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Sample records for matrix promotes neovascularization

  1. Decellularized matrix from tumorigenic human mesenchymal stem cells promotes neovascularization with galectin-1 dependent endothelial interaction.

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    Jorge S Burns

    Full Text Available BACKGROUND: Acquisition of a blood supply is fundamental for extensive tumor growth. We recently described vascular heterogeneity in tumours derived from cell clones of a human mesenchymal stem cell (hMSC strain (hMSC-TERT20 immortalized by retroviral vector mediated human telomerase (hTERT gene expression. Histological analysis showed that cells of the most vascularized tumorigenic clone, -BD11 had a pericyte-like alpha smooth muscle actin (ASMA+ and CD146+ positive phenotype. Upon serum withdrawal in culture, -BD11 cells formed cord-like structures mimicking capillary morphogenesis. In contrast, cells of the poorly tumorigenic clone, -BC8 did not stain for ASMA, tumours were less vascularized and serum withdrawal in culture led to cell death. By exploring the heterogeneity in hMSC-TERT20 clones we aimed to understand molecular mechanisms by which mesenchymal stem cells may promote neovascularization. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative qRT-PCR analysis revealed similar mRNA levels for genes encoding the angiogenic cytokines VEGF and Angiopoietin-1 in both clones. However, clone-BD11 produced a denser extracellular matrix that supported stable ex vivo capillary morphogenesis of human endothelial cells and promoted in vivo neovascularization. Proteomic characterization of the -BD11 decellularized matrix identified 50 extracellular angiogenic proteins, including galectin-1. siRNA knock down of galectin-1 expression abrogated the ex vivo interaction between decellularized -BD11 matrix and endothelial cells. More stable shRNA knock down of galectin-1 expression did not prevent -BD11 tumorigenesis, but greatly reduced endothelial migration into -BD11 cell xenografts. CONCLUSIONS: Decellularized hMSC matrix had significant angiogenic potential with at least 50 angiogenic cell surface and extracellular proteins, implicated in attracting endothelial cells, their adhesion and activation to form tubular structures. hMSC -BD11 surface galectin-1

  2. Injectable skeletal muscle matrix hydrogel promotes neovascularization and muscle cell infiltration in a hindlimb ischemia model

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    JA DeQuach

    2012-06-01

    Full Text Available Peripheral artery disease (PAD currently affects approximately 27 million patients in Europe and North America, and if untreated, may progress to the stage of critical limb ischemia (CLI, which has implications for amputation and potential mortality. Unfortunately, few therapies exist for treating the ischemic skeletal muscle in these conditions. Biomaterials have been used to increase cell transplant survival as well as deliver growth factors to treat limb ischemia; however, existing materials do not mimic the native skeletal muscle microenvironment they are intended to treat. Furthermore, no therapies involving biomaterials alone have been examined. The goal of this study was to develop a clinically relevant injectable hydrogel derived from decellularized skeletal muscle extracellular matrix and examine its potential for treating PAD as a stand-alone therapy by studying the material in a rat hindlimb ischemia model. We tested the mitogenic activity of the scaffold’s degradation products using an in vitro assay and measured increased proliferation rates of smooth muscle cells and skeletal myoblasts compared to collagen. In a rat hindlimb ischemia model, the femoral artery was ligated and resected, followed by injection of 150 µL of skeletal muscle matrix or collagen 1 week post-injury. We demonstrate that the skeletal muscle matrix increased arteriole and capillary density, as well as recruited more desmin-positive and MyoD-positive cells compared to collagen. Our results indicate that this tissue-specific injectable hydrogel may be a potential therapy for treating ischemia related to PAD, as well as have potential beneficial effects on restoring muscle mass that is typically lost in CLI.

  3. Matrix Metalloproteinases Expression in Choroidal Neovascular Membranes

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    Jun Zeng; Deyong Jiang; Xiangping Liu; Xiaohua Zhu; Luosheng Tang

    2004-01-01

    Purpose: To investigate the expression of matrix metalloproteinases (MMPs) in choroidal neovascular membranes with age-related macular degeneration (AMD).Methods: Seventeen choroidal neovascular membranes surgically removed from AMD patients with pars plana vitrectomy and subretinal membranes peeling were investigated.The expression of MMP-2 and MMP-9 was determined with immunohistochemical technique.Results: Immunohistochemistry staining in choroidal neovascular membranes for MMP2 and MMP-9 was observed in 17 specimens. There was no detective of MMP-2 and MMP-9 in normal retinas.Conclusions: MMP-2 and MMP-9 were found in choroidal neovascular membranes, may degrade the Bruch membrane and be associated with the perforation of new vessels into Bruch membrane, involving a basic pathogenic process of AMD.

  4. Placental Growth Factor Promotes Cardiac Muscle Repair via Enhanced Neovascularization

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    Jianfeng Zhang

    2015-06-01

    Full Text Available Background/Aims: Transplantation of mesenchymal stem cells (MSCs improves post-injury cardiac muscle repair using ill-defined mechanisms. Recently, we have shown that production and secretion of placental growth factor (PLGF by MSCs play a critical role in the MSCs-mediated post-injury cardiac muscle repair. In this study, we addressed the underlying molecular mechanisms, focusing specifically on the interactions between MSCs, macrophages and endothelial cells. Methods: We isolated macrophages (BM-MΦ from mouse bone-marrow derived cells based on F4/80 expression by flow cytometry. BM-MΦ were treated with different doses of PLGF. Cell number was analyzed by a MTT assay. Macrophage polarization was examined based on CD206 expression by flow cytometry. PLGF levels in macrophage subpopulations were analyzed by RT-qPCR and ELISA. Effects of macrophages on vascularization were evaluated by a collagen gel assay using Human umbilical vein endothelial cells (HUVECs co-cultured with PLGF-treated macrophages. Results: PLGF did not increase macrophage number, but dose-dependently polarized macrophages into a M2 subpopulation. M2 macrophages expressed high levels of PLGF. PLGF-polarized M2 macrophages significantly increased tubular structures in the collagen gel assay. Conclusion: Our data suggest that MSCs-derived PLGF may induce macrophage polarization into a M2 subpopulation, which in turn releases more PLGF to promote local neovascularization for augmenting post-injury cardiac muscle repair. This study thus sheds novel light on the role of PLGF in cardiac muscle regeneration.

  5. Smooth muscle progenitor cells from peripheral blood promote the neovascularization of endothelial colony-forming cells

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    Joo, Hyung Joon; Seo, Ha-Rim [Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul (Korea, Republic of); Jeong, Hyo Eun [Department of Mechanical Engineering, Korea University, Seoul (Korea, Republic of); Choi, Seung-Cheol; Park, Jae Hyung; Yu, Cheol Woong; Hong, Soon Jun [Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul (Korea, Republic of); Chung, Seok [Department of Mechanical Engineering, Korea University, Seoul (Korea, Republic of); Lim, Do-Sun, E-mail: dslmd@kumc.or.kr [Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul (Korea, Republic of)

    2014-07-11

    Highlights: • Two distinct vascular progenitor cells are induced from adult peripheral blood. • ECFCs induce vascular structures in vitro and in vivo. • SMPCs augment the in vitro and in vivo angiogenic potential of ECFCs. • Both cell types have synergistic therapeutic potential in ischemic hindlimb model. - Abstract: Proangiogenic cell therapy using autologous progenitors is a promising strategy for treating ischemic disease. Considering that neovascularization is a harmonized cellular process that involves both endothelial cells and vascular smooth muscle cells, peripheral blood-originating endothelial colony-forming cells (ECFCs) and smooth muscle progenitor cells (SMPCs), which are similar to mature endothelial cells and vascular smooth muscle cells, could be attractive cellular candidates to achieve therapeutic neovascularization. We successfully induced populations of two different vascular progenitor cells (ECFCs and SMPCs) from adult peripheral blood. Both progenitor cell types expressed endothelial-specific or smooth muscle-specific genes and markers, respectively. In a protein array focused on angiogenic cytokines, SMPCs demonstrated significantly higher expression of bFGF, EGF, TIMP2, ENA78, and TIMP1 compared to ECFCs. Conditioned medium from SMPCs and co-culture with SMPCs revealed that SMPCs promoted cell proliferation, migration, and the in vitro angiogenesis of ECFCs. Finally, co-transplantation of ECFCs and SMPCs induced robust in vivo neovascularization, as well as improved blood perfusion and tissue repair, in a mouse ischemic hindlimb model. Taken together, we have provided the first evidence of a cell therapy strategy for therapeutic neovascularization using two different types of autologous progenitors (ECFCs and SMPCs) derived from adult peripheral blood.

  6. A Chinese 2-herb formula (NF3) promotes hindlimb ischemia-induced neovascularization and wound healing of diabetic rats.

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    Tam, Jacqueline Chor-Wing; Ko, Chun-Hay; Lau, Kit-Man; To, Ming-Ho; Kwok, Hin-Fai; Chan, Yuet-Wa; Siu, Wing-Sum; Etienne-Selloum, Nelly; Lau, Ching-Po; Chan, Wai-Yee; Leung, Ping-Chung; Fung, Kwok-Pui; Schini-Kerth, Valérie B; Lau, Clara Bik-San

    2014-01-01

    Diabetic foot ulcer is closely associated with peripheral vascular disease. Enhancement of tissue oxidative stress, reduction of nitric oxide (NO) and angiogenic growth factors, and abnormal matrix metalloproteinase (MMP) activity are pathophysiological factors in post-ischemic neovascularization and diabetic wound healing. Our previous study demonstrated that the Chinese 2-herb formula, NF3, showed significant wound healing effects on diabetic foot ulcer rats. A novel rat diabetic foot ulcer with hindlimb ischemia model was established in order to strengthen our claims on the diabetic wound healing and post-ischemic neovascularization effects of NF3. Our results demonstrate that NF3 can significantly reduce the wound area of the diabetic foot ulcer rat with hindlimb ischemia by 21.6% (poxidative stress of ischemic muscles (p<0.001). NF3 significantly stimulated MMP activity involved in angiogenesis. Our study shows, for the first time, the beneficial effects of NF3 in wound healing and post-ischemic neovascularization in diabetes.

  7. Moderation of calpain activity promotes neovascular integration and lumen formation during VEGF-induced pathological angiogenesis.

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    Mien V Hoang

    Full Text Available BACKGROUND: Successful neovascularization requires that sprouting endothelial cells (ECs integrate to form new vascular networks. However, architecturally defective, poorly integrated vessels with blind ends are typical of pathological angiogenesis induced by vascular endothelial growth factor-A (VEGF, thereby limiting the utility of VEGF for therapeutic angiogenesis and aggravating ischemia-related pathologies. Here we investigated the possibility that over-exuberant calpain activity is responsible for aberrant VEGF neovessel architecture and integration. Calpains are a family of intracellular calcium-dependent, non-lysosomal cysteine proteases that regulate cellular functions through proteolysis of numerous substrates. METHODOLOGY/PRINCIPAL FINDINGS: In a mouse skin model of VEGF-driven angiogenesis, retroviral transduction with dominant-negative (DN calpain-I promoted neovessel integration and lumen formation, reduced blind ends, and improved vascular perfusion. Moderate doses of calpain inhibitor-I improved VEGF-driven angiogenesis similarly to DN calpain-I. Conversely, retroviral transduction with wild-type (WT calpain-I abolished neovessel integration and lumen formation. In vitro, moderate suppression of calpain activity with DN calpain-I or calpain inhibitor-I increased the microtubule-stabilizing protein tau in endothelial cells (ECs, increased the average length of microtubules, increased actin cable length, and increased the interconnectivity of vascular cords. Conversely, WT calpain-I diminished tau, collapsed microtubules, disrupted actin cables, and inhibited integration of cord networks. Consistent with the critical importance of microtubules for vascular network integration, the microtubule-stabilizing agent taxol supported vascular cord integration whereas microtubule dissolution with nocodazole collapsed cord networks. CONCLUSIONS/SIGNIFICANCE: These findings implicate VEGF-induction of calpain activity and impairment of

  8. Inhibition of PHD3 by salidroside promotes neovascularization through cell–cell communications mediated by muscle-secreted angiogenic factors

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    Zhang, Jing; Kasim, Vivi; Xie, Yu-Dan; Huang, Can; Sisjayawan, Julita; Dwi Ariyanti, Agnes; Yan, Xue-Song; Wu, Xiao-Yan; Liu, Cai-Ping; Yang, Li; Miyagishi, Makoto; Wu, Shou-Rong

    2017-01-01

    Therapeutic angiogenesis has been considered as a potential strategy for treating peripheral artery diseases including hind-limb ischemia (HLI); however, no effective drug-based treatment is currently available. Here we showed that intramuscular administration of salidroside, an active compound of Chinese herb Rhodiola, could robustly enhance blood perfusion recovery by promoting neovascularization in HLI mice. We revealed that salidroside promoted skeletal muscle cell migration and paracrine function through inhibiting the transcriptional level of prolyl-hydroxylase domain 3 (PHD3) without affecting PHD1 and PHD2. Paracrine signals from salidroside-treated skeletal muscle cells enhanced endothelial and smooth muscle cells migration, while inhibition of FGF2/FGF2R and PDGF-BB/PDGFR-β pathways abolished this effect, as well as neovascularization in HLI mice. Furthermore, we elucidated that salidroside inhibition on PHD3 might occur through estrogen receptor alpha (ERα). Together, our findings highlights the potential application of salidroside as a novel pharmalogical inhibitor of ERα/PHD3 axis for therapeutic angiogenesis in HLI diseases. PMID:28266625

  9. CD34 Promotes Pathological Epi-Retinal Neovascularization in a Mouse Model of Oxygen-Induced Retinopathy.

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    Martin J Siemerink

    Full Text Available The sialomucins CD34 and podocalyxin (PODXL are anti-adhesive molecules expressed at the luminal membrane of endothelial cells of small blood vessels and facilitate vascular lumen formation in the developing mouse aorta. CD34 transcript and protein levels are increased during human angiogenesis, its expression is particularly enriched on endothelial tip cell filopodia and CD34 is a marker for tip cells in vitro. Here, we investigated whether CD34 merely marks endothelial tip cells or has a functional role in tip cells and angiogenesis. We assessed that silencing CD34 in human microvascular endothelial cells has little effect on endothelial cell migration or invasion, but has a significant effect on vascular-endothelial growth factor-induced angiogenic sprouting activity in vitro. In vivo, the absence of CD34 reduced the density of filopodia on retinal endothelial tip cells in neonatal mice, but did not influence the overall architecture of the retinal vascular network. In oxygen-induced retinopathy, Cd34-/- mice showed normal intra-retinal regenerative angiogenesis but the number of pathological epi-retinal neovascular tufts were reduced. We conclude that CD34 is not essential for developmental vascularization in the retina, but its expression promotes the formation of pathological, invasive vessels during neovascularization.

  10. CD34 Promotes Pathological Epi-Retinal Neovascularization in a Mouse Model of Oxygen-Induced Retinopathy

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    Siemerink, Martin J.; Dallinga, Marchien G.; Gora, Tomek; Cait, Jessica; Vogels, Ilse M. C.; Yetin-Arik, Bahar; Van Noorden, Cornelis J. F.; Klaassen, Ingeborg; McNagny, Kelly M.; Schlingemann, Reinier O.

    2016-01-01

    The sialomucins CD34 and podocalyxin (PODXL) are anti-adhesive molecules expressed at the luminal membrane of endothelial cells of small blood vessels and facilitate vascular lumen formation in the developing mouse aorta. CD34 transcript and protein levels are increased during human angiogenesis, its expression is particularly enriched on endothelial tip cell filopodia and CD34 is a marker for tip cells in vitro. Here, we investigated whether CD34 merely marks endothelial tip cells or has a functional role in tip cells and angiogenesis. We assessed that silencing CD34 in human microvascular endothelial cells has little effect on endothelial cell migration or invasion, but has a significant effect on vascular-endothelial growth factor-induced angiogenic sprouting activity in vitro. In vivo, the absence of CD34 reduced the density of filopodia on retinal endothelial tip cells in neonatal mice, but did not influence the overall architecture of the retinal vascular network. In oxygen-induced retinopathy, Cd34-/- mice showed normal intra-retinal regenerative angiogenesis but the number of pathological epi-retinal neovascular tufts were reduced. We conclude that CD34 is not essential for developmental vascularization in the retina, but its expression promotes the formation of pathological, invasive vessels during neovascularization. PMID:27352134

  11. Expression of matrix factors in the process of neovascularization of intervertebral disc

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    Pedro Henrique Isoldi Pohl

    2015-06-01

    Full Text Available OBJECTIVE: To investigate the effects of proteins products of endothelial cells (ECs on the annulus fibrosus (AF cell metabolism in an in vitro culture.METHODS:Human AF cells were expanded in monolayer cultures and treated with proteins from the medium of cell line HMEC-1 (Human Microvascular Endothelial Cells (125µg/ml. After 72h of treatment RNA was isolated from AF cells for analysis of gene expression and the culture medium was collected for protein expression analysis.RESULTS: The qRT-PCR analysis demonstrated increased gene expression of matrix metalloproteinases (MMPs in AF cells treated with protein products of endothelial cells compared with cells from control group of AF cells: MMP-1 243.10 times (pCONCLUSIONS: In this study, we observed that the proteins produced by ECs induced the MMPs expression and suppressed the TIMPs as well as the aggrecan in primary cells of the human intervertebral disc, targeting the development of potential treatments for intervertebral disc degeneration and associated discogenic pain.

  12. VEGF is deposited in the subepithelial matrix at the leading edge of branching airways and stimulates neovascularization in the murine embryonic lung.

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    Healy, A M; Morgenthau, L; Zhu, X; Farber, H W; Cardoso, W V

    2000-11-01

    We used whole lung cultures as a model to study blood vessel formation in vitro and to examine the role that epithelial-mesenchymal interactions play during embryonic pulmonary vascular development. Mouse lungs were isolated at embryonic day 11.5 (E11.5) and cultured for up to 4 days prior to blood vessel analysis. Platelet endothelial cell adhesion molecule-1 (PECAM/CD31) and thrombomodulin (TM/CD141) immunolocalization demonstrate that vascular development occurs in lung cultures. The vascular structures identified in lung cultures first appear as a loosely associated plexus of capillary-like structures that with time surround the airways. To investigate the potential role of vascular endothelial cell growth factor (VEGF) during pulmonary neovascularization, we immunolocalized VEGF in embryonic lungs. Our data demonstrate that VEGF is uniformly present in the airway epithelium and the subepithelial matrix of E11.5 lungs. At later time points, E13.5 and E15.5, VEGF is no longer detected in the proximal airways, but is restricted to the branching tips of airways in the distal lung. RT-PCR analysis reveals that VEGF(164) is the predominant isoform expressed in lung cultures. Grafting heparin-bound VEGF(164) beads onto lung explants locally stimulates a marked neovascular response within 48 hr in culture. Semi-quantitative RT-PCR reveals an 18% increase in PECAM mRNA in VEGF(164)-treated whole lung cultures as compared with untreated cultures. The restricted temporal and spatial expression of VEGF suggests that matrix-associated VEGF links airway branching with blood vessel formation by stimulating neovascularization at the leading edge of branching airways.

  13. IL-23-independent induction of IL-17 from γδT cells and innate lymphoid cells promotes experimental intraocular neovascularization.

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    Hasegawa, Eiichi; Sonoda, Koh-Hei; Shichita, Takashi; Morita, Rimpei; Sekiya, Takashi; Kimura, Akihiro; Oshima, Yuji; Takeda, Atsunobu; Yoshimura, Takeru; Yoshida, Shigeo; Ishibashi, Tatsuro; Yoshimura, Akihiko

    2013-02-15

    Choroidal neovascularization (CNV) is a characteristic of age-related macular degeneration. Genome-wide association studies have provided evidence that the immune system is involved in the pathogenesis of age-related macular degeneration; however, the role of inflammatory cytokines in CNV has not been established. In this study, we demonstrated that IL-17 had a strong potential for promoting neovascularization in a vascular endothelial growth factor-independent manner in laser-induced experimental CNV in mice. Infiltrated γδT cells and Thy-1(+) innate lymphoid cells, but not Th17 cells, were the main sources of IL-17 in injured eyes. IL-23 was dispensable for IL-17 induction in the eye. Instead, we found that IL-1β and high-mobility group box 1 strongly promoted IL-17 expression by γδT cells. Suppression of IL-1β and high-mobility group box 1, as well as depletion of γδT cells, reduced IL-17 levels and ameliorated experimental CNV. Our findings suggest the existence of a novel inflammatory cytokine network that promotes neovascularization in the eye.

  14. Osteoprotegerin regulates cancer cell migration through SDF-1/CXCR4 axis and promotes tumour development by increasing neovascularization.

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    Benslimane-Ahmim, Zahia; Pereira, Jessica; Lokajczyk, Anna; Dizier, Blandine; Galy-Fauroux, Isabelle; Fischer, Anne-Marie; Heymann, Dominique; Boisson-Vidal, Catherine

    2017-06-01

    We previously reported that OPG is involved in ischemic tissue neovascularization through the secretion of SDF-1 by pretreated-OPG endothelial colony-forming cells (ECFCs). As the vascularization is one of the key factor influencing the tumour growth and cancer cell dissemination, we investigated whether OPG was able to modulate the invasion of human MNNG-HOS osteosarcoma and DU145 prostate cancer cell lines in vitro and in vivo. Cell motility was analysed in vitro by using Boyden chambers. Human GFP-labelled MMNG-HOS cells were inoculated in immunodeficient mice and the tumour nodules formed were then injected with OPG and/or FGF-2, AMD3100 or 0.9% NaCl (control group). Tumour growth was manually followed and angiogenesis was assessed by immunohistochemistry. In vitro, SDF-1 released by OPG-pretreated ECFCs markedly attracted both MNNG-HOS and DU145 cells and induced spontaneous migration of cancer cells. In vivo, tumour volumes were significantly increased in OPG-treated group compared to the control group and OPG potentiated the effect of FGF-2. Concomitantly, OPG alone or combined with FGF-2 increased the number of new vasculature compared to the control group. Interestingly AMD3100, an inhibitor of SDF-1, prevented the in vivo effects of OPG induced by SDF-1 This study provides experimental evidence that OPG promotes tumour development trough SDF-1/CXCR4 axis.

  15. Lipopolysaccharide Promotes Choroidal Neovascularization by Up-Regulation of CXCR4 and CXCR7 Expression in Choroid Endothelial Cell.

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    Yi-fan Feng

    Full Text Available Stromal cell-derived factor-1 (SDF-1 has been confirmed to participate in the formation of choroidal neovascularization (CNV via its two receptors: CXC chemokine receptors 4 (CXCR4 and CXCR7. Previous studies have indicated that the activation of Toll-like receptors (TLRs by lipopolysaccharide (LPS might elevate CXCR4 and/or CXCR7 expression in tumor cells, enhancing the response to SDF-1 to promote invasion and cell dissemination. However, the impact of LPS on the CXCR4 and CXCR7 expression in endothelial cells and subsequent pathological angiogenesis formation remains to be elucidated. The present study shows that LPS enhanced the CXCR4 and CXCR7 expression via activation of the TLR4 pathway in choroid-retinal endothelial (RF/6A cells. In addition, the transcriptional regulation of CXCR4 and CXCR7 by LPS was found to be mediated by phosphorylation of the extracellular signal-related kinase (ERK 1/2 and activation of nuclear factor kappa B (NF-κB signaling pathways, which were blocked by ERK- or NF-κB-specific inhibitors. Furthermore, the increased CXCR4 and CXCR7 expression resulted in increased SDF-1-induced RF/6A cells proliferation, migration and tube formation. In vivo, LPS-treated rat had significantly higher mRNA levels of CXCR4 and CXCR7 expression and lager laser-induced CNV area than vehicle-treated rat. SDF-1 blockade with a neutralizing antibody attenuated the progression of CNV in LPS-treated rat after a single intravitreal injection. Altogether, these results demonstrated that LPS might influence CNV formation by enhancing CXCR7 and CXCR7 expression in endothelial cells, possibly providing a new perspective for the treatment of CNV-associated diseases.

  16. Decellularized matrix from tumorigenic human mesenchymal stem cells promotes neovascularization with galectin-1 dependent endothelial interaction

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    Burns, Jorge S; Kristiansen, Malthe; Kristensen, Lars P

    2011-01-01

    . Histological analysis showed that cells of the most vascularized tumorigenic clone, -BD11 had a pericyte-like alpha smooth muscle actin (ASMA+) and CD146+ positive phenotype. Upon serum withdrawal in culture, -BD11 cells formed cord-like structures mimicking capillary morphogenesis. In contrast, cells...

  17. Cathepsin L is required for endothelial progenitor cell-induced neovascularization

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    Urbich, Carmen; Heeschen, Christopher; Aicher, Alexandra; Sasaki, Ken-ichiro; Bruhl, Thomas; Hofmann, Wolf K.; Peters, Christoph; Reinheckel, Thomas; Pennacchio, Len A.; Abolmaali, Nasreddin D.; Chavakis, Emmanouil; Zeiher, Andreas M.; Dimmeler, Stefanie

    2004-01-15

    Infusion of endothelial progenitor cells (EPCs), but not of mature endothelial cells (ECs), promotes neovascularization after ischemia. We performed a gene expression profiling of EPCs and ECs to identify genes, which might be important for the neovascularization capacity of EPCs. Intriguingly, the protease cathepsin L (CathL) was highly expressed in EPCs as opposed to ECs and is essential for matrix degradation and invasion by EPCs in vitro. CathL deficient mice showed impaired functional recovery after hind limb ischemia supporting the concept for an important role of CathL in postnatal neovascularization. Infused CathL deficient progenitor cells failed to home to sites of ischemia and to augment neovascularization. In contrast, over expression of CathL in mature ECs significantly enhanced their invasive activity and induced their neovascularization capacity in vivo. Taken together, CathL plays a crucial role for the integration of circulating EPCs into the ischemic tissue and is required for neovascularization mediated by EPCs.

  18. Mesenchymal stromal cells from the human placenta promote neovascularization in a mouse model in vivo.

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    Kinzer, M; Hingerl, K; König, J; Reinisch, A; Strunk, D; Huppertz, B; Lang, I

    2014-07-01

    Cell transplantation is a promising strategy in regenerative medicine for revascularization of ischemic tissues. Based on our observation that placental mesenchymal stromal cells (PMSC) enhance endothelial cell viability in vitro via secretion of angiogenic factors, we asked whether PMSC support vascular growth in vivo. PMSC were isolated from amnion and placental endothelial cells (PLEC) from chorion and either separately or co-transplanted subcutaneously into immune-deficient mice. Co-transplantation resulted in a higher number of perfused human vessels (CD31+/vimentin+) containing mouse glycophorin A+ erythrocytes. Results indicate positive effects of PMSC on neovascularization in vivo, making them attractive candidates to create autologous PMSC/PLEC pairs for research and transplantation.

  19. A plasma-based biomatrix mixed with endothelial progenitor cells and keratinocytes promotes matrix formation, angiogenesis, and reepithelialization in full-thickness wounds.

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    Vermeulen, Pieter; Dickens, Stijn; Degezelle, Karlien; Van den Berge, Stefaan; Hendrickx, Benoit; Vranckx, Jan Jeroen

    2009-07-01

    In search of an autologous vascularized skin substitute, we treated full-thickness wounds (FTWs) with autologous platelet-rich plasma gel (APG) in which we embedded endothelial progenitor cells (EPCs) and basal cell keratinocytes (KCs). We cultivated autologous KCs in low-serum conditions and expanded autologous EPCs from venous blood. FTWs (n = 55) were created on the backs of four pigs, covered with wound chambers, and randomly assigned to the following treatments: (1) APG, (2) APG + KCs, (3) APG + EPCs, (4) APG + KCs + EPCs, and (5) saline. All wounds were biopsied to measure neovascularization (lectin Bandeiraea Simplicifolia-1 (BS-1), alpha smooth muscle actin [alphaSMA], and membrane type 1 matrix metalloproteinase (MT1-MMP)), matrix deposition (fibronectin, collagen type I/III, and alphavbeta3), and reepithelialization. Wound fluids were analyzed for protein expression. All APG-treated wounds showed more vascular structures (p < 0.001), and the addition of EPCs further improved neovascularization, as confirmed by higher lectin, alphaSMA, and MT1-MMP. APG groups had higher collagen I/III (p < 0.05), alphavbeta3, and fibronectin content (p < 0.001), and they exhibited higher concentrations of platelet-derived growth factor subunit bb, basic fibroblast growth factor, hepatocyte growth factor, insulin growth factor-1, transforming growth factor-beta1 and -beta3, matrix metalloproteinase-1 and -z9, and tissue-inhibiting matrix metalloproteinase-1 and -2. Applying APG + KCs resulted in the highest reepithelialization rates (p < 0.001). No differences were found for wound contraction by planimetry. In this porcine FTW model, APG acts as a supportive biomatrix that, along with the embedded cells, improves extracellular matrix organization, promotes angiogenesis, and accelerates reepithelialization.

  20. Matrix metalloproteinase 13-containing exosomes promote nasopharyngeal carcinoma metastasis.

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    You, Yiwen; Shan, Ying; Chen, Jing; Yue, Huijun; You, Bo; Shi, Si; Li, Xingyu; Cao, Xiaolei

    2015-12-01

    Nasopharyngeal cancer (NPC) is an endemic type of head and neck cancer with a high rate of cervical lymph node metastasis. Metastasis is the major cause of death in NPC patients. Increasing evidence indicates that exosomes play a pivotal role in promoting cancer metastasis by enhancing angiogenesis and ECM degradation. Matrix metalloproteinase 13 is an important kind of matrix proteinase that is often overexpressed in various tumors and increases the risk of metastasis. However, little is known about the potential role of MMP13-containing exosomes in NPC. In this study, we found that MMP13 was overexpressed in NPC cells and exosomes purified from conditioned medium (CM) as well as NPC patients' plasma. Transwell analysis revealed that MMP13-containing exosomes facilitated the metastasis of NPC cells. Furthermore, siRNA inhibited the effect of MMP13-containing exosomes on tumor cells metastasis as well as angiogenesis. The current findings provided novel insight into the vital role of MMP13-containing exosomes in NPC progression which might offer unique insights for potential therapeutic strategies for NPC progressions.

  1. Hydrophilic polyurethane matrix promotes chondrogenesis of mesenchymal stem cells.

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    Nalluri, Sandeep M; Krishnan, G Rajesh; Cheah, Calvin; Arzumand, Ayesha; Yuan, Yuan; Richardson, Caley A; Yang, Shuying; Sarkar, Debanjan

    2015-09-01

    Segmental polyurethanes exhibit biphasic morphology and can control cell fate by providing distinct matrix guided signals to increase the chondrogenic potential of mesenchymal stem cells (MSCs). Polyethylene glycol (PEG) based hydrophilic polyurethanes can deliver differential signals to MSCs through their matrix phases where hard segments are cell-interactive domains and PEG based soft segments are minimally interactive with cells. These coordinated communications can modulate cell-matrix interactions to control cell shape and size for chondrogenesis. Biphasic character and hydrophilicity of polyurethanes with gel like architecture provide a synthetic matrix conducive for chondrogenesis of MSCs, as evidenced by deposition of cartilage-associated extracellular matrix. Compared to monophasic hydrogels, presence of cell interactive domains in hydrophilic polyurethanes gels can balance cell-cell and cell-matrix interactions. These results demonstrate the correlation between lineage commitment and the changes in cell shape, cell-matrix interaction, and cell-cell adhesion during chondrogenic differentiation which is regulated by polyurethane phase morphology, and thus, represent hydrophilic polyurethanes as promising synthetic matrices for cartilage regeneration.

  2. Polymeric materials for neovascularization

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    DeVolder, Ross John

    Revascularization therapies have emerged as a promising strategy to treat various acute and chronic wounds, cardiovascular diseases, and tissue defects. It is common to either administer proangiogenic growth factors, such as vascular endothelial growth factor (VEGF), or transplant cells that endogenously express multiple proangiogenic factors. Additionally, these strategies utilize a wide variety of polymeric systems, including hydrogels and biodegradable plastics, to deliver proangiogenic factors in a sophisticated manner to maintain a sustained proangiogenic environment. Despite some impressive results in rebuilding vascular networks, it is still a challenging task to engineer mature and functional neovessels in target tissues, because of the increasing complexities involved with neovascularization applications. To resolve these challenges, this work aims to design a wide variety of proangiogenic biomaterial systems with tunable properties used for neovascularization therapies. This thesis describes the design of several biomaterial systems used for the delivery of proangiogenic factors in neovascularization therapies, including: an electrospun/electrosprayed biodegradable plastic patch used for directional blood vessel growth (Chapter 2), an alginate-g-pyrrole hydrogel system that biochemically stimulates cellular endogenous proangiogenic factor expression (Chapter 3), an enzyme-catalyzed alginate-g-pyrrole hydrogel system for VEGF delivery (Chapter 4), an enzyme-activated alginate-g-pyrrole hydrogel system with systematically controllable electrical and mechanical properties (Chapter 5), and an alginate-g-pyrrole hydrogel that enables the decoupled control of electrical conductivity and mechanical rigidity and is use to electrically stimulate cellular endogenous proangiogenic factor expression (Chapter 6). Overall, the biomaterial systems developed in this thesis will be broadly useful for improving the quality of a wide array of molecular and cellular based

  3. Management of neovascular glaucoma.

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    Ajvazi, Halil; Goranci, Ilhami; Lutaj, Pajtim

    2013-01-01

    Neovascular glaucoma is an atrophic optic neuropathy resulting from the neovascularization of the iridocorneal angle increasing the intraocular pressure. To show the incidence of NVG in comparison to the other types of glaucoma and to compare with the relevant literature data and other referent clinics. In this study were included 116 patients with NVG, of whom 75 or 64.7% male and 41 or 35.3% female, treated from January 2003 until February 2013. Visual acuity damages from NVG, were classified as big damages with 84.7% of cases and minor damages with 15.3% of cases. Cases with heavy damages were the cases with blindness, L+P+/- up to V = 0.3 and cases with slightly damages with V = 0.4-1.0. NVG caused by PDR with 52 cases or 44.8% and CRVO with 12 cases or 10.3%. We should be focused on prevention of diabetic retinopathy which requires interdisciplinary cooperation. In cases when diabetic retinopathy is present, we have to advise patients to undergo PRP as soon as possible, since it is the only way to prevent NVG and heavy consequences.

  4. Inflammatory choroidal neovascularization

    Directory of Open Access Journals (Sweden)

    Neri Piergiorgio

    2009-01-01

    Full Text Available Purpose and Methods: Choroidal neovascularization (CNV can be a severe sight-threatening sequela, which can be secondary to both infectious and noninfectious uveitis. This review summarizes the different diseases associated with CNV, highlighting new treatment modalities and the possible strategies, which could be applied for the therapy of this occurrence. Results: Since CNV can often originate from posterior pole lesions and can be hard to identify, an accurate examination is mandatory in order to identify the correct diagnosis. In the majority of cases, fluorescein angiography (FA, indocyanine green angiography (ICGA and optical coherence tomography (OCT enable the determination of the clinical characteristics of the CNV. An infectious disease should be looked for to include a suitable therapy when available. The treatment strategy for CNV secondary to noninfectious uveal inflammations should be directed at controlling the inflammatory process. Systemic corticosteroids with or without immunosuppressive agents are indicated even when the CNV occurs with apparently inactive uveitis: Chronic subclinical inflammation can be the basis for the pathogenesis of CNV. Additional therapies aimed directly at the neovascular process, such as the intravitreal anti-Vascular Endothelial Growth Factor (VEGF agents, are recommended particularly when the therapy shows an insufficient response. Conclusion: CNV secondary to uveitis is a severe sequela leading to significant visual impairment. ICGA is mandatory in order to obtain relevant information about the choroidal status. Several therapeutic options have been considered, but no guidelines are provided at the moment. Moreover, the current data are still only based on case reports or small series. For such reasons, further trials are mandatory to validate the preliminary available results.

  5. Matrix metalloproteinase 13‐containing exosomes promote nasopharyngeal carcinoma metastasis

    OpenAIRE

    2015-01-01

    Nasopharyngeal cancer (NPC) is an endemic type of head and neck cancer with a high rate of cervical lymph node metastasis. Metastasis is the major cause of death in NPC patients. Increasing evidence indicates that exosomes play a pivotal role in promoting cancer metastasis by enhancing angiogenesis and ECM degradation. Matrix metalloproteinase 13 is an important kind of matrix proteinase that is often overexpressed in various tumors and increases the risk of metastasis. However, little is kno...

  6. The Experimental Study of Promoting Neovascularization from Adipose Tissues Derived Stem Cells Combinding with Fat Particles%脂肪干细胞复合脂肪颗粒促血管化的实验研究

    Institute of Scientific and Technical Information of China (English)

    刘亚南; 范崇盛

    2014-01-01

    This paper disscussed the effect of promoting neovascularization from adipose tissues derived stem cells combining with fat particles .The experimental animals were selected from the same 12 nude ,each nude muse was marked with 3 points and injected into the subcutaneous stratum of the 12 nude mice .Results as the follows :General observation ,When drawn ,we can see a group of tissue blocks in injected subcutaneously of nude mice ,the sizes and shapes of adipose tissue were irregular .Microvessel density ,group A was higher than group B and group C ,and had significant statistically differences (P< 0 .01) ,group B was higher than group C ,and had significant statistically differences (P< 0 .01) . Comparison of survival (% ) ,Group A was higher than group B and group C ,and had significant statistically differences (P<0 .01) ,group B was higher than group C ,and had significant statistically differences (P<0 .01) .As a cellular scaffold ,fat particles can accelerate the vascularization of ADSCs and promote thesurvial and growth of transplanted ADSCs .%本研究探讨脂肪干细胞复合脂肪颗粒对裸鼠皮下血管化的影响。将12只裸鼠身上标记三个点,将三组试剂分别注射,分析结果如下:肉眼观察:取材时,裸鼠背部注射部皮下有一团状组织块,脂肪组织形状不规则,大小不一。微血管密度:A组明显高于B组、C组,且差异有统计学意义(P<0.01);B组明显高于C组,且差异有统计学意义(P<0.01)。存活率比较:A组明显高于B组、C组,且差异有统计学意义(P<0.01);B组明显高于C组,且差异有统计学意义(P<0.01)。脂肪颗粒作为生物支架可加速脂肪干细胞的促血管化作用,从而促进移植物的存活与生长。

  7. Biotin-Avidin Based Universal Cell-Matrix Interaction for Promoting Three-Dimensional Cell Adhesion.

    Science.gov (United States)

    Dou, Xiao-Qiu; Zhang, Jia; Feng, Chuanliang

    2015-09-23

    To promote cell adhesion in three-dimensional (3D) extracellular matrix (ECM) is crucial for avoiding cell anoikis, which is one of the most important issues for fundamental cell biology. Herein, a biotin-avidin based universal cell-matrix interaction for different types of cells is developed in order to achieve the promoted adhesion in 3D ECM. For the purpose, biotinylated nanofibrous hydrogels are constructed by coassembling 1,4-benzyldicarboxamide (C2) based non-biotinylated and biotinylated supramolecular gelators. The used cells are modified by avidin (AV-cells) through biotinylating cells and then interacting with avidin. After in situ encapsulating AV-cells in the hydrogels, the adhered amount can be increased by tens of percent even with adding several percentages of the biotinylated C2 gelators in the coassembly due to the specific biotin-avidin interaction. Reverse transcription polymerase chain reaction (RT-PCR) confirms that AV-cells can proliferate without varying gene expression and denaturation. Compared with the interaction between RGD and cells, this avidin-biotin interaction should be much more universal and it is feasible to be employed to promote cell adhesion for most types of cells in 3D matrix.

  8. Incorporation of pentraxin 3 into hyaluronan matrices is tightly regulated and promotes matrix cross-linking.

    Science.gov (United States)

    Baranova, Natalia S; Inforzato, Antonio; Briggs, David C; Tilakaratna, Viranga; Enghild, Jan J; Thakar, Dhruv; Milner, Caroline M; Day, Anthony J; Richter, Ralf P

    2014-10-31

    Mammalian oocytes are surrounded by a highly hydrated hyaluronan (HA)-rich extracellular matrix with embedded cumulus cells, forming the cumulus cell·oocyte complex (COC) matrix. The correct assembly, stability, and mechanical properties of this matrix, which are crucial for successful ovulation, transport of the COC to the oviduct, and its fertilization, depend on the interaction between HA and specific HA-organizing proteins. Although the proteins inter-α-inhibitor (IαI), pentraxin 3 (PTX3), and TNF-stimulated gene-6 (TSG-6) have been identified as being critical for COC matrix formation, its supramolecular organization and the molecular mechanism of COC matrix stabilization remain unknown. Here we used films of end-grafted HA as a model system to investigate the molecular interactions involved in the formation and stabilization of HA matrices containing TSG-6, IαI, and PTX3. We found that PTX3 binds neither to HA alone nor to HA films containing TSG-6. This long pentraxin also failed to bind to products of the interaction between IαI, TSG-6, and HA, among which are the covalent heavy chain (HC)·HA and HC·TSG-6 complexes, despite the fact that both IαI and TSG-6 are ligands of PTX3. Interestingly, prior encounter with IαI was required for effective incorporation of PTX3 into TSG-6-loaded HA films. Moreover, we demonstrated that this ternary protein mixture made of IαI, PTX3, and TSG-6 is sufficient to promote formation of a stable (i.e. cross-linked) yet highly hydrated HA matrix. We propose that this mechanism is essential for correct assembly of the COC matrix and may also have general implications in other inflammatory processes that are associated with HA cross-linking. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Panretinal cryotherapy in neovascular disease.

    OpenAIRE

    Vernon, S A; Cheng, H.

    1988-01-01

    Panretinal cryotherapy (PRC) was used to treat 15 eyes with rubeosis, nine of which had established neovascular glaucoma, and seven eyes with proliferative diabetic retinopathy. The rubeosis regressed, with preservation of vision and return to normal of intraocular pressure, in all but one eye. With one exception all eyes with proliferative retinopathy also showed new vessel regression after treatment. PRC may be considered an effective alternative to retinal photocoagulation in the treatment...

  10. Neovascularization in Left Atrial Myxoma

    Science.gov (United States)

    Dubey, Laxman; Chaurasia, Amit Kumar

    2012-01-01

    Abstract We report a case with a left atrial mass who underwent coronary angiography to rule out coronary artery disease. Coronary angiography revealed an anomalous tortuous vascular structure originating from the left circumflex coronary artery to the left atrial tumor suggestive of neovascularization. Preoperative coronary angiography is useful for coronary artery evaluation and also provides additional information regarding the feeding vessel supplying the mass. PMID:24757609

  11. [Current trends in neovascular glaucoma treatment].

    Science.gov (United States)

    Vancea, P P; Abu-Taleb, A

    2005-01-01

    Neovascular glaucoma is divided in three clinical stages: rubeosis iridis, secondary open-angle glaucoma, and synechia of the angle-closure glaucoma. 36% of neovascular glaucomas occurs after central retinal vein occlusion, 32% after diabetic proliferative retinopathy, and 13% occurs after carotid artery obstructive. The key of success in the treatment of neovascular glaucoma is the early and rightly diagnosis, the treatment is aimed mainly at relieving pain, as the prognosis for maintaining visual function is extremely poor. The most important surgical procedures are trabeculectomy, artificial drainage shunts and cyclo-distraction by trans-scleral diode laser. This essay presents a synthesis of modern principle data concerning neovascular glaucoma.

  12. Slit2 signaling through Robo1 and Robo2 is required for retinal neovascularization.

    Science.gov (United States)

    Rama, Nicolas; Dubrac, Alexandre; Mathivet, Thomas; Ní Chárthaigh, Róisín-Ana; Genet, Gael; Cristofaro, Brunella; Pibouin-Fragner, Laurence; Ma, Le; Eichmann, Anne; Chédotal, Alain

    2015-05-01

    Ocular neovascular diseases are a leading cause of blindness. Vascular endothelial growth factor (VEGF) blockade improves vision, but not all individuals respond to anti-VEGF treatment, making additional means to prevent neovascularization necessary. Slit-family proteins (Slits) are ligands of Roundabout (Robo) receptors that repel developing axons in the nervous system. Robo1 expression is altered in ocular neovascular diseases, and previous in vitro studies have reported both pro- and anti-angiogenic effects of Slits. However, genetic evidence supporting a role for Slits in ocular neovascularization is lacking. Here we generated conditional knockout mice deficient in various Slit and Robo proteins and found that Slit2 potently and selectively promoted angiogenesis via Robo1 and Robo2 in mouse postnatal retina and in a model of ocular neovascular disease. Mechanistically, Slit2 acting through Robo1 and Robo2 promoted the migration of endothelial cells. These receptors are required for both Slit2- and VEGF-induced Rac1 activation and lamellipodia formation. Thus, Slit2 blockade could potentially be used therapeutically to inhibit angiogenesis in individuals with ocular neovascular disease.

  13. The role of matrix metalloproteinase-2 promoter polymorphisms in coronary artery disease and myocardial infarction.

    Science.gov (United States)

    Alp, Ebru; Menevse, Sevda; Tulmac, Murat; Yilmaz, Akin; Yalcin, Ridvan; Cengel, Atiye

    2011-04-01

    The matrix metalloproteinase (MMP) family are key enzymes involved in the breakdown of the extracellular matrix in normal physiological processes, including tissue remodeling, and disease processes, such as arthritis and metastasis. The promoter polymorphism in the MMP2 gene may be responsible for multiple diseases related to extracellular matrix degradation. Therefore, we aimed to investigate the relationship between genotypes or haplotypes of -1575 G/A, -1306 C/T, -790 T/G, and -735 C/T promoter polymorphisms and coronary artery disease (CAD) with or without myocardial infarction (MI) history. This study included 298 patients with angiographically confirmed CAD and 299 age matched controls. Genomic DNA was isolated from whole blood and genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism method. No significant associations were found between -1575 G/A, -1306 C/T, and -790 T/G polymorphisms and CAD with or without MI history. However, the frequency of the -735 TT genotype was significantly lower in the controls than in the patients with MI alone when compared with the CC genotype (p=0.021). Only the distribution of the ACGC haplotype in CAD patients exhibited a significant difference than that in controls (p<0.05). The distribution of other haplotypes did not differ between CAD patients and controls. The present investigation is the first report to detect an association between MMP2 promoter polymorphisms and CAD with or without MI history in the Turkish population. Further case-control studies in CAD development might be contributed to clarify the role of these polymorphisms.

  14. Lib, transcriptionally induced in senile plaque-associated astrocytes, promotes glial migration through extracellular matrix.

    Science.gov (United States)

    Satoh, Kazuki; Hata, Mitsumi; Shimizu, Tomoko; Yokota, Hiroshi; Akatsu, Hiroyasu; Yamamoto, Takayuki; Kosaka, Kenji; Yamada, Tatsuo

    2005-09-23

    In an effort to identify astrocyte-derived molecules that may be intimately associated with progression of Alzheimer's disease (AD), Lib, a type I transmembrane protein belonging to leucine-rich repeat superfamily, has been identified as a distinctly inducible gene, responsive to beta-amyloid as well as pro-inflammatory cytokines in astrocytes. To evaluate the roles of Lib in AD, we investigated Lib expression in AD brain. In non-AD brain, Lib mRNA has been detected in neurons but not in quiescent astrocytes. On the contrary, in AD brain, Lib mRNA is expressed in activated astrocytes associated with senile plaques, but not expressed in neurons around lesions. Lib-expressing glioma cells displayed promotion of migration ability through reconstituted extracellular matrix and recombinant Lib protein bound to constituents of extracellular matrix. These observations suggest that Lib may contribute to regulation of cell-matrix adhesion interactions with respect to astrocyte recruitment around senile plaques in AD brain.

  15. [Neovascular glaucoma--etipathogeny and diagnosis].

    Science.gov (United States)

    Călugăru, D; Călugăru, M

    2012-01-01

    Neovascular glaucoma is defined as an iris and/or anterior chamber angle neovascularization associated with increased intraocular presure. It is a secondary glaucoma most frequently determined by a severe retinal ischemia. The most common diseases responsible for the development of neovascular glaucoma are diabetic retinopathy, ischemic central retinal vein occlusion and ocular ischemic syndrome; the uncommon causes include ocular radiation, ocular tumors, uveitis and other miscellaneous conditions. Vascular endothelial growth factor is an important and probably predominant agent in the pathogenesis of both intraocular neovascularization and neovascular glaucoma. The evolution of clinical and histopathological changes from predisposing conditions to the occurrence of rubeosis iridis as well as neovacular glaucoma is divided into four grades that is prerubeotic, preglaucomatous, open-angle and angle closure glaucoma stages.

  16. Enamel Matrix Derivative Promote Primary Human Pulp Cell Differentiation and Mineralization

    Directory of Open Access Journals (Sweden)

    Elisabeth Aurstad Riksen

    2014-05-01

    Full Text Available Enamel matrix derivative (EMD has been found to induce reactive dentin formation; however the molecular mechanisms involved are unclear. The effect of EMD (5–50 μg/mL on primary human pulp cells were compared to untreated cells and cells incubated with 10−8 M dexamethasone (DEX for 1, 2, 3, 7, and 14 days in culture. Expression analysis using Affymetrix microchips demonstrated that 10 μg/mL EMD regulated several hundred genes and stimulated the gene expression of proteins involved in mesenchymal proliferation and differentiation. Both EMD and DEX enhanced the expression of amelogenin (amel, and the dentinogenic markers dentin sialophosphoprotein (DSSP and dentin matrix acidic phosphoprotein 1 (DMP1, as well as the osteogenic markers osteocalcin (OC, BGLAP and collagen type 1 (COL1A1. Whereas, only EMD had effect on alkaline phosphatase (ALP mRNA expression, the stimulatory effect were verified by enhanced secretion of OC and COL1A from EMD treated cells, and increased ALP activity in cell culture medium after EMD treatment. Increased levels of interleukin-6 (IL-6, interleukin-8 (IL-8, and monocyte chemoattractant proteins (MCP-1 in the cell culture medium were also found. Consequently, the suggested effect of EMD is to promote differentiation of pulp cells and increases the potential for pulpal mineralization to favor reactive dentine formation.

  17. Transcriptional factor DLX3 promotes the gene expression of enamel matrix proteins during amelogenesis.

    Science.gov (United States)

    Zhang, Zhichun; Tian, Hua; Lv, Ping; Wang, Weiping; Jia, Zhuqing; Wang, Sainan; Zhou, Chunyan; Gao, Xuejun

    2015-01-01

    Mutation of distal-less homeobox 3 (DLX3) is responsible for human tricho-dento-osseous syndrome (TDO) with amelogenesis imperfecta, indicating a crucial role of DLX3 in amelogenesis. However, the expression pattern of DLX3 and its specific function in amelogenesis remain largely unknown. The aim of this study was to investigate the effects of DLX3 on enamel matrix protein (EMP) genes. By immunohistochemistry assays of mouse tooth germs, stronger immunostaining of DLX3 protein was identified in ameloblasts in the secretory stage than in the pre-secretory and maturation stages, and the same pattern was found for Dlx3 mRNA using Realtime PCR. In a mouse ameloblast cell lineage, forced expression of DLX3 up-regulated the expression of the EMP genes Amelx, Enam, Klk4, and Odam, whereas knockdown of DLX3 down-regulated these four EMP genes. Further, bioinformatics, chromatin immunoprecipitation, and luciferase assays revealed that DLX3 transactivated Enam, Amelx, and Odam through direct binding to their enhancer regions. Particularly, over-expression of mutant-DLX3 (c.571_574delGGGG, responsible for TDO) inhibited the activation function of DLX3 on expression levels and promoter activities of the Enam, Amelx, and Odam genes. Together, our data show that DLX3 promotes the expression of the EMP genes Amelx, Enam, Klk4, and Odam in amelogenesis, while mutant-DLX3 disrupts this regulatory function, thus providing insights into the molecular mechanisms underlying the enamel defects of TDO disease.

  18. Aging promotes pro-fibrotic matrix production and increases fibrocyte recruitment during acute lung injury.

    Science.gov (United States)

    Sueblinvong, Viranuj; Neveu, Wendy A; Neujahr, David C; Mills, Stephen T; Rojas, Mauricio; Roman, Jesse; Guidot, David M

    2014-01-01

    Fibrotic lung diseases increase with age. Previously we determined that senescence increases tissue expression of fibronectin EDA (Fn-EDA) and decreases fibroblast expression of Thy-1, and that fibrocytes contribute to fibrosis following bleomycin-induced lung injury in mice. In this study we hypothesized that fibroblasts lacking Thy-1 expression produce an extracellular matrix that promotes fibrocyte retention and myofibroblast transdifferentiation, thereby promoting fibrogenesis. Young and old mice were treated with bleomycin intratracheally; fibrocytes in the bone marrow, blood, and lungs were quantified, and lung fibroblast Thy-1 expression assessed. Bone marrow-derived fibrocytes were cultured on matrices derived from Thy-1(+) or Thy-1(-) fibroblasts ± the pro-fibrotic cytokine TGFβ1. Older mice had more fibrocytes in their bone marrows at baseline and more fibrocytes in their lungs following bleomycin treatment. In parallel, lung fibroblasts in older mice had lower expression of Thy-1 at baseline that increased transiently 7 days after bleomycin treatment but then rapidly waned such that 14 days after bleomycin treatment Thy-1 expression was again markedly lower. Fibrocytes cultured on matrices derived from Thy-1(-) fibroblasts + TGFβ1 had increased gene expression for collagen type 1, fibronectin, Fn-EDA, and α-smooth muscle actin. In parallel, whereas the matrices derived from Thy-1(-) fibroblasts stimulated phosphorylation of Akt in cultured fibrocytes, the matrices derived from Thy-1(+) fibroblasts induced apoptosis. These findings suggest that senescence increases fibrocyte recruitment to the lung following injury and that loss of Thy-1 expression by lung fibroblasts promotes fibrocyte retention and myofibroblast trans-differentiation that renders the "aging lung" susceptible to fibrosis.

  19. Promoter polymorphism in the matrix metalloproteinase-1 and risk of cervical cancer in Korean women.

    Science.gov (United States)

    Ju, Woong; Kang, Sokbom; Kim, Jae Weon; Park, Noh Hyun; Song, Yong Sang; Kang, Soon Beom; Lee, Hyo Pyo

    2005-01-20

    The aim of this investigation was to analyze the association between a single nucleotide polymorphism (SNP) in the matrix metalloproteinase (MMP)-1 promoter gene -1607 bp region and cervical cancer risk in Korean women. The blood samples of 232 cervical cancer patients and 332 non-cancer control subjects who managed at Seoul National University Hospital from 1999 to 2002 were collected. Polymorphism in MMP-1 promoter -1607 region was determined using TaqMan method. Allele frequency and genotype distribution in the cervical cancer group were compared with those of the control group to determine whether this polymorphism elevates the susceptibility of Korean women to cervical cancer. The relationship between this SNP and cancer invasiveness was also evaluated by collating clinicopathologic data of those in the cancer group, such as FIGO stage, lymph node status, histologic type and parametrial invasion. In the cervical cancer group, the allele frequency of 2G was 66.1%, in the control group 68.2%, showing no significant difference (P=0.41). Similarly the genotypes with insertion (2G/2G) or deletion (1G/1G) polymorphism showed no increased risk for cervical cancer susceptibility compared with 1G/2G genotype. A subgroup analysis of the clinicopathologic parameters in cancer group also showed no significant difference suggesting the lack of an association between SNP of the MMP-1 promoter -1607 bp region and cervical cancer invasiveness. In conclusion, this study shows that Korean with specific polymorphism in MMP-1 are neither more susceptible to develop cervical cancer nor more vulnerable for cancer progression.

  20. HPV16 oncoproteins promote cervical cancer invasiveness by upregulating specific matrix metalloproteinases.

    Directory of Open Access Journals (Sweden)

    Jittranan Kaewprag

    Full Text Available Production of matrix metalloproteinases (MMPs for degradation of extracellular matrix is a vital step in cancer metastasis. We investigated the effects of HPV16 oncoproteins (16E6, 16E6*I and 16E7, either individually or combined, on the transcription of 7 MMPs implicated in cervical cancer invasiveness. The levels of 7 MMPs reported to be increased in cervical cancer were determined in C33A stably expressing different HPV16 oncoproteins using quantitative RT-PCR and compared with invasion ability of cell lines using in vitro invasion and wound healing assays. Overexpression of MMP-2 and MT1-MMP was detected in HPV16E6E7 expressing cells which correlated with increased cell invasion. Combination of HPV oncoproteins always showed greater effects than its individual form. Inhibition of cell invasion using a specific MMP-2 inhibitor, OA-Hy, and anti-MT1-MMP antibody confirmed that invasion in these cells was dependent on both MMP-2 and MT1-MMP expression. Depletion of HPV16E6E7 by shRNA-mediated knock-down experiments resulted in decreased MMP-2 and MT1-MMP expression levels as well as reduced invasion ability which strongly suggested specific effects of HPV oncoproteins on both MMPs and on cell invasion. Immunohistochemistry study in invasive cervical cancers confirmed the enhanced in vivo expression of these two MMPs in HPV16-infected cells. In addition, possible sites required by HPV16E6E7 on the MMP-2 and MT1-MMP promoters were investigated and PEA3 (at -552/-540 for MMP-2, -303 for MT1-MMP and Sp1 (at -91 for MMP-2, -102 for MT1-MMP binding sites were shown to be essential for mediating their transactivation activity. In conclusion, our study demonstrated that HPV16E6 and E7 oncoproteins cooperate in promoting cervical cancer invasiveness by specifically upregulating MMP-2 and MT1-MMP transcription in a similar manner.

  1. HPV16 oncoproteins promote cervical cancer invasiveness by upregulating specific matrix metalloproteinases.

    Science.gov (United States)

    Kaewprag, Jittranan; Umnajvijit, Wareerat; Ngamkham, Jarunya; Ponglikitmongkol, Mathurose

    2013-01-01

    Production of matrix metalloproteinases (MMPs) for degradation of extracellular matrix is a vital step in cancer metastasis. We investigated the effects of HPV16 oncoproteins (16E6, 16E6*I and 16E7), either individually or combined, on the transcription of 7 MMPs implicated in cervical cancer invasiveness. The levels of 7 MMPs reported to be increased in cervical cancer were determined in C33A stably expressing different HPV16 oncoproteins using quantitative RT-PCR and compared with invasion ability of cell lines using in vitro invasion and wound healing assays. Overexpression of MMP-2 and MT1-MMP was detected in HPV16E6E7 expressing cells which correlated with increased cell invasion. Combination of HPV oncoproteins always showed greater effects than its individual form. Inhibition of cell invasion using a specific MMP-2 inhibitor, OA-Hy, and anti-MT1-MMP antibody confirmed that invasion in these cells was dependent on both MMP-2 and MT1-MMP expression. Depletion of HPV16E6E7 by shRNA-mediated knock-down experiments resulted in decreased MMP-2 and MT1-MMP expression levels as well as reduced invasion ability which strongly suggested specific effects of HPV oncoproteins on both MMPs and on cell invasion. Immunohistochemistry study in invasive cervical cancers confirmed the enhanced in vivo expression of these two MMPs in HPV16-infected cells. In addition, possible sites required by HPV16E6E7 on the MMP-2 and MT1-MMP promoters were investigated and PEA3 (at -552/-540 for MMP-2, -303 for MT1-MMP) and Sp1 (at -91 for MMP-2, -102 for MT1-MMP) binding sites were shown to be essential for mediating their transactivation activity. In conclusion, our study demonstrated that HPV16E6 and E7 oncoproteins cooperate in promoting cervical cancer invasiveness by specifically upregulating MMP-2 and MT1-MMP transcription in a similar manner.

  2. Transcriptional factor DLX3 promotes the gene expression of enamel matrix proteins during amelogenesis.

    Directory of Open Access Journals (Sweden)

    Zhichun Zhang

    Full Text Available Mutation of distal-less homeobox 3 (DLX3 is responsible for human tricho-dento-osseous syndrome (TDO with amelogenesis imperfecta, indicating a crucial role of DLX3 in amelogenesis. However, the expression pattern of DLX3 and its specific function in amelogenesis remain largely unknown. The aim of this study was to investigate the effects of DLX3 on enamel matrix protein (EMP genes. By immunohistochemistry assays of mouse tooth germs, stronger immunostaining of DLX3 protein was identified in ameloblasts in the secretory stage than in the pre-secretory and maturation stages, and the same pattern was found for Dlx3 mRNA using Realtime PCR. In a mouse ameloblast cell lineage, forced expression of DLX3 up-regulated the expression of the EMP genes Amelx, Enam, Klk4, and Odam, whereas knockdown of DLX3 down-regulated these four EMP genes. Further, bioinformatics, chromatin immunoprecipitation, and luciferase assays revealed that DLX3 transactivated Enam, Amelx, and Odam through direct binding to their enhancer regions. Particularly, over-expression of mutant-DLX3 (c.571_574delGGGG, responsible for TDO inhibited the activation function of DLX3 on expression levels and promoter activities of the Enam, Amelx, and Odam genes. Together, our data show that DLX3 promotes the expression of the EMP genes Amelx, Enam, Klk4, and Odam in amelogenesis, while mutant-DLX3 disrupts this regulatory function, thus providing insights into the molecular mechanisms underlying the enamel defects of TDO disease.

  3. MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators.

    Science.gov (United States)

    Gabriely, Galina; Wurdinger, Thomas; Kesari, Santosh; Esau, Christine C; Burchard, Julja; Linsley, Peter S; Krichevsky, Anna M

    2008-09-01

    Substantial data indicate that microRNA 21 (miR-21) is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins. This microRNA has been implicated in various aspects of carcinogenesis, including cellular proliferation, apoptosis, and migration. We demonstrate that miR-21 regulates multiple genes associated with glioma cell apoptosis, migration, and invasiveness, including the RECK and TIMP3 genes, which are suppressors of malignancy and inhibitors of matrix metalloproteinases (MMPs). Specific inhibition of miR-21 with antisense oligonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of gliomas in nude mice. Moreover, downregulation of miR-21 in glioma cells leads to decreases of their migratory and invasion abilities. Our data suggest that miR-21 contributes to glioma malignancy by downregulation of MMP inhibitors, which leads to activation of MMPs, thus promoting invasiveness of cancer cells. Our results also indicate that inhibition of a single oncomir, like miR-21, with specific antisense molecules can provide a novel therapeutic approach for "physiological" modulation of multiple proteins whose expression is deregulated in cancer.

  4. Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) promotes lung fibroblast proliferation, survival and differentiation to myofibroblasts.

    Science.gov (United States)

    Hasaneen, Nadia A; Cao, Jian; Pulkoski-Gross, Ashleigh; Zucker, Stanley; Foda, Hussein D

    2016-02-17

    Idiopathic pulmonary fibrosis (IPF) is a chronic progressively fatal disease. Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) is a glycosylated transmembrane protein that induces the expression of some matrix metalloproteinase (MMP) in neighboring stromal cells through direct epithelial-stromal interactions. EMMPRIN is highly expressed in type II alveolar epithelial cells at the edges of the fibrotic areas in IPF lung sections. However, the exact role of EMMPRIN in IPF is unknown. To determine if EMMPRIN contributes to lung fibroblast proliferation, resistance to apoptosis, and differentiation to myofibroblasts, normal Human lung fibroblasts (NHLF) transiently transfected with either EMMPRIN/GFP or GFP were treated with TGF- β1 from 0 to 10 ng/ml for 48 h and examined for cell proliferation (thymidine incorporation), apoptosis (FACS analysis and Cell Death Detection ELISA assay), cell migration (Modified Boyden chamber) and differentiation to myofibroblasts using Western blot for α-smooth actin of cell lysates. The effect of EMMPRIN inhibition on NHLF proliferation, apoptosis, migration and differentiation to myofibroblasts after TGF- β1 treatment was examined using EMMPRIN blocking antibody. We examined the mechanism by which EMMPRIN induces its effects on fibroblasts by studying the β-catenin/canonical Wnt signaling pathway using Wnt luciferase reporter assays and Western blot for total and phosphorylated β-catenin. Human lung fibroblasts overexpressing EMMPRIN had a significant increase in cell proliferation and migration compared to control fibroblasts. Furthermore, EMMPRIN promoted lung fibroblasts resistance to apoptosis. Lung fibroblasts overexpressing EMMPRIN showed a significantly increased expression of α- smooth muscle actin, a marker of differentiation to myofibroblasts compared to control cells. TGF-β1 increased the expression of EMMPRIN in lung fibroblasts in a dose-dependent manner. Attenuation of EMMPRIN expression with the use of an

  5. Matrix stiffness promotes cartilage endplate chondrocyte calcification in disc degeneration via miR-20a targeting ANKH expression.

    Science.gov (United States)

    Liu, Ming-Han; Sun, Chao; Yao, Yuan; Fan, Xin; Liu, Huan; Cui, You-Hong; Bian, Xiu-Wu; Huang, Bo; Zhou, Yue

    2016-05-04

    The mechanical environment is crucial for intervertebral disc degeneration (IDD). However, the mechanisms underlying the regulation of cartilage endplate (CEP) calcification by altered matrix stiffness remain unclear. In this study, we found that matrix stiffness of CEP was positively correlated with the degree of IDD, and stiff matrix, which mimicked the severe degeneration of CEP, promoted inorganic phosphate-induced calcification in CEP chondrocytes. Co-expression analysis of the miRNA and mRNA profiles showed that increasing stiffness resulted in up-regulation of miR-20a and down-regulation of decreased ankylosis protein homolog (ANKH) during inorganic phosphate-induced calcification in CEP chondrocytes. Through a dual luciferase reporter assay, we confirmed that miR-20a directly targets 3'-untranslated regions of ANKH. The inhibition of miR-20a attenuated the calcium deposition and calcification-related gene expression, whereas the overexpression of miR-20a enhanced calcification in CEP chondrocytes on stiff matrix. The rescue of ANKH expression restored the decreased pyrophosphate efflux and inhibited calcification. In clinical samples, the levels of ANKH expression were inversely associated with the degeneration degree of CEP. Thus, our findings demonstrate that the miR-20a/ANKH axis mediates the stiff matrix- promoted CEP calcification, suggesting that miR-20a and ANKH are potential targets in restraining the progression of IDD.

  6. Single intravitreal ranibizumab for myopic choroidal neovascularization

    Directory of Open Access Journals (Sweden)

    Shatriah I

    2011-08-01

    Full Text Available Saidin Nor-Masniwati, Ismail Shatriah, Embong ZunainaDepartment of Ophthalmology, Universiti Sains Malaysia, Kelantan, MalaysiaAbstract: We report a case of myopic choroidal neovascularization that showed improvement after a single injection of ranibizumab. A 45-year-old Chinese man with high myopia presented with sudden onset painless central scotoma of his right eye of 2 weeks’ duration. There was no history of trauma. His right eye vision on presentation was 6/30 which showed no improvement with pinhole. The right fundus showed myopic maculopathy at the posterior pole with subretinal hemorrhage at the inferotemporal fovea. The optic disc was tilted with inferotemporal peripapillary atrophy. There was a myopic maculopathy appearance in the macula of the left eye. Fundus fluorescein angiography revealed choroidal neovascularization at the fovea of the right eye. A diagnosis of right eye choroidal neovascularization secondary to myopic maculopathy was made. A single intravitreal injection of ranibizumab 0.05 mL was given. Ten weeks following intravitreal injection, vision had improved to 6/7.5, and repeated fundus fluorescein angiography showed absence of choroidal neovascularization. Follow-up at 6 months showed visual acuity had normalized to 6/6 with glasses, which was maintained up to 12 months following treatment. The right fundus showed no further subretinal hemorrhage with no new lesions.Keywords: myopia, choroidal neovascularization, antivascular endothelial growth factor

  7. Reduced serum content and increased matrix stiffness promote the cardiac myofibroblast transition in 3D collagen matrices.

    Science.gov (United States)

    Galie, Peter A.; Westfall, Margaret V.; Stegemann, Jan P.

    2011-01-01

    Introduction The fibroblast-myofibroblast transition is an important event in the development of cardiac fibrosis and scar formation initiated after myocardial ischemia. The goals of the present study were to better understand the contribution of environmental factors to this transition and determine whether myofibroblasts provide equally important feedback to the surrounding environment. Methods The influence of matrix stiffness and serum concentration on the myofibroblast transition was assessed by measuring message levels of a panel of cardiac fibroblast phenotype markers using quantitative rtPCR. Cell-mediated gel compaction measured the influence of environmental factors on cardiac fibroblast contractility. Immunohistochemistry characterized α-SMA expression and cell morphology, while static and dynamic compression testing evaluated the effect of the cell response on the mechanical properties of the cell-seeded collagen hydrogels. Results Both reduced serum content and increased matrix stiffness contributed to the myofibroblast transition, as indicated by contractile compaction of the gels, increased message levels of col3α1 and α-SMA, and a less stellate morphology. However, the effects of serum and matrix stiffness were not additive. Mechanical testing indicated the cell-seeded gels became less viscoelastic with time, and that reduced serum content also increased the initial elastic properties of the gel. Conclusions The results suggest that reduced serum and increased matrix stiffness promote the myofibroblast phenotype in the myocardium. This transition both enhances and is promoted by matrix stiffness, indicating the presence of positive feedback that may contribute to the pathogenesis of cardiac fibrosis. Summary Lower serum content and increased matrix stiffness accelerated the transition of cardiac fibroblasts seeded in collagen hydrogels to a myofibroblast phenotype, though their effects were not additive. Reduced serum also affected mechanical

  8. Influence of double promotion on HDS catalysts prepared by urea-matrix combustion synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Gonzalez-Cortes, Sergio L. [Laboratorio de Cinetica y Catalisis, Departamento de Quimica, Facultad de Ciencias, Universidad de Los Andes, Merida 5101 (Venezuela); Xiao, Tian-Cun; Lin, Tsung-Wu; Green, Malcolm L.H. [Wolfson Catalysis Centre, Inorganic Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QR (United Kingdom)

    2006-04-11

    The stringent environmental regulations in the US, Japan and Europe are requiring significant improvement in the quality of transportation fuels. A new strategy based on urea-matrix combustion method for the synthesis of alumina-supported molybdate-based mixed oxides (i.e., bimetallic and trimetallic oxides) has been applied. This permits to control the alumina-mixed oxide interaction and therefore the HDS catalytic behaviour. The oxidic and sulfurized states of the HDS catalysts were characterized by X-ray diffraction (XRD), laser Raman spectroscopy (LRS), temperature-programmed reduction (TPR) and high resolution transmission electron microscopy (HRTEM). Catalyst performance was evaluated using a tubular fixed-bed reactor and the hydrodesulfurization of thiophene under normal pressure as model reaction. It has been found that Ni-promoted alumina-supported MoO{sub 3} catalyst precursor presented a non well-ordered structure of Ni-Mo phase supported on alumina surface. However, when cobalt was added to Ni-Mo precursor the {beta}-isomorph stability was significantly improved and the formation of alumina-supported {beta}-Co{sub 0.5}Ni{sub 0.5}MoO{sub 4} was observed. The activation treatments markedly affect the catalyst structure and hence the HDS catalytic performance. The catalyst series pretreated in H{sub 2}S-H{sub 2} was 2-3 times more active than those C{sub 4}H{sub 4}S-H{sub 2}-pretreated catalysts and ca. 2-10 times more active than the pre-reduced samples. A significantly greater HDS activity of H{sub 2}S-H{sub 2}-pretreated Co{sub 0.5}Mg{sub 0.5}MoS{sub x}/{gamma}-Al{sub 2}O{sub 3} catalyst was observed, which is attributed to the fact that both promoters are into the same network interacting directly with the molybdenum. This feature hinders not only the segregation of cobalt sulfide, but also the formation of long MoS{sub 2} slabs. (author)

  9. Extracellular matrix mineralization promotes E11/gp38 glycoprotein expression and drives osteocytic differentiation.

    Science.gov (United States)

    Prideaux, Matthew; Loveridge, Nigel; Pitsillides, Andrew A; Farquharson, Colin

    2012-01-01

    Osteocytes are terminally differentiated osteoblasts which reside in a mineralized extracellular matrix (ECM). The factors that regulate this differentiation process are unknown. We have investigated whether ECM mineralization could promote osteocyte formation. To do this we have utilised MLO-A5 pre-osteocyte-like cells and western blotting and comparative RT-PCR to examine whether the expression of osteocyte-selective markers is elevated concurrently with the onset of ECM mineralization. Secondly, if mineralization of the ECM is indeed a driver of osteocyte formation, we reasoned that impairment of ECM mineralization would result in a reversible inhibition of osteocyte formation. Supplementation of MLO-A5 cell cultures with ascorbic acid and phosphate promoted progressive ECM mineralization as well as temporally associated increases in expression of the osteocyte-selective markers, E11/gp38 glycoprotein and sclerostin. Consistent with a primary role for ECM mineralization in osteocyte formation, we also found that inhibition of ECM mineralization, by omitting phosphate or adding sodium pyrophosphate, a recognized inhibitor of hydroxyapatite formation, resulted in a 15-fold decrease in mineral deposition that was closely accompanied by lower expression of E11 and other osteocyte markers such as Dmp1, Cd44 and Sost whilst expression of osteoblast markers Ocn and Col1a increased. To rule out the possibility that such restriction of ECM mineralization may produce an irreversible modification in osteoblast behaviour to limit E11 expression and osteocytogenesis, we also measured the capacity of MLO-A5 cells to re-enter the osteocyte differentiation programme. We found that the mineralisation process was re-initiated and closely allied to increased expression of E11 protein after re-administration of phosphate or omission of sodium pyrophosphate, indicating an ECM mineralization-induced restoration in osteocyte formation. These results emphasise the importance of cell

  10. CD14{sup +} monocytes promote the immunosuppressive effect of human umbilical cord matrix stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ding, E-mail: qqhewd@gmail.com [The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin 300020 (China); TEDA Life and Technology Research Center, Institute of Hematology, Chinese Academy of Medical Sciences, TEDA, Tianjin (China); Chen, Ke, E-mail: chenke_59@hotmail.com [The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin 300020 (China); TEDA Life and Technology Research Center, Institute of Hematology, Chinese Academy of Medical Sciences, TEDA, Tianjin (China); Du, Wei Ting, E-mail: duwtpumc@yahoo.com.cn [The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin 300020 (China); Han, Zhi-Bo, E-mail: zhibohan@hotmail.com [The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin 300020 (China); TEDA Life and Technology Research Center, Institute of Hematology, Chinese Academy of Medical Sciences, TEDA, Tianjin (China); Ren, He, E-mail: knifesharp2000@hotmail.com [National Engineering Research Center of Cell Products, AmCellGene Co. Ltd, TEDA, Tianjin (China); Chi, Ying, E-mail: caizhuying@hotmail.com [The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin 300020 (China); TEDA Life and Technology Research Center, Institute of Hematology, Chinese Academy of Medical Sciences, TEDA, Tianjin (China); and others

    2010-09-10

    Here, the effect of CD14{sup +} monocytes on human umbilical cord matrix stem cell (hUC-MSC)-mediated immunosuppression was studied in vitro. hUC-MSCs exerted a potent inhibitory effect on the proliferation and interferon-{gamma} (IFN-{gamma}) secretion capacities of CD4{sup +} and CD8{sup +} T cells in response to anti-CD3/CD28 stimulation. Transwell co-culture system revealed that the suppressive effect was primarily mediated by soluble factors. Addition of prostaglandin synthesis inhibitors (indomethacin or NS-398) almost completely abrogated the immunosuppression activity of hUC-MSCs, identifying prostaglandin E{sub 2} (PGE{sub 2}) as an important soluble mediator. CD14{sup +} monocytes were found to be able to enhance significantly the immunosuppressive effect of hUC-MSCs in a dose-dependent fashion. Moreover, the inflammatory cytokine IL-1{beta}, either exogenously added or produced by CD14{sup +} monocytes in culture, could trigger expression of high levels of PGE{sub 2} by hUC-MSCs, whereas inclusion of the IL-1 receptor antagonist (IL-1RA) in the culture down-regulated not only PGE{sub 2} expression, but also reversed the promotional effect of CD14{sup +} monocytes and partially restored CD4{sup +} and CD8{sup +} T cell proliferation and IFN-{gamma} secretion. Our data demonstrate an important role of monocytes in the hUC-MSC-induced immunomodulation, which may have important implications in future efforts to explore the clinical potentials of hUC-MSCs.

  11. Nerve Growth Factor Promotes Corneal Epithelial Migration by Enhancing Expression of Matrix Metalloprotease-9

    Science.gov (United States)

    Blanco-Mezquita, Tomas; Martinez-Garcia, Carmen; Proença, Rui; Zieske, James D.; Bonini, Stefano; Lambiase, Alessandro; Merayo-Lloves, Jesus

    2013-01-01

    Purpose. Nerve growth factor (NGF) is a neuropeptide essential for the development, survival, growth, and differentiation of corneal cells. Its effects are mediated by both TrkA and p75 receptors. Clinically relevant use of NGF was introduced to treat neurotrophic ulcerations in patients. Herein, we examine the mechanisms by which NGF enhances epithelial wound healing both in vivo and in vitro. Methods. An animal model using adult hens was implemented for the in vivo experiments. Laser ablation keratectomy was performed and animals were observed for up to 7 days. Epithelial healing was measured with fluorescein. In addition, proliferation was measured using BrdU incorporation and both TrkA and matrix metalloprotease-9 (MMP-9) expression were measured by immunohistochemistry (IHC) and Western blot (WB). In vitro experiments were carried out with telomerase-immortalized human corneal epithelial cells (HCLE). The rate of proliferation was measured using a colorimetric assay and BrdU incorporation. Real-time migration was evaluated with an inverted microscope. MMP-9 expression was evaluated by immunocytochemistry (ICC), WB, zymography, and RT-PCR. Finally, beta-4 integrin (β4) expression was assessed by ICC and WB. Results. Faster epithelial healing was observed in NGF-treated corneas compared with controls (P < 0.01). These corneas showed increased proliferation, TrkA upregulation, and enhanced MMP-9 presence (P < 0.01). In vitro, faster spreading and migration were observed in response to NGF (P < 0.01). Enhanced proliferation, as well as enhanced TrkA and MMP-9 expression, and decreased β4 levels were observed after adding NGF (P < 0.01). Conclusions. NGF plays a major role during the epithelial healing process by promoting migration, a process that is accelerated by cell spreading. This effect is mediated by both the upregulation of MMP-9 and cleavage of β4 integrin. PMID:23640040

  12. Lenticular neovascularization subsequent to traumatic cataract formation.

    Science.gov (United States)

    Kabat, Alan G

    2011-09-01

    To report a series of cases involving neovascularization within the human crystalline lens-a normally avascular structure-after ocular trauma. This is a retrospective, consecutive observational case series with review of the prevailing literature. Four individuals with a history of ocular trauma and subsequent cataract development were examined between May 2004 and April 2007. All had hypermature cataracts and intraocular inflammation, presumably secondary to phacolysis; two of the four had concurrent hyphema and ocular hypertension in the involved eye. All subjects in this series were found to display a discrete network of blood vessels within the structure of the crystalline lens, just beneath the anterior lens capsule. Neovascularization of the crystalline lens has received little attention in the ophthalmic literature, having been described only rarely in individual case reports. This manuscript details the first known case series involving lenticular neovascularization, and offers insight into its possible developmental mechanism.

  13. Regulation of signaling events involved in the pathophysiology of neovascular AMD.

    Science.gov (United States)

    Wang, Haibo; Hartnett, M Elizabeth

    2016-01-01

    Neovascular age-related macular degeneration (AMD) is a complex disease in which an individual's genetic predisposition is affected by aging and environmental stresses, which trigger signaling pathways involving inflammation, oxidation, and/or angiogenesis in the RPE cells and choroidal endothelial cells (CECs), to lead to vision loss from choroidal neovascularization. Antiangiogenic therapies have greatly improved clinical outcomes in the last decade; however, vision improves in less than half of patients treated for neovascular AMD, and treatments remain inadequate for atrophic AMD. Many studies focus on genetic predisposition or the association of outcomes in trials of human neovascular AMD but are unable to evaluate the effects between different cell types involved in AMD and the signaling events that take place to cause pathologic biologic events. This manuscript complements other reviews in that it describes what is known generally in human AMD studies and clinical trials testing methods to inhibit vascular endothelial growth factor (VEGF inhibitors) and presents pathologic signaling events that develop in two important cell types, the RPE cells and the CECs, when stimulated by stresses or placed into conditions similar to what is currently understood to occur in neovascular AMD. This manuscript complements other reviews by discussing signaling events that are activated by cell-cell or cell-matrix interactions. These considerations are particularly important when considering growth factors, such as VEGF, which are important in physiologic and pathologic processes, or GTPases that are present but active only if GTP bound. In either case, it is essential to understand the role of signaling activation to distinguish what is pathologic from what is physiologic. Particularly important is the essential role of activated Rac1 in CEC transmigration of the RPE monolayer, an important step in blindness associated with neovascular AMD. Other concepts discussed include

  14. Engineering a growth factor embedded nanofiber matrix niche to promote vascularization for functional cardiac regeneration.

