Taiwan ocular inflammation society consensus recommendations for the management of juvenile idiopathic arthritis-associated uveitis.

We presented the development of a consensus guideline for managing juvenile idiopathic arthritis-associated uveitis (JIAU) in Taiwan, considering regional differences in manifestation and epidemiology. The Taiwan Ocular Inflammation Society (TOIS) committee formulated this guideline using a modified Delphi approach with two panel meetings. Recommendations were based on a comprehensive evidence-based literature review and expert clinical experiences, and were graded according to the Oxford Centre for Evidence-Based Medicine's "Levels of Evidence" guideline (March 2009). The TOIS consensus guideline consists of 10 recommendations in four categories: screening and diagnosis, treatment, complications, and monitoring, covering a total of 27 items. These recommendations received over 75% agreement from the panelists. Early diagnosis and a coordinated referral system between ophthalmologists and pediatric rheumatologists are crucial to prevent irreversible visual impairment in children with JIAU. However, achieving a balance between disease activity and medication use remains a key challenge in JIAU management, necessitating further clinical studies.

Nordalbergin Exerts Anti-Neuroinflammatory Effects by Attenuating MAPK Signaling Pathway, NLRP3 Inflammasome Activation and ROS Production in LPS-Stimulated BV2 Microglia.

Microglia-associated neuroinflammation is recognized as a critical factor in the pathogenesis of neurodegenerative diseases; however, there is no effective treatment for the blockage of neurodegenerative disease progression. In this study, the effect of nordalbergin, a coumarin isolated from the wood bark of Dalbergia sissoo, on lipopolysaccharide (LPS)-induced inflammatory responses was investigated using murine microglial BV2 cells. Cell viability was assessed using the MTT assay, whereas nitric oxide (NO) production was analyzed using the Griess reagent. Secretion of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) was detected by the ELISA. The expression of inducible NO synthase (iNOS), cyclooxygenase (COX)-2, mitogen-activated protein kinases (MAPKs) and NLRP3 inflammasome-related proteins was assessed by Western blot. The production of mitochondrial reactive oxygen species (ROS) and intracellular ROS was detected using flow cytometry. Our experimental results indicated that nordalbergin ≤20 µM suppressed NO, IL-6, TNF-α and IL-1ß production; decreased iNOS and COX-2 expression; inhibited MAPKs activation; attenuated NLRP3 inflammasome activation; and reduced both intracellular and mitochondrial ROS production by LPS-stimulated BV2 cells in a dose-dependent manner. These results demonstrate that nordalbergin exhibits anti-inflammatory and anti-oxidative activities through inhibiting MAPK signaling pathway, NLRP3 inflammasome activation and ROS production, suggesting that nordalbergin might have the potential to inhibit neurodegenerative disease progression.

Magnolol regulates miR-200c-3p to inhibit epithelial-mesenchymal transition and retinoblastoma progression by modulating the ZEB1/E-cadherin axis in vitro and in vivo.

