM:To evaluate outcomes and determine factors influencing the outcomes of vitrectomy with silicone oil(SO)endotamponade for the management of rhegmatogenous retinal detachment(RRD)complicated by advanced proliferative vitreoretinopathy(PVR).METHODS:This is a retrospective,interventional case series of eyes with PVR grade C associated RRD with or without prior surgery that underwent vitreoretinal surgery and SO tamponade.Eyes with a minimum follow-up of 6mo after SO extraction were included.Eyes were classified into three PVR subgroups according to severity and extension of proliferation.The influence of several preoperative,intraoperative and postoperative factors upon the functional and anatomical outcomes was assessed using multivariate logistic regression analysis.RESULTS:A hundred and one eyes of 101 patients that met the inclusion criteria were studied.Seventy-five of 101 eyes(74.3%)had successful retinal reattachment after one operation.Increased aqueous cell and flare at the first week exam had a statistically significant association with redetachment,recurrent membrane proliferation and keratopathy.Visual acuity improvement was significantly associated with faint postoperative aqueous inflammation values,primary vitrectomy and PVR outside of the posterior pole.CONCLUSION:Although encouraging anatomical and functional outcomes are achieved after vitrectomy and SO tamponade in eyes with RRD complicated by PVR,an increase in aqueous flare or cells at the first week follow-up is most likely to result in postoperative late complications.Primary vitrectomy,PVR associated with minimal posterior pole extension and absent to mild postoperative aqueous inflammation are associated with improved post-operative final visual acuity.

Anterior proliferative vitreoretinopathy in a patient with Coats disease

Dear Editor,I am Satoru Kase,from the Department of Ophthalmology,Faculty of Medicine and Graduate School of Medicine,Hokkaido University,Sapporo,Japan.I write to present a case of Coats disease showing anterior proliferative vitreoretinopathy(PVR)and neovascular glaucoma.

Upregulation of ASPP2 expression alleviates the development of proliferative vitreoretinopathy in a rat model

AIM:To investigate whether upregulation of apoptosisstimulating p53 protein 2(ASPP2)expression could alleviate the development of proliferative vitreoretinopathy(PVR)in a rat model.METHODS:ASPP2-lentivirus or scrambled-lentivirus were transfected into ARPE-19 cells,followed with measurements of cell cytotoxicity by cell counting kit-8 assay.ASPP2 upregulation was confirmed by Western blotting and immunocytochemistry.Then ARPE-19 cells pretreated with ASPP2-lentivirus were intravitreally injected to Brown Norway rats to induce PVR models.PVR development and retinal function were evaluated by retinal photography and electroretinography,respectively.Finally,epithelial-mesenchymal transition as well as autophagy were investigated in rats’retinas via Western blotting.RESULTS:Protein expression of ASPP2 was significantly upregulated by ASPP2-lentivirus transfection in ARPE-19 cells.The development and progression of PVR were impeded significantly in rats with intravitreal injection of ARPE-19 cells pretreated with ASPP2-lentivirus.Accordingly,retinal functions were less affected and PVR grades were much lower in rats with ASPP2-lentivirus compared to scrambledlentivirus treatment.Moreover,epithelial-mesenchymal transition and autophagy markers were decreased in the retinas of rats treated with ASPP2-lentivirus.CONCLUSION:ASPP2-lentivirus transfected to ARPE-19 cells mitigates the progression of PVR in rat models,which might be partly through reduced autophagy and attenuated epithelial-mesenchymal transition.ASPP2 might stand as a new approach for PVR treatment in the future.

Chronic hypotony management using endoscopy-assisted vitrectomy after severe ocular trauma or vitrectomy

·AIM: To report outcomes of endoscopy-assisted vitrectomy(EAV) in patients with chronic hypotony following severe ocular trauma or vitrectomy.·METHODS: This was a retrospective, noncomparative case series. Ciliary bodies were evaluated using ultrasound biomicroscopy pre-operatively and direct visualisation intraoperatively. All selected individuals(seven patients/seven eyes) underwent EAV. Removal of ciliary membrane and traction, gas/silicone oil tamponade(GT/SOT), and scleral buckling(SB) were performed in selected eyes. Outcome measurements mainly included intraocular pressure(IOP) and best-corrected visual acuity(BCVA).·RESULTS: Seven eyes from 7 male aphakic patients with a mean age of 45(range, 20-68)y were included in this study;the average follow-up time was 12(9-15)mo. GT was performed in 2 eyes;membrane peeling(MP) and SOT in 2 eyes;and MP, SOT, and SB in 3 eyes. The mean preand post-operative IOP were 4.5(range, 4.0±0.11 to 4.8±0.2) mm Hg and 9.9(range, 5.6±0.17 to 12.1±0.2) mm Hg at 52wk(12mo), respectively. BCVA improved in six eyes;one eye still showed light perception, and no bulbi phthisis was observed.·CONCLUSION: Endoscopy offers improved judgment and recognition and has an improved prognosis for chronic hypotony. Therefore, endoscopy can be an effective and promising operative technique for chronic traumatic hypotony management.