    Science.gov (United States)

    Lakshmanan, Rajesh; Kumaraswamy, Priyadharshini; Krishnan, Uma Maheswari; Sethuraman, Swaminathan

    2016-08-01

    The major loss of tissue extracellular matrix (ECM) after myocardial ischemia is a serious burden that gradually leads to heart failure. Due to lack of available treatment methods to restore the cardiac function, various research strategies have come up to treat the ischemic myocardium. However these have met with limited success due to the complexity of the cardiac tissue, which exhibits a nanofibrous collagenous matrix with spatio-temporal localization of a combination of growth factors. To mimic the topographical and chemical cues of the natural cardiac tissue, we have fabricated a growth factor embedded nanofibrous scaffold through electrospinning. In our previous work, we have reported a nanofibrous matrix made of PLCL and PEOz with an average diameter of 500 nm. The scaffold properties were specifically characterized in vitro for cardio-compatibility. In the present study, we have loaded dual growth factors VEGF and bFGF in the nanofiber matrix and investigated its suitability for cardiac tissue engineering. The encapsulation and release of dual growth factors from the matrix were studied using XPS and ELISA. Bioactivity of the loaded growth factors towards proliferation and migration of endothelial cells (HUVECs) was evaluated through MTS and Boyden chamber assays respectively. The efficiency of growth factors on the nanofibrous matrix to activate signaling molecules was studied in HUVECs through gene expression analysis. Preclinical evaluation of the growth factor embedded nanofibrous patch in a rabbit acute myocardial infarction (AMI) model was studied and cardiac function assessment was made through ECG and echocardiography. The evidence for angiogenesis in the patch secured regions was analyzed through histopathology and immunohistochemistry. Our results confirm the effectiveness of growth factor embedded nanofiber matrix in restoration of cardiac function after ischemia when compared to conventional patch material thereby exhibiting promise as a

  15. Fibroblast populated collagen matrix promotes islet survival and reduces the number of islets required for diabetes reversal.

    Science.gov (United States)

    Jalili, Reza B; Moeen Rezakhanlou, Alireza; Hosseini-Tabatabaei, Azadeh; Ao, Ziliang; Warnock, Garth L; Ghahary, Aziz

    2011-07-01

    Islet transplantation represents a viable treatment for type 1 diabetes. However, due to loss of substantial mass of islets early after transplantation, islets from two or more donors are required to achieve insulin independence. Islet-extracellular matrix disengagement, which occurs during islet isolation process, leads to subsequent islet cell apoptosis and is an important contributing factor to early islet loss. In this study, we developed a fibroblast populated collagen matrix (FPCM) as a novel scaffold to improve islet cell viability and function post-transplantation. FPCM was developed by embedding fibroblasts within type-I collagen and used as scaffold for islet grafts. Viability and insulin secretory function of islets embedded within FPCM was evaluated in vitro and in a syngeneic murine islet transplantation model. Islets embedded within acellular matrix or naked islets were used as control. Islet cell survival and function was markedly improved particularly after embedding within FPCM. The composite scaffold significantly promoted islet isograft survival and reduced the critical islet mass required for diabetes reversal by half (from 200 to 100 islets per recipient). Fibroblast embedded within FPCM produced fibronectin and growth factors and induced islet cell proliferation. No evidence of fibroblast over-growth within composite grafts was noticed. These results confirm that FPCM significantly promotes islet viability and functionality, enhances engraftment of islet grafts and decreases the critical islet mass needed to reverse hyperglycemia. This promising finding offers a new approach to reducing the number of islet donors per recipient and improving islet transplant outcome.

  16. Calpain inhibitors reduce retinal hypoxia in ischemic retinopathy by improving neovascular architecture and functional perfusion.

    Science.gov (United States)

    Hoang, Mien V; Smith, Lois E H; Senger, Donald R

    2011-04-01

    In ischemic retinopathies, underlying hypoxia drives abnormal neovascularization that damages retina and causes blindness. The abnormal neovasculature is tortuous and leaky and fails to alleviate hypoxia, resulting in more pathological neovascularization and retinal damage. With an established model of ischemic retinopathy we found that calpain inhibitors, when administered in moderation, reduced architectural abnormalities, reduced vascular leakage, and most importantly reduced retinal hypoxia. Mechanistically, these calpain inhibitors improved stability and organization of the actin cytoskeleton in retinal endothelial cells undergoing capillary morphogenesis in vitro, and they similarly improved organization of actin cables within new blood vessels in vivo. Hypoxia induced calpain activity in retinal endothelial cells and severely disrupted the actin cytoskeleton, whereas calpain inhibitors preserved actin cables under hypoxic conditions. Collectively, these findings support the hypothesis that hyper-activation of calpains by hypoxia contributes to disruption of the retinal endothelial cell cytoskeleton, resulting in formation of neovessels that are defective both architecturally and functionally. Modest suppression of calpain activity with calpain inhibitors restores cytoskeletal architecture and promotes formation of a functional neovasculature, thereby reducing underlying hypoxia. In sharp contrast to "anti-angiogenesis" strategies that cannot restore normoxia and may aggravate hypoxia, the therapeutic strategy described here does not inhibit neovascularization. Instead, by improving the function of neovascularization to reduce underlying hypoxia, moderate calpain inhibition offers a method for alleviating retinal ischemia, thereby suggesting a new treatment paradigm based on improvement rather than inhibition of new blood vessel growth.

  17. PRDM14 Promotes the Migration of Human Non-small Cell Lung Cancer Through Extracellular Matrix Degradation in vitro

    Institute of Scientific and Technical Information of China (English)

    Hong-Xia Bi; Han-Bing Shi; Ting Zhang; Ge Cui

    2015-01-01

    Background:As a novel molecular markerof non-small cell lung cancer (NSCLC),PRDI-BF1 and RIZ homology domain containing protein 14 (PRDM 14) is over-expressed in NSCLC tumor tissues.Extracellular matrix degradation mediated by the balance between matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) is one of the most important mechanism in lung cancer metastasis.This study aimed to determine if PRDM 14 promoted the migration of NSCLC cells through extracellular matrix degradation mediated by change of MMP/TIMP expression.Methods:The expression of PRDM14 was down-regulated in human cell line A 549 after transfection with lentiviral vector-mediated short-hairpin ribonucleic acids (shRNAs) which targeted the PRDM 14 promoter.Cellular migration ofshRNA-infected cells was detected by a scratch wound healing assay and transwell cell migration assay.Expression levels of MMP1,MMP2,TIMP1,and TIMP2 were measured by quantitative real-time polymerase chain reaction (RT-PCR).Results:Migration ofPRDM 14-shRNA-infected cells was significantly inhibited relative to control cells as measured by the scratch wound healing (P < 0.05) and transwell cell migration assays (P < 0.01).The expression of MMP1 in A549 cells infected by PRDM14-shRNA was down-regulated significantly (P < 0.01),whereas the expression of TIMPl and TIMP2 was up-regulated significantly (P < 0.01).Conclusions:PRDM 14 accelerates A549 cells migration in vitro through extracellular matrix degradation.PRDM 14 is considered as a potential therapeutic target in metastatic NSCLC.

  18. Site controlled transgenic mice validating increased expression from human matrix metalloproteinase (MMP-1) promoter due to a naturally occurring SNP.

    Science.gov (United States)

    Coon, Charles I; Fiering, Steven; Gaudet, Justin; Wyatt, Colby A; Brinckerhoff, Constance E

    2009-09-01

    Matrix metalloproteinases (MMPs) comprise a family of more than 20 members, each with the ability to degrade components of the extracellular matrix. The interstitial collagenases have the unique capacity to degrade the stromal collagens, types I, II and III, the body's most abundant proteins. These collagenases include MMP-1, MMP-8, MMP-13 and MMP-14. MMP-1, with a very broad expression pattern, has major roles in mediating matrix destruction in many diseases. We have described a single nucleotide polymorphism (SNP) in the MMP-1 promoter that augments transcription. This SNP is the presence or absence of an extra guanine (G) at -1607 bp, which creates the sequence 5'-GGAA-3'(2G allele), and which is an ETS binding site. Compared to the 1G allele (5'-GAA-3'), the 2G SNP is associated with enhanced transcription of MMP-1 and increased enzymatic activity. Although murine systems are often used to model human diseases, mice have only distant homologues of human MMP-1. Therefore, we used a technique for the targeted insertion of a single copy of a gene at the HPRT locus to compare expression of the 1G and 2G alleles. We generated transgenic mice with -4372 bp of the human MMP-1 promoter containing either the 1G or 2G SNP in front of the lac Z (E.coli ss-galactosidase) gene. We measured the relative expression of the transgenes in vitro in embryonic stem (ES) cells and in fibroblasts derived from embryonic mice. Our data show modest constitutive expression of ss-galactosidase mRNA and protein from these alleles, with the 2G allele more transcriptionally active than the 1G allele. We conclude that these mice represent a model for integration of a single copy of the human MMP-1 promoter into the murine genome, and could be used to study MMP-1 gene expression in a murine system.

  19. [Role of cytokine-matrix metalloproteinase axis on promoting vascular neointima hyperplasia in mice].

    Science.gov (United States)

    Liu, Y; Ning, W H; Shen, X H; Guo, D L; Guo, L

    2016-11-24

    Objective: To observe the effects of tumor necrosis factor-α (TNF-α) and platelet derived growth factor (PDGF) on vascular neointimal hyperplasia on matrix metalloproteinase 9/2 gene knockout (MMP9/2(-/-)) mice and explore related mechanisms. Methods: Mice of control group, MMP9(-/-) group, MMP2(-/-) group and MMP9/2(-/-) group were studied. Femoral artery was injured by transluminal wire, the mRNA expression levels of TNF-α and PDGF on femoral artery were detected by RT-PCR; the protein expression of MMP9 and MMP2 were assessed by Western blot on day 0, 1, 3, 7, 14 and 28 post injury. Mice in control group received TNF-α(5 ng/ml, 0.10 ml), TNF-α(0.05 ml)+ MMP inhibitor SB-3CT(0.50 ng/ml, 0.05 ml) injection, or PDGF-bb (10 ng/ml, 0.10 ml)and PDGF-bb(0.05 ml)+ SB-3CT(0.05 ml)injection around injured artery, intimal hyperplasia at 2 and 4 weeks after injury was observed. Intimal hyperplasia at 2 and 4 weeks after injury was also observed in MMP9/2(-/-) mice. TNF-α(5 ng/ml, 0.10 ml)was injected to MMP2(-/-) mice, PDGF-bb (0.1 ml) was injected to MMP9(-/-) mice around injured artery, intimal hyperplasia at 2 and 4 weeks after injury was observed. The degree of neointimal hyperplasia were observed by the Elastica-van Gieson staining and the area of neointima and media of the arteries were measured by SigmaPlot and intima ratio was calculated. Vascular smooth muscle cell (VSMC) mediums of MMP9(-/-) and MMP2(-/-) mice were stimulated by TNF-α and PDGF-bb, respectively, and migration assay, and proliferation assay were performed, relative migration and proliferation cells numbers were counted. Results: (1) mRNA expression of TNF-α (235.33±23.68) and PDGF-bb (3.30±0.56) in femoral arteries peaked at 1 day after injury, while MMP9 or MMP2 protein expression peaked at 7 or 28 days after injury. (2)In control mice, TNF-α intervention significantly enhanced intimal hyperplasia at 2 weeks after injury (2.21±0.05 vs. 1.55±0.03 in blank control group, Phyperplasia at

  20. The promoter polymorphism -1562C/T in matrix metalloproteinase-9 and COPD severity

    Directory of Open Access Journals (Sweden)

    D. G. Yanbaeva

    2006-12-01

    Full Text Available Chronic obstructive pulmonary disease (COPD is a complex heterogeneous respiratory disease. COPD is characterized by a progressive irreversible airflow limitation that is due to a loss of lung elasticity resulting from peripheral airflow obstruction (chronic bronchitis and parenchymal destruction (emphysema. Matrix metalloproteinases (MMP are a major group of proteases known to regulate extracellular matrix turnover. They have been suggested to be important in the process of lung diseases associated with tissue remodeling. Polymorphisms in MMPs which known to upregulate their activity may result in the degradation of a lung matrix. A case-control study was performed to investigate the association of polymorphisms of MMP type 1 (-1607G/GG, 9 (-1562C/T and 12 (-82A/G genes with COPD and disease severity. A total of 309 COPD patients admitted to departments of respiratory medicine have been recruited in Ufa city hospitals (## 13, 21, and 22. COPD patients have been undergone a spirometry and a physical examination by a chest physician to refer the GOLD II-IV stages. The control group comprised of 305 healthy subjects without evidence of chronic diseases (Table Basic characteristic of study groups.

  1. In Vitro Model of Human Choroidal Neovascular

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Choroidal capillary endothelia cell (CEC) plays a critical role in the development of choroidal neovascularization which is one of the major causes of blindness. An effective method for CEC cultivation was proposed.The isolation of human choroidal CECs using micro dissection followed by the use of superparamagnetic beads (Dynabeads) coated with the CD 31, which selectively binds to the endothelial cell surface. Cells bound to beads were isolated using a magnetic particle concentrator. The CECs were planted into type Ⅳ collagen coated 24 well plates. The results show that the primary cultured CEC is induced to tube formation in collagen Ⅳ coated environment, which can be presented as an in vitro model of choroidal neovascularization.

  2. Transthyretin represses neovascularization in diabetic retinopathy

    Science.gov (United States)

    Shao, Jun

    2016-01-01

    Purpose The apoptosis of human umbilical vein endothelial cells has been reportedly induced by the protein transthyretin (TTR). In human ocular tissue, TTR is generally considered to be secreted mainly by retinal pigment epithelial cells (hRPECs); however, whether TTR affects the development of neovascularization in diabetic retinopathy (DR) remains unclear. Methods Natural and simulated DR media were used to culture human retinal microvascular endothelial cells (hRECs). Hyperglycemia was simulated by increasing the glucose concentration from 5.5 mM up to 25 mM, while hypoxia was induced with 200 µM CoCl2. To understand the effects of TTR on hRECs, cell proliferation was investigated under natural and DR conditions. Overexpression of TTR, an in vitro wound-healing assay, and a tube formation assay were employed to study the repression of TTR on hRECs. Real-time fluorescence quantitative PCR (qRT-PCR) was used to study the mRNA levels of DR-related genes, such as Tie2, VEGFR1, VEGFR2, Angpt1, and Angpt2. Results The proliferation of hRECs was significantly decreased in the simulated hyperglycemic and hypoxic DR environments. The cells were further repressed by added exogenous or endogenous TTR only under hyperglycemic conditions. The in vitro migration and tube formation processes of the hRECs were inhibited with TTR; furthermore, in the hyperglycemia and hyperglycemia/hypoxia environments, the levels of Tie2 and Angpt1 mRNA were enhanced with exogenous TTR, while those of VEGFR1, VEGFR2, and Angpt1 were repressed. Conclusions In hyperglycemia, the proliferation, migration, and neovascularization of hRECs were significantly inhibited by TTR. The key genes for DR neovascularization, including Tie2, VEGFR1, VEGFR2, Angpt1, and Angpt2, were regulated by TTR. Under DR conditions, TTR significantly represses neovascularization by inhibiting the proliferation, migration and tube formation of hRECs. PMID:27746673

  3. Purtscher's retinopathy followed by neovascular glaucoma

    Directory of Open Access Journals (Sweden)

    Kuroda M

    2013-11-01

    Full Text Available Masasko Kuroda,1 Akihiro Nishida,1 Masashi Kikuchi,2 Yasuo Kurimoto11Department of Ophthalmology, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan; 2Kikuchi Eye Clinic, Kobe, Hyogo, JapanAbstract: We report the case of a 66-year-old Japanese man who developed neovascular glaucoma secondary to Purtscher's retinopathy following a head injury. The patient presented at our hospital with blurred vision and a visual field abnormality in his left eye 1 month after suffering from a head injury. Upon initial presentation, his best-corrected visual acuity on a decimal chart was 1.5 oculus dexter and 0.6 oculus sinister. The intraocular pressure (IOP was 12 mmHg in both eyes. Fundus examination of the left eye revealed multiple white lesions in the posterior pole. Optical coherence tomography demonstrated retinal edema, particularly in the inner retina. On the basis of these findings, a diagnosis of Purtscher's retinopathy was made. One month after the initial examination, the visual acuity in the left eye deteriorated to 0.01 in decimal chart, and the IOP increased to 37 mmHg. Gonioscopy showed angle neovascularization. The patient received an intravitreal bevacizumab injection and panretinal photocoagulation. Subsequently, the IOP normalized and the angle neovascularization regressed.Keywords: blurred vision, visual field, retinal edema, head injury, head trauma

  4. Matrix Metalloproteinase-2 Promoter Genotype as a Marker of Cutaneous T-Cell Lymphoma Early Stage

    Directory of Open Access Journals (Sweden)

    Anna Vasku

    2010-01-01

    Full Text Available The aim of the study was to investigate the DNA polymorphic genotype in MMP-2 promoter gene as a potential candidate region for the development of the cutaneous T-cell lymphoma (CTCL and/or its progression. A total of 89 Czech patients with CTCL (including 23 patients with large plaque parapsoriasis were compared to 198 controls of similar age and sex distribution, without personal or family history of chronic skin diseases and without personal history of malignancy. The three selected polymorphisms in the promoter of MMP-2 gene (−1575G/A, −1306C/T, and −790T/G were determined using the PCR-based methodology with RFLP. In our cohort, the associated GGCCTT MMP-2 promoter genotype was highly significantly more frequent in CTCL-Ia stage patients compared to patients with parapsoriasis, the tests having high sensitivity and specificity (78%, 83%, resp.. To conclude, use of associated MMP-2 promoter genotype as a DNA marker might make it possible to distinguish between the patients with parapsoriasis and those with CTCL stage Ia, which could substantially improve possibilities of clinical diagnostics, therapy design, and prognosis of this serious condition in the early stages.

  5. Matrix metalloproteinase-2 promoter genotype as a marker of cutaneous T-cell lymphoma early stage.

    Science.gov (United States)

    Vasku, Anna; Vasku, Julie Bienertova; Necas, Miroslav; Vasku, Vladimir

    2010-01-01

    The aim of the study was to investigate the DNA polymorphic genotype in MMP-2 promoter gene as a potential candidate region for the development of the cutaneous T-cell lymphoma (CTCL) and/or its progression. A total of 89 Czech patients with CTCL (including 23 patients with large plaque parapsoriasis) were compared to 198 controls of similar age and sex distribution, without personal or family history of chronic skin diseases and without personal history of malignancy. The three selected polymorphisms in the promoter of MMP-2 gene (-1575G/A, -1306C/T, and -790T/G) were determined using the PCR-based methodology with RFLP. In our cohort, the associated GGCCTT MMP-2 promoter genotype was highly significantly more frequent in CTCL-Ia stage patients compared to patients with parapsoriasis, the tests having high sensitivity and specificity (78%, 83%, resp.). To conclude, use of associated MMP-2 promoter genotype as a DNA marker might make it possible to distinguish between the patients with parapsoriasis and those with CTCL stage Ia, which could substantially improve possibilities of clinical diagnostics, therapy design, and prognosis of this serious condition in the early stages.

  6. Matrix Metalloproteinase-2 Promoter Genotype as a Marker of Cutaneous T-Cell Lymphoma Early Stage

    OpenAIRE

    Anna Vasku; Julie Bienertova Vasku; Miroslav Nečas; Vladimir Vasku

    2010-01-01

    The aim of the study was to investigate the DNA polymorphic genotype in MMP-2 promoter gene as a potential candidate region for the development of the cutaneous T-cell lymphoma (CTCL) and/or its progression. A total of 89 Czech patients with CTCL (including 23 patients with large plaque parapsoriasis) were compared to 198 controls of similar age and sex distribution, without personal or family history of chronic skin diseases and without personal history of malignancy. The three selected poly...

  7. Promoting neovascularization of adipose tissue derived stem cells compoun -ding with different cellular scaffold in nude mice subcutaneous stratum%脂肪来源干细胞复合不同生物支架在裸鼠皮下的促血管化作用

    Institute of Scientific and Technical Information of China (English)

    徐永飞; 张建文; 暴志国; 李静怡; 王耀聪; 许颖溦

    2013-01-01

    目的:探讨脂肪来源干细胞复合不同生物支架在裸鼠皮下的促血管化作用。方法:根据所选支架的不同,将实验分为4组,A组为脂肪颗粒,B组为透明质酸钠,C组为Ⅰ型胶原支架,分别按体积比1:1与25×106 mL-1的脂肪来源干细胞混合,D组为单纯脂肪来源干细胞,将4组试剂注射到12只裸鼠皮下构建软组织,每只裸鼠各注射4个点,3个月后获取相应标本,测定湿质量、存活率、微血管密度。结果:4组间湿质量、存活率、微血管密度比较,差异均有统计学意义(F=47.523、48.425和47.619,P均<0.05),且A、B、C组湿质量、存活率、微血管密度均高于D组(P均<0.05)。结论:脂肪来源干细胞复合生物支架可加速软组织血管化,且效果优于单纯脂肪来源干细胞。%Aim:To discuss the affection of promoting neovascularization of adipose tissue derived stem cells (ADSCs) compounding with different cellular scaffold in nude mice subcutaneous stratum .Methods:The experiment was divided into four groups depending on the selected scaffold .Group A,B and C were given fat particles, sodium hyaluronate, typeⅠcol-lagen,respectively, mixed with ADSCs at 25 ×106 mL-1 .Group D was given pure ADSCs .Four reagents were injected ran-domly into subcutaneous stratum of 12 nude mice to build soft tissue .Each nude muse was injected 4 points.The appropri-ate specimens were obtained three months later and wet weight , survival rate and microvessel density were detected .Re-sults:The differences were statistically significant regarding the wet weight , survival rate , microvessel density among the four groups(F=47.523,48.425,47.619,P<0.05).The wet weight, survival rate, and microvessel density of group A ,B and C were higher than those of group D (P<0.05).Conclusion: ADSCs compounding with cellular scaffold could pro-mote neovascularization in subcutaneous stratum ,and is better than pure

  8. Extracellular Matrix Hydrogel Promotes Tissue Remodeling, Arteriogenesis, and Perfusion in a Rat Hindlimb Ischemia Model

    Directory of Open Access Journals (Sweden)

    Jessica L. Ungerleider, BS

    2016-01-01

    Full Text Available Although surgical and endovascular revascularization can be performed in peripheral arterial disease (PAD, 40% of patients with critical limb ischemia do not have a revascularization option. This study examines the efficacy and mechanisms of action of acellular extracellular matrix-based hydrogels as a potential novel therapy for treating PAD. We tested the efficacy of using a tissue-specific injectable hydrogel derived from decellularized porcine skeletal muscle (SKM and compared this to a new human umbilical cord-derived matrix (hUC hydrogel, which could have greater potential for tissue regeneration because of the younger age of the tissue source. In a rodent hindlimb ischemia model, both hydrogels were injected 1-week post-surgery and perfusion was regularly monitored with laser speckle contrast analysis to 35 days post-injection. There were significant improvements in hindlimb tissue perfusion and perfusion kinetics with both biomaterials. Histologic analysis indicated that the injected hydrogels were biocompatible, and resulted in arteriogenesis, rather than angiogenesis, as well as improved recruitment of skeletal muscle progenitors. Skeletal muscle fiber morphology analysis indicated that the muscle treated with the tissue-specific SKM hydrogel more closely matched healthy tissue morphology. Whole transcriptome analysis indicated that the SKM hydrogel caused a shift in the inflammatory response, decreased cell death, and increased blood vessel and muscle development. These results show the efficacy of an injectable ECM hydrogel alone as a potential therapy for treating patients with PAD. Our results indicate that the SKM hydrogel improved functional outcomes through stimulation of arteriogenesis and muscle progenitor cell recruitment.

  9. Matrix-Gla protein promotes osteosarcoma lung metastasis and associates with poor prognosis.

    Science.gov (United States)

    Zandueta, Carolina; Ormazábal, Cristina; Perurena, Naiara; Martínez-Canarias, Susana; Zalacaín, Marta; Julián, Mikel San; Grigoriadis, Agamemnon E; Valencia, Karmele; Campos-Laborie, Francisco J; Rivas, Javier De Las; Vicent, Silvestre; Patiño-García, Ana; Lecanda, Fernando

    2016-08-01

    Osteosarcoma (OS) is the most prevalent osseous tumour in children and adolescents and, within this, lung metastases remain one of the factors associated with a dismal prognosis. At present, the genetic determinants driving pulmonary metastasis are poorly understood. We adopted a novel strategy using robust filtering analysis of transcriptomic profiling in tumour osteoblastic cell populations derived from human chemo-naive primary tumours displaying extreme phenotypes (indolent versus metastatic) to uncover predictors associated with metastasis and poor survival. We identified MGP, encoding matrix-Gla protein (MGP), a non-collagenous matrix protein previously associated with the inhibition of arterial calcification. Using different orthotopic models, we found that ectopic expression of Mgp in murine and human OS cells led to a marked increase in lung metastasis. This effect was independent of the carboxylation of glutamic acid residues required for its physiological role. Abrogation of Mgp prevented lung metastatic activity, an effect that was rescued by forced expression. Mgp levels dramatically altered endothelial adhesion, trans-endothelial migration in vitro and tumour cell extravasation ability in vivo. Furthermore, Mgp modulated metalloproteinase activities and TGFβ-induced Smad2/3 phosphorylation. In the clinical setting, OS patients who developed lung metastases had high serum levels of MGP at diagnosis. Thus, MGP represents a novel adverse prognostic factor and a potential therapeutic target in OS. Microarray datasets may be found at: http://bioinfow.dep.usal.es/osteosarcoma/ Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  10. Inhibition of Histone Deacetylase Activity in Human Endometrial Stromal Cells Promotes Extracellular Matrix Remodelling and Limits Embryo Invasion

    Science.gov (United States)

    Atkinson, Stuart P.; Quiñonero, Alicia; Martínez, Sebastián; Pellicer, Antonio; Simón, Carlos

    2012-01-01

    Invasion of the trophoblast into the maternal decidua is regulated by both the trophoectoderm and the endometrial stroma, and entails the action of tissue remodeling enzymes. Trophoblast invasion requires the action of metalloproteinases (MMPs) to degrade extracellular matrix (ECM) proteins and in turn, decidual cells express tissue inhibitors of MMPs (TIMPs). The balance between these promoting and restraining factors is a key event for the successful outcome of pregnancy. Gene expression is post-transcriptionally regulated by histone deacetylases (HDACs) that unpacks condensed chromatin activating gene expression. In this study we analyze the effect of histone acetylation on the expression of tissue remodeling enzymes and activity of human endometrial stromal cells (hESCs) related to trophoblast invasion control. Treatment of hESCs with the HDAC inhibitor trichostatin A (TSA) increased the expression of TIMP-1 and TIMP-3 while decreased MMP-2, MMP-9 and uPA and have an inhibitory effect on trophoblast invasion. Moreover, histone acetylation is detected at the promoters of TIMP-1 and TIMP-3 genes in TSA-treated. In addition, in an in vitro decidualized hESCs model, the increase of TIMP-1 and TIMP-3 expression is associated with histone acetylation at the promoters of these genes. Our results demonstrate that histone acetylation disrupt the balance of ECM modulators provoking a restrain of trophoblast invasion. These findings are important as an epigenetic mechanism that can be used to control trophoblast invasion. PMID:22291969

  11. Cartilage Oligomeric Matrix Protein Angiopoeitin-1 Provides Benefits During Nerve Regeneration In Vivo and In Vitro.

    Science.gov (United States)

    Qiu, Longhai; He, Bo; Hu, Jun; Zhu, Zhaowei; Liu, Xiaolin; Zhu, Jiakai

    2015-12-01

    Our group pioneered the study of nerve regeneration in China and has successfully developed human "acellular nerve grafts (ACNGs)". However, our clinical studies revealed that the effects of ACNGs for long and large nerve defects are far from satisfactory. To improve the efficacy of ACNGs, we combined Cartilage oligomeric matrix protein angiopoietin-1 (COMP-Ang1) with ACNGs in rat sciatic nerve injury models and observed the outcomes via angiographic, morphological, and functional analyses. Co-cultures of endothelial cells (ECs) and dorsal root ganglion neurons (DRGs) were also used to characterize the relationship between neovascularization and nerve regeneration. The results showed significant improvements in early neovascularization, nerve regeneration, and functional outcomes in vivo in the ACNG + COMP-Ang1 group. In vitro, neurite length, and density as well as the expression levels of neurofilament 68 (NF68) and phosphorylated-Tie-2 (p-Tie-2) significantly increased when ECs were co-cultured with DRGs using COMP-Ang1. p-Tie-2 expression dramatically decreased after treatment with a Tie-2 kinase inhibitor (S157701), which consequently decreased the level of NF68. COMP-Ang1 can be concluded to promote early neovascularization followed by brisk nerve regeneration, and the mechanism of this regeneration may involve the modulation of the p-Tie-2 and Tie-2 receptors on ECs. These findings demonstrate that ACNGs can be modified using COMP-Ang1 to improve their efficacy in repairing peripheral nerve defects in clinical trials.

  12. Experimental Study of Shenshuning on the Inhibition of Matrix and Neovascularization ahout Peritoneal Fibrosis Correlating Peritoneal Dialysis in Rat%肾疏宁抑制腹膜透析腹膜纤维化大鼠基质及新生血管的实验研究

    Institute of Scientific and Technical Information of China (English)

    杨洪涛; 尚懿纯; 曹式丽; 窦一田; 黄勇

    2013-01-01

    Objective: To observe the effects of ShenShuNing on the peritoneal function, peritoneal matrix accumulation, neovascularization , the expressions of Connective tissue growth factor( CTGF ), Vascular endothelial growth factor( VEGF ) Hepatocyte growth factor( HGF )、Bone morphogenetic protein,( BMP -7 ) in the peritoneal fibrosis correlating peritoneal dialysis rats. Methods: peritoneal fibrosis correlating peritoneal dialysis SD rat model was induced by injecting adriamycin and peritoneal dialysate. They were randomly divided into the model group,the 1.5% peritoneal dialysate group ,the 4. 25% peritoneal dialysate group,the 1.5% peritoneal dialysate and ShenShuNing group and the 4. 25% peritoneal dialysate and ShenShuNing group according to body weight. Besides, another 15 rats was taken as the blank control group. Of them, ShenShuNing ( 43. 93 g · kg-1· d-1 ) was given to rats in theperitone-al dialysate and ShenShuNing groups by gastrogavage, while the same normal saline was given to rats in other groups by gastrogavage. The changes of glucose in peritoneal fluid , Ultra Filtration volume( UF ), Mass transfer of glucose( MTG )were detected. The patho-morphological changes of the peritoneum were observed. Peritoneal thickness, vessel count, Fibronectin( FN ), expressions of CTGF, VEGF, HGF and BMP - 7 were determined. Results: At the end of the 6th week, significant difference was shown in peritoneal dialysate and ShenShuNing groups UF( - 3. 26 ± 14. 17 )ml and ( - 2. 04 ± 10. 74 )ml, MTG ( 18. 12 ± 0. 81 )mmol/kg and ( 16. 14 ± 1.20 ) mmol/kg,peritoneal thickness ( 74.68 ±15.33 )μm and ( 211.75 ±58.23 )μm,vessel count ( 8.21 ±2.66 ) mm2 and ( 13.70 ± 4.71 ) mm2,FN( 152.47 ±36. 94 )% and (( 231.49 ±53.49 )%,CTGF ( 708.67 ± 127. 22 )% and ( 791. 20 ± 126. 37 )%,VEGF (0.42 ±0.08)% and (0.50 ±0.09)% ,HGF( 245.71 ±24.38)% and (222. 05 ±23.43 )%,BMP-7 ( 351. 27 ± 31. 99 )% and ( 284.43 ±26.82 )% , when compared with the same peritoneal dialysate

  13. Inflammatory Mediators and Angiogenic Factors in Choroidal Neovascularization: Pathogenetic Interactions and Therapeutic Implications

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    Claudio Campa

    2010-01-01

    Full Text Available Choroidal neovascularization (CNV is a common and severe complication in heterogeneous diseases affecting the posterior segment of the eye, the most frequent being represented by age-related macular degeneration. Although the term may suggest just a vascular pathological condition, CNV is more properly definable as an aberrant tissue invasion of endothelial and inflammatory cells, in which both angiogenesis and inflammation are involved. Experimental and clinical evidences show that vascular endothelial growth factor is a key signal in promoting angiogenesis. However, many other molecules, distinctive of the inflammatory response, act as neovascular activators in CNV. These include fibroblast growth factor, transforming growth factor, tumor necrosis factor, interleukins, and complement. This paper reviews the role of inflammatory mediators and angiogenic factors in the development of CNV, proposing pathogenetic assumptions of mutual interaction. As an extension of this concept, new therapeutic approaches geared to have an effect on both the vascular and the extravascular components of CNV are discussed.

  14. PACAP Promotes Matrix-Driven Adhesion of Cultured Adult Murine Neural Progenitors

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    James A. Waschek

    2017-05-01

    Full Text Available New neurons are born throughout the life of mammals in germinal zones of the brain known as neurogenic niches: the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus of the hippocampus. These niches contain a subpopulation of cells known as adult neural progenitor cells (aNPCs, which self-renew and give rise to new neurons and glia. aNPCs are regulated by many factors present in the niche, including the extracellular matrix (ECM. We show that the neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide affects subventricular zone-derived aNPCs by increasing their surface adhesion. Gene array and reconstitution assays indicate that this effect can be attributed to the regulation of ECM components and ECM-modifying enzymes in aNPCs by PACAP. Our work suggests that PACAP regulates a bidirectional interaction between the aNPCs and their niche: PACAP modifies ECM production and remodeling, in turn the ECM regulates progenitor cell adherence. We speculate that PACAP may in this manner help restrict adult neural progenitors to the stem cell niche in vivo, with potential significance for aNPC function in physiological and pathological states.

  15. Haemophilus influenzae P4 Interacts With Extracellular Matrix Proteins Promoting Adhesion and Serum Resistance.

    Science.gov (United States)

    Su, Yu-Ching; Mukherjee, Oindrilla; Singh, Birendra; Hallgren, Oskar; Westergren-Thorsson, Gunilla; Hood, Derek; Riesbeck, Kristian

    2016-01-15

    Interaction with the extracellular matrix (ECM) is one of the successful colonization strategies employed by nontypeable Haemophilus influenzae (NTHi). Here we identified Haemophilus lipoprotein e (P4) as a receptor for ECM proteins. Purified recombinant P4 displayed a high binding affinity for laminin (Kd = 9.26 nM) and fibronectin (Kd = 10.19 nM), but slightly less to vitronectin (Kd = 16.51 nM). A P4-deficient NTHi mutant showed a significantly decreased binding to these ECM components. Vitronectin acquisition conferred serum resistance to both P4-expressing NTHi and Escherichia coli transformants. P4-mediated bacterial adherence to pharynx, type II alveolar, and bronchial epithelial cells was mainly attributed to fibronectin. Importantly, a significantly reduced bacterial infection was observed in the middle ear of the Junbo mouse model when NTHi was devoid of P4. In conclusion, our data provide new insight into the role of P4 as an important factor for Haemophilus colonization and subsequent respiratory tract infection.

  16. Association between promoter polymorphisms of matrix metalloproteinase-1 and risk of gastric cancer.

    Science.gov (United States)

    Peng, Qisong; Xu, Yong

    2015-01-01

    Growing evidences show that matrix metalloproteinase-1 (MMP1) plays important roles in tumorigenesis and cancer metastasis. The interactions between MMP1-1607 1G>2G polymorphism and risk of gastric cancer (GC) have been reported, but results remained ambiguous. To determine the association between MMP1-1607 1G>2G polymorphism and risk of GC, we conducted a meta-analysis and identified the outcome data from all the research papers estimating the association between MMP1-1607 1G>2G polymorphism and GC risk, which was based on comprehensive searches using databases such as PubMed, Elsevier Science Direct, Excerpta Medica Database (EMBASE), and Chinese National Knowledge Infrastructure (CNKI). The fixed-effects model was used in this meta-analysis. Data were extracted, and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. In this meta-analysis, six studies involving 1,377 cases and 1,543 controls were included. We identified the significant association between MMP1-1607 1G>2G polymorphism and GC risk for allele model (OR =1.05; 95% CI, 1.01-1.08), for dominant model (OR =1.11; 95% CI, 1.08-1.15), and for recessive model (OR =1.06; 95% CI, 0.98-1.14). In summary, our analysis demonstrated that MMP1-1607 1G>2G polymorphism was significantly associated with an increased risk of GC.

  17. Choroidal neovascularization secondary to choroidal nevus simulating an inflammatory lesion

    Directory of Open Access Journals (Sweden)

    Samuray Tuncer

    2013-01-01

    Full Text Available Choroidal nevi are the most common benign pigmented lesions of the fundus. Choroidal neovascularization is a rare complication of choroidal nevi. We report herein a young patient managed successfully with intravitreal bevacizumab injections for juxtapapillary choroidal neovascularization secondary to choroidal nevus simulating an inflammatory lesion.

  18. PPARdelta promotes wound healing by up-regulating TGF-beta1-dependent or -independent expression of extracellular matrix proteins.

    Science.gov (United States)

    Ham, Sun Ah; Kim, Hyo Jung; Kim, Hyun Joon; Kang, Eun Sil; Eun, So Young; Kim, Gil Hyeong; Park, Myung Hyun; Woo, Im Sun; Kim, Hye Jung; Chang, Ki Churl; Lee, Jae Heun; Seo, Han Geuk

    2010-06-01

    Although the peroxisome proliferator-activated receptor (PPAR) delta has been implicated in the wound healing process, its exact role and mechanism of action have not been fully elucidated. Our previous findings showed that PPARdelta induces the expression of the transforming growth factor (TGF)-beta1, which has been implicated in the deposit of extracellular matrix proteins. Here, we demonstrate that administration of GW501516, a specific PPARdelta ligand, significantly promoted wound closure in the experimental mouse and had a profound effect on the expression of collagen types I and III, alpha-smooth muscle actin, pSmad3 and TGF-beta1, which play a pivotal role in wound healing processes. Activation of PPARdelta increased migration of human epidermal keratinocytes and dermal fibroblasts in in vitro scrape-wounding assays. Addition of a specific ALK5 receptor inhibitor SB431542 significantly suppressed GW501516-induced migration of human keratinocytes and fibroblasts. In these cells, activated PPARdelta also induced the expression of collagen types I and III and fibronectin in a TGF-beta1-dependent or -independent manner. The effect of PPARdelta on the expression of type III collagen was dually regulated by the direct binding of PPARdelta and Smad3 to a direct repeat-1 site and a Smad-binding element, respectively, of the type III gene promoter. Taken together, these results demonstrated that PPARdelta plays an important role in skin wound healing in vivo and that it functions by accelerating extracellular matrix-mediated cellular interactions in a process mediated by the TGF-beta1/Smad3 signaling-dependent or - independent pathway.

  19. Promotion of hepatic differentiation of bone marrow mesenchymal stem cells on decellularized cell-deposited extracellular matrix.

    Science.gov (United States)

    He, Hongliang; Liu, Xiaozhen; Peng, Liang; Gao, Zhiliang; Ye, Yun; Su, Yujie; Zhao, Qiyi; Wang, Ke; Gong, Yihong; He, Fan

    2013-01-01

    Interactions between stem cells and extracellular matrix (ECM) are requisite for inducing lineage-specific differentiation and maintaining biological functions of mesenchymal stem cells by providing a composite set of chemical and structural signals. Here we investigated if cell-deposited ECM mimicked in vivo liver's stem cell microenvironment and facilitated hepatogenic maturation. Decellularization process preserved the fibrillar microstructure and a mix of matrix proteins in cell-deposited ECM, such as type I collagen, type III collagen, fibronectin, and laminin that were identical to those found in native liver. Compared with the cells on tissue culture polystyrene (TCPS), bone marrow mesenchymal stem cells (BM-MSCs) cultured on cell-deposited ECM showed a spindle-like shape, a robust proliferative capacity, and a suppressed level of intracellular reactive oxygen species, accompanied with upregulation of two superoxide dismutases. Hepatocyte-like cells differentiated from BM-MSCs on ECM were determined with a more intensive staining of glycogen storage, an elevated level of urea biosynthesis, and higher expressions of hepatocyte-specific genes in contrast to those on TCPS. These results demonstrate that cell-deposited ECM can be an effective method to facilitate hepatic maturation of BM-MSCs and promote stem-cell-based liver regenerative medicine.

  20. Promotion of Hepatic Differentiation of Bone Marrow Mesenchymal Stem Cells on Decellularized Cell-Deposited Extracellular Matrix

    Directory of Open Access Journals (Sweden)

    Hongliang He

    2013-01-01

    Full Text Available Interactions between stem cells and extracellular matrix (ECM are requisite for inducing lineage-specific differentiation and maintaining biological functions of mesenchymal stem cells by providing a composite set of chemical and structural signals. Here we investigated if cell-deposited ECM mimicked in vivo liver's stem cell microenvironment and facilitated hepatogenic maturation. Decellularization process preserved the fibrillar microstructure and a mix of matrix proteins in cell-deposited ECM, such as type I collagen, type III collagen, fibronectin, and laminin that were identical to those found in native liver. Compared with the cells on tissue culture polystyrene (TCPS, bone marrow mesenchymal stem cells (BM-MSCs cultured on cell-deposited ECM showed a spindle-like shape, a robust proliferative capacity, and a suppressed level of intracellular reactive oxygen species, accompanied with upregulation of two superoxide dismutases. Hepatocyte-like cells differentiated from BM-MSCs on ECM were determined with a more intensive staining of glycogen storage, an elevated level of urea biosynthesis, and higher expressions of hepatocyte-specific genes in contrast to those on TCPS. These results demonstrate that cell-deposited ECM can be an effective method to facilitate hepatic maturation of BM-MSCs and promote stem-cell-based liver regenerative medicine.

  1. Fibroblast growth factor-2 drives and maintains progressive corneal neovascularization following HSV-1 infection.

    Science.gov (United States)

    Gurung, H R; Carr, M M; Bryant, K; Chucair-Elliott, A J; Carr, D Jj

    2017-04-05

    Herpes simplex virus type 1 (HSV-1) infection of the cornea induces vascular endothelial growth factor A (VEGF-A)-dependent lymphangiogenesis that continues to develop well beyond the resolution of infection. Inflammatory leukocytes infiltrate the cornea and have been implicated to be essential for corneal neovascularization, an important clinically relevant manifestation of stromal keratitis. Here we report that cornea infiltrating leukocytes including neutrophils and T cells do not have a significant role in corneal neovascularization past virus clearance. Antibody-mediated depletion of these cells did not impact lymphatic or blood vessel genesis. Multiple pro-angiogenic factors including IL-6, angiopoietin-2, hepatocyte growth factor, fibroblast growth factor-2 (FGF-2), VEGF-A, and matrix metalloproteinase-9 were expressed within the cornea following virus clearance. A single bolus of dexamethasone at day 10 post infection (pi) resulted in suppression of blood vessel genesis and regression of lymphatic vessels at day 21 pi compared to control-treated mice. Whereas IL-6 neutralization had a modest impact on hemangiogenesis (days 14-21 pi) and lymphangiogenesis (day 21 pi) in a time-dependent fashion, neutralization of FGF-2 had a more pronounced effect on the suppression of neovascularization (blood and lymphatic vessels) in a time-dependent, leukocyte-independent manner. Furthermore, FGF-2 neutralization suppressed the expression of all pro-angiogenic factors measured and preserved visual acuity.Mucosal Immunology advance online publication 5 April 2017; doi:10.1038/mi.2017.26.

  2. Research on inhibition of corneal neovascularization

    Directory of Open Access Journals (Sweden)

    Zhang-Hui Yang

    2015-12-01

    Full Text Available Corneal transparency is the basis of the normal physiological functions.However, corneal neovascularization(CNVmay occur in the infection, mechanical and chemical injury or under other pathological conditions,which make the cornea lose original transparency and severe visual impairment. In recent years, along with the development of immunology, molecular biology, biochemistry and other disciplines, there is more in-depth understanding on the CNV, and clinical treatment of CNV has made new breakthroughs. This article provides an overview of the inhibition of CNV.

  3. Surface-associated plasminogen binding of Cryptococcus neoformans promotes extracellular matrix invasion.

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    Jamal Stie

    Full Text Available BACKGROUND: The fungal pathogen Cryptococcus neoformans is a leading cause of illness and death in persons with predisposing factors, including: malignancies, solid organ transplants, and corticosteroid use. C. neoformans is ubiquitous in the environment and enters into the lungs via inhalation, where it can disseminate through the bloodstream and penetrate the central nervous system (CNS, resulting in a difficult to treat and often-fatal infection of the brain, called meningoencephalitis. Plasminogen is a highly abundant protein found in the plasma component of blood and is necessary for the degradation of fibrin, collagen, and other structural components of tissues. This fibrinolytic system is utilized by cancer cells during metastasis and several pathogenic species of bacteria have been found to manipulate the host plasminogen system to facilitate invasion of tissues during infection by modifying the activation of this process through the binding of plasminogen at their surface. METHODOLOGY: The invasion of the brain and the central nervous system by penetration of the protective blood-brain barrier is a prerequisite to the establishment of meningoencephalitis by the opportunistic fungal pathogen C. neoformans. In this study, we examined the ability of C. neoformans to subvert the host plasminogen system to facilitate tissue barrier invasion. Through a combination of biochemical, cell biology, and proteomic approaches, we have shown that C. neoformans utilizes the host plasminogen system to cross tissue barriers, providing support for the hypothesis that plasminogen-binding may contribute to the invasion of the blood-brain barrier by penetration of the brain endothelial cells and underlying matrix. In addition, we have identified the cell wall-associated proteins that serve as plasminogen receptors and characterized both the plasminogen-binding and plasmin-activation potential for this significant human pathogen. CONCLUSIONS: The results of

  4. Correlations of polymorphisms in matrix metalloproteinase-1, -2, and -7 promoters to susceptibility to malignant gliomas

    Science.gov (United States)

    Kawal, Priyanka; Chandra, Anil; Rajkumar; Dhole, Tapan N.; Ojha, Balkrishna

    2016-01-01

    Background: Oligodendrogliomas are infiltrative astrocytic tumors. They constitute about 1-5% of intracranial tumors. These have been graded into benign and malignant grades. The single nucleotide polymorphisms (SNPs) in the promoter regions of MMP genes may influence tumor development and progression. This study was done to explore the correlations of the promoter SNPs in MMP-1, MMP-2 and MMP-7 genes susceptibility in development and progression of oligodendrogliomas. Objectives: We aimed to investigate the association of MMP1 (−1607A > G), MMP-2 (−1306 C/T) and MMP-7(−181A > G) gene polymorphism in oligodendrogliomas (grade I, II, III). Materials and Methods: In the present case control study, we enrolled a total of 30 cases of oligodendrogliomas (grade I to III) confirmed by histopathology and 30 healthy cases as control. Polymorphism for MMP-1 gene (−1607A > G), MMP-2 (−1306 C/T), MMP-7(−181A > G) were genotyped by restriction fragment length polymorphism. Results: Frequencies of MMP-1 (−1607A > G) genotypes and 2G alleles were significantly associated with the cases of oligodendrogliomas (30%) in relation to healthy controls (13%). [OR = 6.89; P = 0.02; 95%CI= (1.33-35.62)] and [OR = 2.66; P =0.01; 95% CI= (1.26-5.64)]. A significant association of MMP-2 (−1306C/T) polymorphism with oligodendroglioma (P = 0.54) was not found, suggesting that MMP-2 (−1306C/T) polymorphism is not associated with increased oligodendroglioma susceptibility. Frequencies of MMP-7(−181A > G) genotypes and 2G alleles were significantly associated with the cases of oligodendrogliomas (33.33%) in relation to healthy controls (13.33%). [OR = 5.65; P = 0.02; 95%CI= (1.26-25.36)] and [OR = 2.49; P =0.01; 95% CI= (1.17-5.27)]. Conclusions: MMP-1 (−1607 A > G), MMP-7(−181A > G) genotypes and 2G alleles were significantly associated with oligodendroglioma (grade I, II, III), but MMP-2 (−1306C/T) polymorphism is not associated with increased oligodendroglioma

  5. The Ahmed Glaucoma Valve in Neovascular Glaucoma (An AOS Thesis)

    Science.gov (United States)

    Netland, Peter A.

    2009-01-01

    Purpose: To evaluate the results of Ahmed glaucoma valve surgery in neovascular glaucoma and control patients. Methods: In this retrospective comparative study, we reviewed 76 eyes of 76 patients, comparing the surgical outcomes in control patients (N=38) to matched neovascular glaucoma patients (N=38). Success was defined as intraocular pressure (IOP) ≥6 mm Hg and ≤21 mm Hg, without further glaucoma surgery, and without loss of light perception. Results: Average follow-up for control and neovascular glaucoma patients was 18.4 and 17.4 months, respectively (P = .550). At last follow-up, mean IOP was 16.2 ± 5.2 mm Hg and 15.5 ± 12.5 mm Hg (P = .115) in control and neovascular glaucoma patients, respectively. Life-table analysis showed a significantly lower success for neovascular glaucoma patients compared with controls (P = .0096), with success at 1 year of 89.2% and 73.1%, at 2 years of 81.8% and 61.9%, and at 5 years of 81.8% and 20.6% for control and neovascular glaucoma eyes, respectively. Cox proportional hazards regression analysis showed neovascular glaucoma as a risk factor for surgical failure (odds ratio, 5.384, 95% CI, 1.22–23.84, P = .027). Although IOP control and complications were comparable between the two groups, visual outcomes were worse in neovascular glaucoma patients, with 9 eyes (23.7%) with neovascular glaucoma compared with no controls losing light perception vision (P = .002). The majority with loss of vision (5 of 9) had successful control of IOP during the postoperative period. Conclusion: Neovascular glaucoma patients have greater risk of surgical failure after Ahmed glaucoma valve surgery compared with controls. Despite improved mean IOP with drainage implants, visual outcomes may be poor, possibly due to progression of underlying disease. PMID:20126506

  6. Matrix Remodeling Promotes Pulmonary Hypertension through Feedback Mechanoactivation of the YAP/TAZ-miR-130/301 Circuit

    Directory of Open Access Journals (Sweden)

    Thomas Bertero

    2015-11-01

    Full Text Available Pulmonary hypertension (PH is a deadly vascular disease with enigmatic molecular origins. We found that vascular extracellular matrix (ECM remodeling and stiffening are early and pervasive processes that promote PH. In multiple pulmonary vascular cell types, such ECM stiffening induced the microRNA-130/301 family via activation of the co-transcription factors YAP and TAZ. MicroRNA-130/301 controlled a PPARγ-APOE-LRP8 axis, promoting collagen deposition and LOX-dependent remodeling and further upregulating YAP/TAZ via a mechanoactive feedback loop. In turn, ECM remodeling controlled pulmonary vascular cell crosstalk via such mechanotransduction, modulation of secreted vasoactive effectors, and regulation of associated microRNA pathways. In vivo, pharmacologic inhibition of microRNA-130/301, APOE, or LOX activity ameliorated ECM remodeling and PH. Thus, ECM remodeling, as controlled by the YAP/TAZ-miR-130/301 feedback circuit, is an early PH trigger and offers combinatorial therapeutic targets for this devastating disease.

  7. Lonafarnib is a potential inhibitor for neovascularization.

    Directory of Open Access Journals (Sweden)

    Linlin Sun

    Full Text Available Atherosclerosis is a common cardiovascular disease that involves the build-up of plaque on the inner walls of the arteries. Intraplaque neovacularization has been shown to be essential in the pathogenesis of atherosclerosis. Previous studies showed that small-molecule compounds targeting farnesyl transferase have the ability to prevent atherosclerosis in apolipoprotein E-deficient mice, but the underlying mechanism remains to be elucidated. In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner. In addition, we showed that lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation. These data indicate that lonafarnib inhibits neovascularization via directly targeting endothelial cells and disturbing their motility. Moreover, we demonstrated that pharmacological inhibition of farnesyl transferase by lonafarnib significantly impaired centrosome reorientation toward the leading edge of endothelial cells. Mechanistically, we found that the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity. Additionally, we showed that lonafarnib remarkably inhibited the expression of the cytoskeletal protein and interrupted its interaction with farnesyl transferase. Our findings thus offer novel mechanistic insight into the protective effect of farnesyl transferase inhibitors on atherosclerosis and provide encouraging evidence for the potential use of this group of agents in inhibiting plaque neovascularization.

  8. Overload and neovascularization of shoulder tendons in volleyball players

    Directory of Open Access Journals (Sweden)

    Notarnicola Angela

    2012-08-01

    Full Text Available Abstract Background In overhead sports like volleyball, the onset of a rotator cuff tendinopathy due to functional overload is a common observation. An angiofibroblastic etiopathogenesis has been hypothesized, whereby a greater anaerobic metabolism occurs in critical zones of the tendon with a lower degree of vascularization; this would induce collagen and extracellular matrix degradation, that could then trigger a compensatory neovascularization response. We performed a clinical observational study of 80 elite volleyball players, monitoring the perfusion values of the supraspinatus tendons by oximetry. Results No statistically significant differences were found between the oximetry data and age, sex or years of sports activity, nor when comparing the right and left arm or the dominant and non-dominant arm. A statistically significant difference was found for the dominant arm values in relation to the competitive role, higher values being obtained in outside hitters (62.7% than middle hitters (53.7% (p = 0.01, opposite hitters (55.5% (p = 0.02 and libero players (54.4% (p = 0.008, whereas there were no differences in setters (56.2% (p > 0.05. Conclusions The different tendon vascularization values found in players with different roles in the team may be attributed to a response to the specific biomechanical demands posed by the different overhead throwing roles.

  9. Overload and neovascularization of shoulder tendons in volleyball players

    Science.gov (United States)

    2012-01-01

    Background In overhead sports like volleyball, the onset of a rotator cuff tendinopathy due to functional overload is a common observation. An angiofibroblastic etiopathogenesis has been hypothesized, whereby a greater anaerobic metabolism occurs in critical zones of the tendon with a lower degree of vascularization; this would induce collagen and extracellular matrix degradation, that could then trigger a compensatory neovascularization response. We performed a clinical observational study of 80 elite volleyball players, monitoring the perfusion values of the supraspinatus tendons by oximetry. Results No statistically significant differences were found between the oximetry data and age, sex or years of sports activity, nor when comparing the right and left arm or the dominant and non-dominant arm. A statistically significant difference was found for the dominant arm values in relation to the competitive role, higher values being obtained in outside hitters (62.7%) than middle hitters (53.7%) (p = 0.01), opposite hitters (55.5%) (p = 0.02) and libero players (54.4%) (p = 0.008), whereas there were no differences in setters (56.2%) (p > 0.05). Conclusions The different tendon vascularization values found in players with different roles in the team may be attributed to a response to the specific biomechanical demands posed by the different overhead throwing roles. PMID:22853746

  10. Angiogenin expression in burn blister fluid: implications for its role in burn wound neovascularization.

    Science.gov (United States)

    Pan, Shin-Chen; Wu, Li-Wha; Chen, Chung-Lin; Shieh, Shyh-Jou; Chiu, Haw-Yen

    2012-01-01

    Deep partial thickness burn (DPTB) wound fluids have a greater propensity for establishing neovascularization than did superficial partial thickness burn (SPTB) wound fluids in our previous study. To investigate the factors responsible for this activity, cytokine array and enzyme-linked immunosorbent assay were used to perform an expression analysis of angiogenic factors in burn fluid. Although present in approximately equal amounts in both SPTB and DPTB blister fluids from burn patients, angiogenin does appear to be involved in the ability of DPTB blister fluid to promote neovascularization in vitro and in vivo. Angiogenin alone was sufficient to induce endothelial differentiation of circulating angiogenic cells (CAC) without vascular endothelial growth factor A involvement. In addition, angiogenin was positively associated with CAC differentiation in the burn blister fluid. Blocking the effect of angiogenin in burn blister fluids resulted in a significant reduction of endothelial cell proliferation, CAC differentiation, and new blood vessels formation in vivo. Moreover, immunohistochemistry revealed that high angiogenin expression colocalizes with high vascularity in human burn wounds at day 7, further supporting our hypothesis that angiogenin is involved in burn wound neovascularization. © 2012 by the Wound Healing Society.

  11. Swept Source OCT Angiography of Neovascular Macular Telangiectasia Type 2

    Science.gov (United States)

    Zhang, Qinqin; Wang, Ruikang K.; Chen, Chieh-Li; Legarreta, Andrew D.; Durbin, Mary K.; An, Lin; Sharma, Utkarsh; Stetson, Paul F.; Legarreta, John E.; Roisman, Luiz; Gregori, Giovanni; Rosenfeld, Philip J.

    2015-01-01

    Objective To image subretinal neovascularization in proliferative macular telangiectasia type 2 (MacTel2) using swept source optical coherence tomography based microangiography (OMAG). Study Design Patients with MacTel2 were enrolled in a prospective, observational study known as the MacTel Project and evaluated using a high-speed 1050nm swept-source OCT (SS-OCT) prototype system. The OMAG algorithm generated en face flow images from three retinal layers, as well as the region bounded by the outer retina and Bruch’s membrane, the choriocapillaris, and the remaining choroidal vasculature. The en face OMAG images were compared to images from fluorescein angiography (FA) and indocyanine green angiography (ICGA). Results Three eyes with neovascular MacTel2 were imaged. The neovascularization was best identified from the en face OMAG images that included a layer between the outer retinal boundary and Bruch’s membrane. OMAG images identified these abnormal vessels better than FA and were comparable to the images obtained using ICGA. In all three cases, OMAG identified choroidal vessels communicating with the neovascularization, and these choroidal vessels were evident in the two cases with ICGA imaging. In one case, monthly injections of bevacizumab reduced the microvascular complexity of the neovascularization, as well as the telangiectatic changes within the retinal microvasculature. In another case, less frequent bevacizumab therapy was associated with growth of the subretinal neovascular complex. Conclusions OMAG imaging provided detailed, depth-resolved information about subretinal neovascularization in MacTel2 eyes demonstrating superiority to FA imaging and similarities to ICGA imaging for documenting the retinal microvascular changes, the size and extent of the neovascular complex, the communications between the neovascular complex and the choroidal circulation, and the response to monthly bevacizumab therapy. PMID:26457402

  12. [Micro-trephination of the limbus in neovascular glaucoma].

    Science.gov (United States)

    Sergienko, N M; Torchinskaia, N V

    2001-01-01

    Microtrephination of the limb was carried out for neovascular glaucoma on 112 eyes. The technique of the operation is described and its results are analyzed. Electric microtrephine (0.6 mm) allows making perforations in the limb as oblique microchannels connecting the anterior chamber and the subconjunctival space. Mitomycin C, an antimetabolic drug, was used for neovascularization control near the channels and filtration pad. High efficiency, low invasiveness, and low incidence of postoperative complications recommend this operation as an alternative method for the treatment of neovascular glaucoma.

  13. The effect of a single nucleotide polymorphism in the matrix metalloproteinase-1 (MMP-1) promoter on force-induced MMP-1 expression in human periodontal ligament cells

    NARCIS (Netherlands)

    Huang, Sheng-Fu; Li, Yu-Hong; Ren, Yi-Jin; Cao, Zheng-Guo; Long, Xing

    2008-01-01

    Matrix metalloproteinase-1 (MMP-1) 1G/2G (-1,607) polymorphisms have been identified and shown to influence the transcription of the MMP-1 gene. In order to compare the expression of MMP-1 with different MMP-1 gene promoter alleles after force loading, human periodontal ligament (PDL) cells were cul

  14. Association of single nucleotide polymorphisms in promoter of matrix metalloproteinase-2, 8 genes with bladder cancer risk in Northern India.

    Science.gov (United States)

    Srivastava, Priyanka; Kapoor, Rakesh; Mittal, Rama D

    2013-02-01

    Matrix metalloproteinases (MMPs) are expressed in melanocytes and their overexpression has been linked to tumor development, progression, and metastasis. At the genetic level, following functional promoter polymorphisms are known to modify the gene transcription: -1306 C > T, -735 C > T in MMP2, and 799 C > T in MMP8 gene. Hence we hypothesize that functional polymorphisms in the 2 MMP SNPs in promoter region may modulate the risk for bladder cancer (BC) progression in North Indian population. Genotyping for these polymorphisms were done in a group of 200 BC and 200 age matched, similar ethnicity unrelated healthy controls using PCR-based methods. Two-sided χ(2), Cox-regression was utilized to evaluate the associations between genotype and various clinical and epidemiologic factors. Multivariate analyses were conducted using logistic regression, adjusting for known BC confounders such as age and gender. Survival analysis was done using the Kaplan-Meier method and differences in survival were assessed using the log rank test. Individuals with MMP2 (-1306) TT genotype as well as T allele were at higher risk of BC (P, 0.042; OR, 2.85; P, 0.001; OR, 1.76). This effect was even more apparent in case of CT+TT (P T were associated with high risk of recurrence in BCG treated patients (HR, 4.32; P, 0.006 and HR, 2.06; P, 0.047) thus showing reduced recurrence free survival (CT+TT/CC = 34/45 months; log rank P, 0.039). Our data suggested that variant allele of MMP2 1306C > T was associated with high risk of tumor recurrence and reduced recurrence free survival in superficial BC patients. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Promotion of astrocytoma cell invasion by micro RNA-22 targeting of tissue inhibitor of matrix metalloproteinase-2.

    Science.gov (United States)

    Ohnishi, Yu-Ichiro; Iwatsuki, Koichi; Ishihara, Masahiro; Ohkawa, Toshika; Kinoshita, Manabu; Shinzawa, Koei; Fujimoto, Yasunori; Yoshimine, Toshiki

    2017-03-01

    OBJECTIVE Diffuse astrocytomas (DAs) have a high recurrence rate due to diffuse infiltration into the brain and spinal cord. Micro RNAs (miRNAs) are small noncoding RNAs that regulate gene expression by binding to complementary sequences of target messenger RNA (mRNA). It has been reported that miRNA-22 (miR-22) is involved in the invasion of some cancer cell lines. The aim of this study was to identify the biological effects of miR-22 in regard to the invasion of human DAs. METHODS The authors evaluated whether the level of miR-22 is elevated in human spinal DAs by using miRNA chips. Next, the role of miR-22 in 1321N1 human astrocytoma cells was investigated. Finally, to elucidate whether miR-22 promotes invasion by astrocytoma cells in vivo, the authors transplanted miR-22 overexpressed astrocytoma cells into mouse thoracic spinal cord. RESULTS The miR-22 significantly upregulated the invasion capacity of 1321N1 cells. Computational in silico analysis predicted that tissue inhibitor of matrix metalloproteinase-2 (TIMP2) is a target gene of miR-22. This was confirmed by quantitative reverse transcription polymerase chain reaction and Western blotting, which showed that miR-22 inhibited TIMP2 mRNA and protein expression, respectively. Luciferase reporter assays demonstrated that miR-22 directly bound the 3'-untranslated regions of TIMP2. The authors further showed that miR-22 promoted invasiveness in 1321N1 astrocytoma cells when transplanted into mouse spinal cord. CONCLUSIONS These data suggest that miR-22 acts to regulate invasion of 1321N1 astrocytoma cells by targeting TIMP2 expression. Additional studies with more cases and cell lines are required to elucidate the findings of this study for a novel treatment target for spinal DAs.

  16. Corneal neovascularization and contemporary antiangiogenic therapeutics.

    Science.gov (United States)

    Hsu, Chih-Chien; Chang, Hua-Ming; Lin, Tai-Chi; Hung, Kuo-Hsuan; Chien, Ke-Hung; Chen, Szu-Yu; Chen, San-Ni; Chen, Yan-Ting

    2015-06-01

    Corneal neovascularization (NV), the excessive ingrowth of blood vessels from conjunctiva into the cornea, is a common sequela of disease insult that can lead to visual impairment. Clinically, topical steroid, argon laser photocoagulation, and subconjunctival injection of bevacizumab have been used to treat corneal NV. Sometimes, the therapies are ineffective, especially when the vessels are large. Large vessels are difficult to occlude and easily recanalized. Scientists and physicians are now dedicated to overcoming this problem. In this article, we briefly introduce the pathogenesis of corneal NV, and then highlight the existing animal models used in corneal NV research-the alkali-induced model and the suture-induced model. Most of all, we review the potential therapeutic targets (i.e., vascular endothelial growth factor and platelet-derived growth factor) and their corresponding inhibitors, as well as the immunosuppressants that have been discovered in recent years by corneal NV studies.

  17. [Photodynamic therapy in treatment of chorioid neovascularization].

    Science.gov (United States)

    Avetisov, S E; Budzinskaia, M V; Kiseleva, T N; Kazarian, E E; Gurova, I V; Loshchenov, V B; Shevchik, S A; Kuz'min, S G; Vorozhtsov, G N

    2007-01-01

    The authors studied the effectiveness of photodynamic therapy (PDT) with Photosence, a Russian photosensitizer, in treatment of chorioid neovascularization (CNV) in cases of age-related macular degeneration (ARMD) and pathological myopia (PM). The subjects were 73 patients with CNV suffering from ARMD and PM. The efficiency of PDT and complex conservative therapy was compared using vision acuity measurement, retinal morphometry, and fluorescent eye ground angiography (FEGA), performed before treatment, immediately after treatment, and 1, 3, 6, and 12 months later. The study showed that PDT in patients with CNV, ARMD and PM was more efficient than pharmacotherapy. Vision acuity improved or stabilized, and the parameters of retinal morphometry and FEGA improved as well. The results of the study evidence high efficiency of PDT with Photosence in treatment of CNV with ARMD and PM.

  18. Targeting Neovascularization in Ischemic Retinopathy: Recent Advances

    Science.gov (United States)

    Al-Shabrawey, Mohamed; Elsherbiny, Mohamed; Nussbaum, Julian; Othman, Amira; Megyerdi, Sylvia; Tawfik, Amany

    2014-01-01

    Pathological retinal neovascularization (RNV) is a common micro-vascular complication in several retinal diseases including retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration and central vein occlusion. The current therapeutic modalities of RNV are invasive and although they may slow or halt the progression of the disease they are unlikely to restore normal acuity. Therefore, there is an urgent need to develop treatment modalities, which are less invasive and therefore associated with fewer procedural complications and systemic side effects. This review article summarizes our understanding of the pathophysiology and current treatment of RNV in ischemic retinopathies; lists potential therapeutic targets; and provides a framework for the development of future treatment modalities. PMID:25598837

  19. Beals–Hecht syndrome and choroidal neovascularization

    Directory of Open Access Journals (Sweden)

    Roberto Gallego-Pinazo

    2010-07-01

    Full Text Available Roberto Gallego-Pinazo1, Ruth López-Lizcano1, José María Millán2,3, J Fernando Arevalo5, J Luis Mullor6, Manuel Díaz-Llopis1,3,41Department of Ophthalmology, 2Department of Genetics, Unit of Experimental Opthalmology, Hospital Universitario La Fe, Valencia, Spain; 3Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Valencia, Spain; 4Faculty of Medicine, University of Valencia, Valencia, Spain; 5Retina and Vitreous Service, Clínica Oftalmológica Centro Caracas, Caracas, Venezuela; 6Unit of Experimental Opthalmology, Fundación Parala Investigación del Hospital La Fe, Valencia, SpainPurpose: To describe a case of choroidal neovascularization (CNV in a female diagnosed with Beals–Hecht syndrome.Methods: A retrospective, interventional case is described in a 26-year-old female complaining of metamorphopsia and visual loss in her left eye (counting fingers. The fluorescein angiogram and the optical coherence tomography supported the diagnosis of CNV. Intravitreal ranibizumab was administered.Results: After the third intravitreal ranibizumab, her visual acuity improved to 0.8 and the morphology of the macular area was restored.Conclusions: To our knowledge this is the first report of CNV in Beals–Hecht syndrome treated with ranibizumab. Self-monitoring by periodically performing Amsler grid test is strongly recommended in these patients in order to achieve an early diagnosis of eventual CNV and avoid visual acuity loss.Keywords: Beals–Hecht syndrome, connective tissue disease, choroidal neovascularization, ranibizumab

  20. The Promoting Effect of the Extracellular Matrix Peptide TNIIIA2 Derived from Tenascin-C in Colon Cancer Cell Infiltration

    Science.gov (United States)

    Suzuki, Hideo; Sasada, Manabu; Kamiya, Sadahiro; Ito, Yuka; Watanabe, Hikaru; Okada, Yuko; Ishibashi, Kazuma; Iyoda, Takuya; Yanaka, Akinori; Fukai, Fumio

    2017-01-01

    The extracellular matrix (ECM) molecule tenascin C (TNC) is known to be highly expressed under various pathological conditions such as inflammation and cancer. It has been reported that the expression of TNC is correlated with the malignant potential of cancer. In our laboratory, it was found that the peptide derived from the alternative splicing domain A2 in TNC, termed TNIIIA2, has been shown to influence a variety of cellular processes, such as survival, proliferation, migration, and differentiation. In this study, we investigated the effect of TNC/TNIIIA2 on the invasion and metastasis of colon cancer cells, Colon26-M3.1, or PMF-Ko14, using an in vitro and in vivo experimental system. The degree of cell invasion was increased by the addition of TNC and TNIIIA2 in a dose-dependent manner. The invasion by TNC and TNIIIA2 were suppressed by an MMP inhibitor or TNIIIA2-blocking antibody. In an in vivo experiment, pulmonary metastasis was promoted conspicuously by the addition of TNIIIA2. In this study, we found that colon cancer cell invasion and metastasis was accelerated by TNC/TNIIIA2 via MMP induction. This result suggests the possibility of a new strategy targeting TNC/TNIIIA2 for colon cancer. PMID:28106752

  1. Hairy/enhancer-of-split related with YRPW motif protein 1 promotes osteosarcoma metastasis via matrix metallopeptidase 9 expression.

    Science.gov (United States)

    Tsuru, A; Setoguchi, T; Matsunoshita, Y; Nagao-Kitamoto, H; Nagano, S; Yokouchi, M; Maeda, S; Ishidou, Y; Yamamoto, T; Komiya, S

    2015-03-31

    Activation of the Notch pathway has been reported in various types of cancers. However, the role of the hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) in osteosarcoma is unknown. We examined the function of HEY1 in osteosarcoma. Expression of HEY1 was studied in human osteosarcoma. The effects of HEY1 in osteosarcoma were evaluated in vitro and in a xenograft model. Moreover, we examined the function of matrix metallopeptidase 9 (MMP9) as a downstream effector of HEY1. HEY1 was upregulated in human osteosarcoma. Knockdown of HEY1 inhibited the invasion of osteosarcoma cell lines. In contrast, the forced expression of HEY1 increased the invasion of mesenchymal stem cell. In addition, lung metastases were significantly inhibited by the knockdown of HEY1. We found that MMP9 was a downstream effector of HEY1 that promotes the invasion of osteosarcoma cells. Knockdown of HEY1 decreased the expression of MMP9. Addition of MMP9 rescued the invasion of osteosarcoma cells that had been rendered less invasive by knockdown of HEY1 expression. Our findings suggested that HEY1 augmented the metastasis of osteosarcoma via upregulation of MMP9 expression. Therefore, inhibition of HEY1 may be a novel therapeutic strategy for preventing osteosarcoma metastasis.

  2. Effect of matrix metalloproteinase promoter polymorphisms on endometriosis and adenomyosis risk: evidence from a meta-analysis

    Indian Academy of Sciences (India)

    HUI YE; YAZHOU HE; JIARONG WANG; TIANGE SONG; ZHU LAN; YIQI ZHAO; MINGRONG XI

    2016-09-01

    Matrix metalloproteinase (MMP) promoter polymorphisms are considered to play roles in the aetiology of endometriosis and adenomyosis, however, the evidence available are inconsistent. We aimed to systematically review the asscociationbetween MMP-1 -1607 1G/2G MMP-2 -735 C/T, MMP-3 -1171 5A/6A and MMP-9 -1562 C/T polymorphisms and the risk of endometriosis and adenomyosis. A systemic search was conducted in Ovid, PubMed, Chinese National Knowledge Infrastructure and Chinese Wanfang Database. We used the pooled odds ratio (OR) and their corresponding 95% confidence interval (CI) to calculate the statistical power. Besides, we evaluated the quality of individual studies based on Newcastle–Ottawa scale. A total of 13 papers with 18 studies conformed to our inclusion criteria. We observed a significant association betweenMMP-1 -1607 1G/2G polymorphism and the susceptibility of endometriosis and adenomyosis under recessive model (OR =1.25, 95%CI = 1.03–1.53,P=0.03). While no significant association was found in MMP-2 -735 C/T, MMP-3 -1171 5A/6A and MMP-9 -1562 C/T polymorphisms. This systemic review and meta-analysis suggested that the MMP-1 -1607 1G/2G polymorphism might play an important role in the risk of endometriosis and adenomyosis. Further, more well-designed and large-scale studies regarding gene–gene and gene–environment interactions are needed in the future.

  3. Keratoconus associated with choroidal neovascularization: a case report

    Directory of Open Access Journals (Sweden)

    Oh Joo

    2010-02-01

    Full Text Available Abstract Introduction Keratoconus and choroidal neovascularization can occur as a result of dysfunction of the epithelium and its basement membrane. Case presentation A 17-year-old Asian man, who was diagnosed with myopic choroidal neovascularization in both eyes and who subsequently underwent intravitreal injection of ranibizumab (Lucentis® five times over six months, presented with further vision decrease and pain in his right eye. Examination showed corneal steepening and stromal edema in the inferocentral cornea of his right eye, both of which were indicative of advanced keratoconus with acute hydrops. Corneal topography also showed features consistent with keratoconus in his left eye. Fluorescein angiography and optical coherence tomography revealed choroidal neovascularization-associated subretinal hemorrhages and lacquer cracks in both eyes. Conclusion Keratoconus and choroidal neovascularization, possibly resulting from dysfunction of the epithelium and its basement membrane, can occur together in the same individual. This would suggest a possible connection in pathogenesis between these two conditions.

  4. Inhibition of Corneal Neovascularization by Topical and Subconjunctival Tigecycline

    Directory of Open Access Journals (Sweden)

    Sertan Goktas

    2014-01-01

    Full Text Available Objective. To investigate the effects of topical and subconjunctival tigecycline on the prevention of corneal neovascularization. Materials and Methods. Following chemical burn, thirty-two rats were treated daily with topical instillation of 1 mg/mL tigecycline (group 1 or subconjunctival instillation of 1 mg/mL tigecycline (group 3 for 7 days. Control rats received topical (group 2 or subconjunctival (group 4 0.9% saline. Digital photographs of the cornea were taken on the eighth day after treatment and analyzed to determine the percentage area of the cornea covered by neovascularization. Corneal sections were analyzed histopathologically. Results. The median percentages of corneal neovascularization in groups 1 and 3 were 48% (95% confidence interval (CI, 44.2–55.8% and 33.5% (95% CI, 26.6–39.2%, respectively. The median percentages of corneal neovascularization of groups 1 and 3 were significantly lower than that of the control group (P=0.03 and P<0.001, resp.. Histologic examination of samples from groups 1 and 3 showed lower vascularity than that of control groups. Conclusion. Topical and subconjunctival administration of tigecycline seems to be showing promising therapeutic effects on the prevention of corneal neovascularization. Furthermore, subconjunctival administration of tigecycline is more potent than topical administration in the inhibition of corneal neovascularization.

  5. Toll样受体4对氧诱导视网膜新生血管发生的促进作用及其机制%Promoting effect of Toll like receptor 4 on oxygen-induced retinal neovascularization and its mechanism

    Institute of Scientific and Technical Information of China (English)

    徐文芹; 尹婕; 王雨生

    2016-01-01

    +LPS-EB group than that in the OIR group ([95.50±4.77]/5 mm versus [74.83± 4.17]/5 mm;t=8.00,P<0.01).TLR4+ microglia cells were few in the normoxic group,and the cells number were evidently higher in the OIR+LPS-EB group than that in the OIR group ([49.50±6.38]/5 mm versus [28.17 ± 6.24]/5 mm,t =5.86,P<0.01).The number of microglia cells coexpressing CD1 1b with VEGF/IL-1β/TNF-α were (1.17±0.75) /5 mm,0 and 0 in P17 mice of the normoxic group,respectively,and the cells number in the OIR+LPS-EB group was more than that in the OIR group ([44.50±8.78]/5 mm versus [28.50±5.61]/5 mm,F=44.01,P<0.01;[24.10 ± 6.49]/5 mm versus [16.00±3.46]/5 mm,F =11.31,P<0.01;[33.83 ± 14.82]/5 mm versus [23.00 ± 2.83]/5 mm,t=19.92,P<0.01).Conclusions TLR4 promotes retinal neovascularization probably by activating specific signaling pathways downstream of microglia cells and accelerating the release of vascular growth factors and inflammatory factors.%背景 研究发现,Toll样受体(TLRs)在视网膜新生血管的形成中发挥重要作用,但其作用机制尚不清楚. 目的 探讨TLR4对小鼠氧诱导视网膜病变(OIR)中新生血管生成的作用及其机制. 方法 将18只7日龄新生C57BL/6J小鼠以随机数字表法按小鼠窝别分为常氧组、OIR组及OIR+脂多糖(LPS)-EB组,常氧组小鼠在正常氧环境中饲养,OIR组及OIR+LPS-EB组小鼠于生后第7天(P7)与母鼠置于体积分数(75±2)%高氧氧箱中饲养5d以诱导OIR模型,于P12在正常氧环境中饲养,OIR+LPS-EB组P12小鼠腹腔内注射LPS-EB,剂量为1 mg/kg,OIR组同法注射PBS.各组摘取P17小鼠眼球于质量分数4%多聚甲醛中固定并行视网膜铺片和Lectin染色,计算视网膜无血管区和新生血管区面积占全视网膜的百分比.各组制备P17小鼠眼后节组织冰冻切片并行免疫荧光检测,计数小鼠5 mm视网膜全长活化小胶质细胞数目;采用CD11b和TLR4免疫荧光双标记法检测各组小鼠视网膜小胶质细胞中CD11

  6. Functional Haplotypes in the Promoter of Matrix Metalloproteinase-2 Predict Risk of the Occurrence and Metastasis of Esophageal Cancer

    Institute of Scientific and Technical Information of China (English)

    ChunyuanYu; YifengZhou; XiaopingMiao; PingXiong; WenTan; DongxinLin

    2005-01-01

    Matrix metalloproteinase-2 (MMP-2) plays important roles in cancer development and aggression. Our previous studies revealed a strong association between the MMP-2 -1306C/T polymorphism and risk of several cancers. A novel -735C/T polymorphism in MMP-2 promoter has been identified but the function is undefined. This study examined our hypothesis that these two polymorphisms might have functional relevance and impact on risk of esophageal squamous cell carcinoma in the context of haplotype. Genotypes and haplotypes were analyzed in 527 cases and 777 controls and odds ratios (ORs) and 95% confidence intervals (CIs)were estimated by logistic regression. The function of the polymorphisms was examined by electrophoretic mobility shift assays, luciferase gene expression assays, and reverse transcriptase-PCR analyses. It was found that the -735C→T transition disrupts an Spl site and displays a lowerpromoter activity. The C_1306-C-735 haplotype had 7-fold increased luciferase expression and 3.7-fold increased MMPo2 mRNA levels in esopha-gcal tissues compared with the T-1306-T-735 haplotype. A case-control analysis revealed a 1.52-fold (95% CI=1.17-1.96) or 1.30-fold (95%CI = 1.04-1.63) excess risk of developing esophageal squamous cell carcinoma for the -1306CC or -735CC genotype carriers compared with noncarriers, respectively. A greater association was observed between elevated risk of developing esophageal squamous cell carcinoma andC-1306 or C-735 allele containing haplotypes, with the risk being highest for the C-1306-C-735 haplotype compared with the T-1306-T-735 haplotype(OR = 6.53; 95% CI = 2.78-15.33). The C-1306-C-735 haplotype was also associated with increased risk for distant metastasis of esophageal squamous cell carcinoma (OR = 3.34; 95% CI = 1.16-9.63). These findings suggest that the C-1306-C-735 haplotype in the MMpo2 promoter contributes to risk of the occurrence and metastasis of esophageal squamous cell carcinoma by increasing expression of MMP-2.

  7. Demineralized Bone Matrix Scaffolds Modified by CBD-SDF-1α Promote Bone Regeneration via Recruiting Endogenous Stem Cells.

    Science.gov (United States)

    Shi, Jiajia; Sun, Jie; Zhang, Wen; Liang, Hui; Shi, Qin; Li, Xiaoran; Chen, Yanyan; Zhuang, Yan; Dai, Jianwu

    2016-10-07

    The reconstruction of bone usually depends on substitute transplantation, which has drawbacks including the limited bone substitutes available, comorbidity, immune rejection, and limited endogenous bone regeneration. Here, we constructed a functionalized bone substitute by combining application of the demineralized bone matrix (DBM) and collagen-binding stromal-cell-derived factor-1α (CBD-SDF-1α). DBM was a poriferous and biodegradable bone substitute, derived from bovine bone and consisting mainly of collagen. CBD-SDF-1α could bind to collagen and be controllably released from the DBM to mobilize stem cells. In a rat femur defect model, CBD-SDF-1α-modified DBM scaffolds could efficiently mobilize CD34(+) and c-kit(+) endogenous stem cells homing to the injured site at 3 days after implantation. According to the data from micro-CT, CBD-SDF-1α-modified DBM scaffolds could help the bone defects rejoin with mineralization accumulated and bone volume expanded. Interestingly, osteoprotegerin (OPG) and osteopontin (OPN) were highly expressed in CBD-SDF-1α group at an early time after implantation, while osteocalcin (OCN) was more expanded. H&E and Masson's trichrome staining showed that the CBD-SDF-1α-modified DBM scaffold group had more osteoblasts and that the bone defect rejoined earlier. The ultimate strength of the regenerated bone was investigated by three-point bending, showing that the CBD-SDF-1α group had superior strength. In conclusion, CBD-SDF-1α-modified DBM scaffolds could promote bone regeneration by recruiting endogenous stem cells.

