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Search Results: 1 - 10 of 402747 matches for " Rhonda M Cooper-DeHoff "
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Comparing marginal structural models to standard methods for estimating treatment effects of antihypertensive combination therapy
Gerhard Tobias,Delaney Joseph AC,Cooper-DeHoff Rhonda M,Shuster Jonathan
BMC Medical Research Methodology , 2012, DOI: 10.1186/1471-2288-12-119
Abstract: Background Due to time-dependent confounding by blood pressure and differential loss to follow-up, it is difficult to estimate the effectiveness of aggressive versus conventional antihypertensive combination therapies in non-randomized comparisons. Methods We utilized data from 22,576 hypertensive coronary artery disease patients, prospectively enrolled in the INternational VErapamil-Trandolapril STudy (INVEST). Our post-hoc analyses did not consider the randomized treatment strategies, but instead defined exposure time-dependently as aggressive treatment (≥3 concomitantly used antihypertensive medications) versus conventional treatment (≤2 concomitantly used antihypertensive medications). Study outcome was defined as time to first serious cardiovascular event (non-fatal myocardial infarction, non-fatal stroke, or all-cause death). We compared hazard ratio (HR) estimates for aggressive vs. conventional treatment from a Marginal Structural Cox Model (MSCM) to estimates from a standard Cox model. Both models included exposure to antihypertensive treatment at each follow-up visit, demographics, and baseline cardiovascular risk factors, including blood pressure. The MSCM further adjusted for systolic blood pressure at each follow-up visit, through inverse probability of treatment weights. Results 2,269 (10.1%) patients experienced a cardiovascular event over a total follow-up of 60,939 person-years. The HR for aggressive treatment estimated by the standard Cox model was 0.96 (95% confidence interval 0.87-1.07). The equivalent MSCM, which was able to account for changes in systolic blood pressure during follow-up, estimated a HR of 0.81 (95% CI 0.71-0.92). Conclusions Using a MSCM, aggressive treatment was associated with a lower risk for serious cardiovascular outcomes compared to conventional treatment. In contrast, a standard Cox model estimated similar risks for aggressive and conventional treatments. Trial registration Clinicaltrials.gov Identifier: NCT00133692
The Tyrphostin Agent AG490 Prevents and Reverses Type 1 Diabetes in NOD Mice
Abdoreza Davoodi-Semiromi, Clive H. Wasserfall, Chang Qing Xia, Rhonda M. Cooper-DeHoff, Martin Wabitsch, Michael Clare-Salzler, Mark Atkinson
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036079
Abstract: Background Recent studies in the NOD (non-obese diabetic) mouse model of type 1 diabetes (T1D) support the notion that tyrosine kinase inhibitors have the potential for modulating disease development. However, the therapeutic effects of AG490 on the development of T1D are unknown. Materials and Methods Female NOD mice were treated with AG490 (i.p, 1 mg/mouse) or DMSO starting at either 4 or 8 week of age, for five consecutive week, then once per week for 5 additional week. Analyses for the development and/or reversal of diabetes, insulitis, adoptive transfer, and other mechanistic studies were performed. Results AG490 significantly inhibited the development of T1D (p = 0.02, p = 0.005; at two different time points). Monotherapy of newly diagnosed diabetic NOD mice with AG490 markedly resulted in disease remission in treated animals (n = 23) in comparision to the absolute inability (0%; 0/10, p = 0.003, Log-rank test) of DMSO and sustained eugluycemia was maintained for several months following drug withdrawal. Interestingly, adoptive transfer of splenocytes from AG490 treated NOD mice failed to transfer diabetes to recipient NOD.Scid mice. CD4 T-cells as well as bone marrow derived dendritic cells (BMDCs) from AG490 treated mice, showed higher expression of Foxp3 (p<0.004) and lower expression of co-stimulatory molecules, respectively. Screening of the mouse immune response gene arrary indicates that expression of costimulaotry molecule Ctla4 was upregulated in CD4+ T-cell in NOD mice treated with AG490, suggesting that AG490 is not a negative regulator of the immune system. Conclusion The use of such agents, given their extensive safety profiles, provides a strong foundation for their translation to humans with or at increased risk for the disease.
