bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibitory Effects of Standardized Extracts ofPhyllanthus amarusandPhyllanthus urinariaand Their Marker Compounds on Phagocytic Activity of Human Neutrophils
Authors: Yuandani  , Ilangkovan Menaga , Jantan Ibrahim , Mohamad Hazni Falina , Husain Khairana , Abdul Razak Amirul Faiz
Published: May 2013

The standardized methanol extracts ofPhyllanthus amarusandP. urinaria, collected from Malaysia and Indonesia, and their isolated chemical markers, phyllanthin and hypophyllanthin, were evaluated for their effects on the chemotaxis, phagocytosis and chemiluminescence of human phagocytes. All the plant extracts strongly inhibited the migration of polymorphonuclear leukocytes (PMNs) with the MalaysianP. amarusshowing the strongest inhibitory activity (IC50value, 1.1 µg/mL). There was moderate inhibition by the extracts of the bacteria engulfment by the phagocytes with the MalaysianP. amarusexhibiting the highest inhibition (50.8% of phagocytizing cells). The MalaysianP. amarusandP. urinariashowed strong reactive oxygen species (ROS) inhibitory activity, with both extracts exhibiting IC50value of 0.7 µg/mL. Phyllanthin and hypophyllanthin exhibited relatively strong activity against PMNs chemotaxis, with IC50values slightly lower than that of ibuprofen (1.4 µg/mL). Phyllanthin exhibited strong inhibitory activity on the oxidative burst with an IC50value comparable to that of aspirin (1.9 µg/mL). Phyllanthin exhibited strong engulfment inhibitory activity with percentage of phagocytizing cells of 14.2 and 27.1% for neutrophils and monocytes, respectively. The strong inhibitory activity of the extracts was due to the presence of high amounts of phyllanthin and hypophyllanthin although other constituents may also contribute.
Planktonic Foraminiferal Biostratigraphy and Correlation Across the Cretaceous-Paleogene Transition at the Tethyan and the Atlantic Realms
Authors: Gallala Njoud
Published: May 2013

Based on high-resolution planktonic foraminiferal biostratigraphical analysis at El Kef stratotype section (GSSP for the K/Pg boundary), Ellès section in Tunisia, and Agost and Caravaca sections in Spain (Tethyan realm), we attempt to compare biozones and subzones with those of the Bidart section (SW France) (Atlantic realm). TheAbathomphalus mayaroensiszone of the upper Maastrichtian corresponds to the taxon range interval of the nominate species. We have identified thePlummerita hantkeninoidessubzone. This species is present and associated withPseudoguembelina hariaensisat the Tethyan realm. However, this species is absent at the middle latitude of the Atlantic realm (Bidart section, SW France). ThePseudoguembelina hariaensisspecies had larger paleogeographic spread, as it was present in both the Tethys and the Atlantic paleoceans. It is more relevant to be considered as the biomarker of a nominate uppermost Maastrichtian subzone instead ofPlummerita hantkeninoides. The Danian stage is characterized by theGt. cretaceazone,Pv. eugubinazone, and theParasubbotina pseudobulloideszone. The deposition thickness of the zones and subzones at El Kef stratotype section and Ellès section is more expanded than at Agost and Caravaca sections (Spain) and Bidart section (France). They would be controlled by the sedimentary basin morphology.
Metabonomic Strategy to the Evaluation of Chinese Medicine Compound Danshen Dripping Pills Interfering Myocardial Ischemia in Rats
Authors: Xin Xue , Zou Haimiao , Zheng Ningning , Xu Xinchun , Liu Yinmin , Wang Xiaoxian , Wu Hongbing , Lu Lina , Su Jing , Qiu Mingfeng , Wang Xiaoyan
Published: May 2013

Coronary heart disease (CHD) is one of the highest mortality diseases in the world. Traditional Chinese medicine compound Danshen dripping pills (CDDPs) have currently made a great achievement in treating CHD. However, the therapeutic mechanism of CDDP is often poorly interpreted. In this study, a GC-MS-based metabonomic study was conducted to assess the holistic efficacy of CDDP for myocardial infarction in male Sprague-Dawley rats, which were divided into the control group, the sham group, the model group, the control + CDDP group, and the model + CDDP, with CDDP at a dose of 107 mg/kg·d (equal to 1.8 mL/kg·d). The metabonomic findings demonstrated great differences of metabolic pattern among sham, model, and the model + CDDP in the orthogonal partial least squares discriminant analysis (OPLS-DA) models, which coordinated well with the assessment of plasma biochemistry and histopathological assay. Differentially expressed metabolites suggested that energy metabolism, glycolysis, and lipid metabolism might be disrupted by myocardial infarction. Both the potential metabolic biomarkers and the biochemical histopathological indices were regulated effectively by CDDP.
Clustering‐Based Multiple Imputation via Gray Relational Analysis for Missing Data and Its Application to Aerospace Field
Authors: Tian Jing , Yu Bing , Yu Dan , Ma Shilong
Published: May 2013

