bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Mn2+and Compatible Solutes in the Radiation Resistance of Thermophilic Bacteria and Archaea
Authors: Webb Kimberly M. , DiRuggiero Jocelyne
Published: November 2012

Radiation-resistant bacteria have garnered a great deal of attention from scientists seeking to expose the mechanisms underlying their incredible survival abilities. Recent analyses showed that the resistance to ionizing radiation (IR) in the archaeonHalobacterium salinarumis dependent upon Mn-antioxidant complexes responsible for the scavenging of reactive oxygen species (ROS) generated by radiation. Here we examined the role of the compatible solutes trehalose, mannosylglycerate, anddi-myo-inositolphosphate in the radiation resistance of aerobic and anaerobic thermophiles. We found that the IR resistance of the thermophilic bacteriaRubrobacter xylanophilusandRubrobacter radiotoleranswas highly correlated to the accumulation of high intracellular concentration of trehalose in association with Mn, supporting the model of Mn2+-dependent ROS scavenging in the aerobes. In contrast, the hyperthermophilic archaeaThermococcus gammatoleransandPyrococcus furiosusdid not contain significant amounts of intracellular Mn, and we found no significant antioxidant activity from mannosylglycerate and di-myo-inositol phosphatein vitro. We therefore propose that the low levels of IR-generated ROS under anaerobic conditions combined with highly constitutively expressed detoxification systems in these anaerobes are key to their radiation resistance and circumvent the need for the accumulation of Mn-antioxidant complexes in the cell.
Nutrition Therapy for Liver Diseases Based on the Status of Nutritional Intake
Authors: Yasutake Kenichiro , Kohjima Motoyuki , Nakashima Manabu , Kotoh Kazuhiro , Nakamuta Makoto , Enjoji Munechika
Published: November 2012

The dietary intake of patients with nonalcoholic fatty liver disease (NAFLD) is generally characterized by high levels of carbohydrate, fat, and/or cholesterol, and these dietary patterns influence hepatic lipid metabolism in the patients. Therefore, careful investigation of dietary habits could lead to better nutrition therapy in NAFLD patients. The main treatment for chronic hepatitis C (CHC) is interferon-based antiviral therapy, which often causes a decrease in appetite and energy intake; hence, nutritional support is also required during therapy to prevent undernourishment, treatment interruption, and a reduction in quality of life. Moreover, addition of some nutrients that act to suppress viral proliferation is recommended. As a substitutive treatment, low-iron diet therapy, which is relatively safe and effective for preventing hepatocellular carcinoma, is also recommended for CHC patients. Some patients with liver cirrhosis (LC) have decreased dietary energy and protein intake, while the number of LC patients with overeating and obesity is increasing, indicating that the nutritional state of LC patients has a broad spectrum. Therefore, nutrition therapy for LC patients should be planned on an assessment of their complications, nutritional state, and dietary intake. Late evening snacks, branched-chain amino acids, zinc, and probiotics are considered for effective nutritional utilization.
Encounters with Vortices in a Turbine Nozzle Passage
Authors: Gostelow J. P. , Mahallati A. , Carscallen W. E. , Rona A.
Published: November 2012

Experiments were conducted on the flow through a transonic turbine cascade. Secondary flows and a wide range of vortex types were encountered, including horseshoe vortices, shock-induced passage vortices, and streamwise vortices on the suction surface. In the separation region on the suction surface, a large rollup of passage vorticity occurred. The blunt leading edge gave rise to strong horseshoe vortices and secondary flows. The suction surface had a strong convex curvature over the forward portion and was quite flat further downstream. Surface flow visualization was performed and this convex surface displayed coherent streamwise vorticity. At subsonic speeds, strong von Kármán vortex shedding resulted in a substantial base pressure deficit. For these conditions, time-resolved measurements were made of the Eckert-Weise energy separation in the blade wake. At transonic speeds, exotic shedding modes were observed. These phenomena all occurred in experiments on the flow around one particular turbine nozzle vane in a linear cascade.
Complement Diagnostics: Concepts, Indications, and Practical Guidelines
Authors: Nilsson Bo , Ekdahl Kristina Nilsson
Published: November 2012

Aberrations in the complement system have been shown to be direct or indirect pathophysiological mechanisms in a number of diseases and pathological conditions such as autoimmune disease, infections, cancer, allogeneic and xenogeneic transplantation, and inflammation. Complement analyses have been performed on these conditions in both prospective and retrospective studies and significant differences have been found between groups of patients, but in many diseases, it has not been possible to make predictions for individual patients because of the lack of sensitivity and specificity of many of the assays used. The basic indications for serological diagnostic complement analysis today may be divided into three major categories: (a) acquired and inherited complement deficiencies; (b) disorders with complement activation; (c) inherited and acquired C1INH deficiencies. Here, we summarize indications, techniques, and interpretations for basic complement analyses and present an algorithm, which we follow in our routine laboratory.
MPC Schemes Guaranteeing ISDS and ISS for Nonlinear (Time‐Delay) Systems
Authors: Dashkovskiy Sergey , Naujok Lars
Published: November 2012

New directions in model predictive control (MPC) are introduced. On the one hand, we combine the input‐to‐state dynamical stability (ISDS) with MPC for single and interconnected systems. On the other hand, we introduce MPC schemes guaranteeing input‐to‐state stability (ISS) of single systems and networks with time delays. In both directions, recent results of the stability analysis from the mentioned areas are applied using Lyapunov function(al)s to show that the corresponding cost function(al) of the MPC scheme is a Lyapunov function(al). For networks, we show that under a small‐gain condition and with an optimal control obtained by an MPC scheme for networks, it has the ISDS property or ISS property, respectively.
Targeting PPARγSignaling Cascade for the Prevention and Treatment of Prostate Cancer
Authors: Sikka Sakshi , Chen Luxi , Sethi Gautam , Kumar Alan Prem
Published: November 2012