Power to identify a genetic predictor of antihypertensive drug response using different methods to measure blood pressure response
Stephen T Turner, Gary L Schwartz, Arlene B Chapman, Amber L Beitelshees, John G Gums, Rhonda M Cooper-DeHoff, Eric Boerwinkle, Julie A Johnson, Kent R Bailey
Journal of Translational Medicine , 2012, DOI: 10.1186/1479-5876-10-47
Abstract: We analyzed office, home, ambulatory daytime and nighttime BP responses in hypertensive adults randomized to atenolol (N = 242) or hydrochlorothiazide (N = 257) in the Pharmacogenomic Evaluation of Antihypertensive Responses Study. Since different measured BP responses may have different predictors, we tested the "same signal" model by using linear regression methods to determine whether known predictors of BP response depend on the method of BP measurement. We estimated signal-to-noise ratios and compared power to identify a genetic polymorphism predicting BP response measured by each method separately and by weighted averages of multiple methods.After adjustment for pretreatment BP level, known predictors of BP response including plasma renin activity, race, and sex were independent of the method of BP measurement. Signal-to-noise ratios were more than 2-fold greater for home and ambulatory daytime BP responses than for office and ambulatory nighttime BP responses and up to 11-fold greater for weighted averages of all four methods. Power to identify a genetic polymorphism predicting BP response was directly related to the signal-to-noise ratio and, therefore, greatest with the weighted averages.Since different methods of measuring BP response to antihypertensive drug therapy measure the same signal, weighted averages of the BP responses measured by multiple methods minimize measurement error and optimize power to identify genetic predictors of BP response.Although office blood pressure (BP) measurements remain the standard-of-care, averages of out-of-office measurements are more reproducible [1]. Out-of-office averages have also been reported to be more strongly correlated with subclinical target organ damage [2,3] and to better predict future cardiovascular disease events [4-6] than office measurements. Not surprisingly, BP responses to antihypertensive drug therapy are more precisely and accurately determined by out-of-office than office measurements, which are
Adrenergic gene polymorphisms and cardiovascular risk in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation
Michael A Pacanowski, Issam Zineh, Haihong Li, B Delia Johnson, Rhonda M Cooper-DeHoff, Vera Bittner, Dennis M McNamara, Barry L Sharaf, C Noel Merz, Carl J Pepine, Julie A Johnson
Journal of Translational Medicine , 2008, DOI: 10.1186/1479-5876-6-11
Abstract: We genotyped 628 women referred for coronary angiography for eight polymorphisms in the α1A-, β1-, β2- and β3-adrenergic receptors (ADRA1A, ADRB1, ADRB2, ADRB3, respectively), and their signaling proteins, G-protein β 3 subunit (GNB3) and G-protein α subunit (GNAS). We compared the incidence of death, myocardial infarction, stroke, or heart failure between genotype groups in all women and women without obstructive coronary stenoses.After a median of 5.8 years of follow-up, 115 women had an event. Patients with the ADRB1 Gly389 polymorphism were at higher risk for the composite outcome due to higher rates of myocardial infarction (adjusted hazard ratio [HR] 3.63, 95% confidence interval [95%CI] 1.17–11.28; Gly/Gly vs. Arg/Arg HR 4.14, 95%CI 0.88–19.6). The risk associated with ADRB1 Gly389 was limited to those without obstructive CAD (n = 400, Pinteraction = 0.03), albeit marginally significant in this subset (HR 1.71, 95%CI 0.91–3.19). Additionally, women without obstructive CAD carrying the ADRB3 Arg64 variant were at higher risk for the composite endpoint (HR 2.10, 95%CI 1.05–4.24) due to subtle increases in risk for all of the individual endpoints. No genetic associations were present in women with obstructive CAD.In this exploratory analysis, common coding polymorphisms in the β1- and