  8. Regulation of Matrix Metalloproteinase-2 Activity by COX-2-PGE2-pAKT Axis Promotes Angiogenesis in Endometriosis

    Science.gov (United States)

    Ray, Amlan K.; DasMahapatra, Pramathes; Swarnakar, Snehasikta

    2016-01-01

    Endometriosis is characterized by the ectopic development of the endometrium which relies on angiogenesis. Although studies have identified the involvement of different matrix metalloproteinases (MMPs) in endometriosis, no study has yet investigated the role of MMP-2 in endometriosis-associated angiogenesis. The present study aims to understand the regulation of MMP-2 activity in endothelial cells and on angiogenesis during progression of ovarian endometriosis. Histological and biochemical data showed increased expressions of vascular endothelial growth factor (VEGF), VEGF receptor-2, cycloxygenase (COX)-2, von Willebrand factor along with angiogenesis during endometriosis progression. Women with endometriosis showed decreased MMP-2 activity in eutopic endometrium as compared to women without endometriosis. However, ectopic ovarian endometrioma showed significantly elevated MMP-2 activity with disease severity. In addition, increased MT1MMP and decreased tissue inhibitors of metalloproteinases (TIMP)-2 expressions were found in the late stages of endometriosis indicating more MMP-2 activation with disease progression. In vitro study using human endothelial cells showed that prostaglandin E2 (PGE2) significantly increased MMP-2 activity as well as tube formation. Inhibition of COX-2 and/or phosphorylated AKT suppressed MMP-2 activity and endothelial tube formation suggesting involvement of PGE2 in regulation of MMP-2 activity during angiogenesis. Moreover, specific inhibition of MMP-2 by chemical inhibitor significantly reduced cellular migration, invasion and tube formation. In ovo assay showed decreased angiogenic branching upon MMP-2 inhibition. Furthermore, a significant reduction of lesion numbers was observed upon inhibition of MMP-2 and COX-2 in mouse model of endometriosis. In conclusion, our study establishes the involvement of MMP-2 activity via COX-2-PGE2-pAKT axis in promoting angiogenesis during endometriosis progression. PMID:27695098

  9. Complex role of matrix metalloproteinases in angiogenesis

    Institute of Scientific and Technical Information of China (English)

    SANGQINGXIANGAMY

    1998-01-01

    Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a significant role in regulating angiogenesis,the process of new blood vessel formation.Interstitial collagenase (MMP-1),72kDa gelatinase A/type IV collagenase (MMP-2),and 92 kDA gelatinase B/type IV collagenase (MMP-9) dissolve extracellular matrix (ECM) and may initiate and promote angiogenesis.TIMP-1,TIMP-2,TIMP-3,and possibly,TIMP-4 inhibit neovascularization.A new paradign is emerging that matrilysin (MMP-7),MMP-9,and metalloelastase (MMP-12) may block angiogenesis by converting plasminogen to angiostatin,which is one of the most potent angiogenesis antagonists.MMPs and TIMPs play a complex role in regulating angiogenesis.An understanding of the biochemical and cellular pathways and mechanisms of angiogenesis will provide important information to allow the control of angiogenesis,e.g.the stimulation of angiogenesis for coronary collateral circulation formation;while the inhibition for treating arthritis and cancer.

  10. Neovascular events in eyes with central retinal vein occlusion undergoing serial bevacizumab or ranibizumab intravitreal injections: A retrospective review

    Directory of Open Access Journals (Sweden)

    Francis Char DeCroos

    2014-01-01

    Conclusion: Neovascular events occur in eyes with CRVO undergoing serial anti-VEGF therapy, and these events may be delayed compared to the natural history of CRVO-associated neovascularization. Iris neovascularization occurred most frequently.

  11. Characterization of a spontaneous retinal neovascular mouse model.

    Directory of Open Access Journals (Sweden)

    Eiichi Hasegawa

    Full Text Available BACKGROUND: Vision loss due to vascular disease of the retina is a leading cause of blindness in the world. Retinal angiomatous proliferation (RAP is a subgroup of neovascular age-related macular degeneration (AMD, whereby abnormal blood vessels develop in the retina leading to debilitating vision loss and eventual blindness. The novel mouse strain, neoretinal vascularization 2 (NRV2, shows spontaneous fundus changes associated with abnormal neovascularization. The purpose of this study is to characterize the induction of pathologic angiogenesis in this mouse model. METHODS: The NRV2 mice were examined from postnatal day 12 (p12 to 3 months. The phenotypic changes within the retina were evaluated by fundus photography, fluorescein angiography, optical coherence tomography, and immunohistochemical and electron microscopic analysis. The pathological neovascularization was imaged by confocal microscopy and reconstructed using three-dimensional image analysis software. RESULTS: We found that NRV2 mice develop multifocal retinal depigmentation in the posterior fundus. Depigmented lesions developed vascular leakage observed by fluorescein angiography. The spontaneous angiogenesis arose from the retinal vascular plexus at postnatal day (p15 and extended toward retinal pigment epithelium (RPE. By three months of age, histological analysis revealed encapsulation of the neovascular lesion by the RPE in the photoreceptor cell layer and subretinal space. CONCLUSIONS: The NRV2 mouse strain develops early neovascular lesions within the retina, which grow downward towards the RPE beginning at p15. This retinal neovascularization model mimics early stages of human retinal angiomatous proliferation (RAP and will likely be a useful in elucidating targeted therapeutics for patients with ocular neovascular disease.

  12. Intravitreal Bevacizumab (Avastin Injection for Neovascular Glaucoma

    Directory of Open Access Journals (Sweden)

    Shahin Yazdani

    2008-12-01

    Full Text Available

    PURPOSE: To report two cases with neovascular glaucoma secondary to ischemic central retinal vein occlusion (CRVO who were treated with intravitreal bevacizumab. CASE REPORT: Two patients were referred for neovascular glaucoma following CRVO. Visual acuity was light perception. Both eyes had extensive iris neovascularization (NVI, synechial angle closure and high intraocular pressure (IOP in spite of anti-glaucoma medications. After obtaining informed consent, both eye received an intravitreal injection of 2.5 mg (0.1 ml bevacizumab (Avastin. Both eyes demonstrated dramatic IOP reduction together with decreased severity and extent of NVI during 4 weeks of follow up. Visual acuity remained unchanged. CONCLUSION: Despite the dramatic short-term response in terms of IOP reduction and regression of neovascularization, due to limited clinical experience, one should consider this novel indication for bevacizumab cautiously.

  1. Obstructor A Organizes Matrix Assembly at the Apical Cell Surface to Promote Enzymatic Cuticle Maturation in Drosophila*

    Science.gov (United States)

    Pesch, Yanina-Yasmin; Riedel, Dietmar; Behr, Matthias

    2015-01-01

    Assembly and maturation of the apical extracellular matrix (aECM) is crucial for protecting organisms, but underlying molecular mechanisms remain poorly understood. Epidermal cells secrete proteins and enzymes that assemble at the apical cell surface to provide epithelial integrity and stability during developmental growth and upon tissue damage. We analyzed molecular mechanisms of aECM assembly and identified the conserved chitin-binding protein Obst-A (Obstructor A) as an essential regulator. We show in Drosophila that Obst-A is required to coordinate protein and chitin matrix packaging at the apical cell surface during development. Secreted by epidermal cells, the Obst-A protein is specifically enriched in the apical assembly zone where matrix components are packaged into their highly ordered architecture. In obst-A null mutant larvae, the assembly zone is strongly diminished, resulting in severe disturbance of matrix scaffold organization and impaired aECM integrity. Furthermore, enzymes that support aECM stability are mislocalized. As a biological consequence, cuticle architecture, integrity, and function are disturbed in obst-A mutants, finally resulting in immediate lethality upon wounding. Our studies identify a new core organizing center, the assembly zone that controls aECM assembly at the apical cell surface. We propose a genetically conserved molecular mechanism by which Obst-A forms a matrix scaffold to coordinate trafficking and localization of proteins and enzymes in the newly deposited aECM. This mechanism is essential for maturation and stabilization of the aECM in a growing and remodeling epithelial tissue as an outermost barrier. PMID:25737451

  2. Progress of anti-vascular endothelial growth factor therapy for ocular neovascular disease: benefits and challenges

    Institute of Scientific and Technical Information of China (English)

    Xu Jianjiang; Li Yimin; Hong Jiaxu

    2014-01-01

    Objective This review aims to summarize the progress of current clinical studies in ocular angiogenesis treated with antivascular endothelial growth factor (VEGF) therapy and to discuss the benefits and challenges of the treatment.Data sources Pubmed,Embase and the Cochrane Library were searched with no limitations of language and year of publication.Study selection Clinical trials and case studies presented at medical conferences and published in peer-reviewed literature in the past decade were reviewed.Results Anti-VEGF agents have manifested great potential and promising outcomes in treating ocular neovascularization,though some of them are still used as off-label drugs.Intravitreal injection of anti-VEGF agents could be accompanied by devastating ocular or systemic complications,and intimate monitoring in both adult and pediatric population are warranted.Future directions should be focused on carrying out more well-designed large-scale controlled trials,promoting sustained duration of action,developing safer and more efficient generation of anti-VEGF agents.Conclusions Anti-VEGF treatment has proved to be beneficial in treating both anterior and posterior neovascular ocular diseases.However,more safer and affordable antiangiogenic agencies and regimens are warranted to be explored.

  3. Possibility of enhanced risk of retinal neovascularization in repeated blood donors: blood donation and retinal alteration

    Directory of Open Access Journals (Sweden)

    Rastmanesh R

    2011-09-01

    Full Text Available Reza RastmaneshDepartment of Clinical Nutrition and Dietetics, Shahid Beheshti University of Medical Sciences, National Nutrition and Food Technology Research Institute, Tehran, IranAbstract: Repeated blood donors manifest clinical, subclinical, and biochemical signs of iron deficiency anemia, have significantly higher erythropoietin and vascular endothelial growth factor (VEGF concentrations, and decreased tissue oxygen saturation, oxygenated tissue hemoglobin, and regional cerebral oxygen saturation. Erythropoietin and VEGF are potent retinal angiogenic factors which may initiate and promote the retinal angiogenesis process independently or simultaneously. Increases in circulating levels of erythropoietin and VEGF are proportionate to the levels of hematocrit, hypoxemia, and tissue hypoxia. It is suggested that higher erythropoietin production following iron deficiency anemia-induced chronic hypoxemia/hypoxia may, hypothetically, enhance the risk of retinal angiogenesis and/or neovascularization, possibly by inducing hypoxia inducible factor-1 alpha, which consequently upregulates genes stimulating angiogenesis, resulting in formation of a new vasculature, possibly by modulation of signal transducer and activator of transcription 3 signaling in the retina. Implications of this hypothesis cover erythropoietin doping, chronic hypoxia, and hypoxemic situations, such as angiogenesis-related cardiac and pulmonary diseases.Keywords: repeated blood donation, erythropoietin, retinal neovascularization, vascular endothelial growth factor, hypoxia

  4. Neocellularization and neovascularization of nanosized bioactive glass-coated decellularized trabecular bone scaffolds

    KAUST Repository

    Gerhardt, Lutz Christian

    2012-09-11

    In this study, the in vivo recellularization and neovascularization of nanosized bioactive glass (n-BG)-coated decellu-larized trabecular bone scaffolds were studied in a rat model and quantified using stereological analyses. Based on the highest amount of vascular endothelial growth factor (VEGF) secreted by human fibroblasts grown on n-BG coatings (0-1.245 mg/cm 2), decellularized trabecular bone samples (porosity: 43-81%) were coated with n-BG particles. Grown on n-BG particles at a coating density of 0.263 mg/cm2, human fibroblasts produced 4.3 times more VEGF than on uncoated controls. After 8 weeks of implantation in Sprague-Dawley rats, both uncoated and n-BG-coated samples were well infiltrated with newly formed tissue (47-48%) and blood vessels (3-4%). No significant differences were found in cellularization and vascularization between uncoated bone scaffolds and n-BG-coated scaffolds. This finding indicates that the decellularized bone itself may exhibit growth-promoting properties induced by the highly interconnected pore microarchitecture and/or proteins left behind on decellularized scaffolds. Even if we did not find proangiogenic effects in n-BG-coated bone scaffolds, a bioactive coating is considered to be beneficial to impart osteoinductive and osteoconductive properties to decellularized bone. n-BG-coated bone grafts have thus high clinical potential for the regeneration of complex tissue defects given their ability for recellularization and neovascularization. © 2012 Wiley Periodicals, Inc.

  5. A PEDF-Derived Peptide Inhibits Retinal Neovascularization and Blocks Mobilization of Bone Marrow-Derived Endothelial Progenitor Cells

    Directory of Open Access Journals (Sweden)

    Richard Longeras

    2012-01-01

    Full Text Available Proliferative diabetic retinopathy is characterized by pathological retinal neovascularization, mediated by both angiogenesis (involving mature endothelial cells and vasculogenesis (involving bone marrow-derived circulating endothelial progenitor cells (EPCs. Pigment epithelium-derived factor (PEDF contains an N-terminal 34-amino acid peptide (PEDF-34 that has antiangiogenic properties. Herein, we present a novel finding that PEDF-34 also possesses antivasculogenic activity. In the oxygen-induced retinopathy (OIR model using transgenic mice that have Tie2 promoter-driven GFP expression, we quantified Tie2GFP+ cells in bone marrow and peripheral blood by fluorescence-activated cell sorting (FACS. OIR significantly increased the number of circulating Tie2-GFP+ at P16, correlating with the peak progression of neovascularization. Daily intraperitoneal injections of PEDF-34 into OIR mice decreased the number of Tie2-GFP+ cells in the circulation at P16 by 65% but did not affect the number of Tie2-GFP+ cells in the bone marrow. These studies suggest that PEDF-34 attenuates EPC mobilization from the bone marrow into the blood circulation during retinal neovascularization.

  6. PEDF mediates pathological neovascularization by regulating macrophage recruitment and polarization in the mouse model of oxygen-induced retinopathy

    Science.gov (United States)

    Gao, Sha; Li, Changwei; Zhu, Yanji; Wang, Yanuo; Sui, Ailing; Zhong, Yisheng; Xie, Bing; Shen, Xi

    2017-01-01

    Macrophages have been demonstrated to play a proangiogenic role in retinal pathological vascular growth. Pigment epithelium-derived factor (PEDF) works as a powerful endogenous angiogenesis inhibitor, but its role in macrophage recruitment and polarization is largely unknown. To explore the underlying mechanisms, we first evaluated macrophage polarization in the retinas of the oxygen-induced retinopathy (OIR) mouse model. Compared to that in normal controls, M1- and M2-like macrophages were all abundantly increased in the retinas of OIR mice. In addition, both M1 and M2 subtypes significantly promoted neovascularization in vitro and in vivo. In addition, we found that PEDF inhibited retinal neovascularization by dampening macrophage recruitment and polarization. Furthermore, PEDF inhibited macrophage polarization through adipose triglyceride lipase (ATGL) by regulating the activation of MAPKs and the Notch1 pathway, as we found that the phosphorylation of MAPKs, including p38MAPK, JNK and ERK, as well as the accumulation of Notch1 were essential for hypoxia-induced macrophage polarization, while PEDF significantly dampened M1 subtype-related iNOS and M2 subtype-related Arg-1 expression by inhibiting hypoxia-induced activation of Notch1 and MAPKs through ATGL. These findings reveal a protective role of PEDF against retinal neovascularization by regulating macrophage recruitment and polarization. PMID:28211523

  7. Matrix metalloproteinase inhibition delays wound healing and blocks the latent transforming growth factor-beta1-promoted myofibroblast formation and function

    DEFF Research Database (Denmark)

    Mirastschijski, Ursula; Schnabel, Reinhild; Claes, Juliane

    2010-01-01

    The ability to regulate wound contraction is critical for wound healing as well as for pathological contractures. Matrix metalloproteinases (MMPs) have been demonstrated to be obligatory for normal wound healing. This study examined the effect that the broad-spectrum MMP inhibitor BB-94 has when...... applied topically to full-thickness skin excisional wounds in rats and its ability to inhibit the promotion of myofibroblast formation and function by the latent transforming-growth factor-beta1 (TGF-beta1). BB-94 delayed wound contraction, as well as all other associated aspects of wound healing examined...... and may explain why wound contraction and other associated events of wound healing were only delayed and not completely inhibited. BB-94 was also found to inhibit the ability of latent TGF-beta1 to promote the formation and function of myofibroblasts. These results suggest that BB-94 could delay wound...

  8. Neovascularity as a prognostic marker in renal cell carcinoma.

    Science.gov (United States)

    Bauman, Tyler M; Huang, Wei; Lee, Moon Hee; Abel, E Jason

    2016-11-01

    Endothelial markers platelet and endothelial cell adhesion molecule (PECAM-1), cluster of differentiation (CD31) and endoglin (CD105) may be used to identify endothelium and activated endothelium, respectively, with the CD105/CD31 ratio used to measure neovascularity. This study investigated the hypothesis that neovascularity in renal cell carcinoma (RCC) is associated with more aggressive RCC tumors and can be used to predict oncological outcomes. Multiplexed immunohistochemistry using antibodies to detect endoglin and PECAM-1 was performed on tissue microarray of benign kidney samples and RCC tumors including clear cell, papillary, chromophobe, and collecting duct and unclassified tumors (combined for statistics), and multispectral imaging was used for analysis. The CD105/CD31 ratio was compared with clinical and pathologic features of RCC as well as clinical outcomes after surgery using Cox proportional hazards regression and Kaplan-Meier analysis. A total of 502 tumor samples and 122 normal kidney samples from 251 RCC patients were analyzed. The average CD105/CD31 expression ratio, an indicator of neovascularization, was increased in higher pathologic stage tumors (P< .0001). Among RCC morphotypes, the ratio was lower in papillary RCC morphotype tumors (P= .001) and higher in collecting duct/unclassified tumors (P= .0001) compared with clear cell RCC. Among nuclear grades, grade 4 RCC displayed a significantly elevated CD105/CD31 ratio (P< .0001). In multivariable analysis, increased neovascularity was associated with decreased overall survival (hazard ratio, 1.54 [95% confidence interval, 1.06-2.23]; P= .02). In patients receiving anti-vascular endothelial growth factor therapy (VEGF, n = 13) for metastatic RCC, a low CD105/CD31 ratio was associated with increased survival (P= .02). We conclude that higher neovascularity is associated with worse outcomes after surgery for RCC. The ratio of CD105/CD31 expression is a potential indicator of response to anti

  9. Broad spectrum antiangiogenic treatment for ocular neovascular diseases.

    Directory of Open Access Journals (Sweden)

    Ofra Benny

    Full Text Available UNLABELLED: Pathological neovascularization is a hallmark of late stage neovascular (wet age-related macular degeneration (AMD and the leading cause of blindness in people over the age of 50 in the western world. The treatments focus on suppression of choroidal neovascularization (CNV, while current approved therapies are limited to inhibiting vascular endothelial growth factor (VEGF exclusively. However, this treatment does not address the underlying cause of AMD, and the loss of VEGF's neuroprotective can be a potential side effect. Therapy which targets the key processes in AMD, the pathological neovascularization, vessel leakage and inflammation could bring a major shift in the approach to disease treatment and prevention. In this study we have demonstrated the efficacy of such broad spectrum antiangiogenic therapy on mouse model of AMD. METHODS AND FINDINGS: Lodamin, a polymeric formulation of TNP-470, is a potent broad-spectrum antiangiogenic drug. Lodamin significantly reduced key processes involved in AMD progression as demonstrated in mice and rats. Its suppressive effects on angiogenesis, vascular leakage and inflammation were studied in a wide array of assays including; a Matrigel, delayed-type hypersensitivity (DTH, Miles assay, laser-induced CNV and corneal micropocket assay. Lodamin significantly suppressed the secretion of various pro-inflammatory cytokines in the CNV lesion including monocyte chemotactic protein-1 (MCP-1/Ccl2. Importantly, Lodamin was found to regress established CNV lesions, unlike soluble fms-like tyrosine kinase-1 (sFlk-1. The drug was found to be safe in mice and have little toxicity as demonstrated by electroretinography (ERG assessing retinal and by histology. CONCLUSIONS: Lodamin, a polymer formulation of TNP-470, was identified as a first in its class, broad-spectrum antiangiogenic drug that can be administered orally or locally to treat corneal and retinal neovascularization. Several unique properties

  10. A Mouse Model for Laser-induced Choroidal Neovascularization.

    Science.gov (United States)

    Shah, Ronil S; Soetikno, Brian T; Lajko, Michelle; Fawzi, Amani A

    2015-12-27

    The mouse laser-induced choroidal neovascularization (CNV) model has been a crucial mainstay model for neovascular age-related macular degeneration (AMD) research. By administering targeted laser injury to the RPE and Bruch's membrane, the procedure induces angiogenesis, modeling the hallmark pathology observed in neovascular AMD. First developed in non-human primates, the laser-induced CNV model has come to be implemented into many other species, the most recent of which being the mouse. Mouse experiments are advantageously more cost-effective, experiments can be executed on a much faster timeline, and they allow the use of various transgenic models. The miniature size of the mouse eye, however, poses a particular challenge when performing the procedure. Manipulation of the eye to visualize the retina requires practice of fine dexterity skills as well as simultaneous hand-eye-foot coordination to operate the laser. However, once mastered, the model can be applied to study many aspects of neovascular AMD such as molecular mechanisms, the effect of genetic manipulations, and drug treatment effects. The laser-induced CNV model, though useful, is not a perfect model of the disease. The wild-type mouse eye is otherwise healthy, and the chorio-retinal environment does not mimic the pathologic changes in human AMD. Furthermore, injury-induced angiogenesis does not reflect the same pathways as angiogenesis occurring in an age-related and chronic disease state as in AMD. Despite its shortcomings, the laser-induced CNV model is one of the best methods currently available to study the debilitating pathology of neovascular AMD. Its implementation has led to a deeper understanding of the pathogenesis of AMD, as well as contributing to the development of many of the AMD therapies currently available.

  11. Rolipram-induced elevation of cAMP or chondroitinase ABC breakdown of inhibitory proteoglycans in the extracellular matrix promotes peripheral nerve regeneration.

    Science.gov (United States)

    Udina, E; Ladak, A; Furey, M; Brushart, T; Tyreman, N; Gordon, T

    2010-05-01

    The inhibitory growth environment of myelin and extracellular matrix proteoglycans in the central nervous system may be overcome by elevating neuronal cAMP or degrading inhibitory proteoglycans with chondroitinase ABC (ChABC). In this study, we asked whether similar mechanisms operate in peripheral nerve regeneration where effective Wallerian degeneration removes myelin and extracellular proteoglycans slowly. We repaired transected common peroneal (CP) nerve in rats and either elevated cAMP in the axotomized neurons by subcutaneous rolipram, a specific inhibitor of phosphodiesterase IV, and/or promoted degradation of proteoglycans in the distal nerve stump by local ChABC administration. Rolipram treatment significantly increased the number of motoneurons that regenerated axons across the repair site at 1 and 2 weeks, and increased the number of sensory neurons that regenerated axons across the repair site at 2 weeks. Local application of ChABC had a similar effect to rolipram treatment in promoting motor axon regeneration, the effect being no greater when rolipram and ChABC were administered simultaneously. We conclude that blocking inhibitors of axon regeneration by elevating cAMP or degrading proteoglycans in the distal nerve stump promotes peripheral axon regeneration after surgical repair of a transected nerve. It is likely that elevated cAMP is sufficient to encourage axon outgrowth despite the inhibitory growth environment such that simultaneous enzymatic proteoglycan degradation does not promote more axon regeneration than either elevated cAMP or proteoglycan degradation alone.

  12. Prognostic impact of polymorphism of matrix metalloproteinase-2 and metalloproteinase tissue inhibitor-2 promoters in breast cancer in Tunisia: case-control study.

    Science.gov (United States)

    Ben Néjima, Dalel; Ben Zarkouna, Yosr; Gammoudi, Amor; Manai, Mohamed; Boussen, Hamouda

    2015-05-01

    Matrix metalloproteinases (MMPs) are proteolytic enzymes that play important roles in tumor invasion and metastasis by degrading extracellular matrix components. Genetic variations in promoter regions of MMP genes, affecting their expression, have been associated with susceptibility to cancers. The aim of this study was to investigate the susceptibility and prognostic implications of the matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) polymorphism in Tunisian breast cancer patients. MMP-2 genotypes were determined by real-time polymerase chain reaction (RT-PCR), and TIMP-2 genotypes were identified using a PCR-restriction fragment length polymorphism (RFLP) method in 210 breast cancer patients and 250 frequency-matched control women. Association of the clinicopathological parameters and the genetic markers with risk of breast cancer was assessed using univariate analyses. We found that the variant MMP-2 genotype (-1306CT or TT) was associated with substantially reduced risk of breast cancer [odds ratio (OR), 0.49; 95 % confidence interval (95 % CI), 0.033-0.73], compared with the CC genotype. For TIMP-2, a moderately reduced risk of the cancer (OR, 0.57; 95 % CI, 0.37-0.87) was also associated with the variant allele (-418GC or CC), compared with the GG common allele. Furthermore, polymorphisms in both genes seem to have additive effects and the highest risk for breast cancer has been observed in those with MMP-2 CC genotype and TIMP-2 GC or CC genotype (p = 0.006). A significant association was also found between the CC genotype and the aggressive forms of breast cancer as defined by advanced stages at the time of diagnosis and metastasis. This is the first report on the association of MMP-2 and TIMP-2 gene polymorphisms in breast cancer in Tunisian population. Our results suggest that the presence of the variant allele in the promoter of MMP-2 or TIMP-2 may be a protective factor for the development of breast cancer.

  13. Effect of enamel organic matrix on the potential of Galla chinensis to promote the remineralization of initial enamel carious lesions in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Linglin; Zou Ling; Li Jiyao; Hao Yuqing; Xiao Liying; Zhou Xuedong; Li Wei, E-mail: leewei2000@sina.co, E-mail: zhll_sc@yahoo.c [State Key Laboratory of Oral Diseases, West China College of Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu (China)

    2009-06-15

    Galla chinensis, a natural traditional Chinese medicine with main composition of tannic acid and gallic acid, is formed when the Chinese sumac aphid Baker (Melaphis chinensis bell) parasitizes the levels of Rhus chinensis Mill. Galla chinensis has shown the potential to enhance the remineralization of initial enamel carious lesion, but the mechanism is still unknown. This study was to investigate whether the enamel organic matrix plays a significant role in the potential of Galla chinensis to promote the remineralization of initial enamel caries. Bovine sound enamel blocks and non-organic enamel blocks were demineralized and exposed to a 12 day pH cycling. During the pH cycling, 30 specimens with the enamel organic matrix were randomly divided into three groups, and treated with 1 g L{sup -1} NaF (group A), 4 g L{sup -1} Galla chinensis extract (group B1) or double deionized water (group C1). Twenty specimens without the enamel organic matrix were randomly divided into two groups, and treated with 4 g L{sup -1} Galla chinensis extract (group B2) or double deionized water (group C2). The integrated mineral loss and lesion depth of all the specimens were analysed by transverse microradiography. The integrated mineral loss and lesion depth of group B1 were less than those of groups B2, C1 and C2, and there were no statistical differences among groups B2, C1 and C2. In conclusion, Galla chinensis can enhance the remineralization of initial enamel carious lesion, and the enamel organic matrix plays a significant role in this potential of Galla chinensis.

  14. 基质金属蛋白酶抑制剂GM6001抑制大鼠脉络膜新生血管形成的初步研究%Effects of matrix metalloproteinases inhibitor GM6001 on choroidal neovascularization

    Institute of Scientific and Technical Information of China (English)

    陈学国; 何守志

    2012-01-01

    Objective To explore the efficiency of GM6001 for the inhibition of choroidal neovascularization. Methods Experimental study. Twenty-four Brown Norvy ( BN ) rats after photocoagulation were randomly divided into 3 groups as GM6001 group,DMSO group and CONT group.GM6001 (0.2 ml of 0.1% suspension) was injected retrobulbarly for GM6001 group and0.2 ml DMSO was injected for DMSO group on days 1,3,6,9,and 12 after photocoagulation.No injection was performed in the CONT group.Fundus fluorescence angiography,histopathology,immunohistochemistry and quantitative analysis of choroidal neovascularization ( CNV ) were performed 3 weeks after photocoagulation. One-way ANOVA was used in conjunction with SNK-t test to assess statistical significance within groups. Resufts The fluorescein leakage appeared in all three groups; but fluorescein leakage of GM6001 group( 74.56 ± 2.33 ) was less than that of DMSO group ( 119.57 ± 1.15 ) and CONT group ( 122.36 ± 2.38 ) ( F =403.23,P =0.001 ;LSD-t test,all P value <0.01 ),whereas fluoresecin leakage of DMSO group was similar to that in the CONT group.The retinal and choroidal capillaries in the CONT group were damaged and disordered;a great deal of CNV and migration and proliferation of retinal pigment epithelium cells,fibrocytes and collagen fibers were discovered.Pathological changes in DMSO group were similar to those in the CONT group.There were a small quantity of retinal pigment epithelium cells,fibrocytes and CNV in GM6001 group.Although the immunohistochemical staining for CD105 displayed positive results in all three groups,positive staining of GM6001 group ( 19.85 ± 1.59 ) was significantly less than that of the CONT group (38.02 ± 2.57 ) and DMSO group (39.02 ± 3.12 ) (F =55.57,P =0.001 ; LSD-t test,all P value < 0.01 ).Positive staining of CD105 in the CONT group was similar to that of DMSO group (P > 0.05 ).The size of CNV in GM6001 group ( 15.35 ±0.77) was significantly less than that of CONT group( 28.38

  15. Growth factor-and cytokine-stimulated endothelial progenitor cells in post-ischemic cerebral neovascularization

    Institute of Scientific and Technical Information of China (English)

    Philip V.Peplow

    2014-01-01

    Endothelial progenitor cells are resident in the bone marrow blood sinusoids and circulate in the peripheral circulation. They mobilize from the bone marrow after vascular injury and home to the site of injury where they differentiate into endothelial cells. Activation and mobilization of endothelial progenitor cells from the bone marrow is induced via the production and release of endothelial progenitor cell-activating factors and includes speciifc growth factors and cytokines in response to peripheral tissue hypoxia such as after acute ischemic stroke or trauma. Endotheli-al progenitor cells migrate and home to speciifc sites following ischemic stroke via growth factor/cytokine gradients. Some growth factors are less stable under acidic conditions of tissue isch-emia, and synthetic analogues that are stable at low pH may provide a more effective therapeutic approach for inducing endothelial progenitor cell mobilization and promoting cerebral neovas-cularization following ischemic stroke.

  16. TNF-{alpha} promotes human retinal pigment epithelial (RPE) cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression through activation of Akt/mTORC1 signaling

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Cheng-hu; Cao, Guo-Fan [The Affiliated Eye Hospital of Nanjing Medical University, Nanjing 210029 (China); Jiang, Qin, E-mail: Jqin710@vip.sina.com [The Affiliated Eye Hospital of Nanjing Medical University, Nanjing 210029 (China); Yao, Jin, E-mail: dryaojin@yahoo.com [The Affiliated Eye Hospital of Nanjing Medical University, Nanjing 210029 (China)

    2012-08-17

    Highlights: Black-Right-Pointing-Pointer TNF-{alpha} induces MMP-9 expression and secretion to promote RPE cell migration. Black-Right-Pointing-Pointer MAPK activation is not critical for TNF-{alpha}-induced MMP-9 expression. Black-Right-Pointing-Pointer Akt and mTORC1 signaling mediate TNF-{alpha}-induced MMP-9 expression. Black-Right-Pointing-Pointer SIN1 knockdown showed no significant effect on MMP-9 expression by TNF-{alpha}. -- Abstract: Tumor necrosis factor-alpha (TNF-{alpha}) promotes in vitro retinal pigment epithelial (RPE) cell migration to initiate proliferative vitreoretinopathy (PVR). Here we report that TNF-{alpha} promotes human RPE cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression. Inhibition of MMP-9 by its inhibitor or its neutralizing antibody inhibited TNF-{alpha}-induced in vitro RPE cell migration. Reversely, exogenously-added active MMP-9 promoted RPE cell migration. Suppression Akt/mTOR complex 1(mTORC1) activation by LY 294002 and rapamycin inhibited TNF-{alpha}-mediated MMP-9 expression. To introduce a constitutively active Akt (CA-Akt) in cultured RPE cells increased MMP-9 expression, and to block mTORC1 activation by rapamycin inhibited its effect. RNA interference (RNAi)-mediated silencing of SIN1, a key component of mTOR complex 2 (mTORC2), had no effect on MMP-9 expression or secretion. In conclusion, this study suggest that TNF-{alpha} promotes RPE cell migration by inducing MMP-9 expression through activation of Akt/ mTORC1, but not mTORC2 signaling.

  17. Cartilage oligomeric matrix protein deficiency promotes early onset and the chronic development of collagen-induced arthritis

    DEFF Research Database (Denmark)

    Geng, Hui; Carlsen, Stefan; Nandakumar, Kutty;

    2008-01-01

    ABSTRACT: INTRODUCTION: Cartilage oligomeric matrix protein (COMP) is a homopentameric protein in cartilage. The development of arthritis, like collagen-induced arthritis (CIA), involves cartilage as a target tissue. We have investigated the development of CIA in COMP-deficient mice. METHODS: COMP......-deficient mice in the 129/Sv background were backcrossed for 10 generations against B10.Q mice, which are susceptible to chronic CIA. COMP-deficient and wild-type mice were tested for onset, incidence, and severity of arthritis in both the collagen and collagen antibody-induced arthritis models. Serum anti......-collagen II and anti-COMP antibodies as well as serum COMP levels in arthritic and wild-type mice were measured by enzyme-linked immunosorbent assay. RESULTS: COMP-deficient mice showed a significant early onset and increase in the severity of CIA in the chronic phase, whereas collagen II-antibody titers were...

  18. Tenascin-C in the extracellular matrix promotes the selection of highly proliferative and tubulogenesis-defective endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Alves, Tercia Rodrigues [Universidade do Estado do Rio de Janeiro (UERJ), Instituto de Biologia Roberto Alcantara Gomes, Departamento de Biologia Celular, Laboratorio de Biologia da Celula Endotelial e da Angiogenese (LabAngio), Rio de Janeiro (Brazil); Universidade Federal do Rio de Janeiro (UFRJ), Programa de Biologia Celular e do Desenvolvimento, Instituto de Ciencias Biomedicas, INNT/INCT/MCT, Rio de Janeiro (Brazil); Carvalho da Fonseca, Anna Carolina [Universidade Federal do Rio de Janeiro (UFRJ), Programa de Biologia Celular e do Desenvolvimento, Instituto de Ciencias Biomedicas, INNT/INCT/MCT, Rio de Janeiro (Brazil); Nunes, Sara Santana; Oliveira da Silva, Aline [Universidade do Estado do Rio de Janeiro (UERJ), Instituto de Biologia Roberto Alcantara Gomes, Departamento de Biologia Celular, Laboratorio de Biologia da Celula Endotelial e da Angiogenese (LabAngio), Rio de Janeiro (Brazil); Dubois, Luiz Gustavo Feijo; Faria, Jane; Kahn, Suzana Assad [Universidade Federal do Rio de Janeiro (UFRJ), Programa de Biologia Celular e do Desenvolvimento, Instituto de Ciencias Biomedicas, INNT/INCT/MCT, Rio de Janeiro (Brazil); Viana, Nathan Bessa [Universidade Federal do Rio de Janeiro, Laboratorio de Pincas Oticas, Coordenacao de Programas de Estudos Avancados, Instituto de Ciencias Biomedicas, Rio de Janeiro (Brazil); Universidade Federal do Rio de Janeiro, Instituto de Fisica, Rio de Janeiro (Brazil); Marcondes, Jorge [Universidade Federal do Rio de Janeiro, Hospital Universitario Clementino Fraga Filho, Servico de Neurocirurgia, Rio de Janeiro (Brazil); Legrand, Chantal [Institut Universitaire d' Hematologie, Universite Paris-Diderot, Paris 7, INSERM U553, Paris (France); Moura-Neto, Vivaldo [Universidade Federal do Rio de Janeiro (UFRJ), Programa de Biologia Celular e do Desenvolvimento, Instituto de Ciencias Biomedicas, INNT/INCT/MCT, Rio de Janeiro (Brazil); and others

    2011-09-10

    The extracellular matrix (ECM) contains important cues for tissue homeostasis and morphogenesis. The matricellular protein tenascin-C (TN-C) is overexpressed in remodeling tissues and cancer. In the present work, we studied the effect of different ECM-which exhibited a significant diversity in their TN-C content-in endothelial survival, proliferation and tubulogenic differentiation: autologous (endothelial) ECM devoid of TN-C, but bearing large amounts of FN; fibroblast ECM, bearing both high TN-C and FN contents; and finally, glioma-derived matrices, usually poor in FN, but very rich in TN-C. HUVECs initially adhered to the immobilized matrix produced by U373 MG glioma cells, but significantly detached and died by anoikis (50 to 80%) after 24 h, as compared with cells incubated with endothelial and fibroblast matrices. Surviving endothelial cells (20 to 50%) became up to 6-fold more proliferative and formed 74-97% less tube-like structures in vitro than cells grown on non-tumoral matrices. An antibody against the EGF-like repeats of tenascin-C (TN-C) partially rescued cells from the tubulogenic defect, indicating that this molecule is responsible for the selection of highly proliferative and tubulogenic defective endothelial cells. Interestingly, by using defined substrata, in conditions that mimic glioma and normal cell ECM composition, we observed that fibronectin (FN) modulates the TN-C-induced selection of endothelial cells. Our data show that TN-C is able to modulate endothelial branching morphogenesis in vitro and, since it is prevalent in matrices of injured and tumor tissues, also suggest a role for this protein in vascular morphogenesis, in these physiological contexts.

  19. MFGE8 does not influence chorio-retinal homeostasis or choroidal neovascularization in vivo.

    Directory of Open Access Journals (Sweden)

    William Raoul

    Full Text Available PURPOSE: Milk fat globule-epidermal growth factor-factor VIII (MFGE8 is necessary for diurnal outer segment phagocytosis and promotes VEGF-dependent neovascularization. The prevalence of two single nucleotide polymorphisms (SNP in MFGE8 was studied in two exsudative or "wet" Age-related Macular Degeneration (AMD groups and two corresponding control groups. We studied the effect of MFGE8 deficiency on retinal homeostasis with age and on choroidal neovascularization (CNV in mice. METHODS: The distribution of the SNP (rs4945 and rs1878326 of MFGE8 was analyzed in two groups of patients with "wet" AMD and their age-matched controls from Germany and France. MFGE8-expressing cells were identified in Mfge8(+/- mice expressing ß-galactosidase. Aged Mfge8(+/- and Mfge8(-/- mice were studied by funduscopy, histology, electron microscopy, scanning electron microscopy of vascular corrosion casts of the choroid, and after laser-induced CNV. RESULTS: rs1878326 was associated with AMD in the French and German group. The Mfge8 promoter is highly active in photoreceptors but not in retinal pigment epithelium cells. Mfge8(-/- mice did not differ from controls in terms of fundus appearance, photoreceptor cell layers, choroidal architecture or laser-induced CNV. In contrast, the Bruch's membrane (BM was slightly but significantly thicker in Mfge8(-/- mice as compared to controls. CONCLUSIONS: Despite a reproducible minor increase of rs1878326 in AMD patients and a very modest increase in BM in Mfge8(-/- mice, our data suggests that MFGE8 dysfunction does not play a critical role in the pathogenesis of AMD.

  20. CTGF increases matrix metalloproteinases expression and subsequently promotes tumor metastasis in human osteosarcoma through down-regulating miR-519d.

    Science.gov (United States)

    Tsai, Hsiao-Chi; Su, Hong-Lin; Huang, Chun-Yin; Fong, Yi-Chin; Hsu, Chin-Jung; Tang, Chih-Hsin

    2014-06-15

    Osteosarcoma, the most common primary malignant bone tumor, shows potent capacity for local invasion and distant metastasis. Connective tissue growth factor (CTGF/CCN2), a secreted protein, binds to integrins, modulates invasive behavior of certain human cancer cells. Effect of CTGF in metastasis of human osteosarcoma is unknown. We found overexpression of CTGF increasing matrix metalloproteinases (MMPs)-2 and MMP-3 expression as well as promoting cell migration. MicroRNA (miRNA) analysis of CTGF-overexpressed osteosarcoma versus control cells probed mechanisms of CTGF-mediated promotion of migration. Among miRNAs regulated by CTGF, miR-519d was most downregulated after CTGF treatment. Co-transfection with miR-519d mimic reversed CTGF-mediated MMPs expression and cell migration. Also, MEK and ERK inhibitors or mutants reduced CTGF-increased cell migration and miR-519d suppression. By contrast, knockdown of CTGF diminished lung metastasis in vivo. Clinical samples indicate CTGF expression as linked with clinical stage and tumor metastasis. Taken together, data show CTGF elevating MMPs expression and subsequently promoting tumor metastasis in human osteosarcoma, down-regulating miR-519d via MEK and ERK pathways, making CTGF a new molecular therapeutic target in osteosarcoma metastasis.

  1. CTGF increases matrix metalloproteinases expression and subsequently promotes tumor metastasis in human osteosarcoma through down-regulating miR-519d

    Science.gov (United States)

    Tsai, Hsiao-Chi; Su, Hong-Lin; Huang, Chun-Yin; Fong, Yi-Chin; Hsu, Chin-Jung; Tang, Chih-Hsin

    2014-01-01

    Osteosarcoma, the most common primary malignant bone tumor, shows potent capacity for local invasion and distant metastasis. Connective tissue growth factor (CTGF/CCN2), a secreted protein, binds to integrins, modulates invasive behavior of certain human cancer cells. Effect of CTGF in metastasis of human osteosarcoma is unknown. We found overexpression of CTGF increasing matrix metalloproteinases (MMPs)-2 and MMP-3 expression as well as promoting cell migration. MicroRNA (miRNA) analysis of CTGF-overexpressed osteosarcoma versus control cells probed mechanisms of CTGF-mediated promotion of migration. Among miRNAs regulated by CTGF, miR-519d was most downregulated after CTGF treatment. Co-transfection with miR-519d mimic reversed CTGF-mediated MMPs expression and cell migration. Also, MEK and ERK inhibitors or mutants reduced CTGF-increased cell migration and miR-519d suppression. By contrast, knockdown of CTGF diminished lung metastasis in vivo. Clinical samples indicate CTGF expression as linked with clinical stage and tumor metastasis. Taken together, data show CTGF elevating MMPs expression and subsequently promoting tumor metastasis in human osteosarcoma, down-regulating miR-519d via MEK and ERK pathways, making CTGF a new molecular therapeutic target in osteosarcoma metastasis. PMID:25003330

  2. Current and emerging treatment options for myopic choroidal neovascularization

    Directory of Open Access Journals (Sweden)

    El Matri L

    2015-04-01

    Full Text Available Leila El Matri, Ahmed Chebil, Fedra Kort Department B of Ophthalmology, Hedi Rais Institute of Ophthalmology, Faculty of Medicine of Tunis, University of El Manar, Tunis, Tunisia Abstract: Choroidal neovascularization (CNV is the main cause of visual impairment in highly myopic patients younger than 50 years of age. There are different treatments for myopic CNV (mCNV, with 5- to 10-year outcomes currently. Chorioretinal atrophy is still the most important determinant factor for visual outcome. The purpose of this study is to provide an overview of the current treatments for mCNV, including laser, surgical management, verteporfin photodynamic therapy, and mainly anti-vascular endothelial growth factor therapy. Emerging treatment options are also discussed. Keywords: myopia, choroidal neovascularization, current treatment, emerging treatment

  3. Neovascularization and functional recovery after intracerebral hemorrhage is conditioned by the Tp53 Arg72Pro single-nucleotide polymorphism.

    Science.gov (United States)

    Rodríguez, Cristina; Sobrino, Tomás; Agulla, Jesús; Bobo-Jiménez, Verónica; Ramos-Araque, María E; Duarte, Juan J; Gómez-Sánchez, José C; Bolaños, Juan P; Castillo, José; Almeida, Ángeles

    2017-01-01

    Intracerebral hemorrhage (ICH) is a devastating subtype of stroke that lacks effective therapy and reliable prognosis. Neovascularization following ICH is an essential compensatory response that mediates brain repair and modulates the clinical outcome of stroke patients. However, the mechanism that dictates this process is unknown. Bone marrow-derived endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. The human Tp53 gene harbors a common single-nucleotide polymorphism (SNP) at codon 72, which yields an arginine-to-proline amino-acidic substitution (Arg72Pro) that modulates the apoptotic activity of the p53 protein. Previously, we found that this SNP controls neuronal susceptibility to ischemia-induced apoptosis in vitro. Here, we evaluated the impact of the Tp53 Arg72Pro SNP on vascular repair and functional recovery after ICH. We first analyzed EPC mobilization and functional outcome based on the modified Rankin scale scores in a hospital-based cohort of 78 patients with non-traumatic ICH. Patients harboring the Pro allele of the Tp53 Arg72Pro SNP showed higher levels of circulating EPC-containing CD34(+) cells, EPC-mobilizing cytokines - vascular endothelial growth factor and stromal cell-derived factor-1α - and good functional outcome following ICH, when compared with the homozygous Arg allele patients, which is compatible with increased neovascularization. To assess directly whether Tp53 Arg72Pro SNP regulated neovascularization after ICH, we used the humanized Tp53 Arg72Pro knock-in mice, which were subjected to the collagenase-induced ICH. The brain endothelial cells of the Pro allele-carrying mice were highly resistant to ICH-mediated apoptosis, which facilitated cytokine-mediated EPC mobilization, cerebrovascular repair and functional recovery. However, these processes were not observed in the Arg allele-carrying mice. These results reveal that the Tp53 Arg72Pro SNP determines

  4. Neovascular glaucoma treatment with extraction of anterior chamber fibrovascular tissue.

    Science.gov (United States)

    Nadal, Jeroni; Carreras, Elisa; Kudsieh, Bachar; Canut, Maribel

    2013-08-01

    The use of antibody to vascular endothelial growth factor to treat neovascular glaucoma yields good anatomic results in most cases. However, this type of glaucoma can cause angle closure with decompensation of intraocular pressure secondary to fibrovascular tissue contraction in the anterior chamber. Our surgical technique treats the cause by removing the anterior chamber fibrous complex after administration of antibody to vascular endothelial growth factor, thus restoring the chamber angle.

  5. Prevalence of outer retinal tubulation in eyes with choroidal neovascularization

    OpenAIRE

    Giachetti Filho, Richard Geraldo; Zacharias,Leandro Cabral; Monteiro,Thaís Vera; Preti, Rony Carlos; Pimentel, Sérgio Gianoti

    2016-01-01

    Background Outer retinal tubulations (ORTs) are branching tubular structures located in the outer nuclear layer of the retina. The goal of this study is to determine the prevalence of ORTs observed in eyes with choroidal neovascularization (CNV) undergoing treatment with anti-angiogenic intravitreous injection (IVI) with anti-VEGF (vascular endothelial growth factor) at the Ophthalmology Department of a tertiary hospital in São Paulo, Brazil. Methods This is a descriptive study based on medic...

  6. Stereotactic radiotherapy in neovascular age-related macular degeneration

    OpenAIRE

    Ranjbar, Mahdy; Kurz, Maximilian; Holzhey, Annekatrin; Melchert, Corinna; Rades, Dirk; Grisanti, Salvatore

    2016-01-01

    Abstract Stereotactic radiotherapy (SRT) is a new approach to treat neovascular age-related macular degeneration (nAMD). The INTREPID trial suggested that SRT could reduce the frequency of regular intravitreal injections (IVIs) with antivascular endothelial growth factor drugs, which are necessary to control disease activity. However, the efficacy of SRT in nAMD and resulting morphological changes have not been validated under real-life circumstances, an issue, which we would like to address ...

  7. The stereotypical molecular cascade in neovascular age-related macular degeneration: the role of dynamic reciprocity.

    Science.gov (United States)

    Kent, D

    2015-11-01

    This review summarises our current understanding of the molecular basis of subretinal neovascularisation (SRNV) in age-related macular degeneration (AMD). The term neovascular AMD (NVAMD) is derived from the dominant early clinical features of haemorrhage, fluid, and lipid in the subretinal space (SRS) and the historical role of fluorescein angiography in detecting the presence of NV tissue. However, at the cellular level, SRNV resembles an aberrant but stereotypical tissue repair response that incorporates both an early inflammatory phase and a late fibrotic phase in addition to the neovascular (NV) component that dominates the early clinical presentation. This review will seek not only to highlight the important molecules involved in each of these components but to demonstrate that the development of SRNV has its origins in the earliest events in non-NV AMD pathogenesis. Current evidence suggests that this early-stage pathogenesis is characterised by complement-mediated immune dysregulation, leading to a state of chronic inflammation in the retinal pigment epithelium/Bruch's membrane/choriocapillaris complex. These initial events can be seamlessly and inextricably linked to late-stage development of SRNV in AMD by the process of dynamic reciprocity (DyR), the ongoing bidirectional communication between cells, and their surrounding matrix. Moreover, this correlation between disease onset and eventual outcome is reflected in the temporal and spatial correlation between chronic inflammation, NV, and fibrosis within the reparative microenvironment of the SRS. In summary, the downstream consequences of the earliest dysfunctional molecular events in AMD can result in the late-stage entity we recognize clinically as SRNV and is characterized by a spectrum of predictable, related, and stereotypical processes referred to as DyR.

  8. Treatment of neovascular age-related macular degeneration: Current therapies

    Directory of Open Access Journals (Sweden)

    Albert J Augustin

    2009-01-01

    Full Text Available Albert J Augustin, Stefan Scholl, Janna KirchhofDepartment of Ophthalmology, Klinikum Karlsruhe, GermanyAbstract: Choroidal neovascularization (CNV secondary to age-related macular degeneration (AMD is now the leading cause of blindness and severe vision loss among people over the age of 40 in the Western world. Its prevalence is certain to increase substantially as the population ages. Treatments currently available for the disease include laser photocoagulation, verteporfin photodynamic therapy, and intravitreal injections of corticosteroids and anti-angiogenic agents. Many studies have reported the benefits of each of these treatments, although none is without its risks. No intervention actually cures AMD, nor the neovascularization associated with it. However, its symptoms are treated with varying degrees of success. Some treatments stabilize or arrest the progress of the disease. Others have been shown to reverse some of the damage that has already been done. These treatments can even lead to visual improvement. This paper will review the major classes of drugs and therapies designed to treat this condition.Keywords: wet AMD, neovascularization, PDT, steroids, anti-angiogenesis

  9. Treatment of Corneal Neovascularization Using Anti-VEGF Bevacizumab

    Directory of Open Access Journals (Sweden)

    Deli Krizova

    2014-01-01

    Full Text Available Purpose. To evaluate antiangiogenic effect of local use of bevacizumab (anti-VEGF antibody in patients with corneal neovascularization. Methods. Patients were divided into two groups. All patients suffered from some form of corneal neovascularization (NV. Patients in group A received 0.2–0.5 mL of bevacizumab solution subconjunctivally (concentration 25 mg/mL in a single dose. Group A included 28 eyes from 27. Patients in group B applied bevacizumab eye drops twice daily (concentration 2.5 mg/mL for two weeks. Group B included 38 eyes from 35 patients. We evaluated the number of corneal segments affected by NV, CDVA, and the incidence of complications and subjective complaints related to the treatment. The minimum follow-up period was six months. Results. By the 6-month follow-up, in group A the percentage reduction of the affected peripheral segments was 21.6% and of the central segments was 9.6%; in group B the percentage reduction of the central segments was 22.7% and of the central segments was 38.04%. In both groups we noticed a statistically significant reduction in the extent of NV. Conclusion. The use of bevacizumab seems to be an effective and safe method in the treatment of corneal neovascularization, either in the subconjunctival or topical application form.

  10. Ranibizumab: the evidence of its therapeutic value in neovascular age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Peter K. Kaiser

    2008-07-01

    Full Text Available Peter K. KaiserCole Eye Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, USAIntroduction: Neovascular age-related macular degeneration (AMD is the leading cause of severe, irreversible visual impairment in people over 60 years of age. Neovascular AMD is characterized by abnormal growth of blood vessels under the retina, specifically the macula. These vessels leak blood and fluids, damaging the retina and its photoreceptors, resulting in permanent loss of central vision. Vascular endothelial growth factor-A (VEGF-A has been shown to play a critical role in the pathogenesis of neovascular AMD. In the US, ranibizumab, a VEGF-A blocker, is approved and indicated for the treatment of patients with neovascular AMD.Aims: To review the clinical evidence for ranibizumab in the treatment of neovascular AMD.Evidence review: Phase III clinical trial data have established ranibizumab as a safe and well-tolerated treatment for neovascular AMD. Monthly intravitreal injections of ranibizumab result in a statistically significantly greater proportion of patients losing <15 letters of visual acuity (VA and statistically significant increases in the mean number of letters gained compared with controls. Anatomically, ranibizumab results in stabilization in the mean area of choroidal neovascularization (CNV and statistically significant reductions in the mean area of leakage compared with controls. Although there is limited economic evidence available, ranibizumab therapy for neovascular AMD appears to deliver a significant degree of value gain in terms of quality of life when compared with other neovascular AMD interventions.Place in therapy: Clinical evidence establishes ranibizumab as a first-line therapy option for virtually all treatable neovascular AMD patients. Updating neovascular AMD treatment guidelines to reflect the evidence base for ranibizumab as a preferred first-line therapy would be beneficial for physicians in making informed treatment

  11. Promoting extracellular matrix remodeling via ascorbic acid enhances the survival of primary ovarian follicles encapsulated in alginate hydrogels.

    Science.gov (United States)

    Tagler, David; Makanji, Yogeshwar; Tu, Tao; Bernabé, Beatriz Peñalver; Lee, Raymond; Zhu, Jie; Kniazeva, Ekaterina; Hornick, Jessica E; Woodruff, Teresa K; Shea, Lonnie D

    2014-07-01

    The in vitro growth of ovarian follicles is an emerging technology for fertility preservation. Various strategies support the culture of secondary and multilayer follicles from various species including mice, non-human primate, and human; however, the culture of early stage (primary and primordial) follicles, which are more abundant in the ovary and survive cryopreservation, has been limited. Hydrogel-encapsulating follicle culture systems that employed feeder cells, such as mouse embryonic fibroblasts (MEFs), stimulated the growth of primary follicles (70-80 µm); yet, survival was low and smaller follicles (structure and degenerated. These morphologic changes were associated with a breakdown of the follicular basement membrane; hence, this study investigated ascorbic acid based on its role in extracellular matrix (ECM) deposition/remodeling for other applications. The selection of ascorbic acid was further supported by a microarray analysis that suggested a decrease in mRNA levels of enzymes within the ascorbate pathway between primordial, primary, and secondary follicles. The supplementation of ascorbic acid (50 µg/mL) significantly enhanced the survival of primary follicles (alginate hydrogels, which coincided with improved structural integrity. Follicles developed antral cavities and increased to diameters exceeding 250 µm. Consistent with improved structural integrity, the gene/protein expression of ECM and cell adhesion molecules was significantly changed. This research supports the notion that modifying the culture environment (medium components) can substantially enhance the survival and growth of early stage follicles. © 2013 Wiley Periodicals, Inc.

  12. Surface Topography and Mechanical Strain Promote Keratocyte Phenotype and Extracellular Matrix Formation in a Biomimetic 3D Corneal Model.

    Science.gov (United States)

    Zhang, Wei; Chen, Jialin; Backman, Ludvig J; Malm, Adam D; Danielson, Patrik

    2017-03-01

    The optimal functionality of the native corneal stroma is mainly dependent on the well-ordered arrangement of extracellular matrix (ECM) and the pressurized structure. In order to develop an in vitro corneal model, it is crucial to mimic the in vivo microenvironment of the cornea. In this study, the influence of surface topography and mechanical strain on keratocyte phenotype and ECM formation within a biomimetic 3D corneal model is studied. By modifying the surface topography of materials, it is found that patterned silk fibroin film with 600 grooves mm(-1) optimally supports cell alignment and ECM arrangement. Furthermore, treatment with 3% dome-shaped mechanical strain, which resembles the shape and mechanics of native cornea, significantly enhances the expression of keratocyte markers as compared to flat-shaped strain. Accordingly, a biomimetic 3D corneal model, in the form of a collagen-modified, silk fibroin-patterned construct subjected to 3% dome-shaped strain, is created. Compared to traditional 2D cultures, it supports a significantly higher expression of keratocyte and ECM markers, and in conclusion better maintains keratocyte phenotype, alignment, and fusiform cell shape. Therefore, the novel biomimetic 3D corneal model developed in this study serves as a useful in vitro 3D culture model to improve current 2D cultures for corneal studies.

  13. Matrix metalloproteinase-9 silencing by RNA interference promotes the adhesive-invasive switch in HT1080 human fibrosarcoma cells.

    Science.gov (United States)

    Zhu, Xishan; Tai, Weiping; Shi, Wei; Song, Yuguang; Zhang, Hongmei; An, Guangyu

    2012-01-01

    A high level of matrix metalloproteinase-9 (MMP-9) is associated with human tumor invasion and/or metastasis. The HT1080 human fibrosarcoma cell line is highly invasive and metastatic which constitutively express MMP-9. HT1080 cells transfected with a double stranded RNA that targeted the MMP-9 mRNA and the cellular characteristics were examined before and after interference. The inhibition effects of MMP-9 interference on the tumor growth of HT1080 cells in nude mice was also tested by xenograft assay. MMP-9 extinction in HT1080 resulted in the following: (1) inhibited cell mobility; (2) increased cell adhesion, and (3) attenuated tumor cell migration. In addition, MMP-9 knockdown concomitantly resulted in decreased levels of soluble ICAM-1, leading to an adhesion defect and tumor metastasis. Moreover, in vivo assay further demonstrated MMP-9 interference affecting the tumorigenesis of HT1080 cells in mice as follows (1) inhibition of tumor growth; (2) reduced tumor volume, and (3) prolonged survival time. Our observations defined a novel critical role for MMP-9 in the progression of HT1080 fibrosarcoma by changing the inter-cellular adhesion molecular-1 from membrane-anchored state to a soluble one which provides a target for promising tumor therapy in clinics.

  14. Tetraspanin CD9 promotes the invasive phenotype of human fibrosarcoma cells via upregulation of matrix metalloproteinase-9.

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    Michael J Herr

    Full Text Available Tumor cell metastasis, a process which increases the morbidity and mortality of cancer patients, is highly dependent upon matrix metalloproteinase (MMP production. Small molecule inhibitors of MMPs have proven unsuccessful at reducing tumor cell invasion in vivo. Therefore, finding an alternative approach to regulate MMP is an important endeavor. Tetraspanins, a family of cell surface organizers, play a major role in cell signaling events and have been implicated in regulating metastasis in numerous cancer cell lines. We stably expressed tetraspanin CD9 in an invasive and metastatic human fibrosarcoma cell line (CD9-HT1080 to investigate its role in regulating tumor cell invasiveness. CD9-HT1080 cells displayed a highly invasive phenotype as demonstrated by matrigel invasion assays. Statistically significant increases in MMP-9 production and activity were attributed to CD9 expression and were not due to any changes in other key tetraspanin complex members or MMP regulators. Increased invasion of CD9-HT1080 cells was reversed upon silencing of MMP-9 using a MMP-9 specific siRNA. Furthermore, we determined that the second extracellular loop of CD9 was responsible for the upregulation of MMP-9 production and subsequent cell invasion. We demonstrated for the first time that tetraspanin CD9 controls HT1080 cell invasion via upregulation of an integral member of the MMP family, MMP-9. Collectively, our studies provide mounting evidence that altered expression of CD9 may be a novel approach to regulate tumor cell progression.

  15. Tetraspanin CD9 promotes the invasive phenotype of human fibrosarcoma cells via upregulation of matrix metalloproteinase-9.

    Science.gov (United States)

    Herr, Michael J; Kotha, Jayaprakash; Hagedorn, Nikolaus; Smith, Blake; Jennings, Lisa K

    2013-01-01

    Tumor cell metastasis, a process which increases the morbidity and mortality of cancer patients, is highly dependent upon matrix metalloproteinase (MMP) production. Small molecule inhibitors of MMPs have proven unsuccessful at reducing tumor cell invasion in vivo. Therefore, finding an alternative approach to regulate MMP is an important endeavor. Tetraspanins, a family of cell surface organizers, play a major role in cell signaling events and have been implicated in regulating metastasis in numerous cancer cell lines. We stably expressed tetraspanin CD9 in an invasive and metastatic human fibrosarcoma cell line (CD9-HT1080) to investigate its role in regulating tumor cell invasiveness. CD9-HT1080 cells displayed a highly invasive phenotype as demonstrated by matrigel invasion assays. Statistically significant increases in MMP-9 production and activity were attributed to CD9 expression and were not due to any changes in other key tetraspanin complex members or MMP regulators. Increased invasion of CD9-HT1080 cells was reversed upon silencing of MMP-9 using a MMP-9 specific siRNA. Furthermore, we determined that the second extracellular loop of CD9 was responsible for the upregulation of MMP-9 production and subsequent cell invasion. We demonstrated for the first time that tetraspanin CD9 controls HT1080 cell invasion via upregulation of an integral member of the MMP family, MMP-9. Collectively, our studies provide mounting evidence that altered expression of CD9 may be a novel approach to regulate tumor cell progression.

  16. The multifunctional role of the pallilysin-associated Treponema pallidum protein, Tp0750, in promoting fibrinolysis and extracellular matrix component degradation.

    Science.gov (United States)

    Houston, Simon; Russell, Shannon; Hof, Rebecca; Roberts, Alanna K; Cullen, Paul; Irvine, Kyle; Smith, Derek S; Borchers, Christoph H; Tonkin, Michelle L; Boulanger, Martin J; Cameron, Caroline E

    2014-02-01

    The mechanisms that facilitate dissemination of the highly invasive spirochaete, Treponema pallidum, are incompletely understood. Previous studies showed the treponemal metalloprotease pallilysin (Tp0751) possesses fibrin clot degradation capability, suggesting a role in treponemal dissemination. In the current study we report characterization of the functionally linked protein Tp0750. Structural modelling predicts Tp0750 contains a von Willebrand factor type A (vWFA) domain, a protein-protein interaction domain commonly observed in extracellular matrix (ECM)-binding proteins. We report Tp0750 is a serine protease that degrades the major clot components fibrinogen and fibronectin. We also demonstrate Tp0750 cleaves a matrix metalloprotease (MMP) peptide substrate that is targeted by several MMPs, enzymes central to ECM remodelling. Through proteomic analyses we show Tp0750 binds the endothelial fibrinolytic receptor, annexin A2, in a specific and dose-dependent manner. These results suggest Tp0750 constitutes a multifunctional protein that is able to (1) degrade infection-limiting clots by both inhibiting clot formation through degradation of host coagulation cascade proteins and promoting clot dissolution by complexing with host proteins involved in the fibrinolytic cascade and (2) facilitate ECM degradation via MMP-like proteolysis of host components. We propose that through these activities Tp0750 functions in concert with pallilysin to enable T. pallidum dissemination.

  17. Choroidal neovascular membrane associated with choroidal osteoma (CO treated with trans-pupillary thermo therapy.

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    Sharma Sumita

    2004-01-01

    Full Text Available Choroidal neovascular membrane, a known complication of choroidal osteoma causing visual loss when located subfoveally, can be successfully treated with transpupillary thermo therapy.

  18. Peripapillary subretinal neovascularization and serous macular detachment. Association with congenital optic nerve pits.

    Science.gov (United States)

    Borodic, G E; Gragoudas, E S; Edward, W O; Brockhurst, R J

    1984-02-01

    Congenital anomalous disc changes were associated with acquired macular detachment and peripapillary choroidal neovascularization in two cases. The anomalous disc changes resembled optic nerve pits. In one case, the peripapillary choroidal neovascularization was treated with argon laser photocoagulation, with subsequent reattachment of the macula and considerable improvement in the visual acuity. Although the pathogenesis of macular detachment occurring with optic nerve pits is usually not disclosed by fluorescein angiography, leakage from choroidal neovascularization can occur with this congenital defect and may contribute to the formation of a neurosensory macular detachment. If found, choroidal neovascularization may represent a remedial cause for visual loss in a condition with an otherwise poor prognosis.

  19. Peripapillary subretinal neovascularization in sarcoidosis: remission and exacerbation during oral corticosteroid therapy.

    Science.gov (United States)

    Abe, Koji; Shiraki, Kunihiko; Yasunari, Takaharu; Kohno, Takeya; Miki, Tokuhiko

    2002-01-01

    In sarcoidosis, peripapillary subretinal neovascularization is rare. The role of corticosteroid therapy for subretinal neovascularization is controversial. A 38-year-old female patient weighing 38 kg with histologically diagnosed sarcoidosis presented with peripapillary subretinal neovascularization, retinal phlebitis, a hyperemic disc, and snowball vitreous opacities in the left eye. Oral betamethasone therapy at an initial dose of 3 mg/day reduced the size of subretinal neovascular membrane, and the membrane became fibrous. Despite the total initial 140 mg of betamethasone given over 2.5 months and the additional total 700 mg of prednisolone given over the next 2 months, the subretinal neovascularization recurred. Six months after the first recurrence, a second recurrence developed during the tapering-off period of oral corticosteroid therapy. At the second recurrence, the oral corticosteroid therapy was ineffective in reducing the size of the neovascular membrane. In our patient, oral corticosteroids temporarily suppressed peripapillary subretinal neovascularization but failed to prevent extension of neovascular membrane to the fovea because of recurrent sarcoidosis. Over time, oral corticosteroids appear to lose their effectiveness for treating repeated recurrence of peripapillary subretinal neovascularization associated with sarcoidosis.

  20. Suicide gene reveals the myocardial neovascularization role of mesenchymal stem cells overexpressing CXCR4 (MSC(CXCR4.

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    Jialiang Liang

    Full Text Available BACKGROUND: Our previous studies indicated that MSC(CXCR4 improved cardiac function after myocardial infarction (MI. This study was aimed to investigate the specific role of MSC(CXCR4 in neovascularization of infarcted myocardium using a suicide gene approach. METHODS: MSCs were transduced with either lentivirus-null vector/GFP (MSC(Null as control or vector encoding for overexpressing CXCR4/GFP. The MSC derived-endothelial cell (EC differentiation was assessed by a tube formation assay, Dil-ac-LDL uptake, EC marker expression, and VE-cadherin promoter activity assay. Gene expression was analyzed by quantitative RT-PCR or Western blot. The suicide gene approach was under the control of VE-cadherin promoter. In vivo studies: Cell patches containing MSC(Null or MSC(CXCR4 were transduced with suicide gene and implanted into the myocardium of MI rat. Rats received either ganciclovir (GCV or vehicle after cell implantation. After one month, the cardiac functional changes and neovascularization were assessed by echocardiography, histological analysis, and micro-CT imaging. RESULTS: The expression of VEGF-A and HIF-1α was significantly higher in MSC(CXCR4 as compared to MSC(Null under hypoxia. Additionally, MSC(CXCR4 enhanced new vessel formation and EC differentiation, as well as STAT3 phosphorylation under hypoxia. STAT3 participated in the transcription of VE-cadherin in MSC(CXCR4 under hypoxia, which was inhibited by WP1066 (a STAT3 inhibitor. In addition, GCV specifically induced death of ECs with suicide gene activation. In vivo studies: MSC(CXCR4 implantation promoted cardiac functional restoration, reduced infarct size, improved cardiac remodeling, and enhanced neovascularization in ischemic heart tissue. New vessels derived from MSC(CXCR4 were observed at the injured heart margins and communicated with native coronary arteries. However, the derived vessel networks were reduced by GCV, reversing improvement of cardiac function. CONCLUSION: The

  1. Ultrasound imaging of breast tumor perfusion and neovascular morphology.

    Science.gov (United States)

    Hoyt, Kenneth; Umphrey, Heidi; Lockhart, Mark; Robbin, Michelle; Forero-Torres, Andres

    2015-09-01

    A novel image processing strategy is detailed for simultaneous measurement of tumor perfusion and neovascular morphology parameters from a sequence of dynamic contrast-enhanced ultrasound (DCE-US) images. After normalization and tumor segmentation, a global time-intensity curve describing contrast agent flow was analyzed to derive surrogate measures of tumor perfusion (i.e., peak intensity, time-to-peak intensity, area under the curve, wash-in rate, wash-out rate). A maximum intensity image was generated from these same segmented image sequences, and each vascular component was skeletonized via a thinning algorithm. This skeletonized data set and collection of vessel segments were then investigated to extract parameters related to the neovascular network and physical architecture (i.e., vessel-to-tissue ratio, number of bifurcations, vessel count, average vessel length and tortuosity). An efficient computation of local perfusion parameters was also introduced and operated by averaging time-intensity curve data over each individual neovascular segment. Each skeletonized neovascular segment was then color-coded by these local measures to produce a parametric map detailing spatial properties of tumor perfusion. Longitudinal DCE-US image data sets were collected in six patients diagnosed with invasive breast cancer using a Philips iU22 ultrasound system equipped with a L9-3 transducer and Definity contrast agent. Patients were imaged using US before and after contrast agent dosing at baseline and again at weeks 6, 12, 18 and 24 after treatment started. Preliminary clinical results suggested that breast tumor response to neoadjuvant chemotherapy may be associated with temporal and spatial changes in DCE-US-derived parametric measures of tumor perfusion. Moreover, changes in neovascular morphology parametric measures may also help identify any breast tumor response (or lack thereof) to systemic treatment. Breast cancer management from early detection to therapeutic

  2. The effect of subconjunctival suramin on corneal neovascularization in rabbits.

    Science.gov (United States)

    Lee, Hyun Soo; Chung, Sung Kun

    2010-01-01

    To evaluate the effect of subconjunctival injection of suramin on corneal neovascularization in rabbits. Corneal neovascularization was induced by silk suturing of the corneal stroma in 40 eyes of 40 male New Zealand white rabbits. Five days after suture placement, all rabbits were randomly divided into 4 groups of 10 rabbits and were treated subconjunctivally with balanced salt solution 0.1 mL (group 1), suramin 0.1 mL (10 mg/mL and 100 mg/mL, groups 2 and 3, respectively), and bevacizumab 2.5 mg/0.1 mL (group 4). Digital photographs of eyes were obtained and analyzed on days 7, 14, and 28 after subconjunctival injections. In addition, vascular endothelial growth factor (VEGF) enzyme-linked immunosorbent assay (ELISA) and immunohistochemical analyses were used to estimate the level of VEGF and the expression of VEGF and basic FGF in neovascularized cornea, respectively. The neovascularized area in control was increased significantly for 14 days after subconjunctival injection, but slightly decreased on day 28. On days 7 and 14, group 4 exhibited greater antiangiogenic effect than group 3, but group 3 exhibited greater antiangiogenic effect than group 4 on day 28. VEGF ELISA analysis showed the mean concentration of VEGF in group 4 was significantly lower than with other treatments for the first 14 days, but the mean concentration of VEGF in group 4 was similar to that with group 3 on day 28. Immunohistochemical analysis showed that the expressions of both VEGF and basic fibroblast growth factor (FGF) were reduced in group 3 and that bevacizumab reduced VEGF expression relative to basic FGF on day 28. Subconjunctival suramin 100 mg/mL exhibited less antiangiogenic effect than bevacizumab 2.5 mg during the early period of treatment, but it had a longer effect than that of bevacizumab later. Therefore, the combination of subconjunctival bevacizumab and suramin may provide a more potent effect in early treatment as well as a longer antiangiogenic effect in

  3. Rap1 GTPase activation and barrier enhancement in rpe inhibits choroidal neovascularization in vivo.

    Directory of Open Access Journals (Sweden)

    Erika S Wittchen

    Full Text Available Loss of barrier integrity precedes the development of pathologies such as metastasis, inflammatory disorders, and blood-retinal barrier breakdown present in neovascular age-related macular degeneration. Rap1 GTPase is involved in regulating both endothelial and epithelial cell junctions; the specific role of Rap1A vs. Rap1B isoforms is less clear. Compromise of retinal pigment epithelium barrier function is a contributing factor to the development of AMD. We utilized shRNA of Rap1 isoforms in cultured human retinal pigment epithelial cells, along with knockout mouse models to test the role of Rap1 on promoting RPE barrier properties, with emphasis on the dynamic junctional regulation that is triggered when the adhesion between cells is challenged. In vitro, Rap1A shRNA reduced steady-state barrier integrity, whereas Rap1B shRNA affected dynamic junctional responses. In a laser-induced choroidal neovascularization (CNV model of macular degeneration, Rap1b(-/- mice exhibited larger CNV volumes compared to wild-type or Rap1a(-/- . In vivo, intravitreal injection of a cAMP analog (8CPT-2'-O-Me-cAMP that is a known Rap1 activator significantly reduced laser-induced CNV volume, which correlated with the inhibition of CEC transmigration across 8CPT-2'O-Me-cAMP-treated RPE monolayers in vitro. Rap1 activation by 8CPT-2'-O-Me-cAMP treatment increased recruitment of junctional proteins and F-actin to cell-cell contacts, increasing both the linearity of junctions in vitro and in cells surrounding laser-induced lesions in vivo. We conclude that in vitro, Rap1A may be important for steady state barrier integrity, while Rap1B is involved more in dynamic junctional responses such as resistance to junctional disassembly induced by EGTA and reassembly of cell junctions following disruption. Furthermore, activation of Rap1 in vivo inhibited development of choroidal neovascular lesions in a laser-injury model. Our data suggest that targeting Rap1 isoforms in vivo

  4. Solar-simulated ultraviolet radiation induces histone 3 methylation changes in the gene promoters of matrix metalloproteinases 1 and 3 in primary human dermal fibroblasts.

    Science.gov (United States)

    Gesumaria, Lisa; Matsui, Mary S; Kluz, Thomas; Costa, Max

    2015-05-01

    Molecular signalling pathways delineating the induction of matrix metalloproteinases (MMPs) by ultraviolet radiation (UVR) are currently well-defined; however, the effects of UVR on epigenetic mechanisms of MMP induction are not as well understood. In this study, we examined solar-simulated UVR (ssUVR)-induced gene expression changes and alterations to histone methylation in the promoters of MMP1 and MMP3 in primary human dermal fibroblasts (HDF). Gene expression changes, including the increased expression of MMP1 and MMP3, were observed using Affymetrix GeneChip arrays and confirmed by qRT-PCR. Using ChIP-PCR, we showed for the first time that in HDF irradiated with 12 J/cm(2) ssUVR, the H3K4me3 transcriptional activating mark increased and the H3K9me2 transcriptional silencing mark decreased in abundance in promoters, correlating with the observed elevation of MMP1 and MMP3 mRNA levels following ssUVR exposure. Changes in mRNA levels due to a single exposure were transient and decreased 5 days after exposure.

  5. Macrophage activation associated with chronic murine cytomegalovirus infection results in more severe experimental choroidal neovascularization.

    Directory of Open Access Journals (Sweden)

    Scott W Cousins

    Full Text Available The neovascular (wet form of age-related macular degeneration (AMD leads to vision loss due to choroidal neovascularization (CNV. Since macrophages are important in CNV development, and cytomegalovirus (CMV-specific IgG serum titers in patients with wet AMD are elevated, we hypothesized that chronic CMV infection contributes to wet AMD, possibly by pro-angiogenic macrophage activation. This hypothesis was tested using an established mouse model of experimental CNV. At 6 days, 6 weeks, or 12 weeks after infection with murine CMV (MCMV, laser-induced CNV was performed, and CNV severity was determined 4 weeks later by analysis of choroidal flatmounts. Although all MCMV-infected mice exhibited more severe CNV when compared with control mice, the most severe CNV developed in mice with chronic infection, a time when MCMV-specific gene sequences could not be detected within choroidal tissues. Splenic macrophages collected from mice with chronic MCMV infection, however, expressed significantly greater levels of TNF-α, COX-2, MMP-9, and, most significantly, VEGF transcripts by quantitative RT-PCR assay when compared to splenic macrophages from control mice. Direct MCMV infection of monolayers of IC-21 mouse macrophages confirmed significant stimulation of VEGF mRNA and VEGF protein as determined by quantitative RT-PCR assay, ELISA, and immunostaining. Stimulation of VEGF production in vivo and in vitro was sensitive to the antiviral ganciclovir. These studies suggest that chronic CMV infection may serve as a heretofore unrecognized risk factor in the pathogenesis of wet AMD. One mechanism by which chronic CMV infection might promote increased CNV severity is via stimulation of macrophages to make pro-angiogenic factors (VEGF, an outcome that requires active virus replication.

  6. Relationship between neovascularization and clinical severity in Achilles tendinopathy in 556 paired measurements.

    Science.gov (United States)

    De Jonge, S; Warnaars, J L F; De Vos, R J; Weir, A; van Schie, H T M; Bierma-Zeinstra, S M A; Verhaar, J A N; Tol, J L

    2014-10-01

    Neovascularization is frequently observed in tendinopathy. Previous studies have focused on the role of neovascularization in Achilles tendinopathy, but have been conducted in small series. It is still unclear whether the degree of neovascularization is related to severity of symptoms. The purpose was to study the relationship between ultrasonographic neovascularization and clinical severity in patients with Achilles tendinopathy. In this prospective cohort study, data on 127 patients (141 tendons) were assembled from databases of three clinical trials. All patients followed an eccentric exercise program. The Öhberg neovascularization score (0-4+) and Victorian Institute of Sports Assessment-Achilles (VISA-A) score (split into domains: pain, function and activity) were collected during baseline and follow-up. The relationship between neovascularization and VISA-A score was calculated. At baseline, 107 tendons (76%) showed some degree of neovascularization. In 556 coupled measurements, neovascularization was weakly related to the VISA-A score [Exp (B) 1.017, 95% confidence interval (CI), 1.007-1.026]. No significant relationship was found between neovascularization and the pain domain (P = 0.277) and the activity domain (P = 0.283), but there was between neovascularization and the function domain of the VISA-A score [Exp (B) = 1.067, 95% CI 1.018-1.119]. In conclusion, neovascularization in Achilles tendinopathy is weakly related to clinical severity, mainly based on the function domain of the VISA-A score. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Slit2-Robo1 signaling promotes the adhesion, invasion and migration of tongue carcinoma cells via upregulating matrix metalloproteinases 2 and 9, and downregulating E-cadherin

    Science.gov (United States)

    Zhao, Yuan; Zhou, Feng-Li; Li, Wei-Ping; Wang, Jing; Wang, Li-Jing

    2016-01-01

    Whether Slit homologue 2 (Slit2) inhibits or promotes tumor cell migration remains controversial, and the role of Slit2-Roundabout 1 (Robo1) signaling in oral cancer remains to be fully elucidated. The aim of the present study was to investigate the role of Slit2-Robo1 signaling in the adhesion, invasion and migration of tongue carcinoma cells, and the mechanism by which Slit2-Robo1 signaling inhibits or promotes tumor cell migration. Tca8113 tongue carcinoma cells were treated with the monoclonal anti-human Robo1 antibody, R5, to inhibit the Slit2-Robo1 signaling pathway, with immunoglobulin (Ig)G2b treatment as a negative control. The expression levels of Slit2 and Robo1 were determined using flow cytometry. The effects of R5 on the adhesion, invasion and migration of Tca8113 tongue carcinoma cells were investigated. Gelatin zymography was used to investigate the activity of matrix metalloproteinase 2 (MMP2) and MMP9. Western blot analysis was used to evaluate the expression levels of E-cadherin in Tca8113 cells treated with 10 µg/ml of either R5 or IgG2b. Slit2 and Robo1 proteins were found to be expressed in the Tca8113 cells. R5 significantly inhibited the adhesion, invasion and migration of Tca8113 cells in vitro. R5 also inhibited the activities of MMP2 and MMP9, and increased the expression of E-cadherin in the Tca8113 cells. These results suggested that Slit2-Robo1 signaling promoted the adhesion, invasion and migration of tongue carcinoma cells by upregulating the expression levels of MMP2 and MMP9 and, downregulating the expression of E-cadherin. PMID:27431199

  8. RAGE regulates immune cell infiltration and angiogenesis in choroidal neovascularization.

    Directory of Open Access Journals (Sweden)

    Mei Chen

    Full Text Available PURPOSE: RAGE regulates pro-inflammatory responses in diverse cells and tissues. This study has investigated if RAGE plays a role in immune cell mobilization and choroidal neovascular pathology that is associated with the neovascular form of age-related macular degeneration (nvAMD. METHODS: RAGE null (RAGE-/- mice and age-matched wild type (WT control mice underwent laser photocoagulation to generate choroidal neovascularization (CNV lesions which were then analyzed for morphology, S100B immunoreactivity and inflammatory cell infiltration. The chemotactic ability of bone marrow derived macrophages (BMDMs towards S100B was investigated. RESULTS: RAGE expression was significantly increased in the retina during CNV of WT mice (p<0.001. RAGE-/- mice exhibited significantly reduced CNV lesion size when compared to WT controls (p<0.05. S100B mRNA was upregulated in the lasered WT retina but not RAGE-/- retina and S100B immunoreactivity was present within CNV lesions although levels were less when RAGE-/- mice were compared to WT controls. Activated microglia in lesions were considerably less abundant in RAGE-/- mice when compared to WT counterparts (p<0.001. A dose dependent chemotactic migration was observed in BMDMs from WT mice (p<0.05-0.01 but this was not apparent in cells isolated from RAGE-/- mice. CONCLUSIONS: RAGE-S100B interactions appear to play an important role in CNV lesion formation by regulating pro-inflammatory and angiogenic responses. This study highlights the role of RAGE in inflammation-mediated outer retinal pathology.

