bluuebunny/crossref_metadata_2025 huggingface dataset:
Dysfunctional ryanodine receptor and cardiac hypertrophy: role of signaling molecules
Authors: Yamaguchi Naohiro , Chakraborty Asima , Pasek Daniel A. , Molkentin Jeffery D. , Meissner Gerhard
Published: March 2011

Mice with three amino acid mutations in the calmodulin binding domain of type-2 ryanodine receptor ion channel ( Ryr2ADA/ADAmice) have impaired intracellular Ca2+handling and cardiac hypertrophy with death at an early age. In this report, the role of signaling molecules implicated in cardiac hypertrophy of Ryr2ADA/ADAmice was investigated. Calcineurin A-β (CNA-β) and nuclear factor of activated T cell (NFAT) signaling were monitored in mice carrying either luciferase transgene driven by NFAT-dependent promoter or knockout of CNA-β. NFAT transcriptional activity in Ryr2ADA/ADAhearts was not markedly upregulated at embryonic day 16.5 compared with wild-type but significantly increased at postnatal days 1 and 10. Ablation of CNA-β extended the life span of Ryr2ADA/ADAmice and enhanced cardiac function without improving sarcoplasmic reticulum Ca2+handling or suppressing the expression of genes implicated in cardiac hypertrophy. Embryonic day 16.5 Ryr2ADA/ADAmice had normal heart weights with no major changes in Akt1 and class II histone deacetylase phosphorylation and myocyte enhancer factor-2 activity. In contrast, phosphorylation levels of Erk1/2, p90 ribosomal S6 kinases (p90RSKs), and GSK-3β were increased in hearts of embryonic day 16.5 homozygous mutant mice. The results indicate that an impaired calmodulin regulation of RyR2 was neither associated with an altered CNA-β/NFAT, class II histone deacetylase (HDAC)/MEF2, nor Akt signaling in embryonic day 16.5 hearts; rather increased Erk1/2 and p90RSK phosphorylation levels likely leading to reduced GSK-3β activity were found to precede development of cardiac hypertrophy in mice expressing dysfunctional ryanodine receptor ion channel.
Quantification of presystolic blood flow organization and energetics in the human left ventricle
Authors: Eriksson Jonatan , Dyverfeldt Petter , Engvall Jan , Bolger Ann F. , Ebbers Tino , Carlhäll Carl Johan
Published: March 2011

Intracardiac blood flow patterns are potentially important to cardiac pumping efficiency. However, these complex flow patterns remain incompletely characterized both in health and disease. We hypothesized that normal left ventricular (LV) blood flow patterns would preferentially optimize a portion of the end-diastolic volume (LVEDV) for effective and rapid systolic ejection by virtue of location near and motion towards the LV outflow tract (LVOT). Three-dimensional cine velocity and morphological data were acquired in 12 healthy persons and 1 patient with dilated cardiomyopathy using MRI. A previously validated method was used for analysis in which the LVEDV was separated into four functional flow components based on the blood's locations at the beginning and end of the cardiac cycle. Each component's volume, kinetic energy (KE), site, direction, and linear momentum relative to the LVOT were calculated. Of the four components, the LV inflow that passes directly to outflow in a single cardiac cycle ( Direct Flow) had the largest volume. At the time of isovolumic contraction, Direct Flow had the greatest amount of KE and the most favorable combination of distance, angle, and linear momentum relative to the LVOT. Atrial contraction boosted the late diastolic KE of the ejected components. We conclude that normal diastolic LV flow creates favorable conditions for ensuing ejection, defined by proximity and energetics, for the Direct Flow, and that atrial contraction augments the end-diastolic KE of the ejection volume. The correlation of Direct Flow characteristics with ejection efficiency might be a relevant investigative target in cardiac failure.
Phosphatidylinositol 3,5-bisphosphate increases intracellular free Ca2+in arterial smooth muscle cells and elicits vasocontraction
Authors: Silswal Neerupma , Parelkar Nikhil K. , Wacker Michael J. , Brotto Marco , Andresen Jon
Published: March 2011

