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Macular Degeneration (macular + degeneration)
Kinds of Macular Degeneration Selected AbstractsAge-Related Macular Degeneration: Self-Management and Reduction of Depressive Symptoms in a Randomized, Controlled StudyJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 10 2006Barbara L. Brody MPH OBJECTIVES: To assess the effectiveness of a self-management program for age-related macular degeneration (AMD) in reducing depressive symptoms. DESIGN: Analysis of 6-month follow-up for a subset of participants in a randomized, controlled trial who were clinically depressed at baseline. SETTING: University ophthalmology clinic. PARTICIPANTS: Thirty-two depressed older adult volunteers (mean age 81.5) with advanced AMD who had been randomized to a self-management program (n=12) or one of two control conditions (n=20). Subjects were included if at baseline they met criteria from the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Axis, I, Fourth Edition, Research Version, for major or minor depressive disorder with significant depressive symptoms (,5 points) on the 15-item Geriatric Depression Scale (GDS-15). INTERVENTION: AMD self-management program consisting of cognitive and behavioral elements including health education and enhancement of problem-solving skills. MEASUREMENTS: Primary outcome measure was GDS-15. Secondary outcome measures included National Eye Institute Visual Function Questionnaire (NEI-VFQ) and AMD Self-Efficacy Questionnaire. RESULTS: At 6-month follow-up, the self-management group had a significantly greater reduction in depressive symptoms on the GDS-15 than the controls (P=.03). The mean reduction of 2.92 points in the self-management group was more than the 2-point change threshold considered to be clinically meaningful. Change on the NEI-VFQ was nonsignificant. Reduction in depressive symptoms was associated with greater self-efficacy in the self-management group. CONCLUSION: These findings may support the effectiveness of an AMD self-management program for depressed older adults with advanced vision loss from AMD. [source] Obesity, Lutein Metabolism, and Age-Related Macular Degeneration: A Web of ConnectionsNUTRITION REVIEWS, Issue 1 2005Elizabeth J. Johnson PhD Age-related macular degeneration (AMD) is a major cause of visual impairment in the United States. Currently there is no effective cure for this disease. Risk factors include decreased lutein and zeaxanthin status and obesity. Obesity is also an increasing public health concern. The alarming increase in the prevalence of obesity further exacerbates the public health concern of AMD. The mechanism by which obesity increases the risk of AMD may be related to the physiologic changes that occur with this condition. These include increased oxidative stress, changes in the lipoprotein profile, and increased inflammation. These changes would also result in an increased destruction and a decreased circulatory delivery of lutein and zeaxanthin to the macula of the eye. Therefore, the mechanism by which obesity is related to AMD risk may be through indirect effects on changes in lutein and zeaxanthin status and metabolism. [source] Lipofuscin and Macular DegenerationNUTRITION REVIEWS, Issue 10 2003George Wolf DPhil The accumulation of the autofluorescent pigment lipofuscin in the retina that occurs with aging has been explained as a side effect of the visual cycle. It occurs when two molecules of all- trans -retinal condense with one molecule of phosphatidylethanolamine in the discs of the rod outer segments, and is followed by uptake into retinal pigment epithelium (RPE) and conversion to the stable A2E, a pyridinium bisretinoid that is toxic to RPE cells. The accumulation of A2E, the major component of lipofuscin causes RPE cell apoptosis, thereby explaining age-related macular degeneration and macular degeneration characteristic of Stargardt disease. The drug isotretinoin (13- cis - retinoic acid) prevents accumulation of A2E in mice by slowing down the visual cycle and might therefore be used to prevent macular degeneration. [source] Analysis of Single Nucleotide Polymorphisms in the NOS2A Gene and Interaction with Smoking in Age-Related Macular DegenerationANNALS OF HUMAN GENETICS, Issue 3 2010Juan A. Ayala-Haedo Summary Age-related macular degeneration (AMD) is a complex degenerative retinal disease influenced by both genetic and environmental risk factors. We assessed whether single nucleotide polymorphisms (SNPs) in the NOS2A gene increase risk and modulate the effect of smoking in AMD. 998 Caucasian subjects (712 AMD cases and 286 controls) were genotyped for 17 SNPs in NOS2A. Multivariable logistic regression models containing SNP genotypes, age, sex, smoking status and genotype/smoking interaction were constructed. SNP rs8072199 was significantly associated with AMD (OR = 1.3; 95% CI : 1.02, 1.65; P= 0.035). A significant interaction with smoking was detected at rs2248814 (P= 0.037). Stratified data by genotypes demonstrated that the association between AMD and smoking was stronger in carriers of AA genotypes (OR = 35.98; 95% CI: 3.19, 405.98) than in carriers of the AG genotype (OR = 3.05; 95% CI: 1.36, 6.74) or GG genotype (OR = 2.1; 95% CI: 0.91, 4.84). The results suggest a possible synergistic interaction of AA genotype with smoking, although the result bears replication in larger samples. Our data suggests that SNPs in the NOS2A gene are