  9. OCT Angiography Identification of Choroidal Neovascularization Secondary to Acute Zonal Occult Outer Retinopathy.

    Science.gov (United States)

    Levison, Ashleigh L; Baynes, Kimberly; Lowder, Careen Y; Srivastava, Sunil K

    2016-01-01

    A 74-year-old female with acute zonal occult outer retinopathy presented with a new lesion suspicious for choroidal neovascularization (CNV) in her right eye. Optical coherence tomography angiography (OCTA) confirmed the presence of CNV. OCTA is a new imaging technique that may help guide diagnosis and management of choroidal neovascular membranes in uveitic diseases.

  10. Circulating human CD34(+) progenitor cells modulate neovascularization and inflammation in a nude mouse model

    NARCIS (Netherlands)

    van der Strate, B. W. A.; Popa, E. R.; Schipper, M.; Brouwer, L. A.; Hendriks, M.; Harmsen, M. C.; van Luyn, M. J. A.

    2007-01-01

    CD34(+) progenitor cells hold promise for therapeutic neovascularization in various settings. In this study, the role of human peripheral blood CD34(+) cells in neovascularization and inflammatory cell recruitment was longitudinally studied in vivo. Human CD34(+) cells were incorporated in Matrigel,

  11. Correlation between clinical and histological features in a pig model of choroidal neovascularization

    DEFF Research Database (Denmark)

    Lassota, Nathan; Kiilgaard, Jens Folke; Prause, Jan Ulrik;

    2006-01-01

    To analyse the histological changes in the retina and the choroid in a pig model of choroidal neovascularization (CNV) and to correlate these findings with fundus photographic and fluorescein angiographic features.......To analyse the histological changes in the retina and the choroid in a pig model of choroidal neovascularization (CNV) and to correlate these findings with fundus photographic and fluorescein angiographic features....

  12. The Relationship between Neovascular Age-Related Macular Degeneration and Erectile Dysfunction

    Directory of Open Access Journals (Sweden)

    Harun Çakmak

    2013-01-01

    Full Text Available Purpose. To evaluate association between erectile dysfunction (ED and neovascular age-related macular degeneration (AMD. Methods. 195 men enrolled in this cross-sectional study. 90 of them had neovascular AMD and 105 of them were healthy volunteers. The International Index of Erectile Function (IIEF questionnaire’s erectile function (EF domain was used to assess ED. The patients in the study and control groups were statistically compared according to visual acuity, EF score, and body mass index. Results. The mean ages were 62 (54.5–73 and 60 (54–68, in the neovascular AMD and control groups, respectively. The total EF scores were 9 (6–16 in neovascular AMD and 18 (9.5–27 in control group. The results of IIEF questionnaire on neovascular AMD patients revealed that 85 men (94.4% had some degree of ED, whereas 68 men (64.8% had some degree of ED on control group. Patients with neovascular AMD had a significantly higher incidence of ED than control patients (. There was a significant association between ED and neovascular AMD (. Conclusions. Our results suggested that neovascular AMD has a high association with ED.

  13. Moderate GSK-3β inhibition improves neovascular architecture, reduces vascular leakage, and reduces retinal hypoxia in a model of ischemic retinopathy.

    Science.gov (United States)

    Hoang, Mien V; Smith, Lois E H; Senger, Donald R

    2010-09-01

    In ischemic retinopathies, unrelieved hypoxia induces the formation of architecturally abnormal, leaky blood vessels that damage retina and ultimately can cause blindness. Because these newly formed blood vessels are functionally defective, they fail to alleviate underlying hypoxia, resulting in more pathological neovascularization and more damage to retina. With an established model of ischemic retinopathy, we investigated inhibition of glycogen synthase kinase-3β (GSK-3β) as a means for improving the architecture and functionality of pathological blood vessels in retina. In vitro, hypoxia increased GSK-3β activity in retinal endothelial cells, reduced β-catenin, and correspondingly impaired integrity of cell/cell junctions. Conversely, GSK-3β inhibitors restored β-catenin, improved cell/cell junctions, and enhanced the formation of capillary cords in three-dimensional collagen matrix. In vivo, GSK-3β inhibitors, at appropriately moderate doses, strongly reduced abnormal vascular tufts, reduced abnormal vascular leakage, and improved vascular coverage and perfusion during the proliferative phase of ischemia-driven retinal neovascularization. Most importantly, these improvements in neovasculature were accompanied by marked reduction in retinal hypoxia, relative to controls. Thus, GSK-3β inhibitors offer a promising strategy for alleviating retinal hypoxia by correcting key vascular defects typically associated with ischemia-driven neovascularization.

  14. Neovascular Glaucoma in a Patient with X-linked Juvenile Retinoschisis

    Institute of Scientific and Technical Information of China (English)

    Chengguo Zuo; Changzheng Chen; Yiqiao Xing; Lei Du

    2005-01-01

    Purpose: To report the rubeosis iridis and neovascular glaucoma findings in one patient of X-linked juvenile retinoschisis (XLRS).Methods: Color fundus photography, fluorescein angiography (FFA), OCT and B-scan were performed in a patient with X-linked juvenile retinoschisis complicated with neovascular glaucoma.Result: Color fundus photography, fluorescein angiography (FFA), OCT and B-scan unveiled a rare condition of XLRS complicated with neovascular glaucoma.Conclusion: XLRS may complicate with neovascular glaucoma. It is necessary to test OCT, FFA, ERG and carefully examine the fundus of the follow eye when it comes to uncertain neovascular glaucoma of youth and child. And only in this way, can we exclude XLRS.

  15. Multi-scale osteointegration and neovascularization of biphasic calcium phosphate bone scaffolds

    Science.gov (United States)

    Lan, Sheeny K.

    osteoinductive proteins. To further investigate the effects of scaffold osteoinductivity, BCP scaffolds were implanted in porcine mandibular defects with rhBMP-2, which was partially sequestered in the micropores. Cell migration into osteoinductive scaffold micropores can be enhanced through the delivery of exogenous rhBMP-2 further promoting multi-scale osteointegration. Finally, endothelial colony forming cells (ECFCs) isolated from human umbilical cord blood (UCB) were evaluated in terms of their in vivo vasculogenic potential in the context of bone formation. This work was completed to determine if ECFCs could be utilized in a bone tissue engineering construct to promote neovascularization. ECFCs were combined with a BCP scaffold and rhBMP-2 and implanted subcutaneously on the abdominal wall of NOD/SCID mice. The result was formation of perfused human vessels within BCP scaffold macropores that were present at 4 weeks. The high density and persistence of human vessels at four weeks indicates that human UCB ECFCs exceed their reported in vivo vasculogenic potential when combined with rhBMP-2 and a BCP scaffold. This shows a dual role for BMP-2 in the context of bone regeneration. Collectively, the thesis demonstrates that (1) the design of synthetic bone scaffolds should include controlled multi-scale porosity to promote multi-scale osteointegration, which may significantly improve scaffold mechanical properties and (2) human umbilical cord blood-derived endothelial colony forming cells have potential for promoting neovascularization in a bone defect when combined with rhBMP-2.

  16. MicroRNA-106a promotes cell migration and invasion by targeting tissue inhibitor of matrix metalloproteinase 2 in cervical cancer.

    Science.gov (United States)

    Li, Xia; Zhou, Qi; Tao, Ling; Yu, Chunxia

    2017-09-01

    Increasing evidence has demonstrated that miRNAs play a critical role in tumor development and progression. Previous studies have revealed that miR-106a is abnormally expressed in various cancers. However, its function and underlying mechanism in cervical cancer (CC) remains unknown. In this study, we confirmed that the expression of miR-106a was significantly upregulated in both CC cell lines and tissues by qRT-PCR. The increased expression of miR-106a was obviously associated with adverse prognostic features. Moreover, we demonstrated that miR-106a was a novel independent prognostic marker for predicting the 5-year survival of CC patients. The ectopic overexpression of miR‑106a promoted cell migration, invasion and invasion-related gene expression, while downregulated miR-106a reversed the effect. In addition, miR-106a regulated tissue inhibitor of metalloproteinase (TIMP)2 by directly binding to its 3'-UTR, leading to the indution of the expression of matrix metalloproteinases (MMPs). In clinical samples of CC, miR-106a was inversely correlated with TIMP2, which was downregulated in CC. Alteration of TIMP2 expression at least partially abolished the migration, invasion and MMP expression of miR-106a in CC cells. In conclusion, our data indicated that miR-106a promoted the migration, invasion and MMP expression of CC by targeting TIMP2, and may represent a novel potential therapeutic target and prognostic marker for CC.

  17. Presence of Insulin-Like Growth Factor Binding Proteins Correlates With Tumor-Promoting Effects of Matrix Metalloproteinase 9 in Breast Cancer

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    Jae-Hyun Park

    2015-05-01

    Full Text Available The stroma of breast cancer can promote the disease’s progression, but whether its composition and functions are shared among different subtypes is poorly explored. We compared stromal components of a luminal [mouse mammary tumor virus (MMTV–Neu] and a triple-negative/basal-like [C3(1–Simian virus 40 large T antigen (Tag] genetically engineered breast cancer mouse model. The types of cytokines and their expression levels were very different in the two models, as was the extent of innate immune cell infiltration; however, both models showed infiltration of innate immune cells that expressed matrix metalloproteinase 9 (MMP9, an extracellular protease linked to the progression of many types of cancer. By intercrossing with Mmp9 null mice, we found that the absence of MMP9 delayed tumor onset in the C3(1-Tag model but had no effect on tumor onset in the MMTV-Neu model. We discovered that protein levels of insulin-like growth factor binding protein-1 (IGFBP-1, an MMP9 substrate, were increased in C3(1-Tag;Mmp9−/− compared to C3(1-Tag;Mmp9+/+ tumors. In contrast, IGFBP-1 protein expression was low in MMTV-Neu tumors regardless of Mmp9 status. IGFBP-1 binds and antagonizes IGFs, preventing them from activating their receptors to promote cell proliferation and survival. Tumors from C3(1-Tag;Mmp9−/− mice had reduced IGF-1 receptor phosphorylation, consistent with slower tumor onset. Finally, gene expression analysis of human breast tumors showed that high expression of IGFBP mRNA was strongly correlated with good prognosis but not when MMP9 mRNA was also highly expressed. In conclusion, MMP9 has different effects on breast cancer progression depending on whether IGFBPs are expressed.

  18. Platelet-rich fibrin matrix improves wound angiogenesis via inducing endothelial cell proliferation.

    Science.gov (United States)

    Roy, Sashwati; Driggs, Jason; Elgharably, Haytham; Biswas, Sabyasachi; Findley, Muna; Khanna, Savita; Gnyawali, Urmila; Bergdall, Valerie K; Sen, Chandan K

    2011-11-01

    The economic, social, and public health burden of chronic ulcers and other compromised wounds is enormous and rapidly increasing with the aging population. The growth factors derived from platelets play an important role in tissue remodeling including neovascularization. Platelet-rich plasma (PRP) has been utilized and studied for the last four decades. Platelet gel and fibrin sealant, derived from PRP mixed with thrombin and calcium chloride, have been exogenously applied to tissues to promote wound healing, bone growth, hemostasis, and tissue sealing. In this study, we first characterized recovery and viability of as well as growth factor release from platelets in a novel preparation of platelet gel and fibrin matrix, namely platelet-rich fibrin matrix (PRFM). Next, the effect of PRFM application in a delayed model of ischemic wound angiogenesis was investigated. The study, for the first time, shows the kinetics of the viability of platelet-embedded fibrin matrix. A slow and steady release of growth factors from PRFM was observed. The vascular endothelial growth factor released from PRFM was primarily responsible for endothelial mitogenic response via extracellular signal-regulated protein kinase activation pathway. Finally, this preparation of PRFM effectively induced endothelial cell proliferation and improved wound angiogenesis in chronic wounds, providing evidence of probable mechanisms of action of PRFM in healing of chronic ulcers.

  19. Mixed Fibronectin-Derived Peptides Conjugated to a Chitosan Matrix Effectively Promotes Biological Activities through Integrins, α4β1, α5β1, αvβ3, and Syndecan

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    Hozumi Kentaro

    2016-11-01

    Full Text Available Mimicking the biological function of the extracellular matrix is an approach to developing cell adhesive biomaterials. The RGD peptide, derived from fibronectin (Fn, mainly binds to integrin αvβ3 and has been widely used as a cell adhesive peptide on various biomaterials. However, cell adhesion to Fn is thought to be mediated by several integrin subtypes and syndecans. In this study, we synthesized an RGD-containing peptide (FIB1 and four integrin α4β1-binding-related motif-containing peptides (LDV, IDAPS, KLDAPT, and PRARI and constructed peptide-chitosan matrices. The FIB1-chitosan matrix promoted human dermal fibroblast (HDF attachment, and the C-terminal elongated PRARI (ePRARI-C-conjugated chitosan matrix significantly promoted HDF attachment through integrin α4β1 and syndecan binding. Next, we constructed a mixed ePRARI-C- and FIB1-chitosan matrix to develop a Fn mimetic biomaterial. The mixed ePRARI-C/FIB1-chitosan matrix promoted significantly better cell attachment and neurite outgrowth compared to those of either ePRARI-C- or FIB1-chitosan matrices. HDF adhesion to the ePRARI-C/FIB1-chitosan matrix was mediated by integrin, α4β1, α5β1, and αvβ3, similar to HDF adhesion to Fn. These data suggest that an ePRARI-C/FIB1-chitosan matrix can be used as a tool to analyze the multiple functions of Fn and can serve as a Fn-mimetic biomaterial.

  20. Prognostic Factor Analysis of Intraocular Pressure with Neovascular Glaucoma.

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    Nakano, Satoko; Nakamuro, Takako; Yokoyama, Katsuhiko; Kiyosaki, Kunihiro; Kubota, Toshiaki

    2016-01-01

    Purpose. To perform multivariate analysis for identifying independent predictors of elevated intraocular pressure (IOP) with neovascular glaucoma (NVG), including antivascular endothelial growth factor (VEGF) intravitreal injections. Methods. We retrospectively reviewed 142 NVG patients (181 eyes) with ischemic retinal diseases [proliferative diabetic retinopathy (PDR) in 134 eyes, retinal vein occlusion (RVO) in 29, and ocular ischemic syndrome in 18]. We analyzed age, gender, initial/final LogMAR VA, initial/final IOP, extent of iris and/or angle neovascularization, treatments, preexisting complications, concurrent medications, and follow-up duration. Results. The mean follow-up duration was 23.8 ± 18.8 months. At the final follow-up, 125 (72.3%) eyes had IOP ≤ 21 mmHg. NVG patients with RVO had a higher degree of angle closure and higher IOP. NVG with PDR had better IOP and LogMAR VA. Angle closure had the greatest impact on final IOP. Greater than 90% of patients treated with trabeculectomy with mitomycin C (LEC) had persistent declines in IOP (≤21 mmHg). Stand-alone and combination anti-VEGF therapies were not associated with improved long-term prognosis of IOP. Conclusions. Angle closure was found to have the greatest effect on NVG-IOP prognosis. When target IOP values are not obtained after adequate PRP with or without anti-VEGF, early LEC may improve the prognosis of IOP.

  1. Prognostic Factor Analysis of Intraocular Pressure with Neovascular Glaucoma

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    Satoko Nakano

    2016-01-01

    Full Text Available Purpose. To perform multivariate analysis for identifying independent predictors of elevated intraocular pressure (IOP with neovascular glaucoma (NVG, including antivascular endothelial growth factor (VEGF intravitreal injections. Methods. We retrospectively reviewed 142 NVG patients (181 eyes with ischemic retinal diseases [proliferative diabetic retinopathy (PDR in 134 eyes, retinal vein occlusion (RVO in 29, and ocular ischemic syndrome in 18]. We analyzed age, gender, initial/final LogMAR VA, initial/final IOP, extent of iris and/or angle neovascularization, treatments, preexisting complications, concurrent medications, and follow-up duration. Results. The mean follow-up duration was 23.8 ± 18.8 months. At the final follow-up, 125 (72.3% eyes had IOP ≤ 21 mmHg. NVG patients with RVO had a higher degree of angle closure and higher IOP. NVG with PDR had better IOP and LogMAR VA. Angle closure had the greatest impact on final IOP. Greater than 90% of patients treated with trabeculectomy with mitomycin C (LEC had persistent declines in IOP (≤21 mmHg. Stand-alone and combination anti-VEGF therapies were not associated with improved long-term prognosis of IOP. Conclusions. Angle closure was found to have the greatest effect on NVG-IOP prognosis. When target IOP values are not obtained after adequate PRP with or without anti-VEGF, early LEC may improve the prognosis of IOP.

  2. Nanotechnology in corneal neovascularization therapy--a review.

    Science.gov (United States)

    Gonzalez, Lilian; Loza, Raymond J; Han, Kyu-Yeon; Sunoqrot, Suhair; Cunningham, Christy; Purta, Patryk; Drake, James; Jain, Sandeep; Hong, Seungpyo; Chang, Jin-Hong

    2013-03-01

    Nanotechnology is an up-and-coming branch of science that studies and designs materials with at least one dimension sized from 1-100 nm. These nanomaterials have unique functions at the cellular, atomic, and molecular levels. The term "nanotechnology" was first coined in 1974. Since then, it has evolved dramatically and now consists of distinct and independent scientific fields. Nanotechnology is a highly studied topic of interest, as nanoparticles can be applied to various fields ranging from medicine and pharmacology, to chemistry and agriculture, to environmental science and consumer goods. The rapidly evolving field of nanomedicine incorporates nanotechnology with medical applications, seeking to give rise to new diagnostic means, treatments, and tools. Over the past two decades, numerous studies that underscore the successful fusion of nanotechnology with novel medical applications have emerged. This has given rise to promising new therapies for a variety of diseases, especially cancer. It is becoming abundantly clear that nanotechnology has found a place in the medical field by providing new and more efficient ways to deliver treatment. Ophthalmology can also stand to benefit significantly from the advances in nanotechnology research. As it relates to the eye, research in the nanomedicine field has been particularly focused on developing various treatments to prevent and/or reduce corneal neovascularization among other ophthalmologic disorders. This review article aims to provide an overview of corneal neovascularization, currently available treatments, and where nanotechnology comes into play.

  3. MicroRNA signature and function in retinal neovascularization

    Institute of Scientific and Technical Information of China (English)

    Saloni; Agrawal; Brahim; Chaqour

    2014-01-01

    Ischemic retinopathies are clinically well-defined chronic microvascular complications characterized by gradually progressive alterations in the retinal microvasculature and a compensatory aberrant neovascularization of the eye. The subsequent metabolic deficiencies result in structural and functional alterations in the retina which is highly susceptible to injurious stimuli such as diabe-tes, trauma, hyperoxia, inflammation, aging and dys-plipidemia. Emerging evidence indicates that an effec-tive therapy may require targeting multiple components of the angiogenic pathway. Conceptually, mircoRNA(miRNA)-based therapy provides the rationale basis for an effective antiangiogenic treatment. miRNAs are an evolutionarily conserved family of short RNAs, each regulating the expression of multiple protein-coding genes. The activity of specific miRNAs is important for vascular cell signaling and blood vessel formation and function. Recently, important progress has been made in mapping the miRNA-gene target network andmiRNA-mediated gene expression control. Here wehighlight the latest findings on angiogenic and antian-giogenic miRNAs and their targets as well as potentiaimplications in ocular neovascular diseases. Emphasis isplaced on how specific vascular-enriched miRNAs regu-late cell responses to various cues by targeting severafactors, receptors and/or signaling molecules in orderto maintain either vascular function or dysfunction. Fur-ther improvement of our knowledge in not only miRNAspecificity, turnover, and transport but also how miRNAsequences and functions can be altered will enhancethe therapeutic utility of such molecules.

  4. Thrombospondin-1 Expression in RPE and Choroidal Neovascular Membranes

    Institute of Scientific and Technical Information of China (English)

    Shikun He; Francesca Incardona; Manlin Jin; Stephen J. Ryan; David R. Hinton

    2006-01-01

    Purpose: To investigate the expression of thrombospondin 1 (TSP-1) in retinal pigment epithelium (RPE) and choroidal neovascular membranes (CNVMs) from patients with age-related macular degeneration (AMD).Methods: Tissue sections from normal human fetal and adult eyes and surgically removed CNVMs were immunostained for TSP-1 localization. Polymerase chain reaction and Western blotting were used to analyze TSP-1 mRNA and protein from human RPE cells, respectively. TSP-1 in the supernatant of cultured RPE cells and eye explants were measured using enzyme-linked immunosorbent assay. MTT assay was used to evaluate the RPE survival after TSP-1 treatment.Results: The strongest immunostaining for TSP-1 was observed in the RPE monolayer around drusen in early AMD. The intensity of TSP-1 staining in normal eye sections was much weaker than that of early AMD and CNVM. TSP-1 mRNA was positive in cultured fetal and adult RPE cells. There was increasing secretion of TSP-1 into the supernatant of cultured RPE and eye explants. The specific band of TSP-1 was identified by Western blot. No significant inhibition of RPE survival was found with the exposure to TSP-1.Conclusions: TSP-1 expression in drusen and CNVM was upregulated and associated with RPE monolayer. TSP-1 may be a natural negative regulator for choroidal neovascularization.

  5. Matrix metalloproteinase-3 promoter polymorphisms but not dupA-H. pylori correlate to duodenal ulcers in H. pylori-infected females

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    Yeh Yi-Chun

    2010-08-01

    Full Text Available Abstract Background This study investigated if the H. pylori dupA genotype and certain host single nucleotide polymorphisms (SNPs of matrix metalloproteinases (MMPs and their inhibitors (TIMPs, including MMP-3, MMP-7, MMP-9, TIMP-1 and TIMP-2, might correlate with ulcer risk of H. pylori-infected Taiwanese patients. Results Of the 549 H. pylori-infected patients enrolled, 470 patients (265 with gastritis, 118 with duodenal ulcer, and 87 with gastric ulcer received SNPs analysis of MMP-3-1612 6A > 5A, MMP-7-181 A > G, MMP-9exon 6 A > G, TIMP-1372 T > C and TIMP-2-418 G > C by PCR-RFLP. The 181 collected H. pylori isolates were detected for the dupA genotype by PCR. The rates of dupA-positive H. pylori infection were similar among patients with duodenal ulcer (22.8%, gastric ulcer (20.0%, and gastritis (25.5% (p > 0.05. Males had higher rates of duodenal ulcer and gastric ulcer than females (p H. pylori-infected patients, the MMP-3 6A6A genotype were more common in patients with duodenal ulcers than in those with gastritis (87.7% vs. 74.9%, p p H. pylori-infected females. Conclusions The MMP-3 promoter polymorphism, but not the dupA-status, may correlate with susceptibility to duodenal ulcer after H. pylori infection in Taiwanese females.

  6. Achaete-scute complex homolog-1 promotes DNA repair in the lung carcinogenesis through matrix metalloproteinase-7 and O(6-methylguanine-DNA methyltransferase.

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    Xiao-Yang Wang

    Full Text Available Lung cancer is the leading cause of cancer-related deaths in the world. Achaete-scute complex homolog-1 (Ascl1 is a member of the basic helix-loop-helix (bHLH transcription factor family that has multiple functions in the normal and neoplastic lung such as the regulation of neuroendocrine differentiation, prevention of apoptosis and promotion of tumor-initiating cells. We now show that Ascl1 directly regulates matrix metalloproteinase-7 (MMP-7 and O(6-methylguanine-DNA methyltransferase (MGMT. Loss- and gain-of-function experiments in human bronchial epithelial and lung carcinoma cell lines revealed that Ascl1, MMP-7 and MGMT are able to protect cells from the tobacco-specific nitrosamine NNK-induced DNA damage and the alkylating agent cisplatin-induced apoptosis. We also examined the role of Ascl1 in NNK-induced lung tumorigenesis in vivo. Using transgenic mice which constitutively expressed human Ascl1 in airway lining cells, we found that there was a delay in lung tumorigenesis. We conclude that Ascl1 potentially enhances DNA repair through activation of MMP-7 and MGMT which may impact lung carcinogenesis and chemoresistance. The study has uncovered a novel and unexpected function of Ascl1 which will contribute to better understanding of lung carcinogenesis and the broad implications of transcription factors in tobacco-related carcinogenesis.

  7. Heterologous Matrix Metalloproteinase Gene Promoter Activity Allows In Vivo Real-time Imaging of Bleomycin-Induced Lung Fibrosis in Transiently Transgenized Mice

    Science.gov (United States)

    Stellari, Fabio Franco; Ruscitti, Francesca; Pompilio, Daniela; Ravanetti, Francesca; Tebaldi, Giulia; Macchi, Francesca; Verna, Andrea Elizabeth; Villetti, Gino; Donofrio, Gaetano

    2017-01-01

    Idiopathic pulmonary fibrosis is a very common interstitial lung disease derived from chronic inflammatory insults, characterized by massive scar tissue deposition that causes the progressive loss of lung function and subsequent death for respiratory failure. Bleomycin is used as the standard agent to induce experimental pulmonary fibrosis in animal models for the study of its pathogenesis. However, to visualize the establishment of lung fibrosis after treatment, the animal sacrifice is necessary. Thus, the aim of this study was to avoid this limitation by using an innovative approach based on a double bleomycin treatment protocol, along with the in vivo images analysis of bleomycin-treated mice. A reporter gene construct, containing the luciferase open reading frame under the matrix metalloproteinase-1 promoter control region, was tested on double bleomycin-treated mice to investigate, in real time, the correlation between bleomycin treatment, inflammation, tissue remodeling and fibrosis. Bioluminescence emitted by the lungs of bleomycin-treated mice, corroborated by fluorescent molecular tomography, successfully allowed real time monitoring of fibrosis establishment. The reporter gene technology experienced in this work could represent an advanced functional approach for real time non-invasive assessment of disease evolution during therapy, in a reliable and translational living animal model. PMID:28298912

  8. Nuclear factor kappa-B signaling is integral to ocular neovascularization in ischemia-independent microenvironment.

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    Michael DeNiro

    Full Text Available Retinal ischemia promotes the upregulation of VEGF expression and accounts for most pathological features of retinal neovascularization (NV. Paradoxically, VEGF remains the pivotal stimulator of ocular NV, despite the absence of ischemia. Therefore, the central question arises as to how the various molecular mechanisms interplay in ischemia-independent NV. It's been suggested that NFκB plays a crucial role in the pathogenesis of diabetic vasculopathies. Here, we dissected the molecular mechanism of ocular NV in the rho/VEGF transgenic mouse model, which develops subretinal NV in ischemia-independent microenvironment. Furthermore, we examined whether intravitreal administration of YC-1, a HIF-1 inhibitor, can modulate the activation of NFκB and its downstream angiogenic signaling in the mouse retina. We demonstrated that YC-1 inhibited retinal NFκB/p65 DNA binding activity and downregulated NFκB/p65, FAK, α5β1, EPO, ET-1, and MMP-9 expression at the message and the protein levels. In addition, YC-1 significantly inhibited subretinal NV by reducing the number of neovascular lesions, the area of each lesion and the total area of NV per retina. We further investigated the influence of VEGF signaling pathway on HIF-1α transcriptional activity to substantiate that this mouse model develops subretinal NV in an ischemia-independent microenvironment. Our data demonstrated that VEGF overexpression didn't have any impact on HIF-1α transcriptional activity, whereas treatment with YC-1 significantly inhibited endogenous HIF-1 activity. Our study suggests that retinal NFκB transcriptional activity is pivotal to ischemia-independent mechanisms, which lead to the local activation of angiogenic cascades. Our data also indicate that the nexus between VEGF and NFκB is implicated in triggering the angiogenic cascade that promotes retinal NV. Hence, targeting the VEGF/NFκB axis may act in a negative feedback loop to suppress ocular NV. This study suggests

  9. Comparison of the therapeutic effects of extracts from Spirulina platensis and amnion membrane on inflammation-associated corneal neovascularization

    Science.gov (United States)

    Yang, Ling-Ling; Zhou, Qing-Jun; Wang, Yao; Gao, Yan; Wang, Yi-Qiang

    2012-01-01

    AIM To compare the therapeutic effects of polysaccharide extract from Spirulina platensis (PSP) and extract from amnion membrane (AME) on alkali burn-induced corneal neovascularization (CorNV). METHODS PSP and AME were extracted from dry powder of Spirulina platensis and human aminion membrane respectively. Murine CorNV was induced by applying 1N sodiumhydroxide (NaOH) solution directly on the mice corneas. PSP and AME extracts were administered topically on the corneas 4 times daily for 7 days. The therapy effects of PSP and AME extracts were evaluated daily using slit-lamp. At the end of the therapy, corneas were harvested for H&E staining, masson trichrome staining, immunohistochemical study, and semi-quantification reverse transcriptive PCR (RT-PCR) was utilized for measurement of inflammation-related molecules. RESULTS Topical application of PSP extract had significant therapeutic effects on CorNV that could be shown in various assays of the corneas. Compared with AME extract, PSP extract treatment was more effective in suppressing CorNV in terms of vessel length and levels of cluster of differentiation 31 (CD31) proteins or the angiogenesis related genes like vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9). PSP also inhibited inflammation more markedly by more effectively inhibiting mononuclear and polymorphonuclear cells infiltration into the corneal stroma and reducing levels of stromal cell-derived factor-1 (SDF1), tumor necrosis factor-alpha (TNFα) and macrophage inflammatory protein-3 (MIP3a). In additon, corneas of PSP group had a more regular and compact architecture of collagen with thinner corneal thickness than in the AME group. CONCLUSION Polysaccharide extract from Spirulina platensis inhibited alkali burn-induced inflammation and CorNV more effectively than AME extract at the studied doses, thus may be used for the therapy of corneal diseases involving neovascularization and

  10. Synergistic effect of stromelysin-1 (matrix metalloproteinase-3 promoter (-1171 5A->6A polymorphism in oral submucous fibrosis and head and neck lesions

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    Shukla Shirish

    2010-07-01

    Full Text Available Abstract Background Matrix metalloproteinases (MMPs are enzymes that degrade all the components of extra cellular matrix and collagen. Various types of MMPs are known to be expressed and activated in patients with oral submucous fibrosis (OSMF as well as head and neck squamous cell carcinoma (HNSCC. The purpose of this study was to asses the association of the single nucleotide polymorphism (SNP adenosine insertion/deletion polymorphism (-1171 5A->6A in the MMP-3 promoter region in these lesions. Methods MMP-3 SNP was genotyped by polymerase chain reaction-restriction fragment polymorphism (PCR-RFLP analysis in a case control study consisting of 362 participants; 101 cases of OSMF, 135 of HNSCC and 126 controls, compared for age, sex and habits. ROC distribution was plotted to assess the contributions of genetic variation in MMP-3 genotypes with relation to age. Results Analysis of MMP 3 (-1171 5A->6A polymorphism revealed the frequency of 5A allele in OSMF, HNSCC and controls to be 0.15, 0.13 and 0.07, respectively. A significant difference was found in 5A genotype frequency between OSMF (5A genotype frequency = 0.15, p = 0.01, OR = 2.26, 95% CI = 1.22-4.20 and in controls (5A genotype frequency 0.07 as well as HNSCC (5A genotype frequency 0.13, p = 0.03,95%CI = 1.06-3.51 and controls (5A genotype frequency = 0.07 In this study, 5A genotype had greater than two fold risk for developing OSMF (OR = 2.26 and nearly the same in case of HNSCC (OR = 1.94 as compared to controls. In patients with OSMF as well as HNSCC, the ROC analysis between the MMP-3 genotype and age, 6A/6A allele was found to be significant in patients both over and under 45 years of age; while the 5A/5A carrier alleles showed an association only in patients less than 45 years of age. Conclusions This study concluded that the expression of MMP-3 genotype associated with the 5A alleles, it may have an important role in the susceptibility of the patients to develop OSMF and HNSCC.

  11. The role of biomaterial properties in peri-implant neovascularization

    Science.gov (United States)

    Raines, Andrew Lawrence

    An understanding of the interactions between orthopaedic and dental implant surfaces with the surrounding host tissue is critical in the design of next generation implants to improve osseointegration and clinical success rates. Critical to the process of osseointegration is the rapid establishment of a patent neovasculature in the peri-implant space to allow for the delivery of oxygen, nutrients, and progenitor cells. The central aim of this thesis is to understand how biomaterials regulate cellular and host tissue response to elicit a pro-angiogenic microenvironment at the implant/tissue interface. To address this question, the studies performed in this thesis aim to (1) determine whether biomaterial surface properties can modulate the production and secretion of pro-angiogenic growth factors by cells, (2) determine the role of integrin and VEGF-A signaling in the angiogenic response of cells to implant surface features, and (3) to determine whether neovascularization in response to an implanted biomaterial can be modulated in vivo. The results demonstrate that biomaterial surface microtopography and surface energy can increase the production of pro-angiogenic growth factors by osteoblasts and that these growth factors stimulate the differentiation of endothelial cells in a paracrine manner and the results suggest that signaling through specific integrin receptors affects the production of angiogenic growth factors by osteoblast-like cells. Further, using a novel in vivo model, the results demonstrate that a combination of a rough surface microtopography and high surface energy can improve bone-to-implant contact and neovascularization. The results of these studies also suggest that VEGF-A produced by osteoblast-like cells has both an autocrine and paracrine effect. VEGF-A silenced cells exhibited reduced production of both pro-angiogenic and osteogenic growth factors in response to surface microtopgraphy and surface energy, and conditioned media from VEGF

  12. Secondary glaucoma in CAPN5-associated neovascular inflammatory vitreoretinopathy

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    Cham A

    2016-06-01

    Full Text Available Abdourahman Cham,1,2 Mayank Bansal,3 Himanshu K Banda,4 Young Kwon,1 Paul S Tlucek,1 Alexander G Bassuk,5 Stephen H Tsang,6,7 Warren M Sobol,8 James C Folk,1 Steven Yeh,4 Vinit B Mahajan1,2 1Department of Ophthalmology and Visual Sciences, 2Omics Laboratory, University of Iowa, Iowa City, IA, USA; 3Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India; 4Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, 5Department of Pediatrics, University of Iowa, Iowa City, IA, 6Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Pathology and Cell Biology, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, 7Edward S Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, 8Retina Physicians & Surgeons, Inc., Dayton, OH, USA Objective: The objective of this study was to review the treatment outcomes of patients with secondary glaucoma in cases of autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV, a hereditary autoimmune uveitis due to mutations in CAPN5. Patients and methods: A retrospective, observational case series was assembled from ADNIV patients with secondary glaucoma. The main outcome measures were intraocular pressure (IOP, visual acuity, use of antiglaucoma medications, ocular surgeries, and adverse outcomes. Perimetry and optic disk optical coherence tomography (OCT were also analyzed. Results: Nine eyes of five ADNIV patients with secondary glaucoma were reviewed. Each received a fluocinolone acetonide (FA implant for the management of posterior uveitis. Following implantation, no eyes developed neovascular glaucoma. Five eyes (in patients 1, 2, and 5 required Ahmed glaucoma valve surgery for the management of steroid-responsive glaucoma. Patient 2 also developed angle closure with iris bombe and underwent laser

  13. The association between Neovascular Age-related Macular Degeneration and Regulatory T cells in peripheral blood

    DEFF Research Database (Denmark)

    Madelung, Christopher Fugl; Falk, Mads; Sørensen, Torben Lykke

    2015-01-01

    PURPOSE: To investigate regulatory T cells (Tregs) and subsets of the Treg population in patients with neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: Twenty-one neovascular AMD cases and 12 age-matched controls without retinal pathology were selected. Patients were recr...... were found in the percentages of CD4(+) lymphocytes, CD25(high)CD127(low) Tregs, CD45RA(+) naïve Tregs, or CD31(+) recent thymic emigrant Tregs. CONCLUSION: Our data does not indicate an altered state of systemic Treg cells in neovascular AMD....

  14. Application of anti-vascular endothelial growth factor on the treatment of neovascular glaucoma

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    Ping Wu

    2015-11-01

    Full Text Available Neovascular glaucoma(NVGis a common secondary glaucoma, often occurs secondary to diabetic retinopathy, central retinal vein occlusion and retinal ischemia syndrome. Its pathogenesis is complicated. Though conventional treatmentscan brieflyreduce elevated intraocular pressure, degenerate iris neovascularization, the long-term effect for controlling NVG is not obvious. The treatment of NVG ushers in a new dawn with the in-depth study on the pathogenesis of NVG and the use of vascular endothelial growth factor(VEGFinhibitors in ophthalmic diseases. In this paper, the applications of VEGF inhibitors on the treatment of neovascular glaucoma are reviewed to provide new thoughts for the treatment of NVG.

  15. Choroidal Neovascularization in a Patient with Crohn's Disease

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    Giuseppe Casalino

    2014-08-01

    Full Text Available Purpose: To report a case of subfoveal choroidal neovascularization (CNV in a patient with Crohn's disease (CD and to discuss a possible association between these two conditions. Methods: This is an observational case report. Results: A 69-year-old male affected by CD was referred to our department because of sudden visual acuity drop in the left eye. A subfoveal CNV was diagnosed based on slit-lamp fundus biomicroscopy and fluorescein angiography. Color fundus photography, infrared autofluorescence and spectral-domain optical coherence tomography imaging of both eyes were also performed. Following six intravitreal ranibizumab injections, visual improvement was obtained with no related adverse events. Conclusion: We report a case of CNV as a possible rare extraintestinal manifestation of CD. The use of ranibizumab successfully impacted on CNV, while not affecting CD, which remained quiescent.

  16. HTRA1 variant confers similar risks to geographic atrophy and neovascular age-related macular degeneration.

    Science.gov (United States)

    Cameron, D Joshua; Yang, Zhenglin; Gibbs, Daniel; Chen, Haoyu; Kaminoh, Yuuki; Jorgensen, Adam; Zeng, Jiexi; Luo, Ling; Brinton, Eric; Brinton, Gregory; Brand, John M; Bernstein, Paul S; Zabriskie, Norman A; Tang, Shibo; Constantine, Ryan; Tong, Zongzhong; Zhang, Kang

    2007-05-02

    Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy (GA) and choroidal neovascularization (wet AMD), represent two types of degenerative processes in the macula that lead to loss of central vision. Soft confluent drusen, characterized by deposits in macula without visual loss are considered a precursor of advanced AMD. A single nucleotide polymorphism, rs11200638, in the promoter of HTRA1 has been shown to increases the risk for wet AMD. However, its impact on soft confluent drusen and GA or the relationship between them is unclear. To better understand the role the HTRA1 polymorphism plays in AMD subtypes, we genotyped an expanded Utah population with 658 patients having advanced AMD or soft confluent drusen and 294 normal controls and found that the rs11200638 was significantly associated with GA. This association remains significant conditional on LOC387715 rs10490924. In addition, rs11200638 was significantly associated with soft confluent drusen, which are strongly immunolabeled with HTRA1 antibody in an AMD eye with GA similar to wet AMD. Two-locus analyses were performed for CFH Y402H variant at 1q31 and the HTRA1 polymorphism. Together CFH and HTRA1 risk variants increase the odds of having AMD by more than 40 times. These findings expand the role of HTRA1 in AMD. Understanding the underlying molecular mechanism will provide an important insight in pathogenesis of AMD.

  17. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration

    DEFF Research Database (Denmark)

    Larsen, Michael; Schmidt-Erfurth, Ursula; Lanzetta, Paolo;

    2012-01-01

    To compare the efficacy and safety of same-day verteporfin photodynamic therapy (PDT) and intravitreal ranibizumab combination treatment versus ranibizumab monotherapy in neovascular age-related macular degeneration....

  18. Implementation studies of ranibizumab for neovascular age-related macular degeneration

    DEFF Research Database (Denmark)

    Bloch, Sara Brandi

    2013-01-01

    , and type 2 CNV lesions, which have penetrated the RPE and evolve within the subretinal space. The natural course of neovascular AMD leads to visual disability in a majority of cases within the first years after onset, primarily caused by the development of subfoveal fibrous tissue and atrophy of the RPE......The pathogenesis of AMD is associated with age changes plus pathological changes involving oxidative stress and an altered inflammatory response leading to injury of retinal pigment epithelial cells and the adjacent choroidea and photoreceptor cells. AMD is divided into early, intermediate...... and advanced AMD. The advanced form of AMD is further divided into non-neovascular AMD and neovascular AMD. The diagnosis of neovascular AMD is based on FA and clinical characteristics of the eyes. The CNV lesions are by their growth pattern divided into type 1 CNV lesions, which grow primarily beneath the RPE...

  19. Application of Matrix Management Mode in Team Building of Reading Promotion in University Library%矩阵管理模式在高校图书馆阅读推广团队建设中的应用

    Institute of Scientific and Technical Information of China (English)

    雷萍; 杨家燕; 王惠森

    2015-01-01

    This paper summarizes the current situation of reading promotion team building in university library,analyzes the advantages of application of matrix management model in team building of reading promotion in university library,and points out that the application of matrix management for strengthening reading promotion team building in university library should pay attention to the good team leader select off, clear team management processes and the members of the mission requirements,pay attention to adjust the balance of the workload and to promote cooperation,but also optimize performance evaluation,establish the reading promotion activities evaluation and reward and punishment system.%矩阵管理是指为完成某项特定工作任务而形成的工作小组的管理模式。应用矩阵管理模式加强高校图书馆阅读推广团队建设,应注意把好团队负责人选择关,明确团队管理流程和成员的任务要求,注重各业务点的工作量均衡,促进各业务环节的配合,同时优化绩效评估方式,建立阅读推广活动评价和奖惩机制。

  20. Management of neovascular Age-related macular degeneration: A review on landmark randomized controlled trials

    OpenAIRE

    Aniruddha Agarwal; Kanika Aggarwal; Vishali Gupta

    2016-01-01

    In the last decade, a number of prospective clinical trials with carefully designed study protocols have been conducted for the treatment of neovascular age-related macular degeneration (AMD). These landmark clinical trials such as ANCHOR and MARINA and, more recently, the Comparison of AMD Treatment Trials and VIEW studies have revolutionized the management of neovascular AMD. While AMD continues to remain a leading cause of severe visual loss worldwide, advances in pharmacotherapeutics have...

  1. Regulation of signaling events involved in the pathophysiology of neovascular AMD

    OpenAIRE

    Wang, Haibo; Hartnett, M. Elizabeth

    2016-01-01

    Neovascular age-related macular degeneration (AMD) is a complex disease in which an individual’s genetic predisposition is affected by aging and environmental stresses, which trigger signaling pathways involving inflammation, oxidation, and/or angiogenesis in the RPE cells and choroidal endothelial cells (CECs), to lead to vision loss from choroidal neovascularization. Antiangiogenic therapies have greatly improved clinical outcomes in the last decade; however, vision improves in less than ha...

  2. SCORE Study Report #11: Incidences of Neovascular Events in Eyes with Retinal Vein Occlusion

    Science.gov (United States)

    Chan, Clement K.; Ip, Michael S.; VanVeldhuisen, Paul C.; Oden, Neal L.; Scott, Ingrid U.; Tolentino, Michael J.; Blodi, Barbara A.

    2010-01-01

    Purpose To investigate in The Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study: 1) incidences of neovascular events and retinal capillary nonperfusion (abbreviated as “nonperfusion”), and their relationship with treatment groups; 2) neovascular incidences by nonperfusion status; and 3) pertinent baseline factors for their potential risk for neovascular events. Design Two multi-center, randomized clinical trials: one evaluating participants with central retinal vein occlusion (CRVO) and the other evaluating participants with branch retinal vein occlusion (BRVO). Participants At 36 months, data were available for 81 participants with CRVO and 128 with BRVO. Intervention Standard care (observation or grid photocoagulation) versus 1 mg or 4 mg intravitreal triamcinolone. Main Outcome Measures Neovascularization of the iris (NVI), neovascular glaucoma (NVG), disc or retinal neovascularization (NVD/NVE), pre-retinal or vitreous hemorrhage (PRH/VH), and nonperfusion. Results Cumulative 36-month incidences for CRVO and BRVO eyes, respectively, were: 8.5% and 2.4% for NVI or NVG; 8.8 % and 7.6% for NVD/NVE or PRH/VH. There were no differences in incidences of neovascular events or risk of nonperfusion when comparing the 3 treatment groups within diseases. For CRVO at 36 months, 16.6% of eyes with ≥ 5.5 disc areas of nonperfusion vs. 4.0% of eyes with retinal capillary details caused by dense hemorrhage at baseline for CRVO eyes. Increased risk of neovascularization was noted below the historical threshold of 10 disc areas of nonperfusion for retinal vein occlusion. PMID:21440942

  3. Choroidal osteoma with choroidal neovascular membrane: Successful treatment with intravitreal bevacizumab

    Directory of Open Access Journals (Sweden)

    Neeraj Pandey

    2010-09-01

    Full Text Available Neeraj Pandey, Ayachit GuruprasadMM Joshi Eye Institute, Hubli, Karnataka, IndiaAbstract: An otherwise healthy 27-year-old woman presented with complaints of sudden painless blurred vision in the right eye for one week. On examination, visual acuity was 20/30 in the right eye and 20/20 in left eye. Fundus examination OS was normal, but OD demonstrated an elevated, opaque, yellowish parapapillary choroidal lesion with grayish membrane associated with minimal subretinal fluid, suggestive of a choroidal neovascular membrane in the center. B-scan ultrasonography revealed findings consistent with a choroidal osteoma. Fundus fluorescein angiography of the right eye revealed a relatively well defined area of hyperfluorescence that increased in size and intensity in the later phases, suggestive of active extrafoveal choroidal neovascular membrane. Optical coherence tomography confirmed the extrafoveal choroidal neovascular membrane with subfoveal fluid. She was treated with intravitreal bevacizumab OD. At the two-week visit, vision OD improved to 20/20. Fluorescein angiography and optical coherence tomography revealed a resolved choroidal neovascular membrane. Intravitreal bevacizumab may be an effective alternative in the management of choroidal neovascular membrane secondary to choroidal osteoma.Keywords: osteoma, choroidal neovascular membrane, optical coherence tomography, bevacizumab

  4. Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review

    Directory of Open Access Journals (Sweden)

    Yang S

    2016-06-01

    Full Text Available Shiqi Yang,1 Jingke Zhao,1 Xiaodong Sun1–3 1Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 2Eye Research Institute of Shanghai Jiao Tong University, 3Shanghai Key Laboratory of Fundus Disease, Shanghai, People’s Republic of China Abstract: As a progressive chronic disease, age-related macular degeneration (AMD is the leading cause of irreversible vision impairment worldwide. Experimental and clinical evidence has demonstrated that vascular endothelial growth factor (VEGF plays a vital role in the formation of choroidal neovascularization. Intravitreal injections of anti-VEGF agents have been recommended as a first-line treatment for neovascular AMD. However, persistent fluid or recurrent exudation still occurs despite standardized anti-VEGF therapy. Patients suffering from refractory or recurrent neovascular AMD may develop mechanisms of resistance to anti-VEGF therapy, which results in a diminished therapeutic effect. Until now, there has been no consensus on the definitions of refractory neovascular AMD and recurrent neovascular AMD. This article aims at clarifying these concepts to evaluate the efficacy of switching drugs, which contributes to making clinical decision more scientifically. Furthermore, insight into the causes of resistance to anti-VEGF therapy would be helpful for developing possible therapeutic approaches, such as combination therapy and multi-target treatment that can overcome this resistance. Keywords: age-related macular degeneration, vascular endothelial growth factor, choroidal neovascularization, resistance

  5. Effects of aging on time course of neovascularization-related gene expression following acute hindlimb ischemia in mice

    Institute of Scientific and Technical Information of China (English)

    WANG Jin-song; LIU Xia; XUE Zhen-yi; Lee Alderman; Justin U. Tilan; Remi Adenika; Stephen E. Epstein; Mary Susan Burnett

    2011-01-01

    Background Molecular analysis of neovascularization related genes by time course in response to ischemia has not been described in the context of aging. We aimed to provide a progressively deeper understanding of how aging compromises neovascularization.Methods Young (3-month) and old (18-month) C57BI mice were subjected to left hindlimb ischemia. Necrosis score was evaluated in calf muscles. Calf muscles,peripheral blood,bone marrow were harvested at different time points. The expressions of matrix metalloproteiniase-9 (MMPg),endothelial nitric oxide synthase (eNOS),vascular endothelial growth factor (VEGF),stromal derived growth factor-1 (SDF1),hypoxia inducible factor-1α (HIF1α),VEGF receptor-1(Fit1),VEGF receptor-2 (Flk1),angiopoietin-1 (Ang1),CD133,CD26 were detected by RT-PCR or Western blotting.White blood cells were counted in the peripheral blood. Gene expression data were compared by two-way analysis of variance.Results MMP9,HIF-1α and SDF-1 were more upregulated during acute ischemia in old vs. young mice,reflecting increased ischemia in aging mice. However VEGF and eNOS exhibited lower expression in old vs. young mice,despite greater ischemia intensity. Ang1 and Flk1 showed similar expression in old vs. young mice. MMP9 peaked earlier in peripheral blood in young vs. old mice. Concurrent decreasing CD26 and increasing CD133 expression in aging bonemarrow suggest aging impairs progenitor cell mobilization,Conclusions Our results indicate that a complex array of defects occur with aging that interfere with optimal neovascularization. These include potential impaired mobilization of progenitor cells to ischemic tissue,decreased levels of eNOS and VEGF and delayed responses to ischemia.ZLEr. WANG Jin-song,Division of Vascular Surgery,the First Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510080,China (Tel:86-20-87333440.Fax:86-20-87333242. Email:wangjs@mail.sysu.edu.cn)This work was supported by NIH RO1 HL085003-01A2,NNSF30100179.

  6. Demineralized bone matrix combined bone marrow mesenchymal stem cells, bone morphogenetic protein-2 and transforming growth factor-β3 gene promoted pig cartilage defect repair.

    Directory of Open Access Journals (Sweden)

    Xin Wang

    Full Text Available OBJECTIVES: To investigate whether a combination of demineralized bone matrix (DBM and bone marrow mesenchymal stem cells (BMSCs infected with adenovirus-mediated- bone morphogenetic protein (Ad-BMP-2 and transforming growth factor-β3 (Ad-TGF-β3 promotes the repair of the full-thickness cartilage lesions in pig model. METHODS: BMSCs isolated from pig were cultured and infected with Ad-BMP-2(B group, Ad-TGF-β3 (T group, Ad-BMP-2 + Ad-TGF-β3(BT group, cells infected with empty Ad served as a negative group(N group, the expression of the BMP-2 and TGF-β3 were confirmed by immunofluorescence, PCR, and ELISA, the expression of SOX-9, type II collagen(COL-2A, aggrecan (ACAN in each group were evaluated by real-time PCR at 1w, 2w, 3w, respectively. The chondrogenic differentiation of BMSCs was evaluated by type II collagen at 21d with immunohistochemical staining. The third-passage BMSCs infected with Ad-BMP-2 and Ad-TGF-β3 were suspended and cultured with DBM for 6 days to construct a new type of tissue engineering scaffold to repair full-thickness cartilage lesions in the femur condyles of pig knee, the regenerated tissue was evaluated at 1,2 and 3 months after surgery by gross appearance, H&E, safranin O staining and O'driscoll score. RESULTS: Ad-BMP-2 and Ad-TGF-β3 (BT group infected cells acquired strong type II collagen staining compared with Ad-BMP-2 (B group and Ad-TGF-β3 (T group along. The Ad-BMP-2 and Ad-TGF-β3 infected BMSCs adhered and propagated well in DBM and the new type of tissue engineering scaffold produced hyaline cartilage morphology containing a stronger type II collagen and safranin O staining, the O'driscoll score was higher than other groups. CONCLUSIONS: The DBM compound with Ad-BMP-2 and Ad-TGF-β3 infected BMSCs scaffold has a good biocompatibility and could well induce cartilage regeneration to repair the defects of joint cartilage. This technology may be efficiently employed for cartilage lesions repair in vivo.

  7. Matrix metalloproteinase-2 functional promoter polymorphism G1575A is associated with elevated circulatory MMP-2 levels and increased risk of cardiovascular disease in systemic lupus erythematosus patients.

    Science.gov (United States)

    Bahrehmand, F; Vaisi-Raygani, A; Kiani, A; Rahimi, Z; Tavilani, H; Navabi, S J; Shakiba, E; Hassanzadeh, N; Pourmotabbed, T

    2012-05-01

    Matrix metalloproteinase-2 (MMP-2) is a zinc dependent endonuclease that degrades type IV collagen, the major structural component of basement membranes. MMP-2 functional promoter polymorphism G1575A affects circulating level of MMP-2 and may be considered an important genetic determinant of cardiovascular disease (CVD) in systemic lupus erythematosus (SLE) patients. In this study, association between MMP-2 1575A allele with serum MMP-2, neopterin and lipid-lipoprotein levels and with SLE and developing CVD was investigated. The present case-control study consisted of 109 SLE patients with and without CVD (mean age, 35.6 years) and 101 gender- and age-matched, unrelated, healthy controls (mean age, 37.1 years) from the population in the west of Iran. MMP-2 1575G/A polymorphism was detected by polymerase chain reaction (restriction fragment length polymorphism) PCR-RFLP, serum MMP-2, neopterin and lipid levels were determined by enzyme-linked immunosorbent assay (ELISA), high-performance liquid chromatography (HPLC) and enzyme assay, respectively. The presence of MMP-2 G1575A allele was found to be associated with SLE and developed CVD (OR = 1.78, p = 0.029 and OR = 3.43, p = 0.025, respectively). The SLE patients with MMP-2 A (G/A + A/A) allele had higher MMP-2 activity (301 ± 166 vs. 194 ± 35.5, p = 0.002), neopterin (29.4 ± 39.4 vs. 7.3 ± 4.6, p = 0.005), LDL-C (120 ± 25.7 vs. 87 ± 39.3, p = 0.045) and lower HDL-C (39.6 ± 11 vs. 45.9 ± 11.8, p = 0.031) levels than the control subjects. There was a significantly positive correlation between MMP-2 level with neopterin, total cholesterol and TG levels and negative correlation with HDL-C level in SLE patients with CVD. MMP-2 G1575A allele may be a risk factor for SLE. The carriers of this allele have high levels of MMP-2, neopterin, total cholesterol and TG and lower levels of HDL, thus, they are more likely to develop heart disease.

  8. Complement Factor H Expressed by Retinal Pigment Epithelium Cells Can Suppress Neovascularization of Human Umbilical Vein Endothelial Cells: An in vitro Study.

    Directory of Open Access Journals (Sweden)

    Yi Zhang

    Full Text Available Complement factor H (CFH is one of the most important soluble complement regulatory proteins and is closely associated with age-related macular degeneration (AMD, the leading cause of irreversible central vision loss in the elderly population in developed countries. Our study searches to investigate whether CFH expression is changed in oxidative damaged retinal pigment epithelium (RPE cells and the role of CFH in the in vitro neovascularization. First, it was confirmed by immunofluorescence staining that CFH was expressed by ARPE-19 cells. CFH mRNA and protein in oxidative (H2O2 damaged ARPE-19 cells were both reduced, as determined by Real-time PCR and Western blotting analysis. Enzyme-linked immunosorbent assay (ELISA also showed that ARPE-19 cells treated with H2O2 caused an increase in C3a content, which indicates complement activation. Then, wound assays were performed to show that CFH expression suppression promoted human umbilical vein endothelial cell (HUVECs migration. Thereafter, ARPE-19 cells were transfected with CFH-specific siRNA and CFH knockdown was confirmed with the aid of Real-time PCR, immunofluorescence staining and Western blotting. The ELISA results showed that specific CFH knockdown in ARPE-19 cells activated the complement system. Finally, in vitro matrigel tube formation assay was performed to determine whether change of CFH expression in RPE would affect tube formation by HUVECs. More tubes were formed by HUVECs co-cultured with ARPE-19 cells transfected with CFH specific-siRNA when compared with controls. Our results suggested that RPE cells might be the local CFH source, and RPE cell injuries (such as oxidative stress may cause CFH expression suppression, which in turn may lead to complement activation and promotion of tube formation by HUVECs. This finding is of importance in elucidating the role of complement in the pathogenesis of ocular neovascularization including choroidal neovascularization.

  9. Melissa officinalis extract inhibits laser-induced choroidal neovascularization in a rat model.

    Science.gov (United States)

    Lee, Eun Kyoung; Kim, Young Joo; Kim, Jin Young; Song, Hyun Beom; Yu, Hyeong Gon

    2014-01-01

    This study investigated the effect of Melissa officinalis extract on laser-induced choroidal neovascularization (CNV) in a rat model. The mechanism by which M. officinalis extract acted was also investigated. Experimental CNV was induced by laser photocoagulation in Brown Norway rats. An active fraction of the Melissa leaf extract was orally administered (50 or 100 mg/kg/day) beginning 3 days before laser photocoagulation and ending 14 days after laser photocoagulation. Optical coherence tomography and fluorescein angiography were performed in vivo to evaluate the thickness and leakage of CNV. Choroidal flat mount and histological analysis were conducted to observe the CNV in vitro. Vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2, and MMP-9 expression were measured in retinal and choroidal-scleral lysates 7 days after laser injury. Moreover, the effect of M. officinalis extract on tertiary-butylhydroperoxide (t-BH)-induced VEGF secretion and mRNA levels of VEGF, MMP-2, and MMP-9 were evaluated in human retinal epithelial cells (ARPE-19) as well as in human umbilical vein endothelial cells (HUVECs). The CNV thickness in M. officinalis-treated rats was significantly lower than in vehicle-treated rats by histological analysis. The CNV thickness was 33.93±7.64 µm in the high-dose group (Pofficinalis, which was significantly lower than in control rats (53.4%, Pofficinalis extract suppressed t-BH-induced transcription of VEGF and MMP-9 in ARPE-19 cells and HUVECs. Systemic administration of M. officinalis extract suppressed laser-induced CNV formation in rats. Inhibition of VEGF and MMP-9 via anti-oxidative activity may underlie this effect.

  10. Anterior segment changes following intravitreal bevacizumab injection for treatment of neovascular glaucoma

    Directory of Open Access Journals (Sweden)

    Canut MI

    2011-05-01

    Full Text Available MI Canut1, A Alvarez2, J Nadal3, R Abreu4, JA Abreu5, JS Pulido61Glaucoma Section, 2Barraquer Ophthalmology Centre, 3Retina and Vitreous Unit, Macula Section, Institut Universitari Barraquer, Universidad Autonoma de Barcelona, Barcelona, Spain; 4Retina and Vitreous Unit, University Hospital of La Candelaria, Tenerife 5Glaucoma Section, University Hospital of the Canary Islands, Tenerife, Spain; 6Retina and Vitreous Unit, Ophthalmology Department, Mayo Clinic, Rochester, MN, USABackground: The purpose of this study was to describe anterior segment changes in a prospective, interventional, noncomparative case series of patients with neovascular glaucoma secondary to proliferative diabetic retinopathy treated with intravitreal bevacizumab.Methods: Five consecutive patients with neovascular glaucoma and a refractory, symptomatic elevation of intraocular pressure and pronounced anterior segment congestion received intravitreal bevacizumab 1.25 mg/0.05 mL. Follow-up examinations were performed at 4–16 weeks by the same specialists, with testing performed at hour 48, week 1, and months 1, 3, and 6 after intravitreal bevacizumab.Results: We observed a significant difference (P = 0.021 between initial and mean neovascularization at three months in all the quadrants. At three months, median intraocular pressure was 19 ± 5.38 (range 12–26 mmHg. In three of the five cases, diode laser cyclophotocoagulation was required, and in one case a trabeculectomy was performed. One patient showed complete synechial angle closure 48 hours after treatment which required cyclodestructive procedures to normalize intraocular pressure.Conclusion: Intravitreal bevacizumab achieves complete regression of neovascularization in neovascular glaucoma secondary to proliferative diabetic retinopathy, and this regression is stable when associated with treatment of the underlying disease and should be investigated more thoroughly as an adjunct in the management of neovascular

  11. Neovascularization in canine mammary carcinoma – a case report

    Directory of Open Access Journals (Sweden)

    Alexandra Irimie

    2016-11-01

    Full Text Available The frequency of mammary tumors in canines is three times higher than in women. Contrast enhanced ultrasonography (CEUS is a noninvasive clinical method, that uses special contrast agents (CAs, their role being to layout the microvasculature of different lesions. The aim of this particular method, in this case, was to establish if we can evaluate the malignancy of a mass, given the fact that neovascularization is a malignancy marker. The case is represented by a Silky Terrier breed female dog, 5 years old, that was presented initially with an enlarged polycystic mammary gland and a nervous lactation. The female was initially diagnosed with polycystic mastosis. After 2 more months the mass became denser and enlarged. Before the ovariohisterectomy and unilateral mastectomy surgeries have taken place, a B-Mode standard ultrasound, CEUS and a pulmonary X-ray were performed. Our results integrate this case in “fast in” and “slow in” (type 2 curve. The histological diagnosis was established as a simple cystic papillary carcinoma with a malignancy grade 2. The mean value of the MVD was 13.75 which is a low MVD. We cannot determine a correlation between CEUS and a tumor’s malignancy, and so further studies are needed.

  12. Segmentation of choroidal neovascularization in fundus fluorescein angiograms.

    Science.gov (United States)

    Abdelmoula, Walid M; Shah, Syed M; Fahmy, Ahmed S

    2013-05-01

    Choroidal neovascularization (CNV) is a common manifestation of age-related macular degeneration (AMD). It is characterized by the growth of abnormal blood vessels in the choroidal layer causing blurring and deterioration of the vision. In late stages, these abnormal vessels can rupture the retinal layers causing complete loss of vision at the affected regions. Determining the CNV size and type in fluorescein angiograms is required for proper treatment and prognosis of the disease. Computer-aided methods for CNV segmentation is needed not only to reduce the burden of manual segmentation but also to reduce inter- and intraobserver variability. In this paper, we present a framework for segmenting CNV lesions based on parametric modeling of the intensity variation in fundus fluorescein angiograms. First, a novel model is proposed to describe the temporal intensity variation at each pixel in image sequences acquired by fluorescein angiography. The set of model parameters at each pixel are used to segment the image into regions of homogeneous parameters. Preliminary results on datasets from 21 patients with Wet-AMD show the potential of the method to segment CNV lesions in close agreement with the manual segmentation.

  13. Stereotactic radiotherapy in neovascular age-related macular degeneration

    Science.gov (United States)

    Ranjbar, Mahdy; Kurz, Maximilian; Holzhey, Annekatrin; Melchert, Corinna; Rades, Dirk; Grisanti, Salvatore

    2016-01-01

    Abstract Stereotactic radiotherapy (SRT) is a new approach to treat neovascular age-related macular degeneration (nAMD). The INTREPID trial suggested that SRT could reduce the frequency of regular intravitreal injections (IVIs) with antivascular endothelial growth factor drugs, which are necessary to control disease activity. However, the efficacy of SRT in nAMD and resulting morphological changes have not been validated under real-life circumstances, an issue, which we would like to address in this retrospective analysis. Patients who met the INTREPID criteria for best responders were eligible for SRT. A total of 32 eyes of 32 patients were treated. Thereafter, patients were examined monthly for 12 months and received pro re nata IVI of aflibercept or ranibizumab. Outcome measures were: mean number of injections, best-corrected visual acuity, and morphological changes of the outer retina-choroid complex as well as patient safety. Mean number of IVI decreased by almost 50% during the 12 months after SRT compared to the year before, whereas visual acuity increased by one line (logMAR). Morphological evaluation showed that most changes affect outer retinal layers. Stereotactic radiotherapy significantly reduced IVI retreatment in nAMD patients under real-life circumstances. Therefore, SRT might be the first step to stop visual loss as a result of IVI undertreatment, which is a major risk. PMID:28033280

  14. Early detection of choroidal neovascularization in age related macular degeneration

    Directory of Open Access Journals (Sweden)

    Tural Galbinur

    2012-01-01

    Full Text Available Purpose: to identify factors associated with early detection of choroidal neovascularization CNV in clinical practice.Methods: Seventy six AMD patients who had history of CNV in one eye and presented with CNV in the second eye and evaluated for association with visual acuity (VA at time of presentation. Demographics, clinical data and lesion characteristics were retrospectively collected.Results: Better VA was associated with history of CNV in the fellow eye (p<0.0001, adherence to follow-up every four-months (p=0.015, younger age (p=0.03, smaller lesion (p<0.0001, and non-subfoveal localization (p=0.048. VA of the fellow eye did not correlate with VA at presentation with CNV.Conclusion: these data suggest that experience of CNV, regardless of VA, facilitates early diagnosis in the fellow eye. Adherence to follow-up in the routine clinic setting also facilitates early detection of CNV.

  15. Intravitreal ranibizumab as adjuvant treatment for neovascular glaucoma

    Directory of Open Access Journals (Sweden)

    Flavia Gazze Ticly

    2013-04-01

    Full Text Available The purpose of this study was to describe a prospective case series of 5 eyes treated with intravitreal ranibizumab injection for neovascular glaucoma (NVG. Five patients with clinically uncontrolled NVG secondary to proliferative diabetic retinopathy (4 patients and central retinal vein occlusion (1 patient, non-responsive to maximal tolerable medication and panretinal photocoagulation, received intravitreal ranibizumab injection (0.5 mg. Patients were seen at 1st, 3rd and 7th day after the ranibizumab injection and when it was necessary. Success was defined as intraocular pressure (IOP 21, despite maximal tolerable medication, underwent trabeculectomy with 0.5mg/ml mitomycin C (MMC for 1 minute. Failure was defined as IOP > 21 mmHg, phthisis bulbi, loss of light perception or additional glaucoma surgery. The primary outcome was 6-month IOP control. Mean IOP before the ranibizumab injection was 37 mmHg (7 mmHg SD. Two out of five eyes underwent only ranibizumab injection, having an IOP control after the procedure. Three patients were submitted to trabeculectomy with MMC on the 7th day after the injection. At 6-month follow-up, the mean IOP was 12mmHg (3 mmHg SD. All eyes showed regression of rubeosis iridis and IOP control. Visual acuity improved in 2 eyes worsened in 1 eye, and remained stable in 2 eyes. These data suggest that intravitreal ranibizumab injection may be a useful tool in the treatment of NVG.

  16. Sonic hedgehog improves ischemia-induced neovascularization by enhancing endothelial progenitor cell function in type 1 diabetes.

    Science.gov (United States)

    Qin, Yuan; He, Yan-Huan; Hou, Ning; Zhang, Gen-Shui; Cai, Yi; Zhang, Gui-Ping; Xiao, Qing; He, Li-Shan; Li, Su-Juan; Yi, Quan; Luo, Jian-Dong

    2016-03-05

    The Sonic hedgehog (Shh) pathway is downregulated in type 1 diabetes, and it has been reported that augmentation of this pathway may alleviate diabetic complications. However, the cellular mechanisms underlying these protective effects are poorly understood. Recent studies indicate that impaired function of endothelial progenitor cells (EPCs) may contribute to cardiovascular problems in diabetes. We hypothesized that impaired Shh signaling contribute to endothelial progenitor cell dysfunction and that activating the Shh signaling pathway may rescue EPC function and promote diabetic neovascularization. Adult male C57/B6 mice and streptozotocin (STZ)-induced type 1 diabetic mice were used. Gli1 and Ptc1 protein levels were reduced in EPCs from diabetic mice, indicating inhibition of the Shh signaling pathway. EPC migration, tube formation ability, and mobilization were impaired in diabetic mice compared with non-diabetic controls (p < 0.05 vs control), and all were improved by in vivo administration of the Shh pathway receptor agonist SAG (p < 0.05 vs diabetes). SAG significantly increased capillary density and blood perfusion in the ischemic hindlimbs of diabetic mice (p < 0.05 vs diabetes). The AKT activity was lower in EPCs from diabetic mice than those from non-diabetic controls (p < 0.05 vs control). This decreased AKT activity led to an increased GSK-3β activity and degradation of the Shh pathway transcription factor Gli1/Gli2. SAG significantly increased the activity of AKT in EPCs. Our data clearly demonstrate that an impaired Shh pathway mediated by the AKT/GSK-3β pathway can contribute to EPC dysfunction in diabetes and thus activating the Shh signaling pathway can restore both the number and function of EPCs and increase neovascularization in type 1 diabetic mice.

  17. The prevalence of neovascularity in patients clinically diagnosed with rotator cuff tendinopathy

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    Raza Syed A

    2009-12-01

    Full Text Available Abstract Background Shoulder dysfunction is common and pathology of the rotator cuff tendons and subacromial bursa are considered to be a major cause of pain and morbidity. Although many hypotheses exist there is no definitive understanding as to the origin of the pain arising from these structures. Research investigations from other tendons have placed intra-tendinous neovascularity as a potential mechanism of pain production. The prevalence of neovascularity in patients with a clinical diagnosis of rotator cuff tendinopathy is unknown. As such the primary aim of this pilot study was to investigate if neovascularity could be identified and to determine the prevalence of neovascularity in the rotator cuff tendons and subacromial bursa in subjects with unilateral shoulder pain clinically assessed to be rotator cuff tendinopathy. The secondary aims were to investigate the association between the presence of neovascularity and pain, duration of symptoms, and, neovascularity and shoulder function. Methods Patients with a clinical diagnosis of unilateral rotator cuff tendinopathy referred for a routine diagnostic ultrasound (US scan in a major London teaching hospital formed the study population. At referral patients were provided with an information document. On the day of the scan (on average, at least one week later the patients agreeing to participate were taken through the consent process and underwent an additional clinical examination prior to undergoing a bilateral grey scale and colour Doppler US examination (symptomatic and asymptomatic shoulder using a Philips HDI 5000 Sono CT US machine. The ultrasound scans were performed by one of two radiologists who recorded their findings and the final assessment was made by a third radiologist blinded both to the clinical examination and the ultrasound examination. The findings of the radiologists who performed the scans and the blinded radiologist were compared and any disagreements were resolved

  18. Implementation studies of ranibizumab for neovascular age-related macular degeneration.

    Science.gov (United States)

    Bloch, Sara Brandi

    2013-11-01

    The pathogenesis of AMD is associated with age changes plus pathological changes involving oxidative stress and an altered inflammatory response leading to injury of retinal pigment epithelial cells and the adjacent choroidea and photoreceptor cells. AMD is divided into early, intermediate and advanced AMD. The advanced form of AMD is further divided into non-neovascular AMD and neovascular AMD. The diagnosis of neovascular AMD is based on FA and clinical characteristics of the eyes. The CNV lesions are by their growth pattern divided into type 1 CNV lesions, which grow primarily beneath the RPE, and type 2 CNV lesions, which have penetrated the RPE and evolve within the subretinal space. The natural course of neovascular AMD leads to visual disability in a majority of cases within the first years after onset, primarily caused by the development of subfoveal fibrous tissue and atrophy of the RPE. The prognosis of visual acuity in neovascular AMD has been markedly improved by the introduction of an intravitreal administered VEGF inhibitor (ranibizumab) given on a monthly basis. Treatment with ranibizumab for neovascular AMD was introduced in Denmark in 2006 under a fully reimbursed national healthcare plan. Treatment with ranibizumab is given in a variable dosing regimen that varies from the monthly dosing regimen administered in the studies that led to the approval of ranibizumab for neovascular AMD in Europe. The main objectives of this PhD thesis were to evaluate and potentially improve treatment with ranibizumab in a variable OCT guided regimen for neovascular AMD. Another intension of this PhD thesis was to prepare the conditions for future research to further improve the visual prognosis in neovascular AMD treated with anti-VEGF agents. The first study revealed that vision was improved in eyes with active neovascular AMD treated for 1 year in a variable ranibizumab treatment regimen as compared to PDT and the natural course of the disease. We assumed by

  19. Bilateral Hypertensive Retinopathy Complicated with Retinal Neovascularization: Panretinal Photocoagulation or Intravitreal Anti-VEGF Treatment

    Directory of Open Access Journals (Sweden)

    Odysseas Georgiadis

    2014-07-01

    Full Text Available Purpose: To present the case of a patient with bilateral hypertensive retinopathy complicated with retinal neovascularization who received anti-VEGF intravitreal injection in one eye and panretinal photocoagulation (PRP in the fellow eye. Methods: A 33-year-old male patient presented with gradual visual loss in both eyes for the last 5 months. At that time, he was examined by an ophthalmologist and occlusive retinopathy due to malignant systematic hypertension was diagnosed. He was put on antihypertensive treatment but no ophthalmic treatment was undertaken. At presentation, 5 months later, best-corrected visual acuity (BCVA was 0.1 in the right eye (RE and 0.9 in the left eye (LE. Fundus examination was compatible with hypertensive retinopathy complicated with retinal neovascularization. Fluorescein angiography (FFA revealed macular ischemia mainly in the RE and large areas of peripheral retinal ischemia and neovascularization with vascular leakage in both eyes. The patient was treated with two anti-VEGF (ranibizumab injections with 2 months interval in the RE and PRP laser in the LE. Results: Follow-up examination after 12 months showed mild improvement in BCVA, and FFA documented regression of retinal neovascularization in both eyes. Conclusion: Hypertensive retinopathy can be rarely complicated with retinal neovascularization. Treatment with PRP can be undertaken. In our case, the use of an intravitreal anti-VEGF agent seemed to halt its progression satisfactorily.

  20. Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review.

    Science.gov (United States)

    Yang, Shiqi; Zhao, Jingke; Sun, Xiaodong

    2016-01-01

    As a progressive chronic disease, age-related macular degeneration (AMD) is the leading cause of irreversible vision impairment worldwide. Experimental and clinical evidence has demonstrated that vascular endothelial growth factor (VEGF) plays a vital role in the formation of choroidal neovascularization. Intravitreal injections of anti-VEGF agents have been recommended as a first-line treatment for neovascular AMD. However, persistent fluid or recurrent exudation still occurs despite standardized anti-VEGF therapy. Patients suffering from refractory or recurrent neovascular AMD may develop mechanisms of resistance to anti-VEGF therapy, which results in a diminished therapeutic effect. Until now, there has been no consensus on the definitions of refractory neovascular AMD and recurrent neovascular AMD. This article aims at clarifying these concepts to evaluate the efficacy of switching drugs, which contributes to making clinical decision more scientifically. Furthermore, insight into the causes of resistance to anti-VEGF therapy would be helpful for developing possible therapeutic approaches, such as combination therapy and multi-target treatment that can overcome this resistance.

  1. Identification of E-Selectin as a Novel Target for the Regulation of Post-Natal Neovascularization: Implications for Diabetic Wound Healing

    Science.gov (United States)

    Liu, Zhao-Jun; Tian, Runxia; An, Weijun; Zhuge, Ying; Li, Yan; Shao, Hongwei; Habib, Bianca; Livingstone, Alan S.; Velazquez, Omaida C.

    2012-01-01

    Objectives We previously reported that stromal cell-derived factor-1α (SDF-1α, a homing signal for recruiting endothelial progenitor cells (EPC) to areas of neovascularization), is down-regulated in diabetic wounds 1. We now investigate signals whereby mature endothelial cells (EC) and circulating EPC achieve SDF-1α-mediated EPC homing. Methods SDF-1α in diabetic wounds were therapeutically increased by injection of SDF-1α–engineered bone marrow-derived fibroblasts versus control cells (N= 48 (20, NOD), (28, STZ-C57)). PCR-array gene expression differences were validated by Western blotting and immunohistochemistry. The role of adhesion molecule(s) in mediating SDF-1α-induced EPC homing and wound healing was furthered studied using antagonists in vitro and in vivo. Results Increasing wound SDF-1α via cell-base therapy promotes healing in diabetic mice (~20% increase in healing rates by day 3, p=0.006). SDF-1α increased EC-EPC adhesion and specifically upregulated E-selectin expression in human microvascular EC (2.3-fold increase, p<0.01). This effect was also significant in blood vessels of the experimental mice and resulted in increased wound neovascularization. The regulatory effects of SDF-1α on EC-EPC adhesion and EPC homing were specifically mediated by E-selectin, as the application of E-selectin antagonists significantly inhibited SDF-1α-induced EC-EPC adhesion, EPC homing, wound neovascularization, and wound healing. Conclusions SDF-1α–engineered cell-based therapy promotes diabetic wound healing in mice by specifically upregulating E-selectin expression in mature EC leading to increase EC-EPC adhesion, EPC homing and increased wound neovascularization. These findings provide novel insight into the signals underlying the biological effect of SDF-1α on EPC homing and point to E-selectin as a new potential target for therapeutic manipulation of EPC trafficking in diabetic wound healing. PMID:20881769

  2. Matrix theory

    CERN Document Server

    Franklin, Joel N

    2003-01-01

    Mathematically rigorous introduction covers vector and matrix norms, the condition-number of a matrix, positive and irreducible matrices, much more. Only elementary algebra and calculus required. Includes problem-solving exercises. 1968 edition.

  3. Risk of Retinal Neovascularization in Cases of Uveitis.

    Science.gov (United States)

    Patel, Apurva K; Newcomb, Craig W; Liesegang, Teresa L; Pujari, Siddharth S; Suhler, Eric B; Thorne, Jennifer E; Foster, C Stephen; Jabs, Douglas A; Levy-Clarke, Grace A; Nussenblatt, Robert B; Rosenbaum, James T; Sen, H Nida; Artornsombudh, Pichaporn; Kothari, Srishti; Kempen, John H

    2016-03-01

    To evaluate the risk of and risk factors for retinal neovascularization (NV) in cases of uveitis. Retrospective cohort study. Patients with uveitis at 4 US academic ocular inflammation subspecialty practices. Data were ascertained by standardized chart review. Prevalence data analysis used logistic regression. Incidence data analysis used survival analysis with time-updated covariates where appropriate. Prevalence and incidence of NV. Among uveitic eyes of 8931 patients presenting for initial evaluation, 106 of 13,810 eyes had NV (prevalence = 0.77%, 95% confidence interval [CI], 0.60-0.90). Eighty-eight more eyes developed NV over 26,465 eye-years (incidence, 0.33%/eye-year; 95% CI, 0.27-0.41). Factors associated with incident NV include age 35 years (adjusted hazard ratio [aHR], 2.4; 95% CI, 1.5-3.9), current cigarette smoking (aHR, 1.9; 95% CI, 1.1-3.4), and systemic lupus erythematosus (aHR, 3.5, 95% CI, 1.1-11). Recent diagnosis of uveitis was associated with an increased incidence of NV (compared with patients diagnosed >5 years ago, aHR, 2.4 [95% CI, 1.1-5.0] and aHR, 2.6 [95% CI, 1.2-6.0] for diagnosis within uveitis, intermediate uveitis (aHR, 3.1; 95% CI, 1.5-6.6), posterior uveitis (aHR, 5.2; 95% CI, 2.5-11), and panuveitis (aHR, 4.3; 95% CI, 2.0-9.3) were associated with a similar degree of increased NV incidence. Active (aHR, 2.1, 95% CI, 1.2-3.7) and slightly active (aHR, 2.4, 95% CI, 1.3-4.4) inflammation were associated with an increased incidence of NV compared with inactive inflammation. Neovascularization incidence also was increased with retinal vascular occlusions (aHR, 10, 95% CI, 3.0-33), retinal vascular sheathing (aHR, 2.6, 95% CI, 1.4-4.9), and exudative retinal detachment (aHR, 4.1, 95% CI, 1.3-13). Diabetes mellitus was associated with a somewhat increased incidence of retinal NV (aHR, 2.3, 95% CI, 1.1-4.9), and systemic hypertension (aHR 1.5, 95% CI, 0.89-2.4) was associated with nonsignificantly increased NV incidence. Results were

  4. The Active Metabolite of Leflunomide A771726 Inhibits Corneal Neovascularization

    Institute of Scientific and Technical Information of China (English)

    Mingchang ZHANG; Nian HAO; Fang BIAN

    2008-01-01

    The effects of A771726, the active metabolite of leflunomide, on experimental rat corneal neovascularization (NV) in vivo and on cultured human umbilical vein endothelial cells in vitro were studied. The corneal NV was induced by alkali burn in 40 SD rats. The rats were randomly divided into 4 groups with 10 rats in each group. Group A was treated with 0.9% sodium chloride (control group), and group B, group C and group D were given different concentrations of A771726 eye drops (0.5%,l.0%,2.0% respectively) 4 times daily during days 0-28. The occurrence and development of corneal NV were observed at 4,7,14,21 and 28 day after alkali burn by a slit lamp microscope. The cultured human umbilical vein endothelial cells (ECV-304) were incubated with A771726 solution at different concentrations (20,40,80,160,320μmol/L) for 36h. The proliferation of cells was assessed by methyl thiazolyl tetrazolium (MTT), and the expression of proliferating cell nuclear antigen (PCNA) in cells was detected by using immunofluorescence under the laser confocal microscope. The rat model showed that the onset of corneal NV was delayed and progression of corneal NV was inhibited in the groups C and D. The corneal NV areas in groups C and D were significantly smaller than in groups A and B (P0.05). A771726 solution (≥40μmol/L) could inhibit proliferation of human umbilical vein endothelial cells and decrease the expression of PCNA in cells significantly. A771726, as the active metabolite of leflunomide, strongly prevented corneal NV induced by alkali burn in the in vivo model, and inhibited proliferation of human umbilical vein endothelial cells in the in vitro model. Therefore, A771726 may serve as an angiogenic inhibitor in the treatment of corneal NV.