Phosphoinositide (3,5)-bisphosphate [PI(3,5)P2] is a newly identified phosphoinositide that modulates intracellular Ca2+by activating ryanodine receptors (RyRs). Since the contractile state of arterial smooth muscle depends on the concentration of intracellular Ca2+, we hypothesized that by mobilizing sarcoplasmic reticulum (SR) Ca2+stores PI(3,5)P2would increase intracellular Ca2+in arterial smooth muscle cells and cause vasocontraction. Using immunohistochemistry, we found that PI(3,5)P2was present in the mouse aorta and that exogenously applied PI(3,5)P2readily entered aortic smooth muscle cells. In isolated aortic smooth muscle cells, exogenous PI(3,5)P2elevated intracellular Ca2+, and it also contracted aortic rings. Both the rise in intracellular Ca2+and the contraction caused by PI(3,5)P2were prevented by antagonizing RyRs, while the majority of the PI(3,5)P2response was intact after blockade of inositol (1,4,5)-trisphosphate receptors. Depletion of SR Ca2+stores with thapsigargin or caffeine and/or ryanodine blunted the Ca2+response and greatly attenuated the contraction elicited by PI(3,5)P2. The removal of extracellular Ca2+or addition of verapamil to inhibit voltage-dependent Ca2+channels reduced but did not eliminate the Ca2+or contractile responses to PI(3,5)P2. We also found that PI(3,5)P2depolarized aortic smooth muscle cells and that LaCl3inhibited those aspects of the PI(3,5)P2response attributable to extracellular Ca2+. Thus, full and sustained aortic contractions to PI(3,5)P2required the release of SR Ca2+, probably via the activation of RyR, and also extracellular Ca2+entry via voltage-dependent Ca2+channels.
Autophagy limits acute myocardial infarction induced by permanent coronary artery occlusion
Authors: Kanamori Hiromitsu , Takemura Genzou , Goto Kazuko , Maruyama Rumi , Ono Koh , Nagao Kazuya , Tsujimoto Akiko , Ogino Atsushi , Takeyama Toshiaki , Kawaguchi Tomonori , Watanabe Takatomo , Kawasaki Masanori , Fujiwara Takako , Fujiwara Hisayoshi , Seishima Mitsuru , Minatoguchi Shinya
Published: March 2011

Ischemia is known to potently stimulate autophagy in the heart, which may contribute to cardiomyocyte survival. In vitro, transfection with small interfering RNAs targeting Atg5 or Lamp-2 (an autophagy-related gene necessary, respectively, for the initiation and digestion step of autophagy), which specifically inhibited autophagy, diminished survival among cultured cardiomyocytes subjected to anoxia and significantly reduced their ATP content, confirming an autophagy-mediated protective effect against anoxia. We next examined the dynamics of cardiomyocyte autophagy and the effects of manipulating autophagy during acute myocardial infarction in vivo. Myocardial infarction was induced by permanent ligation of the left coronary artery in green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3) transgenic mice in which GFP-LC3 aggregates to be visible in the cytoplasm when autophagy is activated. Autophagy was rapidly (within 30 min after coronary ligation) activated in cardiomyocytes, and autophagic activity was particularly strong in salvaged cardiomyocytes bordering the infarcted area. Treatment with bafilomycin A1, an autophagy inhibitor, significantly increased infarct size (31% expansion) 24 h postinfarction. Interestingly, acute infarct size was significantly reduced (23% reduction) in starved mice showing prominent autophagy before infarction. Treatment with bafilomycin A1 reduced postinfarction myocardial ATP content, whereas starvation increased myocardial levels of amino acids and ATP, and the combined effects of bafilomycin A1 and starvation on acute infarct size offset one another. The present findings suggest that autophagy is an innate and potent process that protects cardiomyocytes from ischemic death during acute myocardial infarction.
Dynamic molecular and histopathological changes in the extracellular matrix and inflammation in the transition to heart failure in isolated volume overload
Authors: Chen Yuan-wen , Pat Betty , Gladden James D. , Zheng Junying , Powell Pamela , Wei Chih-Chang , Cui Xiangqin , Husain Ahsan , Dell'Italia Louis J.
Published: March 2011