BACKGROUND: Retinoblastoma, the most common pediatric intraocular malignancy, can develop during embryogenesis, with most children being diagnosed at 3-4 years of age. Multimodal therapies are typically associated with high levels of cytotoxicity and side effects. Therefore, the development of novel treatments with minimal side effects is crucial. Magnolol has a significant anti-tumor effect on various cancers. However, its antitumor effect on retinoblastoma remains unclear. PURPOSE: The study aimed to determine the effects of magnolol on the regulation of EMT, migration, invasion, and cancer progression in retinoblastoma and the modulation of miR-200c-3p expression and the Wnt/ zinc finger E-box binding homeobox 1 (ZEB1)/E-cadherin axis in vivo and in vitro. METHODS: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay was used to evaluate magnolol-induced cell toxicity in the Y79 retinoblastoma cell line. Flow cytometry and immunostaining assays were performed to investigate the magnolol-regulated mitochondrial membrane potential and the intracellular and mitochondrial reactive oxygen species levels in Y79 retinoblastoma cells. Orthotopic and subcutaneous xenograft experiments were performed in eight-week-old male null mice to study retinoblastoma progression and metastasis. In situ hybridization and quantitative reverse transcription polymerase chain reaction (RT-qPCR) assays were performed to evaluate the level of the anti-cancer miRNA miR-200c-3p. The mRNA and protein levels of E-cadherin, ß-catenin, α-smooth muscle actin (α-SMA), fibronectin-1, and ZEB1 were analyzed using RT-qPCR, immunoblot, immunocytochemistry, and immunohistochemistry assays in vitro and in vivo. RESULTS: Magnolol increased E-cadherin levels and reduced the activation of the EMT signaling pathway, EMT, tumor growth, metastasis, and cancer progression in the Y79 retinoblastoma cell line as well as in the orthotopic and subcutaneous xenograft animal models. Furthermore, magnolol increased the expression of miR-200c-3p. Our results demonstrate that miRNA-200c-3p inhibits EMT progression through the Wnt16/ß-catenin/ZEB1/E-cadherin axis, and the ZEB1 silencing response shows that miR-200c-3p regulates ZEB1-mediated EMT in retinoblastoma. CONCLUSION: Magnolol has an antitumor effect by increasing E-cadherin and miRNA-200c-3p expression to regulate ZEB1-mediated EMT and cancer progression in retinoblastoma. The anti-tumor effect of magnolol by increasing E-cadherin and miRNA-200c-3p expression to regulate ZEB1-mediated EMT and cancer progression in retinoblastoma has been elucidated for the first time.

Polycythemia-Related Proliferative Ischemic Retinopathy Managed with Smoking Cessation: A Case Report.

Ischemic retinopathy characterized by neovascularization could result from several diseases such as proliferative diabetic retinopathy, hypertensive retinopathy, and retinal vein occlusion. However, ocular ischemic conditions caused by polycythemia have rarely been described. We report the first case of polycythemia-related proliferative ischemic retinopathy in a 41-year-old male heavy smoker who had ocular ischemic condition due to secondary polycythemia. He had sudden loss of vision in his right eye vision with vitreous hemorrhage and a tortuous retinal artery. Tracing back to his history, he was a heavy smoker with more than one pack of cigarettes per day for more than 30 years. Laboratory data revealed elevated levels of hemoglobin (17.7 g/dL) and hematocrit (51.6%) without other abnormal findings. We performed retinal photocoagulation on the neovascular areas and the fibrous membrane. Additionally, the patient was advised to quit smoking. Owing to adherence to this treatment, the patient's vision gradually recovered. Although rare, polycythemia can cause retinal ischemic events and should be considered as a sight-threatening disease. Photocoagulation is effective on the regression of the neovascular lesion. Most importantly, changes in lifestyle together with smoking cessation are effective in managing secondary polycythemia. In conclusion, prevention and cessation of tobacco consumption helps improve vision health.

Long-Term Follow-Up of Refractory Large Macular Hole with Autologous Neurosensory Retinal Free Flap Transplantation.

Purpose: To evaluate the long-term anatomic and functional outcomes of autologous neurosensory retinal free flap transplantation (ART) for patients with refractory large macular hole (MH). Design: Retrospective interventional case series. Methods: We reviewed 9 patients who underwent ART for their refractory large MH. In this extended follow-up study, postoperative assessment including spectral-domain optical coherence tomography and best-corrected visual acuity (BCVA) were recorded at 12, 15, 18, 21, and 24 months after surgery. Results: The macular hole of all patients appeared successfully closed during the whole follow-up period. The mean logMAR BCVA improved from 1.61 ± 0.44 (preoperative) to 0.72 ± 0.30 (12 months after surgery) (p < 0.001). Thereafter, the mean BCVA remained stable at each follow-up. At the mean 16.0 ± 0.8 months postoperatively, inner retinal cystic changes were observed in 4 eyes (44.4%), but these did not significantly affect vision. Conclusion: ART is a good alternative technique for closing large refractory macular holes. Although inner retinal cystic changes were observed in 4 eyes (44.4%), this phenomenon did not significantly affect visual acuity. It provides long-term good anatomical and functional results, especially in cases where insufficient ILM or lens capsule are left.

Clinical Manifestations and Outcomes of Tubercular Uveitis in Taiwan-A Ten-Year Multicenter Retrospective Study.

