Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points—Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC)

Bergmeijer, Thomas O.,Reny, Jean-Luc,Pakyz, Ruth E.,Gong, Li,Lewis, Joshua P.,Kim, Eun-Young,Aradi, Daniel,Fernandez-Cadenas, Israel,Horenstein, Richard B.,Lee, Ming Ta Michael,Whaley, Ryan M.,Montane Elsevier 2018 American Heart Journal Vol.198 No.-

<P><B>Rationale</B></P> <P>The P2Y<SUB>12</SUB> receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Platelet inhibition by clopidogrel shows wide interpatient variability, and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. <I>CYP2C19</I> polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response.</P> <P><B>Study design</B></P> <P>Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics, and cardiovascular outcomes to perform candidate gene and genome-wide studies.</P> <P><B>Results</B></P> <P>In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate–stimulated platelet function tests included vasodilator-stimulated phosphoprotein assay, light transmittance aggregometry, and the VerifyNow P2Y<SUB>12</SUB> assay. A proof-of-principle analysis based on genotype data provided by each group showed a strong and consistent association between <I>CYP2C19</I>*2 and platelet reactivity (<I>P</I> value=5.1 × 10<SUP>−40</SUP>).</P> <P><B>Conclusion</B></P> <P>The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic approaches in a large cohort of clopidogrel-treated patients to better understand the genetic basis of on-treatment response variability.</P>

Relationship between Right Ventricular Longitudinal Strain, Invasive Hemodynamics, and Functional Assessment in Pulmonary Arterial Hypertension

박재형,Kenya Kusunose,Deborah H. Kwon,Margaret M. Park,James D. Thomas,Richard A. Grimm,Brian P. Griffin,Thomas H. Marwick,Zoran B. Popović 대한심장학회 2016 Korean Circulation Journal Vol.46 No.2

Background and Objectives Right ventricular longitudinal strain (RVLS) is a new parameter of RV function. We evaluated the relationship of RVLS by speckle-tracking echocardiography with functional and invasive parameters in pulmonary arterial hypertension (PAH) patients. Subjects and Methods Thirty four patients with World Health Organization group 1 PAH (29 females, mean age 45±13 years old). RVLS were analyzed with velocity vector imaging. Results Patients with advanced symptoms {New York Heart Association (NYHA) functional class III/IV} had impaired RVLS in global RV (RVLSglobal, -17±5 vs. -12±3%, p<0.01) and RV free wall (RVLSFW, -19±5 vs. -14±4%, p<0.01 to NYHA class I/II). Baseline RVLSglobal and RVLSFW showed significant correlation with 6-minute walking distance (r=-0.54 and r=-0.57, p<0.01 respectively) and logarithmic transformation of brain natriuretic peptide concentration (r=0.65 and r=0.65, p<0.01, respectively). These revealed significant correlations with cardiac index (r=-0.50 and r=-0.47, p<0.01, respectively) and pulmonary vascular resistance (PVR, r=0.45 and r=0.45, p=0.01, respectively). During a median follow-up of 33 months, 25 patients (74%) had follow-up examinations. Mean pulmonary arterial pressure (mPAP, 54±13 to 46±16 mmHg, p=0.03) and PVR (11±5 to 6±2 wood units, p<0.01) were significantly decreased with pulmonary vasodilator treatment. RVLSglobal (-12±5 to -16±5%, p<0.01) and RVLSFW (-14±5 to -18±5%, p<0.01) were significantly improved. The decrease of mPAP was significantly correlated with improvement of RVLSglobal (r=0.45, p<0.01) and RVLSFW (r=0.43, p<0.01). The PVR change demonstrated significant correlation with improvement of RVLSglobal (r=0.40, p<0.01). Conclusion RVLS correlates with functional and invasive hemodynamic parameters in PAH patients. Decrease of mPAP and PVR as a result of treatment was associated with improvement of RVLS.