Risk factors and prognosis of pediatric rhegmatogenous retinal detachment in Egypt:a university hospital based study

AIM:To study and compare the predisposing factors and clinical features of pediatric,adult,and elderly rhegmatogenous retinal detachment(RRD).METHODS:This is an observational analytic crosssectional study in which patients with RRD admitted for surgery during 6mo period were divided into 3 age groups:pediatric(<18y),adult(18-60y),and elderly(>60y).Patients’demographic data,clinical features,RRD predisposing factors/features including myopia(axial length≥26.5 mm),aphakia/pseudophakia,blunt trauma,peripheral retinal degenerations,history of RRD in the fellow eye,and surgical interventions/findings were recorded and analyzed.RESULTS:Totally 142 patients(142 eyes)were studied:26(18.31%)pediatrics,86(60.56%)adults,and 30(21.13%)elderly.Elderly patients had a significantly higher intraocular pressures and cataracts compared to the other 2 groups(P=0.04).The RRD extent was larger in pediatric group(mostly 4 quadrants)compared to adults and elderly(mostly 2 quadrants),but it was not statistically insignificant(P=0.242).There were not statistically significantly differences in proliferative vitreoretinopathy(PVR)rate,posterior vitreous detachment(PVD)rate,number,site,shape,and size of breaks in three groups.All three groups had macular detachment in all eyes.Myopia and peripheral retinal degenerations were found to be more significant in adults(P=0.049,P=0.035,respectively),while blunt trauma was higher but insignificant in pediatric eyes(P=0.052).Pars plana vitrectomy(PPV)with silicone oil as a tamponade was the most used surgery in all groups.CONCLUSION:There are no significant difference in PVR rate in pediatric eyes but a significant higher rate of total RRD.Blunt trauma is more frequent in pediatrics eyes while myopia and/or peripheral retinal degenerations are more frequent in older ages.The rate of PPV as a choice for surgery is similar among all age groups.

Predictive factors of epiretinal membrane in complicated rhegmatogenous retinal detachment tamponaded with silicone oil

AIM:To determine the incidence and predictive factors for epiretinal membrane(ERM)formation in eyes with complicated primary rhegmatogenous retinal detachment(RRD)tamponaded with silicone oil(SO).METHODS:This retrospective case-control study included 141 consecutive patients with(51 eyes)and without(90 eyes)ERM formation after primary pars plana vitrectomy(PPV)and SO tamponade for complicated RRD.The risk factors for ERM were assessed using logistic regression analysis.RESULTS:The prevalence of postoperative ERM was 36.2%(51/141).Multivariate logistic regression analysis showed that the risk factors for ERM in SO-tamponaded eyes included preoperative proliferative vitreoretinopathy[PVR;odds ratio(OR),2.578;95%confidence interval(CI)1.580–4.205,P<0.001],preoperative choroidal detachment(OR,4.454;95%CI 1.369–14.498,P=0.013),and photocoagulation energy(OR,2.700;95%CI 1.047–6.962,P=0.040).The duration of the preoperative symptoms,intraocular SO tamponade time,giant retinal tear,preoperative vitreous hemorrhage,preoperative bestcorrected visual acuity,number of breaks,quadrants of RRD,axial length,and photocoagulation points were not predictive factors for ERM formation.CONCLUSION:Preoperative PVR,choroidal detachment,and photocoagulation energy are risk factors of ERM formation after complicated RRD repair.Better ophthalmic care as well as patient education are necessary for such patients with risk factors.

GSK3β inhibits epithelial-mesenchymal transition via the Wnt/β-catenin and PI3K/Akt pathways

● AIM: To investigate the regulatory mechanism of glycogen synthase kinase 3β(GSK3β) in epithelialmesenchymal transition(EMT) process after proliferative vitreoretinopathy(PVR) induction. ● METHODS: Experimental PVR was induced by intravitreal injection of retinal pigment epithelium(RPE) cells in the eyes of rabbits. A PI3 K/Akt inhibitor(wortmannin) and a GSK3β inhibitor(Li Cl) were also injected at different time during PVR progress. Electroretinogram(ERG), ocular fundus photographs, and B-scan ultrasonography were used to observe the PVR progress. Western blot test on the extracted retina were performed at 1, 2, 4 wk. The expression of the mesenchymal marker vimentin was determined by immunohistochemistry. Toxicity of wortmannin and Li Cl were evaluated by ERG and Td Tmediated d UTP nick-end labeling(TUNEL) assay. The vitreous was also collected for metabolomic analysis.● RESULTS: Experimental PVR could significantly lead to EMT, along with the suppressed expression of GSK3β and the activation of Wnt/β-catenin and PI3 K/Akt pathways. It was verified that upregulating the expression of GSK3β could effectively inhibit EMT process by suppressing Wnt/β-catenin and PI3 K/Akt pathways. ● CONCLUSION: GSK3β effectively inhibits EMT via the Wnt/β-catenin and PI3 K/Akt pathways. GSK3β may be regarded as a promising target of experimental PVR inhibition.