  5. Choroidal thickness after intravitreal ranibizumab injections for choroidal neovascularization

    Directory of Open Access Journals (Sweden)

    Ellabban AA

    2012-05-01

    Full Text Available Abdallah A Ellabban, Akitaka Tsujikawa, Ken Ogino, Sotaro Ooto, Kenji Yamashiro, Akio Oishi, Nagahisa YoshimuraDepartment of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, JapanPurpose: To study changes in choroidal thickness with ranibizumab treatment for choroidal neovascularization (CNV.Design: Prospective case series.Methods: This prospective study consisted of 60 CNV-affected eyes of 60 patients treated with intravitreal injections of ranibizumab using an on-demand protocol after an initial loading phase. The eyes studied included 20 with age-related macular degeneration (AMD, 20 with polypoidal choroidal vasculopathy (PCV, and 20 with myopic CNV. In the eyes with AMD and PCV, choroidal thickness at the fovea was measured with optical coherence tomography using enhanced depth imaging. In eyes with myopic CNV, the choroidal thickness was measured using standard optical coherence tomography without the enhanced depth imaging technique.Results: With ranibizumab treatment, central retinal thickness decreased significantly (P < 0.001 and visual acuity improved significantly (P < 0.001. However, central choroidal thickness (167.2 ± 108.3 µm showed no significant change at 1 month after the loading phase (165.2 ± 107.8 µm, P = 0.120 or at final examination (164.8 ± 107.7 µm, P = 0.115. At baseline, central retinal thickness in eyes with AMD was significantly greater that those with PCV (P = 0.005 or high myopia (P = 0.029. However, central choroidal thickness in eyes with myopic CNV was significantly thinner than in eyes with AMD (P < 0.001 or PCV (P < 0.001. In each type of disease, there was no significant change in central choroidal thickness with ranibizumab treatment.Conclusion: The effect of ranibizumab on the choroidal thickness is minimal, if any.Keywords: choroidal thickness, ranibizumab, optical coherence tomography

  6. Modified Vitreous Surgery for Subretinal Neovascularization and Hemorrhage

    Institute of Scientific and Technical Information of China (English)

    LinLu; LezhengWU

    1995-01-01

    Purpose:To modify vitreous surgery for subretinal neovascularization(SRNV)and to detrmine the effects of this operation.Methods:Six patients with SRNV were performed with this operation,The meth-ods of examination before and after operation included;testing the best-corrected visual acuity before operation and 1,3or6months after operation;30degrees and visual acuity before operation and 1,3or6months after operation;30degrees and macular 10degrees Humphrey visual field examination:FFA examination preop-eratively and 1,3or6months postoperatiely.Modified surgery procedureis;a preventive buckling;pars plana vitrectomy;peeling the vitreous cortical;no in-traocular diathermy;small retinotomy;subretinal surgery;air-fluid exchang.Results:SRNV was taken off in4cases.Subretinal hemorrhage was washed in2cases.After4to7months follow-up,the visual acuity was improved in 4cases,unchanged in 2cases.The visual field was improved in 4cases.unchanged in 1case,decraesed in 1case,The complications included macular hole due to surgery in lcase and subretinal hemorrage in 1case.Conclusion;The surgery criteria were:1)massive subretinal hemorrhage;2)some patients of SRN V included;FFA evidence they showed the membrane is beneath fovea,the bestV.Ais20/100orlower.and can't be treated by laser and the pa-tient consent.This modified subretinal operation is safe,and effective for massive hemorrhage and some SRNVS.

  7. Modifying Choroidal Neovascularization Development with a Nutritional Supplement in Mice

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    Alina Adriana Ivanescu

    2015-07-01

    Full Text Available We examined the effect of nutritional supplements (modified Age Related Eye Disease Study (AREDS-II formulation containing vitamins, minerals, lutein, resveratrol, and omega-3 fatty acids on choroidal neovascularization (CNV. Supplements were administered alone and combined with intravitreal anti-VEGF in an early-CNV (diode laser-induced murine model. Sixty mice were evenly divided into group V (oral vehicle, intravitreal saline, group S (oral supplement, intravitreal saline, group V + aVEGF (oral vehicle, intravitreal anti-VEGF, and group S + aVEGF (oral supplement, intravitreal anti-VEGF. Vehicle and nutritional supplements were administered daily for 38 days beginning 10 days before laser. Intravitreal injections were administered 48 h after laser. Fluorescein angiography (FA and flat-mount CD31 staining evaluated leakage and CNV lesion area. Expression of VEGF, MMP-2 and MMP-9 activity, and NLRP3 were evaluated with RT-PCR, zymography, and western-blot. Leakage, CNV size, VEGF gene and protein expression were lower in groups V + aVEGF, S + aVEGF, and S than in V (all p < 0.05. Additionally, MMP-9 gene expression differed between groups S + aVEGF and V (p < 0.05 and MMP-9 activity was lower in S + aVEGF than in V and S (both p < 0.01. Levels of MMP-2 and NLRP3 were not significantly different between groups. Nutritional supplements either alone or combined with anti-VEGF may mitigate CNV development and inhibit retinal disease involving VEGF overexpression and CNV.

  8. Ocular neovascularization associated with central and hemicentral retinal vein occlusion.

    Science.gov (United States)

    Hayreh, Sohan Singh; Zimmerman, M Bridget

    2012-09-01

    To investigate the incidence of ocular neovascularization (NV) in central and hemicentral retinal vein occlusion. The study comprised consecutive 912 (673 nonischemic and 239 ischemic) central retinal vein occlusion and 190 (147 nonischemic, 43 ischemic) hemicentral retinal vein occlusion eyes. Ophthalmic evaluation at initial and follow-up visits included recording visual acuity, visual fields, and detailed anterior segment and fundus examinations and fluorescein fundus angiography. In ischemic central retinal vein occlusion, within 6 months from time of onset, the cumulative probability of development of iris NV was 49%, angle NV 37%, NV glaucoma 29%, retinal NV 9%, and disk NV 6%. More severe peripheral retinal hemorrhages were significantly associated with iris NV (P = 0.005), angle NV (P = 0.0004), and NV glaucoma (P = 0.012). Eyes that developed disk NV had more cotton wool spots (P = 0.058) than those without. In ischemic hemicentral retinal vein occlusion, within 12 months of onset, the cumulative probability of development of retinal NV was 29%, disk NV 12%, and iris NV 12%; within 6 months of onset, angle NV was found in 10% and NV glaucoma in 5%. Anterior chamber flare was associated with anterior segment NV and may precede the development of NV. Patients who developed NV were significantly younger, and there was a greater prevalence of NV glaucoma in patients with primary open angle glaucoma. In ischemic central retinal vein occlusion, anterior segment NV is much more common than posterior segment NV, and the cumulative chance of developing anterior segment NV is maximum during the first 6 months. In ischemic hemicentral retinal vein occlusion, posterior segment NV is much more common than anterior segment NV.

  9. Fluorocoxib A enables targeted detection of cyclooxygenase-2 in laser-induced choroidal neovascularization

    Science.gov (United States)

    Uddin, Md. Jashim; Moore, Chauca E.; Crews, Brenda C.; Daniel, Cristina K.; Ghebreselasie, Kebreab; McIntyre, J. Oliver; Marnett, Lawrence J.; Jayagopal, Ashwath

    2016-09-01

    Ocular angiogenesis is a blinding complication of age-related macular degeneration and other retinal vascular diseases. Clinical imaging approaches to detect inflammation prior to the onset of neovascularization in these diseases may enable early detection and timely therapeutic intervention. We demonstrate the feasibility of a previously developed cyclooxygenase-2 (COX-2) targeted molecular imaging probe, fluorocoxib A, for imaging retinal inflammation in a mouse model of laser-induced choroidal neovascularization. This imaging probe exhibited focal accumulation within laser-induced neovascular lesions, with minimal detection in proximal healthy tissue. The selectivity of the probe for COX-2 was validated in vitro and by in vivo retinal imaging with nontargeted 5-carboxy-X-rhodamine dye, and by blockade of the COX-2 active site with nonfluorescent celecoxib prior to injection of fluorocoxib A. Fluorocoxib A can be utilized for imaging COX-2 expression in vivo for further validation as an imaging biomarker in retinal diseases.

  10. Treatment of Neovascular Glaucoma Using Trabeculectomy Combined with Implantation of Silicon Rubber Slice

    Institute of Scientific and Technical Information of China (English)

    Weizhong Yang; Fengang Deng

    2001-01-01

    Purpose: To observe clinical effect of treatment for neovascular glaucoma using trabeculectomy combined with implantation of silicon rubber slice. Methods: 28 cases(28 eyes)with neovascular glaucoma were performed trabeculectomy combined with a piece of 3 × 5 mm silicon rubber implantation, and their lowing intraocular pressure effect was observed.Results: All patients were follow-up for 9 ~ 24 months (mean: 18.3 months). The average intraocular pressure at last visit was 21.65 mmHg (rang: 17.30 ~ 28.97 mmHg , 1mmHg = 0. 133 kPa). The symptom of eye pain was disappeared after surgery.Conclusion: Trabeculectomy with a piece of silicon rubber implantation is ideal therapy for neovascular glaucoma.

  11. Enhanced effect of β-tricalcium phosphate phase on neovascularization of porous calcium phosphate ceramics: in vitro and in vivo evidence.

    Science.gov (United States)

    Chen, Y; Wang, J; Zhu, X D; Tang, Z R; Yang, X; Tan, Y F; Fan, Y J; Zhang, X D

    2015-01-01

    Neovascularization plays a key role in bone repair and regeneration. In the present study, four types of porous calcium phosphate (CaP) ceramics, namely hydroxyapatite (HA), biphasic calcium phosphates (BCP-1 and BCP-2) and β-tricalcium phosphate (β-TCP), with HA to β-TCP ratios of 100/0, 70/30, 30/70 and 2/98, respectively, were investigated in terms of their angiogenic induction. The in vitro cell culture revealed that the ceramics could promote proliferation and angiogenesis of human umbilical vein endothelial cells (HUVECs). This result could be achieved by stimulating CCD-18Co human fibroblasts to secrete angiogenic factors (vascular endothelial growth factor, basic fibroblast growth factor and transforming growth factor-β) as a paracrine effect, as well as by up-regulating HUVECs to express these angiogenic factors and their receptors (KDR, FGFR1 and ACVRL1) and the downstream eNOS as an autocrine effect. These effects were more significant in β-TCP and BCP-2, which had a higher content of β-TCP phase. In the in vivo implantation into the thigh muscles of mice, the process of neovascularization of the ceramics was initiated at 2 weeks and the mature vascular networks were formed at 4 weeks as visualized by hematoxylin and eosin staining and scanning electron microscopy. Microvessel density count confirmed that β-TCP and BCP-2 induced more microvessels to form than HA or BCP-1. This phenomenon was further confirmed by the significantly up-regulated expressions of angiogenesis-related genes in the ingrowth of cells into the inner pores of the two ceramics. All the results confirmed the angiogenic induction of porous CaP ceramics, and a higher content of β-TCP phase had an enhanced effect on the neovascularization of the ceramics.

  12. The inhibitory effect of thalidomide analogue on corneal neovascularization in rabbits.

    Science.gov (United States)

    Lee, You Kyung; Chung, Sung Kun

    2013-08-01

    To evaluate the effect of thalidomide analogue CC-3052 on corneal neovascularization in the rabbit model. Corneal neovascularization was induced in 15 rabbits by a silk suture in the corneal stroma. At 1 week after suturing, 30 eyes were divided into 5 groups of 6 eyes each. Three groups were treated with topical CC-3052 at 3 different concentrations: 0.25% (group 1), 0.5% (group 2), and 1.0% (group 3). All treatments were performed twice a day for a week. A 0.5% concentration of CC-3052 was injected subconjunctivally once in group 4. In group 5, a topical balanced salt solution was added twice a day for a week as the experimental control group. Rabbit corneas were photographed by a digital camera and examined by the operating microscope. Half of the corneal specimens were analyzed histopathologically, and the other half were used to measure the concentration of tumor necrosis factor α and vascular endothelial growth factor (VEGF) messenger RNA by reverse transcriptase-polymerase chain reaction. The neovascularized area was decreased in all treatment groups compared with the control group. There was a significant difference in the percentage and score of corneal neovascularization between the control and all treatment groups. Inflammation, fibroblast, neovascularization, and anti-VEGF antibody intensities were significantly lower in the control group. The concentration of VEGF and tumor necrosis factor α was significantly lower in the control group. There was no difference between the treatment groups. Topical and subconjunctival administration of thalidomide analogue CC-3052 was found to be effective for the inhibition of corneal neovascularization.

  13. Imaging polarimetry in patients with neovascular age-related macular degeneration

    Science.gov (United States)

    Elsner, Ann E.; Weber, Anke; Cheney, Michael C.; VanNasdale, Dean A.; Miura, Masahiro

    2007-01-01

    Imaging polarimetry was used to examine different components of neovascular membranes in age-related macular degeneration. Retinal images were acquired with a scanning laser polarimeter. An innovative pseudo-color scale, based on cardinal directions of color, displayed two types of image information: relative phases and magnitudes of birefringence. Membranes had relative phase changes that did not correspond to anatomical structures in reflectance images. Further, membrane borders in depolarized light images had significantly higher contrasts than those in reflectance images. The retinal birefringence in neovascular membranes indicates optical activity consistent with molecular changes rather than merely geometrical changes. PMID:17429494

  14. Clinical correlates of common corneal neovascular diseases:a literature review

    Directory of Open Access Journals (Sweden)

    Nizar Saleh Abdelfattah

    2015-02-01

    Full Text Available A large subset of corneal pathologies involves the formation of new blood and lymph vessels (neovascularization, leading to compromised visual acuity. This article aims to review the clinical causes and presentations of corneal neovascularization (CNV by examining the mechanisms behind common CNV-related corneal pathologies, with a particular focus on herpes simplex stromal keratitis, contact lenses-induced keratitis and CNV secondary to keratoplasty. Moreover, we reviewed CNV in the context of different types of corneal transplantation and keratoprosthesis, and summarized the most relevant treatments available so far.

  15. Subfoveal choroidal thickness changes after intravitreal bevacizumab therapy for neovascular age-related macular degeneration

    Institute of Scientific and Technical Information of China (English)

    Cihan; ünlü; Gurkan; Erdogan; Betul; Onal; Gunay; Betul; Ilkay; Sezgin; Akcay; Esra; Kardes

    2015-01-01

    <正>Dear Sir,Iam Dr.Cihanünlü,from the Department of Opthalmology,ümraniye Training and Research Hospital,Istanbul,Turkey.I write to present our study findings on subfoveal choroidal thickness(SFCT)changes after intravitreal bevacizumab(IVB)therapy for neovascular age-related macular degeneration(AMD).AMD is the leading cause of severe visual loss in adults older than 60y[1].Visual loss in late stages of AMD may be the result of one of the two processes:geographic atrophy(GA)or choroidal neovascularization(CNV).Many types of

  16. Methylobacterium Species Promoting Rice and Barley Growth and Interaction Specificity Revealed with Whole-Cell Matrix-Assisted Laser Desorption/Ionization-Time-of-Flight Mass Spectrometry (MALDI-TOF/MS) Analysis.

    Science.gov (United States)

    Tani, Akio; Sahin, Nurettin; Fujitani, Yoshiko; Kato, Akiko; Sato, Kazuhiro; Kimbara, Kazuhide

    2015-01-01

    Methylobacterium species frequently inhabit plant surfaces and are able to utilize the methanol emitted from plants as carbon and energy sources. As some of the Methylobacterium species are known to promote plant growth, significant attention has been paid to the mechanism of growth promotion and the specificity of plant-microbe interactions. By screening our Methylobacterium isolate collection for the high growth promotion effect in vitro, we selected some candidates for field and pot growth tests for rice and barley, respectively. We found that inoculation resulted in better ripening of rice seeds, and increased the size of barley grains but not the total yield. In addition, using whole-cell matrix-assister laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF/MS) analysis, we identified and classified Methylobacterium isolates from Methylobacterium-inoculated rice plants. The inoculated species could not be recovered from the rice plants, and in some cases, the Methylobacterium community structure was affected by the inoculation, but not with predomination of the inoculated species. The isolates from non-inoculated barley of various cultivars grown in the same field fell into just two species. These results suggest that there is a strong selection pressure at the species level of Methylobacterium residing on a given plant species, and that selection of appropriate species that can persist on the plant is important to achieve growth promotion.

  17. Methylobacterium Species Promoting Rice and Barley Growth and Interaction Specificity Revealed with Whole-Cell Matrix-Assisted Laser Desorption/Ionization-Time-of-Flight Mass Spectrometry (MALDI-TOF/MS Analysis.

    Directory of Open Access Journals (Sweden)

    Akio Tani

    Full Text Available Methylobacterium species frequently inhabit plant surfaces and are able to utilize the methanol emitted from plants as carbon and energy sources. As some of the Methylobacterium species are known to promote plant growth, significant attention has been paid to the mechanism of growth promotion and the specificity of plant-microbe interactions. By screening our Methylobacterium isolate collection for the high growth promotion effect in vitro, we selected some candidates for field and pot growth tests for rice and barley, respectively. We found that inoculation resulted in better ripening of rice seeds, and increased the size of barley grains but not the total yield. In addition, using whole-cell matrix-assister laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF/MS analysis, we identified and classified Methylobacterium isolates from Methylobacterium-inoculated rice plants. The inoculated species could not be recovered from the rice plants, and in some cases, the Methylobacterium community structure was affected by the inoculation, but not with predomination of the inoculated species. The isolates from non-inoculated barley of various cultivars grown in the same field fell into just two species. These results suggest that there is a strong selection pressure at the species level of Methylobacterium residing on a given plant species, and that selection of appropriate species that can persist on the plant is important to achieve growth promotion.

  18. [Influence of genetic mutations on clinical presentation of subretinal neovascularization. Report 1: The impact of CFH and IL-8 genes polymorphism].

    Science.gov (United States)

    Budzinskaia, M V; Pogoda, T V; Generozov, É V; Chikun, E A; Shchegoleva, I V; Kazarian, É É; Galoian, N S

    2011-01-01

    Genetic analysis was performed in patients with subretinal neovascularization (CNV). The results showed significant association of CFH (compliment factor H) gene polymorphism with increase (rs1061170, rs514943 and rs380390) or decrease (rs529825, rs7524776, rs1831281, rs2274700, rs1576340, rs12144939, rs7540032) of CNV development risk. The incidence of IL-8 gene mutation was significantly (p = 0.008) higher in patients after chorioretinitis. Apparently -125 > A polymorphism in patients with chorioretinitis increases risk of CNV development, thus promoting raise of proangiogenic factors concentration in eyes with inflammatory background. The clinical presentation in patients with AMD and myopic disease associated with (-125) A mutation of promoter region of IL-8 gene was similar to that of patients with chorioretinitis. The features are the following: focal pattern, no drusen and RPE detachment, predominantly classic form of CNV (without occult pattern), formation of well-organized newly developed vessels.

  19. Mechanical Loading Improves Tendon-Bone Healing in a Rabbit Anterior Cruciate Ligament Reconstruction Model by Promoting Proliferation and Matrix Formation of Mesenchymal Stem Cells and Tendon Cells

    Directory of Open Access Journals (Sweden)

    Fanglong Song

    2017-02-01

    Full Text Available Background/Aims: This study investigated the effect of mechanical stress on tendon-bone healing in a rabbit anterior cruciate ligament (ACL reconstruction model as well as cell proliferation and matrix formation in co-culture of bone-marrow mesenchymal stem cells (BMSCs and tendon cells (TCs. Methods: The effect of continuous passive motion (CPM therapy on tendon-bone healing in a rabbit ACL reconstruction model was evaluated by histological analysis, biomechanical testing and gene expressions at the tendon-bone interface. Furthermore, the effect of mechanical stretch on cell proliferation and matrix synthesis in BMSC/TC co-culture was also examined. Results: Postoperative CPM therapy significantly enhanced tendon-bone healing, as evidenced by increased amount of fibrocartilage, elevated ultimate load to failure levels, and up-regulated gene expressions of Collagen I, alkaline phosphatase, osteopontin, Tenascin C and tenomodulin at the tendon-bone junction. In addition, BMSC/TC co-culture treated with mechanical stretch showed a higher rate of cell proliferation and enhanced expressions of Collagen I, Collagen III, alkaline phosphatase, osteopontin, Tenascin C and tenomodulin than that of controls. Conclusion: These results demonstrated that proliferation and differentiation of local precursor cells could be enhanced by mechanical stimulation, which results in enhanced regenerative potential of BMSCs and TCs in tendon-bone healing.

  20. Melissa officinalis extract inhibits laser-induced choroidal neovascularization in a rat model.

    Directory of Open Access Journals (Sweden)

    Eun Kyoung Lee

    Full Text Available PURPOSE: This study investigated the effect of Melissa officinalis extract on laser-induced choroidal neovascularization (CNV in a rat model. The mechanism by which M. officinalis extract acted was also investigated. METHODS: Experimental CNV was induced by laser photocoagulation in Brown Norway rats. An active fraction of the Melissa leaf extract was orally administered (50 or 100 mg/kg/day beginning 3 days before laser photocoagulation and ending 14 days after laser photocoagulation. Optical coherence tomography and fluorescein angiography were performed in vivo to evaluate the thickness and leakage of CNV. Choroidal flat mount and histological analysis were conducted to observe the CNV in vitro. Vascular endothelial growth factor (VEGF, matrix metalloproteinase (MMP-2, and MMP-9 expression were measured in retinal and choroidal-scleral lysates 7 days after laser injury. Moreover, the effect of M. officinalis extract on tertiary-butylhydroperoxide (t-BH-induced VEGF secretion and mRNA levels of VEGF, MMP-2, and MMP-9 were evaluated in human retinal epithelial cells (ARPE-19 as well as in human umbilical vein endothelial cells (HUVECs. RESULTS: The CNV thickness in M. officinalis-treated rats was significantly lower than in vehicle-treated rats by histological analysis. The CNV thickness was 33.93±7.64 µm in the high-dose group (P<0.001, 44.09±12.01 µm in the low-dose group (P = 0.016, and 51.00±12.37 µm in the control group. The proportion of CNV lesions with clinically significant fluorescein leakage was 9.2% in rats treated with high-dose M. officinalis, which was significantly lower than in control rats (53.4%, P<0.001. The levels of VEGF, MMP-2, and MMP-9 were significantly lower in the high-dose group than in the control group. Meanwhile, M. officinalis extract suppressed t-BH-induced transcription of VEGF and MMP-9 in ARPE-19 cells and HUVECs. CONCLUSIONS: Systemic administration of M. officinalis extract suppressed laser

  1. Single-Chain Antibody Fragment VEGF Inhibitor RTH258 for Neovascular Age-Related Macular Degeneration

    DEFF Research Database (Denmark)

    Holz, Frank G; Dugel, Pravin U; Weissgerber, Georges

    2016-01-01

    PURPOSE: To assess the safety and efficacy of different doses of RTH258 applied as single intravitreal administration compared with ranibizumab 0.5 mg in patients with neovascular age-related macular degeneration (AMD). DESIGN: Six-month, phase 1/2, prospective, multicenter, double-masked, random...

  2. Antivascular Endothelial Growth Factor Agents for Neovascular Age-Related Macular Degeneration

    Directory of Open Access Journals (Sweden)

    Ilias Zampros

    2012-01-01

    Full Text Available Age-related macular degeneration (AMD is the leading cause of severe visual loss and blindness over the age of 50 in developed countries. Vascular endothelial growth factor (VEGF is considered as a critical molecule in the pathogenesis of choroidal neovascularization (CNV, which characterizes the neovascular AMD. Anti-VEGF agents are considered the most promising way of effectively inhibition of the neovascular AMD process. VEGF is a heparin-binding glycoprotein with potent angiogenic, mitogenic and vascular permeability-enhancing activities specific for endothelial cells. Two anti-VEGF agents have been approved by the US Food and Drug Administration (FDA for the treatment of neovascular AMD. Pegaptanib sodium, which is an aptamer and ranibizumab, which is a monoclonal antibody fragment. Another humanized monoclonal antibody is currently off-label used, bevacizumab. This paper aims to discuss in details the effectiveness, the efficacy and safety of these three anti-VEGF agents. New anti-VEGF compounds which are recently investigated for their clinical usage (VEGF-trap, small interfering RNA are also discussed for their promising outcomes.

  3. Retinal pigment epithelium tear formation following intravitreal ranibizumab injection in choroidal neovascularization secondary to choroidal osteoma.

    Science.gov (United States)

    Erol, Muhammet K; Coban, Deniz Turgut; Ceran, Basak Bostanci; Bulut, Mehmet

    2014-09-01

    Choroidal osteoma is an extremely rare osseous tumor of the choroid where choroidal neovascularization (CNV) is the major cause of visual loss. We report the case of a 28-year-old female with CNV secondary to choroidal osteoma, who developed RPE tear after intravitreal ranibizumab treatment.

  4. Hedgehog Signaling Components Are Expressed in Choroidal Neovascularization in Laser-induced Retinal Lesion

    Science.gov (United States)

    Nochioka, Katsunori; Okuda, Hiroaki; Tatsumi, Kouko; Morita, Shoko; Ogata, Nahoko; Wanaka, Akio

    2016-01-01

    Choroidal neovascularization is one of the major pathological changes in age-related macular degeneration, which causes devastating blindness in the elderly population. The molecular mechanism of choroidal neovascularization has been under extensive investigation, but is still an open question. We focused on sonic hedgehog signaling, which is implicated in angiogenesis in various organs. Laser-induced injuries to the mouse retina were made to cause choroidal neovascularization. We examined gene expression of sonic hedgehog, its receptors (patched1, smoothened, cell adhesion molecule down-regulated by oncogenes (Cdon) and biregional Cdon-binding protein (Boc)) and downstream transcription factors (Gli1-3) using real-time RT-PCR. At seven days after injury, mRNAs for Patched1 and Gli1 were upregulated in response to injury, but displayed no upregulation in control retinas. Immunohistochemistry revealed that Patched1 and Gli1 proteins were localized to CD31-positive endothelial cells that cluster between the wounded retina and the pigment epithelium layer. Treatment with the hedgehog signaling inhibitor cyclopamine did not significantly decrease the size of the neovascularization areas, but the hedgehog agonist purmorphamine made the areas significantly larger than those in untreated retina. These results suggest that the hedgehog-signaling cascade may be a therapeutic target for age-related macular degeneration. PMID:27239075

  5. Evaluation of 10 AMD Associated Polymorphisms as a Cause of Choroidal Neovascularization in Highly Myopic Eyes

    Science.gov (United States)

    Anter, Jaouad; Bezunartea, Jaione; Hernandez-Sanchez, Maria; García-García, Laura; Alonso, Elena; Ruiz-Moreno, Jose María; Araiz-Iribarren, Javier; Fernandez-Robredo, Patricia; García-Layana, Alfredo

    2016-01-01

    Choroidal neovascularization (CNV) commonly occurs in age related macular degeneration and pathological myopia patients. In this study we conducted a case-control prospective study including 431 participants. The aim of this study was to determine the potential association between 10 single nucleotide polymorphisms (SNPs) located in 4 different genetic regions (CFI, COL8A1, LIPC, and APOE), and choroidal neovascularization in age-related macular degeneration and the development of choroidal neovascularization in highly myopic eyes of a Caucasian population. Univariate and multivariate logistic regression analysis adjusted for age, sex and hypertension was performed for each allele, genotype and haplotype frequency analysis. We found that in the univariate analysis that both single-nucleotide polymorphisms in COL8A1 gene (rs13095226 and rs669676) together with age, sex and hypertension were significantly associated with myopic CNV development in Spanish patients (p0.05); however, analysis of the axial length between genotypes of rs13095226 revealed an important influence of COL8A1 in the development of CNV in high myopia. Furthermore we conducted a meta-analysis of COL8A1, CFI and LIPC genes SNPs (rs669676, rs10033900 and rs10468017) and found that only rs669676 of these SNPs were associated with high myopia neovascularization. PMID:27643879

  6. Role of PTFE Patch Saphenoplasty in Reducing Neovascularization and Recurrence in Varicose Veins.

    Science.gov (United States)

    Vashist, M G; Singhal, Nitin; Verma, Manish; Sen, Jyotsana

    2015-12-01

    Varicose veins have a high recurrence rate following surgery. Besides poor surgical technique, majority of these recurrences are attributable to neovascularization after both primary and repeat surgery. Authors have studied the effectiveness of a polytetrafluoroethylene (PTFE) patch interposition between the ligated vein stump and the overlying soft tissue at saphenofemoral junction in decreasing recurrence of varicose veins after initial surgery. Study was conducted on 50 patients of varicose veins with saphenofemoral junction incompetence. Patients were randomly divided into two groups, group A and group B alternately. In group A, standard surgical procedure was done followed by PTFE patch application. In group B, same surgical procedure was applied as in group A, with the exception of PTFE patch application. Patients in both groups were given similar postoperative care. A full venous duplex ultrasound assessment was performed in all the patients postoperatively. Neovascularization was observed in five patients (20 %) of group B, while it was not seen in any of the patients in group A at 1-year follow-up. This difference in neovascularization across the two groups was found to be statistically significant with a p value of 0.0251. Hence, authors concluded that patch saphenoplasty helps in reducing recurrence in varicose veins by decreasing neovascularization at saphenofemoral junction.

  7. Predicting Non-response to Ranibizumab in Patients with Neovascular Age-related Macular Degeneration

    NARCIS (Netherlands)

    Asten, F. van; Rovers, M.M.; Lechanteur, Y.T.E.; Smailhodzic, D.; Muether, P.S.; Chen, J.; Hollander, A.I. den; Fauser, S.; Hoyng, C.B.; Wilt, G.J. van der; Klevering, B.J.

    2014-01-01

    Abstract Purpose: To validate known and determine new predictors of non-response to ranibizumab in patients with neovascular age-related macular degeneration (AMD) and to incorporate these factors into a prediction rule. METHODS: This multicenter, observational cohort study included 391 patients tre

  8. Breaking barriers: insight into the pathogenesis of neovascular age-related macular degeneration

    Science.gov (United States)

    Wang, Haibo; Wittchen, Erika S; Hartnett, M Elizabeth

    2011-01-01

    Neovascular age-related macular degeneration (AMD) is a leading cause of central visual acuity loss in a growing segment of the population, those over the age of 60 years. Treatment has improved over the last decade, with the availability of agents that inhibit the bioactivity of vascular endothelial growth factor (VEGF), but it is still limited, because of tachyphylaxis and potential risk and toxicity of anti-VEGF agents. The authors have sought to understand the mechanisms of choroidal endothelial cell (CEC) activation and transmigration of the retinal pigment epithelium (RPE) and of RPE barrier dysfunction, events preceding vision-threatening neovascular AMD. The authors developed physiologically relevant human RPE and CEC coculture and transmigration models that have been important in helping to understand causes of events in human neovascular AMD. The authors can control for interactions between these cells and can separately assess activation of signaling pathways in each cell type relevant during CEC transmigration. Using these models, it was found that VEGF, particularly the cell-associated VEGF splice variant VEGF189, accounts for about 40% of CEC transmigration across the RPE. This percentage is in the range of similar reports following clinical inhibition of VEGF in neovascular AMD. RPE VEGF189 working through CEC VEGF receptor 2 activates the small guanosine triphosphatase (GTPase) of the Rho family, Rac1, in CECs, which in turn facilitates CEC transmigration. Conversely, inhibition of Rac1 activity prevents CEC transmigration. Once activated, Rac1 aggregates with subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, resulting in the generation of reactive oxygen species. Activated NADPH oxidase increases choroidal neovascularization in animal models of laser-induced injury. Rac1 is also downstream of the eotaxin-CCR3 pathway, another pathway important in human neovascular AMD. Studies also suggest that active Ras-related protein 1

  9. Small interference RNA targeting vascular endothelial growth factor gene effectively attenuates retinal neovascularization in mice model

    Institute of Scientific and Technical Information of China (English)

    KONG Yi-chun; SUN Bei; ZHAO Kan-xing; HAN Mei; WANG Yu-chuan

    2013-01-01

    Background The mechanism of retinal neovascularization is not understood completely.Many growth factors are involved in the process of retinal neovascularization,such as vascular endothelial growth factor (VEGF) and pigment epithelium-deprived factor (PEDF),which are the representatives of angiogenic and antiangiogenic molecules respectively.Oxygen induced retinopathy (OIR) is a useful model to investigate retinal neovascularization.The present study was conducted to investigate the feasibility of small interference RNA (siRNA) targeting VEGF gene in attenuating oxygen induced retinopathy (OIR) by regulating VEGF to PEDF ratio (VEGF/PEDF).Methods In vitro,cultured EOMA cells were transfected with VEGF-siRNA (psi-HITM/EGFPNEGF siRNA) and LipofectamineTM 2000 for 24,48,and 72 hours,respectively.Expression of VEGF mRNA was evaluated by real time polymerase chain reaction (PCR) and the level of VEGF protein was analyzed by Western blotting.In vivo,OIR model mice were established,the mice (C57BL/6J) received an intra-vitreal injection of 1 μl of mixture of psi-HITM/EGFPNEGF siRNA and Lipofectamine 2000.Expressions of retinal VEGF and PEDF protein were measured by Western blotting,retinal neovascularization was observed by fluorescein angiography,and quantified.Results In vitro psi-HITM/EGFP/VEGF siRNA treatment significantly reduced VEGF mRNA and protein expression.In vivo,with decreased VEGF and VEGF-PEDF ratio,significant attenuation of neovascular tufts,avascular regions,tortuous,and dilated blood vessels were observed in the interfered animals.Conclusions VEGF plays an important role in OIR,and the transfection of VEGF-siRNA can effectively downregulate VEGF expression in vivo,accompanied by the downregulation of VEGF-PEDF ratio,and simultaneous attenuation of retinal neovascularization was also observed.These findings suggest that VEGF/PEDF may serve as a potential target in the treatment of retinal neovascularization and RNA interference targeting VEGF expression

  10. Breaking barriers: insight into the pathogenesis of neovascular age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Hartnett ME

    2011-09-01

    Full Text Available Haibo Wang1, Erika S Wittchen2, M Elizabeth Hartnett11Department of Ophthalmology, John A Moran Eye Center, University of Utah, Salt Lake City, UT; 2Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USAAbstract: Neovascular age-related macular degeneration (AMD is a leading cause of central visual acuity loss in a growing segment of the population, those over the age of 60 years. Treatment has improved over the last decade, with the availability of agents that inhibit the bioactivity of vascular endothelial growth factor (VEGF, but it is still limited, because of tachyphylaxis and potential risk and toxicity of anti-VEGF agents. The authors have sought to understand the mechanisms of choroidal endothelial cell (CEC activation and transmigration of the retinal pigment epithelium (RPE and of RPE barrier dysfunction, events preceding vision-threatening neovascular AMD. The authors developed physiologically relevant human RPE and CEC coculture and transmigration models that have been important in helping to understand causes of events in human neovascular AMD. The authors can control for interactions between these cells and can separately assess activation of signaling pathways in each cell type relevant during CEC transmigration. Using these models, it was found that VEGF, particularly the cell-associated VEGF splice variant VEGF189, accounts for about 40% of CEC transmigration across the RPE. This percentage is in the range of similar reports following clinical inhibition of VEGF in neovascular AMD. RPE VEGF189 working through CEC VEGF receptor 2 activates the small guanosine triphosphatase (GTPase of the Rho family, Rac1, in CECs, which in turn facilitates CEC transmigration. Conversely, inhibition of Rac1 activity prevents CEC transmigration. Once activated, Rac1 aggregates with subunits of nicotinamide adenine dinucleotide phosphate (NADPH oxidase, resulting in the generation of reactive

  11. Matrix Factorization and Matrix Concentration

    OpenAIRE

    Mackey, Lester

    2012-01-01

    Motivated by the constrained factorization problems of sparse principal components analysis (PCA) for gene expression modeling, low-rank matrix completion for recommender systems, and robust matrix factorization for video surveillance, this dissertation explores the modeling, methodology, and theory of matrix factorization.We begin by exposing the theoretical and empirical shortcomings of standard deflation techniques for sparse PCA and developing alternative methodology more suitable for def...

  12. Intravitreal Bevacizumab injection combined duplex technique in treatment of neovascular glaucoma

    Directory of Open Access Journals (Sweden)

    Zheng-Jun Hu

    2015-05-01

    Full Text Available AIM: To observe the clinical curative effect of intravitreal Bevacizumab injection combined duplex technique in treatment of neovascular glaucoma(NVG.METHODS:Totally 25 eyes of 25 patients with NVG who underwent intravitreal Bevacizumab injection of 1.0mg(0.05mL, after the regression of iris neovascularization, 5 eyes with anterior chamber paracentesis fluid auxiliary controlled intraocular pressure. After 2wk, patients were treated by trabeculectomy and phacomulsification(9 eyes were implanted intraocular lens. The changes and complications of intraocular pressure, visual acuity, corneas and neovessels were observed after surgery, and followed up 12mo.RESULTS:After injection Bevacizumab in 25 eyes, iris neovascularization of 20 eyes subsided in 3~5d, and 5 eyes subsided in 7d. After controlling intraocular pressure, count of the corneal endothelial cell were 1 629±226mm2, and none suffered decompensation of corneal endothelium after two-surgery of trabeculectomy and phacomulsification. After followed up 12mo, intraocular pressure of 20 eyes were controlled in normal range; 2 eyes could control in normal range after treated by a kind of anti-glaucoma medicine and 3 eyes was 34~38mmHg after treated by anti-glaucoma medicine. 9 eyes had improved vision after implanted intraocular lens.CONCLUSION:Intravitreal Bevacizumab injection can subside iris and anterior chamber angle neovascularization effectively in a short time and reduce intraocular pressure. It can also reduce the risk of bleeding during operation or after operation. Intravitreal Bevacizumab injection combined with two-surgery of trabeculectomy and phacomulsification can treat neovascular glaucoma effectively.

  13. Honokiol inhibits pathological retinal neovascularization in oxygen-induced retinopathy mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Vavilala, Divya Teja [Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, MO (United States); O’Bryhim, Bliss E. [Department of Ophthalmology, University of Kansas Medical Center, Kansas City, KS (United States); Ponnaluri, V.K. Chaithanya [Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, MO (United States); White, R. Sid; Radel, Jeff [Department of Ophthalmology, University of Kansas Medical Center, Kansas City, KS (United States); Symons, R.C. Andrew [Department of Ophthalmology, University of Kansas Medical Center, Kansas City, KS (United States); Ophthalmology Department, Royal Melbourne Hospital, University of Melbourne, Victoria (Australia); Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Victoria (Australia); Mukherji, Mridul, E-mail: mukherjim@umkc.edu [Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, MO (United States)

    2013-09-06

    Highlights: •Aberrant activation of HIF pathway is the underlying cause of ischemic neovascularization. •Honokiol has better therapeutic index as a HIF inhibitor than digoxin and doxorubicin. •Daily IP injection of honokiol in OIR mouse model reduced retinal neovascularization. •Honokiol also prevents vaso-obliteration, the characteristic feature of the OIR model. •Honokiol enhanced physiological revascularization of the retinal vascular plexuses. -- Abstract: Aberrant activation of the hypoxia inducible factor (HIF) pathway is the underlying cause of retinal neovascularization, one of the most common causes of blindness worldwide. The HIF pathway also plays critical roles during tumor angiogenesis and cancer stem cell transformation. We have recently shown that honokiol is a potent inhibitor of the HIF pathway in a number of cancer and retinal pigment epithelial cell lines. Here we evaluate the safety and efficacy of honokiol, digoxin, and doxorubicin, three recently identified HIF inhibitors from natural sources. Our studies show that honokiol has a better safety to efficacy profile as a HIF inhibitor than digoxin and doxorubicin. Further, we show for the first time that daily intraperitoneal injection of honokiol starting at postnatal day (P) 12 in an oxygen-induced retinopathy (OIR) mouse model significantly reduced retinal neovascularization at P17. Administration of honokiol also prevents the oxygen-induced central retinal vaso-obliteration, characteristic feature of the OIR model. Additionally, honokiol enhanced physiological revascularization of the retinal vascular plexuses. Since honokiol suppresses multiple pathways activated by HIF, in addition to the VEGF signaling, it may provide advantages over current treatments utilizing specific VEGF antagonists for ocular neovascular diseases and cancers.

  14. Potential anti-angiogenic role of Slit2 in corneal neovascularization.

    Science.gov (United States)

    Han, Xi; Zhang, Ming-Chang

    2010-06-01

    Slits are large secreted proteins critical for axon guidance and neuronal precursor cell migration in nervous system. Evidence suggests that classical neuronal guidance cues also regulate vascular development. Our objective was to investigate whether neuronal guidance cue Slit2 and Roundabout (Robo) receptors are involved in corneal neovascularization (NV). Corneal NV model in rats was induced by implantation of agarose-coated gelfoam pellets containing basic fibroblast growth factor (bFGF) into corneal stroma. Differential expression of Slit2 and Robo1-4 between normal and neovascularized cornea was detected by real-time RT-PCR and visualized by immunohistochemistry and in situ hybridization. Primary human umbilical vein endothelial cells (HUVECs) were harvested and their expression of Robo1-4 was detected by RT-PCR. Recombinant human Slit2 protein was prepared and the effect of it on the migration of vascular endothelial cells was examined using cell migration assay. Agarose-coated gelfoam pellets were able to induce well-localized and reproducible corneal NV model. A significant down-regulation of Slit2 and a strong up-regulation of Robo1 and Robo4 were seen in neovascularized cornea when compared with normal cornea (P Slit2, Robo1 and Robo4 were throughout the epithelium in normal cornea and markedly weak or absent in epithelium in neovascularized cornea, with Robo1 and Robo4 being prominent in vascular endothelial cells invading the stroma. Primary HUVECs were confirmed to express both Robo1 and Robo4 receptors and their migration was inhibited by Slit2 (P Slit2 and corneal NV. Our findings suggest that the interaction of Slit2 with Robo1 and Robo4 receptors plays an essential role in inhibiting pathological neovascular processes of the cornea and may represent a new therapeutic target for corneal NV.

  15. Treatment of neovascular age-related macular degeneration in patients with diabetes

    Directory of Open Access Journals (Sweden)

    Michael Cummings

    2008-06-01

    Full Text Available Michael Cummings1, José Cunha-Vaz21Academic Department of Diabetes and Endocrinology, Queen Alexandra Hospital, Portsmouth, UK; 2Department of Ophthalmology, University Hospital of Coimbra, Centre of Ophthalmology, Institute of Biomedical Research on Light and Image, Faculty of Medicine, University of Coimbra, and Association for Innovation and Biomedical Research on Light and Image, Coimbra, PortugalAbstract: The number of patients with type 2 diabetes continues to rise; an anticipated 300 million people will be affected by 2025. The immense social and economic burden of the condition is exacerbated by the initial asymptomatic nature of type 2 diabetes, resulting in a high prevalence of micro- and macrovascular complications at presentation. Diabetic retinopathy, one of the potential microvascular complications associated with diabetes, and neovascular age-related macular degeneration (AMD are the two most frequent retinal degenerative diseases, and are responsible for the majority of blindness due to retinal disease. Both conditions predominantly affect the central macula, and are associated with the presence of retinal edema and an aggressive inflammatory repair process that accelerates disease progression. The associated retinal edema and the inflammatory repair process are directly involved in the breakdown of the blood-retinal barrier (BRB. Yet, the underlying alterations to the BRB caused by the diseases are very different. The coexistence of the two conditions appears to be relatively uncommon, suggesting that diabetes may even protect patients from developing neovascular AMD. However, it is thought that the inflammatory repair responses associated with diabetic retinopathy and neovascular AMD may be cumulative and, in patients affected by both, could result in chronic diffuse cystoid edema. Treatment considerations in such patients should, therefore, include the role of retinal edema and the increased susceptibility of patients with

  16. Pegaptanib sodium for neovascular age-related macular degeneration: clinical experience in the UK

    Directory of Open Access Journals (Sweden)

    Sobha Sivaprasad

    2008-06-01

    Full Text Available Sobha Sivaprasad, Nachiketa Acharya, Phil HykinMoorfields Eye Hospital, London, UKAbstract: The pathogenesis of age-related macular degeneration (AMD is unclear, but it can take either a neovascular/exudative/wet form, characterized by choroidal neovascularization (CNV, or a dry form. No treatments are available for the dry form, but there are a number of pharmacological interventions that inhibit vascular endothelial growth factor (VEGF, which is central to the pathogenesis of CNV and neovascular AMD. Available anti-VEGF agents either target all active VEGF isoforms (eg, ranibizumab, or take a more selective approach and inhibit only VEGF165 (eg, pegaptantib sodium. Current guidance on their use is equivocal and restrictive at best, resulting in associated difficulties in securing adequate, timely funding for treatment. The Moorfields Eye Hospital undertook an audit of 70 patients receiving intravitreal (ITV pegaptanib sodium on a pro re nata (prn dosing schedule. Despite initial funding delays, the audit recorded superior treatment outcomes compared with those reported in the VISION trials at 12 weeks: 88% of audit patients maintained stable vision, 29% gained vision and 6% experienced severe vision loss compared with 70%, ≥6% and ≤10% of patients in VISION at 54 weeks, respectively. The audit indicates a positive correlation between patients with better baseline visual acuity (VA and improved therapeutic benefits, including a greater likelihood of both vision gain and vision preservation. Experience at Moorfields also suggests that pegaptanib sodium is more useful in occult lesions than minimally classic lesions, and clinical experience suggests that combination therapies may offer the best approach with anti-VEGF therapies. Further randomized clinical trials will help better determine the optimal treatment strategies with pegaptanib sodium in neovascular AMD.Keywords: age-related macular degeneration, choroidal neovascularization

  17. Circulating monocytes and B-lymphocytes in neovascular age-related macular degeneration

    Science.gov (United States)

    Hector, Sven Magnus; Sørensen, Torben Lykke

    2017-01-01

    Background Individuals with neovascular age-related macular degeneration (AMD) have altered number and distribution of retinal macrophages and show changes in circulating antibodies. We wanted to investigate the corresponding precursors, with subpopulations. We therefore measured monocyte and B-lymphocyte populations in individuals with neovascular AMD. Design This was an observational case–control study. Participants or samples A total of 31 individuals with neovascular AMD and 30 healthy age-matched controls were included. Methods Patients and controls were interviewed, and ophthalmological examination included visual acuity assessment using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, spectral domain optical coherence tomography (SD-OCT), slit-lamp examination and fundus photography. Moreover, venous blood was drawn and prepared for flow cytometry. Cells were gated and measured for surface markers. Main outcome measures Relative amounts of monocytes and B-lymphocytes with subsets, as well as selected surface markers, were measured. Results The two groups did not significantly differ in age, smoking history, body mass index, physical activity or C-reactive protein (CRP). Total monocytes (percentage of all leukocytes) were lower in the neovascular AMD group (median 5.5%) compared with the level in the control group (6.5%; P-value: 0.028). The percentage of intermediate monocytes positive for cluster of differentiation 11b (CD11b) was lower for AMD patients (99.4%) compared with 100% for the control group (P-value: 0.032). Conclusion We observed lower numbers of monocytes, which show a potentially impaired ability to migrate across the endothelial wall in patients with neovascular AMD. These subtle changes could potentially lead to an imbalance in the recruitment of macrophages into the retina during disease development. PMID:28176950

  18. Matrix calculus

    CERN Document Server

    Bodewig, E

    1959-01-01

    Matrix Calculus, Second Revised and Enlarged Edition focuses on systematic calculation with the building blocks of a matrix and rows and columns, shunning the use of individual elements. The publication first offers information on vectors, matrices, further applications, measures of the magnitude of a matrix, and forms. The text then examines eigenvalues and exact solutions, including the characteristic equation, eigenrows, extremum properties of the eigenvalues, bounds for the eigenvalues, elementary divisors, and bounds for the determinant. The text ponders on approximate solutions, as well

  19. Extracellular Matrix/Integrin Signaling Promotes Resistance to Combined Inhibition of HER2 and PI3K in HER2(+) Breast Cancer.

    Science.gov (United States)

    Hanker, Ariella B; Estrada, Mónica Valeria; Bianchini, Giampaolo; Moore, Preston D; Zhao, Junfei; Cheng, Feixiong; Koch, James P; Gianni, Luca; Tyson, Darren R; Sánchez, Violeta; Rexer, Brent N; Sanders, Melinda E; Zhao, Zhongming; Stricker, Thomas P; Arteaga, Carlos L

    2017-06-15

    PIK3CA mutations are associated with resistance to HER2-targeted therapies. We previously showed that HER2(+)/PIK3CA(H1047R) transgenic mammary tumors are resistant to the HER2 antibodies trastuzumab and pertuzumab but respond to PI3K inhibitor buparlisib (TPB). In this study, we identified mechanisms of resistance to combined inhibition of HER2 and PI3K. TPB-resistant tumors were generated by treating HER2(+)/PIK3CA(H1047R) tumor-bearing mice long term with the drug combination. RNA sequencing of TPB-resistant tumors revealed that extracellular matrix and cell adhesion genes, including collagen II (Col2a1), were markedly upregulated, accompanied by activation of integrin β1/Src. Cells derived from drug-resistant tumors were sensitive to TBP when grown in vitro, but exhibited resistance when plated on collagen or when reintroduced into mice. Drug resistance was partially reversed by the collagen synthesis inhibitor ethyl-3,4-dihydroxybenzoate. Inhibition of integrin β1/Src blocked collagen-induced resistance to TPB and inhibited growth of drug-resistant tumors. High collagen II expression was associated with significantly lower clinical response to neoadjuvant anti-HER2 therapy in HER2(+) breast cancer patients. Overall, these data suggest that upregulation of collagen/integrin/Src signaling contributes to resistance to combinatorial HER2 and PI3K inhibition. Cancer Res; 77(12); 3280-92. ©2017 AACR. ©2017 American Association for Cancer Research.

  20. Regulable vascular endothelial growth factor165 overexpression by ex vivo expanded keratinocyte cultures promotes matrix formation, angiogenesis, and healing in porcine full-thickness wounds.

    Science.gov (United States)

    Dickens, Stijn; Vermeulen, Pieter; Hendrickx, Benoit; Van den Berge, Stefaan; Vranckx, Jan J

    2008-01-01

    The intricate wound repair process involves the interplay of numerous cells and proteins. Using a porcine full-thickness wound (FTW) healing model, we hypothesized that the ex vivo gene transfer of vascular endothelial growth factor (VEGF)-transfected basal keratinocyte (KC) cell suspensions may generate cross-talk and induce matrix formation, angiogenesis, and accelerated healing. Moreover, to regulate overexpression of isoform 165 of VEGF and its effect on healing, we introduced a tetracycline (TC)-inducible gene switch in the expression plasmid. Autologous basal KCs were cultivated from the porcine donor and transfected using cationic liposomes. A dose-response curve was established to determine optimal activation of the gene switch by TC. In vivo, FTWs were treated with VEGF-transfected KCs and controls. Wound fluids were collected daily and examined using enzyme-linked immunosorbent assay. Biopsies were evaluated using hematoxylin and eosin and immunostaining for fibronectin, CD144, and lectin BS-1. In vitro, highest regulable VEGF165-expression was obtained with 1 microg/mL of TCs. In vivo, after induction of the gene switch by adding 1 microg/mL of TCs to the FTW, we obtained upregulated VEGF165 levels and enhanced fibronectin deposition and found more endothelial cell tubular formations and higher rates of reepithelialization than in controls. This ex vivo gene transfer model may serve as a platform for vascular induction in full-thickness tissue repair.

  1. Upregulation of ATG3 contributes to autophagy induced by the detachment of intestinal epithelial cells from the extracellular matrix, but promotes autophagy-independent apoptosis of the attached cells.

    Science.gov (United States)

    Yoo, Byong Hoon; Zagryazhskaya, Anna; Li, Yongling; Koomson, Ananda; Khan, Iman Aftab; Sasazuki, Takehiko; Shirasawa, Senji; Rosen, Kirill V

    2015-01-01

    Detachment of nonmalignant intestinal epithelial cells from the extracellular matrix (ECM) triggers their growth arrest and, ultimately, apoptosis. In contrast, colorectal cancer cells can grow without attachment to the ECM. This ability is critical for their malignant potential. We found previously that detachment-induced growth arrest of nonmalignant intestinal epithelial cells is driven by their detachment-triggered autophagy, and that RAS, a major oncogene, promotes growth of detached cells by blocking such autophagy. In an effort to identify the mechanisms of detachment-induced autophagy and growth arrest of nonmalignant cells we found here that detachment of these cells causes upregulation of ATG3 and that ATG3 upregulation contributes to autophagy and growth arrest of detached cells. We also observed that when ATG3 expression is artificially increased in the attached cells, ATG3 promotes neither autophagy nor growth arrest but triggers their apoptosis. ATG3 upregulation likely promotes autophagy of the detached but not that of the attached cells because detachment-dependent autophagy requires other detachment-induced events, such as the upregulation of ATG7. We further observed that those few adherent cells that do not die by apoptosis induced by ATG3 become resistant to apoptosis caused by cell detachment, a property that is critical for the ability of normal epithelial cells to become malignant. We conclude that cell-ECM adhesion can switch ATG3 functions: when upregulated in detached cells in the context of other autophagy-promoting events, ATG3 contributes to autophagy. However, when overexpressed in the adherent cells, in the circumstances not favoring autophagy, ATG3 triggers apoptosis.

  2. Prophylactic effect of topical silica nanoparticles as a novel antineovascularization agent for inhibiting corneal neovascularization following chemical burn

    Directory of Open Access Journals (Sweden)

    Mehrdad Mohammadpour

    2015-01-01

    Conclusions: SiNPs is an effective modality for inhibiting corneal neovascularization following chemical burn in an experimental model. Further investigations are suggested for evaluation of its safety and efficacy in human eyes.

  3. A 4-Year Longitudinal Study of 555 Patients Treated with Ranibizumab for Neovascular Age-related Macular Degeneration

    DEFF Research Database (Denmark)

    Rasmussen, Annette; Bloch, Sara B; Fuchs, Josefine;

    2013-01-01

    To investigate the visual outcome, pattern of discontinuation, ocular complications, and mortality of patients treated with a variable ranibizumab dosing regimen for neovascular age-related macular degeneration (AMD) for 4 years....

  4. Monocyte chemotactic protein 1 increases homing of mesenchymal stem cell to injured myocardium and neovascularization following myocardial infarction

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective:To investigate the effect of MCP-1 on mesenchymal stem cells(MSCs) homing to injured myocardium in a rat myocardial infarction(MI) model. Methods:Rat myocardial infarction model was established by permanent left anterior descending branch ligation. Mesenchymal stem cells from donor rats were cultured in IMDM and labeled with BrdU. The Rats were divided into two groups. Monocyte chemotactic protein 1(MCP-1) expression were measured by in situ hybridization and immunohistochemistry in the sham operated or infarcted hearts at 1,2, 4,7,14 and 28 days post operation in MCP-1 detection group. The rats were injected with MCP-1, anti-MCP-1 antibody or saline 4 days after myocardial infarction in intervention group. Then, a total of 5 × 106 cells in 2.5 ml of PBS were injected through the tail vein. The number of the labeled MSCs in the infarcted hearts was counted 3 days post injection. Cardiac function and blood vessel density were assessed 28 days post injection. Results:Self-generating MCP-1 expression was increased at the first day, peaked at the 7th day and decreased thereafter post MI and remained unchanged in sham operated hearts. The MSCs enrichment in the host hearts were more abundant in the MI groups than that in the non-Mi group(P = 0.000), the MSCs enrichment in the host hearts were more abundant in the MCP-1 injected group than that in the anti-MCP-1 antibody and saline injected groups (P = 0.000). Cardiac function was improved more in MCP-1 injected group than anti-MCP-1 antibody and saline injected groups(P= 0.000). Neovascularization in MCP-1 injected group significantly increased compared with that of other groups(P = 0.000). Conclusion: Myocardial MCP-1 expression was increased only in the early phase post MI. MCP-1 may enhance MSCs homing to the injured heart and improve cardiac function by promoting neovascularization.

  5. Circulating monocytes and B-lymphocytes in neovascular age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Hector SM

    2017-01-01

    Full Text Available Sven Magnus Hector,1 Torben Lykke Sørensen1,2 1Clinical Eye Research Unit, Zealand University Hospital, Roskilde, 2Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Background: Individuals with neovascular age-related macular degeneration (AMD have altered number and distribution of retinal macrophages and show changes in circulating antibodies. We wanted to investigate the corresponding precursors, with subpopulations. We therefore measured monocyte and B-lymphocyte populations in individuals with neovascular AMD.Design: This was an observational case–control study.Participants or samples: A total of 31 individuals with neovascular AMD and 30 healthy age-matched controls were included.Methods: Patients and controls were interviewed, and ophthalmological examination included visual acuity assessment using the Early Treatment Diabetic Retinopathy Study (ETDRS chart, spectral domain optical coherence tomography (SD-OCT, slit-lamp examination and fundus photography. Moreover, venous blood was drawn and prepared for flow cytometry. Cells were gated and measured for surface markers.Main outcome measures: Relative amounts of monocytes and B-lymphocytes with subsets, as well as selected surface markers, were measured.Results: The two groups did not significantly differ in age, smoking history, body mass index, physical activity or C-reactive protein (CRP. Total monocytes (percentage of all leukocytes were lower in the neovascular AMD group (median 5.5% compared with the level in the control group (6.5%; P-value: 0.028. The percentage of intermediate monocytes positive for cluster of differentiation 11b (CD11b was lower for AMD patients (99.4% compared with 100% for the control group (P-value: 0.032.Conclusion: We observed lower numbers of monocytes, which show a potentially impaired ability to migrate across the endothelial wall in patients with neovascular AMD. These subtle changes could potentially lead to an

  6. Collagen-binding VEGF mimetic peptide: Structure, matrix interaction, and endothelial cell activation

    Science.gov (United States)

    Chan, Tania R.

    Long term survival of artificial tissue constructs depends greatly on proper vascularization. In nature, differentiation of endothelial cells and formation of vasculature are directed by dynamic spatio-temporal cues in the extracellular matrix that are difficult to reproduce in vitro. In this dissertation, we present a novel bifunctional peptide that mimics matrix-bound vascular endothelial growth factor (VEGF), which can be used to encode spatially controlled angiogenic signals in collagen-based scaffolds. The peptide, QKCMP, contains a collagen mimetic domain (CMP) that binds to type I collagen by a unique triple helix hybridization mechanism and a VEGF mimetic domain (QK) with pro-angiogenic activity. We demonstrate QKCMP's ability to hybridize with native and heat denatured collagens through a series of binding studies on collagen and gelatin substrates. Circular dichroism experiments show that the peptide retains the triple helical structure vital for collagen binding, and surface plasmon resonance study confirms the molecular interaction between the peptide and collagen strands. Cell culture studies demonstrate QKCMP's ability to induce endothelial cell morphogenesis and network formation as a matrix-bound factor in 2D and 3D collagen scaffolds. We also show that the peptide can be used to spatially modify collagen-based substrates to promote localized endothelial cell activation and network formation. To probe the biological events that govern these angiogenic cellular responses, we investigated the cell signaling pathways activated by collagen-bound QKCMP and determined short and long-term endothelial cell response profiles for p38, ERK1/2, and Akt signal transduction cascades. Finally, we present our efforts to translate the peptide's in vitro bioactivity to an in vivo burn injury animal model. When implanted at the wound site, QKCMP functionalized biodegradable hydrogels induce enhanced neovascularization in the granulation tissue. The results show QKCMP

  7. Defining response to anti-VEGF therapies in neovascular AMD.

    Science.gov (United States)

    Amoaku, W M; Chakravarthy, U; Gale, R; Gavin, M; Ghanchi, F; Gibson, J; Harding, S; Johnston, R L; Kelly, S P; Kelly, S; Lotery, A; Mahmood, S; Menon, G; Sivaprasad, S; Talks, J; Tufail, A; Yang, Y

    2015-06-01

    The introduction of anti-vascular endothelial growth factor (anti-VEGF) has made significant impact on the reduction of the visual loss due to neovascular age-related macular degeneration (n-AMD). There are significant inter-individual differences in response to an anti-VEGF agent, made more complex by the availability of multiple anti-VEGF agents with different molecular configurations. The response to anti-VEGF therapy have been found to be dependent on a variety of factors including patient's age, lesion characteristics, lesion duration, baseline visual acuity (VA) and the presence of particular genotype risk alleles. Furthermore, a proportion of eyes with n-AMD show a decline in acuity or morphology, despite therapy or require very frequent re-treatment. There is currently no consensus as to how to classify optimal response, or lack of it, with these therapies. There is, in particular, confusion over terms such as 'responder status' after treatment for n-AMD, 'tachyphylaxis' and 'recalcitrant' n-AMD. This document aims to provide a consensus on definition/categorisation of the response of n-AMD to anti-VEGF therapies and on the time points at which response to treatment should be determined. Primary response is best determined at 1 month following the last initiation dose, while maintained treatment (secondary) response is determined any time after the 4th visit. In a particular eye, secondary responses do not mirror and cannot be predicted from that in the primary phase. Morphological and functional responses to anti-VEGF treatments, do not necessarily correlate, and may be dissociated in an individual eye. Furthermore, there is a ceiling effect that can negate the currently used functional metrics such as >5 letters improvement when the baseline VA is good (ETDRS>70 letters). It is therefore important to use a combination of both the parameters in determining the response.The following are proposed definitions: optimal (good) response is defined as when there

  8. Cleavage of E-Cadherin by Matrix Metalloproteinase-7 Promotes Cellular Proliferation in Nontransformed Cell Lines via Activation of RhoA

    Directory of Open Access Journals (Sweden)

    Conor C. Lynch

    2010-01-01

    Full Text Available Perturbations in cell-cell contact machinery occur frequently in epithelial cancers and result in increased cancer cell migration and invasion. Previously, we demonstrated that MMP-7, a protease implicated in mammary and intestinal tumor growth, can process the adherens junction component E-cadherin. This observation leads us to test whether MMP-7 processing of E-cadherin could directly impact cell proliferation in nontransformed epithelial cell lines (MDCK and C57MG. Our goal was to investigate the possibility that MMP-7 produced by cancer cells may have effects on adjacent normal epithelium. Here, we show that MMP-7 processing of E-cadherin mediates, (1 loss of cell-cell contact, (2 increased cell migration, (3 a loss of epithelial cell polarization and (4 increased cell proliferation via RhoA activation. These data demonstrate that MMP-7 promotes epithelial cell proliferation via the processing of E-cadherin and provide insights into the molecular mechanisms that govern epithelial cell growth.

  9. Matrix Information Geometry

    CERN Document Server

    Bhatia, Rajendra

    2013-01-01

    This book is an outcome of the Indo-French Workshop on Matrix Information Geometries (MIG): Applications in Sensor and Cognitive Systems Engineering, which was held in Ecole Polytechnique and Thales Research and Technology Center, Palaiseau, France, in February 23-25, 2011. The workshop was generously funded by the Indo-French Centre for the Promotion of Advanced Research (IFCPAR).  During the event, 22 renowned invited french or indian speakers gave lectures on their areas of expertise within the field of matrix analysis or processing. From these talks, a total of 17 original contribution or state-of-the-art chapters have been assembled in this volume. All articles were thoroughly peer-reviewed and improved, according to the suggestions of the international referees. The 17 contributions presented  are organized in three parts: (1) State-of-the-art surveys & original matrix theory work, (2) Advanced matrix theory for radar processing, and (3) Matrix-based signal processing applications.  

  10. Juxtapapillary neovascular membrane secondary to idiopathic intracranial hypertension treated with intravitreal bevacizumab: A case report.

    Science.gov (United States)

    Hernández-Ortega, V; Soler-Sanchís, M I; Jiménez-Escribano, R M; Sanz-López, A M

    2016-05-01

    A 48 year-old woman with visual acuity loss in left eye (0.3). Funduscopic examination showed papillary oedema and neovascular membrane in the left eye. All neurological tests were normal, except the lumbar puncture with opening pressure of 35cmH2O, being diagnosed with idiopathic intracranial hypertension (IIH). After four doses of bevacizumab, the visual acuity of the left eye has not improved and is counting fingers. Pathogenesis of the juxtapapillary neovascular membrane associated with IIH is not well known. An effect was observed after the anti-VEGF treatment. In our case, there was no improvement after four doses of intravitreal bevacizumab. Copyright © 2016 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

  11. In Vivo Monitoring of Neovascularization in Tumour Angiogenesis by Photoacoustic Tomography

    Institute of Scientific and Technical Information of China (English)

    XIANG Liang-Zhong; XING Da; GU Huai-Min; ZHOU Fei-Fan; YANG Di-Wu; ZENG Lv-Ming; YANG Si-Hua

    2007-01-01

    Photoacoustic tomography (PAT) is presented to in vivo monitor neovascularization in tumout angiogenesis with high resolution and high contrast images in a rat. With a circular scan system, the photoacoustic signal, generated by laser pulses at a wavelength of 532nm from a Q-switched Nd:YAG laser, is captured by a hydrophone with a diameter of 1 mm and a sensitivity of 850nV/Pa. The vascular structure around the rat tumour is imaged clearly, with optimal contrast, because blood has strong absorption near this wavelength. Serial noninvasive photoacoustic images of neovascularization in tumour angiogenesis are also obtained consecutively from a growing tumour implanted under the skin of a rat over a period of two weeks. This work demonstrates that PAT can potentially provide a powerful tool for tumour angiogenesis detection in cancer research. It will bring us closer to clinical applications for tumour diagnosis and treatment monitoring.

  12. Intravitreal bevacizumab for treatment of choroidal neovascularization associated with osteogenesis imperfecta

    Directory of Open Access Journals (Sweden)

    Pukhraj Rishi

    2012-01-01

    Full Text Available A 12-year-old girl, diagnosed of osteogenesis imperfecta, presented with sudden visual loss in the left eye. Investigations revealed an active choroidal neovascular membrane. She underwent treatment with intravitreal Bevacizumab (1.25 mg/0.05 ml. Follow-up at 1 month revealed the development of lacquer crack running through the macula, underlying the fovea. The patient received two re-treatments at 1-month intervals, following which the choroidal neovascularization (CNV regressed completely. However, further progression of lacquer cracks was noted. At the last follow-up, 6 months following the last injection, the fundus remained stable and vision was maintained at 20/200. Considering the natural history of the disease and the increased risk of rupture of the Bruch′s membrane in such eyes, the possible complication of a lacquer crack developing must be borne in mind, before initiating treatment.

  13. Multilayered pigment epithelial detachment in neovascular age-related macular degeneration

    DEFF Research Database (Denmark)

    Rahimy, Ehsan; Freund, K Bailey; Larsen, Michael

    2014-01-01

    PURPOSE: To describe the spectral domain optical coherence tomography findings in eyes with chronic fibrovascular pigment epithelial detachment (PED) receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy. METHODS: Retrospective observational case series of patients...... over a mean of 36.9 months (median, 37.5; range, 6-84). A fusiform, or spindle-shaped, complex of highly organized layered hyperreflective bands was noted within each PED. Nineteen eyes demonstrated heterogenous, dilated, irregular neovascular tissue adherent to the undersurface of the retinal pigment......, hyperreflective bands, termed a "multilayered PED," which is often seen in conjunction with neovascular tissue adherent to the undersurface of the retinal pigment epithelium monolayer. On the basis of previous histopathologic correlations, these bands may represent a fibrous tissue complex with contractile...

  14. Possible vitreous involvement in a case with rapidly progressing choroidal neovascularization

    Directory of Open Access Journals (Sweden)

    Masayuki Hata

    2012-01-01

    Full Text Available A 65-year-old man with subfoveal choroidal neovascularization (CNV underwent photodynamic therapy (PDT. Despite the sequential treatments, the CNV grew larger and finally penetrated the retina. Vitreous adhesion was observed at the edge of the supraretinal fibrotic tissue. The case highlighted the possible unexpected side-effect of PDT. The upregulation of the vascular endothelial growth factor or the enhanced vitreous traction was considered to be responsible for the event.

  15. Intravitreal ranibizumab for the treatment of choroidal neovascularization secondary to ocular toxoplasmosis

    Directory of Open Access Journals (Sweden)

    Nikunj J Shah

    2011-01-01

    Full Text Available The purpose of the study was to report a case of choroidal neovascularization (CNV secondary to ocular toxoplasmosis in an 18-year-old female patient. She was treated with a single intravitreal injection of ranibizumab. The CNV resolved as confirmed by fluorescein angiography and optical coherence tomography (OCT. The visual acuity improved to 20/30, which was maintained till the last follow-up visit at two years, without requisition of a repeat injection.

  16. Inhibitory effects of polysaccharide extract from Spirulina platensis on corneal neovascularization

    OpenAIRE

    Yang, LingLing; Wang, Yao; Zhou, Qingjun; Chen, Peng; Wang, Yiqiang; Wang, Ye; Liu, Ting; Xie, Lixin

    2009-01-01

    Purpose To assess the effects of polysaccharide extract from Spirulina platensis (PSP) on corneal neovascularization (CNV) in vivo and in vitro. Methods PSP was extracted from dry powder of Spirulina platensis. Its anti-angiogenic activity was evaluated in the mouse corneal alkali burn model after topical administration of PSP four times daily for up to seven days. Corneal samples were processed for histochemical, immunohistochemical, and gene expression analyses. The effects of PSP on prolif...

  17. CCR3 is a therapeutic and diagnostic target for neovascular age-related macular degeneration

    OpenAIRE

    2009-01-01

    Age-related macular degeneration (AMD), a leading cause of blindness worldwide, is as prevalent as cancer in industrialized nations. Most blindness in AMD results from invasion of the retina by choroidal neovascularization (CNV). We report that the eosinophil/mast cell chemokine receptor CCR3 is specifically expressed in CNV endothelial cells in humans with AMD, and that, despite the expression of its ligands eotaxin-1, -2, and -3, neither eosinophils nor mast cells are present in human CNV. ...

  18. Endogenous neurogenesis and neovascularization in the neocortex of the rat after focal cerebral ischemia.

    Science.gov (United States)

    Shin, Hye Young; Kim, Jin Hyun; Phi, Ji Hoon; Park, Chul-Kee; Kim, Jung Eun; Kim, Jong-Hoon; Paek, Sun Ha; Wang, Kyu-Chang; Kim, Dong Gyu

    2008-02-01

    The present study was designed to examine whether endogenous neurogenesis and neovascularization occur in the neocortex of the ischemic rat brain after unilateral middle cerebral artery occlusion (MCAO). Sprague-Dawley rats were divided into six groups (n = 29): one control group (n = 4) and five groups composed of animals sacrificed at increasing times post-MCAO (2 days and 1, 2, 4, and 8 weeks; n = 5 per group). To determine the presence of neurogenesis and neovascularization in the ischemic brain, nestin, Tuj1, NeuN, GFAP, Tie2, RECA, and 5-bromo-2'-deoxyuridine (BrdU) were analyzed immunohistochemically. In addition, nestin, GFAP, and Tie2 expression was determined by Western blotting. Triple-labeling of nestin, BrdU, and laminin was performed to visualize the interaction between endogenous neurogenesis and neovascularization. The number of BrdU- and nestin-colabeled cells increased markedly in the neocortex and border zone of the ischemic area up to 1 week after MCAO and decreased thereafter. Western blot analysis revealed that the expression of nestin, Tie-2, and GFAP was amplified in the ipsilateral hemisphere 2 days after MCAO and peaked 1 week after MCAO, compared with that in the normal brain. After ischemic injury, nestin- and BrdU-colabeled cells were observed in the vicinity of the endothelial cells lining cerebral vessels in the ipsilateral neocortex of the ischemic brain. Endogenous neurogenesis and neovascularization were substantially activated and occurred in close proximity to one other in the ipsilateral neocortex of the ischemic rat brain. (c) 2007 Wiley-Liss, Inc.

  19. Economic Burden of Bilateral Neovascular Age-Related Macular Degeneration: Multi-Country Observational Study

    OpenAIRE

    Alan F. Cruess; Gergana Zlateva; Xiao Xu; Gisele Soubrane; Daniel Pauleikhoff; Andrew Lotery; Jordi Mones; Ronald Buggage; Caroline Schaefer; Tyler Knight; Goss, Thomas F

    2008-01-01

    Background: There is limited previous research examining the healthcare costs of neovascular age-related macular degeneration (NV-AMD), which constrains our understanding of the economic impact of this condition. With aging populations, this leading cause of rapid vision loss in Western countries is expected to become a pressing health predicament, requiring decision makers to evaluate alternative treatment strategies for AMD. Objective: To document the economic burden of bilateral NV-AMD, th...

  20. Caregiver Burden in Patients Receiving Ranibizumab Therapy for Neovascular Age Related Macular Degeneration

    OpenAIRE

    Rishma Gohil; Roxanne Crosby-Nwaobi; Angus Forbes; Ben Burton; Phil Hykin; Sobha Sivaprasad

    2015-01-01

    Purpose To assess the caregiver burden and factors determining the burden in patients receiving ranibizumab therapy for neovascular AMD (nAMD). Methods This is a cross-sectional questionnaire survey of 250 matched patient caregiver dyads across three large ophthalmic treatment centres in United Kingdom. The primary outcome was the subjective caregiver burden measured using caregiver reaction assessment scale (CRA). Objective caregiver burden was determined by the caregiver tasks and level of ...

  1. Inhibition of Ocular Neovascularization by Co-Inhibition of VEGF-A and PLGF

    OpenAIRE

    Xiaochuan Huo; Youxiang Li; Yuhua Jiang; Xiaoyun Sun; Lixue Gu; Wenshi Guo; Dapeng Sun

    2015-01-01

    Background/Aims: Age-related macular degeneration (AMD) appears to be a disease with increasing incidence in Western countries and may develop into acquired blindness. Choroidal neovascularization (CNV) is the most frequent cause for AMD, and is commonly induced by regional inflammation. Past studies have highlighted vascular endothelial growth factor A (VEGF-A) as a major trigger for CNV. However, studies on the associated angiogenic factors other than VEGF-A are lacking. Methods: Here, we u...

  2. Choroidal neovascularization associated with coloboma of the choroid: A series of three cases

    Directory of Open Access Journals (Sweden)

    Bhende Muna

    2011-01-01

    Full Text Available Choroidal neovascularization (CNV is a rare complication associated with coloboma of the choroid. We describe three cases of coloboma choroid where there was loss of vision due to CNV development at the edge of the coloboma. One was managed by photodynamic therapy alone and two were managed by a combination of reduced fluence PDT and intravitreal bevacizumab. Significantly we noted that one treatment session was sufficient to achieve regression of the CNV and improvement in visual acuity.

  3. Identification of Chlamydia pneumoniae within human choroidal neovascular membranes secondary to age-related macular degeneration.

    Science.gov (United States)

    Kalayoglu, Murat V; Bula, Deisy; Arroyo, Jorge; Gragoudas, Evangelos S; D'Amico, Donald; Miller, Joan W

    2005-11-01

    Age-related macular degeneration (AMD) is a leading cause of blindness in the United States, and increasing evidence suggests that it is an inflammatory disease. The prokaryotic obligate intracellular pathogen Chlamydia pneumoniae is emerging as a novel risk factor in cardiovascular disease, and recent sero-epidemiological data suggest that C. pneumoniae infection is also associated with AMD. In this study, we examined choroidal neovascular membrane (CNV) tissue from patients with neovascular AMD for the presence of C. pneumoniae and determined whether the pathogen can dysregulate the function of key cell types in ways that can cause neovascular AMD. Nine CNV removed from patients with neovascular AMD were examined for the presence of C. pneumoniae by immunohistochemistry (IHC) and polymerase chain reaction (PCR); in addition, we performed PCR on nine non-AMD eyes, and IHC on five non-AMD CNV, seven non-AMD eyes, and one internal limiting membrane specimen. Finally, human monocyte-derived macrophages and retinal pigment epithelial (RPE) cells were exposed to C. pneumoniae and assayed in vitro for the production of pro-angiogenic immunomodulators (VEGF, IL-8, and MCP-1). C. pneumoniae was detected in four of nine AMD CNV by IHC and two of nine AMD CNV by PCR, induced VEGF production by human macrophages, and increased production of IL-8 and MCP-1 by RPE cells. In contrast, none of the 22 non-AMD specimens showed evidence for C. pneumoniae. These data indicate that a pathogen capable of inducing chronic inflammation and pro-angiogenic cytokines can be detected in some AMD CNV, and suggest that infection may contribute to the pathogenesis of AMD.

  4. Matrix Thermalization

    CERN Document Server

    Craps, Ben; Nguyen, Kévin

    2016-01-01

    Matrix quantum mechanics offers an attractive environment for discussing gravitational holography, in which both sides of the holographic duality are well-defined. Similarly to higher-dimensional implementations of holography, collapsing shell solutions in the gravitational bulk correspond in this setting to thermalization processes in the dual quantum mechanical theory. We construct an explicit, fully nonlinear supergravity solution describing a generic collapsing dilaton shell, specify the holographic renormalization prescriptions necessary for computing the relevant boundary observables, and apply them to evaluating thermalizing two-point correlation functions in the dual matrix theory.

  5. Role of Pigment Epithelium-Derived Factor in Stem/Progenitor Cell-Associated Neovascularization

    Directory of Open Access Journals (Sweden)

    Jung-Tung Liu

    2012-01-01

    Full Text Available Pigment epithelium-derived factor (PEDF was first identified in retinal pigment epithelium cells. It is an endogenously produced protein that is widely expressed throughout the human body such as in the eyes, liver, heart, and adipose tissue; it exhibits multiple and varied biological activities. PEDF is a multifunctional protein with antiangiogenic, antitumorigenic, antioxidant, anti-inflammatory, antithrombotic, neurotrophic, and neuroprotective properties. More recently, PEDF has been shown to be the most potent inhibitor of stem/progenitor cell-associated neovascularization. Neovascularization is a complex process regulated by a large, interacting network of molecules from stem/progenitor cells. PEDF is also involved in the pathogenesis of angiogenic eye disease, tumor growth, and cardiovascular disease. Novel antiangiogenic agents with tolerable side effects are desired for the treatment of patients with various diseases. Here, we review the value of PEDF as an important endogenous antiangiogenic molecule; we focus on the recently identified role of PEDF as a possible new target molecule to influence stem/progenitor cell-related neovascularization.

  6. Management of Neovascular Age-related Macular Degeneration: A Review on Landmark Randomized Controlled Trials.

    Science.gov (United States)

    Agarwal, Aniruddha; Aggarwal, Kanika; Gupta, Vishali

    2016-01-01

    In the last decade, a number of prospective clinical trials with carefully designed study protocols have been conducted for the treatment of neovascular age-related macular degeneration (AMD). These landmark clinical trials such as ANCHOR and MARINA and, more recently, the Comparison of AMD Treatment Trials and VIEW studies have revolutionized the management of neovascular AMD. While AMD continues to remain a leading cause of severe visual loss worldwide, advances in pharmacotherapeutics have led to substantial improvements in the outcome of these patients. The introduction of anti-vascular endothelial growth factor agents has resulted in improvement of visual outcomes and has had a positive impact on the quality of life among elderly population. While the contemporary management of neovascular AMD has been successful in tremendously reducing the visual morbidity, the financial burden of therapy has increased exponentially. To overcome these challenges, newer pharmacologic agents are evaluated for their efficacy and safety in AMD. Ground-breaking advances in bench to bedside research have led to discovery of new pathways that appear to be viable targets for preventing visual loss in AMD. In this review, study designs and results of landmark clinical trials in AMD from the past decade have been summarized.

  7. Management of neovascular Age-related macular degeneration: A review on landmark randomized controlled trials

    Directory of Open Access Journals (Sweden)

    Aniruddha Agarwal

    2016-01-01

    Full Text Available In the last decade, a number of prospective clinical trials with carefully designed study protocols have been conducted for the treatment of neovascular age.related macular degeneration (AMD. These landmark clinical trials such as ANCHOR and MARINA and, more recently, the Comparison of AMD Treatment Trials and VIEW studies have revolutionized the management of neovascular AMD. While AMD continues to remain a leading cause of severe visual loss worldwide, advances in pharmacotherapeutics have led to substantial improvements in the outcome of these patients. The introduction of anti.vascular endothelial growth factor agents has resulted in improvement of visual outcomes and has had a positive impact on the quality of life among elderly population. While the contemporary management of neovascular AMD has been successful in tremendously reducing the visual morbidity, the financial burden of therapy has increased exponentially. To overcome these challenges, newer pharmacologic agents are evaluated for their efficacy and safety in AMD. Ground.breaking advances in bench to bedside research have led to discovery of new pathways that appear to be viable targets for preventing visual loss in AMD. In this review, study designs and results of landmark clinical trials in AMD from the past decade have been summarized.

  8. Effect of photodynamic therapy combined with intravitreal injection of Lucentis therapy on choroidal neovascularization

    Institute of Scientific and Technical Information of China (English)

    Yan-Mei Su

    2016-01-01

    Objective:To analyze the efficacy of photodynamic therapy combined with intravitreal injection of Lucentis therapy for choroidal neovascularization.Methods: A total of 82 cases with choroidal neovascularization receiving inpatient therapy in our hospital from August 2013 to August 2014 were selected as research subjects, and according to random number table method, all enrolled patients were divided into control group (received photodynamic therapy) and observation group (received photodynamic therapy combined with intravitreal injection of Lucentis therapy), each group with 41 cases. Differences in best corrected visual acuity, intraocular pressure and central macular thickness, mean sensitivity of visual field and so on of two groups were compared.Results:After treatment, visual acuity improvement ratio of observation group was significantly higher than that of control group and visual acuity decrease ratio was lower than that of control group (P<0.05); intraocular pressure and central macular thickness were significantly less than those of control group (P<0.05); mean sensitivity of 10o and 30o visual field was higher than that of control group (P<0.05).Conclusions:Photodynamic therapy combined with intravitreal injection of Lucentis therapy can effectively improve vision and visual acuity of patients with choroidal neovascularization and reduce intraocular pressure and central macular thickness; it is an ideal treatment method.