Relationship between Right Ventricular Longitudinal Strain, Invasive Hemodynamics, and Functional Assessment in Pulmonary Arterial Hypertension

박재형,Kenya Kusunose,Deborah H. Kwon,Margaret M. Park,Serpil C. Erzurum,James D. Thomas,Richard A. Grimm,Brian P. Griffin,Thomas H. Marwick,Zoran B. Popović 대한심장학회 2015 Korean Circulation Journal Vol.45 No.5

Background and Objectives: Right ventricular longitudinal strain (RVLS) is a new parameter of RV function. We evaluated the relationship of RVLS by speckle-tracking echocardiography with functional and invasive parameters in pulmonary arterial hypertension (PAH) patients. Subjects and Methods: Thirty four patients with World Health Organization group 1 PAH (29 females, mean age 45±13 years old). RVLS were analyzed with velocity vector imaging. Results: Patients with advanced symptoms {New York Heart Association (NYHA) functional class III/IV} had impaired RVLS in global RV (RVLSglobal, -17±5 vs. -12±3%, p<0.01) and RV free wall (RVLSFW, -19±5 vs. -14±4%, p<0.01 to NYHA class I/II). Baseline RVLSglobal and RVLSFW showed significant correlation with 6-minute walking distance (r=-0.54 and r=-0.57, p<0.01 respectively) and logarithmic transformation of brain natriuretic peptide concentration (r=0.65 and r=0.65, p<0.01, respectively). These revealed significant correlations with cardiac index (r=-0.50 and r=-0.47, p<0.01, respectively) and pulmonary vascular resistance (PVR, r=0.45 and r=0.45, p=0.01, respectively). During a median follow-up of 33 months, 25 patients (74%) had follow-up examinations. Mean pulmonary arterial pressure (mPAP, 54±13 to 46±16 mmHg, p=0.03) and PVR (11±5 to 6±2 wood units, p<0.01) were significantly decreased with pulmonary vasodilator treatment. RVLSglobal (-12±5 to -16±5%, p<0.01) and RVLSFW (-14±5 to -18±5%, p<0.01) were significantly improved. The decrease of mPAP was significantly correlated with improvement of RVLSglobal (r=0.45, p<0.01) and RVLSFW (r=0.43, p<0.01). The PVR change demonstrated significant correlation with improvement of RVLSglobal (r=0.40, p<0.01). Conclusion: RVLS correlates with functional and invasive hemodynamic parameters in PAH patients. Decrease of mPAP and PVR as a result of treatment was associated with improvement of RVLS

Synthesis and Antimicrobial Activity of N-[2-(aryl/substituted aryl)-4-oxo-1,3-thiazolidin-3-yl]pyridine-4-carboxamide

Thomas, Asha B.,Nanda, Rabindra K.,Kothapalli, Lata P.,Deshpande, Avinash D. Korean Chemical Society 2011 대한화학회지 Vol.55 No.6

A series of isonicotinyl hydrazones and their 4-thiazolidinones have been synthesized by condensation of isonicotinic acid hydrazide with various aromatic aldehydes to yield Schiff's bases, followed by the cyclocondensation of Schiff's bases with 2-mercaptoacetic acid to yield their 4-thiazolidinones. The synthesized compounds have been characterized by their elemental, analytical and spectral studies. All these compounds were evaluated for their invitro antimicrobial activity against a spectrum of non-resistant and resistant microbial organisms. These studies proved that compounds 5e,i against B. subtilis; 5e,f,h against B. anthracis; 5g,i against S. aureus showed good activity at lower concentrations. Compounds 5d-5i displayed significant activity against resistant strain of K. pneumonia with minimum inhibitory potency in the concentration range of 2-16 ug/ml.

