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Oklahoma City, OK, United States

Gardner A.W.,Reynolds Oklahoma Center on Aging | Waldstein S.R.,University of Maryland Baltimore County | Montgomery P.S.,Reynolds Oklahoma Center on Aging | Zhao Y.D.,The University of Oklahoma Health Sciences Center
Journal of Vascular Surgery | Year: 2016

Background We determined whether scores on a cognitive screening measure were associated with the primary outcome measure of peak walking time (PWT) and with secondary outcome measures related to mobility, community-based ambulation, health-related quality of life (QoL), and vascular function in patients with claudication and peripheral artery disease (PAD). Methods Gross cognitive status of 246 PAD patients was assessed with the Mini-Mental State Examination (MMSE) questionnaire. Patients were grouped according to whether they had a perfect MMSE score of 30 points (n = 123) or whether they missed one or more points (n = 123). Patients were characterized on numerous outcomes, including PWT during a treadmill test and QoL. Results Compared with the group with the higher MMSE scores, there was a trend for lower PWT in the group with the lower MMSE scores (P =.06) after adjusting for age, sex, race, and education level (model 1), which became significant (380 ± 250 seconds vs 460 ± 270 seconds; P <.05) after adjusting for model 1 plus coronary artery disease, chronic obstructive pulmonary disease, and arthritis (model 2). Multiple domains of QoL were lower (P <.05) in the group with the lower MMSE scores after adjusting for model 1, but only mental health remained lower (75 ± 20% vs 80 ± 5%; P =.02) after further adjustment with model 2. Conclusions In symptomatic patients with PAD, lower cognitive screening scores were associated with greater ambulatory impairment than in patients with higher MMSE scores. Furthermore, worse cognitive status was associated with lower scores in multiple dimensions of health-related QoL, all of which except mental health were explained by the comorbid conditions of coronary artery disease, chronic obstructive pulmonary disease, and arthritis. The clinical significance is that there is a need for enhanced cognitive and mental health screening as potential indicators of poor outcome among symptomatic patients with PAD. Furthermore, patients identified as having worse cognitive status might be in greatest need of intervention to improve ambulation and QoL related to mental health. Copyright © 2016 by the Society for Vascular Surgery. Published by Elsevier Inc. Source

Masser D.R.,Penn State College of Medicine | Masser D.R.,University of Oklahoma | Masser D.R.,Reynolds Oklahoma Center on Aging | VanGuilder Starkey H.D.,Penn State College of Medicine | And 6 more authors.
Experimental Eye Research | Year: 2014

Diabetic retinopathy is one of the leading causes of blindness in developed countries, and a majority of patients with type I and type II diabetes will develop some degree of vision loss despite blood glucose control regimens. The effects of different insulin therapy regimens on early metabolic, inflammatory and neuronal retinal disease processes such as retinal neuroinflammation and synapse loss have not been extensively investigated. This study compared 3 months non-diabetic and streptozotocin (STZ)-induced diabetic Sprague Dawley rats. Diabetic rats received either no insulin treatment, systemic insulin treatment beginning after 1 week uncontrolled diabetes (early intervention, 11 weeks on insulin), or after 1.5 months uncontrolled diabetes (late intervention, 6 weeks on insulin). Changes in both whole animal metabolic and retinal inflammatory markers were prevented by early initiation of insulin treatment. These metabolic and inflammatory changes were also normalized by the later insulin intervention. Insulin treatment begun 1 week after diabetes induction ameliorated loss of retinal synapse markers. Synapse markers and presumably synapse numbers were equivalent in uncontrolled diabetes and when insulin treatment began at 1.5 months of diabetes. These findings are in agreement with previous demonstrations that retinal synapses are lost within 1 month of uncontrolled diabetes and suggest that synapses are not regained with glycemic control and restoration of insulin signaling. However, increased expression of metabolic and inflammatory markers associated with diabetes was reversed in both groups of insulin treatment. This study also emphasizes the need for insulin treatment groups in diabetic retinopathy studies to provide a more faithful modeling of the human condition. © 2014 Elsevier Ltd. Source

Rindler P.M.,Oklahoma Medical Research Foundation | Plafker S.M.,Oklahoma Medical Research Foundation | Plafker S.M.,University of Oklahoma | Szweda L.I.,University of Oklahoma | And 4 more authors.
Journal of Biological Chemistry | Year: 2013