  9. The Application of OCTA in Assessment of Anti-VEGF Therapy for Idiopathic Choroidal Neovascularization

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    Qin Chen

    2016-01-01

    Full Text Available Purpose. To assess the morphology of idiopathic choroidal neovascularization (ICNV by optical coherence tomography angiography (OCTA and determine the therapeutic effects of intravitreal antivascular endothelial growth factor (anti-VEGF. Method. Patients with naive ICNV were assessed by spectral domain optical coherence tomography (SD-OCT and OCTA in this observational study. The timing of observation was before treatment, 1 day after treatment with intravitreal anti-VEGF injection, and 1 month after the treatment. The central retina thickness (CRT on SD-OCT, selected CNV area, and flow area on OCTA were measured. Results. A total of 17 eyes from 17 patients with ICNV were included in this study. OCTA showed visible irregular choroidal neovascularization with “tree-in-bud” form on outer retinal layer. After treatment, as well as in the 1-day follow-up, CNV decreased in size from the periphery, and the vessel density was reduced. As shown on OCTA, the selected CNV area and flow area were significantly reduced compared to pretreatment. The rate of CNV vessel area changes was higher on OCTA than the changes in CRT on SD-OCT at 1-day and 1-month follow-up. Conclusion. Intravitreal injection of anti-VEGF is effective for idiopathic choroidal neovascularization, and the treatment outcomes are observable after 1 day. OCTA provides a useful approach for monitoring and evaluating the treatment of intravitreal anti-VEGF for CNV.

  10. Ethyl Pyruvate Inhibits Retinal Pathogenic Neovascularization by Downregulating HMGB1 Expression

    Directory of Open Access Journals (Sweden)

    Yun Mi Lee

    2013-01-01

    Full Text Available Retinal pathogenic angiogenesis in the eyes is a causative factor in retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. This study was designed to examine the pathogenic role of the high-mobility group box-1 (HMGB1 protein and the inhibitory effect of ethyl pyruvate (EP, a well-known antioxidant substance, in retinal pathogenic angiogenesis in mice with oxygen-induced retinopathy (OIR, one of the animal models of proliferative ischemic retinopathy. The OIR mouse model was used for our in vivo studies. The mice were exposed to 75% oxygen from postnatal day 7 (P7 to P11, after which the mice were brought to room air and intraperitoneally injected with EP (50 mg/kg, or 100 mg/kg for five days. At P17, the mice were perfused with fluorescein isothiocyanate-dextran, and flat-mounted retinas were used to measure nonperfused and neovascular tufts. In OIR mice, an intraperitoneal injection of EP reduced the nonperfused retinal area in the treatment group and significantly reduced the retinal neovascular tufts. In addition, EP inhibited the overexpression of HMGB1 in the retinas of OIR mice. These data suggest that EP could serve as an innovative pharmaceutical agent to prevent retinal neovascularization through inhibiting HMGB1 expression.

  11. Ethyl pyruvate inhibits retinal pathogenic neovascularization by downregulating HMGB1 expression.

    Science.gov (United States)

    Lee, Yun Mi; Kim, Junghyun; Jo, Kyuhyung; Shin, So Dam; Kim, Chan-Sik; Sohn, Eun Jin; Kim, Seon Gi; Kim, Jin Sook

    2013-01-01

    Retinal pathogenic angiogenesis in the eyes is a causative factor in retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. This study was designed to examine the pathogenic role of the high-mobility group box-1 (HMGB1) protein and the inhibitory effect of ethyl pyruvate (EP), a well-known antioxidant substance, in retinal pathogenic angiogenesis in mice with oxygen-induced retinopathy (OIR), one of the animal models of proliferative ischemic retinopathy. The OIR mouse model was used for our in vivo studies. The mice were exposed to 75% oxygen from postnatal day 7 (P7) to P11, after which the mice were brought to room air and intraperitoneally injected with EP (50 mg/kg, or 100 mg/kg) for five days. At P17, the mice were perfused with fluorescein isothiocyanate-dextran, and flat-mounted retinas were used to measure nonperfused and neovascular tufts. In OIR mice, an intraperitoneal injection of EP reduced the nonperfused retinal area in the treatment group and significantly reduced the retinal neovascular tufts. In addition, EP inhibited the overexpression of HMGB1 in the retinas of OIR mice. These data suggest that EP could serve as an innovative pharmaceutical agent to prevent retinal neovascularization through inhibiting HMGB1 expression.

  12. Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment.

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    Alexander G Bassuk

    Full Text Available CAPN5 mutations have been linked to autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV, a blinding autoimmune eye disease. Here, we link a new CAPN5 mutation to ADNIV and model the three-dimensional structure of the resulting mutant protein. In our study, a kindred with inflammatory vitreoretinopathy was evaluated by clinical eye examinations, DNA sequencing, and protein structural modeling to investigate the disease-causing mutation. Two daughters of an affected mother demonstrated symptoms of stage III ADNIV, with posterior uveitis, cystoid macular edema, intraocular fibrosis, retinal neovascularization, retinal degeneration, and cataract. The women also harbored a novel guanine to thymine (c.750G>T, p.Lys250Asn missense mutation in exon 6 of CAPN5, a gene that encodes a calcium-activated cysteine protease, calpain-5. Modeling based on the structures of all known calpains revealed the mutation falls within a calcium-sensitive flexible gating loop that controls access to the catalytic groove. Three-dimensional modeling placed the new mutation in a region adjacent to two previously identified disease-causing mutations, all three of which likely disrupt hydrogen bonding within the gating loop, yielding a CAPN5 with altered enzymatic activity. This is the third case of a CAPN5 mutation leading to inherited uveitis and neovascular vitreoretinopathy, suggesting patients with ADNIV features should be tested for CAPN5 mutations. Structural modeling of novel variants can be used to support mechanistic consequences of the disease-causing variants.

  13. Clinical research of retinal laser photocoagulation and Ranibizumab on the treatment of neovascular glaucoma

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    Wei-Peng Jiang

    2015-10-01

    Full Text Available AIM: To explore the improvement of visual function and the adverse reactions of retinal laser photocoagulation combined with ranibizumab for the treatment of neovascular glaucoma(NVG, to provide the basis for clinical treatment.METHODS: One hundred patients with 129 eyes in our hospital from January 2012 to June 2014 were selected. They were randomly divided into the observation group and the control group, 50 cases in each one. Patients in the control group(67 eyeswere treated with retinal laser photocoagulation, and those in the observation group(62 eyeswere given retinal laser photocoagulation combined with ranibizumab treatment. After the treatment, the degeneration of iris neovascularization, visual acuity, intraocular pressure, ocular fundus and the adverse reactions were evaluated. Optical coherence tomography(OCTwas used to detect retinal nerve fiber layer(RNFLthickness and visual field defect. RESULTS: The degeneration rate of the iris neovascularization in the observation group was 95.2%(59/62, higher than that of the control group 83.6%(56/67(PPPPPP>0.05.CONCLUSION: The treatment of NVG with laser photocoagulation combined with ranibizumab has good clinical efficacy, and can significantly improve the vision and retinal structure and function of the patients, and is safer.

  14. Predictors of Visual Response to Intravitreal Bevacizumab for Treatment of Neovascular Age-Related Macular Degeneration

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    Kai Fang

    2013-01-01

    Full Text Available Purpose. To identify the predictors of visual response to the bevacizumab treatment of neovascular age-related macular degeneration (AMD. Design. A cohort study within the Neovascular AMD Treatment Trial Using Bevacizumab (NATTB. Methods. This was a multicenter trial including 144 participants from the NATTB study. Visual outcomes measured by change in visual acuity (VA score, proportion gaining ≥15 letters, and change in central retinal thickness (CRT were compared among groups according to the baseline, demographic, and ocular characteristics and genotypes. Results. Mean change in the VA score was 9.2 ± 2.3 SD letters with a total of 46 participants (31.9% gaining ≥15 letters. Change in median CRT was −81.5 μm. Younger age, lower baseline VA score, shorter duration of neovascular AMD, and TT genotype in rs10490924 were significantly associated with greater VA score improvement (P=0.028, P<0.001, P=0.02, and P=0.039, resp.. Lower baseline VA score and TT genotype in rs10490924 were significantly associated with a higher likelihood of gaining ≥15 letters (P=0.028, and P=0.021, resp.. Conclusions. Baseline VA and genotype of rs10490924 were both important predictors for visual response to bevacizumab at 6 months. This trial is registered with the Registration no. NCT01306591.

  15. Minimally invasive colorectal resection is associated with significantly elevated levels of plasma matrix metalloproteinase 3 (MMP-3) during the first month after surgery which may promote the growth of residual metastases.

    Science.gov (United States)

    Shantha Kumara, H M C; Gaita, David J; Miyagaki, Hiromichi; Yan, Xiaohong; Herath, Sonali A C; Cekic, Vesna; Whelan, Richard L

    2014-12-01

    MMP-3, a member of the matrix metalloproteinase (MMP) family, is involved in the breakdown of the extracellular matrix in tissue remodeling and may also play a role in cancer progression and metastasis. Minimally invasive colorectal resection (MICR) may increase plasma MMP-3 levels directly via surgical trauma or indirectly due to surgery-associated elevations in TNF-α and IL1 which are regulators of MMP-3. This study's purpose was to evaluate plasma MMP-3 levels during the first month after MICR for colorectal cancer. Patients enrolled in an IRB approved data/plasma bank who underwent elective MICR for CRC. Blood plasma samples had been collected preoperatively, on postoperative day (POD) 1, 3 and at varying postoperative time points and were stored at -80 °C. The late samples (POD 7-41) were bundled into 7 day time blocks and considered as single time points. MMP-3 levels were analyzed in duplicate via ELISA and the results reported as mean ± SD. The paired t test was used for analysis (significance, p MICR met the inclusion criteria. The mean PreOp MMP-3 level was 14.9 ± 7.8 ng/ml (n = 73). Significantly elevated mean plasma levels were noted on POD 1 (21.4 ± 14.7 ng/ml, n = 73, p MICR for CRC. The early postoperative increase in MMP-3 levels may be due to the surgery-related acute inflammatory response; the elevation noted during weeks 2-3 may be related to wound healing. Increased MMP-3 levels may promote metastases or the growth of residual cancer.

  16. Pegaptanib sodium treatment in neovascular age-related macular degeneration: clinical experience in Germany

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    Nikolaus Feucht

    2008-06-01

    Full Text Available Nikolaus Feucht, Huebner Matthias, Chris P Lohmann, Mathias MaierAugenklinik rechts der Isar, Technical University Munich, GermanyBackground: The VEGF Inhibition Study In Ocular Neovascularisation (VISION reported the efficacy of intravitreal (ITV vascular endothelial growth factor (VEGF inhibition with pegaptanib sodium (Macugen® for the treatment of neovascular age-related macular degeneration (AMD. This paper reports clinical experience with pegaptanib sodium for the treatment of occult or minimally classic choroidal neovascularization (CNV due to AMD.Material and methods: The study included 50 eyes (in 49 patients with either occult CNV or minimally classic CNV secondary to neovascular AMD who were not eligible for photodynamic therapy (PDT. Study data were analyzed retrospectively. During the 6-month study, patients were administered an average 2.74 injections of 0.3 mg ITV pegaptanib sodium. Angiography and optical coherence tomography (OCT examinations were carried out and intraocular pressure (IOP and visual acuity (VA were measured at baseline, at 3 months and at 6 months. An eye examination was performed and VA was measured the 2 days following treatment and then again at weeks 4–6, and at 3 and 6 months. OCT, VA, and IOP were also assessed at 1 month.Results: ITV pegaptanib sodium was well tolerated and no treatment complications arose. Mean VA was measured as: 0.37 ± 0.24 at baseline; 0.37 ± 0.25 at 1 month; 0.37 ± 0.25 at 3 months and 0.40 ± 0.26 at 6 months. VA was stabilized in approximately 90% of eyes treated with pegaptanib sodium. OCT examination showed a minimal change in central retinal thickness (CRT during the course of the study, from 251.19 µm at baseline to 251.63 µm at 6 months. No elevation in IOP was measured during treatment at 4–6 months in patients receiving pegaptanib sodium.Conclusions: ITV therapy with pegaptanib sodium for occult and minimally classic CNV secondary to neovascular AMD offered good

  17. Matrix inequalities

    CERN Document Server

    Zhan, Xingzhi

    2002-01-01

    The main purpose of this monograph is to report on recent developments in the field of matrix inequalities, with emphasis on useful techniques and ingenious ideas. Among other results this book contains the affirmative solutions of eight conjectures. Many theorems unify or sharpen previous inequalities. The author's aim is to streamline the ideas in the literature. The book can be read by research workers, graduate students and advanced undergraduates.

  18. Gene Therapy with Endogenous Inhibitors of Angiogenesis for Neovascular Age-Related Macular Degeneration: Beyond Anti-VEGF Therapy

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    Selwyn M. Prea

    2015-01-01

    Full Text Available Age-related macular degeneration (AMD is the leading cause of substantial and irreversible vision loss amongst elderly populations in industrialized countries. The advanced neovascular (or “wet” form of the disease is responsible for severe and aggressive loss of central vision. Current treatments aim to seal off leaky blood vessels via laser therapy or to suppress vessel leakage and neovascular growth through intraocular injections of antibodies that target vascular endothelial growth factor (VEGF. However, the long-term success of anti-VEGF therapy can be hampered by limitations such as low or variable efficacy, high frequency of administration (usually monthly, potentially serious side effects, and, most importantly, loss of efficacy with prolonged treatment. Gene transfer of endogenous antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization and/or excessive vascular leakage in the eye. Preclinical studies of gene transfer in a large animal model have provided impressive preliminary results with a number of transgenes. In addition, a clinical trial in patients suffering from advanced neovascular AMD has provided proof-of-concept for successful gene transfer. In this mini review, we summarize current theories pertaining to the application of gene therapy for neovascular AMD and the potential benefits when used in conjunction with endogenous antiangiogenic proteins.

  19. Retinal pigment epithelial cell expression of active Rap 1a by scAAV2 inhibits choroidal neovascularization

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    Haibo Wang

    2016-01-01

    Full Text Available To test the hypothesis that increased Rap1a activity specifically in retinal pigment epithelial cells resists choroidal neovascularization (CNV, self-complementary adeno-associated virus 2 (scAAV2 with RPE65-promoter-driven GFP vectors were generated and introduced subretinally into Rap1b-deficient mice. Six-week-old mice that received subretinal control (scAAV2-Con or constitutively active Rap1a (scAAV2-CARap1a showed strong GFP at the 5 × 108 viral particle/μl dose 5 weeks later without altering retinal morphology or function. Compared to scAAV2-Con- or phosphate-buffered saline (PBS-injected, eyes injected with scAAV2-CARap1a had increased Rap1 in retinal pigment epithelial (RPE/choroidal lysates and a significant reduction in CNV volume 7 days after laser, comparable to eyes that received intravitreal anti-VEGF versus IgG control. scAAV2-CARap1a-, but not anti-VEGF-, injected eyes had increased pan-cadherin in RPE/choroids. In cultured RPE cells, increased active Rap1a inhibited TNFα-induced disassociation of junctional pan-cadherin/β-catenin complexes, increased transepithelial electrical resistance through an interaction of β-catenin with phosphorylated scaffold protein, IQGAP1, and inhibited choroidal endothelial cell (CEC transmigration of an RPE monolayer. This evidence shows that increased Rap1a activity specifically in RPE cells is sufficient to reduce CEC transmigration and CNV and involves IQGAP1-mediated protection of RPE junctional complexes.

  20. Retinal pigment epithelial cell expression of active Rap 1a by scAAV2 inhibits choroidal neovascularization.

    Science.gov (United States)

    Wang, Haibo; Han, Xiaokun; Bretz, Colin A; Becker, Silke; Gambhir, Deeksha; Smith, George W; Samulski, R Jude; Wittchen, Erika S; Quilliam, Lawrence A; Chrzanowska-Wodnicka, Magdalena; Hartnett, M Elizabeth

    2016-01-01

    To test the hypothesis that increased Rap1a activity specifically in retinal pigment epithelial cells resists choroidal neovascularization (CNV), self-complementary adeno-associated virus 2 (scAAV2) with RPE65-promoter-driven GFP vectors were generated and introduced subretinally into Rap1b-deficient mice. Six-week-old mice that received subretinal control (scAAV2-Con) or constitutively active Rap1a (scAAV2-CARap1a) showed strong GFP at the 5 × 10(8) viral particle/µl dose 5 weeks later without altering retinal morphology or function. Compared to scAAV2-Con- or phosphate-buffered saline (PBS)-injected, eyes injected with scAAV2-CARap1a had increased Rap1 in retinal pigment epithelial (RPE)/choroidal lysates and a significant reduction in CNV volume 7 days after laser, comparable to eyes that received intravitreal anti-VEGF versus IgG control. scAAV2-CARap1a-, but not anti-VEGF-, injected eyes had increased pan-cadherin in RPE/choroids. In cultured RPE cells, increased active Rap1a inhibited TNFα-induced disassociation of junctional pan-cadherin/β-catenin complexes, increased transepithelial electrical resistance through an interaction of β-catenin with phosphorylated scaffold protein, IQGAP1, and inhibited choroidal endothelial cell (CEC) transmigration of an RPE monolayer. This evidence shows that increased Rap1a activity specifically in RPE cells is sufficient to reduce CEC transmigration and CNV and involves IQGAP1-mediated protection of RPE junctional complexes.

  1. Correlation of CD105 and Vascular Endothelial Growth Factor in Laser-induced Choroidal Neovascularization in Rats

    Institute of Scientific and Technical Information of China (English)

    Jianfeng Xu; Yusheng Wang; Xiumei Yang; Peng Zhang; Lijun Chen

    2006-01-01

    Purpose: Choroidal neovascularization (CNV) plays an important role in pathogenesis of age-related macular degeneration (AMD), ocular histoplasmosis syndrome (OHS) and so on. However, mechanisms of CNV formation are not fully understood. The aim of this study is to investigate the correlation between expressions of CD105 and vascular endothelial growth factor (VEGF) in experimental laserinduced CNV in rats.Methods: CNV model was established by 532 nm laser photocoagulation in BrownNorway rats. The expression of CD105 and VEGF in CNV was observed by immunohistochemistry at 3, 7, 14, 21, 28 and 56 days after laser photocoagulation.The image analysis was performed with the professional software of Image-Pro Plus.Results: Fluorescein angiography showed fluorescein leakage in CNV from days 7 to 56 after photocoagulation. VEGF expression was mainly observed in vascular endothelial cells, ganglion cells, inner nuclear layers and retinal pigment epithelial cells in normal retina and vascular endothelial cells in normal choroid of the rats. On day 3 after photocoagulation, VEGF began to express in laser-induced lesions. VEGF was strongly expressed in CNV after 7 days (P<0.05) and decreased after 14 days (P>0.05). CD105 was initially presented in CNV at 7 days and obviously expressed at 14 days after photocoagulation (P<0.05). Four weeks later, when angiogenesis tended toward inactive status, expression of CD 105 was markedly decreased (P>0.05).There was notablely direct correlation between CD105-positive-microvessel density and positively semiquantitative scoring of VEGF in the CNV(r=0.989, P<0.01).Conclusions: There is direct correlation between the expression of CD105 and VEGF in the laser-induced CNV in rat. It suggests that CD105 and VEGF might participate in the new blood vessel formation and promote the growth of CNV.

  2. Tenomodulin Inhibits Retinal Neovascularization in a Mouse Model of Oxygen-Induced Retinopathy

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    Tatsuhiko Sato

    2012-11-01

    Full Text Available We aimed to determine the anti-angiogenic effect of tenomodulin (TeM on retinal neovascularization in an oxygen-induced retinopathy (OIR mouse model. OIR was induced in C57BL/6 mice by exposing seven-day-old mice to 75% oxygen for five days followed by room air for five days. Control mice were exposed to room air from birth until postnatal day 17. Mice received intravitreal injections of 1 μg of TeM in one eye and PBS in the contralateral eye at P7 before being exposed to 75% oxygen. Eyes were collected at postnatal day 17. Retinal blood vessel patterns were visualized by fluorescein angiography. We quantified the number of neovascular nuclei that were present beyond the inner limiting membrane (ILM using histological methods with a masked approach. Furthermore, double immunohistochemical staining of TeM was performed on retinas to identify nuclei protruding into the vitreous cavity. Western blot was used to detect exogenous TeM protein. The central nonperfusion area (NPA, mm2 of TeM-injected eyes was significantly different from that of OIR and PBS-injected eyes, and the number of nuclei in new blood vessels breaking through the ILM in each retinal cross-section significantly differed from that of OIR eyes and PBS-injected control eyes. Cellular nuclei of new blood vessels protruding into the vitreous cavity were also observed in TeM-injected retinas by immunohistochemistry. Western blotting revealed a 16-kDa immunoreactive protein, indicating incorporation of an exogenous TeM fragment into the retina. Our data shows that TeM can effectively inhibit pathological angiogenesis in mouse eyes; indicating its potential role in prevention and treatment of ocular neovascularization.

  3. A novel xenograft model in zebrafish for high-resolution investigating dynamics of neovascularization in tumors.

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    Chengjian Zhao

    Full Text Available Tumor neovascularization is a highly complex process including multiple steps. Understanding this process, especially the initial stage, has been limited by the difficulties of real-time visualizing the neovascularization embedded in tumor tissues in living animal models. In the present study, we have established a xenograft model in zebrafish by implanting mammalian tumor cells into the perivitelline space of 48 hours old Tg(Flk1:EGFP transgenic zebrafish embryos. With this model, we dynamically visualized the process of tumor neovascularization, with unprecedented high-resolution, including new sprouts from the host vessels and the origination from VEGFR2(+ individual endothelial cells. Moreover, we quantified their contributions during the formation of vascular network in tumor. Real-time observations revealed that angiogenic sprouts in tumors preferred to connect each other to form endothelial loops, and more and more endothelial loops accumulated into the irregular and chaotic vascular network. The over-expression of VEGF165 in tumor cells significantly affected the vascularization in xenografts, not only the number and size of neo-vessels but the abnormalities of tumor vascular architecture. The specific inhibitor of VEGFR2, SU5416, significantly inhibited the vascularization and the growth of melanoma xenografts, but had little affects to normal vessels in zebrafish. Thus, this zebrafish/tumor xenograft model not only provides a unique window to investigate the earliest events of tumoral neoangiogenesis, but is sensitive to be used as an experimental platform to rapidly and visually evaluate functions of angiogenic-related genes. Finally, it also offers an efficient and cost-effective means for the rapid evaluation of anti-angiogenic chemicals.

  4. Are the Symptoms of Calcific Tendinitis Due to Neoinnervation and/or Neovascularization?

    Science.gov (United States)

    Hackett, Lisa; Millar, Neal L; Lam, Patrick; Murrell, George A C

    2016-02-03

    Calcific tendinitis can be a substantial cause of pain and dysfunction in the shoulder, and the pathophysiology is unclear. Recent studies have shown a link among nerve ingrowth, neovascularization, and pain in tendinopathy. The aim of this study was to determine whether there is evidence of neoinnervation and/or neovascularization in calcific tendinitis lesions of the shoulder. At arthroscopy, ultrasound was used to identify calcium within the tendon. Samples were taken from the supraspinatus tendon adjacent to the calcific lesion (in the calcific tendinitis group, with ten patients), the torn supraspinatus tendon of patients undergoing rotator cuff repair (the rotator cuff tear group, with ten patients), and the subscapularis tendon of patients undergoing a stabilization surgical procedure (the control group, with ten patients). Biopsied tendon samples were evaluated immunohistochemically by quantifying the presence of macrophages (using CD68 and CD206), T cells (CD3), mast cells (mast cell tryptase), vascular endothelium (CD34), and peripheral nerve markers (PGP 9.5). There was a twofold to eightfold increase of nerve markers, neovascularization, macrophages, M2 macrophages, and mast cells in the calcific tendinitis group compared with the rotator cuff tear group (p tendinitis lesions of the shoulder along with an eightfold increase in mast cells and macrophages. The findings are consistent with the hypothesis that, in calcific tendinitis, the calcific material is inducing a vigorous inflammatory response within the tendon with formation of new blood vessels and nerves. This study helps to explain why calcific tendinitis is related to substantial pain in the clinical setting. Copyright © 2016 by The Journal of Bone and Joint Surgery, Incorporated.

  5. Incidence and Clinical Features of Neovascularization of the Iris following Acute Central Retinal Artery Occlusion.

    Science.gov (United States)

    Jung, Young Ho; Ahn, Seong Joon; Hong, Jeong-Ho; Park, Kyu Hyung; Han, Moon-Ku; Jung, Cheolkyu; Woo, Se Joon

    2016-10-01

    To investigate the incidence of neovascularization of the iris (NVI) and clinical features of patients with NVI following acute central retinal artery occlusion (CRAO). A retrospective review of 214 consecutive CRAO patients who visited one tertiary hospital between January 2009 and January 2015 was conducted. In total, 110 patients were eligible for this study after excluding patients with arteritic CRAO, a lack of follow-up, iatrogenic CRAO secondary to cosmetic filler injection, or NVI detected before CRAO attack. Fluorescein angiography (FA) was applied until retinal arterial reperfusion was achieved, typically within 1 to 3 months. The incidence of NVI was 10.9% (12 out of 110 patients). Neovascular glaucoma was found in seven patients (6.4%). The mean time to NVI diagnosis after CRAO events was 3.0 months (range, 1 week to 15 months). The cumulative incidence was 5.5% at 3 months, 7.3% at 6 months, and 10.9% at 15 months. Severely narrowed ipsilateral carotid arteries were observed in only three patients (27.3%). The other nine patients (75.0%) showed no predisposing conditions for NVI, such as proliferative diabetic retinopathy or central retinal vein occlusion. Reperfusion rate and prevalence of diabetes were significantly different between patients with NVI and patients without NVI (reperfusion: 0% [NVI] vs. 94.7% [no NVI], p < 0.001; diabetes: 50.0% [NVI] vs. 17.3% [no NVI], p = 0.017). CRAO may lead to NVI and neovascular glaucoma caused by chronic retinal ischemia from reperfusion failure. Our results indicate that follow-up fluorescein angiography is important to evaluate retinal artery reperfusion after acute CRAO events, and that prophylactic treatment such as panretinal photocoagulation should be considered if retinal arterial perfusion is not recovered.

  6. Preferential Hyperacuity Perimeter (PreView PHP) for detecting choroidal neovascularization study.

    Science.gov (United States)

    Alster, Yair; Bressler, Neil M; Bressler, Susan B; Brimacombe, Judith A; Crompton, R Michael; Duh, Yi-Jing; Gabel, Veit-Peter; Heier, Jeffrey S; Ip, Michael S; Loewenstein, Anat; Packo, Kirk H; Stur, Michael; Toaff, Techiya

    2005-10-01

    To assess the ability of the Preferential Hyperacuity Perimeter (PreView PHP; Carl Zeiss Meditec, Dublin, CA) to detect recent-onset choroidal neovascularization (CNV) resulting from age-related macular degeneration (AMD) and to differentiate it from an intermediate stage of AMD. Prospective, comparative, concurrent, nonrandomized, multicenter study. Eligible participants' study eyes had a corrected visual acuity of 20/160 or better and either untreated CNV from AMD diagnosed within the last 60 days or an intermediate stage of AMD. After obtaining consent, visual acuity with habitual correction, masked PHP testing, stereoscopic color fundus photography, and fluorescein angiography were performed. Photographs and angiograms were evaluated by graders masked to diagnosis and PHP results. The reading center's diagnosis determined if the patient was categorized as having intermediate AMD or neovascular AMD. A successful study outcome was defined a priori as a sensitivity of at least 80% and a specificity of at least 80%. Of 185 patients who gave consent to be enrolled, 11 (6%) had PHP results judged to be unreliable. An additional 52 were not included because they did not meet all eligibility criteria. Of the remaining 122 patients, 57 had an intermediate stage of AMD and 65 had neovascular AMD. The sensitivity to detect newly diagnosed CNV using PHP testing was 82% (95% confidence interval [CI], 70%-90%). The specificity to differentiate newly diagnosed CNV from the intermediate stage of AMD using PHP testing was 88% (95% CI, 76%-95%). Preferential Hyperacuity Perimeter testing can detect recent-onset CNV resulting from AMD and can differentiate it from an intermediate stage of AMD with high sensitivity and specificity. These data suggest that monitoring with PHP should detect most cases of CNV of recent onset with few false-positive results at a stage when treatment usually would be beneficial. Thus, this monitoring should be considered in the management of the

  7. Incidence and Clinical Features of Neovascularization of the Iris following Acute Central Retinal Artery Occlusion

    Science.gov (United States)

    Jung, Young Ho; Ahn, Seong Joon; Hong, Jeong-Ho; Park, Kyu Hyung; Han, Moon-Ku; Jung, Cheolkyu

    2016-01-01

    Purpose To investigate the incidence of neovascularization of the iris (NVI) and clinical features of patients with NVI following acute central retinal artery occlusion (CRAO). Methods A retrospective review of 214 consecutive CRAO patients who visited one tertiary hospital between January 2009 and January 2015 was conducted. In total, 110 patients were eligible for this study after excluding patients with arteritic CRAO, a lack of follow-up, iatrogenic CRAO secondary to cosmetic filler injection, or NVI detected before CRAO attack. Fluorescein angiography (FA) was applied until retinal arterial reperfusion was achieved, typically within 1 to 3 months. Results The incidence of NVI was 10.9% (12 out of 110 patients). Neovascular glaucoma was found in seven patients (6.4%). The mean time to NVI diagnosis after CRAO events was 3.0 months (range, 1 week to 15 months). The cumulative incidence was 5.5% at 3 months, 7.3% at 6 months, and 10.9% at 15 months. Severely narrowed ipsilateral carotid arteries were observed in only three patients (27.3%). The other nine patients (75.0%) showed no predisposing conditions for NVI, such as proliferative diabetic retinopathy or central retinal vein occlusion. Reperfusion rate and prevalence of diabetes were significantly different between patients with NVI and patients without NVI (reperfusion: 0% [NVI] vs. 94.7% [no NVI], p < 0.001; diabetes: 50.0% [NVI] vs. 17.3% [no NVI], p = 0.017). Conclusions CRAO may lead to NVI and neovascular glaucoma caused by chronic retinal ischemia from reperfusion failure. Our results indicate that follow-up fluorescein angiography is important to evaluate retinal artery reperfusion after acute CRAO events, and that prophylactic treatment such as panretinal photocoagulation should be considered if retinal arterial perfusion is not recovered. PMID:27729755

  8. Inhibitory effect of sub-conjunctival tocilizumab on alkali burn induced corneal neovascularization in rats.

    Science.gov (United States)

    Sari, Esin Sogutlu; Yazici, Alper; Aksit, Hasan; Yay, Arzu; Sahin, Gözde; Yildiz, Onur; Ermis, Sitki Samet; Seyrek, Kamil; Yalcin, Betul

    2015-01-01

    To evaluate the effects of sub-conjunctivally applied interleukin-6 receptor (IL-6R) antibody (tocilizumab) on alkali burn induced corneal neovascularization (CNV) in rats. Alkali burn induced corneal neovascularization was created in 24 right eyes of 24 rats. The rats were then randomized into 2 groups. Group 1 received sub-conjunctival injection of 4 mg/0.2 ml tocilizumab and Group 2 received sub-conjunctival injection of 0.2 ml normal saline at the 5th day of alkali burn. The corneal surface area invaded with neovascular vessels were calculated on photographs. The rats were sacrificed and the corneas were excised at the15th day. The corneal specimens were stained with hemotoxylin-eosin to evaluate tissue morphology and with Willebrand factor (vWF) to evaluate microvascular structures immunohistochemically. Vascular endothelial growth factor (VEGF) expression was analyzed by ELISA. The percent area of CNV was 26.9% in Group 1 and 56.5% in Group 2 (p conjuntival tocilizumab injection. Group 1 showed significantly lower corneal inflammation score than Group 2 (p < 0.001). The number of vessels stained with vWF were significantly higher in Group 2 than Group 1 (15.23 and 5.46, respectively; p < 0.001). ELISA analyses showed that corneal VEGF levels were significantly lower in Group 1 compared to Group 2 (p = 0.013) CONCLUSION: The present data demonstrated first time the beneficial effects of sub-conjunctival tocilizumab on decreasing CNV in alkali burn model of the rat cornea. Further studies are warranted to confirm these findings for the clinical application.

  9. Accelerated reendothelialization, increased neovascularization and erythrocyte extravasation after arterial injury in BAMBI-/- mice.

    Directory of Open Access Journals (Sweden)

    Nicolas Guillot

    Full Text Available BACKGROUND: Intimal injury rapidly activates TGFβ and enhances vascular repair by the growth of endothelial (EC and vascular smooth muscle cells (VSMC. The response to the TGFβ family of growth factors can be modified by BAMBI (BMP, Activin, Membrane Bound Inhibitor acting as a non-signaling, competitive antagonist of TGFβ type I receptors such as ALK 1 and 5. In vivo the effect of BAMBI will depend on its cell-specific expression and of that of the ALK type receptors. We recently reported EC restricted BAMBI expression and genetic elimination of BAMBI resulting in an in vitro and in vivo phenotype characterized by endothelial activation and proliferation involving alternative pathway activation by TGFβ through ALK 1. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis that BAMBI modulates arterial response to injury via its effects on endothelial repair and arterial wall neovascularization we used a model of femoral arterial denudation injury in wild type (WT and BAMBI(-/- mice. Arterial response was evaluated at 2 and 4 weeks after luminal endothelial denudation of femoral arteries. The BAMBI(-/- genotype mice showed accelerated luminal endothelial repair at 2 weeks and a highly unusual increase in arterial wall neovascularization compared to WT mice. The exuberant intimal and medial neovessel formation with BAMBI(-/- genotype was also associated with significant red blood cell extravasation. The bleeding into the neointima at 2 weeks transiently increased it's area in the BAMBI(-/-genotype despite the faster luminal endothelial repair in this group. Vascular smooth muscle cells were decreased at 2 weeks in BAMBI(-/- mice, but comparable to wild type at 4 weeks. CONCLUSIONS/SIGNIFICANCE: The absence of BAMBI results in a highly unusual surge in arterial wall neovascularization that surprisingly mimiks features of intra-plaque hemorrhage of advanced atheroma in a mechanical injury model. This suggests important effects of BAMBI on

  10. Phacoemulsification Surgery in Eyes with Neovascular Age-Related Macular Degeneration

    Science.gov (United States)

    Papavasileiou, Evangelia; Kumar, Balakrishna Vineeth; Prasad, Som

    2014-01-01

    Purpose. To evaluate the visual outcomes and effect of phacoemulsification surgery on the progression of neovascular age-related macular degeneration (AMD). Methods. Retrospective, noncomparative, and interventional case series. Thirty eyes from 29 subjects with neovascular AMD treated with intravitreal antivascular endothelial growth factor (VEGF) injections who underwent phacoemulsification and had a postsurgery follow-up of 6 months were included. LogMAR best corrected visual acuity (BCVA) was assessed preoperatively; 1 month, 3 months, and 6 months postoperatively; and finally at the last visit. The frequency of anti-VEGF therapy, calculated as the number of intravitreal injections per month, and central macular thickness (CMT) before and after cataract surgery were determined. Results. Median (range) logMAR BCVA was 0.69 (0.16 to 1.32) preoperatively; 0.55 (−0.04 to 1.32) at 1 month, 0.52 (−0.1 to 1.32) at 3 months, and 0.50 (0.0 to 1.32) at 6 months postoperatively; and 0.6 (0.0 to 1.4) at final visit (P = 0.0011). There was no difference in the frequency of anti-VEGF injections between the immediate 6 months before and after phacoemulsification, which was equal to 0.1667 injections per month (P = 0.6377). Median CMT measured 203 μm preoperatively, which temporarily increased to 238 μm at 1 month after surgery (P = 0.0093) and then spontaneously returned to baseline, measuring 212.5 μm at 3 months postoperatively (P = 0.3811). Conclusion. Phacoemulsification surgery significantly improved vision in patients with neovascular AMD, with no increased need for anti-VEGF injections to keep the macula dry postoperatively. PMID:24719771

  11. Evaluation of the siRNA PF-04523655 versus ranibizumab for the treatment of neovascular age-related macular degeneration (MONET Study)

    DEFF Research Database (Denmark)

    Nguyen, Quan Dong; Schachar, Ronald A; Nduaka, Chudy I;

    2012-01-01

    To evaluate the efficacy of different dosing paradigms of PF-04523655 (PF) versus ranibizumab (comparator) in subjects with neovascular age-related macular degeneration (AMD).......To evaluate the efficacy of different dosing paradigms of PF-04523655 (PF) versus ranibizumab (comparator) in subjects with neovascular age-related macular degeneration (AMD)....

  12. Increased Expression of CD200 on Circulating CD11b+ Monocytes in Patients with Neovascular Age-related Macular Degeneration

    DEFF Research Database (Denmark)

    Singh, Amardeep; Falk, Mads K; Hviid, Thomas V F

    2013-01-01

    , and detailed retinal imaging was performed: fundus autofluorescence imaging, digital color fundoscopy, and spectral-domain optical coherence tomography. Fluorescein and indocyanine green angiography were performed in patients with suspected neovascular AMD. Visual acuity was measured in both eyes. Fresh venous...... was observed in controls with healthy eyes, but not in patients with neovascular AMD. We did not find any differences in CD200 and CD200R expression between patients with subretinal fibrosis and patients without subretinal fibrosis. CONCLUSIONS: The surface expression of CD200 on circulating CD11b+ monocytes...... was found to be increased in patients with neovascular AMD compared with controls with healthy eyes. This novel finding supports the notion that altered regulation of the inflammatory response plays an integral role in the pathogenesis of AMD. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary...

  13. Neovascularity in patellar tendinopathy and the response to eccentric training: a case report using Power Doppler ultrasound.

    Science.gov (United States)

    McCreesh, Karen M; Riley, Sara J; Crotty, James M

    2013-12-01

    This report describes the case of an amateur soccer player with chronic patellar tendinopathy who underwent ultrasound imaging before and after engaging in an 8-week programme of eccentric exercise. On initial assessment, greyscale ultrasound imaging demonstrated tendon thickening and reduced echogenicity, while Power Doppler imaging demonstrated a large amount of neovascularity. After 8 weeks of an eccentric loading programme, the patient reported significantly improved symptoms and functional scores, while follow-up imaging demonstrated improvement in the echo appearance of the tendon and complete resolution of the neovascularity. The association between neovascularity and symptoms in tendinopathy research is conflicting, with a paucity of research in the area of patellar tendinopathy. While further research is needed to clarify the significance of greyscale and Power Doppler ultrasound changes in relation to symptoms in patellar tendinopathy, ultrasound imaging was shown to be a useful adjunct to diagnosis and outcome assessment in this case. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Quantification of choroidal neovascularization vessel length using optical coherence tomography angiography

    Science.gov (United States)

    Gao, Simon S.; Liu, Li; Bailey, Steven T.; Flaxel, Christina J.; Huang, David; Li, Dengwang; Jia, Yali

    2016-07-01

    Quantification of choroidal neovascularization (CNV) as visualized by optical coherence tomography angiography (OCTA) may have importance clinically when diagnosing or tracking disease. Here, we present an automated algorithm to quantify the vessel skeleton of CNV as vessel length. Initial segmentation of the CNV on en face angiograms was achieved using saliency-based detection and thresholding. A level set method was then used to refine vessel edges. Finally, a skeleton algorithm was applied to identify vessel centerlines. The algorithm was tested on nine OCTA scans from participants with CNV and comparisons of the algorithm's output to manual delineation showed good agreement.

  15. Bilateral choroidal osteoma with choroidal neovascular membrane treated with bevacizumab in a child.

    Science.gov (United States)

    Agarwal, Manisha; Kantha, Meha; Mayor, Rahul; Venkatesh, Ramesh; Shroff, Cyrus M

    2014-01-01

    Choroidal osteoma is a rare benign tumor. We report a male child diagnosed with bilateral choroidal osteoma, high myopia and secondary choroidal neovascularization (CNV) membrane in one eye. Co-existence of posterior staphyloma made the clinical diagnosis of choroidal osteoma difficult due to the osteoma filling the depression of the posterior staphyloma. Typical findings on fundus fluorescein angiography, optical coherence tomography, B-scan and indocyanine green angiography confirmed the diagnosis. A review of literature was performed. CNV secondary to choroidal osteoma was treated with intravitreal bevacizumab and it responded well. Regular follow-up is essential for recurrence of CNV and decalcification of the osteoma.

  16. Photodynamic therapy combined with intravitreal bevacizumab in a patient with choroidal neovascularization secondary to choroidal osteoma.

    Science.gov (United States)

    Jang, Jung Hyun; Kim, Keong Hwan; Lee, Soo Jung; Park, Jung Min

    2012-12-01

    Choroidal osteoma is a benign ossified tumor that is found predominantly in healthy young women during their second and third decades of life. The lesions are white-to-cream or orange in color, are located in the peripapillary and macular areas, and are unilateral in most patients. The symptoms of choroidal osteoma include decreased visual acuity and metamorphopsia or scotoma corresponding to the location of the osteoma, but some patients have no symptoms. Prognosis of vision varies according to tumor location, retinal pigment epithelial and sensory retinal degeneration, subretinal fluid and hemorrhage, and development of a subretinal neovascular membrane.

  17. Posterior capsule opacification and neovascularization treated with intravitreal bevacizumab and Nd:YAG capsulotomy

    Science.gov (United States)

    Sánchez-Castro, Grimelda Yuriana; Hitos-Fájer, Alejandra; Mendoza-Schuster, Erick; Velez-Montoya, Raul; Velasco-Barona, Cecilio Francisco

    2008-01-01

    We reported a 75-year-old diabetic man, who developed opacification and neovascularization of the posterior capsule after extracapsular cataract extraction and posterior chamber intraocular lens implantation. The patient was treated with two injections of 2.5 mg of intravitreal bevacizumab. The treatment produced an important regression of the posterior capsular new vessels, allowing us to perform a successful Nd:YAG capsulotomy, clearing the visual axis and improving the visualization of the posterior pole. Even though, best corrected visual acuity was 20/200 due to diabetic macular edema. PMID:19668770

  18. Surgical choroidal neovascular membrane removal in the era of anti-vascular endothelial growth factor agents

    Directory of Open Access Journals (Sweden)

    Nagpal Manish

    2009-01-01

    Full Text Available Intravitreal anti-vascular endothelial growth factor (VEGF agents have obtained acceptance as the mainstay in the management strategy of subfoveal choroidal neovascular membranes (CNVM due to varying etiologies. Few drawbacks include need for repeated intravitreal injections, with its adjunct risks, and the lack of a predefined treatment end point, which can cause doubts and uncertainty in the mind of the patient. Furthermore, it remains a significant financial burden for the patient. Herein we report our data of three patients who were reluctant for further re-injections of anti-VEGF agents and were therefore offered surgical removal of the CNVM by submacular surgery as an alternative treatment plan.

  19. Role of intravitreal Bevacizumab Injection for Management of Neovascular Age Related Macular Degeneration

    Directory of Open Access Journals (Sweden)

    Neha K Desai

    2016-06-01

    Full Text Available Background: Age related macular degeneration ( ARMD is the major cause of severe visual loss in older adults. Different treatment modalities are available such as: Laser photocoagulation, photodynamic therapy,transpupillary thermotherapy,submacular surgery and anti-veg. Aims and Objectives: The aim of our study was to evaluate the efficacy and safety of intravitreally administered Bevacizumab a humanized monoclonal anti and ndash;VEGF in Neovascular Age related Macular Degeneration. Methodology: This non randomized, prospective study was carried out on 75 eyes of 75 patients attending the OPD at M and J Institute Of Ophthalmology and diagnosed as having Neovascular ARMD confirmed on FFA and SD-OCT . After taking written informed consent all patients were injected with intravitreal Bevacizumab 1.25 mg/0.05 ml. Follow up visits were scheduled one week, one month post procedure and every monthly thereafter. Results: 75 eyes of 75 patients were included in this non randomized prospective study. and 29.33% patients required 2 injections. Visual acuity is improved more than 3 lines from baseline in 21.33% patient, 64% patient have 2-3 lines gain and 6.66% patients showed 0-1 line gain in snellen's visual acuity. 5.33% patients have a loss of 1 line from baseline and 2.66% patients showed loss of 2-3 lines. Central foveal thickness decreased more than 200 microns from baseline in 52% patients, 28% patients have decreased of 100-200 microns and 20% patients have decreased of less than 100 microns. Discussion: Approximately 10 % of ARMD patients manifest the neovascular form of the disease. 12 weeks. Our study showed that 80% patients had decrease in central foveal thickness more than 100 microns from baseline at the end of one year. 85% patients had gain of 2 or more lines on Snellen's visual acuity chart from baseline.No patient had any serious local or systemic adverse reactions.Limitations of our study is small number of patients,ICG not done

  20. Ranibizumab in neovascular age-related macular degeneration: a 5-year follow-up

    Directory of Open Access Journals (Sweden)

    Cvetkova NP

    2016-06-01

    Full Text Available Nadezhda P Cvetkova, Kristina Hölldobler, Philipp Prahs, Viola Radeck, Horst Helbig, David Märker Department of Ophthalmology, University of Regensburg, Regensburg, Germany Purpose: Our aim was to evaluate an optical coherence tomography (OCT and visual acuity (VA-guided, variable-dosing regimen with intravitreal ranibizumab injection for treating patients with neovascular age-related macular degeneration (AMD from 2007 to 2012. Design: This was a retrospective clinical study of 5 years follow-up in a tertiary eye center. Patients and methods: In this study, 66 patients with neovascular AMD (mean age of 74 years, SD 8.7 years were included. We investigated the development of best-corrected visual acuity (BCVA, the number of intravitreal injections, and the central retinal thickness measured with OCT (OCT Spectralis over 5 years of intravitreal treatment. Results: The mean number of intravitreal ranibizumab injections over 5 years was 8.8. The mean BCVA before therapy was 0.4 logarithm of the minimum angle of resolution (logMAR. After 5 years of therapy, the mean BCVA was 0.6 logMAR. In all, 16% of treated patients had stable VA over 5 years and 10% of study eyes approved their VA. The mean OCT-measured central retinal thickness at the beginning of this study was 295 µm; after 5 years of treatment, the mean central retinal thickness was 315 µm. There was an increase in central retinal thickness in 47.5% of examined eyes. Conclusion: Other studies showed VA improvement in OCT-guided variable-dosing regimens. Our study revealed a moderate decrease in VA after a total mean injection number as low as 8.8 injections over 5 years. In OCT, an increase in central retinal thickness over 5 years could be observed. Probably, this is due to deficient treatment when comparing the total injection number to other treatment regimens. Anti-VEGF therapy helps to keep the VA stable for a period of time, but cannot totally stop the progression of

  1. Matrix analysis

    CERN Document Server

    Bhatia, Rajendra

    1997-01-01

    A good part of matrix theory is functional analytic in spirit. This statement can be turned around. There are many problems in operator theory, where most of the complexities and subtleties are present in the finite-dimensional case. My purpose in writing this book is to present a systematic treatment of methods that are useful in the study of such problems. This book is intended for use as a text for upper division and gradu­ ate courses. Courses based on parts of the material have been given by me at the Indian Statistical Institute and at the University of Toronto (in collaboration with Chandler Davis). The book should also be useful as a reference for research workers in linear algebra, operator theory, mathe­ matical physics and numerical analysis. A possible subtitle of this book could be Matrix Inequalities. A reader who works through the book should expect to become proficient in the art of deriving such inequalities. Other authors have compared this art to that of cutting diamonds. One first has to...

  2. Strategies for improving early detection and diagnosis of neovascular age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Keane PA

    2015-02-01

    Full Text Available Pearse A Keane,1 Gabriella de Salvo,2 Dawn A Sim,1 Srini Goverdhan,2 Rupesh Agrawal,1 Adnan Tufail1 1NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, 2Department of Ophthalmology, University Hospital Southampton NHS Foundation Trust, Southampton, UK Abstract: Treatment of the neovascular form of age-related macular degeneration (AMD has been revolutionized by the introduction of such agents as ranibizumab, bevacizumab, and aflibercept. As a result, the incidence of legal blindness occurring secondary to AMD has fallen dramatically in recent years in many countries. While these agents have undoubtedly been successful in reducing visual impairment and blindness, patients with neovascular AMD typically lose some vision over time, and often lose the ability to read, drive, or perform other important activities of daily living. Efforts are therefore under way to develop strategies that allow for earlier detection and treatment of this disease. In this review, we begin by providing an overview of the rationale for, and the benefits of, early detection and treatment of neovascular AMD. To achieve this, we begin by providing an overview of the pathophysiology and natural history of choroidal neovascularization, before reviewing the evidence from both clinical trials and “real-world” outcome studies. We continue by highlighting an area that is often overlooked: the importance of patient education and awareness for early AMD detection. We conclude the review by reviewing an array of both established and emerging technologies for early detection of choroidal neovascularization, ranging from Amsler chart testing, to hyperacuity testing, to advanced imaging techniques, such as optical coherence tomography. Keywords: Amsler, detection, choroidal neovascularization, hyperacuity, optical coherence tomography

  3. Matrix pentagons

    CERN Document Server

    Belitsky, A V

    2016-01-01

    The Operator Product Expansion for null polygonal Wilson loop in planar maximally supersymmetric Yang-Mills theory runs systematically in terms of multiparticle pentagon transitions which encode the physics of excitations propagating on the color flux tube ending on the sides of the four-dimensional contour. Their dynamics was unravelled in the past several years and culminated in a complete description of pentagons as an exact function of the 't Hooft coupling. In this paper we provide a solution for the last building block in this program, the SU(4) matrix structure arising from internal symmetry indices of scalars and fermions. This is achieved by a recursive solution of the Mirror and Watson equations obeyed by the so-called singlet pentagons and fixing the form of the twisted component in their tensor decomposition. The non-singlet, or charged, pentagons are deduced from these by a limiting procedure.

  4. Bilateral choroidal neovascularization associated with optic nerve head drusen treated by antivascular endothelial growth factor therapy

    Directory of Open Access Journals (Sweden)

    Carreras A

    2012-02-01

    Full Text Available Barbara Delas, Lorena Almudí, Anabel Carreras, Mouafk AsaadOphthalmology Service, Hospital de Terrassa, Barcelona, SpainObjective: To report a good clinical outcome in a patient with bilateral choroidal neovascularization (CNV associated with optic nerve head drusen (ONHD treated with intravitreal ranibizumab injection.Methods: A 12-year-old girl was referred for loss of right eye vision detected in a routine check-up. Best-corrected visual acuity (BCVA was hand movements in the right eye and 0.9 in the left eye. Funduscopy revealed the presence of superficial and buried bilateral ONHD, which was confirmed by ultrasonography and computed tomography, and the study was completed with perimetry. The presence of bilateral CNV, active in the right eye, was observed and subsequently confirmed using fluorescein angiography and optical coherence tomography.Results: Treatment with two consecutive injections of intravitreal ranibizumab resulted in inactivation of the neovascular membrane with subretinal fluid reabsorption and improved right eye BCVA. After 12 months’ follow-up, this was 20/60 and stable.Conclusion: Although there are no published studies of safety in children, antiangiogenic therapy for CNV secondary to ONHD may be useful and safe. A search of the literature produced only one previously reported case of ONHD-associated CNV treated with antivascular endothelial growth factor alone.Keywords: optic nerve head drusen, anti-vegf, children, neovascularisation

  5. Clinical efficacy of intravitreal Ranibizumab in idiopathic choroid neovascularization type Ⅰand type Ⅱ

    Directory of Open Access Journals (Sweden)

    Yue-Ming Sun

    2015-07-01

    Full Text Available AIM: To evaluate the efficacy of intravitreal ranibizumab in idiopathic choroid neovascularization(ICNV, compare the difference of the curative effect between type Ⅰand Ⅱof ICNV by optical coherence tomography(OCT, further provide evidence of the to effectiveness of ranibizumab in the treatment of choroidal neovascularization to guide clinical treatment. METHODS: A retrospective analysis on the clinical data who were diagnosed as ICNV between October 2013 and June 2014 in our hospital were carried out. Totally 31 cases(9 cases of type Ⅰ and 22 cases of type Ⅱaccepted ranibizumab injection voluntarily.All of the patients were evaluated by ophthalmic examination, funduscopy and OCT before and after the injection, classificated according to OCT results. The best-corrected visual acuity(BCVAand maximum of edema thickness after ranibizumab treatment at 3mo follow-up were compared. RESULTS: After statistically analyzed, BCVA and maximum thickness of the retinal lesions of 31 patients(type Ⅰ9 cases, type Ⅱ 22 casesbefore and 1, 3mo after treatment had statistical significance. In different types of retinal ICNV patients, BCVA and maximum thickness of the retinal lesions before and after treatment had no statistical significance. It was said that ranibizumab intravitreal injection had effectiveness for ICNV, however, there were no significant effectiveness for typeⅠ andⅡ ICNV. CONCLUSION: Ranibizumab intravitreal injection has obvious effectiveness for ICNV. However, it has no effect on typeⅠ andⅡ ICNV. Its safety and long-term complications need for further study.

  6. Posterior capsule opacification and neovascularization treated with intravitreal bevacizumab and Nd:YAG capsulotomy

    Directory of Open Access Journals (Sweden)

    Grimelda Yuriana Sánchez-Castro

    2008-10-01

    Full Text Available Grimelda Yuriana Sánchez-Castro1, Alejandra Hitos-Fájer1, Erick Mendoza-Schuster1, Raul Velez-Montoya2, Cecilio Francisco Velasco-Barona11Asociación para Evitar la Ceguera en México. Hospital “Dr. Luis Sánchez Bulnes”, México, D.F. Ophthalmology Department – Anterior Segment; 2Asociación para Evitar la Ceguera en México. Hospital “Dr. Luis Sánchez Bulnes”, México, D.F. Ophthalmology Department – Retina departmentAbstract: We reported a 75-year-old diabetic man, who developed opacification and neovascularization of the posterior capsule after extracapsular cataract extraction and posterior chamber intraocular lens implantation. The patient was treated with two injections of 2.5 mg of intravitreal bevacizumab. The treatment produced an important regression of the posterior capsular new vessels, allowing us to perform a successful Nd:YAG capsulotomy, clearing the visual axis and improving the visualization of the posterior pole. Even though, best corrected visual acuity was 20/200 due to diabetic macular edema.Keywords: posterior capsule opacification, posterior capsule neovascularization, cataract surgery, postoperative complications, intravitreal bevacizumab

  7. The Use of Intravitreal Ranibizumab for Choroidal Neovascularization Associated with Vogt-Koyanagi-Harada Syndrome

    Directory of Open Access Journals (Sweden)

    A. M. Kolomeyer

    2011-01-01

    Full Text Available Purpose. To describe the use of intravitreal ranibizumab for choroidal neovascular membrane (CNVM secondary to Vogt-Koyanagi-Harada (VKH syndrome. Methods. Interventional case report. Results. A 50-year-old woman presented with conjunctival injection and bilateral eye pain. Vision was 20/400 and 20/80 in the right and left eyes, respectively. Bilateral iritis, vitritis, and choroidal thickening were evident. Exudative retinal detachment was present in the left eye. Corticosteroid treatment improved vision to 20/40 bilaterally. Methotrexate (MTX was initiated and vision remained stable for 3 months. After a 5-month loss to follow-up, vision in the left eye decreased to finger counting (CF and a parafoveal CNVM was identified. After 3 intravitreal ranibizumab injections, vision improved to 20/40. Twelve months later, despite inflammation control, vision decrease to CF due to recurrent CNVM. A fourth ranibizumab injection was given. Twenty months later, best-corrected vision was 20/400, and an inactive CNVM was present in the left eye. Conclusion. After initial CNVM regression and visual acuity improvement due to ranibizumab, the CNVM recurred and became refractory to treatment. Despite control of inflammation and neovascularization, VKH chronicity lead to permanent vision loss in our patient. A combinational treatment approach may be required in such patients.

  8. Quantitative proteomic analysis of mice corneal tissues reveals angiogenesis-related proteins involved in corneal neovascularization.

    Science.gov (United States)

    Shen, Minqian; Tao, Yimin; Feng, Yifan; Liu, Xing; Yuan, Fei; Zhou, Hu

    2016-07-01

    Corneal neovascularization (CNV) was induced in Balb/c mice by alkali burns in the central area of the cornea with a diameter of 2.5mm. After fourteen days, the cornea from one eye was collected for histological staining for CNV examination, while the cornea from the other eye of the same mouse was harvested for proteomic analysis. The label-free quantitative proteomic approach was applied to analyze five normal corneal tissues (normal group mice n=5) and five corresponding neovascularized corneal tissues (model group mice n=5). A total of 2124 proteins were identified, and 1682 proteins were quantified from these corneal tissues. Among these quantified proteins, 290 proteins were significantly changed between normal and alkali burned corneal tissues. Of these significantly changed proteins, 35 were reported or predicted as angiogenesis-related proteins. Then, these 35 proteins were analyzed using Ingenuity Pathway Analysis Software, resulting in 26 proteins enriched and connected to each other in the protein-protein interaction network, such as Lcn-2, αB-crystallin and Serpinf1 (PEDF). These three significantly changed proteins were selected for further Western blotting validation. Consistent with the quantitative proteomic results, Western blotting showed that Lcn-2 and αB-crystallin were significantly up-regulated in CNV model, while PEDF was down-regulated. This study provided increased understanding of angiogenesis-related proteins involved in corneal vascular development, which will be useful in the ophthalmic clinic of specifically target angiogenesis.

  9. Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization

    Energy Technology Data Exchange (ETDEWEB)

    Song, Yao; Baba, Tomohisa [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192 (Japan); Li, Ying-Yi [Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Furukawa, Kaoru; Tanabe, Yamato [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192 (Japan); School of Natural System Bioengineering Course, College of Science and Engineering, Kanazawa University, Kanazawa, Ishikawa (Japan); Matsugo, Seiichi [School of Natural System Bioengineering Course, College of Science and Engineering, Kanazawa University, Kanazawa, Ishikawa (Japan); Sasaki, Soichiro [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192 (Japan); Mukaida, Naofumi, E-mail: mukaida@staff.kanazawa-u.ac.jp [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192 (Japan)

    2015-03-06

    Patients with pancreatic ductal adenocarcinoma (PDAC) are frequently complicated with metastatic disease or locally advanced tumors, and consequently need chemotherapy. Gemcitabine is commonly used for PDAC treatment, but with limited efficacy. The capacity of gemcitabine to generate reactive oxygen species (ROS) in human pancreatic cancer cells, prompted us to examine its effects on the expression of pro-inflammatory cytokines and chemokines. We observed that gemcitabine enhanced selectively the expression of CXCL8 in human pancreatic cancer cells through ROS generation and NF-κB activation. In vitro blocking of CXCL8 failed to modulate gemcitabine-mediated inhibition of cell proliferation in human pancreatic cancer cells. Gemcitabine also enhanced CXCL8 expression in pancreatic cancer cells in xenografted tumor tissues. Moreover, anti-CXCL8 antibody treatment in vivo attenuated tumor formation as well as intra-tumoral vascularity in nude mice, which were transplanted with Miapaca-2 cells and treated with gemcitabine. Thus, gemcitabine-induced CXCL8 may counteract the drug through inducing neovascularization. - Highlights: • Gemcitabine induced CXCL8 expression in human pancreatic cancer cells. • CXCL8 expression required ROS generation and NF-κB activation. • CXCL8 did not affect in vitro proliferation of human pancreatic cancer cells. • CXCL8 in vivo counteracted gemcitabine by inducing neovascularization.

  10. Topographical distribution of retinal and optic disc neovascularization in early stages of proliferative diabetic retinopathy.

    Science.gov (United States)

    Jansson, Ragnhild W; Frøystein, Torbjørn; Krohn, Jørgen

    2012-12-17

    We analyzed the topography of proliferative diabetic retinopathy (PDR), and visualized the distribution of neovascularization of the optic disc (NVD) and elsewhere in the retina (NVE). The study included 174 eyes of 106 patients with early PDR. Data on the size and location of 391 NVE and 73 NVD were converted into a database of two-dimensional retinal and optic disc charts. The geometric centers of the neovascular lesions were plotted into corresponding areas of the charts, and the topographic distributions of the NVE and NVD were visualized by merging the charts and displaying the number of overlapping lesions on color-coded contour maps. A total of 141 (36%) NVE was located in the temporal and 250 (64%) in the nasal hemisphere (P distribution of the NVD in the temporal and nasal half of the optic disc was 46 (63%) and 27 (37%), respectively (P = 0.03). NVE in type 1 diabetes were located significantly farther from the fovea and optic disc, and were more numerous and larger than in type 2 diabetes. The number and diameter of the NVE were also significantly higher when the time from the last examination to the appearance of PDR exceeded 12 months. The majority of NVE lesions are located inferonasal to the optic disc and along the superior vascular arcades, while NVD have a predilection for the upper temporal disc rim. More extensive PDR is found in patients with type 1 diabetes and those with examination intervals longer than one year.

  11. Transpupillary thermotherapy in subfoveal choroidal neovascular membrane secondary to age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Verma Lalit

    2004-01-01

    Full Text Available Purpose: To report our initial experience in the treatment of subfoveal choroidal neovascular membrane, secondary to age-related macular degeneration (AMD by transpupillary thermotherapy (TTT. Methods: Fifty consecutive patients with subfoveal choroidal neovascularisation (CNV secondary to AMD, were included in the study. The parameters assessed before the TTT were visual acuity by ETDRS chart, scotoma score by Amsler grid chart, reading speed, fundus examination by direct and indirect ophthalmoscope as well as +90 Diopter lens followed by digital fundus photography and fluorescein angiography (FA. Results: The letter visual acuity improved or stabilized in 72% cases up to 12 weeks after TTT. Mean scotoma score decreased from a mean of 47.56, to 43.56 at 6 weeks and to 37 at 12 weeks. Mean reading speed increased from 27.04 words/minute at pretreatment to 34.52 words/minute at 6 weeks and 37.33 words/minute 12 weeks after TTT. Conclusion: TTT is not only a cheaper alternative to photodynamic therapy (PDT, but also is an efficacious tool in stabilisation or improvement of visual acuity in the management of subfoveal choroidal neovascular membrane due to AMD.

  12. Photodynamic therapy of choroidal neovascularization with enlargement of the spot size to include the feeding complex

    Directory of Open Access Journals (Sweden)

    Ilias Georgalas

    2008-12-01

    Full Text Available Ilias Georgalas, Alexandros A Rouvas, Dimitrios A Karagiannis, Athanasios I Kotsolis, Ioannis D LadasDepartment of Ophthalmology, Medical School of Athens University, Athens, GreeceAbstract: This is a case report of a 83-year-old man with choroidal neovascularization (CNV, due to age-related macular degeneration (AMD in his right eye. Digital fluorescein (FA and indocyanine green angiography (ICG were performed, which disclosed predominantly classic subfoveal CNV and a dilated and tortuous feeding complex. The visual acuity was 20/800. Anti-vascular endothelial growth factor (anti-VEGF treatment was suggested, however, the patient was not keen to receive an intraocular injection. Modified photodynamic therapy (PDT with spot size enlarged, to include not only the CNV lesion but the feeding complex as well, was performed. Ten days after one session of PDT, ICG showed absence of leakage from the CNV and complete occlusion of the feeding complex. The visual acuity gradually improved to 20/100 and remained stable during the following 23 months. No evidence of CNV leakage was seen in the FA and ICG during the follow up period. Adjustment of the PDT spot size to include the detectable by ICG feeding complex might be an additional option in order to close the subfoveal CNV and might be considered as an alternative to intravitreal injection of anti-VEGF in selected cases where anti-VEGF treatment is not available.Keywords: age-related macular degeneration, choroidal neovascularization, photodynamic treatment, feeder vessel

  13. Effects of intravitreal injection of netrin-1 in retinal neovascularization of streptozotocin-induced diabetic rats

    Directory of Open Access Journals (Sweden)

    Yu Y

    2015-12-01

    Full Text Available Yao Yu,1,2,* Jing Zou,3,* Yun Han,4 Luowa Quyang,4 Hui He,4 Peihong Hu,2 Yi Shao,2 Ping Tu11Nanchang Key Laboratory of Diabetes, Department of Endocrinology and Metabolism, The Third Hospital of Nanchang, Jiangxi, People’s Republic of China; 2Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Province Clinical Ophthalmology Institute, Jiangxi, People’s Republic of China; 3Department of Ophthalmology, Xiangya Hospital, Central South University, Hunan, People’s Republic of China; 4Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, Fujian, People’s Republic of China*These authors have contributed equally to this workBackground: In a previous study, we confirmed that netrin-1 acts as an antiangiogenic factor by inhibiting alkali burn-induced corneal neovascularization in rats. Here, we continue working on the role of netrin-1 in retinal neovascularization.Methods: Using an in vitro angiogenesis assay, we detected the effects of netrin-1 on human umbilical vein endothelial cell tube formation, viability and proliferation, migration, and invasion at concentrations of 0.1 µg/mL or 5 µg/mL. We intravitreally injected 0.1 µg/mL or 5 µg/mL netrin-1 into streptozotocin-induced rats to assess retinal neovascularization using retinal electrophysiology and electroretinography, enzyme-linked immunosorbent assay, fundus fluoresce in angiography, measurement of inner blood retinal barrier, retinal hematoxylin-eosin staining, and retinal flat-mount fluorescence assays.Results: Human umbilical vein endothelial cell tube formation, viability and proliferation, migration, and invasion were upregulated by netrin-1 at a concentration of 0.1 µg/mL (P<0.05, while 5 µg/mL netrin-1 had an opposite effect (P<0.05 in our in vitro angiogenesis assay. Retinal electrophysiology testing revealed that intravitreal injection of netrin-1 affected the amplitude of a- and b

  14. Johne's disease in cattle is associated with enhanced expression of genes encoding IL-5, GATA-3, tissue inhibitors of matrix metalloproteinases 1 and 2, and factors promoting apoptosis in peripheral blood mononuclear cells

    DEFF Research Database (Denmark)

    Coussens, P.M.; Pudrith, C.B.; Skovgaard, Kerstin

    2005-01-01

    remodeling deficiencies through higher expression of tissue inhibitor of matrix metalloproteinase (TIMP) 1 and TIMP2 RNA and lower expression of matrix metalloproteinase (MMP) 14 RNA than similar cells from healthy controls, and that cells within the PBMC population of M. paratuberculosis-infected cows...

  15. Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA)

    DEFF Research Database (Denmark)

    Schmidt-Erfurth, Ursula; Chong, Victor; Loewenstein, Anat

    2014-01-01

    , and valid biomarkers have yet to be identified to provide a practical base for disease management. The European Society of Retina Specialists offers expert guidance for diagnostic and therapeutic management of neovascular AMD supporting healthcare givers and doctors in providing the best state...

  16. SEMIAUTOMATED QUANTITATIVE APPROACH TO CHARACTERIZE TREATMENT RESPONSE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Real-World Study.

    Science.gov (United States)

    Roberts, Philipp K; Nesper, Peter L; Gill, Manjot K; Fawzi, Amani A

    2017-08-01

    To perform a quantitative study of the vascular microstructure in actively treated choroidal neovascularization by optical coherence tomographic angiography. Patients undergoing individualized anti-vascular endothelial growth factor therapy of minimum 12 months duration were included in this cross-sectional observational study and imaged using optical coherence tomographic angiography. En face optical coherence tomographic angiography images were analyzed for quantitative features, such as junction density, vessel length, and lacunarity using validated software (Angiotool). Patients were divided into 2 groups depending on their individualized treatment interval: "good responders, treated less frequently than 6 weeks" versus "poor responders, treated every 6 weeks or more frequently." Nonparametric testing was used to assess differences between these groups. Twenty-five eyes of 23 consecutive patients with a median 58-month history of choroidal neovascularization, treated by median of 34 anti-vascular endothelial growth factor injections, were included in the analysis. There was no significant difference between any of the microvascular choroidal neovascularization features between the 2 groups (P > 0.05). The semiautomated vessel segmentation software provides an objective and quantitative approach for choroidal neovascularization characterization. The consistently nonsignificant outcomes between the groups may provide evidence to support the "normalization hypothesis." This would suggest that regardless of treatment interval, individualized therapy in these eyes established vessel stability.

  17. The SECURE study: long-term safety of ranibizumab 0.5 mg in neovascular age-related macular degeneration

    NARCIS (Netherlands)

    Silva, R. de; Axer-Siegel, R.; Eldem, B.; Guymer, R.; Kirchhof, B.; Papp, A.; Seres, A.; Gekkieva, M.; Nieweg, A.; Pilz, S.; Hoyng, C.B.

    2013-01-01

    OBJECTIVE: To evaluate long-term safety of intravitreal ranibizumab 0.5-mg injections in neovascular age-related macular degeneration (nAMD). DESIGN: Twenty-four-month, open-label, multicenter, phase IV extension study. PARTICIPANTS: Two hundred thirty-four patients previously treated with ranibizum

  18. Ranibizumab for choroidal neovascular membrane in a rare case of Bietti′s crystalline dystrophy: A case report

    OpenAIRE

    Kasinathan Nachiappan; Tandava Krishnan; Jagadeesan Madhavan

    2012-01-01

    We report a rare case of Bietti's crystalline dystrophy presenting with choroidal neovascular membrane (CNVM) which was treated with three injections of intravitreal ranibizumab. The CNVM underwent scarring after the injections with stabilization of visual acuity at a follow-up period of 12 months suggesting that intravitreal ranibizumab may have a role in the management of CNVM in these rare cases.

  19. Repeatability of swept-source optical coherence tomography retinal and choroidal thickness measurements in neovascular age-related macular degeneration

    DEFF Research Database (Denmark)

    Hanumunthadu, Daren; Ilginis, Tomas; Restori, Marie

    2017-01-01

    BACKGROUND: The aim was to determine the intrasession repeatability of swept-source optical coherence tomography (SS-OCT)-derived retinal and choroidal thickness measurements in eyes with neovascular age-related macular degeneration (nAMD). METHODS: A prospective study consisting of patients with...

  20. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration.

    NARCIS (Netherlands)

    Chakravarthy, U.; Adamis, A.P.; Cunningham Jr, E.T.; Goldbaum, M.; Guyer, D.R.; Katz, B.; Patel, M.

    2006-01-01

    OBJECTIVE: To evaluate the efficacy of a second year of pegaptanib sodium therapy in patients with neovascular age-related macular degeneration (AMD). DESIGN: Two concurrent, multicenter, randomized, double-masked, sham-controlled studies (V.I.S.I.O.N. [Vascular Endothelial Growth Factor Inhibition

  1. Ocular neovascularization in eyes with a central retinal artery occlusion or a branch retinal artery occlusion

    Directory of Open Access Journals (Sweden)

    Mason lll JO

    2015-06-01

    Full Text Available John O Mason III,1,2 Shyam A Patel,1 Richard M Feist,1,2 Michael A Albert Jr,1,2 Carrie Huisingh,1 Gerald McGwin Jr,1,3 Martin L Thomley1,2 1Department of Ophthalmology, University of Alabama School of Medicine, Birmingham, AL, USA; 2Retina Consultants of Alabama, Callahan Eye Foundation Hospital, Birmingham, AL, USA; 3Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA Purpose: To investigate the ocular neovascularization (ONV rate in eyes with a branch retinal artery occlusion (BRAO or a central retinal artery occlusion (CRAO, and to study factors that may influence the ONV rate secondary to CRAO.Methods: This was a retrospective case series of consecutive patients (286 total eyes: 83 CRAOs and 203 BRAOs who were diagnosed with a retinal artery occlusion from 1998 to 2013 at the Retina Consultants of Alabama and University of Alabama at Birmingham, Birmingham, AL, USA. Generalized estimating equations were used to evaluate the association between hypothesized risk factors and ONV development.Results: Twelve (14.5% of the 83 eyes with a CRAO developed ONV. Eleven of 12 eyes (91.7% had iris neovascularization, ten of 12 eyes (83.3% had neovascular glaucoma, and two of 12 eyes (16.7% had neovascularization of the optic disc. The average time for ONV development secondary to CRAO was 30.7 days, ranging from the date of presentation to 137 days. Only two (<1.0% of the 203 eyes with a BRAO developed iris neovascularization. Diabetes mellitus type 2 was a risk factor for ONV development following a CRAO with an adjusted odds ratio of 5.2 (95% confidence interval: 1.4–19.8 (P=0.02.Conclusion: ONV is an important complication of CRAO and is a less-frequent complication of BRAO. Patients with a CRAO, especially those with diabetes mellitus type 2, should be closely monitored for the first 6 months for ONV. Keywords: neovascularization, neovascular glaucoma, retinal artery occlusion, central

  2. WKYMVm-induced activation of formyl peptide receptor 2 stimulates ischemic neovasculogenesis by promoting homing of endothelial colony-forming cells.

    Science.gov (United States)

    Heo, Soon Chul; Kwon, Yang Woo; Jang, Il Ho; Jeong, Geun Ok; Yoon, Jung Won; Kim, Chi Dae; Kwon, Sang Mo; Bae, Yoe-Sik; Kim, Jae Ho

    2014-03-01

    Endothelial colony-forming cells (ECFCs) are recruited to the sites of ischemic injury in order to contribute to neovascularization and repair of injured tissues. However, therapeutic potential of ECFCs is limited due to low homing and engraftment efficiency of transplanted ECFCs. The G-protein-coupled formyl peptide receptor (FPR) 2 has been implicated in regulation of inflammation and angiogenesis, while the role of FPR2 in homing and engraftment of ECFCs and neovascularization in ischemic tissues has not been fully defined. This study was undertaken to investigate the effects of WKYMVm, a selective FPR2 agonist isolated by screening synthetic peptide libraries, on homing ability of ECFCs and vascular regeneration of ischemic tissues. WKYMVm stimulated chemotactic migration, angiogenesis, and proliferation ability of human ECFCs in vitro. Small interfering RNA-mediated silencing of FPR2, but not FPR3, abrogated WKYMVm-induced migration and angiogenesis of ECFCs. Intramuscular injection of WKYMVm resulted in attenuation of severe hind limb ischemia and promoted neovascularization in ischemic limb. ECFCs transplanted via tail vein into nude mice were incorporated into capillary vessels in the ischemic hind limb, resulting in augmented neovascularization and improved ischemic limb salvage. Intramuscular injection of WKYMVm promoted homing of exogenously administered ECFCs to the ischemic limb and ECFC-mediated vascular regeneration. Silencing of FPR2 expression in ECFCs resulted in abrogation of WKYMVm-induced in vivo homing of exogenously transplanted ECFCs to the ischemic limb, neovascularization, and ischemic limb salvage. These results suggest that WKYMVm promotes repair of ischemic tissues by stimulating homing of ECFCs and neovascularization via a FPR2-dependent mechanism. © AlphaMed Press.

  3. NADPH oxidase-derived overproduction of reactive oxygen species impairs postischemic neovascularization in mice with type 1 diabetes.

    Science.gov (United States)

    Ebrahimian, Téni G; Heymes, Christophe; You, Dong; Blanc-Brude, Olivier; Mees, Barend; Waeckel, Ludovic; Duriez, Micheline; Vilar, José; Brandes, Ralph P; Levy, Bernard I; Shah, Ajay M; Silvestre, Jean-Sébastien

    2006-08-01

    We hypothesized that diabetes-induced oxidative stress may affect postischemic neovascularization. The response to unilateral femoral artery ligation was studied in wild-type or gp91(phox)-deficient control or type 1 diabetic mice or in animals treated with the anti-oxidant N-acetyl-l-cysteine (NAC) or with in vivo electrotransfer of a plasmid encoding dominant-negative Rac1 (50 microg) for 21 days. Postischemic neovascularization was reduced in diabetic mice in association with down-regulated vascular endothelial growth factor-A protein levels. In diabetic animals vascular endothelial growth factor levels and postischemic neovascularization were restored to nondiabetic levels by the scavenging of reactive oxygen species (ROS) by NAC administration or the inhibition of ROS generation by gp91(phox) deficiency or by administration of dominant-negative Rac1. Finally, diabetes reduced the ability of adherent bone marrow-derived mononuclear cells (BM-MNCs) to differentiate into endothelial progenitor cells. Treatment with NAC (3 mmol/L), apocynin (200 micromol/L), or the p38MAPK inhibitor LY333351 (10 micromol/L) up-regulated the number of endothelial progenitor cell colonies derived from diabetic BM-MNCs by 1.5-, 1.6-, and 1.5-fold, respectively (P < 0.05). In the ischemic hindlimb model, injection of diabetic BM-MNCs isolated from NAC-treated or gp91(phox)-deficient diabetic mice increased neovascularization by approximately 1.5-fold greater than untreated diabetic BM-MNCs (P < 0.05). Thus, inhibition of NADPH oxidase-derived ROS overproduction improves the angiogenic and vasculogenic processes and restores postischemic neovascularization in type 1 diabetic mice.

  4. Aflibercept: a review of its use in the treatment of choroidal neovascularization due to age-related macular degeneration.

    Science.gov (United States)

    Balaratnasingam, Chandrakumar; Dhrami-Gavazi, Elona; McCann, Jesse T; Ghadiali, Quraish; Freund, K Bailey

    2015-01-01

    Choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) is an important cause of visual morbidity globally. Modern treatment strategies for neovascular AMD achieve regression of CNV by suppressing the activity of key growth factors that mediate angiogenesis. Vascular endothelial growth factor (VEGF) has been the major target of neovascular AMD therapy for almost two decades, and there have been several intravitreally-administered agents that have enabled anatomical restitution and improvement in visual function with continual dosing. Aflibercept (EYLEA(®)), initially named VEGF Trap-eye, is the most recent anti-VEGF agent to be granted US Food and Drug Administration approval for the treatment of neovascular AMD. Biologic advantages of aflibercept include its greater binding affinity for VEGF, a longer intravitreal half-life relative to other anti-VEGF agents, and the capacity to antagonize growth factors other than VEGF. This paper provides an up-to-date summary of the molecular mechanisms mediating CNV. The structural, pharmacodynamic, and pharmacokinetic advantages of aflibercept are also reviewed to rationalize the utility of this agent for treating CNV. Results of landmark clinical investigations, including VIEW 1 and 2 trials, and other important studies are then summarized and used to illustrate the efficacy of aflibercept for managing treatment-naïve CNV, recalcitrant CNV, and CNV due to polypoidal choroidal vasculopathy. Safety profile, patient tolerability, and quality of life measures related to aflibercept are also provided. The evidence provided in this paper suggests aflibercept to be a promising agent that can be used to reduce the treatment burden of neovascular AMD.

  5. Androgen Receptor-Mediated Genomic Androgen Action Augments Ischemia-Induced Neovascularization.

    Science.gov (United States)

    Lam, Yuen Ting; Lecce, Laura; Tan, Joanne T M; Bursill, Christina A; Handelsman, David J; Ng, Martin K C

    2016-12-01

    Increasing evidence indicates that androgens regulate ischemia-induced neovascularization. However, the role of genomic androgen action mediated by androgen receptor (AR), a ligand-activated nuclear transcription factor, remains poorly understood. Using an AR knockout (KO) mouse strain that contains a transcriptionally inactive AR (AR(Δex3)KO), we examined the role of AR genomic function in modulating androgen-mediated augmentation of ischemia-induced neovascularization. Castrated wild-type (AR(WT)) and AR(Δex3)KO mice were implanted with 5α-dihydrotestosterone (DHT) or placebo pellets after hindlimb ischemia (HLI). DHT modulation of angiogenesis and vasculogenesis, key processes for vascular repair and regeneration, was examined. Laser Doppler perfusion imaging revealed that DHT enhanced blood flow recovery in AR(WT) mice post-HLI. In AR(WT) mice, DHT enhanced angiogenesis by down-regulating prolyl hydroxylase 2 and augmenting hypoxia-inducible factor-1α (HIF-1α) levels in the ischemic tissues post-HLI. DHT also enhanced the production and mobilization of Sca1+/CXCR4+ progenitor cells in the bone marrow (BM) and circulating blood, respectively, in AR(WT) mice. By contrast, DHT-mediated enhancement of blood flow recovery was abrogated in AR(Δex3)KO mice. DHT modulation of HIF-1α expression was attenuated in AR(Δex3)KO mice. DHT-induced HIF-1α transcriptional activity and DHT-augmented paracrine-mediated endothelial cell tubule formation were attenuated in fibroblasts isolated from AR(Δex3)KO mice in vitro. Furthermore, DHT-induced augmentation of Sca1+/CXCR4+ progenitor cell production and mobilization was absent in AR(Δex3)KO mice post-HLI. BM transplantation revealed that ischemia-induced mobilization of circulating progenitor cells was abolished in recipients of AR(Δex3)KO BM. Together, these results indicate that androgen-mediated augmentation of ischemia-induced neovascularization is dependent on genomic AR transcriptional activation.

  6. Efficacy of patterned scan laser in treatment of macular edema and retinal neovascularization

    Directory of Open Access Journals (Sweden)

    Dimple Modi

    2009-08-01

    Full Text Available Dimple Modi, Paulpoj Chiranand, Levent AkdumanSaint Louis University School of Medicine, Department of Ophthalmology, Saint Louis University Eye Institute, St. Louis, Missouri, USAPurpose: To analyze the benefits, efficacy, and complications of the PASCAL® photocoagulation laser system (OptiMedica, Santa Clara, CA, USA in patients treated at our institution.Methods: We conducted a retrospective chart review of 19 patients (28 eyes who underwent laser treatment using the PASCAL® photocoagulation system from November 2006 to November 2007. These 28 eyes were divided into two groups; group 1 eyes underwent macular grid laser and group 2 eyes underwent panretinal photocoagulation. Treatment was performed for macular edema or for iris or retinal neovascularization. Outcomes measured included best-corrected visual acuity (BCVA, efficacy of laser treatment, complications, duration of the procedure, and pain perception, which were noted in the charts for panretinal treatments.Results: Follow-up was 5.9 ± 2.6 months for group 1 and 5.9 ± 4.0 months for group 2. In group 1, 9/28 eyes required a second treatment for remaining edema. BCVA was stable or better in 66% (14/21 and average central foveal thickness on ocular coherence tomography improved in 71% (15/21. Time to completion for a number of laser patterns for grid photocoagulation was felt to be too long for completing the total pattern safely, although we have not noted any related complications. In group 2, the neovascularization regressed at least partially in 3/7 patients. Patient-reported pain perception was 3.6 on a scale of 1 to 10 for group 2. Occasional hemorrhages occurred secondary to irregular laser uptake at different spots in the patterns. We observed no visual outcome consequences because of these hemorrhages during follow-up.Conclusions: Retinal photocoagulation by the PASCAL® laser has comparable efficacy to historical results with conventional retinal photocoagulation in short

  7. Zoledronate inhibits ischemia-induced neovascularization by impairing the mobilization and function of endothelial progenitor cells.

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    Shih-Hung Tsai

    Full Text Available BACKGROUND: Bisphosphonates are a class of pharmacologic compounds that are commonly used to treat postmenopausal osteoporosis and malignant osteolytic processes. Studies have shown that bone marrow-derived endothelial progenitor cells (EPCs play a significant role in postnatal neovascularization. Whether the nitrogen-containing bisphosphonate zoledronate inhibits ischemia-induced neovascularization by modulating EPC functions remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: Unilateral hindlimb ischemia was surgically induced in wild-type mice after 2 weeks of treatment with vehicle or zoledronate (low-dose: 30 μg/kg; high-dose: 100 μg/kg. Doppler perfusion imaging demonstrated that the ischemic limb/normal side blood perfusion ratio was significantly lower in wild-type mice treated with low-dose zoledronate and in mice treated with high-dose zoledronate than in controls 4 weeks after ischemic surgery (control vs. low-dose vs. high-dose: 87±7% vs. *61±18% vs. **49±17%, *p<0.01, **p<0.005 compared to control. Capillary densities were also significantly lower in mice treated with low-dose zoledronate and in mice treated with high-dose zoledronate than in control mice. Flow cytometry analysis showed impaired mobilization of EPC-like cells (Sca-1(+/Flk-1(+ after surgical induction of ischemia in mice treated with zoledronate but normal levels of mobilization in mice treated with vehicle. In addition, ischemic tissue from mice that received zoledronate treatment exhibited significantly lower levels of the active form of MMP-9, lower levels of VEGF, and lower levels of phosphorylated eNOS and phosphorylated Akt than ischemic tissue from mice that received vehicle. Results of the in vitro studies showed that incubation with zoledronate inhibited the viability, migration, and tube-forming capacities of EPC. CONCLUSIONS/SIGNIFICANCE: Zoledronate inhibited ischemia-induced neovascularization by impairing EPC mobilization and angiogenic functions

  8. A circulating microrna profile is associated with late-stage neovascular age-related macular degeneration.

    Directory of Open Access Journals (Sweden)

    Felix Grassmann

    Full Text Available Age-related macular degeneration (AMD is the leading cause of severe vision impairment in Western populations over 55 years. A growing number of gene variants have been identified which are strongly associated with an altered risk to develop AMD. Nevertheless, gene-based biomarkers which could be dysregulated at defined stages of AMD may point toward key processes in disease mechanism and thus may support efforts to design novel treatment regimens for this blinding disorder. Circulating microRNAs (cmiRNAs which are carried by nanosized exosomes or microvesicles in blood plasma or serum, have been recognized as valuable indicators for various age-related diseases. We therefore aimed to elucidate the role of cmiRNAs in AMD by genome-wide miRNA expression profiling and replication analyses in 147 controls and 129 neovascular AMD patients. We identified three microRNAs differentially secreted in neovascular (NV AMD (hsa-mir-301-3p, pcorrected = 5.6*10-5, hsa-mir-361-5p, pcorrected = 8.0*10-4 and hsa-mir-424-5p, pcorrected = 9.6*10-3. A combined profile of the three miRNAs revealed an area under the curve (AUC value of 0.727 and was highly associated with NV AMD (p = 1.2*10-8. To evaluate subtype-specificity, an additional 59 AMD cases with pure unilateral or bilateral geographic atrophy (GA were analyzed for microRNAs hsa-mir-301-3p, hsa-mir-361-5p, and hsa-mir-424-5p. While we found no significant differences between GA AMD and controls neither individually nor for a combined microRNAs profile, hsa-mir-424-5p levels remained significantly higher in GA AMD when compared to NV (pcorrected<0.005. Pathway enrichment analysis on genes predicted to be regulated by microRNAs hsa-mir-301-3p, hsa-mir-361-5p, and hsa-mir-424-5p, suggests canonical TGFβ, mTOR and related pathways to be involved in NV AMD. In addition, knockdown of hsa-mir-361-5p resulted in increased neovascularization in an in vitro angiogenesis assay.

  9. Retinal Inhibition of CCR3 Induces Retinal Cell Death in a Murine Model of Choroidal Neovascularization.

    Directory of Open Access Journals (Sweden)

    Haibo Wang

    Full Text Available Inhibition of chemokine C-C motif receptor 3 (CCR3 signaling has been considered as treatment for neovascular age-related macular degeneration (AMD. However, CCR3 is expressed in neural retina from aged human donor eyes. Therefore, broad CCR3 inhibition may be harmful to the retina. We assessed the effects of CCR3 inhibition on retina and choroidal endothelial cells (CECs that develop into choroidal neovascularization (CNV. In adult murine eyes, CCR3 colocalized with glutamine-synthetase labeled Műller cells. In a murine laser-induced CNV model, CCR3 immunolocalized not only to lectin-stained cells in CNV lesions but also to the retina. Compared to non-lasered controls, CCR3 mRNA was significantly increased in laser-treated retina. An intravitreal injection of a CCR3 inhibitor (CCR3i significantly reduced CNV compared to DMSO or PBS controls. Both CCR3i and a neutralizing antibody to CCR3 increased TUNEL+ retinal cells overlying CNV, compared to controls. There was no difference in cleaved caspase-3 in laser-induced CNV lesions or in overlying retina between CCR3i- or control-treated eyes. Following CCR3i, apoptotic inducible factor (AIF was significantly increased and anti-apoptotic factor BCL2 decreased in the retina; there were no differences in retinal vascular endothelial growth factor (VEGF. In cultured human Műller cells exposed to eotaxin (CCL11 and VEGF, CCR3i significantly increased TUNEL+ cells and AIF but decreased BCL2 and brain derived neurotrophic factor, without affecting caspase-3 activity or VEGF. CCR3i significantly decreased AIF in RPE/choroids and immunostaining of phosphorylated VEGF receptor 2 (p-VEGFR2 in CNV with a trend toward reduced VEGF. In cultured CECs treated with CCL11 and/or VEGF, CCR3i decreased p-VEGFR2 and increased BCL2 without increasing TUNEL+ cells and AIF. These findings suggest that inhibition of retinal CCR3 causes retinal cell death and that targeted inhibition of CCR3 in CECs may be a safer if CCR3

  10. VEGF Mediates ApoE4-Induced Neovascularization and Synaptic Pathology in the Choroid and Retina.

    Science.gov (United States)

    Antes, Ran; Salomon-Zimri, Shiran; Beck, Susanne C; Garcia Garrido, Marina; Livnat, Tami; Maharshak, Idit; Kadar, Tamar; Seeliger, Mathias; Weinberger, Dov; Michaelson, Daniel M

    2015-01-01

    Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is associated with neuronal and vascular impairments. Recent findings suggest that retina of apoE4 mice have synaptic and functional impairments. We presently investigated the effects of apoE4 on retinal and choroidal vasculature and the possible role of VEGF in these effects. There were no histological differences between the retinal and choroidal vasculatures of naïve apoE3 and apoE4 mice. In contrast, laserdriven choroidal injury induced higher levels of choroidal neovascularization (CNV) in apoE4 than in apoE3 mice. These effects were associated with an inflammatory response and with activation of the Muller cells and asrocytic markers gluthatione synthetase and GFAP, all of which were more pronounced in the apoE4 mice. CNV also induced a transient increase in the levels of the synaptic markers synaptophysin and PSD95 which were however similar in the apoE4 and apoE3 naive mice. Retinal and choroidal VEGF and apoE levels were lower in naïve apoE4 than in corresponding apoE3 mice. In contrast, VEGF and apoE levels rose more pronouncedly following laser injury in the apoE4 than in apoE3 mice. Taken together, these findings suggest that the apoE4-induced retinal impairments, under basal conditions, may be related to reduced VEGF levels in the eyes of these mice. The hyper-neovascularization in the apoE4 mice might be driven by increased inflammation and the associated surge in VEGF following injury. Retinal and choroidal VEGF and apoE levels were lower in naïve apoE4 than in corresponding apoE3 mice. In contrast, VEGF and apoE levels rose more pronouncedly following laser injury in the apoE4 than in apoE3 mice. Taken together, these findings suggest that the apoE4-induced retinal impairments, under basal conditions, may be related to reduced VEGF levels in the eyes of these mice. The hyper-neovascularization in the apoE4 mice might be driven by increased inflammation

  11. Riemann Zeta Matrix Function

    OpenAIRE

    Kargın, Levent; Kurt, Veli

    2015-01-01

    In this study, obtaining the matrix analog of the Euler's reflection formula for the classical gamma function we expand the domain of the gamma matrix function and give a infinite product expansion of sinπxP.  Furthermore we define Riemann zeta matrix function and evaluate some other matrix integrals. We prove a functional equation for Riemann zeta matrix function.

  12. Combined choroidal neovascularization and hypopituitarism in a patient with homozygous mutation in methylenetetrahydrofolate reductase gene

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    Aydogan Aydogdu

    2014-01-01

    Full Text Available We report a case of choroidal neovascularization (CNV secondary to methylenetetrahydrofolate reductase (MTHFR gene mutation in a 20-year-old male patient with hypopituitarism. Treatment with three consecutive injections of intravitreal ranibizumab (anti-vascular endothelial growth factor resulted in significant improvement of the patient′s vision and the appearance of the macula. A search of the literature produced no previously reported case of MTHFR gene mutation associated both CNV and possibly hypopituitarism. With hormone replacement therapy of hypopituitarism, acetyl salicylic acid 100 mg/day also was started. The patient was clinically stable both for CNV and other thromboembolic disorders over a 6-month follow-up and also 1-year follow-up period.

  13. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration in treatment-naive patients

    DEFF Research Database (Denmark)

    Pedersen, Karen Bjerg; Sjølie, Anne Katrin; Møller, Flemming

    2008-01-01

    , pilot study of 26 eyes of 26 patients, all previously treatment-naive to photodynamic therapy, argon laser or anti-vascular endothelial growth factor (VEGF), were treated with one or more intravitreal injections of 1.25 mg bevacizumab. Of the 26 patients, 15 (57.7%) had occult choroidal...... neovascularization (CNV), 6 (23.1%) had predominantly classic CNV and 5 (19.2%) had minimally classic CNV. Ophthalmic outcome measures included changes in standardized Early Treatment Diabetic Research Study (ETDRS) VA, contrast sensitivity and OCT. The patients were examined at baseline and 1 week, 6 weeks, 3...... months and 6 months after the first injection. Re-treatment was given on an 'as needed' basis. Results: Twenty-four eyes of 24 patients completed 6 months of follow-up. Two patients chose to discontinue the study. Mean ETDRS VA score improved from 55 letters at baseline to 60 letters at 1 week (P

  14. Management of Myopic Choroidal Neovascularization: Focus on Anti-VEGF Therapy.

    Science.gov (United States)

    Teo, Kelvin Yi Chong; Ng, Wei Yan; Lee, Shu Yen; Cheung, Chui Ming Gemmy

    2016-07-01

    Myopic choroidal neovascularization (mCNV) is the second most common form of CNV after age-related macular degeneration (AMD). It is a sight-threatening complication of pathologic myopia (PM) and often affects patients in their working years causing significant impact on quality of life. Previous therapies such as photodynamic therapy with verteporfin have shown limited success. Due to the similarities in pathogenesis of mCNV and AMD CNV, anti-vascular endothelial growth factor therapy (anti-VEGF), which has so far been the mainstay of treatment for AMD CNV, has been shown to be effective in the treatment of mCNV and has become the first-line treatment of choice. This article aims to examine briefly the epidemiology and pathophysiology of mCNV, as well as review the evidence for efficacy, safety, and clinical use of anti-VEGF treatment for mCNV.

  15. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration.

    Science.gov (United States)

    Solomon, Sharon D; Lindsley, Kristina; Vedula, Satyanarayana S; Krzystolik, Magdalena G; Hawkins, Barbara S

    2014-08-29

    Age-related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal neovascularization (CNV) secondary to neovascular AMD accounts for most AMD-related severe vision loss. Anti-vascular endothelial growth factor (anti-VEGF) agents, injected intravitreally, aim to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, improve vision. To investigate: (1) the ocular and systemic effects of, and quality of life associated with, intravitreally injected anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) for the treatment of neovascular AMD compared with no anti-VEGF treatment; and (2) the relative effects of one anti-VEGF agent compared with another when administered in comparable dosages and regimens. We searched Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to March 2014), EMBASE (January 1980 to March 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to March 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We used no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 27 March 2014. We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or a control treatment (e.g., sham treatment or photodynamic therapy). All trials followed participants for at least one year. Two review authors independently screened records, extracted data, and

  16. Optical Coherence Tomography Angiography for Detecting Choroidal Neovascularization Secondary to Choroidal Osteoma.

    Science.gov (United States)

    Szelog, Jason T; Bonini Filho, Marco A; Lally, David R; de Carlo, Talisa E; Duker, Jay S

    2016-01-01

    Choroidal osteoma is an ossifying tumor that is found predominantly in the peripapillary and macular areas. It typically affects otherwise healthy females. Vision loss may occur secondary to the development of choroidal neovascularization (CNV). Fluorescein angiography (FA) remains the gold standard for diagnosing CNV; however, the use of optical coherence tomography angiography (OCTA) as an adjunct to FA is growing. In this report, a 16-year-old female with a large, unilateral peripapillary choroidal osteoma presented with blurred vision. Exam revealed scattered intraretinal hemorrhage, but FA was unable to detect CNV overlying the tumor. OCTA detected abnormal flow in the outer retina corresponding to a type 2 CNV. Following intravitreal anti-vascular endothelial growth factor therapy, the CNV regressed, the hemorrhage resolved, and there was less fluid. OCTA may be helpful in detecting CNV noninvasively in eyes in which FA is equivocal, such as those with choroidal osteoma.

  17. Natural history of choroidal neovascularization after surgical induction in an animal model

    DEFF Research Database (Denmark)

    Lassota, Nathan; Kiilgaard, Jens Folke; la Cour, Morten

    2008-01-01

    PURPOSE: To study an expanded time course of surgically induced choroidal neovascularization (CNV) in a porcine model applying fluorescence angiography and immunohistology. METHODS: Twenty-two porcine eyes underwent vitrectomy, a retinal bleb was raised and the detached retina perforated using...... endodiathermy. Bruch's membrane was perforated with a retinal perforator at a site where the overlying neuroretina was normal. Eyes were enucleated in a time interval between 30 min and 42 days after the perforation, and the pigs were subsequently killed. Immediately prior to enucleation, fundus photographs...... and fluorescein angiograms were obtained. Sections of paraffin-embedded eyes were immunohistochemically stained. RESULTS: On fluorescein angiography, membranes aged 14 days or less exhibited leakage in 10/11 cases while the remaining showed persistent staining. The propensity to leak diminished with time and only...

  18. Cataract surgery in patients with neovascular age-related macular degeneration

    DEFF Research Database (Denmark)

    Kessel, Line; Koefoed Theil, Pernille; Lykke Sørensen, Torben;

    2016-01-01

    being treated with a median of 10 (range 3-36) anti-VEGF injections for neovascular AMD. Visual acuity improved by a mean of 7.1 [95% confidence interval (CI) 4.6-9.6] ETDRS letters in the first 6 months after cataract surgery. The need of anti-VEGF injections did not change after cataract surgery...... in electronic databases managing anti-VEGF injections and cataract surgery. We compared Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity and frequency of anti-VEGF injections before and after cataract surgery. RESULTS: We identified 89 eyes from 89 patients who had cataract surgery after...... AMD. Cataract surgery was not associated with an increased need for anti-VEGF treatment and patients who were in active anti-VEGF treatment had better visual outcomes than patients who had cataract surgery after long injection-free periods....

  19. Visual outcomes in relation to time to treatment in neovascular age-related macular degeneration

    DEFF Research Database (Denmark)

    Rasmussen, Annette; Bloch, Sara Brandi; Fuchs, Josefine;

    2015-01-01

    1185 eyes in 1099 patients who began vascular endothelial growth factor inhibitor treatment for nAMD during four separate periods in 2007, 2009, 2011 and 2012 using a fixed loading-dose regimen of three ranibizumab injections. RESULTS: Mean best-corrected visual acuity (BCVA) at presentation remained......PURPOSE: To study the relation between the interval from diagnosis to initiation of intravitreal injection therapy and visual outcome in neovascular age-related macular degeneration (nAMD) and to report changes over time in fellow-eye status. METHODS: Retrospective chart review. The study included....... CONCLUSION: In this study, 2-week-earlier injection was associated with the equivalent of a 5-Early Treatment Diabetic Retinopathy Study letter-gain in mean visual acuity at 3 months after presentation. The difference is larger than expected from the 2-week-longer duration of disease at the study end...

  20. Modeling Stem/Progenitor Cell-Induced Neovascularization and Oxygenation Around Solid Implants

    KAUST Repository

    Jain, Harsh Vardhan

    2012-07-01

    Tissue engineering constructs and other solid implants with biomedical applications, such as drug delivery devices or bioartificial organs, need oxygen (O(2)) to function properly. To understand better the vascular integration of such devices, we recently developed a novel model sensor containing O(2)-sensitive crystals, consisting of a polymeric capsule limited by a nanoporous filter. The sensor was implanted in mice with hydrogel alone (control) or hydrogel embedded with mouse CD117/c-kit+ bone marrow progenitor cells in order to stimulate peri-implant neovascularization. The sensor provided local partial O(2) pressure (pO(2)) using noninvasive electron paramagnetic resonance signal measurements. A consistently higher level of peri-implant oxygenation was observed in the cell-treatment case than in the control over a 10-week period. To provide a mechanistic explanation of these experimental observations, we present in this article a mathematical model, formulated as a system of coupled partial differential equations, that simulates peri-implant vascularization. In the control case, vascularization is considered to be the result of a foreign body reaction, while in the cell-treatment case, adipogenesis in response to paracrine stimuli produced by the stem cells is assumed to induce neovascularization. The model is validated by fitting numerical predictions of local pO(2) to measurements from the implanted sensor. The model is then used to investigate further the potential for using stem cell treatment to enhance the vascular integration of biomedical implants. We thus demonstrate how mathematical modeling combined with experimentation can be used to infer how vasculature develops around biomedical implants in control and stem cell-treated cases.

  1. Ephrin-a4 is involved in retinal neovascularization by regulating the VEGF signaling pathway.

    Science.gov (United States)

    Du, Wei; Yu, Wenzhen; Huang, Lvzhen; Zhao, Min; Li, Xiaoxin

    2012-04-18

    Retinal neovascularization (NV) is a major cause of blindness. Recent research suggests that factors other than VEGF participate in this process. This study aimed to determine the role of ephrin-A4 in retinal NV. The expression and effect of ephrin-A4 was investigated in a mouse model of oxygen-induced retinopathy (OIR) and the RF/6A retina endothelial cell line. Ephrin-A4 expression and VEGF signaling pathway phosphorylation were determined by PCR, immunohistochemistry, and western blot analyses. ShRNA was used to silence ephrin-A4 in vitro and in vivo. Retinal flat mounts and tube formation assays were performed to evaluate ephrin-A4 function in the NV process in vivo and in vitro. Ephrin-A4 was overexpressed in the retina of OIR mice and in RF/6A and RPE cells after CoCl₂ stimulation. In vitro, Ephrin-A4/Fc treatment significantly increased the tube number of RF/6A cells on a membrane preparation and the phosphorylation levels of VEGR2, Akt1, and ERK1/2 in RF/6A cells. Moreover, ephrin-A4 knockout markedly suppressed pathologic neovascularization in vivo and inhibited the proliferation and tube formation capacity of RF/6A cells in vitro. Furthermore, in the absence of ephrin-A4, the phosphorylation of VEGFR2, Akt1, and ERK1/2 was defective under VEGF₁₆₅ stimulation, and the proangiogenic function of VEGF₁₆₅ was also compromised. This study suggests that ephrin-A4 plays an important role in retinal NV and is a potential target against retinal NV. The proangiogenic function of ephrin-A4 may be linked to its crucial role in the VEGF signaling pathway.

  2. Predictors of anti-VEGF treatment response in neovascular age-related macular degeneration.

    Science.gov (United States)

    Finger, Robert P; Wickremasinghe, Sanjeewa S; Baird, Paul N; Guymer, Robyn H

    2014-01-01

    Currently available evidence on predictors of anti-vascular endothelial growth factor (VEGF) treatment response in neovascular age-related macular degeneration was reviewed. No meta-analysis of results is possible because of a lack of controlled and randomized trials, varying treatment regimes and outcome measures used, as well as suboptimal reporting. For genetic factors, most evidence to date has been generated for single nucleotide polymorphisms (SNPs) in the complement factor H (CFH), and VEGF-A genes. Just under half of the SNPs assessed in the CFH gene and 15% of the SNPs assessed in the VEGF gene were found to be associated with visual outcomes or the number of injections required during follow-up. Some evidence suggests association of worse treatment outcomes as well as a younger age at treatment onset with an increasing number of risk alleles in known risk genes (CFH and ARMS2/HTRA1) and polymorphisms in the VEGF-A gene. Clinical factors such as higher age, a better visual acuity (VA), a larger choroidal neovascularization (CNV) lesion at baseline, and a delay between symptom onset and initiation of treatment of more than 3 weeks also impact outcomes. Conversely, a worse acuity at baseline predicted more gain in vision. Overall, patients presenting with good acuity at baseline were more likely to have good VA at follow up, but the gain afforded by treatment was impacted by a ceiling effect. Most available evidence suggests a strong association of clinical factors such as age, baseline VA, and CNV lesion size with anti-VEGF treatment outcomes. No behavioral factors such as smoking influence treatment outcomes. Based on the studies conducted so far, the evidence suggests that underlying genotype of known AMD risk associated genes or of the VEGF-A gene have a limited effect, whereas presenting clinical factors appear to be more important in determining treatment outcomes.

  3. Transscleral sustained vasohibin-1 delivery by a novel device suppressed experimentally-induced choroidal neovascularization.

    Directory of Open Access Journals (Sweden)

    Hideyuki Onami

    Full Text Available We established a sustained vasohibin-1 (a 42-kDa protein, delivery device by a novel method using photopolymerization of a mixture of polyethylene glycol dimethacrylate, triethylene glycol dimethacrylate, and collagen microparticles. We evaluated its effects in a model of rat laser-induced choroidal neovascularization (CNV using a transscleral approach. We used variable concentrations of vasohibin-1 in the devices, and used an enzyme-linked immunosorbent assay and Western blotting to measure the released vasohibin-1 (0.31 nM/day when using the 10 μM vasohibin-1 delivery device [10VDD]. The released vasohibin-1 showed suppression activity comparable to native effects when evaluated using endothelial tube formation. We also used pelletized vasohibin-1 and fluorescein isothiocyanate-labeled 40 kDa dextran as controls. Strong fluorescein staining was observed on the sclera when the device was used for drug delivery, whereas pellet use produced strong staining in the conjunctiva and surrounding tissue, but not on the sclera. Vasohibin-1 was found in the sclera, choroid, retinal pigment epithelium (RPE, and neural retina after device implantation. Stronger immunoreactivity at the RPE and ganglion cell layers was observed than in other retinal regions. Significantly lower fluorescein angiography (FA scores and smaller CNV areas in the flat mounts of RPE-choroid-sclera were observed for the 10VDD, VDD (1 μM vasohibin-1 delivery device, and vasohibin-1 intravitreal direct injection (0.24 μM groups when compared to the pellet, non-vasohibin-1 delivery device, and intravitreal vehicle injection groups. Choroidal neovascularization can be treated with transscleral sustained protein delivery using our novel device. We offer a safer sustained protein release for treatment of retinal disease using the transscleral approach.

  4. Six-year outcomes in neovascular age-related macular degeneration with ranibizumab

    Science.gov (United States)

    Jacob, Julie; Brié, Heidi; Leys, Anita; Levecq, Laurent; Mergaerts, Filip; Denhaerynck, Kris; Vancayzeele, Stefaan; Van Craeyveld, Eline; Abraham, Ivo; MacDonald, Karen

    2017-01-01

    AIM To evaluate the outcomes of ≥6y ranibizumab therapy in neovascular age-related macular degeneration (AMD). METHODS HELIX was a retrospective, observational effectiveness study using medical records of patients treated in three clinics in Belgium. Patients had neovascular AMD and were initially treated with intravitreal ranibizumab (0.5 mg) between November 1, 2007 and October 31, 2008, had ≥6y of data available, and were treated on an ongoing, as-needed basis. Outcomes included best-corrected visual acuity (BCVA) and central retinal thickness (CRT). RESULTS The sample consisted of 88 eyes from 69 patients. Mean age was 76.4±6.5y, most patients were female (62.3%). Most eyes (62.5%) were treatment-naive, 33 previously treated eyes had received predominantly other anti-vascular endothelial growth factor agents and verteporfin. Mean baseline BCVA was 57.4±12.7 ETDRS letters and CRT was 291.5±86.1 μm. On average, patients received 20.6±11.9 ranibizumab injections over the ≥6y. Intervals between injections were on average 12.7±16.1wk. Mean change in BCVA from baseline to last observation for the sample was less than one letter (-0.9±17.3 letters), with an average loss of -3.2±15.6 letters in previously treated eyes versus a gain of 0.6±18.4 letters in treatment-naïve eyes. When considering a loss of AMD patients treated for ≥6y with ranibizumab demonstrates long-term visual stabilization. In light of the natural evolution of the disease, these data confirm that ranibizumab is effective long-term under real-world conditions of heterogeneity of patients, clinicians, and centers. PMID:28149782

  5. Topical application of PPADS inhibits complement activation and choroidal neovascularization in a model of age-related macular degeneration.

    Directory of Open Access Journals (Sweden)

    Kerstin Birke

    Full Text Available Age-related macular degeneration (AMD is the most common cause of blindness among the elderly. AMD patients have elevated levels of membrane attack complex (MAC in their choroidal blood vessels and retinal pigment epithelium (RPE. MAC forms pores in cell membranes. Low levels of MAC result in an elevation of cytokine release such as vascular endothelial growth factor (VEGF that promotes the formation of choroidal neovascularization (CNV. High levels of MAC result in cell lysis and RPE degeneration is a hallmark of advanced AMD. The current standard of care for CNV associated with wet AMD is intravitreal injection of anti-VEGF molecules every 4 to 12 weeks. Such injections have significant side effects. Recently, it has been found that membrane pore-forming proteins such as α-haemolysin can mediate their toxic effects through auto- and paracrine signaling and that complement-induced lysis is amplified through ATP release followed by P2X receptor activation. We hypothesized that attenuation of P2X receptor activation may lead to a reduction in MAC deposition and consequent formation of CNV. Hence, in this study we investigated topical application of the purinergic P2X antagonist Pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS as a potential treatment for AMD. We found that 4.17 µM PPADS inhibited formation of HUVEC master junctions and master segments by 74.7%. In a human complement mediated cell lysis assay, 104 µM PPADS enabled almost complete protection of Hepa1c1c7 cells from 1% normal human serum mediated cell lysis. Daily topical application of 4.17 mM PPADS for 3 days attenuated the progression of laser induced CNV in mice by 41.8% and attenuated the deposition of MAC at the site of the laser injury by 19.7%. Our data have implications for the future treatment of AMD and potentially other ocular disorders involving CNV such as angioid streaks, choroidal rupture and high myopia.

  6. Prostaglandin E2 promotes endothelial differentiation from bone marrow-derived cells through AMPK activation.

    Directory of Open Access Journals (Sweden)

    Zhenjiu Zhu

    Full Text Available Prostaglandin E2 (PGE2 has been reported to modulate angiogenesis, the process of new blood vessel formation, by promoting proliferation, migration and tube formation of endothelial cells. Endothelial progenitor cells are known as a subset of circulating bone marrow mononuclear cells that have the capacity to differentiate into endothelial cells. However, the mechanism underlying the stimulatory effects of PGE2 and its specific receptors on bone marrow-derived cells (BMCs in angiogenesis has not been fully characterized. Treatment with PGE2 significantly increased the differentiation and migration of BMCs. Also, the markers of differentiation to endothelial cells, CD31 and von Willebrand factor, and the genes associated with migration, matrix metalloproteinases 2 and 9, were significantly upregulated. This upregulation was abolished by dominant-negative AMP-activated protein kinase (AMPK and AMPK inhibitor but not protein kinase, a inhibitor. As a functional consequence of differentiation and migration, the tube formation of BMCs was reinforced. Along with altered BMCs functions, phosphorylation and activation of AMPK and endothelial nitric oxide synthase, the target of activated AMPK, were both increased which could be blocked by EP4 blocking peptide and simulated by the agonist of EP4 but not EP1, EP2 or EP3. The pro-angiogenic role of PGE2 could be repressed by EP4 blocking peptide and retarded in EP4(+/- mice. Therefore, by promoting the differentiation and migration of BMCs, PGE2 reinforced their neovascularization by binding to the receptor of EP4 in an AMPK-dependent manner. PGE2 may have clinical value in ischemic heart disease.

  7. Comparative study of the effects of recombinant human epidermal growth factor and basic fibroblast growth factor on corneal epithelial wound healing and neovascularization in vivo and in vitro.

    Science.gov (United States)

    Yan, Limeng; Wu, Wei; Wang, Zhichong; Li, Chaoyang; Lu, Xiaohe; Duan, Hucheng; Zhou, Jin; Wang, Xiaoran; Wan, Pengxia; Song, Yiyue; Tang, Jing; Han, Yu

    2013-01-01

    This study was undertaken to investigate the effects of recombinant human epidermal growth factor (rhEGF) and basic fibroblast growth factor (bFGF) on corneal wound healing and neovascularization (CNV). The positive effects of 10 ng/ml rhEGF and bFGF on the proliferation of corneal epithelial cells (SD-HCEC1s), rabbit keratocyte cells (RKCs) and human umbilical vein endothelial cells (HUVECs) as well as the effects on the migration capacity on HUVECs were observed. An animal central corneal wound and CNV model was established in rabbits. One eye of each group was chosen randomly for topical administration of rhEGF, bFGF or normal saline, and variability in the area of corneal epithelial wound healing and CNV was observed. The optimal concentration of rhEGF and bFGF for the proliferation of corneal epithelial cells was 10 ng/ml. The promotive effect of 10 ng/ml rhEGF on the proliferation of RKCs and HUVECs was less than that of 10 ng/ml bFGF. In the animal experiment, the healing rate of the corneal epithelium in the rhEGF group was better than in the other groups on day 1. On day 3, the healing rates of the 3 groups were nearly equal. The CNV area in the rhEGF group was less than that of the bFGF group. rhEGF and bFGF both had promotive effects on corneal epithelial wound healing, but rhEGF had a weaker promotive effect on CNV than bFGF. With long-term application of growth factor drugs, rhEGF is suggested for lessening the growth of CNV. Copyright © 2012 S. Karger AG, Basel.

  8. Chemokine stromal cell-derived factor 1/CXCL12 increases homing of mesenchymal stem cells to injured myocardium and neovascularization following myocardial infarction

    Institute of Scientific and Technical Information of China (English)

    ZHUANG Yu; CHEN Xin; XU Ming; ZHANG Lei-yang; XIANG Fei

    2009-01-01

    = 0.000). Conclusion Myocardial SDF-1 expression was increased only in the early phase post MI. SDF-1 may enhance MSCs homing to the injured heart and improve cardiac function by promoting neovascularization.

  9. Aflibercept: a review of its use in the treatment of choroidal neovascularization due to age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Balaratnasingam C

    2015-12-01

    Full Text Available Chandrakumar Balaratnasingam,1–3 Elona Dhrami-Gavazi,1,2,4 Jesse T McCann,1,2,4,5 Quraish Ghadiali,1,2 K Bailey Freund1,2,4,5 1Vitreous-Retina-Macula Consultants of New York, NY, USA; 2LuEsther T Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital, New York, NY, USA; 3Centre for Ophthalmology and Visual Sciences, Lions Eye Institute, University of Western Australia, Perth, WA, Australia; 4Department of Ophthalmology, Edward S Harkness Eye Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA; 5Department of Ophthalmology, New York University School of Medicine, New York, NY, USA Abstract: Choroidal neovascularization (CNV due to age-related macular degeneration (AMD is an important cause of visual morbidity globally. Modern treatment strategies for neovascular AMD achieve regression of CNV by suppressing the activity of key growth factors that mediate angiogenesis. Vascular endothelial growth factor (VEGF has been the major target of neovascular AMD therapy for almost two decades, and there have been several intravitreally-administered agents that have enabled anatomical restitution and improvement in visual function with continual dosing. Aflibercept (EYLEA®, initially named VEGF Trap-eye, is the most recent anti-VEGF agent to be granted US Food and Drug Administration approval for the treatment of neovascular AMD. Biologic advantages of aflibercept include its greater binding affinity for VEGF, a longer intravitreal half-life relative to other anti-VEGF agents, and the capacity to antagonize growth factors other than VEGF. This paper provides an up-to-date summary of the molecular mechanisms mediating CNV. The structural, pharmacodynamic, and pharmacokinetic advantages of aflibercept are also reviewed to rationalize the utility of this agent for treating CNV. Results of landmark clinical investigations, including VIEW 1 and 2 trials, and other important studies are then summarized and used to

  10. Effect of vascular endothelial growth factor inhibitors on choroid in patients with macular choroid neovascular membrane and degenerative myopia . Preliminary report

    OpenAIRE

    V. A. Solomin; D.A. Magaramov; G. F. Kachalina

    2012-01-01

    Purpose: to assess the effect of vascular endothelial growth factor inhibitors on choroid in patients with myopic macular choroid neovascular membrane.Methods: 12 eyes (12 patients) aged 19-47 years with myopia and macular choroid neovascular membrane (mCNV) were enrolled in a study group. A control group included fellow eyes with early «dry» form age-related macular degeneration. Eyes with mCNV under- went one intravitreal injection of vascular endothelial growth factor inhibitor Ranibizumab...

  11. Corneal Regeneration by Deep Anterior Lamellar Keratoplasty (DALK Using Decellularized Corneal Matrix.

    Directory of Open Access Journals (Sweden)

    Yoshihide Hashimoto

    Full Text Available The purpose of this study is to demonstrate the feasibility of DALK using a decellularized corneal matrix obtained by HHP methodology. Porcine corneas were hydrostatically pressurized at 980 MPa at 10°C for 10 minutes to destroy the cells, followed by washing with EGM-2 medium to remove the cell debris. The HHP-treated corneas were stained with H-E to assess the efficacy of decellularization. The decellularized corneal matrix of 300 μm thickness and 6.0 mm diameter was transplanted onto a 6.0 mm diameter keratectomy wound. The time course of regeneration on the decellularized corneal matrix was evaluated by haze grading score, fluorescein staining, and immunohistochemistry. H-E staining revealed that no cell nuclei were observed in the decellularized corneal matrix. The decellularized corneal matrices were opaque immediately after transplantation, but became completely transparent after 4 months. Fluorescein staining revealed that initial migration of epithelial cells over the grafts was slow, taking 3 months to completely cover the implant. Histological sections revealed that the implanted decellularized corneal matrix was completely integrated with the receptive rabbit cornea, and keratocytes infiltrated into the decellularized corneal matrix 6 months after transplantation. No inflammatory cells such as macrophages, or neovascularization, were observed during the implantation period. The decellularized corneal matrix improved corneal transparency, and remodelled the graft after being transplanted, demonstrating that the matrix obtained by HHP was a useful graft for corneal tissue regeneration.

  12. Long-Term Visual Outcomes for a Treat and Extend Anti-Vascular Endothelial Growth Factor Regimen in Eyes with Neovascular Age-Related Macular Degeneration.

    Science.gov (United States)

    Mrejen, Sarah; Jung, Jesse J; Chen, Christine; Patel, Samir N; Gallego-Pinazo, Roberto; Yannuzzi, Nicolas; Xu, Luna; Marsiglia, Marcela; Boddu, Sucharita; Freund, K Bailey

    2015-07-08

    With the advent of anti-vascular endothelial growth factor (VEGF) therapy, clinicians are now focused on various treatment strategies to better control neovascular age-related macular degeneration (NVAMD), a leading cause of irreversible blindness. Herein, we retrospectively reviewed consecutive patients with treatment-naïve NVAMD initially classified based on fluorescein angiography (FA) alone or with an anatomic classification utilizing both FA and optical coherence tomography (OCT) and correlated long-term visual outcomes of these patients treated with an anti-VEGF Treat-and-Extend Regimen (TER) with baseline characteristics including neovascular phenotype. Overall, 185 patients (210 eyes) were followed over an average of 3.5 years (range 1-6.6) with a retention rate of 62.9%, and visual acuity significantly improved with a TER that required a mean number of 8.3 (±1.6) (± standard deviation) intravitreal anti-VEGF injections/year (range 4-13). The number of injections and the anatomic classification were independent predictors of visual acuity at 6 months, 1, 2, 3 and 4 years. Patients with Type 1 neovascularization had better visual outcomes and received more injections than the other neovascular subtypes. There were no serious adverse events. A TER provided sustained long-term visual gains. Eyes with Type 1 neovascularization had better visual outcomes than those with other neovascular subtypes.

  13. Long-Term Visual Outcomes for a Treat and Extend Anti-Vascular Endothelial Growth Factor Regimen in Eyes with Neovascular Age-Related Macular Degeneration

    Directory of Open Access Journals (Sweden)

    Sarah Mrejen

    2015-07-01

    Full Text Available With the advent of anti-vascular endothelial growth factor (VEGF therapy, clinicians are now focused on various treatment strategies to better control neovascular age-related macular degeneration (NVAMD, a leading cause of irreversible blindness. Herein, we retrospectively reviewed consecutive patients with treatment-naïve NVAMD initially classified based on fluorescein angiography (FA alone or with an anatomic classification utilizing both FA and optical coherence tomography (OCT and correlated long-term visual outcomes of these patients treated with an anti-VEGF Treat-and-Extend Regimen (TER with baseline characteristics including neovascular phenotype. Overall, 185 patients (210 eyes were followed over an average of 3.5 years (range 1–6.6 with a retention rate of 62.9%, and visual acuity significantly improved with a TER that required a mean number of 8.3 (±1.6 (± standard deviation intravitreal anti-VEGF injections/year (range 4–13. The number of injections and the anatomic classification were independent predictors of visual acuity at 6 months, 1, 2, 3 and 4 years. Patients with Type 1 neovascularization had better visual outcomes and received more injections than the other neovascular subtypes. There were no serious adverse events. A TER provided sustained long-term visual gains. Eyes with Type 1 neovascularization had better visual outcomes than those with other neovascular subtypes.

  14. Effects of rhGM-CSF on scalding wound healing and neovascularization in rats%重组人粒细胞巨噬细胞集落刺激因子对烫伤大鼠创面愈合及新生血管化的影响

    Institute of Scientific and Technical Information of China (English)

    刘继松; 方勇; 姚敏; 俞为荣; 杜娟

    2012-01-01

    Objective: To evaluate the effect of rhGM-CSF on scalding wound healing and neovascularization. Methods: Deep Ⅱ degree bum wound was made in72 SD rate on the back with diameter of3 cm. Rate were randomly divided into experinent group( n = 36, local wound was treated with rhGM-CSF gel) and control group(n =36, bcal wound were treated with gel matrix without rhGM-CSF). The process of wound healing was observed, and the percentages of wound closure were calculated on the day, the 1st,2 nd,3 rd, 7 th,10 th,14 th, and 21 st day after scald The expression of CD31, the surfacemaker of neovascularendothelial cells was detetcted with in the wound sites by immunoh istochamical staining, and the microvessel density was calculated. Results: The percentages of wound closure in experinent group were significantly higher than that in control group from the 7 th day to the21 st day. Immunohistochanical detection revealed that the expression of CD31 and the microvessel densily in experinent group were significantly higher than those in control group from7 th day to21 stday(P <0.01). Conclusions: The treatment of rhGM-CSF may promote scalding wound healing in rate The mechanisn may be associated with upregulation of CD31 expression and acceleration of neovascularization.%目的:研究重组人粒细胞巨噬细胞集落刺激因子(recombinant human granulocyte-macrophage colony-stimulating factor,rhGM-CSF)对烫伤创面组织愈合及新生血管化的影响.方法:72只SD大鼠于背部制备直径3 cm的深Ⅱ度烫伤创面.根据创面不同处理方式将大鼠随机分为实验组(创面局部应用rhGM-CSF凝胶剂)和对照组(创面局部应用不含rhGM-CSF的凝胶基质),每组36只.分别于创面形成后当日和第1、3、7、10、14、21天观察创面并计算创面愈合率;免疫组织化学染色观察创面组织中新生血管内皮细胞表面标志物CD31表达,计算微血管密度.结果:自创面形成后第7天起,实验组创面愈

  15. Clinical and histological findings after intravitreal injection of bevacizumab (Avastin) in a porcine model of choroidal neovascularization

    DEFF Research Database (Denmark)

    Lassota, Nathan; Prause, Jan Ulrik; Scherfig, Erik;

    2010-01-01

    was identified immunohistochemically in the inner limiting membrane (ILM) and to a lesser degree in the remaining retina. Strong staining was also detected in both retinal blood vessels and entire CNV membranes with no cellular predisposition. Vascular endothelial growth factor expression was found in the CNV...... membranes, in the ILM, in the ganglion cell layer, in Müller cells throughout the neuroretina and in retinal blood vessels. CONCLUSIONS: Bevacizumab significantly reduced the proliferation of vascular endothelial cells in CNV membranes and showed a strong trend towards a reduction of leakage from......PURPOSE: To examine the effect of intravitreally injected bevacizumab (Avastin) on the histological and angiographic morphology of choroidal neovascularization (CNV) in a masked and placebo-controlled animal study. METHODS: Choroidal neovascularization was induced surgically in 11 porcine eyes...

  16. Relapse of choroidal neovascularization in Bietti's crystalline retinopathy following anti-vascular endothelial growth factor therapy: A case report

    Science.gov (United States)

    HUA, RUI; CHEN, KANG; HU, YUEDONG; WANG, XINLING; CHEN, LEI

    2015-01-01

    Choroidal neovascularization secondary to retinitis pigmentosa is rarely observed in clinical practice. The present study describes a case of atypical retinitis pigmentosa, crystalline retinal pigmentary degeneration, complicated by choroidal neovascularization (CNV) in a 26-year-old man presenting with blurred vision in the right eye. Heidelberg multimodality imaging was performed to achieve a confirmed diagnosis. Bevacizumab was injected once intravitreally. The 3-month follow-up included visualization of the lesion's regression with spectral domain optical coherence tomography (SD-OCT). However, at 3 months after the injection, the CNV reoccurred. To the best of our knowledge, this is the first time that a case of CNV secondary to retinitis pigmentosa, in which the diagnosis was confirmed via multimodality imaging and the therapeutic efficacy was evaluated by SD-OCT, has been reported in China. PMID:26640540

  17. Nanocarriers for treatment of ocular neovascularization in the back of the eye: new vehicles for ophthalmic drug delivery.

    Science.gov (United States)

    Shen, Hsin-Hui; Chan, Elsa C; Lee, Jia Hui; Bee, Youn-Shen; Lin, Tsung-Wu; Dusting, Gregory J; Liu, Guei-Sheung

    2015-01-01

    Pathologic neovascularization of the retina is a major cause of substantial and irreversible loss of vision. Drugs are difficult to deliver to the lesions in the back of the eye and this is a major obstacle for the therapeutics. Current pharmacological approach involves an intravitreal injection of anti-VEGF agents to prevent aberrant growth of blood vessels, but it has limitations including therapeutic efficacy and side-effects associated with systemic exposure and invasive surgery. Nanotechnology provides novel opportunities to overcome the limitations of conventional delivery system to reach the back of the eye through fabrication of nanostructures capable of encapsulating and delivering small molecules. This review article introduces various forms of nanocarrier that can be adopted by ocular drug delivery systems to improve current therapy. The application of nanotechnology in medicine brings new hope for ocular drug delivery in the back of the eye to manage the major causes of blindness associated with ocular neovascularization.

  18. Metabolic syndrome triggered by high-fructose diet favors choroidal neovascularization and impairs retinal light sensitivity in the rat.

    Science.gov (United States)

    Thierry, Magalie; Pasquis, Bruno; Acar, Niyazi; Grégoire, Stéphane; Febvret, Valérie; Buteau, Bénédicte; Gambert-Nicot, Ségolène; Bron, Alain M; Creuzot-Garcher, Catherine P; Bretillon, Lionel

    2014-01-01

    Diabetic retinopathy and age-related macular degeneration are the leading causes of blindness in Western populations. Although it is a matter of controversy, large-scale population-based studies have reported increased prevalence of age-related macular degeneration in patients with diabetes or diabetic retinopathy. We hypothesized that metabolic syndrome, one of the major risk factors for type 2 diabetes, would represent a favorable environment for the development of choroidal neovascularization, the main complication of age-related macular degeneration. The fructose-fed rat was used as a model for metabolic syndrome in which choroidal neovascularization was induced by laser photocoagulation. Male Brown Norway rats were fed for 1, 3, and 6 months with a standard equilibrated chow diet or a 60%-rich fructose diet (n = 24 per time point). The animals expectedly developed significant body adiposity (+17%), liver steatosis at 3 and 6 months, hyperleptinemia at 1 and 3 months (two-fold increase) and hyperinsulinemia at 3 and 6 months (up to two-fold increase), but remained normoglycemic and normolipemic. The fructose-fed animals exhibited partial loss of rod sensitivity to light stimulus and reduced amplitude of oscillatory potentials at 6 months. Fructose-fed rats developed significantly more choroidal neovascularization at 14 and 21 days post-laser photocoagulation after 1 and 3 months of diet compared to animals fed the control diet. These results were consistent with infiltration/activation of phagocytic cells and up-regulation of pro-angiogenic gene expression such as Vegf and Leptin in the retina. Our data therefore suggested that metabolic syndrome would exacerbate the development of choroidal neovascularization in our experimental model.

  19. Anti-angiogenic effects of a mutant endostatin: a new prospect for treating retinal and choroidal neovascularization.

    Directory of Open Access Journals (Sweden)

    Yujing Bai

    Full Text Available Pathological fundus angiogenesis is a major cause of vision loss in retina diseases. Endostatin, a C-terminal fragment of collagen XVIII, is an endogenous anti-angiogenic protein. The present study aimed to investigate the in vitro and in vivo anti-angiogenic properties of two proteins: an N-terminal H1D/H3D mutant endostatin (M-ES and a polyethylene glycol propionaldehyde (PEG covalent M-ES (PEG-M-ES.M-ES and PEG-M-ES properties were characterized in vitro using a zinc ion binding assay and a stability test. Activity assays, including migration, proliferation, and tube formation assays, were performed with human retinal microvascular endothelial cells (HRMECs and human umbilical vein endothelial cells (HUVECs. Mouse oxygen-induced retinopathy (OIR and choroidal neovascularization (CNV models were used to evaluate in vivo anti-angiogenic effects. In addition, a rabbit model was used to study the retinal pharmacokinetic profile following an intravitreal injection.The results indicated that the H1D/H3D mutations of endostatin reduced the zinc binding capacity of M-ES and facilitated PEG covalent binding. PEG-M-ES was more stable and persisted longer in the retina compared with M-ES. The in vitro studies demonstrated that M-ES and PEG-M-ES inhibited HRMEC and HUVEC proliferation, migration, and tube formation more efficiently than ES. In vivo, a single intravitreal injection of M-ES and PEG-M-ES significantly decreased neovascularization in both the OIR and CNV animal models.The present study demonstrated for the first time that PEG-M-ES exhibits a long-term inhibitory effect on neovascularization in vitro and in vivo. These data suggest that PEG-M-ES may represent an innovative therapeutic strategy to prevent fundus neovascularization.

  20. Effects of nuclear factor κB expression on retinal neovascularization and apoptosis in a diabetic retinopathy rat model

    Institute of Scientific and Technical Information of China (English)

    Ning; Jiang; Xiao-Long; Chen; Hong-Wei; Yang; Yu-Ru; Ma

    2015-01-01

    AIM: To investigate the expression and role of nuclear factor κB(NF-κB) in diabetic retinopathy(DR) and its relationship with neovascularization and retinal cell apoptosis. METHODS: A total of 80 male Wistar rats were randomly assigned to control(4, 8, 12 and 16 wk, n =10 in each group) and diabetes mellitus(DM) groups(4, 8, 12 and 16wk, n =10 in each group). A diabetic rat model was established by intraperitoneal injection of streptozotocin(60 mg/kg). After 4, 8, 12 and 16 wk, rats were sacrificed.Retinal layers and retinal neovascularization growth were stained with hematoxylin-eosin and examined under light microscopy. Cell apoptosis in the retina was detected by Td T-mediated d UTP nick end labeling, and NF-κB distribution and expression in the retina was determined using immunohistochemistry. RESULTS: DM model success rate up to 100%.Diabetes model at each time point after the experimental groupcompared with the control group, the blood glucose was significantly increased, decreased body weight, each time point showed significant differences compared with the control group(P <0.01). After 12 wk other pathological changes in the retina of diabetic rats were observed; after 16 wk, neovascularization were observed. After 1mo, retinal cell apoptosis was observed.Compared with the control group, NF-κB expression in the DM group significantly increased with disease duration.CONCLUSION: With the prolonging of DM progression,the expression NF-κB increases. NF-κB may be related to retinal cell apoptosis and neovascularization.

  1. Visual Function and Its Relationship with Severity of Early, and Activity of Neovascular, Age-Related Macular Degeneration

    OpenAIRE

    Loughman, James; Sabour-Pickett, Sarah; Nolan, John M.; Klein, Barbara; Klein, Ron; Beatty, Stephen

    2015-01-01

    Purpose: To investigate the relationship between visual function and severity of early age-related macular degeneration (AMD) and activity of neovascular (nv-) AMD. Methods: The following data was collected from 66 eyes of 66 subjects with early AMD and 47 eyes of 47 subjects with active nv-AMD: corrected distance visual acuity (CDVA); contrast sensitivity (CS); glare disability (GD); and retinotopic ocular sensitivity (ROS) of the central 5° of the retina, by microperimetry. Fundus photog...

  2. Ranibizumab for choroidal neovascular membrane in a rare case of Bietti′s crystalline dystrophy: A case report

    Directory of Open Access Journals (Sweden)

    Kasinathan Nachiappan

    2012-01-01

    Full Text Available We report a rare case of Bietti′s crystalline dystrophy presenting with choroidal neovascular membrane (CNVM which was treated with three injections of intravitreal ranibizumab. The CNVM underwent scarring after the injections with stabilization of visual acuity at a follow-up period of 12 months suggesting that intravitreal ranibizumab may have a role in the management of CNVM in these rare cases.

  3. Worsening anatomic outcomes following aflibercept for neovascular age-related macular degeneration in eyes previously well controlled with ranibizumab

    Directory of Open Access Journals (Sweden)

    Nudleman E

    2016-06-01

    Full Text Available Eric Nudleman,1 Jeremy D Wolfe,2,3 Maria A Woodward,4 Yoshihiro Yonekawa,2,3 George A Williams,2,3 Tarek S Hassan2,3 1Department of Ophthalmology, Shiley Eye Center, University of California, San Diego, La Jolla, CA, 2Beaumont Eye Institute, Oakland University William Beaumont School of Medicine, 3Associated Retinal Consultants, Royal Oak, 4Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA Purpose: Antivascular endothelial growth factor injection is the mainstay of treating neovascular age-related macular degeneration (AMD. Previous studies have shown that switching treatment from ranibizumab to aflibercept led to an improvement in eyes with recalcitrant activity. Herein, we identify a unique subset of patients whose eyes with neovascular AMD were previously well controlled with ranibizumab injections were then worsened after being switched to aflibercept. Methods: This is a retrospective interventional case series. Eyes with neovascular AMD, previously well controlled with monthly injections of ranibizumab, which then developed worsening of subretinal fluid after being switched to aflibercept were included. Results: A total of 17 eyes were included. All eyes developed increased subretinal fluid when switched from ranibizumab to aflibercept. Fourteen patients were switched back to ranibizumab after a single injection of aflibercept and had subsequent rapid resolution of subretinal fluid. Three patients continued with monthly aflibercept injections for two subsequent months and demonstrated the persistence of the increased subretinal fluid until they were switched back to treatment with ranibizumab at which time the fluid resolved. No eye had persistent decline in visual acuity. Conclusion: Switching from intravitreal ranibizumab to aflibercept in eyes with well-controlled neovascular AMD may result in worsening in a subset of patients and resolves when therapy is switched back to ranibizumab. Keywords: anti

  4. Intravitreal bevacizumab has initial clinical benefit lasting eight weeks in eyes with neovascular age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    P William Conrad

    2008-06-01

    Full Text Available P William Conrad, David N Zacks, Mark W JohnsonDepartment of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USAPurpose: To determine whether the effect of a single initial intravitreal injection of bevacizumab for neovascular age-related macular degeneration (AMD persists for 8 weeks.Methods: We reviewed the records of 25 consecutive patients with neovascular AMD treated with intravitreal bevacizumab. Patients were included (n = 15 if follow up data were available from 4 and 8 week visits after a single initial injection. Additionally, optical coherence tomography (OCT images were graded qualitatively in a masked fashion by a single reader.Results: Baseline mean visual acuity was 20/200, improving to 20/125 at 4 weeks (p = 0.0153 and 20/100 at 8 weeks (p = 0.0027. Mean central retinal thickness was 316 ± 107 µm at baseline and decreased to 223 ± 70 µm and 206 ± 45 µm at 4 and 8 weeks post-injection, respectively (p = 0.0003 and 0.0005. By masked OCT grading, macular fluid was resolved in 10/15 (66.7% and 11/15 (73.3% eyes at 4 and 8 weeks, respectively, and 3/15 (20% eyes had continued reduction in residual macular fluid between 4 and 8 weeks.Conclusions: A single initial bevacizumab injection has persistent clinical benefit lasting 8 weeks in most eyes with neovascular AMD. Results of prospective randomized studies are needed before changes in treatment regimens can be recommended.Keywords: age-related macular degeneration, bevacizumab, choroidal neovascular membrane, optical coherence tomography

  5. Intravitreal Expansile Gas and Bevacizumab Injection for Submacular Hemorrhage Due to Neovascular Age-related Macular Degeneration

    Directory of Open Access Journals (Sweden)

    Ramin Nourinia

    2010-01-01

    Full Text Available Purpose: To evaluate the results of intravitreal expansile gas injection, with or without recombinant tissue plasminogen activator (rtPA, followed by intravitreal bevacizumab injection for treatment of submacular hemorrhage (SMH secondary to neovascular age-related macular degeneration (AMD. Methods: In this interventional case series, 5 eyes of 5 patients with SMH secondary to choroidal neovascularization (CNV due to neovascular AMD were treated with 0.3 cc intravitreal SF6 (and 50 μg of rtPA in two eyes, followed by face-down positioning; 24 hours later, 1.25 mg of bevacizumab was injected intravitreally. Main outcome measures included displacement of SMH and best corrected visual acuity (BCVA. Results: Mean patient age was 75.6±9.2 (range, 60-83 years, mean duration of symptoms was 6.4±3.2 (range, 3-10 days, and mean number of bevacizumab injections was 1.8 (range, 1-3. Mean preoperative BCVA was 1.28±0.27 logMAR which improved significantly to 0.57±0.33 logMAR at 12 months (P=0.042. SMH displacement occurred in all eyes, and visual acuity improved and remained stable during the follow-up period of 12 months. Conclusion: Intravitreal expansile gas injection, with or without rtPA, followed by intravitreal bevacizumab injection, seems to be an effective modality for SMH displacement and treatment of the underlying CNV in neovascular AMD.

  6. Clinical Observation on Cyclocryotherapy and Trabeculectomy Combined with Wufeng Jueming and Raw Typha Decoction for 15 Cases of Neovascular Glaucoma%睫状体冷凝及小梁切除术联合乌风决明合生蒲黄汤治疗新生血管性青光眼15例临床观察

    Institute of Scientific and Technical Information of China (English)

    陈宗贤; 张敏; 向红; 李雪娜

    2013-01-01

    differences between groups in IOP after one month or six months of treatment (P0. 05). There were 9 cases (60. 00%) of complete regression of iris neovascularization, 4 cases (26. 67%) of partial regression of iris neovascularization and 2 cases (13. 33%) without regression of iris neovascularization after 6 months in the test group. There were 3 cases (20.00%) of complete regression of iris neovascularization, 7 cases (46. 67%) of partial regression of iris neovascularization and 5 cases (33. 33%) without regression of iris neovascularization after 6 months in the control group. There was a significant difference between groups in the regression of iris neovascularization after treatment (P<0. 05). Conlcusion The combo therapy of cyclocryotherapy, trabeculectomy, Wufeng Jueming and Raw Typha Decoction is effective for neovascular glaucoma with controlling the IOP, relieving the pain and promoting the regression of iris neovascularization.

  7. Prorenin induces ERK activation in endothelial cells to enhance neovascularization independently of the renin-angiotensin system

    Energy Technology Data Exchange (ETDEWEB)

    Uraoka, Maki [Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566 (Japan); Ikeda, Koji, E-mail: ikedak@koto.kpu-m.ac.jp [Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566 (Japan); Nakagawa, Yusuke; Koide, Masahiro; Akakabe, Yoshiki; Nakano-Kurimoto, Ritsuko; Takahashi, Tomosaburo; Matoba, Satoaki; Yamada, Hiroyuki; Okigaki, Mitsuhiko; Matsubara, Hiroaki [Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566 (Japan)

    2009-12-25

    Prorenin is an enzymatically inactive precursor of renin, and its biological function in endothelial cells (ECs) is unknown despite its relevance with the incidence of diabetic microvascular complications. Recently, (pro)renin receptor was identified, and the receptor-associated prorenin system has been discovered, whereas its expression as well as function in ECs remain unclear. In the present study, we found that ECs express the (pro)renin receptor, and that prorenin provoked ERK activation through (pro)renin receptor independently of the renin-angiotensin system (RAS). Prorenin stimulated the proliferation, migration and tube-formation of ECs, while it inhibited endothelial apoptosis induced by serum and growth factor depletion. MEK inhibitor abrogated these proangiogenic effects of prorenin, while AT1 receptor antagonist or angiotensin-converting enzyme inhibitor failed to block them. In vivo neovascularization in the Matrigel-plugs implanted into mouse flanks was significantly enhanced by prorenin, in which significant ERK activation was detected in ECs. Furthermore, tumor xenografts stably transfected with prorenin demonstrated the significantly accelerated growth rate concomitantly with enhanced intratumoral neovascularization. Our data demonstrated that the RAS-independent (pro)renin receptor-mediated signal transduction plays a pivotal role in the regulation of ECs function as well as in the neovascularization, and thus prorenin is potentially involved in the pathophysiology of diabetic microvascular complications as well as cancers.

  8. The effect of subconjunctival bevacizumab on corneal neovascularization, inflammation and re-epithelization in a rabbit model

    Directory of Open Access Journals (Sweden)

    Glauco Reggiani Mello

    2011-01-01

    Full Text Available PURPOSE: To evaluate the use of subconjunctival bevacizumab on corneal neovascularization in an experimental rabbit model for its effect on vessel extension, inflammation, and corneal epithelialization. METHODS: In this prospective, randomized, blinded, experimental study, 20 rabbits were submitted to a chemical trauma with sodium hydroxide and subsequently divided into two groups. The experimental group received a subconjunctival injection of bevacizumab (0.15 m; 3.75 mg, and the control group received an injection of 0.15 ml saline solution. After 14 days, two blinded digital photograph analyses were conducted to evaluate the inflammation/diameter of the vessels according to pre-established criteria. A histopathological analysis of the cornea evaluated the state of the epithelium and the number of polymorphonuclear cells. RESULTS: A concordance analysis using Kappa's statistic showed a satisfactory level of agreement between the two blinded digital photography analyses. The neovascular vessel length was greater in the control group (p<0.01 than in the study group. However, the histopathological examination revealed no statistically significant differences between the groups in terms of the state of the epithelium and the number of polymorphonuclear cells. CONCLUSIONS: Subconjunctival bevacizumab inhibited neovascularization in the rabbit cornea. However, this drug was not effective at reducing inflammation. The drug did not induce persistent corneal epithelial defects.

  9. Corneal Neovascularization Suppressed by TIMP2 Released from Human Amniotic Membranes

    Institute of Scientific and Technical Information of China (English)

    Xiang Ma; Jun Li

    2005-01-01

    Purpose: To investigate the effects of culture medium of human amniotic membrane (AM) on corneal neovascularization (CNV) induced by basic fibroblast growth factor (bFGF) in mice.Methods: Culture medium of amniotic membrane was prepared by cultivating AM (with epithelium side up) in EGM basic medium for 3 days, and was collected separately to three groups, e.g. Control (EGM only), AM with epithelium (AM) and AM without epithelium (De-AM). Corneal neovascularization was induced in mice by using micropocket assay with Hydron polymer pellets containing 100 ng bFGF. Migration and proliferation of human umbilical cord vein endothelial cells (HUVEC) were performed in Boyden chambers and by using the CyQUANT fluorescence binding assay respectively.The levels of tissue inhibitors of metalloproteinase 1 and 2 (TIMP1, TIMP2) in culture medium were determined by ELISA assay.Results: CNV induced by bFGF was significantly suppressed by culture medium of amniotic membrane. When the medium was applied as an eyedrop 4 times a day for 7 days,the area of CNV was (2.48±0.76) mm2,(0.64±0.52) mm2 and (1.96±0.65) mm2 incontrol, AM and De-AM group respectively. The migration and proliferation of HUVEC were strongly inhibited by culture medium of AM with epithelium, while the De-AM had no effect on the migration of HUVEC cells. The high level of TIMP2 was found in AM group, but not in De-AM group, while there was no difference in the amount of TIMP1 in medium among three groups.Conclusion: Culture medium of amniotic membrane significantly suppresses the corneal nevovascularization induced by bFGF. The mechanism of which at least in part is that high level of TIMP2 protein secreted or released into the culture medium of AM and inhibition of migration and growth of vascular endothelial cells.

  10. A prospective comparative study on neovascular glaucoma and nonneovascular refractory glaucoma following Ahmed glaucoma valve implantation

    Institute of Scientific and Technical Information of China (English)

    Li Zheng; Zhou Minwen; Wang Wei; Huang Wenbin; Chen Shida; Li Xingyi; Gao Xinbo

    2014-01-01

    Background Neovascular glaucoma is a refractory disease,and difficult to manage.The aim of this study was to evaluate the clinical outcomes of Ahmed glaucoma valve implantation (AGVI) in neovascular glaucoma (NVG) and nonNVG patients.Methods This prospective,non-randomized study included 55 eyes of 55 patients with refractory glaucoma; 27 had NVG (NVG group) and 28 had non-NVG (non-NVG group).All of the patients underwent AGVI.The NVG group was adjunctively injected with intravitreal ranibizumab/bevacizumab (IVR/IVB) before AGVI.Intraocular pressure (IOP) was the primary outcome measure in this study.Surgical success rate,number of antiglaucoma medications used,best corrected visual acuity (BCVA),and postoperative complications were analyzed between the groups.Results All of the patients completed the study (follow-up of 12 months).Kaplan-Meier survival curve analysis indicated that the qualified success rates in the NVG and non-NVG groups at 12 months were 70.5% and 92.9%,respectively; this difference was significant (P=0.036).The complete success rates in the NVG and non-NVG groups at 12 months were 66.7% and 89.3%,respectively (P=0.049).Compared with preoperative examinations,the postoperative mean IOP and use of medications were significantly lower at all follow-up time points in both groups (all P <0.05).There were significant differences in BCVA between the two groups at the 12-month follow-up (x2=9.86,P=0.020).Cox proportional hazards regression showed NVG as a risk factor for surgical failure (RR=15.08,P=0.033).Postoperative complications were similar between the two groups.Conclusions AGVI is a safe and effective procedure in refractory glaucoma,but the success rate of surgery was related to the type of refractory glaucoma.The complete and qualified success rates of NVG patient adjunctive anti-vascular endothelial growth factor treatment are still lower than those of non-NVG patients.

  11. Bevacizumab treatment reduces retinal neovascularization in a mouse model of retinopathy of prematurity

    Institute of Scientific and Technical Information of China (English)

    Fei; Feng; Yan; Cheng; Qing-Huai; Liu

    2014-01-01

    ·AIM: To evaluate the effect of different bevacizumab concentrations on retinal neovascularization in a retinopathy of prematurity(ROP) mouse model.·METHODS: A total of 60 of C57BL/6 J mice were exposed to 75% ±2% oxygen from postnatal d7 to postnatal d12. Fifteen nonexposed mice served as negative controls(group A). On d12, 30 mice(group C)were injected with 2.5 μg intravitreal bevacizumab(IVB),30 mice(group D) were injected with 1.25 μg IVB in one eye. The contralateral eyes were injected with balanced salt solution(BSS)(control group =group B). The adenosine diphosphatase(ADPase) histochemical technique was used for retinal flat mount to assess the oxygen-induced changes of retinal vessels.Neovascularization was quantified by counting the endothelial cell proliferation on the vitreal side of the inner limiting membrane of the retina. Histological changes were examined by light microscopy. The mRNA levels of vascular endothelial growth factor(VEGF) were quantified by Real-time PCR. Western-blotting analysis was performed to examine the expression of P-VEGFR.· RESULTS: Comparing with the control group B,regular distributions and reduced tortuosity of vessels were observed in our retinal flat mounts in groups C and D. The endothelial cell count per histological section was lower in groups C(P <0.0001) and D(P <0.0001) compared with the control group B. Histological evaluation showed no retinal toxicity in any group. In all oxygen treated groups VEGF mRNA expression was significantly increased as compared to age-matched controls. No significant change in VEGF mRNA expression could be achieved in either of the treatments or the oxygen controls. The results of the Western blot were consistent with that of the Real-time PCR analysis.·CONCLUSION: An intravitreal injection of bevacizumab is able to reduce angioproliferative retinopathy in a mouse model for oxygen-induced retinopathy.

  12. Targeting non-canonical nuclear factor-κB signalling attenuates neovascularization in a novel 3D model of rheumatoid arthritis synovial angiogenesis.

    Science.gov (United States)

    Maracle, Chrissta X; Kucharzewska, Paulina; Helder, Boy; van der Horst, Corine; Correa de Sampaio, Pedro; Noort, Ae-Ri; van Zoest, Katinka; Griffioen, Arjan W; Olsson, Henric; Tas, Sander W

    2017-02-01

    Angiogenesis is crucial in RA disease progression. Lymphotoxin β receptor (LTβR)-induced activation of the non-canonical nuclear factor-κB (NF-κB) pathway via NF-κB-inducing kinase (NIK) has been implicated in this process. Consequently, inhibition of this pathway may hold therapeutic potential in RA. We describe a novel three-dimensional (3D) model of synovial angiogenesis incorporating endothelial cells (ECs), RA fibroblast-like synoviocytes (RAFLSs) and RA synovial fluid (RASF) to further investigate the contributions of NF-κB in this process. Spheroids consisting of RAFLSs and ECs were stimulated with RASF, the LTβR ligands LTβ and LIGHT, or growth factor bFGF and VEGF, followed by quantification of EC sprouting using confocal microscopy and digital image analysis. Next, the effects of anginex, NIK-targeting siRNA (siNIK), LTβR-Ig fusion protein (baminercept) and a novel pharmacological NIK inhibitor were investigated. RASF significantly promoted sprout formation, which was blocked by the established angiogenesis inhibitor anginex (P factors (P model of synovial angiogenesis incorporating RAFLSs, ECs and RASF that mimics the in vivo situation. Using this system, we demonstrate that non-canonical NF-κB signalling promotes neovascularization and show that this model is useful for dissecting relative contributions of signalling pathways in specific cell types to angiogenic responses and for testing pharmacological inhibitors of angiogenesis. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. Intravitreal ranibizumab for symptomatic drusenoid pigment epithelial detachment without choroidal neovascularization in age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Roberto Gallego-Pinazo

    2011-02-01

    Full Text Available Roberto Gallego-Pinazo1,2, Ana Marina Suelves-Cogollos1, Ester Francés-Muñoz1, J María Millán2,3, J Fernando Arevalo4, J Luis Mullor5, Manuel Díaz-Llopis1,2,61Department of Ophthalmology, Hospital Universitario La Fe, Valencia, Spain; 2Centro de Investigación Biomédica en Red de Enfermedades Raras, Valencia, Spain; 3Department of Genetics, Hospital Universitario La Fe, Valencia, Spain; 4Retina and Vitreous Service, Clínica Oftalmológica Centro Caracas, Caracas, Venezuela; 5Unit of Experimental Ophthalmology, Fundación para la Investigación del Hospital Universitario La Fe, Valencia, Spain; 6University of Valencia, Faculty of Medicine, Valencia, SpainBackground: The aim of our study was to evaluate the functional and anatomic outcomes of intravitreal ranibizumab for the treatment of symptomatic drusenoid pigment epithelial detachment without choroidal neovascularization in age-related macular degeneration.Methods: This was a prospective, single-center, uncontrolled, interventional pilot study. Six consecutive eyes (six patients with drusenoid pigment epithelial detachment with a visual acuity of 20/63 to 20/100 and no evidence of choroidal neovascularization in age-related macular degeneration participated. Patients were given at least one intravitreal ranibizumab injection and were followed for a mean of 66.67 ± 10.3 weeks. Main outcome measures included best-corrected visual acuity (BCVA measured by Early Treatment Diabetic Retinopathy Study charts and optical coherence tomography, and central macular thickness measured by optical coherence tomography.Results: The mean number of intravitreal ranibizumab injections was 3.0 at the end of follow-up. Regarding BCVA and optical coherence tomography, 33.3% of eyes gained between 19 and 21 letters of BCVA, with a median decrease in central macular thickness of 21 µm. There was a statistically significant difference between baseline and final BCVA (P = 0.046. There was a positive

  14. Choroidal neovascularization in pathologic myopia: intravitreal ranibizumab versus bevacizumab--a randomized controlled trial.

    Science.gov (United States)

    Gharbiya, Magda; Giustolisi, Rosalia; Allievi, Francesca; Fantozzi, Nicoletta; Mazzeo, Luigi; Scavella, Vittorio; Gabrieli, Corrado Balacco

    2010-03-01

    To compare the short-term efficacy and safety of intravitreal ranibizumab versus bevacizumab in treating myopic choroidal neovascularization (CNV). Prospective, comparative, randomized, interventional study. Thirty-two eyes from 32 patients with myopic CNV were consecutively enrolled and randomly treated, in a 1:1 ratio, with intravitreal ranibizumab (0.5 mg) or bevacizumab (1.25 mg) as needed, after the first injection. ETDRS best-corrected visual acuity (BCVA), foveal center thickness (FCT) on optical coherence tomography (OCT), and fluorescein angiographic findings were examined before and after treatment. Patients were followed up for 6 months. No statistically significant difference in the BCVA improvement, as well as in the FCT reduction, was found between groups during follow-up (P value at 1, 3, 6 months > .05). Complete resolution of fluorescein leakage was observed in all 16 bevacizumab-treated eyes and in 15 out of 16 (93.7%) ranibizumab-treated eyes. No ocular or systemic adverse effects from treatment were encountered. This randomized clinical study cannot determine a statistically significant difference in anti-VEGF treatment effect between ranibizumab and bevacizumab for the treatment of CNV secondary to pathologic myopia. A larger study is required to determine the relative efficacy and duration of action of these drugs. (c) 2010 Elsevier Inc. All rights reserved.

  15. Monitoring neovascularization in aggressive posterior retinopathy of prematurity using optical coherence tomography angiography.

    Science.gov (United States)

    Vinekar, Anand; Chidambara, Lavanya; Jayadev, Chaitra; Sivakumar, Munusamy; Webers, Carroll A B; Shetty, Bhujang

    2016-06-01

    We describe the use of optical coherence tomography angiography (OCTA) in detecting and monitoring regression of the neovascular complex (NVC) in a case of aggressive posterior retinopathy of prematurity (AP-ROP). A premature Asian Indian girl with AP-ROP underwent laser photoablation at 26 days of life. Persistent NVC at the posterior border of the lasered retinal bed was detected clinically. On en face spectral domain optical coherence tomography (SD-OCT) and OCTA, the NVC appeared as an arborizing vascular net in the superficial capillary plexus. The deep capillary plexus and outer retinal layers showed corresponding flow outlines that suggested deeper extensions of the lesion. Supplemental laser treatment of the NVC was performed. Ten days later repeat en face SD-OCT and OCTA of the identical retinal location revealed that the vascular tortuosity and dilatation had reduced and that the flow lesions in the deeper layers were undetectable. Our findings in this case suggest that the NVC in AP-ROP extends beyond the superficial retina.

  16. Visual Performance in Patients with Neovascular Age-Related Macular Degeneration Undergoing Treatment with Intravitreal Ranibizumab

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    Sarah Sabour-Pickett

    2013-01-01

    Full Text Available Purpose. To assess visual function and its response to serial intravitreal ranibizumab (Lucentis, Genentech in patients with neovascular age-related macular degeneration (nv-AMD. Methods. Forty-seven eyes of 47 patients with nv-AMD, and corrected distance visual acuity (CDVA logMAR 0.7 or better, undergoing intravitreal injections of ranibizumab, were enrolled into this prospective study. Visual function was assessed using a range of psychophysical tests, while mean foveal thickness (MFT was determined by optical coherence tomography (OCT. Results. Group mean (±sd MFT reduced significantly from baseline (233 (±59 to exit (205 (±40 (P=0.001. CDVA exhibited no change between baseline and exit visits (P=0.48 and P=0.31, resp.. Measures of visual function that did exhibit statistically significant improvements (P<0.05 for all included reading acuity, reading speed, mesopic and photopic contrast sensitivity (CS, mesopic and photopic glare disability (GD, and retinotopic ocular sensitivity (ROS at all eccentricities. Conclusion. Eyes with nv-AMD undergoing intravitreal ranibizumab injections exhibit improvements in many parameters of visual function. Outcome measures other than CDVA, such as CS, GD, and ROS, should not only be considered in the design of studies investigating nv-AMD, but also in treatment and retreatment strategies for patients with the condition.

  17. Extracellular superoxide dismutase deficiency impairs wound healing in advanced age by reducing neovascularization and fibroblast function.

    Science.gov (United States)

    Fujiwara, Toshihiro; Duscher, Dominik; Rustad, Kristine C; Kosaraju, Revanth; Rodrigues, Melanie; Whittam, Alexander J; Januszyk, Michael; Maan, Zeshaan N; Gurtner, Geoffrey C

    2016-03-01

    Advanced age is characterized by impairments in wound healing, and evidence is accumulating that this may be due in part to a concomitant increase in oxidative stress. Extended exposure to reactive oxygen species (ROS) is thought to lead to cellular dysfunction and organismal death via the destructive oxidation of intra-cellular proteins, lipids and nucleic acids. Extracellular superoxide dismutase (ecSOD/SOD3) is a prime antioxidant enzyme in the extracellular space that eliminates ROS. Here, we demonstrate that reduced SOD3 levels contribute to healing impairments in aged mice. These impairments include delayed wound closure, reduced neovascularization, impaired fibroblast proliferation and increased neutrophil recruitment. We further establish that SOD3 KO and aged fibroblasts both display reduced production of TGF-β1, leading to decreased differentiation of fibroblasts into myofibroblasts. Taken together, these results suggest that wound healing impairments in ageing are associated with increased levels of ROS, decreased SOD3 expression and impaired extracellular oxidative stress regulation. Our results identify SOD3 as a possible target to correct age-related cellular dysfunction in wound healing.

  18. The neurotrophic receptor Ntrk2 directs lymphoid tissue neovascularization during Leishmania donovani infection.

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    Jane E Dalton

    2015-02-01

    Full Text Available The neurotrophic tyrosine kinase receptor type 2 (Ntrk2, also known as TrkB and its ligands brain derived neurotrophic factor (Bdnf, neurotrophin-4 (NT-4/5, and neurotrophin-3 (NT-3 are known primarily for their multiple effects on neuronal differentiation and survival. Here, we provide evidence that Ntrk2 plays a role in the pathologic remodeling of the spleen that accompanies chronic infection. We show that in Leishmania donovani-infected mice, Ntrk2 is aberrantly expressed on splenic endothelial cells and that new maturing blood vessels within the white pulp are intimately associated with F4/80(hiCD11b(loCD11c(+ macrophages that express Bdnf and NT-4/5 and have pro-angiogenic potential in vitro. Furthermore, administration of the small molecule Ntrk2 antagonist ANA-12 to infected mice significantly inhibited white pulp neovascularization but had no effect on red pulp vascular remodeling. We believe this to be the first evidence of the Ntrk2/neurotrophin pathway driving pathogen-induced vascular remodeling in lymphoid tissue. These studies highlight the therapeutic potential of modulating this pathway to inhibit pathological angiogenesis.

  19. Evaluation of Idiopathic Choroidal Neovascularization with Indocyanine Green Angiography in Patients Undergoing Bevacizumab Therapy

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    Ryan B. Rush

    2015-01-01

    Full Text Available Purpose. To examine the clinical implications of change in choroidal neovascularization (CNV size on indocyanine green (ICG angiography in subjects with idiopathic CNV undergoing bevacizumab therapy. Methods. The charts of subjects with an idiopathic CNV treated by a modified PRN regimen with intravitreal bevacizumab over a 12-month period were retrospectively reviewed. Results. There were 34 subjects included in the analysis. Baseline CNV sizes of less than 1.0 mm2 on ICG angiography correlated with complete CNV resolution (P=0.0404, fewer injections delivered (P=0.0002, and better Snellen visual acuity (P=0.0098 at 12 months. Subjects that experienced a 33% or more reduction in CNV size on ICG angiography at 2 months had complete CNV resolution (P=0.0047 and fewer injections (P<0.0001 at 12 months compared to subjects that did not experience a 33% or more reduction in CNV size on ICG angiography at 2 months. Conclusions. Smaller baseline CNV size on ICG angiography resulted in better visual acuity and fewer injections at 12 months, and a reduction of 33% or more in CNV size after 2 months may predict a better clinical course in subjects with idiopathic CNV undergoing bevacizumab therapy.

  20. Inflammatory choroidal neovascular membrane in posterior uveitis-pathogenesis and treatment

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    Dhingra Narendra

    2010-01-01

    Full Text Available Choroidal neovascular membrane (CNVM formation is a well-documented sight-threatening complication of posterior segment intraocular inflammation (PSII. The aim of this article is to review the basic and clinical science literature on the pathogenesis of CNVM formation in PSII and to present results of a case series. We searched the literature using the mesh terms- inflammation, CNVM, age-related macular degeneration, immunosuppression, photodynamic therapy, steroids, vascular endothelial growth factors and posterior uveitis. Additionally, we evaluated the visual outcome of and clinical response to our standard treatment protocol involving a combination treatment for young patients with inflammatory CNVM. The development of CNVM in PSII is promulgated by infiltrating myeloid cells as well as choroidal and retinal myeloid cell activation, subsequent vascular endothelial growth factors, cytokine and chemokine production and complement activation acting in consort to mediate angiogenic responses. No clear standard of care currently exists for the treatment of inflammatory CNVM and various combinations have been tried. Using our combination treatment, visual acuity improved in four, stabilized in one and worsened in four patients. Though significant advances have occurred in the understanding of the pathogenesis and management of this condition, optimizing therapeutic regimens will require further well-constructed prospective cohort series.

  1. Antiangiogenic immunotherapy targeting Flk-1, DNA vaccine and adoptive T cell transfer, inhibits ocular neovascularization

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    Zhang, Han [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan); Sonoda, Koh-Hei, E-mail: sonodak@med.kyushu-u.ac.jp [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan); Hijioka, Kuniaki; Qiao, Hong; Oshima, Yuji; Ishibashi, Tatsuro [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan)

    2009-04-17

    Ocular neovascularization (NV) is the primary cause of blindness in a wide range of ocular diseases. The exact mechanism underlying the pathogenesis of ocular NV is not yet well understood, and so there is no satisfactory therapy for ocular NV. Here, we describe a strategy targeting Flk-1, a self-antigen overexpressed on proliferating endothelial cells in ocular NV, by antiangiogenic immunotherapy-DNA vaccine and adoptive T cell therapy. An oral DNA vaccine encoding Flk-1 carried by attenuated Salmonella typhimurium markedly suppressed development of laser-induced choroidal NV. We further demonstrated that adoptive transfer of vaccine-induced CD8{sup +} T cells reduced pathological preretinal NV, with a concomitant facilitation of physiological revascularization after oxygen-induced retinal vessel obliteration. However, physiological retinal vascular development was unaffected in neonatal mice transferred with vaccine-induced CD8{sup +} T cells. These findings suggested that antiangiogenic immunotherapy targeting Flk-1 such as vaccination and adoptive immunotherapy may contribute to future therapies for ocular NV.