The role of mechanical stretch and TGF-β2 in epithelial-mesenchymal transition of retinal pigment epithelial cells

AIM: To explore the effects and mechanisms of mechanical stress and transforming growth factor-beta2(TGF-β2) on epithelial-mesenchymal transition(EMT) in cultured human retinal pigment epithelial(RPE) cells. METHODS: Human RPE cells were inoculated on BioF ex 6-well plates and RPE cells received 0, 1, 2, 3, or 4 mild stretch injuries delivered 3h apart after 24h of culture. The device of mechanical stress parameters were set to sine wave, frequency 1 Hz, stretch strength 20%. For treatment with TGF-β2, when the inoculated RPE cells in 6-well plates were around 60% confluent, serum was reduced to 0 for 12h and recombinant human TGF-β2(0, 1, 5, 10 ng/mL)was added for 48h. α-SMA, Vimentin and N-Cadherin, fibronectin proteins expressions were detected by Western blotting, confocal cell immunofluorescence and quantitative real-time polymerase chain reaction(q RT-PCR). Then we detected the change of mi RNA-29b and ascertained the changes of phosphatidylinositol 3-kinase-serine threonine protein kinase(PI3K/Akt) pathway after RPE cells were stretched by the device of mechanical stress and induced by TGF-β2 by Western blotting, confocal cell immunofluorescence and qR T-PCR. RESULTS: Mechanical stress induce EMT and activate the PI3K/Akt pathway in ways that lead to the EMT process. TGF-β2 induce RPE cells EMT and in a certain range and TGF-β2 decrease the miR NA-29b expression in RPE cells, and the inhibitory effect is more obvious with the increase of TGF-β2 concentration. CONCLUSION: Our findings are crucial steps in determining the critical roles of the PI3K/Akt signaling pathway and mi RNA-29b in pathogenesis of proliferative vitreoretinopathy(PVR) which may be a potential target for preventing or treating PVR.

Final anatomic and visual outcomes appear independent of duration of silicone oil intraocular tamponade in complex retinal detachment surgery

AIM: To report anatomic and visual outcomes following silicone oil removal in a cohort of patients with complex retinal detachment, to determine association between duration of tamponade and outcomes and to compare patients with oil removed and those with oil in situ in terms of demographic, surgical and visual factors. METHODS: We reported a four years retrospective case series of 143 patients with complex retinal detachments who underwent intraocular silicone oil tamponade. Analysis between anatomic and visual outcomes, baseline demographics, duration of tamponade and number of surgical procedures were carried out using Fisher's exact test and unpaired two-tailed t-test. RESULTS: One hundred and six patients(76.2%) had undergone silicone oil removal at the time of review with 96 patients(90.6%) showing retinal reattachment following oil removal. Duration of tamponade was not associated with final reattachment rate or with a deterioration in best corrected visual acuity(BCVA). Patients with oil removed had a significantly better baseline and final BCVA compared to those under oil tamponade(P=0.0001, <0.0001 respectively). CONCLUSION: Anatomic and visual outcomes in this cohort are in keeping with those reported in the literature. Favorable outcomes were seen with oil removal but duration of oil tamponade does not affect final attachment rate with modern surgical techniques and should be managed on a case by case basis.

Artesunate inhibits proliferation and migration of RPE cells and TGF-β2 mediated epithelial mesenchymal transition by suppressing PI3K/AKT pathway

AIM:To study the braking effectiveness of artesunate on transforming growth factor(TGF)-β2 mediated epithelial-mesenchymal transition(EMT)in retinal pigment epithelium(RPE)in vitro.METHODS:The fostered ARPE-19 cells were processed with artesunate alone or combined with the TGF-β2.The CCK-8 examination was utilized to test the cell propagation.Cell migration was detected by scratch as well as the Transwell examination.The EMT characters and activation of PI3K/Akt signal channel were estimated by Western blotting and immunofluorescence.The Western blotting was utilized in order to confirm the vitreous of controls as well as patients with proliferative vitreoretinopathy(PVR)were collected and the levels of PI3K,phospho-PI3K,Akt.RESULTS:Disposal of ARPE-19 cells with artesunate(50-150μmol/L)obviously suppressed their propagation and immigration,which dependent on the concentration and time.Artesunate suppressed the EMT which was induced by TGF-β2 in ARPE-19 cells through sustaining the expression of vimentin andα-SMA through the suppression of PI3K,phospho-PI3K,phospho-Akt and Akt.Levels of PI3K,phospho-PI3K,AKT and phospho-Akt was increased in the vitreous in PVR(P<0.05).CONCLUSION:Such findings indicate that PI3K/Akt signal channel is highly activated in vitreous of PVR.Artesuante is an operative depressor of the propagation,immigration and TGF-β2-mediated EMT of ARPE-19 cells by reduced the expression of PI3K/Akt channel.

