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Li X.,Peking University | Li X.,Key Laboratory of Vision Loss and Restoration | Hu Y.,Peking University | Sun X.,Shanghai JiaoTong University | And 2 more authors.
Ophthalmology | Year: 2012

Objective: To evaluate 2 different dosing regimens of intravitreal bevacizumab for the treatment of neovascular age-related macular degeneration (AMD) patients in China. Design: Multicenter, randomized, prospective, open-label clinical trial. Participants: One hundred eighty-five patients with active neovascular AMD, exclusion of a macular scar, choroidal neovascularization not resulting from AMD, and polypoidal choroidal vasculopathy. Intervention: Patients were assigned randomly to receive intravitreal injections of bevacizumab every 6 weeks for the first 3 injections followed by injections every 6 weeks (regimen A, n = 91) or every 12 weeks (regimen B, n = 94). Main Outcome Measures: The primary outcome measure was a comparison of the mean change in visual acuity from baseline. The secondary outcome measure was a comparison of the proportion of patients with a change in visual acuity of 15 letters or more. Adverse events were monitored. Results: One-hundred eighty five patients were enrolled. At 48 weeks, the increase in the mean visual acuity measurements from baseline were 12.58 letters in regimen A and 10.06 letters in regimen B (P = 0.288). At 48 weeks, the percentage of eyes losing fewer than 15 letters was 96.2% in regimen A and 93.9% in regimen B (P = 0.720). At 48 weeks, the median decrease in central retinal thickness measurements from baseline was 119 μm in regimen A and 60 μm in regimen B (P = 0.221). Adverse events during the 48 weeks included anterior chamber inflammation in 17 patients (18.7%) from regimen A and 9 patients (9.6%) from regimen B (P = 0.075). There were no other notable ocular adverse events in either group. Conclusions: Intravitreal bevacizumab improved visual acuity and decreased macular thickness in patients with neovascular AMD when dosed either every 6 weeks or every 12 weeks after 3 doses given at 6-week intervals. Although there were no statistically significant differences between the 2 regimens, the results tended to favor the group dosed every 6 weeks (regimen A). Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. © 2012 American Academy of Ophthalmology.


Lu Q.,Peking University | Lu Q.,Key Laboratory of Vision Loss and Restoration | Feng J.,Peking University | Feng J.,Key Laboratory of Vision Loss and Restoration | And 2 more authors.
PLoS ONE | Year: 2013

Purpose:Apelin is a novel adipocytokine participating in diabetes, but its role in diabetic retinopathy (DR) is unknown. Our study aimed to investigate the effect of apelin on the proliferative potential in DR along with its antagonist inhibitory effects.Principal Findings:Strong staining of apelin, co-localized with glial fibrillary acidic protein (GFAP) and vascular endothelial growth factor (VEGF) was observed in the retina of diabetic rats. Apelin, GFAP, and VEGF mRNA and protein levels were significantly increased in the sample's retinas. Moreover, exogenous apelin promoted retinal Müller cell proliferation in vivo. Simultaneously, apelin induced GFAP and VEGF expression. F13A markedly reduced retinal gliosis caused by diabetes. Furthermore, F13A suppressed both GFAP and VEGF expression in vivo.Significance:Our results strongly suggest that apelin is associated with the development of DR and contributes to changes in the retinas of diabetic rats. Apelin induced promotion of cell proliferation lends support to the possibility that apelin may play a role in the progression of DR to a proliferative phase. This possible role deserves further investigation, which may offer new perspectives in the early prevention and treatment of DR. © 2013 Lu et al.