β3-adrenergic receptors increased cardiovascular risk in women referred for diagnostic angiography, and could improve risk assessment, particularly for women without evidence of obstructive CAD.ClinicalTrials.gov NCT00000554.Coronary artery disease (CAD) is the leading cause of morbidity and mortality among women in the United States [1]. More than half of women presenting with chest pain or suspected myocardial ischemia do not have angiographic evidence of stenosis [2]. Despite the absence of obstructive lesions, many of these women have been shown to have myocardial ischemia due to microvascular disease [3,4] and are at high risk for cardiovascular events [5,6]. Diagnosing CAD an
Aromatase Gene Polymorphisms Are Associated with Survival among Patients with Cardiovascular Disease in a Sex-Specific Manner
Amber L. Beitelshees,Julie A. Johnson,Megan L. Hames,Yan Gong,Rhonda M. Cooper-DeHoff,Jun Wu,Sharon Cresci,Cynthia X. Ma,Carl J. Pepine,Michael A. Province,John A. Spertus,Howard L. McLeod
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015180
Abstract: CYP19A1 encodes aromatase, the enzyme responsible for the conversion of androgens to estrogens, and may play a role in variation in outcomes among men and women with cardiovascular disease. We sought to examine genetic variation in CYP19A1 for its potential role in sex differences in cardiovascular disease outcomes.
Pharmacometabolomics Reveals Racial Differences in Response to Atenolol Treatment
William R. Wikoff, Reginald F. Frye, Hongjie Zhu, Yan Gong, Stephen Boyle, Erik Churchill, Rhonda M. Cooper-Dehoff, Amber L. Beitelshees, Arlene B. Chapman, Oliver Fiehn, Julie A. Johnson, Rima Kaddurah-Daouk, Pharmacometabolomics Research Network
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057639
Abstract: Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p<0.0005, q<0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p<0.0001, q<0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p<0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p<0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug.
Atenolol Induced HDL-C Change in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study
Caitrin W. McDonough, Nancy K. Gillis, Abdullah Alsultan, Shin-Wen Chang, Marina Kawaguchi-Suzuki, Jason E. Lang, Mohamed Hossam A. Shahin, Thomas W. Buford, Nihal M. El Rouby, Ana C.C. Sá, Taimour Y. Langaee, John G. Gums, Arlene B. Chapman, Rhonda M. Cooper-DeHoff, Stephen T. Turner, Yan Gong, Julie A. Johnson
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076984
Abstract: We sought to identify novel pharmacogenomic markers for HDL-C response to atenolol in participants with mild to moderate hypertension. We genotyped 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study on the Illumina HumanCVD Beadchip. During PEAR, participants were randomized to receive atenolol or hydrochlorothiazide. Blood pressure and cholesterol levels were evaluated at baseline and after treatment. This study focused on participants treated with atenolol monotherapy. Association with atenolol induced HDL-C change was evaluated in 232 whites and 152 African Americans using linear regression. No SNPs achieved a Bonferroni corrected P-value. However, we identified 13 regions with consistent association across whites and African Americans. The most interesting of these regions were seven with prior associations with HDL-C, other metabolic traits, or functional implications in the lipid pathway: GALNT2, FTO, ABCB1, LRP5, STARD3NL, ESR1, and LIPC. Examples are rs2144300 in GALNT2 in whites (P=2.29x10-4, β=-1.85 mg/dL) and rs12595985 in FTO in African Americans (P=2.90x10-4, β=4.52 mg/dL), both with consistent regional association (P<0.05) in the other race group. Additionally, baseline GALNT2 expression differed by rs2144300 genotype in whites (P=0.0279). In conclusion, we identified multiple gene regions associated with atenolol induced HDL-C change that were consistent across race groups, several with functional implications or prior associations with HDL-C.