Background andObjectives: This 10-year multicenter retrospective study reviewed the clinical manifestations, diagnostic tests, and treatment modalities of tubercular uveitis (TBU), including direct infection and indirect immune-mediated hypersensitivity to mycobacterial antigens in Taiwan. Materials and Methods: This retrospective chart review of patients with TBU was conducted at 11 centers from 1 January 2008 to 31 December 2017. We used a multiple regression model to analyze which factors influenced best-corrected visual acuity (BCVA) improvement. Results: A total of 79 eyes from 51 patients were included in the study. The mean age was 48.9 ± 16.4 years. The mean change of LogMAR BCVA at last visit was -0.21 ± 0.45. Diagnostic tools used include chest X-ray, chest computed tomography, Mantoux test, interferon gamma release test (QuantiFERON-TB Gold test), intraocular fluid tuberculosis polymerase chain reaction, and bronchial alveolar lavage. The clinical manifestations included 48% posterior uveitis and 37% panuveitis. In the sample, 55% of the cases were bilateral and 45% unilateral. There was 60.76% retinal vasculitis, 35.44% choroiditis, 21.52% serpiginous-like choroiditis, 17.72% vitreous hemorrhage, 12.66% posterior synechiae, 6.33% retinal detachment, and 3.80% choroidal granuloma. Treatment modalities included rifampicin, isoniazid, pyrazinamide, ethambutol, oral steroid, posterior triamcinolone, non-steroidal anti-inflammatory drugs, vitrectomy, and immunosuppressants. BCVA improved in 53.2% of eyes and remained stable in 32.9% of eyes. In the final model of multiple regression, worse initial BCVA, pyrazinamide, and receiving vitrectomy predicted better BCVA improvement. Ethambutol was associated with worse visual outcomes. Seven eyes experienced recurrence. Conclusions: This is the largest 10-year multicenter retrospective study of TBU in Taiwan to date, demonstrating the distribution of clinical manifestations and clinical associations with better treatment outcomes. The study provides a comprehensive description of TBU phenotypes in Taiwan and highlights considerations for the design of further prospective studies to reliably assess the role of ATT and vitrectomy in patients with TBU.

Triamcinolone acetonide modulates TGF­ß2­induced angiogenic and tissue­remodeling effects in cultured human retinal pigment epithelial cells.

Transforming growth factor­ß2 (TGF­ß2) has been implicated in the pathogenesis of proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR), due to its ability to stimulate the overproduction of pro­angiogenic factors, such as vascular endothelial growth factor (VEGF), and remodeling of the extracellular matrix (ECM). Although intravitreal triamcinolone acetonide (TA) is clinically useful in the treatment of PVR and PDR, its molecular mechanism has yet to be fully elucidated. The present study investigated whether TA treatment altered TGF­ß2­driven biological effects on the behavior of cultured human retinal pigment epithelial (RPE) cells, in order to determine which signaling pathway may be essential for the pharmacological action of TA. The R­50 human RPE cell line was treated with TA in the presence of TGF­ß2, followed by analyses of cell viability and contraction using cell viability and collagen gel contraction assays. VEGF mRNA expression and protein production were measured using reverse transcription­quantitative PCR and ELISA, respectively. The phosphorylation status of signaling mediators and the protein expression of type I collagen (COL1A1), α­smooth muscle actin (α­SMA), and ECM­remodeling enzymes, including MMP­2 and MMP­9, were analyzed using western blotting. The gelatinolytic activity of MMPs was detected using gelatin zymography. TA treatment exhibited no prominent cytotoxicity but markedly antagonized TGF­ß2­induced cytostatic effects on RPE cell viability and TGF­ß2­enhanced contractility in collagen gels. In the context of TGF­ß2­related signaling, TA significantly attenuated TGF­ß2­elicited Smad2, extracellular­regulated kinase (ERK)1/2 and p38 mitogen­activated protein kinase (MAPK) phosphorylation. Moreover, TA markedly mitigated TGF­ß2­induced VEGF upregulation through ablation of p38 signaling activity. TA also partially attenuated TGF­ß2­elicted expression of COL1A1, α­SMA, MMP­2, and MMP­9, but only suppressed TGF­ß2­induced MMP­9 gelatinolytic activity. Mechanistically, the MEK/ERK signaling pathway may have a critical role in the TGF­ß2­induced upregulation of COL1A1, α­SMA and MMP­9. In conclusion, TA may be considered a useful therapeutic agent for treating TGF­ß2­associated intraocular angiogenesis and tissue remodeling, the underlying mechanism of which may involve the ERK and p38 MAPK signaling pathways.