Left ventricular (LV) volume overload (VO) causes eccentric remodeling with inflammatory cell infiltration and extracellular matrix (ECM) degradation, for which there is currently no proven therapy. To uncover new pathways that connect inflammation and ECM homeostasis with cellular dysfunction, we determined the cardiac transciptome in subacute, compensated, and decompensated stages based on in vivo hemodynamics and echocardiography in the rat with aortocaval fistula (ACF). LV dilatation at 5 wk was associated with a normal LV end-diastolic dimension-to-posterior wall thickness ratio (LVEDD/PWT; compensated), whereas the early 2-wk (subacute) and late 15-wk (decompensated) ACF groups had significant increases in LVEDD/PWT. Subacute and decompensated stages had a significant upregulation of genes related to inflammation, the ECM, the cell cycle, and apoptosis. These changes were accompanied by neutrophil and macrophage infiltration, nonmyocyte apoptosis, and interstitial collagen loss. At 15 wk, there was a 40-fold increase in the matricellular protein periostin, which inhibits connections between collagen and cells, thereby potentially mediating a side-to-side slippage of cardiomyocytes and LV dilatation. The majority of downregulated genes was composed of mitochondrial enzymes whose suppression progressed from 5 to 15 wk concomitant with LV dilatation and systolic heart failure. The profound decrease in gene expression related to fatty acid, amino acid, and glucose metabolism was associated with the downregulation of peroxisome proliferator associated receptor (PPAR)-α-related and bioenergetic-related genes at 15 wk. In VO, an early phase of inflammation subsides at 5 wk but reappears at 15 wk with marked periostin production along with the suppression of genes related to PPAR-α and energy metabolism.
Ischemic preconditioning attenuates mitochondrial localization of PTEN induced by ischemia-reperfusion
Authors: Zu Lingyun , Zheng Xiaoxu , Wang Bing , Parajuli Nirmal , Steenbergen Charles , Becker Lewis C. , Cai Zheqing P.
Published: March 2011

Although the induction of myocyte apoptosis by ischemia-reperfusion (I/R) is attenuated by ischemic preconditioning (IPC), the underlying mechanism is not fully understood. Phosphatase and tensin homologs deleted on chromosome 10 (PTEN) promotes apoptosis through Akt-dependent and -independent mechanisms. We tested the hypothesis that IPC attenuates the mitochondrial localization of PTEN in the myocardium induced by I/R. Isolated hearts from wild-type mice were exposed to IPC or normal perfusion followed by 30 min of ischemia and reperfusion. IPC attenuated myocardial infarct size and apoptosis after I/R. Heart fractionation showed that mitochondrial PTEN and Bax protein levels and the physical association between them were increased by 30 min of I/R and that IPC attenuated all of these effects of I/R. Muscle-specific PTEN knockout decreased mitochondrial Bax protein levels in the reperfused myocardium and increased cell survival. To determine whether PTEN relocalization to mitochondria was influenced by I/R-induced production of ROS, hearts were perfused with N-acetylcysteine (NAC) to scavenge ROS or H2O2 to mimic I/R-induced ROS. Mitochondrial PTEN protein levels were decreased by NAC and increased by H2O2. PTEN protein overexpression was generated in mouse hearts by adenoviral gene transfer. PTEN overexpression increased mitochondrial PTEN and Bax protein levels and ROS production, whereas muscle-specific PTEN knockout produced the opposite effects. In conclusion, myocardial I/R causes PTEN localization to the mitochondria, related to the generation of ROS; IPC attenuates the mitochondrial localization of PTEN after I/R, potentially inhibiting the translocation of Bax to the mitochondria and resulting in improved cell viability.
Impaired vascular responses of insulin-resistant rats after mild subarachnoid hemorrhage
Authors: Institoris Adam , Snipes James A. , Katakam Prasad V. , Domoki Ferenc , Boda Krisztina , Bari Ferenc , Busija David W.
Published: March 2011