associated with increased risk for AMD and might modulate the effect of smoking on AMD. [source] 1332: Fluorescein angiography: first step for macular degeneration diagnosisACTA OPHTHALMOLOGICA, Issue 2010G SOUBRANE Purpose To recall that fluorescein angiography (FA) is not only the basis of our knowledge but also mandatory to improve our understanding. Methods Macular disciform lesions have been described and drawed since about 150 years. It is only in 1977 with the advent of fluorescein that the connection with choroidal new vessels (CNV) was performed. The identification of drusen as precursors of CNV was the following stage. With time a number of precursors and clinical forms of macular degeneration were described. Results Currently, the precursors (Age-Related Maculopathy) are distinguished from the neovasdcular or atrophic complications (Age-Related Macular Degeneration). The precursors presenting an early hyperfuorescence can be either hard drusen or RPE atrophy distinguished from each other on the late phase of FA. The late hyperfluorescence of soft drusen particularly when confluent requires a careful analysis of the complete FA sequence to ensure the diagnosis. The neovascular stage presents mainly as sub epithelial occult lesions of which the other types develop that display different angiographic behaviours. Specific aspects have been described gradually based on their FA features. The atrophic stage of the disease seems to behave in a stereotyped way but sub goups are presently identified. Conclusion The fluorescein features of the different component of AMD remain the reference for all other more recent imaging technics and helps to understand and differentiate the various aspects of the disease. [source] 1333: OCT: from single use to combined use in macular degenerationACTA OPHTHALMOLOGICA, Issue 2010C CREUZOT Purpose Optical Coherence Tomography (OCT) plays a key role in the diagnosis and the treatment of Age Macular Degeneration (AMD). Authors will present the different signs observed in OCT in exudative AMD. Methods Authors will present clinical cases to illustrate the place of the OCT in AMD diagnosis. OCT has progressively replaced the first-line tool played by angiography especially for the following of the patient once the treatment initiated. The different schemas currently proposed emphasize the role of the OCT combined with visual acuity measurement and fundus examination. Results However, the role of fluorescein and indocyanin green angiography remained essential especially to precise the clinical form before treatment. The combination of OCT and angiography remained a "key association" especially when there is some discrepancy between results or in case of treatment failure to consider another option. It is also the only opportunity for us to understand better the prognosis of these cases under treatment. Conclusion OCT has dramatically changed the supervision of exudative AMD especially during treatment. However, the combination with fluorescein and indocyanin angiograms is highly recommended not only for initial diagnosis but also in difficult cases during follow-up. [source] 4211: Xanthophylls from blood to retinaACTA OPHTHALMOLOGICA, Issue 2010L BRETILLON Xanthophylls are dietary lipophilic compounds. Among them, lutein and zeaxanthin are the major carotenoids found in the human lens and retina, and referred as macular pigment within the retina. Lutein and zeaxanthin cannot be synthesized endogenously. They may therefore be considered as essential and must be provided by adequate dietary intakes. Lutein and zeaxanthin are present in various food items, mainly in plants and fruits such as green vegetables or yellow-orange fruits, as well as in a few animal sources, such as egg yolk. Epidemiological studies consistently suggest that dietary lutein and zeaxanthin are protective factors against the development of Age-Related Maculopathies and Age-related Macular Degeneration. Intervention trials consisting in supplementing the diet with lutein and zeaxanthin demonstrate the bioavailability of those carotenoids in plasma and, in some of them, their efficacy in increasing the density of the macular pigment. An overview will be presented on the mechanisms of xanthophyll bioavailability in blood and retina. [source] Spectral domain OCT of exudative AMDACTA OPHTHALMOLOGICA, Issue 2009N LEVEZIEL Age-related Macular Degeneration (AMD) is the main cause of vision loss in developed countries. Spectral domain OCT (SD-OCT) is a non invasive technique providing in vivo imaging of the retina, with a higher resolution than time domain OCT. This SIS will describe the clinical features of exudative AMD with SD-OCT, including occult choroidal neovascularization (CNV), classic CNV, idiopathic polypoïdal vasculopathy, and chorioretinal anastomosis. The improvement of the resolution of retinal imaging will provide a better classification and explanation of the pathological processes observed during AMD. [source] Photodynamic therapy with verteporfin in age-related macular degeneration: a systematic review of efficacy, safety, treatment modifications and pharmacoeconomic propertiesACTA OPHTHALMOLOGICA, Issue 2 2009Alan F. Cruess Abstract. Photodynamic therapy (PDT) with verteporfin has been used less comprehensively in the treatment of exudative age-related macular degeneration (AMD), and specifically of choroidal neovascularization (CNV), since the advent of antiangiogenic