Thrombospondin 1-induced exosomal proteins attenuate hypoxia-induced paraptosis in corneal epithelial cells and promote wound healing.

Thrombospondin-1 (TSP1) is involved in corneal wound healing caused by chemical injury. Herein, we examined the effects of TSP1 on hypoxia-induced damages and wound-healing activity in human corneal epithelial (HCE) cells. Exosomal protein expression was determined using liquid chromatography-tandem mass spectrometry, and HCE cell migration and motility were examined through wound-healing assay and time-lapse microscopy. Reestablishment of cell junctions by TSP1 was assessed through confocal microscopy and 3D image reconstruction. Our results show that CoCl2 -induced hypoxia promoted HCE cell death by paraptosis. TSP1 protected these cells against paraptosis by attenuating mitochondrial membrane potential depletion, swelling and dilation of endoplasmic reticulum and mitochondria, and mitochondrial fission. Exosomes isolated from HCE cells treated with TSP1 contained wound healing-associated proteins that were taken up by HCE cells to promote tissue remodeling and repair. TSP1 protected HCE cells against hypoxia-induced damages and inhibited paraptosis progression by promoting cell migration, cell-cell adhesion, and extracellular matrix remodeling. These findings indicate that TSP1 ameliorates hypoxia-induced paraptosis in HCE cells and promotes wound healing and remodeling by regulating exosomal protein expression. TSP1 may, therefore, play important roles in the treatment of hypoxia-associated corneal diseases.

Infusion of Human Mesenchymal Stem Cells Improves Regenerative Niche in Thioacetamide-Injured Mouse Liver.

BACKGROUND: This study investigated whether xenotransplantation of human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) reduces thioacetamide (TAA)-induced mouse liver fibrosis and the underlying molecular mechanism. METHODS: Recipient NOD/SCID mice were injected intraperitoneally with TAA twice weekly for 6 weeks before initial administration of WJ-MSCs. Expression of regenerative and pro-fibrogenic markers in mouse fibrotic livers were monitored post cytotherapy. A hepatic stallate cell line HSC-T6 and isolated WJ-MSCs were used for in vitro adhesion, migration and mechanistic studies. RESULTS: WJ-MSCs were isolated from human umbilical cords by an explant method and characterized by flow cytometry. A single infusion of WJ-MSCs to TAA-treated mice significantly reduced collagen deposition and ameliorated liver fibrosis after 2-week therapy. In addition to enhanced expression of hepatic regenerative factor, hepatocyte growth factor, and PCNA proliferative marker, WJ-MSC therapy significantly blunted pro-fibrogenic signals, including Smad2, RhoA, ERK. Intriguingly, reduction of plasma fibronectin (pFN) in fibrotic livers was noted in MSC-treated mice. In vitro studies further demonstrated that suspending MSCs triggered pFN degradation, soluble pFN conversely retarded adhesion of suspending MSCs onto type I collagen-coated surface, whereas pFN coating enhanced WJ-MSC migration across mimicked wound bed. Moreover, pretreatment with soluble pFN and conditioned medium from MSCs with pFN strikingly attenuated the response of HSC-T6 cells to TGF-ß1-stimulation in Smad2 phosphorylation and RhoA upregulation. CONCLUSION: These findings suggest that cytotherapy using WJ-MSCs may modulate hepatic pFN deposition for a better regenerative niche in the fibrotic livers and may constitute a useful anti-fibrogenic intervention in chronic liver diseases.

Monounsaturated oleic acid modulates autophagy flux and upregulates angiogenic factor production in human retinal pigment epithelial ARPE-19 cells.

