Relationship between Medication Use and Cardiovascular Disease Health Outcomes in the Jackson Heart Study

Even though some medications have the potential to slow the progress of atherosclerosis and development of CVD, there are many at-risk individuals who continue to resist the benefits that are available by not following the advice of medical professionals. Non-adherence to prescribed drug regimens is a pervasive medical problem that negatively affects treatment outcomes. Information from standardized interviews of 5301 African Americans participating in the Jackson Heart Study was examined to determine the association between demographic parameters, behavior including adherence to prescribed medical regimens, and health outcomes. Data were also collected at Annual Follow-Up and Surveillance visits. During the two weeks prior to the examination visit, almost 52% of the participants reported taking blood pressure medication, 14% took cholesterol medication, 16% took medication for diabetes, and 19% took blood thinning medication. Of those who did not take the prescribed medications, the reasons given were the following: 47% were in a hurry, too busy, or forgot to take medications; 23% were trying to do without medications; 18% had no money to purchase medications; 19% indicated that the medications made them feel bad; 17% felt that they could not carry out daily functions when taking medications. The African American population can benefit from heightened awareness of the risk factors that are associated with CVD and the benefits of following a prescribed treatment regimen. Unacceptable secondary effects of prescribed medication comprised an important cause of non-compliance. Encouragement of this population to communicate with their healthcare providers to ensure that medication regimens are better tolerated could increase compliance and improve health outcomes

Cost-effectiveness of initiating extrafine- or standard size-particle inhaled corticosteroid for asthma in two health-care systems: a retrospective matched cohort study

Data acquisition and analyses were funded by Teva Pharmaceuticals

Towards a matrix mechanics framework for dynamic protein network

Protein–protein interaction networks are currently visualized by software generated interaction webs based upon static experimental data. Current state is limited to static, mostly non-compartmental network and non time resolved protein interactions. A satisfactory mathematical foundation for particle interactions within a viscous liquid state (situation within the cytoplasm) does not exist nor do current computer programs enable building dynamic interaction networks for time resolved interactions. Building mathematical foundation for intracellular protein interactions can be achieved in two increments (a) trigger and capture the dynamic molecular changes for a select subset of proteins using several model systems and high throughput time resolved proteomics and, (b) use this information to build the mathematical foundation and computational algorithm for a compartmentalized and dynamic protein interaction network. Such a foundation is expected to provide benefit in at least two spheres: (a) understanding physiology enabling explanation of phenomenon such as incomplete penetrance in genetic disorders and (b) enabling several fold increase in biopharmaceutical production using impure starting materials

Genome-wide association analysis of thirty one production, health, reproduction and body conformation traits in contemporary U.S. Holstein cows

<p>Abstract</p> <p>Background</p> <p>Genome-wide association analysis is a powerful tool for annotating phenotypic effects on the genome and knowledge of genes and chromosomal regions associated with dairy phenotypes is useful for genome and gene-based selection. Here, we report results of a genome-wide analysis of predicted transmitting ability (PTA) of 31 production, health, reproduction and body conformation traits in contemporary Holstein cows.</p> <p>Results</p> <p>Genome-wide association analysis identified a number of candidate genes and chromosome regions associated with 31 dairy traits in contemporary U.S. Holstein cows. Highly significant genes and chromosome regions include: BTA13's <it>GNAS </it>region for milk, fat and protein yields; BTA7's <it>INSR </it>region and BTAX's <it>LOC520057 </it>and <it>GRIA3 </it>for daughter pregnancy rate, somatic cell score and productive life; BTA2's <it>LRP1B </it>for somatic cell score; BTA14's <it>DGAT1-NIBP </it>region for fat percentage; <it>BTA1</it>'s <it>FKBP2 </it>for protein yields and percentage, BTA26's <it>MGMT </it>and BTA6's <it>PDGFRA </it>for protein percentage; BTA18's 53.9-58.7 Mb region for service-sire and daughter calving ease and service-sire stillbirth; BTA18's <it>PGLYRP1</it>-<it>IGFL1 </it>region for a large number of traits; BTA18's <it>LOC787057 </it>for service-sire stillbirth and daughter calving ease; BTA15's <it>CD82</it>, BTA23's <it>DST </it>and the <it>MOCS1</it>-<it>LRFN2 </it>region for daughter stillbirth; and BTAX's <it>LOC520057 </it>and <it>GRIA3 </it>for daughter pregnancy rate. For body conformation traits, BTA11, BTAX, BTA10, BTA5, and BTA26 had the largest concentrations of SNP effects, and <it>PHKA2 </it>of BTAX and <it>REN </it>of BTA16 had the most significant effects for body size traits. For body shape traits, BTAX, BTA19 and BTA3 were most significant. Udder traits were affected by BTA16, BTA22, BTAX, BTA2, BTA10, BTA11, BTA20, BTA22 and BTA25, teat traits were affected by BTA6, BTA7, BTA9, BTA16, BTA11, BTA26 and BTA17, and feet/legs traits were affected by BTA11, BTA13, BTA18, BTA20, and BTA26.</p> <p>Conclusions</p> <p>Genome-wide association analysis identified a number of genes and chromosome regions associated with 31 production, health, reproduction and body conformation traits in contemporary Holstein cows. The results provide useful information for annotating phenotypic effects on the dairy genome and for building consensus of dairy QTL effects.</p

The CD34-Related Molecule Podocalyxin Is a Potent Inducer of Microvillus Formation