therapies. Recently, there has been a renewed interest in PDT as an adjunct to these and other agents in the treatment of neovascular AMD. In light of this new development and the European Medicines Evaluation Agency's (EMEA) recent labelling decision to rescind approval for the use of PDT in occult CNV lesions, the present systematic review was undertaken to revisit the evidence supporting its clinical application. Photodynamic therapy provided the first pharmacological treatment for patients suffering from subfoveal CNV, the major cause of severe vision loss in AMD. Key clinical trials evaluating efficacy and safety have examined patients with all lesion subtypes, with the primary labelled indication (i.e. lesions containing a classic component of , 50% ) deriving from the results of the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study. The subsequent TAP Study Group post hoc categorization of lesions as predominantly classic is open to question, however, as it appears that the overall efficacy in this group only may have reflected the especially strong response in 100% classic lesions. Based on a subgroup analysis of the Verteporfin in Photodynamic Therapy Study, the indication for PDT subsequently was expanded in some jurisdictions, including that of the EMEA, to include occult lesions with no classic component. However, the subsequent Visudyne in Occult Study found no benefit in 100% occult lesions, resulting in the EMEA rescinding its approval for this indication. [source] Diode laser photocoagulation of choroidal neovascularization associated with retinal pigment epithelial detachmentACTA OPHTHALMOLOGICA, Issue 1 2001Francisco Gomez-Ulla ABSTRACT. Aims/Background: Association of choroidal neovascularization with pigment epithelial detachment is not an uncommon feature. Since this condition usually has a poor visual outcome, new treatments should be developed. Methods: We studied the anatomical and visual results of 11 eyes with this association as a manifestation of an Exudative Age Related Macular Degeneration which were treated with diode laser photocoagulation guided by indocyanine green angiography. The average follow up time was 25.5 months (from 12 to 48 months). Results: Complete closure with complete resolution of the exudates and flattening of the detachment was observed in five eyes (45%). Visual acuity in the final examination improved or remained stable in 6 cases (55%). Conclusion: These results indicate that diode laser photocoagulation guided by indocyanine green angiography is at least as effective as conventional lasers with shorter wavelengths for treatment of vascularized pigment epithelial detachments in Age Related Macular Degeneration. [source] Methods for detecting age-related maculopathy: a comparison between photographic and clinical assessmentCLINICAL & EXPERIMENTAL OPHTHALMOLOGY, Issue 5 2000Gabriella Tikellis GradDip ABSTRACT Purpose: To examine the sensitivity, specificity and overall agreement between photographic and clinical assessment in detecting age-related maculopathy (ARM) features in the context of an epidemiological study, the Vitamin E, Cataract and Age-related Maculopathy Study (VECAT). Methods: A total of 1204 volunteers aged between 55 and 80 years of age, who were enrolled in the VECAT Study, had both slit-lamp biomicroscopy examination and fundus photos taken as part of the baseline ophthalmic examination. The Nidek 3-DX fundus camera (Nidek, Gamagori, Japan) was used to produce paired, one-framed, coloured, 15° stereoslides of the macular area at a fixed angle. An International Classification and Grading System for Age-related Maculopathy and Age-related Macular Degeneration was used to grade the stereoslides. Agreement in the detection of drusen, pigment abnormalities, and late stage ARM features was assessed using unweighted kappa statistic. Cases of disagreement were verified using clinical data records, grading documentation and the review of stereoslides. Results: Macula status was available for 2386 eyes. For drusen of size < 63 ,m, sensitivity was 47%, specificity was 68% with a kappa value of 0.20. For drusen , 125 ,m, sensitivity and specificity were , 81%. Kappa values ranged from 0.56 to 0.71. Levels of agreement for pigment abnormalities and late ARM were in the substantial range (i.e. kappa values from 0.70 to 1.00). Conclusions: Slit-lamp biomicroscopy was found to be comparable to photograding (using the Nidek 3-DX fundus camera) for detecting features pertaining to ARM. However, given the objectivity and permanency of stereoslides, photograding is still the more reliable and the preferred system of assessing ARM in the context of an epidemiological study. [source] The Y402H variant of complement factor H is associated with age-related macular degeneration but not with diabetic retinal disease in the Go-DARTS studyDIABETIC MEDICINE, Issue 5 2009A. S. F. Doney Abstract Aims, The Y402H variant of complement factor H (CFH) is associated with risk of age-related macular degeneration (ARMD). In common with ARMD, diabetic retinal disease also appears to involve complement activation. The aim was to investigate the impact of Y402H on both retinal pathologies in patients with Type 2 diabetes (T2DM) undergoing systematic eye screening. Methods, Patients with T2DM (n = 2350) were genotyped for the CFH Y402H variant. The association of genotype with retinal disease was determined in both retrospective and prospective models. Results, The retrospective study demonstrated that the HH genotype was associated with an age-adjusted odds ratio of 7.4 for ARMD (P = 2.9 × 10,11). In a longitudinal study in the disease-free cohort, the age-adjusted hazard ratio was 2.8 (P = 2.4 × 10,7). The life-time hazard ratio was 3.4 (P = 2.1 × 10,16). We found no association of Y402H with development of referable diabetic retinal disease. Conclusion, The ARMD-associated Y402H variant in CFH does not appear to be associated with diabetic retinal disease, although complement activation is involved in the pathoaetiology of both conditions. [source] Oxidative damage of retinal pigment epithelial cells and age-related macular degenerationDRUG DEVELOPMENT RESEARCH, Issue 5 2007Suofu Qin Abstract Damage to the retinal pigment epithelial (RPE) cells is an early and crucial event in the molecular pathways leading to clinically relevant age-related macular degeneration (AMD) changes. Oxidative stress, the major environmental risk factor for atrophic AMD, causes RPE injury that results in a chronic inflammatory response, drusen formation, and RPE atrophy. RPE degeneration ultimately leads to a progressive irreversible degeneration of photoreceptors. In vitro studies show that oxidant-treated RPE cells undergo apoptosis, a possible mechanism by which RPE cells are lost during the early phase of atrophic AMD. The main target of oxidative injury appears to be mitochondria, an organelle known to accumulate genomic damage during aging. Addition of GSH, the most abundant intracellular thiol antioxidant, protects RPE cells from oxidant-induced apoptosis. Similar protection occurs with dietary enzyme inducers that increase GSH synthesis. In addition, enhancing survival signaling preserves RPE cells under oxidative stress. These results indicate that therapeutic or nutritional intervention to enhance the antioxidant capacity and survival signaling of RPE may provide an effective way to prevent or treat AMD. This review describes major molecular and cellular events leading to RPE death, and presents currently used and new experimental, forthcoming therapeutic strategies. Drug Dev Res 68:213,225, 2007. © 2007 Wiley-Liss, Inc. [source] Pegaptanib sodium for age-related macular degenerationFUTURE PRESCRIBER, Issue 3 2006Phil Hykin FRCOphth, Sobha Sivaprasad FRCS [source] Testing association for markers on the X chromosome,GENETIC EPIDEMIOLOGY, Issue 8 2007Gang Zheng Abstract Test statistics for association between markers on autosomal chromosomes and a disease have been extensively studied. No research has been reported on performance of such test statistics for association on the X chromosome. With 100,000 or more single-nucleotide polymorphisms (SNPs) available for genome-wide association studies, thousands of them come from the X chromosome. The X chromosome contains rich information about population history and linkage disequilibrium. To identify X-linked marker susceptibility to a disease, it is important to study properties of various statistics that can be used to test for association on the X chromosome. In this article, we compare performance of several approaches for testing association on the X chromosome, and examine how departure from Hardy-Weinberg equilibrium would affect type I error and power of these association tests using X-linked SNPs. The results are applied to the X chromosome of Klein et al. [2005], a genome-wide association study with 100K SNPs for age-related macular degeneration. We found that a SNP (rs10521496) covered by DIAPH2, known to cause premature ovarian failure (POF) in females, is associated with age-related macular degeneration. Genet. Epidemiol. 2007. Published 2007 Wiley-Liss, Inc. [source] Interpreting analyses of continuous covariates in affected sibling pair linkage studiesGENETIC EPIDEMIOLOGY, Issue 6 2007Silke Schmidt Abstract Datasets collected for linkage analyses of complex human diseases often include a number of clinical or environmental covariates. In this study, we evaluated the performance of three linkage analysis methods when the relationship between continuous covariates and disease risk or linkage heterogeneity was modeled in three different ways: (1) The covariate distribution is determined by a quantitative trait locus (QTL), which contributes indirectly to the disease risk; (2) the covariate is not genetically determined, but influences the disease risk through statistical interaction with a disease susceptibility locus; (3) the covariate distribution differs in families linked or unlinked to a particular disease susceptibility locus. We analyzed simulated datasets with a regression-based QTL analysis, a nonparametric analysis of the binary affection status, and the ordered subset analysis (OSA). We found that a significant OSA result may be due to a gene that influences variability in the population distribution of a continuous disease risk factor. Conversely, a regression-based QTL analysis may detect the presence of gene-environment (G × E) interaction in a sample of primarily affected individuals. The contribution of unaffected siblings and the size of baseline lod scores may help distinguish between QTL and G × E models. As illustrated by a linkage study of multiplex families with age-related macular degeneration, our findings assist in the interpretation of analysis results in real datasets. They suggest that the side-by-side evaluation of OSA and QTL results may provide important information about the relationship of measured covariates with either disease risk or linkage heterogeneity. Genet. Epidemiol. 2007. © 2007 Wiley-Liss, Inc. [source] Case,control genetic association study of fibulin-6 (FBLN6 or HMCN1) variants in age-related macular degeneration (AMD),HUMAN MUTATION, Issue 4 2007Sheila A. Fisher Abstract This article reports a well-powered age-related macular degeneration (AMD) case,control association study in the HMCN1 gene, showing that common variants do not account for a substantial proportion of AMD cases. Thus, the consistent linkage peak observed by several genome-wide linkage scans within the 1q32 region is unlikely to be attributed to polymorphisms at the HMCN1 locus. In addition, the analysis provides comprehensive data suggesting that low-frequency variants encoding possible functional amino acid polymorphisms in the HMCN1 gene may not contribute substantially to disease, although HMCN1 mutations may still confer disease susceptibility in a small subset of patients. Interestingly, the HMCN1 p.Gln5346Arg mutation, which is thought to be a causal mutation in a large AMD pedigree segregating the disease as a single-gene trait, appears to occur in our control cohort as a low-frequency polymorphism with an allele frequency of approximately 0.0026. Hum Mutat 28(4), 406,413, 2007. © 2007 Wiley-Liss, Inc. [source] Ethnic variation in AMD-associated complement factor H polymorphism p.Tyr402His,HUMAN MUTATION, Issue 9 2006Michael A. Grassi Abstract Age-related macular degeneration (AMD) is the most common cause of irreversible visual loss in the developed world. Previous studies have demonstrated that the c.1204T>C, p.Tyr402His allelic variant in the complement factor H (CFH) gene is associated with an approximately three-fold increased risk for AMD in Caucasians of predominantly European descent. Both the prevalence as well as the phenotypic spectrum of AMD varies widely among persons of different ethnicities. We hypothesized that populations with a lower prevalence of AMD might also have a lower prevalence of the CFH risk allele. In this study we sought to determine the frequency of this sequence variant in control populations of Caucasians, African Americans, Hispanics, Somalis, and Japanese. Normal control populations were assembled for each ethnic group: Caucasian (n=148), Somali (n=128), African American (n=75), Hispanic (n=81), and Japanese (n=82). Individuals were genotyped using a restriction digest assay and the frequency of the C allele at nucleotide position 1204 of the CFH gene was determined. A bioinformatic approach was used to identify SNPs in linkage disequilibrium with rs1061170 (c.1204T>C, p.Tyr402His) from the human haplotype map project database (HapMap) in order to validate the findings. We found widely discordant frequencies of the risk allele between some of the different ethnic groups: Japanese 0.07±0.02, Hispanics 0.17±0.03, African-Americans 0.35±0.04, Caucasians 0.34±0.03, and Somalis 0.34±0.03. Allele frequencies generated by analysis of the HapMap database were consistent with these findings. This study suggests that there are other yet unidentified genetic factors important in the pathogenesis of AMD that may mitigate the effects of c.1204T>C, p.Tyr402His variant. Hum Mutat 27(9), 921,925, 2006. © 2006 Wiley-Liss, Inc. [source] Dip-Pen Nanolithography of Bioactive Peptides on Collagen-Terminated Retinal Membrane,ADVANCED MATERIALS, Issue 19 2008Rizaldi Sistiabudi Dip-pen nanolithography is used to directly modify freshly dissected eye tissues with biologically active collagen-binding peptide molecules. The results address the challenge of surface heterogeneity and utilize dip-pen nanolithography to control the localization and concentration of molecules on a collagen-terminated tissue-derived surface. This method can allow the development of scaffolds for treatment of age-related macular degeneration. [source] Age-Related Macular Degeneration: Self-Management and Reduction of Depressive Symptoms in a Randomized, Controlled StudyJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 10 2006Barbara L. Brody MPH OBJECTIVES: To assess the effectiveness of a self-management program for age-related macular degeneration (AMD) in reducing depressive symptoms. DESIGN: Analysis of 6-month follow-up for a subset of participants in a randomized, controlled trial who were clinically depressed at baseline. SETTING: University ophthalmology clinic. PARTICIPANTS: Thirty-two depressed older adult volunteers (mean age 81.5) with advanced AMD who had been randomized to a self-management program (n=12) or one of two control conditions (n=20). Subjects were included if at baseline they met criteria from the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Axis, I, Fourth Edition, Research Version, for major or minor depressive disorder with significant depressive symptoms (,5 points) on the 15-item Geriatric Depression Scale (GDS-15). INTERVENTION: AMD self-management program consisting of cognitive and behavioral elements including health education and enhancement of problem-solving skills. MEASUREMENTS: Primary outcome measure was GDS-15. Secondary outcome measures included National Eye Institute Visual Function Questionnaire (NEI-VFQ) and AMD Self-Efficacy Questionnaire. RESULTS: At 6-month follow-up, the self-management group had a significantly greater reduction in depressive symptoms on the GDS-15 than the controls (P=.03). The mean reduction of 2.92 points in the self-management group was more than the 2-point change threshold considered to be clinically meaningful. Change on the NEI-VFQ was nonsignificant. Reduction in depressive symptoms was associated with greater self-efficacy in the self-management group. CONCLUSION: These findings may support the effectiveness of an AMD self-management program for depressed older adults with advanced vision loss from AMD. [source] Crosstalk between Hsp70 molecular chaperone, lysosomes and proteasomes in autophagy-mediated proteolysis in human retinal pigment epithelial cellsJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 9b 2009Tuomas Ryhänen Abstract The pathogenesis of age-related macular degeneration involves chronic oxidative stress, impaired degradation of membranous discs shed from photoreceptor outer segments and accumulation of lysosomal lipofuscin in retinal pigment epithelial (RPE) cells. It has been estimated that a major part of cellular proteolysis occurs in proteasomes, but the importance of proteasomes and the other proteolytic pathways including autophagy in RPE cells is poorly understood. Prior to proteolysis, heat shock proteins (Hsps), agents that function as molecular chaperones, attempt to refold misfolded proteins and thus prevent the accumulation of cytoplasmic protein aggregates. In the present study, the roles of the Hsp70 molecular chaperone and proteasomal and lysosomal proteolytic pathways were evaluated in human RPE cells (ARPE-19). The Hsp70 and ubiquitin protein levels and localization were analysed by Western blotting and immunofluorescense. Confocal and transmission electron microscopy were used to detect cellular organelles and to evaluate the morphological changes. Hsp70 levels were modulated using RNA interference and overexpression techniques. Cell viability was measured by colorimetric assay. The proteasome inhibitor MG-132 evoked the accumulation of perinuclear aggregates positive for Hsp70, ubiquitin-protein conjugates and the lysosomal membrane protein LAMP-2. Interestingly, the hsp70 mRNA depletion significantly increased cell death in conjunction with proteasome inhibition. We found that the accumulation of lysosomes was reversible: a cessation of proteasome inhibition led to clearance of the deposits via a mechanism believed to include autophagy. The molecular chaperone Hsp70, proteasomes and autophagy have an important regulatory role in the protein turnover of human RPE cells and may thus open new avenues for understanding degenerative processes in retinal cells. [source] Genetics, epigenetics and pharmaco-(epi)genomics in angiogenesisJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 6b 2008Ian Buysschaert ,,Introduction ,,Angiogenesis is genetically pre-determined ,,Mutations causing vascular anomalies -,Venous anomalies -,Haemangiomas -,The transforming growth factor-ß in vascular anomalies -,Cerebral cavernous malformations ,,Translocations reveal novel angiogenic genes ,,Single nucleotide polymorphisms shape the angio-genome -,SNPs in VEGF and their association with cancer -,SNPs in VEGF pathway genes associated with other diseases -,Genetic variability in VEGFR-2 -,Genetic variability in HIF-1, -,SNPs in VEGFR-1 integrate angiogenesis within the P53 pathway -,Variations in angiogenic genes are linked with neurodegeneration -,Angiogenic factors in genome-wide association studies ,,Copy number variability affects angiogenesis ,,Epigenetic regulation of angiogenesis -,Methylation of anti-angiogenic factors -,Methylation as a second hit event in cancer -,Histone modifications determine angiogenesis ,,Micromanagers of angiogenesis ,,Perspectives Abstract Angiogenesis is controlled by a balance between pro- and anti-angiogenic factors. Studies in mice and human beings have shown that this balance, as well as the general sensitivity of the endothelium to these factors, is genetically pre-determined. In an effort to dissect this genetic basis, different types of genetic variability have emerged: mutations and translocations in angiogenic factors have been linked to several vascular malformations and haemangiomas, whereas SNPs have been associated with complex genetic disorders, such as cancer, neurodegeneration and diabetes. In addition, copy number alterations of angiogenic factors have been reported in several tumours. More recently, epigenetic changes caused by aberrant DNA methylation or histone acetylation of anti-angiogenic molecules have been shown to determine angiogenesis as well. Initial studies also revealed a crucial role for microRNAs in stimulating or reducing angiogenesis. So far, most of these genetic studies have focused on tumour angiogenesis, but future research is expected to improve our understanding of how genetic variants determine angiogenesis in other diseases. Importantly, these genetic insights might also be of important clinical relevance for the use of anti-angiogenic strategies in cancer or macular degeneration. [source] Cholinergic modulation of angiogenesis: Role of the 7 nicotinic acetylcholine receptorJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2009Jenny C.F. Wu Abstract Pathological angiogenesis contributes to tobacco-related diseases such as malignancy, atherosclerosis and age-related macular degeneration. Nicotine acts on endothelial nicotinic acetylcholine receptors (nAChRs) to activate endothelial cells and to augment pathological angiogenesis. In the current study, we studied nAChR subunits involved in these actions. We detected mRNA for all mammalian nAChR subunits except ,2, ,4, ,, and , in four different types of ECs. Using siRNA methodology, we found that the ,7 nAChR plays a dominant role in nicotine-induced cell signaling (assessed by intracellular calcium and NO imaging, and studies of protein expression and phosphorylation), as well as nicotine-activated EC functions (proliferation, survival, migration, and tube formation). The ,9 and ,7 nAChRs have opposing effects on nicotine-induced cell proliferation and survival. Our studies reveal a critical role for the ,7 nAChR in mediating the effects of nicotine on the endothelium. Other subunits play a modulatory role. These findings may have therapeutic implications for diseases characterized by pathological angiogenesis. J. Cell. Biochem. 108: 433,446, 2009. © 2009 Wiley-Liss, Inc. [source] VEGF in biological controlJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2007Ellen C. Breen Abstract Vascular endothelial growth factor A (VEGF-A) belongs to a family of heparin binding growth factors that include VEGF-B, VEGF-C, VEGF-D, and placental-like growth factor (PLGF). First discovered for its ability to regulate vascular endothelial cell permeability, VEGF is a well-known angiogenic factor that is important for vascular development and maintenance in all mammalian organs. The development of molecular tools and pharmacological agents to selectively inhibit VEGF function and block angiogenesis and/or vascular permeability has led to great promise in the treatment of various cancers, macular degeneration, and wound healing. However, VEGF is also important in animals for the regulation of angiogenesis, stem cell and monocyte/macrophage recruitment, maintenance of kidney and lung barrier functions and neuroprotection. In addition to its role in regulating endothelial cell proliferation, migration, and cell survival, VEGF receptors are also located on many non-endothelial cells and act through autrocrine pathways to regulate cell survival and function. The following review will discuss the role of VEGF in physiological angiogenesis as well as its role in non-angiogenic processes that take place in adult organs. J. Cell. Biochem. 102: 1358,1367, 2007. © 2007 Wiley-Liss, Inc. [source] Effects of intravitreal bevacizumab (Avastin®) therapy on retrobulbar blood flow parameters in patients with neovascular age-related macular degenerationJOURNAL OF CLINICAL ULTRASOUND, Issue 2 2010Ahmet Mete MD Abstract Background. To investigate the effects of intravitreal bevacizumab on retrobulbar circulation in patients with neovascular age-related macular degeneration (AMD). Method. Thirty patients with neovascular age-related macular degeneration were assessed prospectively by both color Doppler imaging and fundus fluorescein angiography. Spectral Doppler analysis allowed the measurement of the maximum velocity (Vmax) and minimum velocity (Vmin) of the central retinal vein (CRV), and peak systolic (PSV), end-diastolic (EDV) velocities of blood flows, and pulsatility index (PI) and resistance index (RI) values in the central retinal artery (CRA), nasal and temporal posterior ciliary arteries (NPCA, TPCA), and ophthalmic artery (OA). The t test for paired samples was used to compare retrobulbar blood flow values before and after intravitreal bevacizumab injection. Result. PSV and EDV of the NPCA and PSV of the TPCA were significantly decreased after intravitreal bevacizumab injection (p < 0.05). There was no statistically significant difference in the other parameters. Conclusion. Our results suggest that intravitreal bevacizumab therapy has a measurable effect on retrobulbar blood flow. © 2009 Wiley Periodicals, Inc. J Clin Ultrasound 2010 [source] Amyloid-,(1-42) alters structure and function of retinal pigmented epithelial cellsAGING CELL, Issue 2 2009Julien Bruban Summary Age-related macular degeneration (AMD) is characterized by the formation of drusen, extracellular deposits associated with atrophy of the retinal pigmented epithelium (RPE), disturbance of the transepithelial barrier and photoreceptor death. Amyloid-, (A,) is present in drusen but its role during AMD remains unknown. This study investigated the in vitro and in vivo effects of the oligomeric form of A,(1-42) , OA,(1-42) , on RPE and found that it reduced mitochondrial redox potential and increased the production of reactive oxygen species, but did not induce apoptosis in RPE cell cultures. It also disorganized the actin cytoskeleton and halved occludin expression, markedly decreasing attachment capacity and abolishing the selectivity of RPE cell transepithelial permeability. Antioxidant pretreatment partially reversed the effects of OA,(1-42) on mitochondrial redox potential and transepithelial permeability. Subretinally injected OA,(1-42) induced pigmentation loss and RPE hypertrophy but not RPE cell apoptosis in C57BL/6 J mice. Rapid OA,(1-42)-induced disorganization of cytoskeletal actin filaments was accompanied by decreased RPE expression of the tight junction proteins occludin and zonula occludens-1 and of the visual cycle proteins cellular retinaldehyde-binding protein and RPE65. The number of photoreceptors decreased by half within a few days. Our study pinpoints the role of A, in RPE alterations and dysfunctions leading to retinal degeneration and suggests that targeting A, may help develop selective methods for treating diseases involving retinal degeneration, such as AMD. [source] Age-related reduction in retinal deimination levels in the F344BN ratAGING CELL, Issue 3 2008Sanjoy K. Bhattacharya Summary Increased deimination and peptidyl arginine deiminase type 2 (PAD2) expression has been observed in age-related neurodegenerative diseases without discrimination between their aging and disease component. Here, we describe reduced levels of deimination commensurate with reduced protein, mRNA and activity of peptidylarginine deiminase type 2 in the retina, optic nerve and plasma of aged rats when compared to young rats. The decrease was significant in the ganglion cell layer, inner plexiform layer and inner nuclear layer. Because our observations suggest reduced deimination is a consequence of aging, we conclude that increased deimination must be a consequence of disease. Our findings are important to understand late-onset and progressive diseases such as glaucoma, pseudoexfoliation syndrome, age-related macular degeneration and Oguchi's disease. [source] Flowers and Leaves of Tropaeolum majus L. as Rich Sources of LuteinJOURNAL OF FOOD SCIENCE, Issue 9 2005P.Y. Niizu ABSTRACT: As increasing evidence supports the role of lutein and zeaxanthin in reducing the risk of cataract and macular degeneration, food sources of these carotenoids are being sought. In the present study, the lutein content of the edible flowers and leaves of Tropaeolum majus L. was determined by high-performance liquid chromatography-photodiode array detector (HPLC-PDAD), complemented by HPLC-mass spectrometry (MS) for identification. Chemical reactions were also used as identifying parameters. The yellow and brownish orange flowers had 450 ± 60 ,g/g and 350 ± 50 ,g/g lutein, respectively. Violaxanthin, antheraxanthin, zeaxanthin, zeinoxanthin, ,-cryptoxanthin, ,-carotene, and ,-carotene were also detected at very low levels. The leaves had 136 ± 18 ,g/g lutein, 69 ± 7 ,g/g ,-carotene, 74 ± 23 ,g/g violaxanthin, and 48 ± 13 ,g/g neoxanthin. Lutein was partly esterified in the flowers and unesterified in the leaves. The flowers of T. majus are therefore excellent food sources of lutein and the leaves good sources of both lutein and the provitamin A ,-carotene. [source] Increased expression of glial cell line-derived neurotrophic factor protects against oxidative damage-induced retinal degenerationJOURNAL OF NEUROCHEMISTRY, Issue 3 2007Aling Dong Abstract Oxidative damage contributes to retinal cell death in patients with age-related macular degeneration or retinitis pigmentosa. One approach to treatment is to identify and eliminate the sources of oxidative damage. Another approach is to identify treatments that protect cells from multiple sources of oxidative damage. In this study, we investigated the effect of increased expression of glial cell line-derived neurotrophic factor (GDNF) in three models of oxidative damage-induced retinal degeneration. Double transgenic mice with doxycycline-inducible expression of GDNF in the retina were exposed to paraquat, FeSO4, or hyperoxia, all sources of oxidative damage and retinal cell death. Compared to controls, mice with increased expression of GDNF in the retina showed significant preservation of retinal function measured by electroretinograms, reduced thinning of retinal cell layers, and fewer TUNEL-positive cells indicating less retinal cell death. Mice over-expressing GDNF also showed less staining for acrolein, nitrotyrosine, and 8-hydroxydeoxyguanosine, indicating less oxidative damage to lipids, proteins, and DNA. This suggests that GDNF did not act solely to allow cells to tolerate higher levels of oxidative damage before initiation of apoptosis, but also reduced damage from oxidative stress to critical macromolecules. These data suggest that gene transfer of Gdnf should be considered as a component of therapy for retinal degenerations in which oxidative damage plays a role. [source] Effects of lutein and zeaxanthin on aspects of eye healthJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 1 2010Le Ma Abstract Lutein and zeaxanthin are members of the oxygenated carotenoids found particularly in egg yolks and dark-green leafy vegetables. A great deal of research has focused on their beneficial roles in eye health. The present article summarises the current literature related to the bioactivity of these carotenoids, emphasising their effects and possible mechanisms of action in relation to human eye health. Available evidence demonstrates that lutein and zeaxanthin are widely distributed in a number of body tissues and are uniquely concentrated in the retina and lens, indicating that each has a possible specific function in these two vital ocular tissues. Most of epidemiological studies and clinical trials support the notion that lutein and zeaxanthin have a potential role in the prevention and treatment of certain eye diseases such as age-related macular degeneration, cataract and retinitis pigmentosa. The biological mechanisms for the protective effects of these carotenoids may include powerful blue-light filtering activities and antioxidant properties. Although most studies point towards significant health benefits from lutein and zeaxanthin, further large-scale randomised supplementation trials are needed to define their effects on ocular function in health and disease. Copyright © 2009 Society of Chemical Industry [source] | ||||||||||||||||