AIMS: Dyslipidemia-associated diabetic retinopathy is featured by macular edema and retinal angiogenesis. This study investigated the in vitro lipotoxicity of free fatty acids and their modulatory roles in regulation of autophagy and angiogenic factor production in cultured human retinal pigment epithelium (RPE) ARPE-19 cells. MAIN METHODS: ARPE-19 cells were exposed to monounsaturated oleic acid (OA), saturated palmitic acid (PA), or both. Cell viability, cell cycle distribution, migration, and autophagy of the treated cells were monitored. Angiogenic factor production was determined by RT-qPCR and ELISA. KEY FINDINGS: OA, but not PA, at doses higher than 500 µM significantly induced cytostasis and lipotoxicity in ARPE-19 cells. OA exposure not only markedly enhanced autophagy flux, but also enhanced cell migration, while PA suppressed motility of RPE cells. Meanwhile, OA stimulated de novo synthesis of angiogenic factors including VEGF and bFGF in ARPE-19 cells. Mechanistically, OA treatment stimulated not only AMPK/mTOR/p70S6K signaling, but also induced hyperphosphorylation of MAPK pathway mediators, including ERK, JNK and p38 MAPK, as well as NF-κB activation. Kinase inhibition assays showed that blockade of PI3K/Akt, MAPK and NF-κB pathways prevented the OA-upregulated VEGF transcription and its peptide release. Comparatively, only NF-κB inhibition significantly suppressed bFGF peptide release from ARPE-19 cells. SIGNIFICANCE: Out findings support the OA-exhibited cytostasis, autophagy modulation and angiogenic factor production in RPE cells. This study sheds light on the interrelationship between metabolic disorder and retinopathy and provides molecular strategies for preventing and treating choroidal neovascularization in diabetic retinopathy.

MANAGEMENT OF REFRACTORY LARGE MACULAR HOLE WITH AUTOLOGOUS NEUROSENSORY RETINAL FREE FLAP TRANSPLANTATION.

PURPOSE: To investigate the morphological and functional outcome of refractory large macular hole (MH) with autologous neurosensory retinal free flap transplantation. METHODS: This case series enrolled 10 patients suffering from refractory large MH at Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. All eyes underwent pars plana vitrectomy, a neurosensory retinal free flap with a 1.5 to 2-MH diameter was harvested. We used an adhesive agent such as whole blood or Viscoat to assist the stabilization of the retinal free flap and then use tamponade silicone oil to tamponade the vitreous cavity. Silicone oil was removed 6 months postoperatively. Main outcome measures including closure of MH and change in best-corrected visual acuity change were recorded. RESULTS: The mean age was 64.9 ± 11.5 years. Before presentation, all cases had received at least two vitreoretinal procedures including vitrectomy, internal limiting membrane peeling, and fluid-gas exchange. At last visit, closure of the MH was achieved in 9 of 10 (90%) cases. The mean preoperative best-corrected visual acuity and that after 12 months of surgery improved from 1.65 ± 0.43 logarithm of minimum angle of resolution to 0.88 ± 0.49 logarithm of minimum angle of resolution (P < 0.001). CONCLUSION: For eyes with refractory or large MH, autologous neurosensory retinal free flap under silicone oil tamponade may provide a new option to improve the anatomical and function outcome, especially in cases where insufficient internal limiting membrane is left.

THE ASSOCIATION BETWEEN CENTRAL SEROUS CHORIORETINOPATHY AND SLEEP APNEA: A Nationwide Population-Based Study.

PURPOSE: To identify the association between sleep apnea (SA) and central serous chorioretinopathy (CSC). METHODS: In this nationwide population-based study using the Taiwan National Health Insurance Database, we enrolled adult patients with a diagnosis of SA and matched each patient to 30 age- and gender-matched control subjects without any SA diagnosis. Using Poisson regression analyses, the incidence rate of CSC was compared between SA patients and control subjects. RESULTS: A total of 10,753 SA patients and 322,590 control subjects were identified. After adjusting for age, gender, residency, income level, and comorbidities, the incidence rate of CSC was significantly higher in SA patients than in the control subjects (adjusted incident rate ratio for probable SA: 1.2 [95% CI: 1.1-1.4], P < 0.0001). Analyses of the propensity score-matched subpopulations also confirmed our findings. Risk factors for CSC in SA patients included male gender, age ≤50 years, higher income, presence of heart disease, absence of chronic pulmonary disease, and presence of liver disease. In SA patients, those who had received continuous positive airway pressure titration had a significantly lower incidence rate of CSC than the others. CONCLUSION: Our study revealed a significantly higher incidence rate of CSC in SA patients compared with the control subjects.

