Intra-Ocular Inflammation and Occlusive Retinal Vasculitis Following Intravitreal Injections of Faricimab: A Case Report.

PURPOSE: Faricimab is a bispecific antibody that inhibits angiopoietin-2 and vascular endothelial growth factor-A action and has been approved for the treatment of neovascular age-related macular degeneration and diabetic macular edema. Clinical trials have demonstrated its favorable safety profile. This report presents a case of intra-ocular inflammation and occlusive retinal vasculitis following a second intravitreal injection of faricimab. METHODS: A single case report was obtained from a tertiary referral center. RESULTS: A 73-year-old Asian man diagnosed with polypoidal choroidal vasculopathy presented with decreased vision in the left eye (OS) 2 weeks after the second faricimab administration. In the fourth week after the second faricimab injection, swept-source optical coherence tomography (OCT) revealed hyperreflective dots in the vitreous cavity, indicating vitreous cells. Color fundus photography showed new-onset perivenular hemorrhages and pallor of the inferonasal retina OS, of which OCT revealed retinal inner layer thickening, suggestive of retinal arteriolar occlusions. Retinal fluorescein angiography revealed delayed filling of the inferior temporal vein. The patient was diagnosed with intraocular inflammation and occlusive retinal vasculitis OS associated with repeated intravitreal faricimab administrations. Intravitreal dexamethasone implant was used instead of faricimab at this visit. CONCLUSIONS: The findings of this case hint towards the potential risk of retinal occlusive events associated with intravitreal faricimab injections.

Veliparib exerts protective effects in intracerebral hemorrhage mice by inhibiting the inflammatory response and accelerating hematoma resolution.

Poly (ADP-ribose) polymerase (PARP) inhibitors have potent anti-inflammatory effects, including the suppression of brain microglial activation. Veliparib, a well-known PARP1/2 inhibitor, exhibits particularly high brain penetration, but its effects on stroke outcome is unknown. Here, the effects of veliparib on the short-term outcome of intracerebral hemorrhage (ICH), the most lethal type of stroke, were investigated. Collagenase-induced mice ICH model was applied, and the T2-weighted magnetic resonance imaging was performed to evaluate lesion volume. Motor function and hematoma volume were also measured. We further performed immunofluorescence, enzyme linked immunosorbent assay, flow cytometry, and blood-brain barrier assessment to explore the potential mechanisms. Our results demonstrated veliparib reduced the ICH lesion volume dose-dependently and at a dosage of 5 mg/kg, veliparib significantly improved mouse motor function and promoted hematoma resolution at days 3 and 7 post-ICH. Veliparib inhibited glial activation and downregulated the production of pro-inflammatory cytokines. Veliparib significantly decreased microglia counts and inhibited peripheral immune cell infiltration into the brain on day 3 after ICH. Veliparib improved blood-brain barrier integrity at day 3 after ICH. These findings demonstrate that veliparib improves ICH outcome by inhibiting inflammatory responses and may represent a promising novel therapy for ICH.

P2X7 receptor antagonists modulate experimental autoimmune neuritis via regulation of NLRP3 inflammasome activation and Th17 and Th1 cell differentiation.