Emerging roles of circular RNAs in retinal diseases

Retinal disorders are a group of ocular diseases whose onset is associated with a number of aberrant molecular and cellular processes or physical damages that affect retinal structure and function resulting in neural and vascular degeneration in the retina.Current research has primarily focused on delaying retinal disease with minimal success in preventing or reversing neuronal degeneration.In this review,we explore a relatively new field of research involving circular RNAs,whose potential roles as biomarkers and mediators of retinal disease pathogenesis have only just emerged.While knowledge of circular RNAs function is limited given its novelty,current evidence has highlighted their roles as modulators of microRNAs,regulators of gene transcription,and biomarkers of disease development and progression.Here,we summarize how circular RNAs may be implicated in the pathogenesis of common retinal diseases including diabetic retinopathy,glaucoma,proliferative vitreoretinopathy,and age-related macular degeneration.Further,we explore the potential of circular RNAs as novel biomarkers and therapeutic targets for the diagnosis and treatment of retinal diseases.

Pars Plana Vitrectomy versus Combined Scleral Buckling—Pars Plana Vitrectomy for Phakic Rhegmatogenous Retinal Detachment with Inferior Breaks

Aims: To compare the results of pars plana vitrectomy (PPV) and combined scleral buckling—PPV (SB/PPV) in phakic rhegmatogenous retinal detachments with inferior breaks. Methods: Randomized, prospective, clinical controlled trial of forty consecutive phakic eyes with primary rhegmatogenous retinal detachment, associated with inferior breaks and not complicated by proliferative vitreoretinopathy ≥grade C, to either PPV (group 1) or combined SB/PPV (group 2). Results: At 6 months follow up the primary reattachment rate was 100% (20/20 cases) in group 2 and 70% (14/20 cases) in the group 1, the difference being statistically significant (p = 0.027). The best corrected visual acuity improved significantly from a preoperative mean of 1.65 ± 1.13 (Range: 0.6 to 3) to a mean of 0.45 ± 0.11 (Range: 0.3 to 0.6) in the group 2 and in the group 1 improved from a preoperative mean of 2.34 ± 0.92 (Range: 0.48 to 3) to a mean of 0.668 ± 0.20 (Range: 0.48 to 1), the difference between the two groups being statistically significant (p = 0.001). Conclusion: Anatomical and functional success rates are significantly better with the use of a scleral explant during PPV for uncomplicated forms of phakic rhegmatogenous retinal detachments with inferior breaks.

Comparison of the effects of intravitreal bevacizumab and dexamethasone in experimental posterior penetrating eye injury

AIM: To compare the effects of intravitreal anti-vascular endothelial growth factor(VEGF) and dexamethasone in an experimental rabbit model of posterior penetrating ocular injury.METHODS: Thirty white New Zealand rabbits were included in the study. A posterior penetrating ocular injury was performed at the superotemporal quadrant. They were randomly divided into three groups. The rabbits in group 1 received intravitreal dexamethasone, in group 2 they received intravitreal bevacizumab and those in group 3 received intravitreal physiological saline solution in both eyes. All eyes were examined ophthalmologically on the 1^(st), 3^(rd), 7^(th), 14^(th) and 28^(th) days following the injury and the clinical findings were scored. On the day 28, the eyes were enucleated, evaluated and scored macroscopically, histopathologically and scanning electron microscopically.RESULTS: The median clinical score on the 14 th and 28 th days and the median macroscopic score of the dexamethasone group was significantly better than that of control(P=0.004, 0.018). Dexamethasone group was also better than that of bevacizumab group but the differences did not reach statistical significance. Retinal detachment rate was 8.3%, 16.6% and 12.5% in the dexamethasone group, bevacizumab group and control group, respectively(P=0.476). More extensive fibrocelluler proliferations were observed in controls compared with dexamethasone and bevacizumab groups. But these differences did not reach the statistical significance(P=0.538). In scanning electron microscopy all groups showed fibreous stalk and dense collagen fibrils in vitreous. CONCLUSION: This study shows that intravitreal injection of both dexamethasone and bevacizumab may reduce the intraocular fibrous proliferation after an experimental posterior penetrating ocular injury in rabbits.