Management of Giant Retinal Tear with microincision vitrectomy and metallic retinal tacks fixation-a case report.

BACKGROUND: Giant retinal tear is usually challenging among retinal detachment with recurrent rate up to 45%. Here we presented a case of giant retinal tear being treated by microincision vitrectomy and retinal tacks fixation. CASE PRESENTATION: A 53-year-old male presented to our hospital with blurred vision of his right eye for one week with floaters and obscured sensation over nasal visual field. Ocular examination showed a 120 degree giant tear with large inverted flap and retinal detachment of his right eye. The BCVA was only naming digit. Under the impression of giant retinal tear with retinal detachment, 23-gauge pars plana vitrectomy were performed using Constellation high speed vitrectomy system and Topcon non-contact wide angle viewing system. During surgery, the vitreous was removed and perfluorocarbon liquids (PFCL) was injected to help unfolding the large inverted retinal flap. Three retinal tacks were applied to help fixating the large inverted retinal flap. Then, fluid-gas exchange, endolaser photocoagulation and intraocular silicone oil tamponade were performed as well. Initial reattachment of his right retina was achieved and his best corrected visual acuity improved to 0.3 of his right eye postoperatively. There was no recurrent retinal detachment during follow up period of 19 months. CONCLUSIONS: Primary microincision vitrectomy using wide-angle viewing system with intraoperative perfluorocarbon liquids (PFCL) assistant, retinal tacks fixation and intraocular silicone oil tamponade appears to be safe and feasible for managing giant retinal tear with retinal detachment.

Recommendation of using systemic anti-tumor necrosis factor-alpha for the treatment of noninfectious uveitis in Taiwan.

Noninfectious uveitis is a sight-threatening disease with an autoimmune or autoinflammatory basis. Systemic treatment is required if intraocular inflammation threatens a patient's vision or cannot be controlled locally and when it is associated with systemic rheumatic diseases. Corticosteroids and immunomodulatory chemotherapy are the conventional initial treatments. However, the various side effects of these therapies increase the burden on patients, not only physically but also mentally. Moreover, uncontrolled inflammation and poor visual outcomes have sometimes been recorded despite the combination of these medications or their high dosage. Antitumor necrosis factor-alpha (anti-TNF-α) and other biologic agents have been widely used to treat rheumatic diseases for >15 years. Randomized controlled clinical trials have demonstrated that anti-TNF-α can reduce and delay episodes of intraocular inflammation not only in patients with active uveitis but also in corticosteroid-dependent patients with inactive uveitis. The Taiwan Food and Drug Administration approved the use of adalimumab, an anti-TNF-α agent, for treating nonanterior noninfectious uveitis (NANIU) in 2017. This report provides a recommendation and a proposed stepladder approach for using anti-TNF-α agents to treat NANIU in Taiwan.

Management of refractory macular hole with blood and gas-assisted autologous neurosensory retinal free flap transplantation: a case report.

BACKGROUND: Macular hole (MH) may become refractory if the hole does not close after multiple surgeries. We provide a modified surgical technique for refractory MH repair with neurosensory retinal free flap transplantation. CASE PRESENTATION: To treat a 68-year-old female patient with refractory MH after multiple surgeries, we harvested a neurosensory retinal free flap with a 2-MH diameter area. A drop of whole blood was placed within the MH as an adhesive to fix the neurosensory retinal free flap at the MH under gas tamponade. Two months after surgery, optical coherence tomography (OCT) revealed closure of the MH. The flap was visible on OCT and had filled the MH without overlapping the neurosensory retina. The patient's best-corrected visual acuity (BCVA) improved from 20/500 preoperatively to 20/50 at 2 months postoperatively. CONCLUSIONS: Using whole blood as an adhesive to aid in the fixation of an autologous neurosensory retinal free flap under gas tamponade provides another option for patients with refractory MH due to multiple prior surgeries.

Comparison of Visual Outcome and Morphologic Change between Different Surgical Techniques in Idiopathic Epiretinal Membrane Surgery.