Insulin resistance (IR) impairs cerebrovascular responses to several stimuli in Zucker obese (ZO) rats. However, cerebral artery responses after subarachnoid hemorrhage (SAH) have not been described in IR. We hypothesized that IR worsens vascular reactions after a mild SAH. Hemolyzed blood (300 μl) or saline was infused (10 μl/min) into the cisterna magna of 11–13-wk-old ZO ( n = 25) and Zucker lean (ZL) rats ( n = 25). One day later, dilator responses of the basilar artery (BA) and its side branch (BA-Br) to acetylcholine (ACh, 10−6 M), cromakalim (10−7 M, 10−6 M), and sodium nitroprusside (10−7 M) were recorded with intravital videomicroscopy. The baseline diameter of the BA was increased both in the ZO and ZL rats 24 h after the hemolysate injection. Saline-injected ZO animals showed reduced dilation to ACh (BA = 9 ± 3 vs. 22 ± 4%; and BA-Br = 23 ± 5 vs. 37 ± 7%) compared with ZL rats. Hemolysate injection blunted the response to ACh in both the ZO (BA = 4 ± 2%; and BA-Br = 12 ± 3%) and ZL (BA = 7 ± 2%; and BA-Br = 11 ± 3%) rats. Cromakalim (10−6 M)-induced dilation was significantly reduced in the hemolysate-injected ZO animals compared with the saline control (BA = 13 ± 3 vs. 26 ± 5%; and BA-Br = 28 ± 8 vs. 44 ± 9%) and in the hemolysate-injected ZL rats compared with their saline control (BA = 24 ± 4 vs. 32 ± 4%; but not BA-Br = 39 ± 6 vs. 59 ± 9%). No significant difference in sodium nitroprusside reactivity was observed. Western blot analysis of the BA showed a lower baseline level of neuronal nitric oxide synthase expression and an enhanced cyclooxygenase-2 level in the hemolysate-injected ZO animals. In summary, cerebrovascular reactivity to both endothelium-dependent and -independent stimuli is severely compromised by SAH in IR animals.
Hydrogen sulfide dilates cerebral arterioles by activating smooth muscle cell plasma membrane KATP channels
Authors: Liang Guo Hua , Adebiyi Adebowale , Leo M. Dennis , McNally Elizabeth M. , Leffler Charles W. , Jaggar Jonathan H.
Published: March 2011

Hydrogen sulfide (H2S) is a gaseous signaling molecule that appears to contribute to the regulation of vascular tone and blood pressure. Multiple potential mechanisms of vascular regulation by H2S exist. Here, we tested the hypothesis that piglet cerebral arteriole smooth muscle cells generate ATP-sensitive K+ (KATP) currents and that H2S induces vasodilation by activating KATP currents. Gas chromatography/mass spectrometry data demonstrated that after placing Na2S, an H2S donor, in solution, it rapidly (1 min) converts to H2S. Patch-clamp electrophysiology indicated that pinacidil (a KATP channel activator), Na2S, and NaHS (another H2S donor) activated K+ currents at physiological steady-state voltage (−50 mV) in isolated cerebral arteriole smooth muscle cells. Glibenclamide, a selective KATP channel inhibitor, fully reversed pinacidil-induced K+ currents and partially reversed (∼58%) H2S-induced K+ currents. Western blot analysis indicated that piglet arterioles expressed inwardly rectifying K+ 6.1 (Kir6.1) channel and sulfonylurea receptor 2B (SUR2B) KATP channel subunits. Pinacidil dilated pressurized (40 mmHg) piglet arterioles, and glibenclamide fully reversed this effect. Na2S also induced reversible and repeatable vasodilation with an EC50 of ∼30 μM, and this effect was partially reversed (∼55%) by glibenclamide. Vasoregulation by H2S was also studied in pressurized resistance-size cerebral arteries of mice with a genetic deletion in the gene encoding SUR2 (SUR2 null). Pinacidil- and H2S-induced vasodilations were smaller in arterioles of SUR2 null mice than in wild-type controls. These data indicate that smooth muscle cell KATP currents control newborn cerebral arteriole contractility and that H2S dilates cerebral arterioles by activating smooth muscle cell KATP channels containing SUR2 subunits.
Glycogen synthase kinase-3 regulates cigarette smoke extract- and IL-1β-induced cytokine secretion by airway smooth muscle
Authors: Baarsma Hoeke A. , Meurs Herman , Halayko Andrew J. , Menzen Mark H. , Schmidt Martina , Kerstjens Huib A. M. , Gosens Reinoud
Published: March 2011