  2. Choroidal neovascularization induced by immunogenic alteration of the retinal pigment epithelium in dengue Fever.

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    Veloso, Carlos Eduardo; Schmidt-Erfurth, Ursula; Nehemy, Márcio B

    2015-01-01

    To report the first case of choroidal neovascularization (CNV) secondary to dengue fever. A 54-year-old female was referred to our department with blurred vision and metamorphopsia in her left eye. Two weeks earlier, she had presented all of the classic symptoms of dengue fever including a positive serology. Her best-corrected visual acuity (BCVA) was 20/150 in the left eye. She underwent a fundus examination, fluorescein angiography (FA) and spectral domain optical coherence tomography. All findings were consistent with CNV secondary to dengue fever. FA revealed a classic CNV associated with focal retinal pigment epithelium (RPE) destruction and detachment. Three consecutive monthly injections of intravitreal ranibizumab resulted in functional and anatomical improvement for as long as 6 months with a BCVA of 20/25. However, CNV recurred 2 years later, again with an improvement after ranibizumab therapy, but with persistence of a fibrovascular RPE detachment, highlighting the pathomechanism of a classic CNV formation. Maculopathy in dengue fever may be followed by CNV as a result of the immunologic alteration of the RPE. Physicians should be aware of this manifestation to be able to initiate adequate treatment with excellent functional and anatomical results.

  3. Functional expression of a proliferation-related ligand in hepatocellular carcinoma and its implications for neovascularization

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    Hiroshi Okano; Norihiko Yamamoto; Kazushi Sugimoto; Kazumoto Murata; Takeshi Nakano; Katsuya Shiraki; Yutaka Yamanaka; Hidekazu Inoue; Tomoyuki Kawakita; Yukiko Saitou; Yumi Yamaguchi; Naoyuki Enokimura; Keiichi Ito

    2005-01-01

    AIM: To detect the expression of a proliferation-related ligand on human hepatocellular carcinoma (HCC) cell lines (SK-Hep1, HLE and HepG2) and in culture medium.METHODS: APRIL expression was analyzed by Western blotting in HCC cell lines. Effects of APRIL to cell count and angiogenesis were analyzed, too.RESULTS: Recombinant human APRIL (rhAPRIL) increased cell viability of HepG2 cells and, in HUVEC, rhAPRIL provided slight tolerance to cell death from serum starvation. Soluble APRIL (sAPRIL) from HLE cells increased after serum starvation, but did not change in SK-Hep1 or HepG2 cells. These cells showed down-regulation of VEGF after incubation with anti-APRIL antibody.Furthermore, culture medium from the HCC cells treated with anti-APRIL antibody treatment inhibited tube formation of HUVECs.CONCLUSION: Functional expression of APRIL might contribute to neovascularization via an upregulation of VEGF in HCC.

  4. Bevacizumab (Avastin and Thermal Laser Combination Therapy for Peripapillary Choroidal Neovascular Membranes

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    Sean D. Adrean

    2017-01-01

    Full Text Available Objective. This is a retrospective interventional case series describing the results of 5 eyes from 5 patients with symptomatic peripapillary choroidal neovascularization (CNVM receiving initial bevacizumab treatment followed by thermal laser and bevacizumab combination therapy. Methods. Patients received intravitreal bevacizumab injections until the lesions were well-defined. Thermal laser ablation was then administered and followed by an additional bevacizumab injection after one week. Visual outcomes, OCT changes, and rates of recurrence were recorded and analyzed. Results. Median visual outcomes improved from 20/50 to 20/30 (p=0.0232. Median central macular thickness decreased from 347 μm to 152 μm (p=0.0253. The mean visual improvement was 3 lines. An average of 3.8 bevacizumab injections per patient were given overall. Patients were followed for an average of 24 months, during which all eyes were absent for recurrence. Conclusion. Symptomatic peripapillary CNVM may be successfully managed with bevacizumab followed by a combination of thermal laser and bevacizumab without the need for frequent retreatment. The area requiring treatment may be better defined using bevacizumab, limiting the ablation of the healthy retina and improving treatment margins. With this treatment regimen, the patients experience improved visual outcomes and have a low rate of recurrence.

  5. Quantitative evaluation and modeling of two-dimensional neovascular network complexity: the surface fractal dimension

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    Franceschini Barbara

    2005-02-01

    Full Text Available Abstract Background Modeling the complex development and growth of tumor angiogenesis using mathematics and biological data is a burgeoning area of cancer research. Architectural complexity is the main feature of every anatomical system, including organs, tissues, cells and sub-cellular entities. The vascular system is a complex network whose geometrical characteristics cannot be properly defined using the principles of Euclidean geometry, which is only capable of interpreting regular and smooth objects that are almost impossible to find in Nature. However, fractal geometry is a more powerful means of quantifying the spatial complexity of real objects. Methods This paper introduces the surface fractal dimension (Ds as a numerical index of the two-dimensional (2-D geometrical complexity of tumor vascular networks, and their behavior during computer-simulated changes in vessel density and distribution. Results We show that Ds significantly depends on the number of vessels and their pattern of distribution. This demonstrates that the quantitative evaluation of the 2-D geometrical complexity of tumor vascular systems can be useful not only to measure its complex architecture, but also to model its development and growth. Conclusions Studying the fractal properties of neovascularity induces reflections upon the real significance of the complex form of branched anatomical structures, in an attempt to define more appropriate methods of describing them quantitatively. This knowledge can be used to predict the aggressiveness of malignant tumors and design compounds that can halt the process of angiogenesis and influence tumor growth.

  6. CD105与脉络膜新生血管%CD105 and choroidal neovascularization

    Institute of Scientific and Technical Information of China (English)

    徐建锋; 王雨生

    2008-01-01

    CD105(endoglin)为一种同型二聚体的膜结合性糖蛋白,是转化生长因子-β(transforming growth factor, TGF-β)受体超家族的成员之一.它参与TGF-β受体的信号转导,调节细胞对TGF-β的反应,在新生血管组织及肿瘤组织边缘部分血管起源的内皮细胞中高度表达,是新生血管的标志物之一.脉络膜新生血管(choroidal neovascularization, CNV)的生成是年龄相关性黄斑变性(age-related macular degeneration, AMD)、眼拟组织胞浆菌病综合征(presumed ocular histoplasmosis syndrome, POHS)和病理性近视黄斑变性等CNV相关疾病的的主要病理特征.近年研究表明,CD105与CNV密切相关,可能成为治疗CNV重要的靶分子之一.

  7. Investigation of polymeric scaffold degradation for drug delivery and neovascularization applications

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    Bulusu, Kartik V.; Alibouzar, Mitra; Castro, Nathan J.; Zhang, Lijie G.; Sarkar, Kausik; Plesniak, Michael W.

    2016-11-01

    Degradable polymer-based prosthetics for the treatment of osseous tissue defects, maxillo-/cranio-facial trauma and brain injury face two common clinical obstacles impeding efficient tissue engraftment i.e., controlled material release and neovascularization. Ascertaining the time scales of polymer degradation for controlled delivery of drugs and nutrients is critical to treatment efficacy and strategy. We incorporated multiple experimental methodologies to understand the driving forces of transport mechanisms in polyvinyl alcohol-based (PVA) 3D-printed scaffolds of different porosity. Scaffold degradation was monitored various pulsatile flow conditions using MEMS-based pressure catheters and an ultrasonic flow rate sensor. Ultrasonic properties (bulk attenuation and sound velocity) were measured to monitor the degradation process in a static, alkaline medium. Viscosity and the absorption spectra variations with PVA-solute concentrations were measured using a rheometer and a spectrophotometer, respectively. A simple mathematical model based on Fick's law of diffusion provides the fundamental description of solute transport from the scaffold matrices. However, macroscopic material release could become anomalous or non-Fickian in complex polymeric scaffold matrices. Supported by the GW Center for Biomimetics and Bioinspired Engineering and NIH Director's New Innovator Award 1DP2EB020549-01.

  8. Efficacy of intravitreal Ranibizumab injection for choroidal neovascularization secondary to pathologic myopia

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    Li-Hong Cui

    2016-03-01

    Full Text Available AIM:To observe the efficacy and safety of intravitreal Ranibizumab injection in patiens with choroidal neovascularization(CNVsecondary to pathologic myopia.METHODS:In this retrospective and comparative study,24 patients(25 eyeswith CNV secondary to pathologic myopia were enrolled. All patients were assessed by examinations of ETDRS visual acuity chart, preplaced-mirror ophthalmoscopy, fundus fluorescein angiography(FFA, indocyanine green angiography(ICGAand optical coherence tomography(OCT. Patiens received intravitreally injected ranibizumab 0.5mg(0.05mL. Treatments were repeated if the follow-up indicated that it was necessary. The follow-up periods were 4~10mo. Best corrected visual acuity(BCVA, central macular thickness(CMTand leakage of CNV before and after the treatment were compared. RESULTS:No local or systemic complications occurred in any patients during the treatment or follow-up. The average time of injection was 1.52. The mean BCVA was 23.93±12.46 letters before the therapy. In the last follow-up, the mean BCVA was 40.63±7.25 letters, improved by 14.27±9.36 letters and the difference was statically significant(t=5.74, Pt=3.96, PCONCLUSION:Intravitreal ranibizumab injection for CNV secondary to pathologic myopia is safe and effective, and this treatment can improve visual acuity, reduce retina edema and leakage of CNV.

  9. Caregiver Burden in Patients Receiving Ranibizumab Therapy for Neovascular Age Related Macular Degeneration.

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    Rishma Gohil

    Full Text Available To assess the caregiver burden and factors determining the burden in patients receiving ranibizumab therapy for neovascular AMD (nAMD.This is a cross-sectional questionnaire survey of 250 matched patient caregiver dyads across three large ophthalmic treatment centres in United Kingdom. The primary outcome was the subjective caregiver burden measured using caregiver reaction assessment scale (CRA. Objective caregiver burden was determined by the caregiver tasks and level of care provided. The factors that may predict the caregiver burden such as the patient's visual acuity of the better eye and vision related quality of life, demographics, satisfaction and support provided by the healthcare and the health status of the dyads were also collected and assessed in a hierarchical regression model.The mean CRA score was 3.2±0.5, similar to the score reported by caregivers for atrial fibrillation who require regular hospital appointments for monitoring their thromboprophylaxis. Caregiver tasks including accompanying for hospital appointments for eye treatment and patient's visual acuity in the better eye were the biggest contributors to the caregiver burden hierarchical model explaining 18% and 11% of the variance respectively.Ranibizumab therapy for nAMD is associated with significant caregiver burden. Both disease impact and treatment frequency contributed to the overall burden.

  10. Visual performance in patients with neovascular age-related macular degeneration undergoing treatment with intravitreal ranibizumab.

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    Sabour-Pickett, Sarah; Loughman, James; Nolan, John M; Stack, Jim; Pesudovs, Konrad; Meagher, Katherine A; Beatty, Stephen

    2013-01-01

    Purpose. To assess visual function and its response to serial intravitreal ranibizumab (Lucentis, Genentech) in patients with neovascular age-related macular degeneration (nv-AMD). Methods. Forty-seven eyes of 47 patients with nv-AMD, and corrected distance visual acuity (CDVA) logMAR 0.7 or better, undergoing intravitreal injections of ranibizumab, were enrolled into this prospective study. Visual function was assessed using a range of psychophysical tests, while mean foveal thickness (MFT) was determined by optical coherence tomography (OCT). Results. Group mean (±sd) MFT reduced significantly from baseline (233 (±59)) to exit (205 (±40)) (P = 0.001). CDVA exhibited no change between baseline and exit visits (P = 0.48 and P = 0.31, resp.). Measures of visual function that did exhibit statistically significant improvements (P disability (GD), and retinotopic ocular sensitivity (ROS) at all eccentricities. Conclusion. Eyes with nv-AMD undergoing intravitreal ranibizumab injections exhibit improvements in many parameters of visual function. Outcome measures other than CDVA, such as CS, GD, and ROS, should not only be considered in the design of studies investigating nv-AMD, but also in treatment and retreatment strategies for patients with the condition.

  11. En face OCT angiography demonstrates flow in early type 3 neovascularization (retinal angiomatous proliferation)

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    Dansingani, K K; Naysan, J; Freund, K B

    2015-01-01

    Introduction The characteristics of type 3 neovascularization (NV), also known as retinal angiomatous proliferation, have been well described clinically, as well as with fluorescein angiography (FA), indocyanine green angiography, and optical coherence tomography (OCT). OCT angiography (OCT-A) is a novel and non-invasive technique for imaging retinal microvasculature by detecting changes, with respect to time, in reflectivity related to blood flow. Method In this case series, we describe two patients who presented with type 3 NV and underwent clinical examination and multimodal imaging, including OCT-A. Results In the first patient, OCT-A demonstrated flow within two separate lesions in the same eye, one of which was only weakly detected by FA. In the second patient, sequential OCT-A demonstrated a reduction in intralesional flow following intravitreal therapy. Conclusions OCT-A may have a role in the early diagnosis of type 3 NV and in assessing the response to treatment. Further studies are needed to determine sensitivity and specificity. PMID:25744441

  12. The Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization

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    Zhang, Feng; Prahst, Claudia; Mathivet, Thomas; Pibouin-Fragner, Laurence; Zhang, Jiasheng; Genet, Gael; Tong, Raymond; Dubrac, Alexandre; Eichmann, Anne

    2016-01-01

    Vascular permeability and neovascularization are implicated in many diseases including retinopathies and diabetic wound healing. Robo4 is an endothelial-specific transmembrane receptor that stabilizes the vasculature, as shown in Robo4−/− mice that develop hyperpermeability, but how Robo4 signals remained unclear. Here we show that Robo4 deletion enhances permeability and revascularization in oxygen-induced retinopathy (OIR) and accelerates cutaneous wound healing. To determine Robo4 signalling pathways, we generated transgenic mice expressing a truncated Robo4 lacking the cytoplasmic domain (Robo4ΔCD). Robo4ΔCD expression is sufficient to prevent permeability, and inhibits OIR revascularization and wound healing in Robo4−/− mice. Mechanistically, Robo4 does not affect Slit2 signalling, but Robo4 and Robo4ΔCD counteract Vegfr2-Y949 (Y951 in human VEGFR2) phosphorylation by signalling through the endothelial UNC5B receptor. We conclude that Robo4 inhibits angiogenesis and vessel permeability independently of its cytoplasmic domain, while activating VEGFR2-Y951 via ROBO4 inhibition might accelerate tissue revascularization in retinopathy of prematurity and in diabetic patients. PMID:27882935

  13. Detection of neovascularization based on fractal and texture analysis with interaction effects in diabetic retinopathy.

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    Jack Lee

    Full Text Available Diabetic retinopathy is a major cause of blindness. Proliferative diabetic retinopathy is a result of severe vascular complication and is visible as neovascularization of the retina. Automatic detection of such new vessels would be useful for the severity grading of diabetic retinopathy, and it is an important part of screening process to identify those who may require immediate treatment for their diabetic retinopathy. We proposed a novel new vessels detection method including statistical texture analysis (STA, high order spectrum analysis (HOS, fractal analysis (FA, and most importantly we have shown that by incorporating their associated interactions the accuracy of new vessels detection can be greatly improved. To assess its performance, the sensitivity, specificity and accuracy (AUC are obtained. They are 96.3%, 99.1% and 98.5% (99.3%, respectively. It is found that the proposed method can improve the accuracy of new vessels detection significantly over previous methods. The algorithm can be automated and is valuable to detect relatively severe cases of diabetic retinopathy among diabetes patients.

  14. Neovascularization after ischemic injury: evaluation with {sup 99m}Tc-HYNIC-RGD

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    Faintuch, Bluma Linkowski; Teodoro, Rodrigo, E-mail: blfaintuch@hotmail.co [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil). Radiopharmacy Center; Oliveira, Erica Aparecida de; Fernandez Nunez, Eutimio Gustavo [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil). Postgraduation Program; Faintuch, Joel [Universidade de Sao Paulo (USP), SP (Brazil). Medical School. Dept. of Gastroenterology

    2011-01-15

    Purpose: angiogenesis involves many mediators including integrins, and the tripeptide RGD is a target amino acid recognition sequence for many of them. Hindlimb ischemia is a simple and convenient animal model however standardization of the injection procedures in the devascularized and control limb is lacking, thus rendering difficult the interpretation of results. The aim of this investigations was to evaluate neovascularization in a hindlimb murine model by means of {sup 99m}Tc-HYNIC-{beta}-Ala-RGD. Methods: {sup 99m}Tc-HYNIC-RGD analog was prepared using coligands. Ischemia was induced in Wistar rats by double- ligation of the common femoral artery. Radiolabeled RGD was injected after 2h, as well as 1, 3, 5, 7, 10 and 14 days. Uptake was evaluated by planar imaging and biodistribution studies. Results: the highest ratio between ischemia and control was achieved at the 7th day (2.62 {+-} 0.95), with substantial decrease by the 14th day. For pertechnetate the 7th day ratio was 0.87 {+-} 0.23. Scintigraphic image confirmed different uptakes. Conclusion: {sup 99m}Tc-HYNIC-RGD analog concentrated in ischemic tissue by the time of widespread angiogenesis and pertechnetate confirmed reduction in blood flow. In this sense, the protocol can be recommended for ischemic models. (author)

  15. Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neo-Vascularization

    Science.gov (United States)

    Dubrac, Alexandre; Genet, Gael; Ola, Roxana; Zhang, Feng; Pibouin-Fragner, Laurence; Han, Jinah; Zhang, Jiasheng; Thomas, Jean-Léon; Chedotal, Alain; Schwartz, Martin A.; Eichmann, Anne

    2015-01-01

    Background Sprouting angiogenesis is a key process driving blood vessel growth in ischemic tissues and an important drug target in a number of diseases, including wet macular degeneration and wound healing. Endothelial cells forming the sprout must develop front-rear polarity to allow sprout extension. The adaptor proteins Nck1 and 2 are known regulators of cytoskeletal dynamics and polarity, but their function in angiogenesis is poorly understood. Here we show that the Nck adaptors are required for endothelial cell front-rear polarity and migration downstream of the angiogenic growth factors VEGF-A and Slit2. Methods and Results Mice carrying inducible, endothelial-specific Nck1/2 deletions fail to develop front-rear polarized vessel sprouts and exhibit severe angiogenesis defects in the postnatal retina and during embryonic development. Inactivation of NCK1 and 2 inhibits polarity by preventing Cdc42 and Pak2 activation by VEGF-A and Slit2. Mechanistically, NCK binding to ROBO1 is required for both Slit2 and VEGF induced front-rear polarity. Selective inhibition of polarized endothelial cell migration by targeting Nck1/2 prevents hypersprouting induced by Notch or Bmp signaling inhibition, as well as pathological ocular neovascularization and wound healing. Conclusions These data reveal a novel signal integration mechanism involving NCK1/2, ROBO1/2 and VEGFR2 that controls endothelial cell front-rear polarity during sprouting angiogenesis. PMID:26659946

  16. Inhibition of the recombinant human endostatin adenavirus on experimental choroidal neovascularization in rats

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    Li-Juan Chen

    2017-06-01

    Full Text Available AIM: To investigate the inhibition of the recombinant human endostatin adenavirus(Ad-Eson the experimental choroidal neovascularization(CNVmodels by intravitreous injection. METHODS: Experimental CNV models were induced by semiconductor laser in 30 male Brown Norway(BNrats and randomly divided into 3 groups with 10 rats in each group. At 21d after photocoagulation, the single administration group were given intravitreous injection with Ad-Es 0.01mL; the repeated administration group were given intravitreous injection with Ad-Es 0.01mL and a repeated injection 7d later; the saline control group were given intravitreous injection with saline 0.01mL. At 7d after final administration, the leakage of fundus fluorescein angiography(FFAwas observed. Various CNV areas were measured by using laser confocal microscopy of choroidal flatmount method. Pathology and ultrastructure were observed with light microscopy, the expressions of CD105 were measured by immunohistochemistry. RESULTS: The leakage of CNV of the administration group abviously decreased as compared with those in the saline group, the leakage of repeated administration group decreased compared with that of single administration group(PPCONCLUSION: Ad-Es can effectively inhibit semiconductor laser induced CNV in BN rats, and the inhibition effect of repeated administration group is better than that of single administration group. It may be a useful new method in the treatment of CNV.

  17. [Retracted] Slit-miR-218-Robo axis regulates retinal neovascularization.

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    Kong, Yichun; Sun, Bei; Han, Quanhong; Han, Shuang; Wang, Yuchuan; Chen, Ying

    2016-12-01

    Following the publication of this article, it was brought to our attention that five of the Figures contained in this study were published entirely, or in part, in the following publication, on which several of us were co-authors: Han S, Kong YC, Sun B, Han QH, Chen Y and Wang YC: microRNA-218 inhibits oxygen-induced retinal neovascularization via reducing the expression of roundabout 1. Chin Med J (Engl) 129: 709-715, 2016. While we had intended that these papers offered different research perspectives, we were reminded of the fact that, in submitting the article to International Journal of Molecular Medicine, the work described therein was required to be "original research that has not been published previously, and is not under consideration for publication elsewhere, in whole or in part". Therefore, owing to the redundancy in the data between these publications, the above paper is to be retracted. All the authors have agreed to the retraction. We sincerely apologize for our misunderstanding, and deeply regret any inconvenience this mistake has caused.[the original article was published in the International Journal of Molecular Medicine 37: 1139-1145, 2016; DOI: 10.3892/ijmm.2016.2511].

  18. Oxidative Stress, Hypoxia, and Autophagy in the Neovascular Processes of Age-Related Macular Degeneration

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    Janusz Blasiak

    2014-01-01

    Full Text Available Age-related macular degeneration (AMD is the leading cause of severe and irreversible loss of vision in the elderly in developed countries. AMD is a complex chronic neurodegenerative disease associated with many environmental, lifestyle, and genetic factors. Oxidative stress and the production of reactive oxygen species (ROS seem to play a pivotal role in AMD pathogenesis. It is known that the macula receives the highest blood flow of any tissue in the body when related to size, and anything that can reduce the rich blood supply can cause hypoxia, malfunction, or disease. Oxidative stress can affect both the lipid rich retinal outer segment structure and the light processing in the macula. The response to oxidative stress involves several cellular defense reactions, for example, increases in antioxidant production and proteolysis of damaged proteins. The imbalance between production of damaged cellular components and degradation leads to the accumulation of detrimental products, for example, intracellular lipofuscin and extracellular drusen. Autophagy is a central lysosomal clearance system that may play an important role in AMD development. There are many anatomical changes in retinal pigment epithelium (RPE, Bruch’s membrane, and choriocapillaris in response to chronic oxidative stress, hypoxia, and disturbed autophagy and these are estimated to be crucial components in the pathology of neovascular processes in AMD.

  19. Oxidative stress, hypoxia, and autophagy in the neovascular processes of age-related macular degeneration.

    Science.gov (United States)

    Blasiak, Janusz; Petrovski, Goran; Veréb, Zoltán; Facskó, Andrea; Kaarniranta, Kai

    2014-01-01

    Age-related macular degeneration (AMD) is the leading cause of severe and irreversible loss of vision in the elderly in developed countries. AMD is a complex chronic neurodegenerative disease associated with many environmental, lifestyle, and genetic factors. Oxidative stress and the production of reactive oxygen species (ROS) seem to play a pivotal role in AMD pathogenesis. It is known that the macula receives the highest blood flow of any tissue in the body when related to size, and anything that can reduce the rich blood supply can cause hypoxia, malfunction, or disease. Oxidative stress can affect both the lipid rich retinal outer segment structure and the light processing in the macula. The response to oxidative stress involves several cellular defense reactions, for example, increases in antioxidant production and proteolysis of damaged proteins. The imbalance between production of damaged cellular components and degradation leads to the accumulation of detrimental products, for example, intracellular lipofuscin and extracellular drusen. Autophagy is a central lysosomal clearance system that may play an important role in AMD development. There are many anatomical changes in retinal pigment epithelium (RPE), Bruch's membrane, and choriocapillaris in response to chronic oxidative stress, hypoxia, and disturbed autophagy and these are estimated to be crucial components in the pathology of neovascular processes in AMD.

  20. Alterations in Circulating Immune Cells in Neovascular Age-Related Macular Degeneration.

    Science.gov (United States)

    Lechner, Judith; Chen, Mei; Hogg, Ruth E; Toth, Levente; Silvestri, Giuliana; Chakravarthy, Usha; Xu, Heping

    2015-11-17

    Neovascular age-related macular degeneration (nAMD) is the leading cause of irreversible blindness in developed countries. Recent advances have highlighted the essential role of inflammation in the development of the disease. In addition to local retinal chronic inflammatory response, systemic immune alterations have also been observed in AMD patients. In this study we investigated the association between the frequency of circulating leukocyte populations and the prevalence as well as clinical presentations of nAMD. Leukocyte subsets of 103 nAMD patients (most of them were receiving anti-VEGF therapy prior to enrolment) and 26 controls were analysed by flow cytometry by relative cell size, granularity and surface markers. Circulating CD11b(+) cells and CD16(hi)HLA-DR(-) neutrophils were significantly increased (P = 0.015 and 0.009 respectively) in nAMD when compared to controls. The percentage of circulating CD4(+) T-cells was reduced in nAMD patients without subretinal fibrosis (P = 0.026) compared to patients with subretinal fibrosis. There was no correlation between the percentage of circulating leukocytes and the responsiveness to anti-VEGF therapy in nAMD patients. Our results suggest that higher levels of circulating CD11b(+) cells and neutrophils are associated with nAMD and that reduced levels of CD4(+) T-cells are associated with the absence of subretinal fibrosis in nAMD.

  1. The Matrix Cookbook

    DEFF Research Database (Denmark)

    Petersen, Kaare Brandt; Pedersen, Michael Syskind

    Matrix identities, relations and approximations. A desktop reference for quick overview of mathematics of matrices.......Matrix identities, relations and approximations. A desktop reference for quick overview of mathematics of matrices....

  2. The use of urinary bladder matrix in the treatment of trauma and combat casualty wound care.

    Science.gov (United States)

    Valerio, Ian L; Campbell, Paul; Sabino, Jennifer; Dearth, Christopher L; Fleming, Mark

    2015-01-01

    Treatment of combat injuries and resulting wounds can be difficult to treat due to compromised and evolving tissue necrosis, environmental contaminants, multidrug resistant microbacterial and/or fungal infections, coupled with microvascular damage and/or hypovascularized exposed vital structures. Our group has developed surgical care algorithms with identifiable salvage techniques to achieve stable, definitive wound coverage often with the aid of certain regenerative medicine biologic scaffold materials and advanced wound care to facilitate tissue coverage and healing. This case series reports on the role of urinary bladder matrix scaffolds in the wound care and reconstruction of traumatic and combat wounds. Urinary bladder matrix was found to facilitate definitive soft tissue reconstruction by establishing a neovascularized soft tissue base acceptable for second stage wound and skin coverage options within traumatic and combat-related wounds.

  3. An Immunohistochemical Study of Inflammatory Cell Changes and Matrix Remodeling With and Without Acute Hydrops in Keratoconus.

    Science.gov (United States)

    Fan Gaskin, Jennifer C; Loh, I-Ping; McGhee, Charles N J; Sherwin, Trevor

    2015-09-01

    To determine the inflammatory cell and matrix changes in advanced keratoconus, including acute hydrops, using immunohistochemical analysis. The corneal tissue from eight subjects with keratoconus undergoing corneal transplantation (three keratoconic buttons, five buttons post acute hydrops—one of them with extensive neovascularization following hydrops) was compared with tissue from two normal corneoscleral rims (n = 10). The corneas were sectioned and analyzed with specific markers for macrophages, lymphocytes, dendritic cells, and scar associated matrix molecules laminin, fibronectin, tenascin-C, and type III collagen. Populations of cells using markers for macrophages, leucocytes and antigen presenting cells were found to be associated with the epithelium and stroma of keratoconic tissue. Populations of these cells appeared decreased in hydrops-associated keratoconus except for a large increase in leucocytes in the stroma and endothelium associated with neovascularization. Extracellular matrix deposition was found to be uniquely demonstrated in localized areas of the stroma, corresponding to the site of hydrops involvement. Immunohistochemical analysis revealed a chronic, inflammatory process with recruitment of immunoinflammatory cells and deposition of scar tissue in keratoconus. The inflammatory markers were somewhat attenuated in hydrops-associated keratoconus corneas and thus inflammation was not considered to be a major factor in the development of acute corneal hydrops.

  4. Matrix with Prescribed Eigenvectors

    Science.gov (United States)

    Ahmad, Faiz

    2011-01-01

    It is a routine matter for undergraduates to find eigenvalues and eigenvectors of a given matrix. But the converse problem of finding a matrix with prescribed eigenvalues and eigenvectors is rarely discussed in elementary texts on linear algebra. This problem is related to the "spectral" decomposition of a matrix and has important technical…

  5. MDA-MB-231 and 8701BC breast cancer lines promote the migration and invasiveness of ECV304 cells on 2D and 3D type-I collagen matrix.

    Science.gov (United States)

    Saladino, Silvia; Salamone, Monica; Ghersi, Giulio

    2017-09-01

    Tumor angiogenesis is a multiphasic process, having the extracellular matrix remodeling as critical step. Different classes of proteolytic enzymes in matrix digestion/remodeling are involved. The role of lytic enzymes and their activation mode have not been completely elucidated. Herein, the crosstalk between endothelia and tumor cells, by realization of bi- and three-dimensional endothelial and breast cancer cells co-cultures, were studied in vitro. Particularly, the effects of two tumor conditioned media (TCM) were assessed about endothelial proliferation, migration, and invasiveness. An increase in expression of pro-MMP9 was detected when endothelial cells were cultured in the presence of both TCM; such as an up-regulation of MMP1 and MMP14 and a down-regulation of MMP7. Moreover the increased MMP2 gene expression from one of them and the stimulation MMP3 synthesis from the other one were observed; an increases of β3-integrin, VEGFA, and DPP4 molecules were detected when endothelia cells are cultured with both TCM. The selection/characterization of elements present in conditioned media from breast cancer cells differently affect endothelial cells, make them potential effectors useful in breast cancer treatment. © 2017 International Federation for Cell Biology.

  6. Neovascularization of coronary tunica intima (DIT is the cause of coronary atherosclerosis. Lipoproteins invade coronary intima via neovascularization from adventitial vasa vasorum, but not from the arterial lumen: a hypothesis

    Directory of Open Access Journals (Sweden)

    Subbotin Vladimir M

    2012-04-01

    Full Text Available Abstract Background An accepted hypothesis states that coronary atherosclerosis (CA is initiated by endothelial dysfunction due to inflammation and high levels of LDL-C, followed by deposition of lipids and macrophages from the luminal blood into the arterial intima, resulting in plaque formation. The success of statins in preventing CA promised much for extended protection and effective therapeutics. However, stalled progress in pharmaceutical treatment gives a good reason to review logical properties of the hypothesis underlining our efforts, and to reconsider whether our perception of CA is consistent with facts about the normal and diseased coronary artery. Analysis To begin with, it must be noted that the normal coronary intima is not a single-layer endothelium covering a thin acellular compartment, as claimed in most publications, but always appears as a multi-layer cellular compartment, or diffuse intimal thickening (DIT, in which cells are arranged in many layers. If low density lipoprotein cholesterol (LDL-C invades the DIT from the coronary lumen, the initial depositions ought to be most proximal to blood, i.e. in the inner DIT. The facts show that the opposite is true, and lipids are initially deposited in the outer DIT. This contradiction is resolved by observing that the normal DIT is always avascular, receiving nutrients by diffusion from the lumen, whereas in CA the outer DIT is always neovascularized from adventitial vasa vasorum. The proteoglycan biglycan, confined to the outer DIT in both normal and diseased coronary arteries, has high binding capacity for LDL-C. However, the normal DIT is avascular and biglycan-LDL-C interactions are prevented by diffusion distance and LDL-C size (20 nm, whereas in CA, biglycan in the outer DIT can extract lipoproteins by direct contact with the blood. These facts lead to the single simplest explanation of all observations: (1 lipid deposition is initially localized in the outer DIT; (2 CA

  7. Ranibizumab Plus Combined Surgery for Treatment of Neovascular Glaucoma with Vitreous Hemorrhage

    Institute of Scientific and Technical Information of China (English)

    Xiu-Juan Li; Xiao-Peng Yang; Qiu-Ming Li; Yu-Ying Wang; Xiao-Bei Lyu

    2015-01-01

    Background:Neovascular glaucoma (NVG) is a refractory glaucoma.The management of NVG is very difficult,and it is more difficult when combined with vitreous hemorrhage.The aim of this study was to investigate the effects of ranibizumab plus combined surgery for NVG with vitreous hemorrhage.Methods:A total of 26 eyes of 26 NVG patients with vitreous hemorrhage were recruited in this study.The patients aged from 36 to 63 years with a mean age of 51.97 ± 7.60 years.The mean intraocular pressure (IOP) was 46.38 ± 5.75 mmHg (1 mmHg =0.133 kPa) while being treated with the maximum medical therapy.The mean best-corrected visual acuities converted to logarithm of the minimum angle of resolution (logMAR BCVA) was 2.62 ± 0.43.All the patients underwent intravitreal injection of 0.5 mg (0.05 ml) ranibizumab combined with pars plana vitrectomy (PPV),pars plana lensectomy (PPL) with a preserved anterior capsule,panretinal photocoagulation (PRP),and trabeculectomy (intravitreal ranibizumab [IVR] + PPV + PPL + PRP + trabeculectomy).The IOP and logMAR BCVA were the main outcome measures in this study.Results:The follow-up period was 12 months.The mean postoperative IOPs were 26.38 ± 3.75 mmHg,21.36 ± 3.32 mmHg,1 8.57 ± 3.21 mmHg,and 16.68 ± 2.96 mmHg,respectively at 7 days,1 month,3 months,and 12 months after PPV + PPL + PRP + trabeculectomy.At the last follow-up,the mean IOP was significantly lower than the preoperative one (t =6.612,P =0.001).At 7 days,1 month,3 months,and 12 months after PPV + PPL + PRP + trabeculectomy,the mean logMAR BCVA were 1.30 ± 0.36,1.29 ± 0.37,1.29 ± 0.39,and 1.26 ± 0.29,respectively.At the last follow-up,the mean logMAR BCVA was significantly improved,and the difference was statistically significant compared with preoperative one (t =6.133,P =0.002).The logMAR BCVA improved in 22 eyes (84.62%),and remained stable in 4 eyes (15.38%).The neovascularization in the iris and the angle regressed significantly in all patients 7 days after

  8. Ranibizumab Plus Combined Surgery for Treatment of Neovascular Glaucoma with Vitreous Hemorrhage

    Directory of Open Access Journals (Sweden)

    Xiu-Juan Li

    2015-01-01

    Full Text Available Background: Neovascular glaucoma (NVG is a refractory glaucoma. The management of NVG is very difficult, and it is more difficult when combined with vitreous hemorrhage. The aim of this study was to investigate the effects of ranibizumab plus combined surgery for NVG with vitreous hemorrhage. Methods: A total of 26 eyes of 26 NVG patients with vitreous hemorrhage were recruited in this study. The patients aged from 36 to 63 years with a mean age of 51.97 ± 7.60 years. The mean intraocular pressure (IOP was 46.38 ± 5.75 mmHg (1 mmHg = 0.133 kPa while being treated with the maximum medical therapy. The mean best-corrected visual acuities converted to logarithm of the minimum angle of resolution (logMAR BCVA was 2.62 ± 0.43. All the patients underwent intravitreal injection of 0.5 mg (0.05 ml ranibizumab combined with pars plana vitrectomy (PPV, pars plana lensectomy (PPL with a preserved anterior capsule, panretinal photocoagulation (PRP, and trabeculectomy (intravitreal ranibizumab [IVR] + PPV + PPL + PRP + trabeculectomy. The IOP and logMAR BCVA were the main outcome measures in this study. Results: The follow-up period was 12 months. The mean postoperative IOPs were 26.38 ± 3.75 mmHg, 21.36 ± 3.32 mmHg, 18.57 ± 3.21 mmHg, and 16.68 ± 2.96 mmHg, respectively at 7 days, 1 month, 3 months, and 12 months after PPV + PPL + PRP + trabeculectomy. At the last follow-up, the mean IOP was significantly lower than the preoperative one (t = 6.612, P = 0.001. At 7 days, 1 month, 3 months, and 12 months after PPV + PPL + PRP + trabeculectomy, the mean logMAR BCVA were 1.30 ± 0.36, 1.29 ± 0.37, 1.29 ± 0.39, and 1.26 ± 0.29, respectively. At the last follow-up, the mean logMAR BCVA was significantly improved, and the difference was statistically significant compared with preoperative one (t = 6.133, P = 0.002. The logMAR BCVA improved in 22 eyes (84.62%, and remained stable in 4 eyes (15.38%. The neovascularization in the iris and the angle

  9. Long-term follow-up of patients with choroidal neovascularization due to angioid streaks

    Directory of Open Access Journals (Sweden)

    Martinez-Serrano MG

    2016-12-01

    Full Text Available Maria Guadalupe Martinez-Serrano,1 Abelardo Rodriguez-Reyes,2 Jose Luis Guerrero-Naranjo,1,3 Guillermo Salcedo-Villanueva,1 Jans Fromow-Guerra,1,3 Gerardo García-Aguirre,1,3 Virgilio Morales-Canton,1 Raul Velez-Montoya1,3 1Retina Department, 2Pathology Department, Asociación para Evitar la Ceguera en Mexico, Hospital “Dr Luis Sanchez Bulnes” IAP, 3Macula Retina Consultants, Mexico City, Mexico Background: The following case series describes the long-term anatomical and functional outcome of a group of seven patients with choroidal neovascularization (CNV, secondary to angioid streaks (AS, who were treated with antiangiogenic drugs in a pro re nata (PRN regimen. After the 4-year mark, visual acuity tends to return to pretreatment level. Treatment delays and lack of aware­ness and self-referral by the patients are believed to be the cause of the PRN regimen failure. Purpose: To assess the long-term outcomes (>4 years of patients with CNV due to AS treated with a PRN regimen of antiangiogenic. Methods: This was a retrospective, case series, single-center study. We reviewed the electronic medical records from patients with CNV due to AS. From each record, we noted general demographic data and relevant medical history; clinical presentation, changes in best-corrected visual acuity (BCVA over time, optical coherent tomography parameters, treatment and retreatment details, and systemic associations. Changes in BCVA and central macular thickness were assessed with a Wilcoxon two-sample test, with an alpha value of ≤0.05 for statistical significance. Results: The mean follow-up time was 53.8±26.8 months. BCVA at baseline was: 1.001±0.62 logMAR; at the end of follow-up: 0.996±0.56 logMAR (P=0.9. Central macular thickness at baseline was: 360.85±173.82 µm; at the end of follow-up: 323.85±100.34 µm (P=0.6. Mean number of intravitreal angiogenic drugs: 6±4.16 injections (range 4–15. Mean time between injections was 3.8±2.7 months (range

  10. Forty-two-month outcome of intravitreal bevacizumab in myopic choroidal neovascularization.

    Science.gov (United States)

    Traversi, Claudio; Nuti, Elisabetta; Marigliani, Davide; Cevenini, Gabriele; Balestrazzi, Angelo; Martone, Gianluca; Caporossi, Tomaso; Tosi, Gian Marco

    2015-04-01

    To evaluate the long-term efficacy of bevacizumab in the treatment of choroidal neovascularization (CNV) secondary to pathological myopia. In this retrospective single-center non-comparative study the medical records of 29 eyes from 29 patients with naïve CNV secondary to high myopia and at least 42 months of follow up were reviewed. All eyes received a loading dose of one intravitreal injection per month for two consecutive months and were retreated on an as-needed basis during the course of follow up. The main outcome measures were post-treatment ETDRS best-corrected visual acuity (BCVA) and visual stabilization over time. Stepwise linear regression analysis was performed to identify prognostic factors for visual acuity gain and final visual acuity outcome at 42 months. At 42 months of follow-up bevacizumab was associated with the maintenance of significant benefits in visual acuity compared to baseline. No adverse ocular or systemic effects from treatment were encountered. No statistically significant correlations were found between BCVA change and any of the quantitative variables. However, when final BCVA was taken as a dependent variable and CNV size and pre-treatment VA were included as predictors, a bivariate model was identified by stepwise regression which gave a 75 % of explained variance. Bevacizumab treatment was found to be efficacious in the treatment of myopic CNV, resulting in stable gains in visual acuity lasting at least 42 months, without any adverse ocular or general events. Myopic CNV size was identified as a significant prognostic factor.

  11. A comparison about the inhibitory effect of curcunmin and Avastin on the rat corneal neovascularization

    Directory of Open Access Journals (Sweden)

    Yi Wu

    2013-06-01

    Full Text Available AIM: To compare the inhibitory effect of curcunmin and Avastin on the rat corneal neovascularization(CNV, and approach the mechanism of the curcunmin's inhibition. METHODS: CNV was established in thirty SD rats by alkaline burning. Rats were divided equally to group A and group B at random. In group A, right eyes were experimental group A1, treated by 40μmol/L curcunmin solution, and left eyes were control group A2, treated by 0.09% sodium chloride. In group B, right eyes were experimental group group B1, treated by 5g/L avastin, and left eyes were control group B2, treated by 0.09% sodium chloride. Cornea and aqueous humor were collected by time spot. The capillary vessels were study, and the expressions of VEGF were detected by Enzyme-Linked immunosorbnent Assay(ELISA. RESULTS: No toxic effects of the drugs were found. The capillary vessels in experimental group were less than those of control group(P<0.01. No statistical different of the capillary vessels between two drugs were found. The expressions of VEGF in experimental group were less than those in control group(P<0.01. The expressions of VEGF in B1 group were less than in group A1. CONCLUSION: The inhibitory effect to CNV of curcunmin and avastin have no statistical different in the experiment, but curcunmin has the less inhibitory effect to the expressions of VEGF than avastin. Curcunmin may have other mechanism in the inhibitory action on CNV.

  12. Optimization of an Image-Guided Laser-Induced Choroidal Neovascularization Model in Mice.

    Directory of Open Access Journals (Sweden)

    Yan Gong

    Full Text Available The mouse model of laser-induced choroidal neovascularization (CNV has been used in studies of the exudative form of age-related macular degeneration using both the conventional slit lamp and a new image-guided laser system. A standardized protocol is needed for consistent results using this model, which has been lacking. We optimized details of laser-induced CNV using the image-guided laser photocoagulation system. Four lesions with similar size were consistently applied per eye at approximately double the disc diameter away from the optic nerve, using different laser power levels, and mice of various ages and genders. After 7 days, the mice were sacrificed and retinal pigment epithelium/choroid/sclera was flat-mounted, stained with Isolectin B4, and imaged. Quantification of the area of the laser-induced lesions was performed using an established and constant threshold. Exclusion criteria are described that were necessary for reliable data analysis of the laser-induced CNV lesions. The CNV lesion area was proportional to the laser power levels. Mice at 12-16 weeks of age developed more severe CNV than those at 6-8 weeks of age, and the gender difference was only significant in mice at 12-16 weeks of age, but not in those at 6-8 weeks of age. Dietary intake of omega-3 long-chain polyunsaturated fatty acid reduced laser-induced CNV in mice. Taken together, laser-induced CNV lesions can be easily and consistently applied using the image-guided laser platform. Mice at 6-8 weeks of age are ideal for the laser-induced CNV model.

  13. En-face optical coherence tomography angiography of neovascularization elsewhere in hemicentral retinal vein occlusion

    Directory of Open Access Journals (Sweden)

    Sogawa K

    2015-10-01

    Full Text Available Kenji Sogawa, Taiji Nagaoka, Akihiro Ishibazawa, Atsushi Takahashi, Tomofumi Tani, Akitoshi Yoshida Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan Purpose: To evaluate how the growth of neovascularization elsewhere (NVE was delineated in an eye with hemicentral retinal vein occlusion (CRVO using optical coherence tomography (OCT angiography. Patients and methods: We examined a 64-year-old man diagnosed with hemi-CRVO. The area around the occluded vein was scanned using a spectral-domain OCT device (RTVue XR Avanti. Blood flow was detected using the split-spectrum amplitude-decorrelation angiography (SSADA algorithm. Color fundus photography, fluorescein angiography (FA, and OCT angiography examinations were performed at the first visit and at 3 and 6 months postpresentation. Results: At the first visit, FA revealed delayed retinal venous filling and extensive areas of capillary nonperfusion. The patient underwent a trial of intravitreal ranibizumab injection (0.5 mg/0.05 mL for the treatment of macular edema. At 3 months postpresentation, there was no NVE around the occluded vein in the en-face SSADA image, but at 6 months, NVE appeared on the occluded veins. The en-face SSADA image showed the NVE structure in the fibrovascular membrane on the occluded vein more clearly than FA images. Conclusion: OCT angiography clearly visualized the sprouting of NVE in an eye with hemi-CRVO. New findings of the vascular structure of NVE in hemi-CRVO were revealed using the en-face SSADA algorithm. Keywords: OCT angiography, hemi-CRVO, NVE

  14. Galectin-3 Inhibition by a Small-Molecule Inhibitor Reduces Both Pathological Corneal Neovascularization and Fibrosis

    Science.gov (United States)

    Chen*, Wei-Sheng; Cao, Zhiyi; Leffler, Hakon; Nilsson, Ulf J.; Panjwani, Noorjahan

    2017-01-01

    Purpose Corneal neovascularization and scarring commonly lead to significant vision loss. This study was designed to determine whether a small-molecule inhibitor of galectin-3 can inhibit both corneal angiogenesis and fibrosis in experimental mouse models. Methods Animal models of silver nitrate cautery and alkaline burn were used to induce mouse corneal angiogenesis and fibrosis, respectively. Corneas were treated with the galectin-3 inhibitor, 33DFTG, or vehicle alone and were processed for whole-mount immunofluorescence staining and Western blot analysis to quantify the density of blood vessels and markers of fibrosis. In addition, human umbilical vein endothelial cells (HUVECs) and primary human corneal fibroblasts were used to analyze the role of galectin-3 in the process of angiogenesis and fibrosis in vitro. Results Robust angiogenesis was observed in silver nitrate–cauterized corneas on day 5 post injury, and markedly increased corneal opacification was demonstrated in alkaline burn–injured corneas on days 7 and 14 post injury. Treatment with the inhibitor substantially reduced corneal angiogenesis and opacification with a concomitant decrease in α-smooth muscle actin (α-SMA) expression and distribution. In vitro studies revealed that 33DFTG inhibited VEGF-A–induced HUVEC migration and sprouting without cytotoxic effects. The addition of exogenous galectin-3 to corneal fibroblasts in culture induced the expression of fibrosis-related proteins, including α-SMA and connective tissue growth factor. Conclusions Our data provide proof of concept that targeting galectin-3 by the novel, small-molecule inhibitor, 33DFTG, ameliorates pathological corneal angiogenesis as well as fibrosis. These findings suggest a potential new therapeutic strategy for treating ocular disorders related to pathological angiogenesis and fibrosis. PMID:28055102

  15. Intravitreal bevacizumab and Ahmed glaucoma valve implantation in patients with neovascular glaucoma

    Institute of Scientific and Technical Information of China (English)

    Hai-Tao; Zhang; Yu-Xin; Yang; Ying-Ying; Xu; Rui-Min; Yang; Bao-Jun; Wang; Jun-Xi; Hu

    2014-01-01

    AIM:To explore the efficacy of preoperative intravitreal bevacizumab(IVB) injection combined with Ahmed glaucoma valve(AGV) implantation in the treatment of neovascular glaucoma(NVG).METHODS:This retrospective study included 35 eyes from 35 patients who underwent preoperative IVB and AGV implantation for treatment of NVG. Findings such as intraocular pressure(IOP) number of anti-glaucoma medications, visual acuity(VA), surgical success rates,and complications were recorded.RESULTS:AfterAGVimplantation,IOPwas18.2±4.0mmHg,15.5±3.3 mm Hg and 9.8±2.6 mm Hg at 6, 12 and 36 mo,significantly decreased compared with pre-IOP(P <0.01).The number of anti-glaucoma medications was 0.9 ±0.5,0.8 ±0.9 and 0.8 ±0.6 at 6, 12 and 36 mo, significantly decreased compared to pre-treatment(P <0.01). At last visit, there were 19 eyes with stable VA, 4 with VA improvement, 12 with diminished VA and 3 with complete loss light perception. There were 7 cases that failed during 3-year fellow up period. Cumulative probabilities of valve survival by Kaplan-Meier analysis were 82.9%,74.1% and 71.0% at 12, 24 and 36 mo, respectively. Cox stepwise regression analysis found that the survival time was significant associated with the pre-visual acuity <2/400(P <0.05). Post-operative complications occurred in 8eyes, of which hyphema presented in 2 eyes, choroidal effusion in 2 eyes.CONCLUSION:The procedure of preoperative IVB andAGV implantation should be one of treatments for NVG because of its safety and effectiveness.

  16. Expression of hypoxia-inducible factor-1α and erythropoietin at corneal neovascularization in rats

    Directory of Open Access Journals (Sweden)

    Ji-Min Wang

    2014-12-01

    Full Text Available AIM: To describe the expression of hypoxia-inducible factor-1α(HIF-1αand erythropoietin(EPOin rats' corneal and evaluate its potential effect on corneal neovascularization(CNVgrowth. METHODS: The young SD rats(3mowas chosen and randomly divided into 2 groups, which were experimental group and normal control group. CNV model was established by alkali burn, and the length and area of CNV was observed everyday after operation by slit lamp. After that, the expression of HIF-1α and EPO was measured by SABC and RT-PCR methods at 1, 3, 5, 7, and 14d after alkali burn. The data was analyzed by SPSS 20.0. RESULTS: The area of CNV was increasing at 1, 3, 5, 7, and 14d after alkali burn, and the peak point appear at 7d. The growth speed was decreased after 14d. SABC method told us that no HIF-1α and very tiny amount EPO was detected at normal rats' corneal. The expression of the two factors increased at 1d after alkali burn in corneal epithelium and endoderm. The results of RT-PCR showed that a few amounts of HIF-1α and EPO mRNA were detected at normal group. The expression of the two factors was increased at 3d after alkali burn, and the peak value was found at 7d, however, it was decreased at 14d. Statistical difference was found at different time(PCONCLUSION: HIF-1α and EPO is closely related to CNV.

  17. Individualized Treatment of Neovascular Age-Related Macular Degeneration: What are Patients Gaining? Or Losing?

    Directory of Open Access Journals (Sweden)

    Michael W. Stewart

    2015-05-01

    Full Text Available The widespread use of drugs that bind diffusible vascular endothelial growth factor (VEGF has revolutionized the treatment of neovascular age-related macular degeneration (AMD. The pivotal ranibizumab and aflibercept registration trials featured monthly intravitreal injections for 12 months, during which visual acuities and macular edema rapidly improved for the first 3 months and modest gains or stabilization continued until the primary endpoint. In many subsequent trials, patients were evaluated monthly and treated as-needed (PRN according to the results of visual acuity (VA testing, fundus examinations and optical coherence tomography scans. Compared to monthly-treated control groups, PRN treated patients require fewer injections during the first year but they also experience smaller VA gains (1–3 letters. A small number of prospective trials that directly compared monthly with PRN therapy showed that VA gains with discontinuous therapy lag slightly behind those achieved with monthly injections. Physicians recognize that monthly office visits with frequent intraocular injections challenge patients’ compliance, accrue high drug and professional service costs, and clog office schedules with frequently returning patients. To decrease the numbers of both office visits and anti-VEGF injections without sacrificing VA gains, physicians have embraced the treat-and-extend strategy. Treat-and-extend has not been studied as rigorously as PRN but it has become popular among both vitreoretinal specialists and patients. Despite the possible risks associated with discontinuous therapy (decreased VA and increased macular fluid, most physicians individualize treatment (PRN or treat-and-extend for the majority of their patients. This review chapter explores the many advantages of individualized therapy, while balancing these against suboptimal responses due to the decreased frequency of anti-VEGF injections.

  18. The complement regulatory protein CD59: insights into attenuation of choroidal neovascularization.

    Science.gov (United States)

    Schnabolk, Gloriane; Tomlinson, Stephen; Rohrer, Bärbel

    2014-01-01

    Complement activation is associated with age-related macular degeneration (AMD), with the retinal pigment epithelium (RPE) being one of the main target tissues. In AMD, disease severity is correlated with the formation of the membrane attack complex (MAC), the terminal step in the complement cascade, as well as diminished RPE expression of CD59, a membrane-bound regulatory protein of MAC formation. This has prompted the search for therapeutic strategies based on MAC inhibition, and soluble forms of CD59 (sCD59) have been investigated in mouse laser-induced choroidal neovascularization, a model for "wet" AMD. Unlike membrane-bound CD59, sCD59 provides relatively poor cell protection from complement, and different strategies to increase sCD59 activity at the cell membrane level have been investigated. These include increasing the circulatory half-life of sCD59 by the addition of an Fc moiety; increasing the half-life of sCD59 in target tissues by modifying CD59 with a (non-specific) membrane-targeting domain; and by locally overexpressing sCD59 via adenoviral vectors. Finally, a different strategy currently under investigation employs complement receptor (CR)2-mediated targeting of CD59 exclusively to membranes under complement attack. CR2 recognizes long-lasting membrane-bound breakdown activation fragments of complement C3. CR2-CD59 may have greater therapeutic potential than other complement inhibitory approaches, since it can be administered either systemically or locally, it will bind specifically to membranes containing activated complement activation fragments, and dosing can be regulated. Hence, this strategy might offer opportunities for site-specific inhibition of complement in diseases with restricted sites of inflammation such as AMD.

  19. Interruption of Wnt signaling in Muller cells ameliorates ischemia-induced retinal neovascularization.

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    Kelu Kevin Zhou

    Full Text Available Retinal Müller cells are major producers of inflammatory and angiogenic cytokines which contribute to diabetic retinopathy (DR. Over-activation of the Wnt/β-catenin pathway has been shown to play an important pathogenic role in DR. However, the roles of Müller cell-derived Wnt/β-catenin signaling in retinal neovascularization (NV and DR remain undefined. In the present study, mice with conditional β-catenin knockout (KO in Müller cells were generated and subjected to oxygen-induced retinopathy (OIR and streptozotocin (STZ-induced diabetes. Wnt signaling was evaluated by measuring levels of β-catenin and expression of its target genes using immunoblotting. Retinal vascular permeability was measured using Evans blue as a tracer. Retinal NV was visualized by angiography and quantified by counting pre-retinal nuclei. Retinal pericyte loss was evaluated using retinal trypsin digestion. Electroretinography was performed to examine visual function. No abnormalities were detected in the β-catenin KO mice under normal conditions. In OIR, retinal levels of β-catenin and VEGF were significantly lower in the β-catenin KO mice than in littermate controls. The KO mice also had decreased retinal NV and vascular leakage in the OIR model. In the STZ-induced diabetic model, disruption of β-catenin in Müller cells attenuated over-expression of inflammatory cytokines and ameliorated pericyte dropout in the retina. These findings suggest that Wnt signaling activation in Müller cells contributes to retinal NV, vascular leakage and inflammation and represents a potential therapeutic target for DR.

  20. Association of neovascular age-related macular degeneration with month and season of birth in Italy

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    Longo, Antonio; Casuccio, Alessandra; Pani, Luca; Avitabile, Teresio; Cillino, Salvatore; Uva, Maurizio G.; Bonfiglio, Vincenza; Russo, Andrea; Parisi, Guglielmo; Cennamo, Gilda; Furino, Claudio; Parravano, Mariacristina; Xoxi, Entela; Reibaldi, Michele

    2017-01-01

    In order to investigate the influence of season and month of birth on the risk of neovascular age-related macular degeneration (n-AMD) in Italy, we evaluated the month birth and sex of all patients, recorded in the anti-vascular endothelial growth factor (VEGF) monitoring registry of the Italian Medicines Agency, born between 1925–1944, who received intravitreal anti-VEGF injections for n-AMD between January 1, 2013 and July 29, 2015. The numbers of all births in Italy in the same years, extracted from the Italian National Institute of Statistics, were used to calculate the expected number of n-AMD cases. Overall, 45,845 patients (19,207 men, 26,638 women) received intravitreal anti-VEGF for n-AMD; in the same years, 20,140,426 people (10,334,262 male, 9,806,164 female) were born in Italy. Comparing the observed number of n-AMD cases with the expected number of n- AMD cases in each season, we found that the season-specific risk for n-AMD was 2.5% higher for those born in summer (OR=1.03, Bonferroni-corrected P=0.008) and 3% lower for those born in winter (OR=0.96, Bonferroni-corrected P=0.0004). When considering the month of birth, the risk of n-AMD was 5.9% lower for people born in January (OR=0.93, Bonferroni-corrected P=0.0012). The factors causing such differences should be determined. PMID:27997361

  1. Bevacizumab vs ranibizumab for neovascular age-related macular degeneration in Chinese patients

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    Zhe-Li Liu

    2013-04-01

    Full Text Available AIM:To compare the clinical efficacy of intravitreal injections of bevacizumab and ranibizumab for treating Chinese patients with neovascular age-related macular degeneration (AMD. METHODS: Among 60 Chinese patients with exudative AMD (60 eyes, 28 received intravitreal bevacizumab injections (1.25mg and 32 received intravitreal ranibizumab injections (0.5mg, once a month for 3 months and were followed for a total of 6 months. Monthly optical coherence tomography (OCT was used to determine whether the patients received additional treatments during the follow-up. We compared the baseline and 6-month follow-up values of mean best-corrected visual acuity (BCVA and central retinal thickness (CRT in both groups of patients. We also compared the occurrence of adverse events. RESULTS:At the 6-month follow-up, the mean BCVA (logMAR of the bevacizumab and ranibizumab treatment groups improved from the baseline measurements of 0.72±0.23 and 0.73±0.22 to 0.47±0.14 and 0.45±0.20, respectively (P<0.05 for both groups. However, the change was not significantly different between the two groups. As evaluated by OCT, CRT decreased from 366.71±34.72μm and 352±36.9μm at baseline to 250.86±41.51μm and 243.22±41.38μm in the bevacizumab and ranibizumab groups, respectively (P<0.05 for both groups. However, the change was not significantly different between the two groups. There were no severe local adverse reactions or systemic adverse events. CONCLUSION:Intravitreal bevacizumab and ranibizumab have equivalent effects on BCVA and CRT and appeare safe over the short-term.

  2. Functional characterization and multimodal imaging of treatment-naive "quiescent" choroidal neovascularization.

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    Querques, Giuseppe; Srour, Mayer; Massamba, Nathalie; Georges, Anouk; Ben Moussa, Naima; Rafaeli, Omer; Souied, Eric H

    2013-10-21

    To investigate the multimodal morphological and functional characteristics of treatment-naïve "quiescent" choroidal neovascularization (CNV) secondary to AMD. Eleven patients with treatment-naïve "quiescent" CNV that consecutively presented over a 6-month period, underwent multimodal morphological and functional assessment (including indocyanine green angiography [ICGA], spectral-domain optical coherence tomography [SD-OCT], microperimetry, and preferential hyperacuity perimeter [PHP]). For the purpose of this study, asymptomatic previously untreated CNVs showing absence of intraretinal/subretinal exudation in two consecutive visits (at least 6 months apart) were defined as treatment-naïve "quiescent" CNV. Eleven eyes of 11 patients (9 females; mean age 76.5 ± 8.5 years) were included. On fluorescein angiography (FA), "quiescent" CNVs appeared as late speckled hyperfluorescent lesions lacking well-demarcated borders. Mid-late phase ICGA allowed visualizing the hyperfluorescent "quiescent" CNV network and delineating the plaque. Mean lesion area (mid-late phase ICGA) appeared larger compared with earliest previous examination performed 23.8 ± 16.0 months before (3.24 ± 2.51 mm(2) vs. 3.52 ± 2.46 mm(2), respectively; P = 0.01). SD-OCT revealed, at the site of "quiescent" CNV, an irregularly slightly elevated RPE, without hyporeflective intraretinal/subretinal fluid, showing a major axis in the horizontal plane, which was characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane. Hypergeometric distribution revealed a significant correlation between microperimetry and PHP with respect to locations of "affected areas" (P = 0.001). "Quiescent" CNVs are sub-RPE CNVs secondary to AMD, showing absence of intraretinal/subretinal exudation on repeated OCT. "Quiescent" CNVs enlarge over time and may contribute to local reduced retinal sensitivity and metamorphopsia.

  3. Rate of vision loss in neovascular age-related macular degeneration explored.

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    Real, Juan P; Granero, Gladys E; De Santis, Mariana O; Juarez, Claudio P; Palma, Santiago D; Kelly, Simon P; Luna, José D

    2015-11-01

    To explore decline in visual acuity in patients with neovascular age-related macular degeneration (n-AMD) awaiting intravitreal bevacizumab or ranibizumab treatment following initial diagnosis and after disease reactivation. Retrospective analysis of 74 treatment-naïve patients (84 eyes) in two centers in Córdoba, Argentina. The time between treatment indication and intravitreal injection, and the changes in BCVA produced during this delay were studied in both periods. A linear regression model to search the impact of time on progression visual impairment was conducted. In both periods, a significant reduction in vision occurred awaiting intravitreal injection. The longer the delay, the greater the vision loss (R2 = 0.55 p < 0.01) and the less improvement following treatment (Pearson coefficient -0.26). The result of the model shows that the change in vision as a function of initial delay were best described by a polynomic model with a mean loss of 5 letters in the first 3 weeks, a slowdown in the rate of change of VA, and a dependence of visual acuity at the moment of diagnosis . The loss of visual acuity after reactivation shows the same behavior as at the onset of the disease but independent of visual acuity prior to reactivation. Visual loss awaiting injection intravitreal anti-VEGF is clinically significant and with an asymptotic pattern, with early rapid loss of vision in both the onset of the disease and the reactivation. Initiation of anti-VEGF treatment must be undertaken urgently, as should retreatment of disease activation to reduce visual loss.

  4. Cytokines in neovascular age-related macular degeneration: fundamentals of targeted combination therapy.

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    de Oliveira Dias, João Rafael; Rodrigues, Eduardo Büchele; Maia, Mauricio; Magalhães, Octaviano; Penha, Fernando Marcondes; Farah, Michel Eid

    2011-12-01

    The neovascular form of age-related macular degeneration (AMD), called wet-AMD or choroidal neovascularisation, begins with damage to the outer retinal cells and retinal pigment epithelium (RPE), which elicits a cascade of inflammatory and angiogenic responses leading to neovascularisation under the macula. Studies showed that oxidative damage, chronic inflammation of the RPE and complement misregulation work at different steps of this disease. After established neovascularisation, several pro- and antiangiogenic agents start to play an important role. Vascular endothelial growth factors (VEGFs) are the most specific and potent regulators of angiogenesis, which are inhibited by intravitreal injections of ranibizumab, bevacizumab, VEGF Trap, pegaptanib sodium and other agents under investigation. Pigment epithelium-derived factor, on the other hand, shows neuroprotective and antiangiogenic activities. Hepatocyte growth factor (HGF) has a mitogenic effect on a wide range of epithelial and endothelial cells, and it is inhibited by an anti-HGF monoclonal antibody. Platelet-derived growth factor is a potent chemoattractant and mitogen for both fibroblasts and retinal RPE cells, which has been inhibited experimentally by VEGF Trap and human anti-platelet-derived growth factor-D monoclonal antibody. Fibroblast growth factor-2 has pleiotropic effects in different cell and organ systems, and it is blocked by anti-FGF antibodies, with a greater benefit regarding antiangiogenesis when combined treatment with anti-VEGF is performed. Tumour necrosis factor alpha is expressed in the retina and the choroid, and its blockade in choroidal neovascularisation includes the use of monoclonals such as infliximab. This paper reviews the most important cytokines involved in the pathogenesis of wet-AMD, with emphasis on potential combined therapies for disease control.

  5. Nanoparticle-Mediated Expression of a Wnt Pathway Inhibitor Ameliorates Ocular Neovascularization

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    Wang, Zhongxiao; Cheng, Rui; Lee, Kyungwon; Puneet, Tyagi; Ding, Lexi; Kompella, Uday B.; Chen, Jing; Xu, Xun; Ma, Jian-xing

    2015-01-01

    Objective The deficiency of very low-density lipoprotein receptor (VLDLR) resulted in Wnt signaling activation and neovascularization (NV) in the retina. The present study sought to determine if the VLDLR extracellular domain (VLN) is responsible for the inhibition of Wnt signaling in ocular tissues. Approach and Results A plasmid expressing the soluble VLN was encapsulated with poly (lactide-co-glycolide acid) (PLGA) to form VLN nanoparticles (VLN-NP). Nanoparticles containing a plasmid expressing the low-density lipoprotein receptor extracellular domain (LN-NP) were used as negative control. MTT, modified Boyden chamber and Matrigel (™) assays were used to evaluate the inhibitory effect of VLN-NP on Wnt3a-stimulated endothelial cell (EC) proliferation, migration and tube formation. Vldlr−/− mice, oxygen-induced retinopathy (OIR) and alkali burn-induced corneal NV models were used to evaluate the effect of VLN-NP on ocular NV. Wnt reporter mice (BAT-gal), Western blotting and luciferase assay were used to evaluate Wnt pathway activity. Our results showed that VLN-NP specifically inhibited Wnt3a-induced EC proliferation, migration and tube formation. Intravitreal injection of VLN-NP inhibited abnormal NV in Vldlr−/−, OIR and alkali burn-induced corneal NV models, compared with LN-NP. VLN-NP significantly inhibited the phosphorylation of LRP6, the accumulation of β-catenin and the expression of VEGF in vivo and in vitro. Conclusions Taken together, these results suggest that the soluble VLN is a negative regulator of the Wnt pathway and has anti-angiogenic activities. Nanoparticle-mediated expression of VLN may thus represent a novel therapeutic approach to treat pathologic ocular angiogenesis and potentially other vascular diseases impacted by Wnt signaling. PMID:25657312

  6. Anti-VEGF treatment for myopic choroid neovascularization: from molecular characterization to update on clinical application

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    Zhang Y

    2015-07-01

    Full Text Available Yan Zhang,1 Qian Han,2 Yusha Ru,1 Qiyu Bo,1 Rui Hua Wei1 1Tianjin Medical University Eye Hospital, Tianjin Medical University Eye Institute, College of Optometry and Ophthalmology, Tianjin Medical University, Tianjin, 2Tangshan Eye Hospital, Tangshan, Hebei Province, People’s Republic of China Abstract: Choroidal neovascularization (CNV secondary to pathologic myopia has a very high incidence in global, especially in Asian, populations. It is a common cause of irreversible central vision loss, and severely affects the quality of life in the patients with pathologic myopia. The traditional therapeutic modalities for CNV secondary to pathologic myopia include thermal laser photocoagulation, surgical management, transpupillary thermotherapy, and photodynamic therapy with verteporfin. However, the long-term outcomes of these modalities are disappointing. Recently, intravitreal administration of anti-VEGF biological agents, including bevacizumab, ranibizumab, pegaptanib, aflibercept, and conbercept, has demonstrated promising outcomes for this ocular disease. The anti-VEGF regimens are more effective on improving visual acuity, reducing central fundus thickness and central retina thickness than the traditional modalities. These anti-VEGF agents thus hold the potential to become the first-line medicine for treatment of CNV secondary to pathologic myopia. This review follows the trend of “from bench to bedside”, initially discussing the pathogenesis of myopic CNV, delineating the molecular structures and mechanisms of action of the currently available anti-VEGF drugs, and then systematically comparing the up to date clinical applications as well as the efficacy and safety of the anti-VEGF drugs to the CNV secondary to pathologic myopia. Keywords: formation of new vessels, choroid membrane, pathologic myopia, vascular endothelial growth factor, molecular mechanisms, clinical trials

  7. Cost-effectiveness of ranibizumab for neovascular age-related macular degeneration

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    Matthews Jane P

    2008-06-01

    Full Text Available Abstract Background Intravitreal ranibizumab prevents vision loss and improves visual acuity in patients with neovascular age-related macular degeneration, but it is expensive, and efficacy beyond 2 years is uncertain. Methods We assessed the cost-effectiveness of ranibizumab compared with no ranibizumab over 10 years, using randomized trial efficacy data for the first 2 years, post-trial efficacy assumptions, and ranibizumab acquisition costs ranging from the wholesale price ($1,950 per dose to the price of bevazicumab ($50, a similar molecule which may be equally efficacious. We used a computer simulation model to estimate the probability of blindness, the number of quality-adjusted life-years (QALYs, direct costs (in 2004 U.S. dollars, and cost-effectiveness ratios for a 67-year old woman. Costs and QALYs were discounted at 3% per year. Results The probability of blindness over 10 years was reduced from 56% to 34% if ranibizumab was efficacious for only 2 years, 27% if efficacy was maintained for a further 2 years only (base-case scenario, and 17% if visual acuity at 4 years was then sustained. It was cost-saving under all price assumptions, when caregiver costs were included. When caregiver costs were excluded, the cost per QALY for the base-case ranged from $5,600, assuming the bevazicumab price, to $91,900 assuming the wholesale ranibizumab price. The cost per QALY was Conclusion From a societal perspective, ranibizumab was cost-saving. From a health care funder's perspective, ranibizumab was an efficient treatment when it cost less than $1000 per dose.

  8. Oscillatory Photodynamic Therapy for Choroidal Neovascularization and Central Serous Retinopathy; a Pilot Study

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    Gholam A Peyman

    2011-01-01

    Full Text Available Purpose: To report the preliminary results of oscillatory photodynamic therapy (OPDT for choroidal neovascularization (CNV and central serous retinopathy (CSR. Methods: This study included 7 eyes of 6 patients with CSR (2 eyes, idiopathic CNV (2 eyes, CNV due to age-related macular degeneration (AMD (2 eyes, and peripapillary CNV secondary to presumed ocular histoplasmosis syndrome (1 eye. Intravenous verteporfin (6 mg/m2 body surface area was infused over 10 minutes followed by oscillating laser (wavelength 689 nm covering slightly beyond the entire lesion. An Area Centralis lens was applied and laser was delivered (600 mW/cm2 fluence rate and 50 J/cm2 dose. Intravitreal bevacizumab and dexamethasone combination therapy was used with OPDT in 4 eyes with CNV; intravitreal dexamethasone and triamcinolone acetonide were injected in the other eye with CNV. Clinical examination, funduscopy, fluorescein angiography, and optical coherence tomography (OCT were performed at baseline and after treatment. Results: After mean follow-up of 7.1±5.1 months, visual acuity improved from 0.87±0.69 logMAR (20/160 to 0.60±0.65 logMAR (20/80 (P = 0.027; central foveal thickness decreased from 322±62.1 to 240.7±34.8 microns as measured by OCT (P = 0.018. Fluorescein angiography and OCT demonstrated cessation of vascular leakage, and resolution of hemorrhage and subretinal fluid in all eyes. No adverse events or recurrence were noted. Conclusion: OPDT was effective in treating CNV lesions and CSR. OPDT may be an improvement on standard PDT due to reduced side effects, thermal damage and scarring.

  9. Identification of genes and pathways involved in retinal neovascularization by microarray analysis of two animal models of retinal angiogenesis.

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    Recchia, Franco M; Xu, Lili; Penn, John S; Boone, Braden; Dexheimer, Phillip J

    2010-02-01

    Comparative retinal gene expression analysis in two rodent models of oxygen-induced retinopathy (OIR) was performed to identify the genes and pathways involved in retinal neovascularization. Three independent experimental runs were conducted for each species, according to standard protocols for induction of OIR. Total retinal RNA was isolated at two time points, corresponding to the early response to relative hypoxia (P13 in mouse, P15 in rat) and to the later phase of maximum retinal neovascularization (P18 in mouse, P20 in rat) and was used to prepare labeled probes for hybridization. Gene expression was compared between normal and experimental conditions for each species at each time point. Probesets with a false-discovery rate of neovascularization and identification of potential rational targets for antiangiogenic therapy.

  10. Fibroblast-Specific Deletion of Hypoxia Inducible Factor-1 Critically Impairs Murine Cutaneous Neovascularization and Wound Healing.

    Science.gov (United States)

    Duscher, Dominik; Maan, Zeshaan N; Whittam, Alexander J; Sorkin, Michael; Hu, Michael S; Walmsley, Graham G; Baker, Hutton; Fischer, Lauren H; Januszyk, Michael; Wong, Victor W; Gurtner, Geoffrey C

    2015-11-01

    Diabetes and aging are known risk factors for impaired neovascularization in response to ischemic insult, resulting in chronic wounds, and poor outcomes following myocardial infarction and cerebrovascular injury. Hypoxia-inducible factor (HIF)-1α, has been identified as a critical regulator of the response to ischemic injury and is dysfunctional in diabetic and elderly patients. To better understand the role of this master hypoxia regulator within cutaneous tissue, the authors generated and evaluated a fibroblast-specific HIF-1α knockout mouse model. The authors generated floxed HIF-1 mice (HIF-1) by introducing loxP sites around exon 1 of the HIF-1 allele in C57BL/6J mice. Fibroblast-restricted HIF-1α knockout (FbKO) mice were generated by breeding our HIF-1 with tamoxifen-inducible Col1a2-Cre mice (Col1a2-CreER). HIF-1α knockout was evaluated on a DNA, RNA, and protein level. Knockout and wild-type mice were subjected to ischemic flap and wound healing models, and CD31 immunohistochemistry was performed to assess vascularity of healed wounds. Quantitative real-time polymerase chain reaction of FbKO skin demonstrated significantly reduced Hif1 and Vegfa expression compared with wild-type. This finding was confirmed at the protein level (p wound closure and vascularity (p fibroblasts results in delayed wound healing, reduced wound vascularity, and significant impairment in the ischemic neovascular response. These findings provide new insight into the importance of cell-specific responses to hypoxia during cutaneous neovascularization.

  11. Functional impact of treatment with ranibizumab under a reactive strategy in patients with neovascular age-related macular degeneration.

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    Gallego-Pinazo, R; Dolz-Marco, R; Andreu-Fenoll, M; Farrés, J; Monclús, L

    2017-03-01

    To analyse the functional recovery using a pro re nata (PRN) dosing strategy with intravitreal injections of ranibizumab for patients with neovascular age-related macular degeneration (AMD). An observational, retrospective, single-centre study, was conducted on patients with neovascular AMD managed with a PRN strategy with ranibizumab, and were followed-up for a minimum of 18 months. Sociodemographic and clinical data were collected from medical records. The percentage of visual acuity (VA) recovered after losing 5 or more letters was calculated taking into account the previous visit, as well as considering the best VA recorded prior to the retreament. The analysis included 128 patients. The mean (SD) follow-up period was 18.9 (2.3) months. The mean (SD) elapsed days between onset of symptoms and diagnosis, and between prescription and administration of treatment was 50.2 (57.4) and 10.9 (16.0), respectively. Only 108 patients were prescribed ranibizumab after losing 5 or more letters of VA. The mean (SD) VA recovery compared to the previous VA was 70.3% (114.4). On the other hand, the mean (SD) VA recovery when considering the best VA registered before the retreatment was 43.5% (112.9), with 59.4% of re-treatments having a VA recovery below 75%, and with 11.7% not presenting any VA recovery. A PRN dosing strategy with intravitreal ranibizumab for neovascular AMD may not be efficient in preserving and/or recovering VA in the long-term, due to a cumulative irreversible VA loss. Copyright © 2016 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  12. Polarisation-sensitive OCT is useful for evaluating retinal pigment epithelial lesions in patients with neovascular AMD

    Science.gov (United States)

    Schütze, Christopher; Teleky, Katharina; Baumann, Bernhard; Pircher, Michael; Götzinger, Erich; Hitzenberger, Christoph K; Schmidt-Erfurth, Ursula

    2016-01-01

    Background/aims To examine the reproducibility of lesion dimensions of the retinal pigment epithelium (RPE) in neovascular age-related macular degeneration (AMD) with polarisation-sensitive optical coherence tomography (PS-OCT), specifically imaging the RPE. Methods Twenty-six patients (28 eyes) with neovascular AMD were included in this study, and examined by a PS-OCT prototype. Each patient was scanned five times at a 1-day visit. The PS-OCT B-scan located closest to the macular centre presenting with RPE atrophy was identified, and the longitudinal diameter of the lesion was quantified manually using AutoCAD 2008. This procedure was followed for the identical B-scan position in all five scans per eye and patient. Reproducibility of qualitative changes in PS-OCT was evaluated. Interobserver variability was assessed. Results were compared with intensity-based spectral-domain OCT (SD-OCT) imaging. Results Mean variability of all atrophy lesion dimensions was 0.10 mm (SD±=0.06 mm). Coefficient of variation (SD±/mean) was 0.06 on average (SD±=0.03). Interobserver variability assessment showed a mean difference of 0.02 mm across all patients regarding RPE lesion size evaluation (paired t test: p=0.38). Spearman correlation coefficient was r=0.98, p<0.001. Results revealed a good overall reproducibility of ∼90%. PS-OCT specifically detected the RPE in all eyes compared with conventional intensity-based SD-OCT that was not capable to clearly identify RPE atrophy in 25 eyes (89.3%, p<0.01). Conclusions PS-OCT offers good reproducibility of RPE atrophy assessment in neovascular AMD, and may be suitable for precise RPE evaluation in clinical practice. PS-OCT unambiguously identifies RPE changes in choroidal neovascularisation compared with intensity-based SD-OCT that does not identify the RPE status reliably. PMID:26183936

  13. Simple, reliable and fast spectrofluorometric method for determination of plasma Verteporfin (Visudyne) levels during photodynamic therapy for choroidal neovascularization.

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    Aquaron, R; Forzano, O; Murati, J L; Fayet, G; Aquaron, C; Ridings, B

    2002-12-01

    Photodynamic therapy with Verteporfin, a potent photosensitizer dye, is a very effective treatment for age related macular degeneration due to choroidal neovascularization. Photodynamic therapy offers the potential for selective tissue injury in part attributable to preferential localization of Verteporfin, administrated by intravenous infusion, to the choroidal neovascularization complex and irradiation of the complex with non-laser thermal light at 690 nm resulting in at least temporary thrombosis and vessel closure. Verteporfin is a benzoporphyrin derivative monoacid ring A formulated as a unilamellar liposome. In the blood Verteporfin is associated with lipoprotein fractions and is rapidly cleared via a receptor-mediated uptake mechanism due the high expression of LDL receptors in neovascular tissues. Verteporfin was undetectable in plasma 24 hr after infusion of the recommended dose: 6 mg/m2 of body surface area. The main side effect is photosensitivity of skin which is usually short-lived (24-48 hr) with a low incidence (2.3%). As skin photosensitivity depends on circulating rather than tissue drug levels, we investigate the possibility of developing a simple, fast and reliable spectrofluorometric method to measure plasma Verteporfin levels. Fluorescence emission spectrum (550-750 nm) of 1:10 saline diluted plasma with lambda exc=430 nm showed a characteristic emission peak at 692 nm, the height being proportional to the Verteporfin levels. The sensitivity is around 100 ng/ml and the pharmacokinetics of Verteporfin has been studied from 0 to 5 hr after infusion in six patients older than 65 years with age-related macular degeneration.

  14. Is monthly retreatment with intravitreal bevacizumab (Avastin® necessary in neovascular age-related macular degeneration?

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    Nicola G Ghazi

    2010-04-01

    Full Text Available Nicola G Ghazi, Tyler Q Kirk, Robert M Knape, James S Tiedeman, Brian P ConwayDepartment of Ophthalmology, University of Virginia Health System, Charlottesville, VA, USAPurpose: To report our short-term experience with bevacizumab in neovascular age-related macular degeneration (AMD and recommend a new treatment strategy.Methods: Retrospective chart review of 29 consecutive patients receiving 1.25 mg of intravitreal bevacizumab for AMD and completing 12 weeks of follow up. Outcome measures were best corrected visual acuity (BCVA and optical coherence tomography (OCT central macular thickness. Injections were repeated if no further improvement was observed.Results: Twenty-nine eyes of 29 patients were included. The average BCVA improved from 20/148 at baseline to 20/106 at twelve weeks (P = 0.041. Of the 29 eyes, 25 (86.2% had stable or improved BCVA. Average mean central macular thickness measured by OCT improved from 351 μm at baseline to 278 μm at 12 weeks (P = 0.003. Stabilization of vision and improved OCT central macular thickness were maintained for at least eight weeks following only a single injection in the majority of eyes. During the three months of follow up, only five eyes (17.2% required repeat injections, with only three (10.3% requiring retreatment at eight weeks and none at four weeks. No significant ocular or systemic side effects were observed. Conclusion: This short-term data suggests that bevacizumab appears to be a safe and effective treatment for neovascular AMD. Injections as frequent as every month do not appear to be necessary since initial treatment effect appears to be maintained for at least eight weeks in almost all of our patients.Keywords: retina, Avastin®, bevacizumab, neovascular age-related macular degeneration, AMD

  15. Diagnosis and Follow-Up of Nonexudative Choroidal Neovascularization With Multiple Optical Coherence Tomography Angiography Devices: A Case Report

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    Lane, Mark; Ferrara, Daniela; Louzada, Ricardo Noguera; Fujimoto, James G.; Seddon, Johanna M.

    2017-01-01

    Nonexudative choroidal neovascularization (CNV) is a new phenomenon that has only recently been described in the literature with the advent of optical coherence tomography angiography (OCTA) imaging. The authors present a 1-year longitudinal follow-up of a nonexudative CNV lesion secondary to age-related macular degeneration. This report describes the appearance of the lesion on two commercially available spectral-domain OCTA devices and one prototype swept-source OCTA device. Management of these cases is still debatable. Watchful waiting with regular follow-up using serial OCTA to monitor disease progression has been valuable in this case. PMID:27548457

  16. Combination therapy of low-fluence photodynamic therapy and intravitreal ranibizumab for choroidal neovascular membrane in choroidal osteoma</