BACKGROUND: Guillain-Barré syndrome (GBS), a post-infectious, immune-mediated, acute demyelinating disease of the peripheral nerves and nerve roots, represents the most prevalent and severe acute paralyzing neuropathy. Purinergic P2X7 receptors (P2X7R) play a crucial role in central nervous system inflammation. However, little is known about their role in the immune-inflammatory response within the peripheral nervous system. METHODS: Initially, we assessed the expression of purinergic P2X7R in the peripheral blood of patients with GBS using flow cytometry and qRT-PCR. Next, we explored the expression of P2 X7R in CD4+ T cells, CD8+ T cells, and macrophages within the sciatic nerves and spleens of rats using immunofluorescence labeling and flow cytometry. The P2X7R antagonist brilliant blue G (BBG) was employed to examine its therapeutic impact on rats with experimental autoimmune neuritis (EAN) induced by immunization with the P0180 - 199 peptide. We analyzed CD4+ T cell differentiation in splenic mononuclear cells using flow cytometry, assessed Th17 cell differentiation in the sciatic nerve through immunofluorescence staining, and examined the expression of pro-inflammatory cytokine mRNA using RT-PCR. Additionally, we performed protein blotting to assess the expression of P2X7R and NLRP3-related inflammatory proteins within the sciatic nerve. Lastly, we utilized flow cytometry and immunofluorescence labeling to examine the expression of NLRP3 on CD4+ T cells in rats with EAN. RESULTS: P2X7R expression was elevated not only in the peripheral blood of patients with GBS but also in rats with EAN. In rats with EAN, inhibiting P2X7R with BBG alleviated neurological symptoms, reduced demyelination, decreased inflammatory cell infiltration of the peripheral nerves, and improved nerve conduction. BBG also limited the production of pro-inflammatory molecules, down-regulated the expression of P2X7R and NLRP3, and suppressed the differentiation of Th1 and Th17 cells, thus protecting against EAN. These effects collectively contribute to modifying the inflammatory environment and enhancing outcomes in EAN rats. CONCLUSIONS: Suppression of P2X7R relieved EAN manifestation by regulating CD4+ T cell differentiation and NLRP3 inflammasome activation. This finding underscores the potential significance of P2X7R as a target for anti-inflammatory treatments, advancing research and management of GBS.

Using Deep Learning to Segment Retinal Vascular Leakage and Occlusion in Retinal Vasculitis.

PURPOSE: Retinal vasculitis (RV) is characterised by retinal vascular leakage, occlusion or both on fluorescein angiography (FA). There is no standard scheme available to segment RV features. We aimed to develop a deep learning model to segment both vascular leakage and occlusion in RV. METHODS: Four hundred and sixty-three FA images from 82 patients with retinal vasculitis were used to develop a deep learning model, in 60:20:20 ratio for training:validation:testing. Parameters, including deep learning architectures (DeeplabV3+, UNet++ and UNet), were altered to find the best binary segmentation model separately for retinal vascular leakage and occlusion, using a Dice score to determine the reliability of each model. RESULTS: Our best model for vascular leakage had a Dice score of 0.6279 (95% confidence interval (CI) 0.5584-0.6974). For occlusion, the best model achieved a Dice score of 0.6992 (95% CI 0.6109-0.7874). CONCLUSION: Our RV segmentation models could perform reliable segmentation for retinal vascular leakage and occlusion in FAs of RV patients.

Longitudinal Analysis of Ocular Manifestation and Interleukin During Intravitreal Treatment of Vitreoretinal Lymphoma With Methotrexate.

PURPOSE: To explore the trend of ocular manifestations and interleukin (IL) during the treatment of vitreoretinal lymphoma (VRL) and to evaluate the potential effects of different intravitreal administration schedules on the therapeutic response. DESIGN: Interventional comparative nonrandomized clinical study. METHODS: Patients diagnosed with VRL between January 2011 and January 2022 were included. Intravitreal methotrexate (MTX) injections consisting of induction, consolidation, and maintenance were scheduled. At baseline and each visit, ocular manifestations and IL in aqueous humor were recorded. Effects of the variations (eg, frequency and number) in the injection schedule on the therapeutic response were analyzed. RESULTS: Fifty-eight eyes of 33 patients were treated with intravitreal MTX chemotherapy. A mean ± standard deviation of 9 ± 3 injections were given; 52 eyes achieved complete remission (CR). IL-10, keratic precipitates, and subretinal lesions correlated well with the course of treatment (all P < .001). Initial injection given twice weekly was correlated with a higher rate of CR (36/36) than given once weekly or less frequently (16/22; P = .011). Ocular progression occurred in 13 eyes of 8 patients. The completion of schedule was correlated with PFS (induction + consolidation + maintenance: 547 [335-874] days; induction + consolidation: 355 [322-831] days; induction only: 147 [116-187.5] days; P < .001). IL-10 >50 pg/mL was a feasible threshold for the detection of ocular relapse (sensitivity 100.0%, specificity 95.1%). CONCLUSION: Keratic precipitates, subretinal lesions, and IL-10 could serve as indicators for therapeutic response. Intensive initial administration and adequate injection numbers would help to improve the response and prognosis. IL-10 >50 pg/mL could help detect ocular relapse.