Sun C.,Peking University | Sun C.,Key Laboratory of Vision Loss and Restoration | Sun C.,China Japan Friendship Hospital | Li X.-X.,Peking University | And 5 more authors.
Experimental Eye Research | Year: 2013

Branch retinal vein occlusion (BRVO) is the second most frequent retinal vascular disorder. Currently the first-line therapies for BRVO include anti-VEGF and dexamethasone implant treatment, however, with direct or indirect damage on retinal neurons, it has limited effect in improving patients visual acuity. Therefore, novel treatments with neuroprotective effect for BRVO retina were expected. Minocycline is a semisynthetic, broad spectrum tetracycline antibiotic with high penetration through the blood brain barrier. The neuroprotective effects of minocycline have been shown in various central nervous system (CNS) disease. Since both CNS and retina were composed of neurons and glials, it is reasonable to expect a neuroprotective effect by minocycline for BRVO retina. Therefore, the aim of the present study was to study whether minocycline has neuroprotective effect in branch retinal vein occlusion (BRVO) and the possible underlying molecular basis. We created BRVO in rats using laser photocoagulation. The animals were then randomly divided into 4 groups to evaluate the effect of minocycline: group A: minocycline 45mg/kg intraperitoneal injection (i.p.), group B: minocycline 90mg/kg i.p., group C: normal saline i.p., group D: sham injection. Fundus photography and fluorescein angiography (FA) were conducted. Thechanges in thickness of retinal layers were measured with optical coherence tomography (OCT) invivo. We found that retinal edema occurred predominantly in the inner retinal layers. Intraperitoneal administration of minocycline significantly ameliorated retinal edema in the early stage of BRVO. We performed Full field Electroretinography (ffERG) to evaluate retinal function and found that the reduction of b wave amplitude decreased in the combined maximal response. The expressional levels of apoptosis related genes (Bax, Bcl-2) and inflammation related genes (IL-1 β, TNF α, MCP-1 and CCR2) were measured by real-time PCR, the results showed that minocycline treatment upregulated Bcl-2 expression and inhibits TNF α expression since early stage of BRVO. We also performed Hematoxylin-Eosin (HE) and immunostaining for Iba 1 (a microgilal marker), active caspase-3, Bax, Bcl-2, IL-1 β, TNF α and found that minocycline inhibits retinal microglial activation, prevents retinal ganglion cell loss, and inhibits retinal caspase-3 activation. Thus, our study indicates that systemic administration of minocycline ameliorates retinal edema and preserves retinal function in the early stage of BRVO possibly via inhibiting microglia activation and protecting RGC from apoptosis. © 2013 Elsevier Ltd.


Qin D.,Peking University | Qin D.,Key Laboratory of Vision Loss and Restoration | Zheng X.-X.,Peking University | Jiang Y.-R.,Peking University | Jiang Y.-R.,Key Laboratory of Vision Loss and Restoration
Molecular Vision | Year: 2013

Purpose: Our previous study showed that apelin was increased in the vitreous and fibrotic membranes of patients with proliferative diabetic retinopathy (PDR) in vivo, which suggested that apelin may be involved in the development of PDR. In this study, we investigated whether the expression of apelin was upregulated in human retinal pigment epithelial (RPE) cells in vitro under high glucose conditions. Furthermore, to explore the role of apelin in RPE cells, we investigated the effect of exogenous recombinant apelin on proliferation, migration, and collagen I (a major component of extracellular matrix molecules, associated with PDR) expression and investigated the signaling pathways involved in these processes. Methods: Real-time PCR and western blot were performed to determine the apelin expression in ARPE-19 cells under high glucose conditions. Exogenous recombinant apelin was used to study the effect of apelin on ARPE-19 cells in vitro. Cell proliferation, migration, and collagen I expression were assessed using an MTT assay, a transwell assay, and real-time PCR analysis. LY294002 (an inhibitor of phosphatidylinositol 3-kinase) and PD98059 (an inhibitor of mitogen-activated protein kinase) were used to help to determine the apelin signaling mechanism. Results: High glucose upregulated apelin expression in RPE cells. Exogenous recombinant apelin activated protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) phosphorylation and promoted proliferation, migration, and collagen I expression in RPE cells. Pretreatment with LY294002 and PD98059 abolished apelin-induced activation of Akt and Erk, proliferation, and collagen I expression. Apelin-induced migration was partially blocked by pretreatment with LY294002 and PD98059. Conclusions: The expression of apelin was upregulated under high glucose conditions in RPE cells in vitro. Exogenous recombinant apelin increased the biologic activity of RPE cells, as well as the expression of collagen I. Apelin promoted proliferation, migration, and collagen I expression through the PI3K/Akt and MEK/Erk signaling pathways in RPE cells. From these results, we revealed the role of apelin in regulating proliferation, migration, and collagen I expression in RPE cells and the signaling mechanism under these processes, which suggested that apelin may play a profibrotic role in the development of PDR. © 2013 Molecular Vision.