Improving the Nutritive Value of Full-Fat Rice Bran for Broiler Chickens Using a Lipase-Based Enzyme Preparation

Tan, S.H.,Thomas, D.V.,Camden, B.J.,Kadim, I.T.,Morel, P.C.H.,Pluske, J.R. Asian Australasian Association of Animal Productio 2000 Animal Bioscience Vol.13 No.3

Two experiments were conducted to test the hypothesis that a lipase-based enzyme preparation would increase the AME content of full-fat rice bran (FFRB) by increasing fat digestibility when fed to broiler chickens. Experiment 1 used FFRB from Australia and lasted for 35 days, while Experiment 2 used FFRB from Thailand and lasted for 14 days. Rice bran was substituted in a maize-soybean diet at levels of 90 g/kg (Experiment 1) and at 90 and 180 g/kg in Experiment 2. Total collections of excreta were used for determination of AME content and fat digestibility. In Experiment 1, the enzyme increased the AME content of FFRB between days 4-7, 18-21 and 32-35 by 6.1-16.1% (p>0.05), however this was not associated with improved fat digestibility. In Experiment 2, the enzyme enhanced the AME content of FFRB between days 4-7 (10.42 vs. 9.06, p=0.107) and 11-14 (11.94 vs. 9.93, p=0.041), but again, this was not caused by increased fat digestibility. Inclusion of 180 g/kg depressed the AME content of FFRB by 7.4-11.5% (p>0.10) in conjunction with decreased (p<0.05) fat digestibility between 0-14 days of age. Improvements in bird growth with the enzyme were seen in Experiment 2 but not in Experiment 1. Increases in AME content of FFRB per se were not caused by enhanced fat digestibility, suggesting that the side activities associated with the preparation must have acted singularly or in combination to improve AME content and bird performance. These data show that the response of FFRB to the lipase-based enzyme preparation was dependent upon the geographical origin of the rice bran and the level of FFRB substituted in the basal diet.

Synergistic Oxygen Evolving Activity of a TiO₂-Rich Reconstructed SrTiO₃(001) Surface

Martirez, John Mark P.,Kim, Seungchul,Morales, Erie H.,Diroll, Benjamin T.,Cargnello, Matteo,Gordon, Thomas R.,Murray, Christopher B.,Bonnell, Dawn A.,Rappe, Andrew M. American Chemical Society 2015 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY - Vol.137 No.8

<P>In addition to composition, the structure of a catalyst is another fundamental determinant of its catalytic reactivity. Recently, anomalous Ti oxide-rich surface phases of ternary oxides have been stabilized as nonstoichiometric epitaxial overlayers. These structures give rise to different modes of oxygen binding, which may lead to different oxidative chemistry. Through density functional theory investigations and electrochemical measurements, we predict and subsequently show that such a TiO<SUB>2</SUB> double-layer surface reconstruction enhances the oxygen evolving activity of the perovskite-type oxide SrTiO<SUB>3</SUB>. Our theoretical work suggests that the improved activity of the restructured TiO<SUB>2</SUB>(001) surface toward oxygen formation stems from (i) having two Ti sites with distinct oxidation activity and (ii) being able to form a strong O–O moiety (which reduces overbonding at Ti sites), which is a direct consequence of (iii) having a labile lattice O that is able to directly participate in the reaction. Here, we demonstrate the improvement of the catalytic performance of a well-known and well-studied oxide catalyst through more modern methods of materials processing, predicted through first-principles theoretical modeling.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/2015/jacsat.2015.137.issue-8/ja511332y/production/images/medium/ja-2014-11332y_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ja511332y'>ACS Electronic Supporting Info</A></P>

Classical natural ovine scrapie prions detected in practical volumes of blood by lamb and transgenic mouse bioassays

Rohana P. Dassanayake,Thomas C. Truscott,Dongyue Zhuang,David A. Schneider,Sally A. Madsen-Bouterse,Alan J. Young,James B. Stanton,William C. Davis,Katherine I. O’Rourke 대한수의학회 2015 Journal of Veterinary Science Vol.16 No.2

Scrapie is diagnosed antemortem in sheep by detecting misfolded isoforms of prion protein (PrPSc) in lymphoid follicles of the rectal mucosa and nictitating membranes. Assay sensitivity is limited if (a) the biopsy is collected early during disease development, (b) an insufficient number of follicles is collected, or (c) peripheral accumulation of PrPSc is reduced or delayed. A blood test would be convenient for mass live animal scrapie testing. Currently approved techniques, however, have their own detection limits. Novel detection methods may soon offer a non-animal-based, rapid platform with detection sensitivities that rival the prion bioassay. In anticipation, we sought to determine if diseased animals could be routinely identified with a bioassay using B lymphocytes isolated from blood sample volumes commonly collected for diagnostic purposes in small ruminants. Scrapie transmission was detected in five of six recipient lambs intravenously transfused with B lymphocytes isolated from 5∼10 mL of blood from a naturally scrapie-infected sheep. Additionally, scrapie transmission was observed in 18 ovinized transgenic Tg338 mice intracerebrally inoculated with B lymphocytes isolated from 5∼10 mL of blood from two naturally scrapie-infected sheep. Based on our findings, we anticipate that these blood sample volumes should be of diagnostic value.

Evaluation of imputation-based association in and around the integrin- -M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE)

Han, S.,Kim-Howard, X.,Deshmukh, H.,Kamatani, Y.,Viswanathan, P.,Guthridge, J. M.,Thomas, K.,Kaufman, K. M.,Ojwang, J.,Rojas-Villarraga, A.,Baca, V.,Orozco, L.,Rhodes, B.,Choi, C.-B.,Gregersen, P. K. Oxford University Press 2009 Human Molecular Genetics Vol.18 No.6

<P>We recently identified a novel non-synonymous variant, rs1143679, at exon 3 of the ITGAM gene associated with systemic lupus erythematosus (SLE) susceptibility in European-Americans (EAs) and African-Americans. Using genome-wide association approach, three other studies also independently reported an association between SLE susceptibility and ITGAM or ITGAM-ITGAX region. The primary objectives of this study are to assess whether single or multiple causal variants from the same gene or any nearby gene(s) are involved in SLE susceptibility and to confirm a robust ITGAM association across nine independent data sets (n = 8211). First, we confirmed our previously reported association of rs1143679 (risk allele 'A') with SLE in EAs (P = 1.0 x 10(-8)) and Hispanic-Americans (P = 2.9 x 10(-5)). Secondly, using a comprehensive imputation-based association test, we found that ITGAM is one of the major non-human leukocyte antigen susceptibility genes for SLE, and the strongest association for EA is the same coding variant rs1143679 (log(10)Bayes factor=20, P = 6.17 x 10(-24)). Thirdly, we determined the robustness of rs1143679 association with SLE across three additional case-control samples, including UK (P = 6.2 x 10(-8)), Colombian (P = 3.6 x 10(-7)), Mexican (P = 0.002), as well as two independent sets of trios from UK (P(TDT) = 1.4 x 10(-5)) and Mexico (P(TDT) = 0.015). A meta-analysis combing all independent data sets greatly reinforces the association (P(meta) = 7.1 x 10(-50), odds ratio = 1.83, 95% confidence interval = 1.69-1.98, n = 10 046). However, this ITGAM association was not observed in the Korean or Japanese samples, in which rs1143679 is monomorphic for the non-risk allele (G). Taken together along with our earlier findings, these results demonstrate that the coding variant, rs1143679, best explains the ITGAM-SLE association, especially in European- and African-derived populations, but not in Asian populations.</P>

The Effect of STW5 (Iberogast) on Reflux Symptoms in Patients With Concurrent Dyspeptic Symptoms: A Double-blind Randomized Placebo-controlled Crossover Trial

Renske A B Oude Nijhuis,Thijs Kuipers,Jac M Oors,Thomas V K Herregods,Boudewijn F Kessing,Jeroen M Schuitenmaker,Andreas J P M Smout,Albert J Bredenoord 대한소화기 기능성질환∙운동학회 2024 Journal of Neurogastroenterology and Motility (JNM Vol.30 No.1