BACKGROUND: Podocalyxin is a CD34-related transmembrane protein involved in hematopoietic cell homing, kidney morphogenesis, breast cancer progression, and epithelial cell polarization. Although this sialomucin has been shown to block cell adhesion, the mechanisms involved remain enigmatic. It has, however, been postulated that the adaptor proteins NHERF-1 and 2 could regulate apical targeting of Podocalyxin by linking it to the actin cytoskeleton. PRINCIPAL FINDINGS: Here, in contrast, we find that full-length Podocalyxin acts to recruit NHERF-1 to the apical domain. Moreover, we show that ectopic expression of Podocalyxin in epithelial cells leads to microvillus formation along an expanded apical domain that extends laterally to the junctional complexes. Removal of the C-terminal PDZ-binding domain of Podocalyxin abolishes NHERF-1 recruitment but, surprisingly, has no effect on the formation of microvilli. Instead, we find that the extracellular domain and transmembrane region of Podocalyxin are sufficient to direct recruitment of filamentous actin and ezrin to the plasma membrane and induce microvillus formation. CONCLUSIONS/SIGNIFICANCE: Our data suggest that this single molecule can modulate NHERF localization and, independently, act as a key orchestrator of apical cell morphology, thereby lending mechanistic insights into its multiple roles as a polarity regulator, tumor progression marker, and anti-adhesin

PP1A-Mediated Dephosphorylation Positively Regulates YAP2 Activity

Background: The Hippo/MST1 signaling pathway plays an important role in the regulation of cell proliferation and apoptosis. As a major downstream target of the Hippo/MST1 pathway, YAP2 (Yes-associated protein 2) functions as a transcriptional cofactor that has been implicated in many biological processes, including organ size control and cancer development. MST1/Lats kinase inhibits YAP2’s nuclear accumulation and transcriptional activity through inducing the phosphorylation at serine 127 and the sequential association with 14-3-3 proteins. However, the dephosphorylation of YAP2 is not fully appreciated. Methodology/Principal Findings: In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2. Inhibition of PP1 by okadiac acid (OA) increases the phosphorylation at serine 127 and cytoplasmic translocation of YAP2 proteins, thereby mitigating its transcription activity. PP1A expression enhances YAP2’s pro-survival capability and YAP2 knockdown sensitizes ovarian cancer cells to cisplatin treatment. Conclusions/Significance: Our findings define a novel molecular mechanism that YAP2 is positively regulated by PP1mediate

Using quantile regression to investigate racial disparities in medication non-adherence

<p>Abstract</p> <p>Background</p> <p>Many studies have investigated racial/ethnic disparities in medication non-adherence in patients with type 2 diabetes using common measures such as medication possession ratio (MPR) or gaps between refills. All these measures including MPR are quasi-continuous and bounded and their distribution is usually skewed. Analysis of such measures using traditional regression methods that model mean changes in the dependent variable may fail to provide a full picture about differential patterns in non-adherence between groups.</p> <p>Methods</p> <p>A retrospective cohort of 11,272 veterans with type 2 diabetes was assembled from Veterans Administration datasets from April 1996 to May 2006. The main outcome measure was MPR with quantile cutoffs Q1-Q4 taking values of 0.4, 0.6, 0.8 and 0.9. Quantile-regression (QReg) was used to model the association between MPR and race/ethnicity after adjusting for covariates. Comparison was made with commonly used ordinary-least-squares (OLS) and generalized linear mixed models (GLMM).</p> <p>Results</p> <p>Quantile-regression showed that Non-Hispanic-Black (NHB) had statistically significantly lower MPR compared to Non-Hispanic-White (NHW) holding all other variables constant across all quantiles with estimates and p-values given as -3.4% (p = 0.11), -5.4% (p = 0.01), -3.1% (p = 0.001), and -2.00% (p = 0.001) for Q1 to Q4, respectively. Other racial/ethnic groups had lower adherence than NHW only in the lowest quantile (Q1) of about -6.3% (p = 0.003). In contrast, OLS and GLMM only showed differences in mean MPR between NHB and NHW while the mean MPR difference between other racial groups and NHW was not significant.</p> <p>Conclusion</p> <p>Quantile regression is recommended for analysis of data that are heterogeneous such that the tails and the central location of the conditional distributions vary differently with the covariates. QReg provides a comprehensive view of the relationships between independent and dependent variables (i.e. not just centrally but also in the tails of the conditional distribution of the dependent variable). Indeed, without performing QReg at different quantiles, an investigator would have no way of assessing whether a difference in these relationships might exist.</p

Next-Generation Sequencing of Apoptotic DNA Breakpoints Reveals Association with Actively Transcribed Genes and Gene Translocations

DNA fragmentation is a well-recognized hallmark of apoptosis. However, the precise DNA sequences cleaved during apoptosis triggered by distinct mechanisms remain unclear. We used next-generation sequencing of DNA fragments generated in Actinomycin D-treated human HL-60 leukemic cells to generate a high-throughput, global map of apoptotic DNA breakpoints. These data highlighted that DNA breaks are non-random and show a significant association with active genes and open chromatin regions. We noted that transcription factor binding sites were also enriched within a fraction of the apoptotic breakpoints. Interestingly, extensive apoptotic cleavage was noted within genes that are frequently translocated in human cancers. We speculate that the non-random fragmentation of DNA during apoptosis may contribute to gene translocations and the development of human cancers