PURPOSE: To investigate the morphological and functional outcomes of idiopathic epiretinal membrane (ERM) surgery between three different surgical techniques: ERM peeling only, whole-piece ILM peeling, and maculorrhexis ILM peeling. PATIENTS AND METHODS: This is a retrospective, consecutive, and comparative study enrolling 60 patients from Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Surgery performed between July 2011 and June 2012 was done with ERM peeling only (group I). ERM peeling and ILM peeling as a whole piece (group II) were performed between July 2012 and July 2013. Surgery performed between August 2013 and December 2014 was done with maculorrhexis ILM peeling (group III). Main outcome measures include visual acuity change (BCVA) and central foveal thickness (CFT). RESULTS: At 12 months postoperation, the mean BCVA in group III was significantly better than in group I and group II. Comparison of CFT reduction between the three groups revealed significantly more reduction in group III than in group II at all postoperative follow-up periods. Eyes with restoration of foveal depression were observed in 52.6% in group I, 52.4% in group III, but only 20% of eyes in group II. None of the eyes in both ILM peeling groups encountered recurrence of macular pucker formation. CONCLUSION: All three techniques can achieve visual acuity improvement and macular thickness reduction. Maculorrhexis ILM peeling achieves more rapid improvement of visual function, better final visual outcome, and a higher rate of normal foveal contour than whole-piece ILM peeling.

Cyclic Mechanical Stretch Up-regulates Hepatoma-Derived Growth Factor Expression in Cultured Rat Aortic Smooth Muscle Cells.

Hepatoma-derived growth factor (HDGF) is a potent mitogen for vascular smooth muscle cells (SMCs) during embryogenesis and injury repair of vessel walls. Whether mechanical stimuli modulate HDGF expression remains unknown. This study aimed at investigating whether cyclic mechanical stretch plays a regulatory role in HDGF expression and regenerative cytokine production in aortic SMCs. A SMC cell line was grown on a silicone-based elastomer chamber with extracellular matrix coatings (either type I collagen or fibronectin) and received cyclic and uni-axial mechanical stretches with 10% deformation at frequency 1 Hz. Morphological observation showed that fibronectin coating provided better cell adhesion and spreading and that consecutive 6 hours of cyclic mechanical stretch remarkably induced reorientation and realignment of SMCs. Western blotting detection demonstrated that continuous mechanical stimuli elicited up-regulation of HDGF and PCNA, a cell proliferative marker. Signal kinetic profiling study indicated that cyclic mechanical stretch induced signaling activity in RhoA/ROCK and PI3K/Akt cascades. Kinase inhibition study further showed that blockade of PI3K activity suppressed the stretch-induced TNF-a, whereas RhoA/ROCK inhibition significantly blunted the IL-6 production and HDGF over-expression. Moreover, siRNA-mediated HDGF gene silencing significantly suppressed constitutive expression of IL-6, but not TNF-α, in SMCs. These findings support the role of HDGF in maintaining vascular expression of IL-6, which has been regarded a crucial regenerative factor for acute vascular injury. In conclusion, cyclic mechanical stretch may maintain constitutive expression of HDGF in vascular walls and be regarded an important biophysical regulator in vascular regeneration.

Dexamethasone Intravitreal Implant (Ozurdex) for Long-Term Macular Edema after Epiretinal Membrane Peeling Surgery.

PURPOSE: To investigate the functional and anatomical outcome of the 0.7 mg dexamethasone (Ozurdex) intravitreal implant (IVD) in eyes with long-term macular edema after macular epiretinal membrane removal. METHODS: We enrolled 40 eyes with persistent macular edema at least 12 months after epiretinal membrane removal. Twenty eyes in the IVD group received IVD and the other 20 eyes were in the control group. The main outcome measures were change in best-corrected visual acuity (BCVA) and central foveal thickness (CFT). RESULTS: For eyes in the IVD group, the mean BCVA improved by 3.45 lines to 0.47 logMAR one month after IVD. However, the mean BCVA improved by only 0.14 lines to 0.74 logMAR at the same time in eyes in the control group. Six months later, the mean BCVA improved to 0.31 and 0.74 logMAR in the IVD and control groups, respectively. In the IVD group, the mean CFT decreased rapidly by 116.8 µm to 333.9 µm one month after IVD. Thereafter the CFT decreased at a slower pace. In the control group, the CFT remained static during the follow-up period. However, in the IVD group, 6 months after IVD, the CFT seemed to have a tendency to increase. CONCLUSIONS: Single IVD could significantly decrease macular edema and improve visual outcome for eyes with persistent long-term macular edema after macular ERM removal and the effect can be sustained as long as 6 months after the initial injection. However, in order to maintain the visual and anatomical outcome, repeat IVD might be considered if macular edema recurs.

High mobility group B1 up-regulates angiogenic and fibrogenic factors in human retinal pigment epithelial ARPE-19 cells.

Hypoxia-induced retinal neovascularization plays a central role in the pathogenesis of diabetic retinopathy. This study aimed to investigate whether hypoxia leads to the release of nuclear high mobility group box 1 (HMGB1) peptides from cultured retinal pigment epithelial ARPE-19 cells, to determine the effect of HMGB1 on angiogenic cytokine production and elucidate the involved signaling pathways. A chemical hypoxia mimetic agent, cobalt chloride, induced SIRT1 downregulation, HMGB1 nucleocytoplasmic relocation and extracellular release from ARPE-19 cells, implicating its autocrine function. Resveratrol treatment significantly reduced secretion of HMGB1 from ARPE-19 cells exposed to hypoxia. Cell proliferation and cell cycle analyses demonstrated that exogenous HMGB1 caused significant growth suppression and G1 cell cycle arrest in ARPE-19 cells. Morphological observations showed that HMGB1 enhanced adhesion, but suppressed migration of ARPE-19 cells. More intriguingly, HMGB1 up-regulated expression of angiofibrogenic factors in ARPE-19 cells, including VEGF, bFGF, TGF-ß2, and CTGF. Signal profiling characterization indicated that HMGB1 triggered hyperphosphorylation of Akt, p38 MAPK, and NF-κB, but not that of ERK, JNK, and Smad2, whereas inhibition of PI3K, MAPK, or NF-κB significantly attenuated the HMGB1-driven cytokine overproduction in ARPE-19 cells. Functional neutralization with anti-TLR4 and -RAGE antibodies confirmed that both receptors were involved in the cytokine overproduction. In conclusion, chemically-mimicked hypoxia induced nucleocytoplasmic relocation and release of HMGB1 peptides, which in turn up-regulated the production of angiofibrogenic factors in RPE cells, thereby contributing to the pathogenesis of hypoxia-associated diabetic retinopathies. Conversely, blockades of intraocular HMGB1 bioavailability or signal activation may prevent angiofibrogenesis in development of diabetic retinopathy.

Modified internal limiting membrane peeling technique (maculorrhexis) for myopic foveoschisis surgery.

PURPOSE: Myopic foveoschisis occurs in 9-34% of highly myopic eyes with posterior staphyloma. The pathogenesis is still not fully understood. But the relative inflexibility of the inner retina and a tangential traction induced inward traction force in the posterior staphyloma are possible mechanisms. Conventional internal limiting membrane (ILM) peeling generally yields good results. However, a postoperative full-thickness macular hole happens in 13-28% of cases. Therefore, this study describes a modified ILM peeling technique named 'ILM maculorrhexis' to minimize the occurrence of postoperative macular hole in patients with foveoschisis. METHODS: This retrospective case review that included 10 eyes of 10 consecutive patients who underwent vitrectomy with ILM maculorrhexis to treat myopic foveoschisis was studied. After surgery, complete ophthalmic examination and SD-optic coherence tomographic examinations were performed 1, 3, 6, 9 and 12 months postoperatively. RESULTS: After surgical intervention, the foveoschisis resolved dramatically in all 10 eyes. The mean central foveal thickness decreased significantly from 840 µ to 273 µ at 12 months postoperatively. Mean LogMAR best-corrected visual acuity improved from 1.04 preoperatively to 0.59 12 months postoperatively. After the follow-up time of at least 12 months, all 10 eyes remained fovea attached, and none of the 10 eyes developed macular hole. CONCLUSIONS: This technique minimizes traction force over the extremely thinned foveal tissue in highly myopic eyes. In the long-term follow-up of at least 12 months, all 10 cases had good anatomic and visual results. But we still need a larger case number and longer follow-up for further evaluation.