Background/AimsIt has been suggested that STW5 (Iberogast) reduces heartburn symptoms in patients with functional dyspepsia, but underlying mechanisms of action are unclear. The aim of this study is to investigate whether STW5 affects esophageal sensitivity or esophageal motility, thereby reducing occurrence and perception of reflux events. MethodsWe performed a double-blind, randomized, placebo-controlled, crossover trial in patients with functional dyspepsia (Rome IV) and reflux symptoms. After 4 weeks of treatment with either placebo or STW5, patients were studied with an esophageal acid perfusion test and ambulatory 24-hour pH-impedance monitoring. ResultsA total of 18 patients (7 men, median age 54, range [19-76]), were included in the study. Although we found no statistical difference in our primary outcome the total Reflux Disease Questionnaire score 2.33 (0.25-4.33) vs 2.67 (1.17-4.00), P = 0.347, “gastroesophageal reflux disease” and “regurgitation” subscale scores were lower after STW5 treatment compared to placebo (P = 0.049 and P = 0.007). There was no statistical difference in number of reflux events, acid exposure time and acid sensitivity scores between STW5 and placebo. In a subgroup analysis of patients with pH-metry confirmed gastroesophageal reflux disease, treatment with STW5 significantly reduced the total number of acidic reflux events (P = 0.028). Moreover, in patients with reflux esophagitis, the median lag time to acid perception increased after STW5 treatment (P = 0.042). ConclusionsWe found some indications pointing towards a beneficial effect of STW5 on reflux symptoms in dyspeptic patients, with reduction of esophageal hypersensitivity as a potential underlying mechanism. Our findings will have to be confirmed in larger studies.

Nighttime Chemical Transformation in Biomass Burning Plumes: A Box Model Analysis Initialized with Aircraft Observations

Decker, Zachary C. J.,Zarzana, Kyle J.,Coggon, Matthew,Min, Kyung-Eun,Pollack, Ilana,Ryerson, Thomas B.,Peischl, Jeff,Edwards, Pete,Dubé,, William P.,Markovic, Milos Z.,Roberts, James M.,Veres, American Chemical Society 2019 Environmental science & technology Vol.53 No.5

<P>Biomass burning (BB) is a large source of reactive compounds in the atmosphere. While the daytime photochemistry of BB emissions has been studied in some detail, there has been little focus on nighttime reactions despite the potential for substantial oxidative and heterogeneous chemistry. Here, we present the first analysis of nighttime aircraft intercepts of agricultural BB plumes using observations from the NOAA WP-3D aircraft during the 2013 Southeast Nexus (SENEX) campaign. We use these observations in conjunction with detailed chemical box modeling to investigate the formation and fate of oxidants (NO<SUB>3</SUB>, N<SUB>2</SUB>O<SUB>5</SUB>, O<SUB>3</SUB>, and OH) and BB volatile organic compounds (BBVOCs), using emissions representative of agricultural burns (rice straw) and western wildfires (ponderosa pine). Field observations suggest NO<SUB>3</SUB> production was approximately 1 ppbv hr<SUP>-1</SUP>, while NO<SUB>3</SUB> and N<SUB>2</SUB>O<SUB>5</SUB> were at or below 3 pptv, indicating rapid NO<SUB>3</SUB>/N<SUB>2</SUB>O<SUB>5</SUB> reactivity. Model analysis shows that >99% of NO<SUB>3</SUB>/N<SUB>2</SUB>O<SUB>5</SUB> loss is due to BBVOC + NO<SUB>3</SUB> reactions rather than aerosol uptake of N<SUB>2</SUB>O<SUB>5</SUB>. Nighttime BBVOC oxidation for rice straw and ponderosa pine fires is dominated by NO<SUB>3</SUB> (72, 53%, respectively) but O<SUB>3</SUB> oxidation is significant (25, 43%), leading to roughly 55% overnight depletion of the most reactive BBVOCs and NO<SUB>2</SUB>.</P> [FIG OMISSION]</BR>