Hemorrhagic Retinal Detachment Treated by Drainage Sclerotomy Combined with Subretinal and Submacular Tissue Plasminogen Activator.

INTRODUCTION: The aim of this study was to evaluate the therapeutic effect of a new drainage procedure for treating subretinal hemorrhage (SRH) in hemorrhagic retinal detachment (RD) in patients with polypoidal choroidal vasculopathy (PCV). METHODS: Forty-three eyes with hemorrhagic RD attributable to PCV underwent vitrectomy. External drainage via sclerotomy was performed in 25 eyes and internal drainage via retinotomy was performed in 18 eyes, respectively. Based on different surgical techniques, the external drainage group was divided into simple external drainage subgroup (10 eyes), external drainage combined with intravitreal injections of recombinant tissue plasminogen activator (tPA) subgroup (7 eyes), and external drainage combined with subretinal and/or submacular injections of tPA subgroup (8 eyes). The internal drainage group was divided into small retinotomy subgroup (7 eyes) and large retinotomy subgroup (11 eyes). The anatomic reattachment of the retina and postoperative complications were compared between different groups and subgroups. RESULTS: The external drainage technique had shorter mean operation time, higher retinal reattachment rate, and fewer postoperative complications rate compared to the internal drainage procedure. The subfoveal hemorrhage subsided significantly sooner in the large retinotomy subgroup and external drainage combined with subretinal and/or submacular injections of tPA subgroup compared to the small retinotomy subgroup and the external drainage without tPA group (p < 0.05). The small retinotomy subgroup had higher rates of hemorrhage and elevated IOP compared to other subgroups during the first week of the postoperative period (p < 0.05). CONCLUSION: Our results suggest that external drainage of SRH combined with subretinal and/or submacular injections of tPA can make the operation simpler, shorten the operation time, reduce the postoperative complications with rapid regression of subfoveal hemorrhage, resulting in an effective and safe therapeutic strategy for treating hemorrhagic RD.

OCT Macular Volume as a Predictor of Vascular Leakage in Uveitis.

INTRODUCTION: This study aimed to evaluate the optical coherence tomography (OCT) macular volume as a marker for active vascular leakage in patients with intermediate and pan uveitis. METHODS: In this single-center prospective longitudinal study, patients were included under three criteria: diagnosed with noninfectious intermediate or pan uveitis; presented vascular leakage at their initial visit; and were imaged with concurrent wide-field fluorescein angiography (FA) and OCT. A scoring system was employed to measure vascular leakage. OCT volume scans were performed on the patients to produce the corresponding thickness map. The central subfield thickness (CST) and macular volume (MV) were calculated. CST is defined as the average thickness within the 1-mm fovea circle, while MV includes the 3-mm and 6-mm circles on the thickness map. Mixed-effects models were applied to analyze the correlation between each patient's OCT and FA imaging results. RESULTS: A total of 72 patients (115 eyes) were included. The median follow-up time was 11 months (interquartile range 1.8-16.1 months). A total of 679 observations across all time points were analyzed. Both CST and MV were found to be positively associated with the leakage scores (p < 0.001). In the mixed-effects models, MV in the 6-mm circle presented the strongest correlation with leakage scores, which explained 57% of the variation in leakage (p < 0.001). MV in the 3-mm circle and CST explained 45.8% and 39.5%, respectively. CONCLUSION: CST and MV in both the 6-mm and the 3-mm circles demonstrated significant correlations with angiographic inflammatory activity. Among those imaging parameters, MV in the 6-mm circle has the highest correlation. The study results suggest that this parameter can be considered a quantitative and non-invasive alternative to FA for monitoring vasculitic inflammation in uveitis.