Effects of genetic variation in H3K79 methylation regulatory genes on clinical blood pressure and blood pressure response to hydrochlorothiazide
Julio D Duarte, Issam Zineh, Ben Burkley, Yan Gong, Taimour Y Langaee, Stephen T Turner, Arlene B Chapman, Eric Boerwinkle, John G Gums, Rhonda M Cooper-DeHoff, Amber L Beitelshees, Kent R Bailey, Roger B Fillingim, Bruce C Kone, Julie A Johnson
Journal of Translational Medicine , 2012, DOI: 10.1186/1479-5876-10-56
Abstract: We investigated associations between genetic variations in this candidate pathway and HCTZ blood pressure response in two separate hypertensive cohorts (clinicaltrials.gov NCT00246519 and NCT00005520). In a secondary, exploratory analysis, we measured associations between these same genetic variations and untreated blood pressure. Associations were measured by linear regression, with only associations with P ≤ 0.01 in one cohort and replication by P ≤ 0.05 in the other cohort considered significant.In one cohort, a polymorphism in DOT1L (rs2269879) was strongly associated with greater systolic (P = 0.0002) and diastolic (P = 0.0016) blood pressure response to hydrochlorothiazide in Caucasians. However, this association was not replicated in the other cohort. When untreated blood pressure levels were analyzed, we found directionally similar associations between a polymorphism in MLLT3 (rs12350051) and greater untreated systolic (P < 0.01 in both cohorts) and diastolic (P < 0.05 in both cohorts) blood pressure levels in both cohorts. However, when further replication was attempted in a third hypertensive cohort and in smaller, normotensive samples, significant associations were not observed.Our data suggest polymorphisms in DOT1L, MLLT3, SIRT1, and SGK1 are not likely associated with blood pressure response to HCTZ. However, a possibility exists that rs2269879 in DOT1L could be associated with HCTZ response in Caucasians. Additionally, exploratory analyses suggest rs12350051 in MLLT3 may be associated with untreated blood pressure in African-Americans. Replication efforts are needed to verify roles for these polymorphisms in human blood pressure regulation.Hydrochlorothiazide (HCTZ) is one of the most commonly prescribed antihypertensive drug in the US, with approximately 118 million prescriptions dispensed in 2010, either alone or combined with another antihypertensive [1,2]. HCTZ and other thiazide diuretics are recommended by current hypertension treatment guidelin
Carbohydrate metabolism and metabolic disorders in horses
Hoffman, Rhonda M.;
Revista Brasileira de Zootecnia , 2009, DOI: 10.1590/S1516-35982009001300027
Abstract: horses evolved consuming primarily fermentable forage carbohydrates, but forage diets have been traditionally supplemented with grain meals rich in starch and sugar in order to provide additional calories, protein and micronutrients. starch and sugar are important for performance horses, but the consumption starch-rich meals may cause equine digestive and metabolic disorders. the critical capacity for preileal starch digestibility appears to be 0.35 to 0.4% but may be as little, depending on the source of starch. small intestinal absorption of simple sugars is limited by the activity and expression of two classes of glucose carrier proteins, which are affected by chronic intake of hydrolyzable carbohydrate but may be sluggish to respond to abrupt changes in diet, further exacerbating the risk of overload. the most rapid fermentation occurs during starch overload or in the presence of fructans. rapid fermentation perturbs the microbial and ph balance of the cecum and colon, favoring proliferation of lactobacillus spp and acid production and increasing the risk of colic and laminitis. in addition to digestive disturbances, feeding grain concentrates rich in hydrolyzable carbohydrate may increase the risk of insulin resistance, which has been associated with obesity, laminitis and chronic founder, developmental orthopedic disease, and cushing's disease in horses. this threshold concentration of starch intake may be a starting point for horse owners, feed manufacturers and veterinarians that may be claimed to be "low" enough to reduce risk in insulin resistant horses sensitive to grain-associated disorders.
Addressing challenges in participatory research partnerships in the North: opening a conversation
Rhonda M. Johnson
International Journal of Circumpolar Health , 2012, DOI: 10.3402/ijch.v71i0.18477
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