Background: High dietary fat is linked to cardiac oxidative stress, however, little is known about the endogenous antioxidant response. Results: High fat feeding and fasting rapidly up-regulate catalase. Conclusion: Up-regulation of catalase is designed to protect mitochondria from oxidative damage while not perturbing H2O2-mediated signaling. Significance: Coupling fatty acid oxidation to H2O2 production creates a mechanism for sensing and communicating diet composition. Obesity is a predictor of diabetes and cardiovascular disease. One consequence of obesity is dyslipidemia characterized by high blood triglycerides. It has been proposed that oxidative stress, driven by utilization of lipids for energy, contributes to these diseases. The effects of oxidative stress are mitigated by an endogenous antioxidant enzyme network, but little is known about its response to high fat utilization. Our experiments used a multiplexed quantitative proteomics method to measure antioxidant enzyme expression in heart tissue in a mouse model of diet-induced obesity. This experiment showed a rapid and specific up-regulation of catalase protein, with subsequent assays showing increases in activity and mRNA. Catalase, traditionally considered a peroxisomal protein, was found to be present in cardiac mitochondria and significantly increased in content and activity during high fat feeding. These data, coupled with the fact that fatty acid oxidation enhances mitochondrialH 2O2 production, suggest that a localized catalase increase is needed to consume excessive mitochondrial H2O2 produced by increased fat metabolism. To determine whether the catalase-specific response is a common feature of physiological conditions that increase blood triglycerides and fatty acid oxidation, we measured changes in antioxidant expression in fasted versus fed mice. Indeed, a similar specific catalase increase was observed in mice fasted for 24 h. Our findings suggest a fundamental metabolic process in which catalase expression is regulated to prevent damage while preserving anH2O2-mediated sensing of diet composition that appropriately adjusts insulin sensitivity in the short term as needed to prioritize lipid metabolism for complete utilization. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Hadad N.,Oklahoma Center for Neuroscience | Hadad N.,Reynolds Oklahoma Center on Aging | Masser D.R.,Reynolds Oklahoma Center on Aging | Masser D.R.,The University of Oklahoma Health Sciences Center | And 23 more authors.
Epigenetics and Chromatin | Year: 2016

Background: Changes to the epigenome with aging, and DNA modifications in particular, have been proposed as a central regulator of the aging process, a predictor of mortality, and a contributor to the pathogenesis of age-related diseases. In the central nervous system, control of learning and memory, neurogenesis, and plasticity require changes in cytosine methylation and hydroxymethylation. Although genome-wide decreases in methylation with aging are often reported as scientific dogma, primary research reports describe decreases, increases, or lack of change in methylation and hydroxymethylation and their principle regulators, DNA methyltransferases and ten-eleven translocation dioxygenases in the hippocampus. Furthermore, existing data are limited to only male animals. Results: Through examination of the hippocampus in young, adult, and old male and female mice by antibody-based, pyrosequencing, and whole-genome oxidative bisulfite sequencing methods, we provide compelling evidence that contradicts the genomic hypomethylation theory of aging. We also demonstrate that expression of DNA methyltransferases and ten-eleven translocation dioxygenases is not differentially regulated with aging or between the sexes, including the proposed cognitive aging regulator DNMT3a2. Using oxidative bisulfite sequencing that discriminates methylation from hydroxymethylation and by cytosine (CG and non-CG) context, we observe sex differences in average CG methylation and hydroxymethylation of the X chromosome, and small age-related differences in hydroxymethylation of CG island shores and shelves, and methylation of promoter regions. Conclusion: These findings clarify a long-standing misconception of the epigenomic response to aging and demonstrate the need for studies of base-specific methylation and hydroxymethylation with aging in both sexes. © 2016 The Author(s). Source

Masser D.R.,The University of Oklahoma Health Sciences Center | Masser D.R.,Reynolds Oklahoma Center on Aging | Masser D.R.,Harold Hamm Diabetes Center | Stanford D.R.,The University of Oklahoma Health Sciences Center | And 16 more authors.
Age | Year: 2016

Epigenetic regulation through DNA methylation (5mC) plays an important role in development, aging, and a variety of diseases. Genome-wide studies of base- and strand-specific 5mC are limited by the extensive sequencing required. Targeting bisulfite sequencing to specific genomic regions through sequence capture with complimentary oligonucleotide probes retains the advantages of bisulfite sequencing while focusing sequencing reads on regions of interest, enables analysis of more samples by decreasing the amount of sequence required per sample, and provides base- and strand-specific absolute quantitation of CG and non-CG methylation levels. As an example, an oligonucleotide capture set to interrogate 5mC levels in all rat RefSeq gene promoter regions (18,814) and CG islands, shores, and shelves (18,411) was generated. Validation using whole-genome methylation standards and biological samples demonstrates enrichment of the targeted regions and accurate base-specific quantitation of CG and non-CG methylation for both forward and reverse genomic strands. A total of 170 Mb of the rat genome is covered including 6.6 million CGs and over 67 million non-CG sites, while reducing the amount of sequencing required by ~85 % as compared to existing whole-genome sequencing methods. This oligonucleotide capture targeting approach and quantitative validation workflow can also be applied to any genome of interest. © 2016, American Aging Association. Source

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