Miao H.,Peking University | Miao H.,Key Laboratory of Vision Loss and Restoration | Tao Y.,Peking University | Tao Y.,Key Laboratory of Vision Loss and Restoration | And 2 more authors.
Molecular Vision | Year: 2012

Objective: To investigate the correlations between aqueous concentrations of interleukin 1β, 6, 8, 10, 12p (IL-1β, IL-6, IL-8, IL-10, IL-12p), and tumor necrosis factor α (TNF-α) and the parameters of macular edema acquired by optical coherence tomography (OCT) in patients with choroidal neovascularization. Methods: IL-1β, IL-6, IL-8, IL-10, IL-12p, and TNF-α in the aqueous humor samples of 17 patients with exudative agerelated macular degeneration (AMD), ten patients with pathological myopia (PM), seven patients with idiopathic choroidal neovascularization (CNV), and 14 patients with cataract and idiopathic epiretinal membrane or macular hole in the control group were measured with cytometric bead array. The maximum macular thickness and macular volume within 1 mm, 3 mm, and 6 mm were measured with OCT. Results: In the CNV groups, the aqueous levels of IL-6 and IL-8 were significantly associated with macular volume within 6 mm (p=0.011, p=0.008, respectively), while IL-1β, IL-10, IL-12p, and TNF-α showed no significant correlation with either the maximum macular thickness or the macular volume. By further selecting patients with CNV who had accepted their last intravitreal injection of bevacizumab within 3 months, the level of IL-6 still significantly correlated with the maximum macular thickness (p=0.019) and macular volume within 1 mm (p=0.018), 3 mm (p=0.018), and 6 mm (p=0.022). In patients with exudative AMD, the level of IL-6 was significantly associated with the maximum macular thickness (p=0.025) and macular volume within 1 mm (p=0.025), 3 mm (p=0.006), and 6 mm (p=0.002). The aqueous level of all cytokines did not vary significantly between the CNV patients who had accepted their last intravitreal injection of bevacizumab within 3 months and the other patients, nor was a difference found among patients with exudative AMD, PM, and idiopathic CNV, and the control group. Conclusions: Intraocular concentrations of IL-6 and IL-8 (particularly IL-6) are significantly associated with the volume of macular edema in patients with CNV. However, intravitreal injection of antivascular endothelial growth factor drugs did not change the intraocular level of these inflammation cytokines. © 2012 Molecular Vision.


Tian J.,Peking University | Yu W.,Key Laboratory of Vision Loss and Restoration | Qin X.,Peking University | Fang K.,Peking University | And 8 more authors.
Investigative Ophthalmology and Visual Science | Year: 2012

PURPOSE. We explored associations between age-related macular degeneration (AMD) and genetic variants of 10 genes in a nationwide Chinese population. METHODS. In this multicenter case-control study, 535 AMD patients and 469 controls were recruited from 16 centers that spread from the north to the south of China. All participants underwent comprehensive eye examinations, and 40 single nucleotide polymorphisms (SNPs) of 10 genes were selected. DNA samples were genotyped with the MassArray system. The effect of the genotypes and haplotypes on AMD was assessed with logistic regression analysis, adjusted for age, sex, longterm residence, and family origin. RESULTS. In our study, 11 SNPs in complement H (CFH), 2 in age-related maculopathy susceptibility 2 (ARMS2), and 2 in high-temperature requirement factor A1 (HTRA1) were associated significantly with AMD. They were rs551397, rs800292, rs1329424, rs1061170, rs10801555, rs12124794, rs10733086, rs10737680, rs2274700, rs1410996, and rs380390 in CFH; rs10490924 and rs2736912 in ARMS2; and rs11200638 and rs3793917 in HTRA1. Three haplotypes in CFH, predisposed the patients significantly to AMD (P < 0.001, P = 0.001, and P < 0.001, respectively). With the sample size of our study, no relationship was found for AMD and the SNPs tested in complement 3 (C3); serpin peptidase inhibitor, clade G, member 1 (SERPING1); vascular endothelial growth factor (VEGF); cholesterol ester transfer protein (CETP); lipoprotein lipase (LPL); hepatic lipase (LIPC); and metallopeptidase inhibitor 3 (TIMP3) genes. CONCLUSIONS. Gene variants in CFH, ARMS2, and HTRA1 contribute to AMD in the Chinese population. © 2012 The Association for Research in Vision and Ophthalmology, Inc.


Zhou P.,Peking University | Zhou P.,Key Laboratory of Vision Loss and Restoration | Zhou P.,Fudan University | Fan L.,Fudan University | And 5 more authors.
FASEB Journal | Year: 2011

The genetic association between a variant in the Toll-like receptor 3 (TLR3) gene (C1234T in mRNA, L412F in protein, Reference SNP Cluster Report rs3775291) and geographic atrophy (GA; also called advanced "dry" age-related macular degeneration) was controversial in previous studies. We performed a meta-analysis by pooling the current evidence in literature and found that the T allele of the TLR3 C1234T variant showed a summary odds ratio of 0.753 (95% confidence interval: 0.612-0.927; P=0.007). Further experiments were performed to analyze how this mutant influences the function of TLR3. We found that this SNP did not affect mRNA, protein, or surface expression of TLR3. However, the binding capacity of L412F mutation of TLR3 for double-stranded RNA in the TLR3 protein was only 51.12 ± 3.96% (P<0.001) of the wild-type level. There was a consistently reduced TLR3-mediated NF-κB activation. Therefore, TLR3 C1234T (L412F in the protein) may protect against GA by reduced binding capacity of TLR3 to dsRNA. This study may provide a better understanding of the genetic architecture underlying disease susceptibility and may advance the potential for preclinical prediction in future genetic testing. © FASEB.


Lu Q.,Peking University | Lu Q.,Key Laboratory of Vision Loss and Restoration | Jiang Y.-R.,Peking University | Jiang Y.-R.,Key Laboratory of Vision Loss and Restoration | And 4 more authors.
Diabetes Research and Clinical Practice | Year: 2013

Aims: To investigate the effect of apelin-13 and the antagonist of apelin receptor (F13A) on retinal Müller cells in vitro. Methods: Localization of apelin-13, GFAP and VEGF of Müller cells was detected by immunofluorescence. The effects of apelin-13 and F13A on cell function were assessed by MTT, spreading assay, apoptosis and Boyden chamber assay in vitro. Additionally, the mRNA and protein of apelin-13, GFAP and VEGF in cultured Müller cells were measured by real-time PCR and western blot. Results: Under hypoxia, strong positive staining of apelin-13 was observed and particularly evident in the cytosol and around the nucleus. Exposure of Müller cells to hypoxia led to a progressive increase in mRNA (p< 0.01) and protein levels of apelin-13 (p< 0.01), with a maximal 2.5-fold and 2-fold stimulation at 4 h respectively, compared with normoxic controls. Treated with 0.1, 1, 10 and 100 ng/ml apelin-13, the protein level of GFAP (p< 0.01) and VEGF (p< 0.01) increased significantly in Müller cells in a dose-dependent manner after 24 h. Compared with the untreated cells, 10 ng/ml apelin-13 significantly promoted Müller cells migration (p<0.01). Annexin/PI staining showed that apelin-13 can downregulate cell apoptosis with 30% to the most (p< 0.05). On the contrary, 20. ng/ml F13A-treated Müller cells spread less than the control cells, with significantly lower number of migrated cells and significantly higher rate of apoptosis. Conclusions: The results of this study showed that apelin-13 modulated the proliferation, migration, spreading, survival of Müller cells and the expressions of GFAP and VEGF. © 2012 Elsevier Ireland Ltd.


Cheng Y.,Peking University | Cheng Y.,Key Laboratory of Vision Loss and Restoration | Huang L.Z.,Peking University | Huang L.Z.,Key Laboratory of Vision Loss and Restoration | And 5 more authors.
PLoS ONE | Year: 2013

Age-related maculopathy susceptibility 2(ARMS2) was suggested to be associated with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) in multiple genetic studies in Caucasians and Japanese. To date, no biological properties have been attributed to the putative protein in nAMD and PCV. The complete genes of ARMS2 and HTRA1 including all exons and the promoter region were assessed using direct sequencing technology in 284 unrelated mainland northern Chinese individuals: 96 nAMD patients, 92 PCV patients and 96 controls. Significant associations with both nAMD and PCV were observed in 2 polymorphisms of ARMS2 and HTRA1 rs11200638, with different genotypic distributions between nAMD and PCV (p<0.001). After adjusting for rs11200638, ARMS2 rs10490924 remained significantly associated with nAMD and PCV (p<0.001). Then we overexpressed wild-type ARMS2 and ARMS2 A69S mutation (rs10490924) in RF/6A cells and RPE cells as in vitro study model. Cell proliferation, attachment, migration and tube formation were analyzed for the first time. Compare with wild-type ARMS2, A69S mutation resulted in a significant increase in proliferation and attachment but inhibited cell migration. Moreover, neither wild-type ARMS2 nor A69S mutation affected tube formation of RF/6A cells. There is a strong and consistent association of the ARMS2/HTRA1 locus with both nAMD and PCV, suggesting the two disorders share, at least partially, similar molecular mechanisms. Neither wild-type ARMS2 nor A69S mutation had direct association with neovascularisation in the pathogenesis of AMD. © 2013 Cheng et al.


Chen W.-C.,Peking University | Chen W.-C.,Key Laboratory of Vision Loss and Restoration | Wang Y.,Tianjin Medical University | Li X.-X.,Peking University | Li X.-X.,Key Laboratory of Vision Loss and Restoration
Retina | Year: 2012

PURPOSE: To evaluate photoreceptor inner/outer segment (IS/OS) defects, best-corrected visual acuity (BCVA), macular sensitivity, and fixation stability to correlate morphologic changes with visual functional outcomes at different stages after macular hole surgery using spectral-domain optical coherence tomography combined with microperimetry. METHODS: This study was an interventional, retrospective case series. Sixteen eyes of 16 patients with successfully operated idiopathic full-thickness macular holes were included in this study. The IS/OS defect maximal diameter and area, BCVA, central macular sensitivity, mean macular sensitivity, and fixation stability were measured using spectral-domain optical coherence tomography combined with microperimetry, preoperatively, and with a follow-up of 3 months postoperatively. RESULTS: Both the IS/OS defect diameter and area improved after successful macular hole surgery (P < 0.001; P < 0.001). The BCVA, central macular sensitivity, mean macular sensitivity, and fixation stability of the central 2° also improved (P = 0.001; P = 0.004; P = 0.036; P = 0.031). Stable BCVA improvement was achieved as early as 1-month postoperation despite continuous repair of the IS/OS junction defect diameter and area and improvement in fixation and macular sensitivity within the first 3 months after surgery. The postoperative central macular sensitivity and mean macular sensitivity negatively correlated with preoperative linear IS/OS junction defect diameter (P = 0.033; P = 0.006) and the defect area (P < 0.001; P = 0.002). However, the postoperative BCVA and the improvement in BCVA, macular sensitivity, and fixation stability were not correlated with preoperative IS/OS defect diameter or area. CONCLUSION: Continuous anatomical and functional improvements can be observed after successful microinvasive macular hole surgery. The preoperative extent of the IS/OS junction defect is of good predictive value for postoperative macular sensitivity. However, the factors that influence BCVA are multiple. Prediction of BCVA based on a single anatomical parameter or assessment of macular function only based on BCVA should be avoided. © Lippincott Williams & Wilkins.

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