Transcriptome analysis of long non-coding RNAs reveals NR_015556 lncRNA is a novel regulator for adipocyte differentiation.

Long non-coding RNAs (lncRNAs) have gained extensive attentions due to their significant roles in diverse biological process. However, the potential functions of lncRNAs participation in adipocyte differentiation have not been fully explored. In the present study, we globally profiled lncRNA expression using lncRNA microarray and identified 1745 lncRNA probes with differential expression on day 0 and day 4 post-induction in both C3H10T1/2 mesenchymal stem cells and 3T3-L1 preadipocytes. Furthermore, we showed that stable shRNA knockdown (KD) of NR_015556, a novel lncRNA that was significantly down-regulated in adipocyte differentiation, promoted adipocyte differentiation by increasing the number of lipid droplets and adipocyte markers such as Fabp4, Adipsin and Fasn. Mechanistically, NR_015556 KD attenuated the expression of Wnt signaling components Wnt10b and non-phospho (active) ß-catenin, and elevated adipocyte master factors Ppar-γ and C/EBPα levels. Conversely, pharmacological activation of Wnt10b-ß-catenin signaling by LiCl suppressed NR_015556 KD-induced enhancement of adipocyte differentiation and Ppar-γ and C/EBPα expression levels. Taken together, these results indicate that down-regulation of NR_015556 promotes adipocyte differentiation through inhibiting Wnt10b-ß-catenin signaling pathway and then elevating Ppar-γ and C/EBPα triggered transcriptional cascades.

Ocular Adverse Events after Inactivated COVID-19 Vaccination in Xiamen.

Aims: To report potential vaccine-induced ocular adverse events following inactivated COVID-19 vaccination (Sinopharm and Sinovac). Methods: This case series took place at a tertiary referral center in the southeast of China (Xiamen Eye Center in Fujian Province) from February 2021 to July 2021. Patients who received the first dose of inactivated COVID-19 vaccine and developed vaccine-related ocular adverse events within 10 days were included. The diagnosis of vaccine-related ocular adverse events was guided by the World Health Organization causality assessment and the Naranjo criteria. Results: Ten eyes of seven patients (two male individuals) presenting with ocular complaints following COVID-19 vaccine were included in the study. The mean (SD) age was 41.4 (9.3) years (range, 30-55 years). The mean time of ocular adverse event manifestations was 4.9 days (range, 1-10 days). Three patients were diagnosed with Vogt-Koyanagi-Harada (VKH)-like uveitis, one with multifocal choroiditis, one with episcleritis, one with iritis, and one with acute idiopathic maculopathy. Two patients received the second dose of vaccine. One patient had exacerbation of VKH, and one patient had no symptoms. An aqueous humor analysis in three patients revealed elevated proinflammatory cytokines and negative virus copy. All the patients had transient ocular disturbance and responded well to steroids. No recurrence was noted during 6 months of follow-up. Conclusions: Potential ocular adverse events should be reported to increase the awareness of the health community for timely detection and proper treatment.

Acute-onset Vogt-Koyanagi-Harada like uveitis following Covid-19 inactivated virus vaccination.

PURPOSE: We report a case of a 19-year-old male who presented with bilateral Vogt-Koyanagi-Harada (VKH)-like panuveitis following an injection of an inactivated Covid-19 vaccine. OBSERVATIONS: A 19-year-old male was referred to our clinic with a 2-week history of blurred vision on both eyes and headaches, 12 hours following the administration of the first dose of an inactivated Covid-19 virus vaccine (Sinovac). He denied any past ocular or medical history. Clinical examination and multimodal imaging tests identified serous retinal detachment and choroidal thickening posteriorly and deep yellow foci in the far peripheral retina. Aqueous humor analysis ruled out viral and bacterial infection including Covid-19, but demonstrated an elevated interleukin-6 level. A workup ruled out systemic infection or autoimmune disease. Although the patient received a single positive T-SPOT result, no other clinical evidence supported active tuberculosis infection. Non-infectious panuveitis was diagnosed and treated with periocular steroids that quickly resolved the serous retinal detachment. CONCLUSIONS AND IMPORTANCE: This is the first report of VKH-like uveitis following an inactivated Covid-19 vaccine, with aqueous humor analysis ruling out viral or bacterial infection and demonstrating an elevated interleukin-6 level. Though rare, VKH-like uveitis may be associated with administration of an inactivated Covid-19 vaccine.

A 3-Gene-Based Diagnostic Signature in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disease. In this study, potential diagnostic biomarkers were identified for AD. METHODS: All AD samples and healthy samples were collected from 2 datasets in the GEO database, in which differentially expressed genes (DEGs) were analyzed by using the limma package of R language. GO and KEGG pathway enrichment was conducted basing on the DEGs via the clusterProfiler package of R. And, the PPI network construction and gene prediction were performed using the STRING database and Cytoscape. Then, a logistic regression model was constructed to predict the sample type. RESULTS: Bioinformatic analysis of GEO datasets revealed 2,063 and 108 DEGs in GSE5281 and GSE4226 datasets, separately, and 15 overlapping DEGs were found. GO and KEGG enrichment analysis revealed terms associated with neurodevelopment. Then, we built a logistic regression model based on the hub genes from the PPI network and optimized the model to 3 genes (ALDOA, ENC1, and NFKBIA). The values of area under the curve of the training set GSE5281 and testing set GSE4226 were 0.9647 and 0.7857, respectively, which implied the efficacy of this model. CONCLUSION: The comprehensive bioinformatic analysis of gene expression in AD patients and the effective logistic regression model built in our study may provide promising research value for diagnostic methods of AD.

Prophylactic intravitreal injection of aflibercept for preventing postvitrectomy hemorrhage in proliferative diabetic retinopathy: A randomized controlled trial.

Introduction: The aim of this study was to assess the effects of preoperative intravitreal aflibercept (IVA) injection on the incidence of postoperative vitreous hemorrhage (VH) after vitrectomy for proliferative diabetic retinopathy (PDR). Methods: This study involved a prospective, randomized clinical trial. One hundred twenty-eight eyes of 128 patients of PDR who underwent pars plana vitrectomy (PPV) were enrolled. Sixty-four eyes were assigned randomly to either the IVA group (IVA injection 1 to 5 days before PPV) or the control group (no IVA injection). The primary outcome was the incidence of VH at 1 month after PPV. Secondary outcome measures were best-corrected visual acuity (BCVA) changes from baseline to at 1 week, 1 month, 2 months, and 3 months after surgery. Results: The VH incidences in the IVA group and the control group were 14.8 and 39.3% at week 1, 8.6 and 31.7% at month 1, 11.7 and 30.5% at month 2, and 8.6 and 30.5% at month 3, respectively. Intergroup differences showed a significantly decreased VH rate in the IVA group compared with that in the control group at week 1, month 1, and month 3 (p = 0.021, 0.006, and 0.047, respectively). Compared to the baseline, neither the mean BCVA nor the BCVA change in the Logarithm of the Minimum Angle of Resolution (logMAR) scale did differ significantly between the two groups at each visit point. There are a greater number of eyes with BCVA improvement of more than 2 logMAR in the IVA group than in the control group at week 1 (8 vs. 2, p = 0.048). Conclusions: This study found that the adjunctive use of preoperative IVA reduces early and late postoperative VH in vitrectomy for PDR.

Discovering Cerebral Ischemic Stroke Associated Genes Based on Network Representation Learning.

Cerebral ischemic stroke (IS) is a complex disease caused by multiple factors including vascular risk factors, genetic factors, and environment factors, which accentuates the difficulty in discovering corresponding disease-related genes. Identifying the genes associated with IS is critical for understanding the biological mechanism of IS, which would be significantly beneficial to the diagnosis and clinical treatment of cerebral IS. However, existing methods to predict IS-related genes are mainly based on the hypothesis of guilt-by-association (GBA). These methods cannot capture the global structure information of the whole protein-protein interaction (PPI) network. Inspired by the success of network representation learning (NRL) in the field of network analysis, we apply NRL to the discovery of disease-related genes and launch the framework to identify the disease-related genes of cerebral IS. The utilized framework contains three main parts: capturing the topological information of the PPI network with NRL, denoising the gene feature with the participation of a stacked autoencoder (SAE), and optimizing a support vector machine (SVM) classifier to identify IS-related genes. Superior to the existing methods on IS-related gene prediction, our framework presents more accurate results. The case study also shows that the proposed method can identify IS-related genes.

Recent Development of Graphene Based Electrochemical Sensor for Detecting Hematological Malignancies-Associated Biomarkers: A Mini-Review.

Hematologic malignancies are a group of malignant diseases of the hematologic system that seriously endanger human health, mainly involving bone marrow, blood and lymphatic tissues. However, among the available treatments for malignant hematologic diseases, low detection rates and high recurrence rates are major problems in the treatment process. The quantitative detection of hematologic malignancies-related biomarkers is the key to refine the pathological typing of the disease to implement targeted therapy and thus improve the prognosis. In recent years, bioelectrochemical methods for tumor cell and blood detection have attracted the attention of an increasing number of scientists. The development of biosensor technology, nanotechnology, probe technology, and lab-on-a-chip technology has greatly facilitated the development of bioelectrochemical studies of cells, especially for blood and cell-based assays and drug resistance differentiation. To improve the sensitivity of detection, graphene is often used in the design of electrochemical sensors. This mini-review provides an overview of the types of hematological malignancies-associated biomarkers and their detection based on graphene assisted electrochemical sensors.

A Novel Long Noncoding RNA, Lnc-OAD, Is Required for Bone Morphogenetic Protein 2- (BMP-2-) Induced Osteoblast Differentiation.

Long noncoding RNAs (lncRNAs) play very important roles in cell differentiation. Our recent study has demonstrated that a novel lncRNA named lnc-OAD modulated 3T3-L1 adipocyte differentiation. In the present study, we examined the roles of lnc-OAD in bone morphogenetic protein 2- (BMP-2-) induced osteoblast differentiation. Lnc-OAD expression was increased during BMP-2-induced osteoblast differentiation in C3H10T1/2 mesenchymal stem cells and MC3T3-E1 preosteoblast cells. Knockdown of lnc-OAD expression by specific siRNA remarkably decreased early osteoblast differentiation. In addition, stable knockdown of lnc-OAD by lentivirus vector also significantly inhibited late osteoblast differentiation and matrix mineralization in vitro. Conversely, stably overexpressed lnc-OAD with lentiviral vector accelerated osteoblast differentiation. Mechanistically, knockdown of lnc-OAD reduced significantly the phosphorylation of AKT and the expression of Osterix induced by BMP-2, while overexpression of lnc-OAD enhanced the phosphorylation of AKT and the expression of Osterix. Taken together, our study suggests that lnc-OAD plays an important role in modulating BMP-2-induced osteoblast differentiation via, at least in part, regulating the AKT-Osterix signaling axis.

Miconazole alleviates peripheral nerve crush injury by mediating a macrophage phenotype change through the NF-κB pathway.

BACKGROUND: Peripheral nerve injury (PNI) causes motor and sensory defects, has strong impact on life quality and still has no effective therapy. Miconazole is one of the most widely used antifungal drugs; the aims of the study were to investigate the effects of miconazole during sciatic nerve regeneration in a mouse model of sciatic nerve crush injury. METHODS: We established peripheral nerve crush model and investigated the effects of miconazole by multiple aspects. We further studied the potential mechanism of action of miconazole by Western blotting, fluorescence immunohistochemistry, and PCR analysis. RESULTS: Miconazole improves the symptoms of crushed nerve by improving inflammatory cell infiltration and demyelinating myelin of sciatic nerve. Affected by miconazole, the proportion of inflammatory M1 macrophages in the distal part of the sciatic nerve was reduced, and the proportion of anti-inflammatory M2 macrophages was increased. Finally, the neuroprotective properties of miconazole may be regulated by the nuclear factor (NF)-κB pathway. CONCLUSIONS: Our data suggest that miconazole can effectively alleviate PNI, and the mechanism involves mediating a phenotype change of M1/ M2 macrophages. Thus, miconazole may represent a potential therapeutic intervention for nerve crush injury.

The effect of single periocular injection of methylprednisolone and drainage of suprachoroidal fluid in the treatment of rhegmatogenous retinal detachment combined with choroidal detachment.

PURPOSE: In this study we compared the anatomic and functional outcomes of two steroid treatments on rhegmatogenous retinal detachment (RRD) combined with choroidal detachment (CD), namely treatment with oral prednisolone (1 mg/kg daily) for 3-7 days before vitrectomy or a single periocular injection of methylprednisolone (40 mg) 1-3 days before vitrectomy. We also analyzed the outcomes of the eyes with subsided CD and the eyes with persistent CD that underwent drainage of suprachoroidal fluids during the vitrectomy. METHODS: This was a prospective randomized study. Seventy five eyes with RRD combined with CD were divided into 2 groups based on the two different treatment regimens as above. The eyes in each group were further divided into 2 subgroups (A: CD subsided eyes; B: CD persistent eyes) according to the response of CD to the treatment of steroids. Retinal reattachment rates were measured at 6 months after the removal of silicone oil. RESULTS: At 6 months after silicone oil removal, the retinal reattachment rate was similar (p = 0.666) in the oral prednisolone group (91.7%, 33/36) and the periocular injection group (94.9%, 37/39). Similar retinal reattachment rates (p = 0.364) were also found in the CD subsided eyes (97.1%, 34/35) and the CD persistent eyes (90.0%, 36/40). The retinal reattachment rate was comparable among the subgroups (p = 0.395; oral prednisolone A group: 95.2%, 20/21; oral prednisolone B group: 86.7%, 13/15; periocular injection A group: 100%, 14/14; periocular injection B group: 92.0%, 23/25). CONCLUSIONS: For RRD combined with CD, eyes treated with a single periocular injection of methylprednisolone (40 mg, 1-3 days before pars plana vitrectomy) combined with the drainage of suprachoroidal fluids during the surgery had similar anatomic and functional outcomes compared to the eyes treated with oral prednisolone for 3-7 days before vitrectomy.

Class I PI3K inhibitor ZSTK474 attenuates experimental autoimmune neuritis by decreasing the frequency of Th1/Th17 cells and reducing the production of proinflammatory cytokines.

The Class I phosphatidylinositol 3-kinase inhibitor, 2-(2-difluoromethy lbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine (ZSTK474), has anti-inflammatory and immunoregulatory properties. However, whether it can be used to treat Guillain-Barré syndrome (GBS)-a neuroinflammatory disorder-is unknown. We induced experimental autoimmune neuritis (EAN) in Lewis rats, an established model of GBS. Orally administered ZSTK474 decreased neurological deficits in the GBS model, as demonstrated by diminished inflammatory cell infiltration, and ameliorated demyelination of sciatic nerves. Additionally, ZSTK474 decreased the number of Th1/Th17 cells and levels of the proinflammatory cytokines interleukin (IL)-1α, IL-1ß, IL-17, IL-23, interferon-γ, and tumor necrosis factor-α. We propose that the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin complex 1 (PI3K/AKT/mTORC1) pathway likely contributed to the neuroprotective effect of ZSTK474. ZSTK474 effectively decreases the frequency of Th1/Th17 cells, thereby reducing the production of proinflammatory cytokines and successfully alleviating the symptoms of EAN. Thus, the neuroprotective effect of ZSTK474 indicates its potential utility as anti-inflammatory therapy for GBS.

A multi­targeted tyrosine kinase inhibitor lenvatinib for the treatment of mice with advanced glioblastoma.

Glioblastoma is the most aggressive primary brain tumor that originates from the glial cells in adults. Aberrant angiogenesis is essential for malignant glioblastoma tumorigenesis, development and metastasis. Lenvatinib is a multi­targeted anticancer agent that targets of receptor tyrosine kinases including vascular endothelial growth factor receptor 1 and 2, fibroblast growth factor receptor 1, platelet­derived growth factor receptor ß and v­kit Hardy­Zuckerman 4 feline sarcoma viral oncogene homolog. In the present study, the therapeutic effects of lenvatinib as a treatment for glioblastoma were investigated in vivo and in vitro. The maximum dose toxicity (MDT) and treatment­associated adverse events of lenvatinib were identified by cytotoxicity assay in experimental mice. Increasing levels of the pro­apoptosis genes caspase­3, -8, -9 and -10 following lenvatinib treatment were determined by reverse transcription­quantitative polymerase chain reaction, and apoptosis of the malignant gliomas cells was analyzed by FACS. In vivo treatment with lenvatinib for BV­2 bearing male BALC/c nude mice was assessed via tumor growth suppression and long­term observation of survival. Subsequent cytotoxic T lymphocyte responses were further analyzed to determine the in vivo efficacy of lenvatinib treatment in mice with glioblastoma. The MDT of lenvatinib was identified as 0.24 mg, with relatively few side effects and improved efficacy in mice. Lenvatinib (0.24 mg) significantly increased apoptosis in BV­2, C6, BC3H1 and G422 glioma cell lines. Tumor growth was significantly inhibited and tumor­bearing mice demonstrated an improved survival rate following treatment with lenvatinib. In conclusion, lenvatinib provided an effective treatment outcome, and the results of the present study may help to achieve a comprehensive therapeutic schedule for clinical application.

Melatonin protects against the pathological cardiac hypertrophy induced by transverse aortic constriction through activating PGC-1ß: In vivo and in vitro studies.

Melatonin, a circadian molecule secreted by the pineal gland, confers a protective role against cardiac hypertrophy induced by hyperthyroidism, chronic hypoxia, and isoproterenol. However, its role against pressure overload-induced cardiac hypertrophy and the underlying mechanisms remains elusive. In this study, we investigated the pharmacological effects of melatonin on pathological cardiac hypertrophy induced by transverse aortic constriction (TAC). Male C57BL/6 mice underwent TAC or sham surgery at day 0 and were then treated with melatonin (20 mg/kg/day, via drinking water) for 4 or 8 weeks. The 8-week survival rate following TAC surgery was significantly increased by melatonin. Melatonin treatment for 8 weeks markedly ameliorated cardiac hypertrophy. Compared with the TAC group, melatonin treatment for both 4 and 8 weeks reduced pulmonary congestion, upregulated the expression level of α-myosin heavy chain, downregulated the expression level of ß-myosin heavy chain and atrial natriuretic peptide, and attenuated the degree of cardiac fibrosis. In addition, melatonin treatment slowed the deterioration of cardiac contractile function caused by pressure overload. These effects of melatonin were accompanied by a significant upregulation in the expression of peroxisome proliferator-activated receptor-gamma co-activator-1 beta (PGC-1ß) and the inhibition of oxidative stress. In vitro studies showed that melatonin also protects against angiotensin II-induced cardiomyocyte hypertrophy and oxidative stress, which were largely abolished by knocking down the expression of PGC-1ß using small interfering RNA. In summary, our results demonstrate that melatonin protects against pathological cardiac hypertrophy induced by pressure overload through activating PGC-1ß.