Glycogen synthase kinase-3 (GSK-3) is a constitutively active kinase that regulates multiple signaling proteins and transcription factors involved in inflammation. Its role in inflammatory lung diseases, including chronic obstructive pulmonary disease (COPD), is largely unknown. We investigated the role of GSK-3 in the secretion of chemokines and growth factors by human airway smooth muscle cells after exposure to cigarette smoke extract (CSE) or interleukin-1β (IL-1β), important factors involved in the development of COPD. Cultured human airway smooth muscle cells were exposed to increasing concentrations of CSE (1–15%) and IL-1β (0.01–1.0 ng/ml), which induced the secretion of VEGF-A and IL-8, whereas eotaxin secretion was induced by IL-1β only. Inhibition of GSK-3 by the selective inhibitor SB216763 or CHIR/CT99021 attenuated the cytokine and growth factor release induced by CSE and/or IL-1β, without affecting the basal release. Secretion of the cytokines by airway smooth muscle partially depends on NF-κB signaling, and GSK-3 has been implicated in regulating multiple steps in activating the NF-κB signaling pathway. IL-1β treatment induced degradation of the NF-κB inhibitory protein Iκ-Bα followed by nuclear translocation and DNA binding of p65 NF-κB, which were unaffected by inhibition of GSK-3. However, induction of NF-κB-dependent transcriptional activity by IL-1β and CSE was largely reduced upon GSK-3 inhibition by SB216763. Collectively, we demonstrate that CSE and IL-1β activate airway smooth muscle cells to secrete the proinflammatory cytokines IL-8, eotaxin, and VEGF-A. Furthermore, we show that GSK-3 regulates the release of these cytokines induced by CSE and IL-1β by promoting NF-κB-dependent gene transcription.
Effects of a synthetic PEG-ylated Tie-2 agonist peptide on endotoxemic lung injury and mortality
Authors: David Sascha , Ghosh Chandra C. , Kümpers Philipp , Shushakova Nelli , Van Slyke Paul , Khankin Eliyahu V. , Karumanchi S. Ananth , Dumont Dan , Parikh Samir M.
Published: March 2011

A synthetic 7-mer, HHHRHSF, was recently identified by screening a phage display library for binding to the Tie-2 receptor. A polyethylene-oxide clustered version of this peptide, termed vasculotide (VT), was reported to activate Tie-2 and promote angiogenesis in a mouse model of diabetic ulcer. We hypothesized that VT administration would defend endothelial barrier function against sepsis-associated mediators of permeability, prevent lung vascular leakage arising in endotoxemia, and improve mortality in endotoxemic mice. In confluent human microvascular endothelial cells, VT prevented endotoxin-induced (lipopolysaccharides, LPS O111:B4) gap formation, loss of monolayer resistance, and translocation of labeled albumin. In 8-wk-old male C57Bl6/J mice given a ∼70% lethal dose of endotoxin (15 mg/kg ip), VT prevented lung vascular leakage and reversed the attenuation of lung vascular endothelial cadherin induced by endotoxemia. These protective effects of VT were associated with activation of Tie-2 and its downstream mediator, Akt. Echocardiographic studies showed only a nonsignificant trend toward improved myocardial performance associated with VT. Finally, we evaluated survival in this mouse model. Pretreatment with VT improved survival by 41.4% ( n = 15/group, P = 0.02) and post-LPS administration of VT improved survival by 33.3% ( n = 15/group, P = 0.051). VT-mediated protection from LPS lethality was lost in Tie-2 heterozygous mice, in agreement with VT's proposed receptor specificity. We conclude that this synthetic Tie-2 agonist, completely unrelated to endogenous Tie-2 ligands, is sufficient to activate the receptor and its downstream pathways in vivo and that the Tie-2 receptor may be an important target for therapeutic evaluation in conditions of pathological vascular leakage.
Generate n‐Scroll Attractor via Composite Switching Controls
Authors: Ou Baiyu , Liu Desheng
Published: March 2011

We propose a method for designing chaos generators. We introduce a switched system with three‐dimensional space functions for generating a new type of chaotic attractor, and then we introduce saturated function series for generating n‐scroll chaotic attractor. Moreover, we present some examples with numerical simulations that illustrate the efficiency of our method. The statistic behavior is also discussed, which reveals the regularities in the complex dynamics.
Approximate Method for Studying the Waves Propagating along the Interface between Air‐Water
Authors: Khader M. M. , Al-Bar R. F.
Published: March 2011

This paper is devoted to consider the approximate solutions of the nonlinear water wave problem for a fluid layer of finite depth in the presence of gravity. The method of multiple‐scale expansion is employed to obtain the Korteweg‐de Vries (KdV) equations for solitons, which describes the behavior of the system for free surface between air and water in a nonlinear approach. The solutions of the water wave problem split up into two wave packets, one moving to the right and one to the left, where each of these wave packets evolves independently as the solutions of KdV equations. The solution of KdV equations is obtained analytically by using a reliable modification of Laplace decomposition method (LDM), namely, the modified Laplace decomposition method (MLDM) is presented. This procedure is a powerful tool for solving large amount of nonlinear problems. The proposed method provides the solution as a series which may converge to the exact solution of the problem. Also, the convergence analysis of the proposed method is given. Finally, we observe that the elevation of the water waves is in form of traveling solitary waves. The horizontal and vertical of the velocity components have nonlinear characters.
Algorithms Construction for Variational Inequalities
Authors: Yao Yonghong , Liou Yeong-Cheng , Kang Shin Min
Published: March 2011