The peroxisome proliferator-activated receptor-gamma (PPARγ) is a member of the hormone-activated nuclear receptor superfamily. PPARγcan be activated by a diverse group of agents, such as endogenous polyunsaturated fatty acids, 15-deoxy-Δ12,14-prostaglandin J2(15d-PGJ2), and thiazolidinedione (TZD) drugs. PPARγinduces antiproliferative, antiangiogenic, and prodifferentiation pathways in several tissue types, thus making it a highly useful target for downregulation of carcinogenesis. These TZD-derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment. TZDs have been proven for antitumor activity in a wide variety of experimental cancer models, bothin vitroandin vivo, by affecting the cell cycle, inducing cell differentiation and apoptosis, as well as by inhibiting tumor angiogenesis. Angiogenesis inhibition mechanisms of TZDs include direct inhibition of endothelial cell proliferation and migration, as well as reduction in tumor cell vascular endothelial growth factor production. In prostate cancer, PPARγligands such as troglitazone and 15d-PGJ2have also shown to inhibit tumor growth. This paper will focus on current discoveries in PPARγactivation, targeting prostate carcinogenesis as well as the role of PPARγas a possible anticancer therapeutic option. Here, we review PPARγas an antitumor agent and summarize the antineoplastic effects of PPARγagonists in prostate cancer.
Verifying Elimination Programs with a Special Emphasis on Cysticercosis Endpoints and Postelimination Surveillance
Authors: Handali Sukwan , Pawitan Yudi
Published: November 2012

Methods are needed for determining program endpoints or postprogram surveillance for any elimination program. Cysticercosis has the necessary effective strategies and diagnostic tools for establishing an elimination program; however, tools to verify program endpoints have not been determined. Using a statistical approach, the present study proposed that taeniasis and porcine cysticercosis antibody assays could be used to determine with a high statistical confidence whether an area is free of disease. Confidence would be improved by using secondary tests such as the taeniasis coproantigen assay and necropsy of the sentinel pigs.
Kinetics and Mechanism of meso‐Tetraphenylporphyrin Iron(III) Chloride Catalysed Oxidation of Indole‐3‐Acetic Acid by Peroxomonosulphate
Authors: Kungumathilagam Durairaj , Karunakaran Kulanthaivel
Published: November 2012

Mechanistic study on meso‐tetraphenylporphyrin iron(III) chloride (TPP) catalysed oxidation of indole‐3‐acetic acid by peroxomonosulphate (oxone) in aqueous acetonitrile medium has been carried out. The reaction follows a first order with respect to both substrate and oxidant. The order with respect to catalyst was found to be fractional. The order of reaction with respect to catalyst varies with a concentration of catalyst. Increase in percentage of acetonitrile decreased the rate. The reaction fails to initiate polymerization, and a radical mechanism is ruled out. Activation and thermodynamic parameters have been computed. A suitable kinetic scheme based on these observations is proposed. Significant catalytic activity is observed for the reaction system in the presence of TPP.
Evaluation of Thermodynamic Parameters of 2, 4‐Dichlorophenoxyacetic Acid (2, 4‐D) Adsorption
Authors: Ghatbandhe A. S. , Jahagirdar H. G. , Yenkie M. K. N. , Deosarkar S. D.
Published: November 2012

Thermodynamic parameters of 2, 4‐Dichlorophenoxyacetic acid (2, 4‐D) adsorption were evaluated by studying the adsorption equilibrium and kinetics of 2, 4‐D at different temperatures. Uptake capacity of activated carbon increases with temperature. Langmuir isotherm models were applied to experimental data of 2, 4‐D adsorption. Equilibrium data fitted very well to the Langmuir equilibrium model. Adsorbent monolayer capacity Q0, Langmuir constant a and adsorption rate constant ka were evaluated at different temperatures for activated carbon adsorption. The activation energy of adsorption (Ea) was determined using the Arrhenius equation. Using the thermodynamic equilibrium coefficients obtained at different temperatures, the thermodynamic constants of adsorption (ΔG0, ΔH0, and ΔS0) were evaluated. The obtained values of thermodynamic parameters show that the adsorption of 2, 4‐D is an endothermic process.
mTOR Inhibitor RAD001 Promotes Metastasis in a Rat Model of Pancreatic Neuroendocrine Cancer
Authors: Pool Stefan E. , Bison Sander , Koelewijn Stuart J. , van der Graaf Linda M. , Melis Marleen , Krenning Eric P. , de Jong Marion
Published: November 2012

Inhibition of mTOR is commonly considered a valid target in cancer treatment, but this assertion does not address effects on the immune microenvironment that may be detrimental to cancer treatment. Here we show how administration of the mTOR inhibitor RAD001 (everolimus) results in the occurrence of distant metastasis in a rat model of pancreatic cancer. RAD001 was administered twice weekly for 4.5 weeks as a single treatment or combined with [177Lu-DOTA,Tyr3]octreotate (177Lu-DOTATATE), where the latter targets the somatostatin receptor-2. The hypothesized synergistic therapeutic effect of RAD001 combined with 177Lu-DOTATATE was, however, not observed in our experiments. The combination was shown to be less effective than 177Lu-DOTATATE alone. Unexpectedly, tumor metastasis was observed in 77% of the subjects treated with RAD001, either alone or as part of the combination treatment. This was a striking effect, because metastasis did not occur in control or 177Lu-DOTATATE-treated animals, including those where the primary tumor was surgically removed. These findings may be important clinically among noncompliant patients or patients that discontinue RAD001 therapy because of adverse effects. Cancer Res; 73(1); 12–18. ©2012 AACR.
Autophagy Control by the VEGF-C/NRP-2 Axis in Cancer and Its Implication for Treatment Resistance
Authors: Stanton Marissa J. , Dutta Samikshan , Zhang Heyu , Polavaram Navatha S. , Leontovich Alexey A. , Hönscheid Pia , Sinicrope Frank A. , Tindall Donald J. , Muders Michael H. , Datta Kaustubh
Published: November 2012

A major contributor to cancer mortality is recurrence and subsequent metastatic transformation following therapeutic intervention. Therefore, in order to develop new treatment modalities and improve the efficacy of current ones, it is important to understand the molecular mechanisms that promote resistance to therapy in cancer cells. One pathway contributing to therapy resistance is autophagy, a self-digestive process that can eliminate unnecessary or damaged organelles to protect cancer cells from death. We have found that the VEGF-C/NRP-2 axis is involved in the activation of autophagy, which helps cancer cell survival following treatment. Inhibition of mTOR complex 1 activity by this axis is the underlying mechanism for the activation of autophagy. Furthermore, we identified two VEGF-C/NRP-2-regulated genes, LAMP-2 and WDFY-1, that have previously been suggested to participate in autophagy and vesicular trafficking. Upregulation of WDFY-1 following VEGF-C or NRP-2 depletion contributes to cytotoxic drug-mediated cell death. Together, these data suggest a link between the VEGF-C/NRP-2 axis and cancer cell survival despite the presence of chemotherapy-induced stress. Effective targeting of this pathway may lead to the development of new cancer therapies. Cancer Res; 73(1); 160–71. ©2012 AACR.
STAT5 Is Crucial to Maintain Leukemic Stem Cells in Acute Myelogenous Leukemias Induced by MOZ-TIF2
Authors: Tam Winnie F. , Hähnel Patricia S. , Schüler Andrea , Lee Benjamin H. , Okabe Rachel , Zhu Nan , Pante Saskia V. , Raffel Glen , Mercher Thomas , Wernig Gerlinde , Bockamp Ernesto , Sasca Daniel , Kreft Andreas , Robinson Gertraud W. , Hennighausen Lothar , Gilliland D. Gary , Kindler Thomas
Published: November 2012

MOZ-TIF2 is a leukemogenic fusion oncoprotein that confers self-renewal capability to hematopoietic progenitor cells and induces acute myelogenous leukemia (AML) with long latency in bone marrow transplantation assays. Here, we report that FLT3-ITD transforms hematopoietic cells in cooperation with MOZ-TIF2 in vitro and in vivo. Coexpression of FLT3-ITD confers growth factor independent survival/proliferation, shortens disease latency, and results in an increase in the number of leukemic stem cells (LSC). We show that STAT5, a major effector of aberrant FLT3-ITD signal transduction, is both necessary and sufficient for this cooperative effect. In addition, STAT5 signaling is essential for MOZ-TIF2–induced leukemic transformation itself. Lack of STAT5 in fetal liver cells caused rapid differentiation and loss of replating capacity of MOZ-TIF2–transduced cells enriched for LSCs. Furthermore, mice serially transplanted with Stat5−/− MOZ-TIF2 leukemic cells develop AML with longer disease latency and finally incomplete penetrance when compared with mice transplanted with Stat5+/+ MOZ-TIF2 leukemic cells. These data suggest that STAT5AB is required for the self-renewal of LSCs and represents a combined signaling node of FLT3-ITD and MOZ-TIF2 driven leukemogenesis. Therefore, targeting aberrantly activated STAT5 or rewired downstream signaling pathways may be a promising therapeutic option. Cancer Res; 73(1); 373–84. ©2012 AACR.
Common Single-Nucleotide Polymorphisms in the Estrogen Receptor β Promoter Are Associated with Colorectal Cancer Survival in Postmenopausal Women
Authors: Passarelli Michael N. , Phipps Amanda I. , Potter John D. , Makar Karen W. , Coghill Anna E. , Wernli Karen J. , White Emily , Chan Andrew T. , Hutter Carolyn M. , Peters Ulrike , Newcomb Polly A.
Published: November 2012

Loss of estrogen receptor β (ERβ) expression in the gut is associated with colorectal cancer (CRC) initiation and progression. Germline single-nucleotide polymorphisms (SNP) in genes for the sex-steroid hormone receptors are not strongly associated with CRC risk; however, these SNPs have not previously been evaluated in relation to survival after diagnosis. We enrolled 729 women, ages 50 to 74, diagnosed with invasive CRC between 1997 and 2002 in 13 counties covered by the Seattle-Puget Sound Surveillance Epidemiology and End Results cancer registry. Participants provided germline DNA. We selected 99 tag-SNPs for the androgen receptor (AR), ERα (ESR1), ERβ (ESR2), and progesterone receptor (PGR) genes. Mortality outcomes were ascertained from the National Death Index. During a median of 6.6 years of follow-up, 244 deaths occurred (161 from CRC). We identified 20 SNPs (12 of ESR2 and 8 of PGR) for replication in 1,729 women diagnosed with incident invasive CRC (555 deaths; 405 from CRC) from three prospective cohort studies that participate in the Genetics and Epidemiology of Colorectal Cancer Consortium. Three correlated SNPs in the promoter of ESR2 (rs2987983, rs3020443, and rs2978381) were statistically significant predictors of CRC-specific and overall survival. Minor alleles of each were associated with improved survival [for rs2987983, CRC-specific HR, 0.77; 95% confidence interval (CI), 0.60–0.99 in the initial study, and HR, 0.79; CI, 0.64–0.98 in replication]. No associations were noted for SNPs of AR, ESR1, or PGR. SNPs in the promoter of ESR2 may be important to pathways related to the association between ERβ and tumor progression and metastasis. Cancer Res; 73(2); 767–75. ©2012 AACR.
Progression-Free Survival as a Surrogate Endpoint for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis from 50 Randomized First-Line Trials
Authors: Giessen Clemens , Laubender Ruediger Paul , Ankerst Donna Pauler , Stintzing Sebastian , Modest Dominik Paul , Mansmann Ulrich , Heinemann Volker
Published: November 2012

Purpose: To evaluate progression-free survival (PFS) as a potential surrogate endpoint (SEP) for overall survival (OS) in metastatic colorectal cancer (mCRC) with a focus on applicability to trials containing targeted therapy with anti-VEGF- or anti-EGF receptor (EGFR)–directed monoclonal antibodies.

Experimental Design: A systematic literature search of randomized trials of first-line chemotherapy for mCRC reported from January 2000 to January 2012 was conducted. Adjusted weighted linear regression was used to calculate correlations within PFS and OS (endpoints; REP) and between treatment effects on PFS and on OS (treatment effects; RTE).

Results: Fifty trials reflecting 22,736 patients met the inclusion criteria. Correlation between treatment effects on PFS and OS and between the endpoints PFS and OS was high across all studies (RTE = 0.87, REP = 0.86). This was also observed in chemotherapy-only trials (RTE = 0.93, REP = 0.81) but less so for trials containing monoclonal antibodies (RTE = 0.47; REP = 0.52). Limiting the analysis to bevacizumab-based studies (11 trials, 3,310 patients) again yielded high correlations between treatment effects on PFS and on OS (RTE = 0.84), whereas correlation within PFS and OS was low (REP = 0.45). In 7 trials (1,335 patients) investigating cetuximab- or panitumumab-based studies, contrasting correlations with very wide confidence intervals were observed (RTE = 0.28; REP = 0.96).

Conclusions: PFS showed consistently high correlation with OS of an order that would justify its use as an SEP in chemotherapy regimens. For validation of surrogacy in anti-VEGF and anti-EGFR–directed therapies, further research and a larger set of trials is needed. Clin Cancer Res; 19(1); 225–35. ©2012 AACR.
High-Density Lipoprotein Function, Dysfunction, and Reverse Cholesterol Transport
Authors: Fisher Edward A. , Feig Jonathan E. , Hewing Bernd , Hazen Stanley L. , Smith Jonathan D.
Published: November 2012

Although high high-density lipoprotein (HDL)-cholesterol levels are associated with decreased cardiovascular risk in epidemiological studies, recent genetic and pharmacological findings have raised doubts about the beneficial effects of HDL. Raising HDL levels in animal models by infusion or overexpression of apolipoprotein A-I has shown clear vascular improvements, such as delayed atherosclerotic lesion progression and accelerated lesion regression, along with increased reverse cholesterol transport. Inflammation and other factors, such as myeloperoxidase-mediated oxidation, can impair HDL production and HDL function, with regard to its reverse cholesterol transport, antioxidant, and anti-inflammatory activities. Thus, tests of HDL function, which have not yet been developed as routine diagnostic assays, may prove useful and be a better predictor of cardiovascular risk than HDL-cholesterol levels.
Bivalirudin for Primary Percutaneous Coronary Interventions
Authors: Hibbert Benjamin , MacDougall Andrea , Labinaz Marino , O’Brien Edward R. , So Derek Y.F. , Dick Alexander , Glover Christopher , Froeschl Michael , Marquis Jean-Francois , Wells George A. , Blondeau Melissa , Le May Michel R.
Published: November 2012

Background—

Data from randomized trials has demonstrated the superiority of bivalirudin to glycoprotein IIb/IIIa inhibitors plus heparin in patients undergoing primary percutaneous coronary intervention. Real-world performance of bivalirudin in primary percutaneous coronary intervention and the benefit of bivalirudin over heparin remain unknown in an era of routine dual antiplatelet therapy.

Methods and Results—

From July 2004 to December 2010, 2317 consecutive patients were indexed in the University of Ottawa Heart Institute ST-segment–elevation myocardial infarction registry. During this period 748 patients received bivalirudin, 699 patients received glycoprotein IIb/IIIa inhibitors, and 676 patients received unfractionated heparin alone. The primary outcome was the rate of noncoronary artery bypass graft related thrombolysis in myocardial infarction major bleeding. Bivalirudin significantly reduced the primary outcome compared with heparin plus glycoprotein IIb/IIIa inhibitors (2.7% versus 7.3%, adjusted OR 2.96, 95% CI: 1.61–5.45,
P
<0.001) and the composite end point of death, stroke, reinfarction and major bleed (OR 1.66, 95% CI: 1.12–2.45,
P
=0.01). Compared with heparin alone, a reduction in major bleeds (OR 1.21, 95% CI: 0.60–2.44,
P
=0.59) or the composite end point (1.05, 95% CI: 0.68–1.63,
P
=0.83) with bivalirudin could not be demonstrated. Notably, major bleeding was associated with a 5-fold increase in the risk of mortality both in-hospital (3.5% versus 20.6%) and out to 180 days (5.6% versus 25.8%).

Conclusions—

Bivalirudin use compared with glycoprotein IIb/IIIa inhibitors plus heparin as an antithrombotic strategy in primary percutaneous coronary intervention results in less major bleeding in contemporary practice. A benefit of bivalirudin over heparin could not be established with this registry and requires additional investigations to either confirm or refute.
Effects of Rare and Common Blood Pressure Gene Variants on Essential Hypertension
Authors: Nguyen Khanh-Dung H. , Pihur Vasyl , Ganesh Santhi K. , Rakha Ankit , Cooper Richard S. , Hunt Steven C. , Freedman Barry I. , Coresh Joe , Kao W.H. Linda , Morrison Alanna C. , Boerwinkle Eric , Ehret Georg B. , Chakravarti Aravinda
Published: November 2012

Rationale:

Hypertension affects ≈30% of adults in industrialized countries and is the major risk factor for cardiovascular disease.

Objective:

We sought to study the genetic effect of coding and conserved noncoding variants in syndromic hypertension genes on systolic blood pressure (BP) and diastolic BP to assess their overall impact on essential hypertension.

Methods and Results:

We resequenced 11 genes (
AGT
,
CYP11B1
,
CYP17A1
,
HSD11B2
,
NR3C1
,
NR3C2
,
SCNN1A
,
SCNN1B
,
SCNN1G
,
WNK1
, and
WNK4
) in 560 European American (EA) and African American ancestry GenNet participants with extreme systolic BP. We investigated genetic associations of 2535 variants with BP in 19997 EAs and in 6069 African Americans in 3 types of analyses. First, we studied the combined effects of all variants in GenNet. Second, we studied 1000 Genomes imputed polymorphic variants in 9747 EA and 3207 African American Atherosclerosis Risk in Communities subjects. Finally, we genotyped 37 missense and common noncoding variants in 6591 EAs and in 6521 individuals (3659 EA/2862 African American) from the CLUE and Family Blood Pressure Program studies, respectively. None of the variants individually reached significant false-discovery rates ≤0.05 for systolic BP and diastolic BP. However, on pooling all coding and noncoding variants, we identified at least 5 loci (
AGT
,
CYP11B1
,
NR3C2
,
SCNN1G
, and
WNK1)
with higher association at evolutionary conserved sites.

Conclusions:

Both rare and common variants at these genes affect BP in the general population with modest effects sizes (<0.05 standard deviation units), and much larger sample sizes are required to assess the impact of individual genes. Collectively, conserved noncoding variants affect BP to a greater extent than missense mutations.
Timing, Predictive Factors, and Prognostic Value of Cerebrovascular Events in a Large Cohort of Patients Undergoing Transcatheter Aortic Valve Implantation
Authors: Nombela-Franco Luis , Webb John G. , de Jaegere Peter P. , Toggweiler Stefan , Nuis Rutger-Jan , Dager Antonio E. , Amat-Santos Ignacio J. , Cheung Anson , Ye Jian , Binder Ronald K. , van der Boon Robert M. , Van Mieghem Nicolas , Benitez Luis M. , Pérez Sergio , Lopez Javier , San Roman José A. , Doyle Daniel , DeLarochellière Robert , Urena Marina , Leipsic Jonathon , Dumont Eric , Rodés-Cabau Josep
Published: November 2012

Background—

The objective of this study was to evaluate the timing, predictive factors, and prognostic value of cerebrovascular events (CVEs) after transcatheter aortic valve implantation.

Methods and Results—

The study included 1061 consecutive patients who underwent transcatheter aortic valve implantation with a balloon-expandable (64%) or self-expandable (36%) valve. CVEs were classified as acute (≤24 hours), subacute (1–30 days), or late (>30 days). CVEs occurred in 54 patients (5.1%; stroke, 4.2%) within 30 days after transcatheter aortic valve implantation (acute in 54% of cases). The predictors of acute CVEs were balloon postdilation of the valve prosthesis (odds ratio, 2.46; 95% confidence interval,1.07–5.67) and valve dislodgment/embolization (odds ratio, 4.36; 95% CI, 1.21–15.69); new-onset atrial fibrillation (odds ratio, 2.76; 95% CI, 1.11–6.83) was a predictor of subacute CVEs. Late CVEs occurred in 35 patients (3.3%; stroke, 2.1%) at a median follow-up of 12 months (3–23 months). The predictors of late CVEs were chronic atrial fibrillation (2.84; 95% CI, 1.46–5.53), peripheral vascular disease (hazard ratio, 2.02; 95% CI, 1.02–3.97), and prior cerebrovascular disease (hazard ratio, 2.04; 95% CI, 1.01–4.15). Major stroke was associated with 30-day (odds ratio, 7.43; 95% CI, 2.45–22.53) and late (hazard ratio, 1.75; 95% CI, 1.01–3.04) mortality.

Conclusions—

In a large cohort of patients undergoing transcatheter aortic valve implantation, the rates of acute and subacute CVEs were 2.7% and 2.4%, respectively. While balloon postdilation and valve dislodgment/embolization were the predictors of acute CVEs, new-onset atrial fibrillation determined a higher risk for subacute events. Late events were determined mainly by a history of chronic atrial fibrillation and peripheral and cerebrovascular disease. The occurrence of major stroke was associated with increased early and late mortality. These results provide important insights for the implementation of preventive measures for CVEs after transcatheter aortic valve implantation.
Does Dairy Food Intake Predict Arterial Stiffness and Blood Pressure in Men?
Authors: Livingstone Katherine M. , Lovegrove Julie A. , Cockcroft John R. , Elwood Peter C. , Pickering Janet E. , Givens D. Ian
Published: November 2012

Arterial stiffness is an independent predictor of cardiovascular disease events and mortality, and like blood pressure, may be influenced by dairy food intake. Few studies have investigated the effects of consumption of these foods on prospective measures of arterial stiffness. The present analysis aimed to investigate the prospective relationship between milk, cheese, cream, and butter consumption and aortic pulse wave velocity, augmentation index, systolic and diastolic blood pressure, as well as cross-sectional relationships between these foods and systolic and diastolic blood pressure and metabolic markers using data from the Caerphilly Prospective Study. Included in this cohort were 2512 men, aged 45 to 59 years, who were followed up at 5-year intervals for a mean of 22.8 years (number follow-up 787). Augmentation index was 1.8% lower in subjects in the highest quartiles of dairy product intake compared with the lowest (
P
trend=0.021), whereas in the highest group of milk consumption systolic blood pressure was 10.4 mm Hg lower (
P
trend=0.033) than in nonmilk consumers after a 22.8-year follow-up. Cross-sectional analyses indicated that across increasing quartiles of butter intake, insulin (
P
trend=0.011), triacylglycerol (
P
trend=0.023), total cholesterol (
P
trend=0.002), and diastolic blood pressure (
P
trend=0.027) were higher. Across increasing groups of milk intake and quartiles of dairy product intake, glucose (
P
trend=0.032) and triglyceride concentrations (
P
trend=0.031) were lower, respectively. The present results confirm that consumption of milk predicts prospective blood pressure, whereas dairy product consumption, excluding butter, is not detrimental to arterial stiffness and metabolic markers. Further research is needed to better understand the mechanisms that underpin these relationships.
Functional Regulation of ClC-3 in the Migration of Vascular Smooth Muscle Cells
Authors: Ganapathi Sindura B. , Wei Shun-Guang , Zaremba Angelika , Lamb Fred S. , Shears Stephen B.
Published: November 2012

Migration of vascular smooth muscle cells (VSMCs) into neointima contributes to atherosclerosis and restenosis. This migration requires coordinated plasmalemmal fluxes of water and ions. Here, we show that aortic VSMC migration depends on the regulation of transmembrane Cl
−
flux by ClC-3, a Cl
−
channel/transporter. The contribution of ClC-3 to plasmalemmal Cl
−
current was studied in VSMCs by electrophysiological recordings. Cl
−
current was negligible in cells perfused with 0 [Ca
2+
]. Raising intracellular [Ca
2+
] to 0.5 μM activated a Cl
−
current (I
Cl.Ca
), approximately half of which was eliminated on inhibition by KN-93 of calmodulin-dependent protein kinase II. I
Cl.Ca
was also halved by inositol-3,4,5,6-tetrakisphosphate, a cellular signal with the biological function of specifically preventing calmodulin-dependent protein kinase II from activating I
Cl.Ca
. Gene disruption of ClC-3 reduced I
Cl.Ca
by 50%. Moreover, I
Cl.Ca
in the ClC-3 null VSMCs was not affected by either KN-93 or inositol-3,4,5,6-tetrakisphosphate. We conclude that I
Cl.Ca
is composed of 2 components, one is ClC-3 independent whereas the other is ClC-3 dependent, activated by calmodulin-dependent protein kinase II and inhibited by inositol-3,4,5,6-tetrakisphosphate. We also assayed VSMC migration in transwell assays. Migration was halved in ClC-3 null cells versus wild-type cells. In addition, inhibition of ClC-3 by niflumic acid, KN-93, or inositol-3,4,5,6-tetrakisphosphate each reduced cell migration in wild-type cells but not in ClC-3 null cells. These cell-signaling roles of ClC-3 in VSMC migration suggest new therapeutic approaches to vascular remodeling diseases.
Physical Activity and Blood Pressure in Primary School Children
Authors: Knowles Gemma , Pallan Miranda , Thomas G. Neil , Ekelund Ulf , Cheng Kar Keung , Barrett Timothy , Adab Peymane
Published: November 2012

High blood pressure (BP) is becoming increasingly common during childhood. Regular physical activity (PA) reduces BP in adults, but limited studies have reported inconsistent results among children. The aim of this study is to examine, for the first time, the cross-sectional and longitudinal associations between BP and objectively measured PA in young children of predominantly South Asian background. Data from the Birmingham healthy Eating and Active lifestyle for CHildren Study were analyzed. Five hundred seventy-four children, aged 5 to 7 years, underwent a series of measures at baseline and were followed up 2 years later. PA was objectively measured using accelerometry and converted to counts per minute (total PA, cpm), and time spent in moderate-vigorous PA (minutes per day). BP was measured by trained staff using standard protocols. Data were available for 512 children at baseline (mean age 6.5 years, range 5.4–7.8 years), and 427 of these children were followed up. Baseline total PA was inversely associated with diastolic BP at both baseline (adjusted regression coefficient: −0.75 mm Hg [95% CI −1.33 to −0.18] per 20 cpm) and follow-up (−0.74 mm Hg [95% CI −1.40 to −0.08]). All associations remained unchanged after further adjustment for weight status. This study strengthens evidence of a causal association between higher PA and lower BP in children as young as 5, independent of weight status. The results provide support for development of interventions to increase PA in young children.
A Role for TRPV1 in Influencing the Onset of Cardiovascular Disease in Obesity
Authors: Marshall Nichola J. , Liang Lihuan , Bodkin Jennifer , Dessapt-Baradez Cecile , Nandi Manasi , Collot-Teixeira Sophie , Smillie Sarah-Jane , Lalgi Kamal , Fernandes Elizabeth S. , Gnudi Luigi , Brain Susan D.
Published: November 2012

Obesity induced by Western diets is associated with type 2 diabetes mellitus and cardiovascular diseases, although underlying mechanisms are unclear. We investigated a murine model of diet-induced obesity to determine the effect of transient potential receptor vanilloid 1 (TRPV1) deletion on hypertension and metabolic syndrome. Wild-type and TRPV1 knockout mice were fed normal or high-fat diet from 3 to 15 weeks. High-fat diet-fed mice from both genotypes became obese, with similar increases in body and adipose tissue weights. High-fat diet-fed TRPV1 knockout mice showed significantly improved handling of glucose compared with high-fat diet-fed wild-type mice. Hypertension, vascular hypertrophy, and altered nociception were observed in high-fat diet-fed wild-type but not high-fat diet-fed TRPV1 knockout mice. Wild-type, but not high-fat diet-fed TRPV1 knockout, mice demonstrated remodeling in terms of aortic vascular hypertrophy and increased heart and kidney weight, although resistance vessel responses were similar in each. Moreover, the wild-type mice had significantly increased plasma levels of leptin, interleukin 10 and interleukin 1β, whereas samples from TRPV1 knockout mice did not show significant increases. Our results do not support the concept that TRPV1 plays a major role in influencing weight gain. However, we identified a role of TRPV1 in the deleterious effects observed with high-fat feeding in terms of inducing hypertension, impairing thermal nociception sensitivity, and reducing glucose tolerance. The observation of raised levels of adipokines in wild-type but not TRPV1 knockout mice is in keeping with TRPV1 involvement in stimulating the proinflammatory network that is central to obesity-induced hypertension and sensory neuronal dysfunction.
Influence of Lower Body Positive Pressure on Upper Airway Cross-Sectional Area in Drug-Resistant Hypertension
Authors: Friedman Oded , Bradley T. Douglas , Logan Alexander G.
Published: November 2012

We previously showed that in hypertensive patients the amount of fluid displaced from the legs overnight is directly related to the severity of obstructive sleep apnea and that the rostral fluid shift was greater in drug-resistant hypertensive patients. The findings suggested that this fluid redistribution increases upper airway collapsibility, yet more direct evidence is lacking. The present study examines the effects of graded lower body positive pressure on leg fluid volume, upper airway cross-sectional area, and neck circumference in patients with drug-resistant hypertension (n=25) and controlled hypertension (n=15). In both groups, the reduction in mean upper airway cross-sectional area and oropharyngeal junction area, assessed by acoustic pharyngometry, and the increase in neck circumference, determined by mercury strain gauge plethysmography, were related to the amount of fluid displaced from the legs (
R
2
=0.41,
P
<0.0001;
R
2
=0.42,
P
<0.0001; and
R
2
=0.47,
P
<0.0001, respectively). Displacement of leg fluid volume was significantly greater in patients with drug-resistant hypertension than in controlled hypertension (
P
<0.0001), and as a consequence, the former experienced greater reductions in mean upper airway cross-sectional area and oropharyngeal junction area (
P
=0.001 and
P
<0.0001, respectively). The findings support the concept that in hypertensive subjects, rostral fluid displacement may participate in the pathogenesis of obstructive sleep apnea by narrowing the upper airway and making it more susceptible to collapse during sleep. The exaggerated fluid volume displacement from the legs and upper airway response to lower body positive pressure in patients with drug-resistant hypertension provide additional evidence of an important link between drug-resistant hypertension and obstructive sleep apnea.
Lack of Specificity of Commercial Antibodies Leads to Misidentification of Angiotensin Type 1 Receptor Protein
Authors: Herrera Marcela , Sparks Matthew A. , Alfonso-Pecchio Adolfo R. , Harrison-Bernard Lisa M. , Coffman Thomas M.
Published: November 2012

The angiotensin II type 1 receptor (AT
1
R) mediates most hypertensive actions of angiotensin II. To understand the molecular regulation of the AT
1
R in normal physiology and pathophysiology, methods for sensitive and specific detection of AT
1
R protein are required. Here, we examined the specificity of a panel of putative AT
1
R antibodies that are commonly used by investigators in the field. For these studies, we carried out Western blotting and immunohistochemistry with kidney tissue from wild-type mice and genetically modified mice lacking the major murine AT
1
R isoform, AT
1A
(AT
1A
KO), or with combined deficiency of both the AT
1A
and AT
1B
isoforms (AT
1AB
KO). For the 3 antibodies tested, Western blots of protein homogenates from wild-type kidneys yielded distinct bands with the expected size range for AT
1
R. In addition, these bands appeared identical in samples from mice lacking 1 or both murine AT
1
R isoforms. Additionally, the pattern of immunohistochemical staining in kidneys, liver, and adrenal glands of wild-type mice was very similar to that of AT
1AB
KO mice completely lacking all AT
1
R. We verified the absence of AT
1
R subtypes in each mouse line by the following: (1) quantitative polymerase chain reaction documenting the absence of mRNA species, and (2) functionally by assessing angiotensin II–dependent vasoconstriction, which was substantially blunted in both AT
1A
KOs and AT
1AB
KOs. Finally, these antibodies failed to detect epitope-tagged AT
1A
R protein overexpressed in human embryonic kidney cells. We conclude that anti-AT
1
R antibodies available from commercial sources and commonly used in published studies exhibit nonspecific binding in mouse tissue that may lead to erroneous results.
Antithrombotic Therapy and Bleeding Risk in a Prospective Cohort Study of Patients With Cerebral Cavernous Malformations
Authors: Schneble Hans-Martin , Soumare Aicha , Hervé Dominique , Bresson Damien , Guichard Jean-Pierre , Riant Florence , Tournier-Lasserve Elisabeth , Tzourio Christophe , Chabriat Hugues , Stapf Christian
Published: November 2012

Background and Purpose—

Cerebral cavernous malformations (CCMs) are one of the most frequently diagnosed vascular malformations of the brain and constitute a potential source of intracranial hemorrhage. In CCM patients suffering ischemic stroke or heart disease, the use of anticoagulants or antiplatelet therapy is generally avoided by fear of hemorrhagic complications, but no systematic studies exist to support this hypothesis.

Methods—

We prospectively followed-up consecutive patients with a diagnosis of one or more CCMs in a prospective database since 2008. Retrospective data collection was used for patients with a diagnostic event or imaging studies done before first assessment. Symptomatic hemorrhage and other focal neurological events during prospective follow-up were defined according to the current guidelines of the Angioma Alliance Scientific Advisory board.

Results—

A total of 87 patients were prospectively enrolled in our cohort [50 women (57%), mean age 44.8 years (SD ± 17.6), mean follow-up 3.9 years], harboring a total of 738 CCMs. Fifty-five patients (63%) had a single CCM, and 32 patients (37%) had multiple CCMs. Longitudinal follow-up included 16 (18%) patients receiving long-term antithrombotic therapy by antiplatelet treatment (n=11) or oral anticoagulants (n=5). During 5536 lesion-years of observation, none of the patients under antithrombotic therapy experienced CCM hemorrhage on follow-up.