A large number of scientific researches and industrial applications commonly suffer from missing data. Some inappropriate techniques of missing value treatment compromise data quality, which detrimentally influences the knowledge discovery. In this paper, we propose a missing data completion method named CBGMI. Firstly, it separates the nonmissing data instances into several clusters by excluding the missing‐valued entries. Then, it utilizes the entropy of the proximal category for each incomplete instance in terms of the similarity metric based on gray relational analysis. Experiments on UCI datasets and aerospace datasets demonstrate that the superiority of our algorithm to other approaches on validity.
Update on the Protective Molecular Pathways Improving Pancreatic Beta-Cell Dysfunction
Authors: Puddu Alessandra , Sanguineti Roberta , Mach François , Dallegri Franco , Viviani Giorgio Luciano , Montecucco Fabrizio
Published: May 2013

The primary function of pancreatic beta-cells is to produce and release insulin in response to increment in extracellular glucose concentrations, thus maintaining glucose homeostasis. Deficient beta-cell function can have profound metabolic consequences, leading to the development of hyperglycemia and, ultimately, diabetes mellitus. Therefore, strategies targeting the maintenance of the normal function and protecting pancreatic beta-cells from injury or death might be crucial in the treatment of diabetes. This narrative review will update evidence from the recently identified molecular regulators preserving beta-cell mass and function recovery in order to suggest potential therapeutic targets against diabetes. This review will also highlight the relevance for novel molecular pathways potentially improving beta-cell dysfunction.
The Current Situation of Wind Energy in Turkey
Authors: Ata Raşit
Published: May 2013

Wind energy applications and turbine installations at different scales have increased since the beginning of this century. As wind energy is an alternative clean energy source compared to the fossil fuels that pollute the atmosphere, systems that convert wind energy to electricity have developed rapidly. Turkey’s domestic fossil fuel resources are extremely limited. In addition, Turkey’s geographical location has several advantages for extensive use of wind power. In this context, renewable energy resources appear to be one of the most efficient and effective solutions for sustainable energy development and environmental pollution prevention in Turkey. Among the renewable sources, Turkey has very high wind energy potential. According to the Organization for Economic Cooperation and Development (OECD) Turkey theoretically has 166 TWh a year of wind potential. However the installed wind power capacity is approximately 14% of total economical wind potential. In this study, Turkey’s installed electric power capacity and electric energy production are investigated and also the current situation of wind energy in Turkey is examined. The wind data used in this study were taken from Turkish Wind Energy Association (TUREB) for the year 2012. This paper reviews the assessment of wind energy in Turkey as of the end of July 2012 including wind energy applications.
Numerical Simulation of Mixed Convection in a Rotating Cylindrical Cavity: Influence of Prandtl Number
Authors: Urquiza Gustavo , Castro Laura , García Juan , Basurto Miguel , Bogarin Enoc
Published: May 2013

A numerical study of the flow and heat transfer on a rotating cylindrical cavity solving the mass, momentum, and energy equations is presented in this work. The study describes the influence of the Prandtl number on flow in critical state on a cavity which contains a cooling fluid. Problem studied includes Prandtl numbers 0.001 < Pr > 15, aspect ratios 0.25 < A > 1, and Reynolds numbers 0.001 < Re > 600. Differential equations have been discretised using the finite differences method. The results show a tendency followed by heat transfer as the Reynolds number increases from 300 to 600; in addition, emphasis on the critical values of the Rayleigh number for small Prandtl numbers shows that thermal instability in mixed convection depends on the Prandtl number.
PI3K/mTOR Inhibitor PF-04691502 Antitumor Activity Is Enhanced with Induction of Wild-Type TP53 in Human Xenograft and Murine Knockout Models of Head and Neck Cancer
Authors: Herzog Amanda , Bian Yansong , Vander Broek Robert , Hall Bradford , Coupar Jamie , Cheng Hui , Sowers Anastasia L. , Cook John D. , Mitchell James B. , Chen Zhong , Kulkarni Ashok B. , Van Waes Carter
Published: May 2013

Purpose: Phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway activation is often associated with altered expression or mutations of PIK3CA, TP53/p73, PTEN, and TGF-β receptors (TGFBR) in head and neck squamous cell carcinomas (HNSCC). However, little is known about how these alterations affect response to PI3K/mTOR–targeted agents.

Experimental Design: In this preclinical study, PI3K/Akt/mTOR signaling was characterized in nine HNSCC (UM-SCC) cell lines and human oral keratinocytes. We investigated the molecular and anticancer effects of dual PI3K/mTOR inhibitor PF-04691502(PF-502) in UM-SCC expressing PIK3CA with decreased wild-type TP53, mutant TP53−/+ mutantTGFBR2, and in HNSCC of a conditional Pten/Tgfbr1 double knockout mouse model displaying PI3K/Akt/mTOR activation.

Results: UM-SCC showed increased PIK3CA expression and Akt/mTOR activation, and PF-502 inhibited PI3K/mTORC1/2 targets. In human HNSCC expressing PIK3CA and decreased wtTP53 and p73, PF-502 reciprocally enhanced TP53/p73 expression and growth inhibition, which was partially reversible by p53 inhibitor pifithrin-α. Most UM-SCC with wtTP53 exhibited a lower IC50 than those with mtTP53 status. PF-502 blocked growth in G0–G1 and increased apoptotic sub-G0 DNA. PF-502 suppressed tumorigenesis and showed combinatorial activity with radiation in a wild-type TP53 UM-SCC xenograft model. PF-502 also significantly delayed HNSCC tumorigenesis and prolonged survival of Pten/Tgfbr1-deficient mice. Significant inhibition of p-Akt, p-4EBP1, p-S6, and Ki67, as well as increased p53 and TUNEL were observed in tumor specimens.