We devote this paper to solving the variational inequality of finding "Equation missing" with property "Equation missing" such that "Equation missing" for all "Equation missing". Note that this hierarchical problem is associated with some convex programming problems. For solving the above VI, we suggest two algorithms: Implicit Algorithmml: "Equation missing" for all "Equation missing" and Explicit Algorithm: "Equation missing" for all "Equation missing". It is shown that these two algorithms converge strongly to the unique solution of the above VI. As special cases, we prove that the proposed algorithms strongly converge to the minimum norm fixed point of "Equation missing".
Dependence on the MUC1-C Oncoprotein in Non–Small Cell Lung Cancer Cells
Authors: Raina Deepak , Kosugi Michio , Ahmad Rehan , Panchamoorthy Govind , Rajabi Hasan , Alam Maroof , Shimamura Takeshi , Shapiro Geoffrey I. , Supko Jeffrey , Kharbanda Surender , Kufe Donald
Published: March 2011

Non–small cell lung cancer (NSCLC) cells are often associated with constitutive activation of the phosphoinositide 3-kinase (PI3K) → Akt → mTOR pathway. The mucin 1 (MUC1) heterodimeric glycoprotein is aberrantly overexpressed in NSCLC cells and induces gene signatures that are associated with poor survival of NSCLC patients. The present results show that the MUC1 C-terminal subunit (MUC1-C) cytoplasmic domain associates with PI3K p85 in NSCLC cells. We show that inhibition of MUC1-C with cell-penetrating peptides blocks this interaction with PI3K p85 and suppresses constitutive phosphorylation of Akt and its downstream effector, mTOR. In concert with these results, treatment of NSCLC cells with the MUC1-C peptide inhibitor GO-203 was associated with downregulation of PI3K → Akt signaling and inhibition of growth. GO-203 treatment was also associated with increases in reactive oxygen species (ROS) and induction of necrosis by a ROS-dependent mechanism. Moreover, GO-203 treatment of H1975 (EGFR L858R/T790M) and A549 (K-Ras G12S) xenografts growing in nude mice resulted in tumor regressions. These findings indicate that NSCLC cells are dependent on MUC1-C both for activation of the PI3K → Akt pathway and for survival. Mol Cancer Ther; 10(5); 806–16. ©2011 AACR.
β-Cryptoxanthin Supplementation Prevents Cigarette Smoke-Induced Lung Inflammation, Oxidative Damage, and Squamous Metaplasia in Ferrets
Authors: Liu Chun , Bronson Roderick T. , Russell Robert M. , Wang Xiang-Dong
Published: March 2011

In epidemiologic studies, high intake of β-cryptoxanthin has been associated with a decreased risk of lung cancer, particularly among current smokers. However, data are not available from well-controlled animal studies to examine the effects of β-cryptoxanthin on cigarette smoke-induced lung lesions, and the biological mechanisms by which β-cryptoxanthin might affect lung carcinogenesis. We evaluated the effects of β-cryptoxanthin supplementation on cigarette smoke-induced squamous metaplasia, inflammation, and changes in protein levels of proinflammatory cytokine [tumor necrosis factor alpha (TNFα)] and transcription factors [nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1)], as well as on smoke-induced oxidative DNA damage [8-hydroxy-2′-deoxyguanosine (8-OHdG)] in the lung tissue of ferrets. Thirty-six male ferrets were assigned to cigarette smoke exposure or no exposure and to low-dose, or high-dose β-cryptoxanthin, or no dose (2 × 3 factorial design) for 3 months. β-Cryptoxanthin supplementation dose-dependently increased plasma and lung β-cryptoxanthin levels in ferrets, whereas cigarette smoke exposure lowered plasma and lung β-cryptoxanthin levels. β-Cryptoxanthin at both doses significantly decreased smoke-induced lung squamous metaplasia and inflammation. β-Cryptoxanthin also substantially reduced smoke-elevated TNFα levels in alveolar, bronchial, bronchiolar, and bronchial serous/mucous gland epithelial cells and in lung macrophages. Moreover, β-cryptoxanthin decreased smoke-induced activation of NF-κB, expression of AP-1 and levels of 8-OHdG. The beneficial effects of β-cryptoxanthin were stronger for high-dose β-cryptoxanthin than for low-dose β-cryptoxanthin. Data from this study indicate that β-cryptoxanthin provides a beneficial effect against cigarette smoke-induced inflammation, oxidative DNA damage and squamous metaplasia in the lungs. Cancer Prev Res; 4(8); 1255–66. ©2011 AACR.
Autonomic Remodeling in the Left Atrium and Pulmonary Veins in Heart Failure
Authors: Ng Jason , Villuendas Roger , Cokic Ivan , Schliamser Jorge E. , Gordon David , Koduri Hemanth , Benefield Brandon , Simon Julia , Murthy S.N. Prasanna , Lomasney Jon W. , Wasserstrom J. Andrew , Goldberger Jeffrey J. , Aistrup Gary L. , Arora Rishi
Published: March 2011

Background—

Atrial fibrillation (AF) is commonly associated with congestive heart failure (CHF). The autonomic nervous system is involved in the pathogenesis of both AF and CHF. We examined the role of autonomic remodeling in contributing to AF substrate in CHF.

Methods and Results—

Electrophysiological mapping was performed in the pulmonary veins and left atrium in 38 rapid ventricular–paced dogs (CHF group) and 39 control dogs under the following conditions: vagal stimulation, isoproterenol infusion, β-adrenergic blockade, acetylcholinesterase (AChE) inhibition (physostigmine), parasympathetic blockade, and double autonomic blockade. Explanted atria were examined for nerve density/distribution, muscarinic receptor and β-adrenergic receptor densities, and AChE activity. In CHF dogs, there was an increase in nerve bundle size, parasympathetic fibers/bundle, and density of sympathetic fibrils and cardiac ganglia, all preferentially in the posterior left atrium/pulmonary veins. Sympathetic hyperinnervation was accompanied by increases in β
1
-adrenergic receptor R density and in sympathetic effect on effective refractory periods and activation direction. β-Adrenergic blockade slowed AF dominant frequency. Parasympathetic remodeling was more complex, resulting in increased AChE activity, unchanged muscarinic receptor density, unchanged parasympathetic effect on activation direction and decreased effect of vagal stimulation on effective refractory period (restored by AChE inhibition). Parasympathetic blockade markedly decreased AF duration.

Conclusions—

In this heart failure model, autonomic and electrophysiological remodeling occurs, involving the posterior left atrium and pulmonary veins. Despite synaptic compensation, parasympathetic hyperinnervation contributes significantly to AF maintenance. Parasympathetic and/or sympathetic signaling may be possible therapeutic targets for AF in CHF.
Cardiac Sympathetic Reserve and Response to Cardiac Resynchronization Therapy
Authors: Cha Yong-Mei , Chareonthaitawee Panithaya , Dong Ying-Xue , Kemp Bradley J. , Oh Jae K. , Miyazaki Chinami , Hayes David L. , Rea Robert F. , Asirvatham Samuel J. , Webster Tracy L. , Dalzell Connie M. , Hodge David O. , Herges Regina M. , Yong Yan-zhong , Zhang Yanhua , Chen Peng-Sheng
Published: March 2011

Background—

The objective of the present study was to investigate the effect of cardiac resynchronization therapy (CRT) on cardiac autonomic function.

Methods and Results—

This prospective study included 45 consecutive patients with heart failure who received CRT devices with defibrillator and 20 age-matched, healthy control subjects. At baseline and 3 months and 6 months after CRT, we assessed New York Heart Association (NYHA) class, 6-minute walk distance, plasma sympathetic biomarker nerve growth factor, echocardiography, heart rate variability and cardiac presynaptic sympathetic function determined by iodine 123 metaiodobenzylguanidine scintigraphy. After CRT, NYHA class improved by 1 class (
P
<0.001), and left ventricular ejection fraction increased by 8% (
P
<0.001). Along with improvement in the standard deviation of all normal-to-normal R-R intervals (85.63±31.66 ms versus 114.79±38.99 ms;
P
=0.004) and the standard deviation of the averaged normal-to-normal R-R intervals (82.62±23.03 ms versus 100.50±34.87 ms;
P
=0.004), the delayed heart/mediastinum (H/M) ratio increased (1.82 [0.58] versus 1.97 [0.59];
P
=0.03), whereas the mean (SD) H/M washout rate was reduced (48% [19%] versus 37% [22%];
P
=0.01). Twenty-two of 45 study patients responded to CRT, with a reduction of left ventricular end-systolic volume index >15%. Compared with nonresponders, responders had a higher delayed H/M ratio (2.11 versus 1.48;
P
=0.003) and lower H/M washout rate (37% versus 62%;
P
=0.003) at baseline.

Conclusions—

CRT improved sympathetic function. Cardiac sympathetic reserve may be a marker for the reversibility of failing myocardial function.
Dilatation and Dysfunction of the Right Ventricle Immediately After Ultraendurance Exercise
Authors: Oxborough David , Shave Robert , Warburton Darren , Williams Karen , Oxborough Adele , Charlesworth Sarah , Foulds Heather , Hoffman Martin D. , Birch Karen , George Keith
Published: March 2011

Background—

Running an ultramarathon has been shown to have a transient negative effect on right ventricular (RV) and left ventricular (LV) function. Additionally, recent findings suggested that ultraendurance athletes may be more at risk of developing a RV cardiomyopathy. The standard echocardiographic assessment of RV function is problematic; however, the introduction of ultrasonic speckle tracking technology has the potential to yield a comprehensive evaluation of RV longitudinal function, providing new insights into this phenomenon. Thus, the primary aim of this exploratory study was to evaluate comprehensively RV structure and function after a 161-km ultramarathon and establish whether changes in the RV are associated with alterations in LV function.

Methods and Results—

Myocardial speckle tracking echocardiograms of the RV and LV were obtained before and immediately after a 161-km ultramarathon in 16 healthy adults. Standard echocardiography was used to determine RV size and function and LV eccentricity index. Speckle tracking was used to determine the temporal evaluation of indices of RV and LV function. RV size was significantly increased postrace (RV outflow, 32 to 35 mm,
P
=0.002; RV inflow, 42 to 45 mm,
P
=0.027) with an increase in LV eccentricity index (1.03 to 1.13,
P
=0.006). RV strain (ε) was significantly reduced postrace (−27% to −24%,
P
=0.004), but there was no change in the rates of ε. Peak ε in all planes of LV motion were reduced postrace (longitudinal, −18.3 to −16.3%,
P
=0.012; circumferential, −20.2% to −15.7%,
P
=0.001; radial, 53.4% to 40.3%,
P
=0.009). Changes in RV size and function correlated with diastolic strain rates in the LV.

Conclusions—

This exploratory study demonstrates RV dilatation and reduction in function after an ultramarathon. Further research is warranted to elucidate the mechanisms responsible for these findings. It is not clear what clinical impact might result from consecutive bouts of postexercise RV dysfunction.
Microcosming the Nahah: Mayy Ziyādah’s Salon as a Hybrid Space
Authors: Khaldi Boutheina
Published: March 2011

This article delineates the actual role played by Mayy Ziyādah, not only as a salonnière, but also as an intellectual in her own right with a significant role in the Nahah in twentieth-century Egypt. As her name is most often associated with the salon, I will demonstrate the intellectual climate of that salon, its capacity to bring together different factions and to emerge thereby as a microcosm of the Nahah, in its complexity and hybrid nature. With these goals in mind, I will draw on an extensive amount of material, supported by a theoretical framework that helps in envisioning the salon as a public sphere.
The ardiyyahs of Ibn al-Mu‘tazz: Breakthrough into Lyricism
Authors: Stetkevych Jaroslav
Published: March 2011

This study presents an analytical review of the genre of the “hunt-poem” (ardiyyah) at the hand of the ‘Abbāsid poet Ibn al-Mu‘tazz (d. 296/908). It is in this period that the genre of the ardiyyah reaches its second apogee after the great pioneering Abū Nuwās. After dealing with issues of genre and prosody (rajaz versus the qaīdah meters), the study focuses its critical attention on Ibn al-Mu‘tazz’s overcoming of the strictly formulaic opening lyrical phrasing of the majority of the ardiyyahs, especially as the genre was formalized by Abū Nuwās. It is in overcoming the limitations of the formulaism of Abū Nuwās, which does not do justice to the genre’s lyrical promise, that Ibn al-Mu‘tazz achieves his breakthrough into lyricism and a reinvigoration of the genre. