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Search Results: 1 - 10 of 329622 matches for " Gregory S Hageman "
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Clinical validation of a genetic model to estimate the risk of developing choroidal neovascular age-related macular degeneration
Gregory S Hageman, Karen Gehrs, Serguei Lejnine, Aruna T Bansal, Margaret M DeAngelis, Robyn H Guymer, Paul N Baird, Rando Allikmets, Cosmin Deciu, Paul Oeth, Lorah T Perlee
Human Genomics , 2011, DOI: 10.1186/1479-7364-5-5-420
Abstract: Many diseases of ageing characterised by complex inheritance patterns are progressive; the individual may be asymptomatic in the early stages. One of these diseases, age-related macular degeneration (AMD), is the most common cause of visual impairment and the leading cause of blindness in the elderly population in the developed world. The prevalence of AMD increases with advancing age in all populations studied. Thus, in developed nations such as the USA, UK, Canada and Australia, with increasingly aged populations, the condition affects a progressively larger segment of the population and has become a major public health issue. Early- or late-stage AMD is present in 15 per cent of individuals over the age of 60 years [1]. It is estimated that there are currently 9.1 million patients in the USA with AMD, of which 1.7 million suffer with the vision-threatening late-stage complications of choroidal neovascularisation (CNV) or geographic atrophy [1]. Moreover, it is predicted that the number of cases of early AMD will increase to 17.8 million by 2050 and, if untreated, cases of late-stage blinding AMD will increase to 3.8 million [1]. It has been determined that vision loss from AMD decreases quality of life by 60 per cent, similar to the experience of dealing with a stroke that requires intensive nursing care [2].The clinical presentation and natural course of AMD are highly variable. The disease may present as early as the fifth decade of life or as late as the ninth decade. The clinical symptoms of AMD range from no visual disturbances in early disease to profound loss of central vision in the advanced late stages of the disease. Some patients never progress beyond early AMD; however, in 10-15 per cent of Caucasian patients with early-stage disease, the condition progresses to an exudative neovascular (or 'wet' form) or geographic atrophic (or 'dry' form) AMD, which threatens vision. The phenotype is characterised by development of subretinal choroidal neovascular c
Systems-level analysis of age-related macular degeneration reveals global biomarkers and phenotype-specific functional networks
Aaron M Newman, Natasha B Gallo, Lisa S Hancox, Norma J Miller, Carolyn M Radeke, Michelle A Maloney, James B Cooper, Gregory S Hageman, Don H Anderson, Lincoln V Johnson, Monte J Radeke
Genome Medicine , 2012, DOI: 10.1186/gm315
Abstract: RPE-choroid and retina tissue samples were obtained from a common cohort of 31 normal, 26 AMD, and 11 potential pre-AMD human donor eyes. Transcriptome profiles were generated for macular and extramacular regions, and statistical and bioinformatic methods were employed to identify disease-associated gene signatures and functionally enriched protein association networks. Selected genes of high significance were validated using an independent donor cohort.We identified over 50 annotated genes enriched in cell-mediated immune responses that are globally over-expressed in RPE-choroid AMD phenotypes. Using a machine learning model and a second donor cohort, we show that the top 20 global genes are predictive of AMD clinical diagnosis. We also discovered functionally enriched gene sets in the RPE-choroid that delineate the advanced AMD phenotypes, neovascular AMD and geographic atrophy. Moreover, we identified a graded increase of transcript levels in the retina related to wound response, complement cascade, and neurogenesis that strongly correlates with decreased levels of phototransduction transcripts and increased AMD severity. Based on our findings, we assembled protein-protein interactomes that highlight functional networks likely to be involved in AMD pathogenesis.We discovered new global biomarkers and gene expression signatures of AMD. These results are consistent with a model whereby cell-based inflammatory responses represent a central feature of AMD etiology, and depending on genetics, environment, or stochastic factors, may give rise to the advanced AMD phenotypes characterized by angiogenesis and/or cell death. Genes regulating these immunological activities, along with numerous other genes identified here, represent promising new targets for AMD-directed therapeutics and diagnostics.Please see related commentary: http://www.biomedcentral.com/1741-7015/10/21/abstract webciteThe neural retina, retinal pigmented epithelium (RPE), and choroid tissue complex is o
Influence of ROBO1 and RORA on Risk of Age-Related Macular Degeneration Reveals Genetically Distinct Phenotypes in Disease Pathophysiology
Gyungah Jun, Michael Nicolaou, Margaux A. Morrison, Jacqueline Buros, Denise J. Morgan, Monte J. Radeke, Yoshihiro Yonekawa, Evangelia E. Tsironi, Maria G. Kotoula, Fani Zacharaki, Nissa Mollema, Yang Yuan, Joan W. Miller, Neena B. Haider, Gregory S. Hageman, Ivana K. Kim, Debra A. Schaumberg, Lindsay A. Farrer, Margaret M. DeAngelis
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025775
Abstract: ROBO1 is a strong candidate gene for age-related macular degeneration (AMD) based upon its location under a linkage peak on chromosome 3p12, its expression pattern, and its purported function in a pathway that includes RORA, a gene previously associated with risk for neovascular AMD. Previously, we observed that expression of ROBO1 and RORA is down-regulated among wet AMD cases, as compared to their unaffected siblings. Thus, we hypothesized that contribution of association signals in ROBO1, and interaction between these two genes may be important for both wet and dry AMD. We evaluated association of 19 single nucleotide polymorphisms (SNPs) in ROBO1 with wet and dry stages of AMD in a sibling cohort and a Greek case-control cohort containing 491 wet AMD cases, 174 dry AMD cases and 411 controls. Association signals and interaction results were replicated in an independent prospective cohort (1070 controls, 164 wet AMD cases, 293 dry AMD cases). The most significantly associated ROBO1 SNPs were rs1387665 under an additive model (meta P = 0.028) for wet AMD and rs9309833 under a recessive model (meta P = 6×10?4) for dry AMD. Further analyses revealed interaction between ROBO1 rs9309833 and RORA rs8034864 for both wet and dry AMD (interaction P<0.05). These studies were further supported by whole transcriptome expression profile studies from 66 human donor eyes and chromatin immunoprecipitation assays from mouse retinas. These findings suggest that distinct ROBO1 variants may influence the risk of wet and dry AMD, and the effects of ROBO1 on AMD risk may be modulated by RORA variants.
Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration
Margaux A Morrison, Alexandra C Silveira, Nancy Huynh, Gyungah Jun, Silvia E Smith, Fani Zacharaki, Hajime Sato, Stephanie Loomis, Michael T Andreoli, Scott M Adams, Monte J Radeke, Austin S Jelcick, Yang Yuan, Aristoteles N Tsiloulis, Dimitrios Z Chatzoulis, Giuliana Silvestri, Maria G Kotoula, Evangelia E Tsironi, Bruce W Hollis, Rui Chen, Neena B Haider, Joan W Miller, Lindsay A Farrer, Gregory S Hageman, Ivana K Kim, Debra A Schaumberg, Margaret M DeAngelis
Human Genomics , 2011, DOI: 10.1186/1479-7364-5-6-538
Abstract: Based on the relationship between ultraviolet irradiance and vitamin D production, we employed a candidate gene approach for evaluating common variation in key vitamin D pathway genes (the genes encoding the vitamin D receptor [VDR]; cytochrome P450, family 27, subfamily B, polypeptide 1 [CYP27B1]; cytochrome P450, family 24, subfamily A, polypeptide 1 [CYP24A1]; and CYP27A1) in this same family-based cohort. Initial findings were then validated and replicated in the extended family cohort, an unrelated case-control cohort from central Greece and a prospective nested case-control population from the Nurse's Health Study and Health Professionals Follow-Up Studies, which included patients with all subtypes of AMD for a total of 2,528 individuals. Single point variants in CYP24A1 (the gene encoding the catabolising enzyme of the vitamin D pathway) were demonstrated to influence AMD risk after controlling for smoking history, sex and age in all populations, both separately and, more importantly, in a meta-analysis. This is the first report demonstrating a genetic association between vitamin D metabolism and AMD risk. These findings were also supplemented with expression data from human donor eyes and human retinal cell lines. These data not only extend previous biological studies in the AMD field, but further emphasise common antecedents between several disorders with an inflammatory/immunogenic component such as cardiovascular disease, cancer and AMD.Several biological processes/cellular pathways involved in conditions such as cancer, cardiovascular disease and type 1 diabetes have also been implicated in the pathophysiology of the neovascular form of age-related macular degeneration (AMD). AMD, a disease characterised by the loss of ability to drive, recognise faces and read, is the leading cause of blindness in the US elderly population. Most prominent among these shared disease-associated processes is angiogenesis, the defining hallmark of neovascular AMD [1-3]. Add
Science Fiction, Ecological Futures, and the Topography of Fritz Lang’s Metropolis
Andrew Hageman
Ecozon@ : European Journal of Literature, Culture and Environment , 2012,
Abstract: Since 1927, Fritz Lang’s Metropolis has circulated as stills, clips, and a sequence ofincreasingly more complete cuts in the global social imaginary. Whilst scholars havecritiqued this science fiction film from gender, techno-culture, and German sociopoliticalperspectives, this article analyzes the film afresh by reading it ecocritically. Thearticle moves through three key components of Metropolis. The first movementexamines the representational and ideological contradictions within the variety ofmachines inside the diegetic city to deconstruct the common interpretation of the film’smachines as dehumanizing and alienating people from a “natural” world. The secondmovement reads the film’s urban topography, dwelling particularly on Rotwang’s houseas indigestible history and the Club of the Sons as “nature”-themed fantasy place. Third,the article analyzes what I am calling the film’s “organ dialectic” of antithetical hand andhead sublated in the heart to show how this metaphor structure complicates not onlythe film’s conclusion but also common ecological epistemological and ontologicaltheories that invoke the organic and the mechanic. Ultimately, the article assemblesthese three analytical components to argue that contradictions within the narrative,representational, and rhetorical structures of Metropolis illuminate crucial ideologicalchallenges of thinking ecology and technology together, whether in 1927 or today.
Associations of Cardiorespiratory Fitness and Fatness with Metabolic Syndrome in Rural Women with Prehypertension
Patricia A. Hageman,Carol H. Pullen,Melody Hertzog,Linda S. Boeckner,Susan Noble Walker
Journal of Obesity , 2012, DOI: 10.1155/2012/618728
Abstract: Background. This study investigated the associations of fitness and fatness with metabolic syndrome in rural women, part of a recognized US health disparities group. Methods. Fitness, percentage body fat, BMI, and metabolic syndrome criteria were assessed at baseline in 289 rural women with prehypertension, ages 40–69, enrolled in a healthy eating and activity community-based clinical trial for reducing blood pressure. Results. Ninety (31%) women had metabolic syndrome, of which 70% were obese by BMI (≥30 kg/m2), 100% by percentage body fat (≥30%), and 100% by revised BMI standards (≥25 kg/m2) cited in current literature. Hierarchical logistic regression models, adjusted for age, income, and education, revealed that higher percentage body fat (P < 0.001) was associated with greater prevalence of metabolic syndrome. Alone, higher fitness lowered the odds of metabolic syndrome by 7% (P < 0.001), but it did not lower the odds significantly beyond the effects of body fat. When dichotomized into “fit” and “unfit” groups, women categorized as “fat” had lower odds of metabolic syndrome if they were “fit” by 75% and 59%, for percentage body fat and revised BMI, respectively. Conclusion. Among rural women with prehypertension, obesity and fitness were associated with metabolic syndrome. Obesity defined as ≥25 kg/m2 produced results more consistent with percentage body fat as compared to the ≥30 kg/m2 definition.
Web-based interventions for weight loss and weight maintenance among rural midlife and older women: protocol for a randomized controlled trial
Patricia A Hageman, Carol H Pullen, Melody Hertzog, Linda S Boeckner, Susan Walker
BMC Public Health , 2011, DOI: 10.1186/1471-2458-11-521
Abstract: This Women Weigh-In for Wellness (The WWW study) randomized-controlled trial is designed to compare the effectiveness of theory-based behavior-change interventions using (1) website only, (2) website with peer-led support, or (3) website with professional email-counseling to facilitate initial weight loss (baseline to 6 months), guided continuing weight loss and maintenance (7-18 months) and self-directed weight maintenance (19-30 months) among rural women ages 45-69 with a BMI of 28-45. Recruitment efforts using local media will target 306 rural women who live within driving distance of a community college site where assessments will be conducted at baseline, 3, 6, 12, 18, 24 and 30 months by research nurses blinded to group assignments. Primary outcomes include changes in body weight, % weight loss, and eating and activity behavioral and biomarkers from baseline to each subsequent assessment. Secondary outcomes will be percentage of women achieving at least 5% and 10% weight loss without regain from baseline to 6, 18, and 30 months and achieving healthy eating and activity targets. Data analysis will use generalized estimating equations to analyze average change across groups and group differences in proportion of participants achieving target weight loss levels.The Women Weigh-In for Wellness study compares innovative web-based alternatives for providing lifestyle behavior-change interventions for promoting weight loss and weight maintenance among rural women. If effective, such interventions would offer potential for reducing overweight and obesity among a vulnerable, hard-to-reach, population of rural women.ClinicalTrials.gov: NCT01307644With obesity now considered an epidemic, multiple national initiatives are emphasizing the need to assist Americans in balancing healthful eating with regular physical activity [1-5]. The Strategic Plan for NIH Obesity Research emphasizes the need to include understudied rural populations and to design and test interventions us
Associations of Cardiorespiratory Fitness and Fatness with Metabolic Syndrome in Rural Women with Prehypertension
Patricia A. Hageman,Carol H. Pullen,Melody Hertzog,Linda S. Boeckner,Susan Noble Walker
Journal of Obesity , 2012, DOI: 10.1155/2012/618728
Abstract: Background. This study investigated the associations of fitness and fatness with metabolic syndrome in rural women, part of a recognized US health disparities group. Methods. Fitness, percentage body fat, BMI, and metabolic syndrome criteria were assessed at baseline in 289 rural women with prehypertension, ages 40–69, enrolled in a healthy eating and activity community-based clinical trial for reducing blood pressure. Results. Ninety (31%) women had metabolic syndrome, of which 70% were obese by BMI (≥30?kg/m2), 100% by percentage body fat (≥30%), and 100% by revised BMI standards (≥25?kg/m2) cited in current literature. Hierarchical logistic regression models, adjusted for age, income, and education, revealed that higher percentage body fat (P < 0.001) was associated with greater prevalence of metabolic syndrome. Alone, higher fitness lowered the odds of metabolic syndrome by 7% (P < 0.001), but it did not lower the odds significantly beyond the effects of body fat. When dichotomized into “fit” and “unfit” groups, women categorized as “fat” had lower odds of metabolic syndrome if they were “fit” by 75% and 59%, for percentage body fat and revised BMI, respectively. Conclusion. Among rural women with prehypertension, obesity and fitness were associated with metabolic syndrome. Obesity defined as ≥25?kg/m2 produced results more consistent with percentage body fat as compared to the ≥30?kg/m2 definition. 1. Introduction Although substantial progress has been made in the awareness, prevention, and treatment of cardiovascular disease in women in the United States (USA) over the past 10 years, women’s lifetime risk of cardiovascular disease is high [1]. Adverse trends in cardiovascular disease risk factors are a growing concern, partly due to an ongoing increase in average body weight, with nearly two of every three women in the United States (USA) over 20 years of age now being classified as overweight or obese [2]. However, data from the National Health and Nutrition Survey (NHANES) collected from a series of cross-sectional national representative health surveys suggest that obesity prevalence among women in the USA has been stable for more than 10 years and that cardiovascular disease risk factors have been declining in the population, particularly among those with overweight or obesity [3, 4]. Yet, NHANES data also show that the prevalence of obesity and metabolic syndrome is markedly higher in rural women than urban residents [5, 6]. Metabolic syndrome is a designation given to individuals who have a cluster of risk factors characterized by abdominal
Mathematical and Statistical Modeling in Cancer Systems Biology
Rachael Hageman Blair
Frontiers in Physiology , 2012, DOI: 10.3389/fphys.2012.00227
Abstract: Cancer is a major health problem with high mortality rates. In the post-genome era, investigators have access to massive amounts of rapidly accumulating high-throughput data in publicly available databases, some of which are exclusively devoted to housing Cancer data. However, data interpretation efforts have not kept pace with data collection, and gained knowledge is not necessarily translating into better diagnoses and treatments. A fundamental problem is to integrate and interpret data to further our understanding in Cancer Systems Biology. Viewing cancer as a network provides insights into the complex mechanisms underlying the disease. Mathematical and statistical models provide an avenue for cancer network modeling. In this article, we review two widely used modeling paradigms: deterministic metabolic models and statistical graphical models. The strength of these approaches lies in their flexibility and predictive power. Once a model has been validated, it can be used to make predictions and generate hypotheses. We describe a number of diverse applications to Cancer Biology, including, the system-wide effects of drug-treatments, disease prognosis, tumor classification, forecasting treatment outcomes, and survival predictions.
Age Dependence of the Menstrual Cycle Correlation Dimension  [PDF]
Gregory N. Derry, Paula S. Derry
Open Journal of Biophysics (OJBIPHY) , 2012, DOI: 10.4236/ojbiphy.2012.22006
Abstract: Time series analysis, based on the idea that female reproductive endocrine physiology can be construed as a nonlinear dynamical system in a chaotic trajectory, is performed to measure the correlation dimension of the menstrual cycle data from subjects in two different age cohorts. The dimension is computed using a method proposed by Judd (Physica D, vol. 56, 1992, pp. 216-228) that does not assume the correlation dimension to be necessarily constant for all appropriate time scales of the system’s strange attractor. Significant time scale differences are found in the behavior of the dimension between the two age cohorts, but at the shortest time scales the correlation dimension converges to the same value, approximately 5.5, in both cases.
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