Conclusions: PI3K-mTOR inhibition can enhance TP53/p73 expression and significantly inhibit tumor growth alone or when combined with radiation in HNSCC with wild-type TP53. PIK3CA, TP53/p73, PTEN, and TGF-β alterations are potential modifiers of response and merit investigation in future clinical trials with PI3K-mTOR inhibitors. Clin Cancer Res; 19(14); 3808–19. ©2013 AACR.
microRNA Expression Profiles Identify Subtypes of Mantle Cell Lymphoma with Different Clinicobiological Characteristics
Authors: Navarro Alba , Clot Guillem , Prieto Miriam , Royo Cristina , Vegliante Maria Carmela , Amador Virginia , Hartmann Elena , Salaverria Itziar , Beà Sílvia , Martín-Subero Jose Ignacio , Rosenwald Andreas , Ott German , Wiestner Adrian , Wilson Wyndham H. , Campo Elías , Hernández Luis
Published: May 2013

Purpose: microRNAs (miRNA) are posttranscriptional gene regulators that may be useful as diagnostic and/or prognostic biomarkers. We aim to study the expression profiles of a high number of miRNAs and their relationship with clinicopathologic and biologic relevant features in leukemic mantle cell lymphomas (MCL).

Experimental Design: Expression profiling of 664 miRNAs was investigated using a high-throughput quantitative real-time PCR platform in 30 leukemic MCLs. Statistical and bioinformatic analyses were conducted to define miRNAs associated with different clinicopathologic parameters. Gene expression profiling was investigated by microarrays in 16 matching cases to study the potential genes and pathways targeted by selected miRNAs. The prognostic value of miR-34a was investigated in 2 independent series of 29 leukemic and 50 nodal MCLs.

Results: Robust consensus clustering defined 2 main MCL subgroups with significant differences in the immunoglobulin (IGHV) mutational status, SOX11 expression, genomic complexity, and nodal clinical presentation. Supervised analyses of IGHV and SOX11 categories identified 17 and 22 miRNAs differentially expressed, respectively. Enriched targets of these miRNAs corresponded to relevant pathways in MCL pathogenesis such as DNA stress response, CD40 signaling, and chromatin modification. In addition, we found 7 miRNAs showing prognostic significance independently of IGHV status and SOX11 expression. Among them, miR-34a was also associated with poor prognosis in 2 independent series of leukemic and nodal MCL, and in cooperation with high expression of the MYC oncogene.

Conclusion: We have identified miRNAs and target pathways related to clinical and biologic variants of leukemic MCL, and validated miR-34a as a prognostic marker in MCL. Clin Cancer Res; 19(12); 3121–9. ©2013 AACR.
CYP3A4*22 Genotype and Systemic Exposure Affect Paclitaxel-Induced Neurotoxicity
Authors: de Graan Anne-Joy M. , Elens Laure , Sprowl Jason A. , Sparreboom Alex , Friberg Lena E. , van der Holt Bronno , de Raaf Pleun J. , de Bruijn Peter , Engels Frederike K. , Eskens Ferry A.L.M. , Wiemer Erik A.C. , Verweij Jaap , Mathijssen Ron H.J. , van Schaik Ron H.N.
Published: May 2013

Purpose: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity.

Experimental Design: In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239).

Results: Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P < 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T>0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001).

Conclusions: Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment. Clin Cancer Res; 19(12); 3316–24. ©2013 AACR.
Grape Seed Extract Efficacy against Azoxymethane-Induced Colon Tumorigenesis in A/J Mice: Interlinking miRNA with Cytokine Signaling and Inflammation
Authors: Derry Molly M. , Raina Komal , Balaiya Velmurugan , Jain Anil K. , Shrotriya Sangeeta , Huber Kendra M. , Serkova Natalie J. , Agarwal Rajesh , Agarwal Chapla
Published: May 2013

Colorectal cancer (CRC) is the second leading cause of cancer-associated deaths, suggesting that additional strategies are needed to prevent/control this malignancy. As CRC growth and progression involve a large window (10–15 years), chemopreventive intervention could be a practical/translational strategy. Azoxymethane (AOM)-induced colon tumorigenesis in mice resembles human CRC in terms of progression of ACF to polyps, adenoma, and carcinomas and associated molecular mechanisms. Accordingly, herein we investigated grape seed extract (GSE) efficacy against AOM-induced colon tumorigenesis in A/J mice. GSE was fed in diet at 0.25% or 0.5% (w/w) dose starting 2 weeks after last AOM injection for 18 or 28 weeks. Our results showed that GSE feeding significantly decreases colon tumor multiplicity and overall tumor size. In biomarker analysis, GSE showed significant antiproliferative and pro-apoptotic activities. Detailed mechanistic studies highlighted that GSE strongly modulates cytokines/interleukins and miRNA expression profiles as well as miRNA processing machinery associated with alterations in NF-κB, β-catenin, and mitogen-activated protein kinase (MAPK) signaling. Additional studies using immunohistochemical analyses found that indeed GSE inhibits NF-κB activation and decreases the expression of its downstream targets (COX-2, iNOS, VEGF) related to inflammatory signaling, downregulates β-catenin signaling and decreases its target gene c-myc, and reduces phosphorylated extracellular signal—regulated kinase (ERK)1/2 levels. Together, these finding suggested that inflammation, proliferation, and apoptosis are targeted by GSE to prevent CRC. In summary, this study for the first time shows alterations in the expression of miRNAs and cytokines by GSE in its efficacy against AOM-induced colon tumorigenesis in A/J mouse sporadic CRC model, supporting its translational potential in CRC chemoprevention. Cancer Prev Res; 6(7); 625–33. ©2013 AACR.
p21 Activated Kinase Signaling Coordinates Glycoprotein Receptor VI–Mediated Platelet Aggregation, Lamellipodia Formation, and Aggregate Stability Under Shear
Authors: Aslan Joseph E. , Itakura Asako , Haley Kristina M. , Tormoen Garth W. , Loren Cassandra P. , Baker Sandra M. , Pang Jiaqing , Chernoff Jonathan , McCarty Owen J.T.
Published: May 2013

Objective—

Rho GTPase proteins play a central role in regulating the dynamics of the platelet actin cytoskeleton. Yet, little is known regarding how Rho GTPase activation coordinates platelet activation and function. In this study, we aimed to characterize the role of the Rho GTPase effector, p21 activated kinase (PAK), in platelet activation, lamellipodia formation, and aggregate formation under shear.

Approach and Results—

Stimulation of platelets with the glycoprotein receptor VI agonist, collagen-related peptide, rapidly activated PAK in a time course preceding phosphorylation of PAK substrates, LIM domain kinase LIMK1 and the MAPK/ERK kinase MEK, and the subsequent activation of MAPKs and Akt. Pharmacological inhibitors of PAK blocked signaling events downstream of PAK and prevented platelet secretion as well as platelet aggregation in response to collagen-related peptide. PAK inhibitors also prevented PAK activation and platelet spreading on collagen surfaces. PAK was also required for the formation of platelet aggregates and to maintain aggregate stability under physiological shear flow conditions.

Conclusions—

These results suggest that PAK serves as an orchestrator of platelet functional responses after activation downstream of the platelet collagen receptor, glycoprotein receptor VI.
4-Hydroxy-2-Nonenal Enhances Tissue Factor Activity in Human Monocytic Cells via p38 Mitogen-Activated Protein Kinase Activation-Dependent Phosphatidylserine Exposure
Authors: Vatsyayan Rit , Kothari Hema , Pendurthi Usha R. , Rao L. Vijaya Mohan
Published: May 2013

Objective—

4-hydroxy-2-nonenal (HNE) is one of the major aldehydes formed during lipid peroxidation and is believed to play a role in the pathogenesis of atherosclerosis. The objective of the present study is to investigate the effect of HNE on tissue factor (TF) procoagulant activity expressed on cell surfaces.

Approach and Results—

TF activity and antigen levels on intact cells were measured using factor Xa generation and TF monoclonal antibody binding assays, respectively. Exposure of phosphatidylserine on the cell surface was analyzed using thrombin generation assay or by binding of a fluorescent dye–conjugated annexin V. 2′,7′-dichlorodihydrofluorescein diacetate was used to detect the generation of reactive oxygen species. Our data showed that HNE increased the procoagulant activity of unperturbed THP-1 cells that express traces of TF antigen, but had no effect on unperturbed endothelial cells that express no measurable TF antigen. HNE increased TF procoagulant activity but not TF antigen of both activated monocytic and endothelial cells. HNE treatment generated reactive oxygen species, activated p38 mitogen-activated protein kinase, and increased the exposure of phosphatidylserine at the outer leaflet in THP-1 cells. Treatment of THP-1 cells with an antioxidant, N-acetyl cysteine, suppressed the above HNE-induced responses and negated the HNE-mediated increase in TF activity. Blockade of p38 mitogen-activated protein kinase activation inhibited HNE-induced phosphatidylserine exposure and increased TF activity.

Conclusions—

HNE increases TF coagulant activity in monocytic cells through a novel mechanism involving p38 mitogen-activated protein kinase activation that leads to enhanced phosphatidylserine exposure at the cell surface.
Macrophage Function and Polarization in Cardiovascular Disease
Authors: Bolego Chiara , Cignarella Andrea , Staels Bart , Chinetti-Gbaguidi Giulia
Published: May 2013

Macrophages are plastic and versatile cells adapting their function/phenotype to the microenvironment. Distinct macrophage subpopulations with different functions, including classically (M1) and (M2) activated macrophages, have been described. Reciprocal skewing of macrophage polarization between the M1 and M2 state is a process modulated by transcription factors, such as the nuclear peroxisome proliferator–activated receptors. However, whether the estrogen/estrogen receptor pathways control the balance between M1/M2 macrophages is only partially understood. Estrogen-dependent effects on the macrophage system may be regarded as potential targets of pharmacological approaches to protect postmenopausal women from the elevated risk of cardiovascular disease.
KRP-203, Sphingosine 1-Phosphate Receptor Type 1 Agonist, Ameliorates Atherosclerosis in LDL-R
−/−
Mice
Authors: Potì Francesco , Gualtieri Fabio , Sacchi Sandro , Weißen-Plenz Gabriele , Varga Georg , Brodde Martin , Weber Christian , Simoni Manuela , Nofer Jerzy-Roch
Published: May 2013

Objective—

Sphingosine 1-phosphate (S1P) partly accounts for antiatherogenic properties of high-density lipoproteins. We previously demonstrated that FTY720, a synthetic S1P analog targeting all S1P receptors but S1P receptor type 2, inhibits murine atherosclerosis. Here, we addressed the identity of S1P receptor mediating atheroprotective effects of S1P.

Approach and Results—

Low-density lipoprotein receptor–deficient mice on cholesterol-rich diet were given selective S1P receptor type 1 agonist KRP-203 (3.0 mg/kg per day; 6 and 16 weeks). KRP-203 substantially reduced atherosclerotic lesion formation without affecting plasma lipid concentrations. However, KRP-203 induced lymphopenia, reduced total (CD4
+
, CD8
+
) and activated (CD69
+
/CD8
+
, CD69
+
/CD4
+
) T cells in peripheral lymphoid organs, and interfered with lymphocyte function, as evidenced by decreased T-cell proliferation and interleukin-2 and interferon-γ production in activated splenocytes. Cyto- and chemokine (tumor necrosis factor-α, regulated and normal T cell expressed and secreted) levels in plasma and aortas were reduced by KRP-203 administration. Moreover, macrophages from KRP-203–treated mice showed reduced expression of activation marker MCH-II and poly(I:C)-elicited production of tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-6. In vitro studies demonstrated that KRP-203 reduced tumor necrosis factor-α, interleukin-6, and interferon-γ–induced protein-10 production; IκB and signal transducer and activator of transcription-1 phosphorylation; and nuclear factor κB and signal transducer and activator of transcription-1 activation in poly(I:C)-, lipopolysaccharide-, or interferon-γ–stimulated bone marrow macrophages, respectively.

Conclusions—

Present results demonstrate that activation of S1P signaling pathways inhibit atherosclerosis by modulating lymphocyte and macrophage function and suggest that S1P receptor type 1 at least partially mediates antiatherogenic effects of S1P.
Post-transcriptional Regulation of α-1-Antichymotrypsin by MicroRNA-137 in Chronic Heart Failure and Mechanical Support
Authors: Lok Sjoukje I. , van Mil Alain , Bovenschen Niels , van der Weide Petra , van Kuik Joyce , van Wichen Dick , Peeters Ton , Siera Erica , Winkens Bjorn , Sluijter Joost P.G. , Doevendans Pieter A. , da Costa Martins Paula A. , de Jonge Nicolaas , de Weger Roel A.
Published: May 2013

Background—

Better understanding of the molecular mechanisms of remodeling has become a major objective of heart failure (HF) research to stop or reverse its progression. Left ventricular assist devices (LVADs) are being used in patients with HF, leading to partial reverse remodeling. In the present study, proteomics identified significant changes in α-1-antichymotrypsin (ACT) levels during LVAD support. Moreover, the potential role of ACT in reverse remodeling was studied in detail.

Methods and Results—

Expression of ACT mRNA (quantitative-polymerase chain reaction) decreased significantly in post-LVAD myocardial tissue compared with pre-LVAD tissue (n=15;
P
<0.01). Immunohistochemistry revealed that ACT expression and localization changed during LVAD support. Circulating ACT levels were elevated in HF patients (n=18) as compared with healthy controls (n=6;
P
=0.001) and normalized by 6 months of LVAD support. Because increasing evidence implicates that microRNAs (miRs) are involved in myocardial disease processes, we also investigated whether ACT is post-transcriptionally regulated by miRs. Bioinformatics analysis pointed miR-137 as a potential regulator of ACT. The miR-137 expression is inversely correlated with ACT mRNA in myocardial tissue. Luciferase activity assays confirmed ACT as a direct target for miR-137, and in situ hybridization indicated that ACT and miR-137 were mainly localized in cardiomyocytes and stromal cells.

Conclusions—

High ACT plasma levels in HF normalized during LVAD support, which coincides with decreased ACT mRNA in heart tissue, whereas miR-137 levels increased. MiR-137 directly targeted ACT, thereby indicating that ACT and miR-137 play a role in the pathophysiology of HF and reverse remodeling during mechanical support.
Efficacy and Safety of Apixaban Compared With Warfarin at Different Levels of Predicted International Normalized Ratio Control for Stroke Prevention in Atrial Fibrillation
Authors: Wallentin Lars , Lopes Renato D. , Hanna Michael , Thomas Laine , Hellkamp Anne , Nepal Sunil , Hylek Elaine M. , Al-Khatib Sana M. , Alexander John H. , Alings Marco , Amerena John , Ansell Jack , Aylward Philip , Bartunek Jozef , Commerford Patrick , De Caterina Raffaele , Erol Cetin , Harjola Veli-Pekka , Held Claes , Horowitz John D. , Huber Kurt , Husted Steen , Keltai Matyas , Lanas Fernando , Lisheng Liu , McMurray John J.V. , Oh Byung-Hee , Rosenqvist Mårten , Ruzyllo Witold , Steg Philippe Gabriel , Vinereanu Dragos , Xavier Denis , Granger Christopher B.
Published: May 2013

Background—

In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR).

Methods and Results—

The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an individual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66% (interquartile limits, 61% and 71%). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and individual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53–1.00) and 0.88 (95% CI, 0.57–1.35) (
P
interaction
=0.078), for mortality were 0.91 (95% CI, 0.74–1.13) and 0.91 (95% CI, 0.71–1.16) (
P
interaction
=0.34), and for major bleeding were 0.50 (95% CI, 0.36–0.70) and 0.75 (95% CI, 0.58–0.97) (
P
interaction
=0.095), respectively. Similar results were seen for quartiles of individual TTR.

Conclusions—

The benefits of apixaban compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers’ and patients’ predicted quality of international normalized ratio control.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00412984.
Disparities in Evaluation at Certified Primary Stroke Centers
Authors: Mullen Michael T. , Judd Suzanne , Howard Virginia J. , Kasner Scott E. , Branas Charles C. , Albright Karen C. , Rhodes J. David , Kleindorfer Dawn O. , Carr Brendan G.
Published: May 2013

Background and Purpose—

Evaluation at primary stroke centers (PSCs) has the potential to improve outcomes for patients with stroke. We looked for differences in evaluation at Joint Commission certified PSCs by race, education, income, and geography (urban versus nonurban; Southeastern Stroke Belt versus non-Stroke Belt).

Methods—

Community-dwelling, black and white participants from the national Reasons for Geographic And Racial Differences in Stroke (REGARDS) prospective population–based cohort were enrolled between January 2003 and October 2007. Participants were contacted at 6-month intervals for suspected stroke events. For suspected stroke events, it was determined whether the evaluating hospital was a certified PSC.

Results—

Of 1000 suspected strokes, 204 (20.4%) strokes were evaluated at a PSC. A smaller proportion of women than men (17.8% versus 23.0%;
P
=0.04), those with a previous stroke (15.1% versus 21.6%;
P
=0.04), those living in the Stroke Belt (14.7% versus 27.3%;
P
<0.001), and those in a nonurban area (9.1% versus 23.1%;
P
<0.001) were evaluated at a PSC. There were no differences by race, education, or income. In multivariable analysis, subjects were less likely to be evaluated at a PSC if they lived in a nonurban area (odds ratio, 0.39; 95% confidence interval, 0.22–0.67) or lived in the Stroke Belt (odds ratio, 0.54; 95% confidence interval, 0.38–0.77) or had a previous stroke (odds ratio, 0.46; 95% confidence interval, 0.27–0.78).

Conclusions—

Disparities in evaluation by PSCs are predominately related to geographic factors but not to race, education, or low income. Despite an increased burden of cerebrovascular disease in the Stroke Belt, subjects there were less likely to be evaluated at certified hospitals.
Incidence and Predictors of Late Seizures in Intracerebral Hemorrhages
Authors: Rossi Costanza , De Herdt Veerle , Dequatre-Ponchelle Nelly , Hénon Hilde , Leys Didier , Cordonnier Charlotte
Published: May 2013

Background and Purpose—

To identify incidence and predictors of late seizures (LS, occurring >1 week of stroke) in a cohort of patients with intracerebral hemorrhage (ICH).

Methods—

Prospective cohort of consecutive adults with spontaneous ICH. Incidence and predictors were identified with Cox regression. We included multivariate analyses on MRI biomarkers (global cortical atrophy, leukoaraiosis, brain microbleeds).

Results—

Our study population consisted of 325 patients: 54% men, median age 70 years (interquartile range, 58–79). During 778 person-years of follow-up, the incidence rate was 4 new cases/100 person-years (95% confidence interval, 3–6). The median delay between ICH and LS was 9 months (interquartile range, 3–23). The only factor independently associated with the occurrence of LS was a cortical involvement of the ICH (hazard ratio, 2.8; 95% confidence interval, 1.3–6.1). Concerning MRI biomarkers, multivariate analyses found lobar brain microbleeds to be associated with LS (hazard ratio, 2.4; 95% confidence interval, 1.1–5.4), especially if ≥3 (hazard ratio, 2.7; 95% confidence interval, 1.1–6.8). LS were associated with a worse functional outcome after 3 years of follow-up (
P
=0.009).

Conclusions—

LS frequently occur >9 months after ICH onset, imposing a long-term follow-up. The association of lobar brain microbleeds with the risk of LS might suggest a link with the underlying vasculopathy (cerebral amyloid angiopathy).
Influence of the Great East Japan Earthquake and Tsunami 2011 on Occurrence of Cerebrovascular Diseases in Iwate, Japan
Authors: Omama Shinichi , Yoshida Yuki , Ogasawara Kuniaki , Ogawa Akira , Ishibashi Yasuhiro , Nakamura Motoyuki , Tanno Kozo , Ohsawa Masaki , Onoda Toshiyuki , Itai Kazuyoshi , Sakata Kiyomi
Published: May 2013

Background and Purpose—

Little information is available regarding the occurrence of cerebrovascular diseases after tsunamis. This study was performed to determine the influence of the tsunami damage caused by the Great East Japan earthquake on occurrence of cerebrovascular diseases.

Methods—

Subjects from the coastline and inland areas of Iwate Prefecture who developed cerebrovascular diseases before and after the disaster were included in the analysis. Standardized incidence ratios of 2011 against the previous 3 years were calculated in two 4-week periods before and four 4-week periods after the disaster, according to stroke subtype, sex, age group, and flood damage.

Results—

The standard incidence ratio for cerebrovascular diseases was 1.20 (1.00–1.40) in the first 4-week period after the disaster and was not significant in other periods. The standard incidence ratios in the first 4-week period for cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage were 1.22 (0.98–1.46), 1.15 (0.76–1.55), and 1.20 (0.52–1.88), respectively. These values were 1.51 (1.19–1.88) for men, 1.35 (1.06–1.64) for subjects aged ≥75 years, and 1.35 (1.06–1.64) for the high flooding areas. The standard incidence ratio of cerebral infarction in the first 4-week period for men aged ≥75 years in the high flooding areas was 2.34 (1.34–3.34).

Conclusions—

In the areas highly flooded by the tsunami caused by the Great East Japan earthquake, the occurrence of cerebral infarction among elderly men more than doubled in the first 4 weeks after the disaster.
A Clustering Strategy for the Key Segmentation of Musical Audio
Authors: Kaliakatsos-Papakostas Maximos A. , Floros Andreas , Vrahatis Michael N.
Published: May 2013

Key changes are common in Western classical music. The precise segmentation of a music piece at instances where key changes occur allows for further analysis, like self-similarity analysis, chord recognition, and several other techniques that mainly pertain to the characterization of music content. This article examines the automatic segmentation of audio data into parts composed in different keys, using clustering on chroma-related spaces. To this end, the k-means algorithm is used and a methodology is proposed so that useful information about key changes can be derived, regardless of the number of clusters or key changes. The proposed methodology is evaluated by experimenting on the segmentation of recordings of existing compositions from the Classic-Romantic repertoire. Additional analysis is performed using artificial data sets. Specifically, the construction of artificial pieces is proposed as a means to investigate the potential of the strategy under discussion in predefined key-change scenarios that encompass different musical characteristics. For the existing compositions, we compare the results of our proposed methodology with others from the music information retrieval literature. Finally, although the proposed methodology is only capable of locating key changes and not the key identities themselves, we discuss results regarding the labeling of a composition's key in the located segments.
Unconsidered Intentional Actions
Authors: Cova Florian
Published: May 2013

The ‘Knobe effect’ is the name given to the empirical finding that judgments about whether an action is intentional or not seems to depend on the moral valence of this action. To account for this phenomenon, Scaife and Webber have recently advanced the ‘Consideration Hypothesis’, according to which people’s ascriptions of intentionality are driven by whether they think the agent took the outcome in consideration when taking his decision. In this paper, I examine Scaife and Webber’s hypothesis and conclude that it is supported neither by the existing literature nor by their own experiments, whose results I did not replicate, and that the ‘Consideration Hypothesis’ is not the best available account of the ‘Knobe Effect’.
Conscious Propositional Attitudes and Moral Responsibility
Authors: Peters Uwe
Published: May 2013

By drawing on empirical evidence, Matt King and Peter Carruthers (2012) have recently argued that there are no conscious propositional attitudes, such as decisions, and that this undermines moral responsibility. Neil Levy (2012, forthcoming) responds to King and Carruthers, and claims that their considerations needn’t worry theorists of moral responsibility. I argue that Levy’s response to King and Carruthers’ challenge to moral responsibility is unsatisfactory. After that, I propose what I take to be a preferable way of dealing with their challenge. I offer an account of moral responsibility that ties responsibility to consciously deciding to do X, as opposed to a conscious decision to do X. On this account, even if there are no conscious decisions, moral responsibility won’t be undermined.
Filial Piety with a Zen Twist: Universalism and Particularism Surrounding the Sutra on the Difficulty of Reciprocating the Kindness of Parents
Authors: Mohr Michel
Published: May 2013

Abstract

This article examines the Sutra on the Difficulty of Reciprocating the Kindness of Parents and its reinterpretation by the Japanese Rinzai Zen monk Tōrei Enji 東嶺圓慈 (1721-1792). In the context of the Tokugawa period (1600-1867) where filial piety was upheld as one of the pillars of morality and Neo-confucian orthodoxy, Tōrei’s commentary of this sutra skillfully combined the particularist understanding of filiality as limited to one’s relatives with its broader construal as a universal attitude of reverence directed toward all sentient beings. The father is envisioned as the wisdom and the excellence of the Buddha, the mother as the compassionate vows of the Bodhisattva, and the children as those who emit the thought of awakening. Tōrei further pushed this interpretation by adding the distinct Zen idea that the initial insight into one’s true nature needs to be surpassed and refined by perfecting the going beyond (kōjō 向上) phase of training, where the child/disciple’s legacy and his indebtedness towards his spiritual mentors is recast in terms of overcoming one’s attainments and attachment to them.
A New Species of Seed-harvester Ant, Pogonomyrmex hoelldobleri (Hymenoptera: Formicidae), from the Mohave and Sonoran Deserts of North America
Authors: JOHNSON ROBERT A. , OVERSON RICK P. , MOREAU CORRIE S.
Published: May 2013

Pogonomyrmex magnacanthus Cole was described as a distinct species; unusually large eyes and a high ocular index (maximum eye diameter/head width) were listed as diagnostic characters. However, examination of numerous series of P. magnacanthus revealed that both characters were highly variable, and that these series consisted of P. magnacanthus plus an undescribed species, Pogonomyrmex hoelldobleri Johnson, Overson & Moreau sp. nov. This paper describes all three castes of P. hoelldobleri as well as the alate queen of P. mohavensis, which is very similar to that of P. hoelldobleri. A molecular phylogeny that consisted of 3,703 bp from one mitochondrial and five nuclear gene fragments supported the monophyly of P. hoelldobleri, P. magnacanthus, and P. mohavensis. Pogonomyrmex magnacanthus can be separated from other P. californicus group species based on: (1) its unusually large eyes, (2) a high ocular index, and (3) a malar ratio that is typically < 1.0. Pogonomyrmex hoelldobleri can be separated from other P. californicus group species based on the combination of: (1) eyes not unusually large, (2) cephalic rugae not forming circumocular whorls, but rather converging posterior to the eyes, usually near the vertex, (3) mandible with seven teeth, and (4) interrugal spaces on pronotal sides moderately to strongly granulate, dull to weakly shining. Pogonomyrmex mohavensis can be separated from other P. californicus group species based on the combination of: (1) eyes not unusually large, (2) cephalic rugae not forming circum-ocular whorls, but rather extending more or less directly to the vertex or converging only slightly near the vertex, (3) mandible with six teeth (a seventh sometimes occurs as a denticle between the basal and sub-basal teeth), and (4) interrugal spaces on pronotal sides smooth and shining to weakly punctate and moderately shining. We also provide field observations and distribution maps for P. magnacanthus, P. hoelldobleri, and P. mohavensis, and an updated key to P. californicus group species that occur in central and western North America.
Distribution of Sipuncula in the Gulf of Valencia and Cape Nao (western Mediterranean)
Authors: FERRERO-VICENTE L. M. , DE-LA-OSSA-CARRETERO J. A. , DEL-PILAR-RUSO Y. , SÁNCHEZ-LIZASO J. L.
Published: May 2013

The present study analyses the distribution and diversity of sipunculan species inhabiting soft substrata in the Gulf of Va-lencia and Cape Nao (western Mediterranean) in relation to the characteristics of the sediment. Eighty-seven stations in 14 localities were sampled annually from 2004 to 2008. Nine species were reported, with Aspidosiphon (Aspidosiphon) muelleri being the dominant species in the area and Thysanocardia procera the most widely distributed. Pearson correla-tion coefficient and multivariate analysis showed how sipunculan abundances of certain species were related to the sedi-ment characteristics, especially grain size. The shell-dwelling species A. (A.) muelleri and Phascolion (Phascolion) caupo were dominant in stations with high amount of coarse sand and gravel, while Sipunculus (Sipunculus) nudus appeared in stations dominated by fine sand with low organic content. Pn. (Pn.) caupo and T. procera were reported for the first time in the study area. Moreover, it was the second record of Pn. (Pn.) caupo for the Mediterranean Sea.
The identity of Rana margaritifera Laurenti, 1768 (Anura, Bufonidae)
Authors: LAVILLA ESTEBAN O. , CARAMASCHI ULISSES , LANGONE JOSÉ A. , POMBAL JOSÉ Jr. P. , DE SÁ RAFAEL O.
Published: May 2013

Rana margaritifera was described by Laurenti in 1768 and currently is associated to the genus Rhinella, under the com-bination Rhinella margaritifera. Currently, the R. margaritifera species group consists of 16 recognized species. Further-more, many additional species have been suggested to exist in this group which highlights the ambiguity surrounding the identity of Rhinella margaritifera and impend further description of the species in this group. After an exhaustive biblio-graphic review, we concluded that the recent designation of a lectotype for R. margaritifera is invalid according with Art. 73, ICZN, 1999. Herein, we designate and provide the description of a neotype for Rana margaritifera Laurenti, 1768.
Implementation of a Silver Iodide Cloud-Seeding Parameterization in WRF. Part I: Model Description and Idealized 2D Sensitivity Tests
Authors: Xue Lulin , Hashimoto Akihiro , Murakami Masataka , Rasmussen Roy , Tessendorf Sarah A. , Breed Daniel , Parkinson Shaun , Holbrook Pat , Blestrud Derek
Published: May 2013

A silver iodide (AgI) cloud-seeding parameterization has been implemented into the Thompson microphysics scheme of the Weather Research and Forecasting model to investigate glaciogenic cloud-seeding effects. The sensitivity of the parameterization to meteorological conditions, cloud properties, and seeding rates was examined by simulating two-dimensional idealized moist flow over a bell-shaped mountain. The results verified that this parameterization can reasonably simulate the physical processes of cloud seeding with the limitations of the constant cloud droplet concentration assumed in the scheme and the two-dimensional model setup. The results showed the following: 1) Deposition was the dominant nucleation mode of AgI from simulated aircraft seeding, whereas immersion freezing was the most active mode for ground-based seeding. Deposition and condensation freezing were also important for ground-based seeding. Contact freezing was the weakest nucleation mode for both ground-based and airborne seeding. 2) Diffusion and riming on AgI-nucleated ice crystals depleted vapor and liquid water, resulting in more ice-phase precipitation on the ground for all of the seeding cases relative to the control cases. Most of the enhancement came from vapor depletion. The relative enhancement by seeding ranged from 0.3% to 429% under various conditions. 3) The maximum local AgI activation ratio was 60% under optimum conditions. Under most seeding conditions, however, this ratio was between 0.02% and 2% in orographic clouds. 4) The seeding effect was inversely related to the natural precipitation efficiency but was positively related to seeding rates. 5) Ground-based seeding enhanced precipitation on the lee side of the mountain, whereas airborne seeding from lower flight tracks enhanced precipitation on the windward side of the mountain.