Conclusions—

Our observational data suggest that long-term antithrombotic treatment by antiplatelet drugs or warfarin does not increase the frequency of CCM-related hemorrhage. Patients harboring single or multiple CCMs suffering ischemic stroke or heart disease should not be withheld antithrombotic therapy.
Nonvitamin-K-Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Previous Stroke or Transient Ischemic Attack
Authors: Ntaios George , Papavasileiou Vasileios , Diener Hans-Christoph , Makaritsis Konstantinos , Michel Patrik
Published: November 2012

Background and Purpose—

To assess whether the combined analysis of all phase III trials of nonvitamin-K-antagonist (non-VKA) oral anticoagulants in patients with atrial fibrillation and previous stroke or transient ischemic attack shows a significant difference in efficacy or safety compared with warfarin.

Methods—

We searched PubMed until May 31, 2012, for randomized clinical trials using the following search items: atrial fibrillation, anticoagulation, warfarin, and previous stroke or transient ischemic attack. Studies had to be phase III trials in atrial fibrillation patients comparing warfarin with a non-VKA currently on the market or with the intention to be brought to the market in North America or Europe. Analysis was performed on intention-to-treat basis. A fixed-effects model was used as more appropriate than a random-effects model when combining a small number of studies.

Results—

Among 47 potentially eligible articles, 3 were included in the meta-analysis. In 14 527 patients, non-VKAs were associated with a significant reduction of stroke/systemic embolism (odds ratios, 0.85 [95% CI, 074–0.99]; relative risk reduction, 14%; absolute risk reduction, 0.7%; number needed to treat, 134 over 1.8–2.0 years) compared with warfarin. Non-VKAs were also associated with a significant reduction of major bleeding compared with warfarin (odds ratios, 0.86 [95% CI, 075–0.99]; relative risk reduction, 13%; absolute risk reduction, 0.8%; number needed to treat, 125), mainly driven by the significant reduction of hemorrhagic stroke (odds ratios, 0.44 [95% CI, 032–0.62]; relative risk reduction, 57.9%; absolute risk reduction, 0.7%; number needed to treat, 139).

Conclusions—

In the context of the significant limitations of combining the results of disparate trials of different agents, non-VKAs seem to be associated with a significant reduction in rates of stroke or systemic embolism, hemorrhagic stroke, and major bleeding when compared with warfarin in patients with previous stroke or transient ischemic attack.
Quantificational Binding Does Not Require C-Command
Authors: Barker Chris
Published: November 2012

Some version of the following claim is almost universally assumed: a quantifier must c-command any pronoun that it binds. Yet as I show, the evidence motivating this claim is not particularly strong. In addition, I gather here a wide variety of systematic counterexamples, some well-known, others new. I conclude that c-command is not relevant for quantificational binding in English (nor is any refinement or extension of c-command).
Classifiers and DP
Authors: Cheng Lisa Lai-Shen , Sybesma Rint
Published: November 2012

Wu and Bodomo (2009) argue against claims made in Cheng and Sybesma 1999 . Gebhardt (2011) has contested their arguments related to the status of classifiers and the question whether all nouns in Chinese are mass. In this reply, we discuss some of the points Wu and Bodomo raise, arguing that (a) sortal classifiers are not lexical elements; (b) generic interpretation is not the same as kind interpretation; (c) demonstrative noun phrases do not have the same distribution and interpretation as definite noun phrases in Mandarin and Cantonese; and (d) the DP structure that Wu and Bodomo propose runs into serious problems with phrasal possessors. Finally, we discuss an alternative approach to the structure of the nominal domain in Chinese languages.
Flavors of Division
Authors: Mathieu Éric
Published: November 2012

The theoretical aim of this article is to integrate the singulative into the theory of division proposed by Borer (2005) and other theoretical linguists (e.g., Krifka 1995 , Doetjes 1996 , 1997 , Chierchia 1998 , Cheng and Sybesma 1999 ). To illustrate my claim, I offer a brief case study of Ojibwe, an Algonquian language, which I argue uses gender shift (from inanimate to animate) to mark singulativization. Singulatives, as morphological markers, are primarily known from Celtic, Afro-Asiatic, and Nilo-Saharan languages, but are not a known feature of Algonquian languages. Further support for my claim that the grammar of Algonquian languages embeds a singulative system comes from Fox (Mesquakie).
Estimating the Permafrost-Carbon Climate Response in the CMIP5 Climate Models Using a Simplified Approach
Authors: Burke Eleanor J. , Jones Chris D. , Koven Charles D.
Published: November 2012

Under climate change, thawing permafrost may cause a release of carbon, which has a positive feedback on the climate. The permafrost-carbon climate response (γPF) is the additional permafrost-carbon made vulnerable to decomposition per degree of global temperature increase. A simple framework was adopted to estimate γPF using the database for phase 5 of the Coupled Model Intercomparison Project (CMIP5). The projected changes in the annual maximum active layer thicknesses (ALTmax) over the twenty-first century were quantified using CMIP5 soil temperatures. These changes were combined with the observed distribution of soil organic carbon and its potential decomposability to give γPF. This estimate of γPF is dependent on the biases in the simulated present-day permafrost. This dependency was reduced by combining a reference estimate of the present-day ALTmax with an estimate of the sensitivity of ALTmax to temperature from the CMIP5 models. In this case, γPF was from −6 to −66 PgC K−1(5th–95th percentile) with a radiative forcing of 0.03–0.29 W m−2 K−1. This range is mainly caused by uncertainties in the amount of soil carbon deeper in the soil profile and whether it thaws over the time scales under consideration. These results suggest that including permafrost-carbon within climate models will lead to an increase in the positive global carbon climate feedback. Under future climate change the northern high-latitude permafrost region is expected to be a small sink of carbon. Adding the permafrost-carbon response is likely to change this region to a source of carbon.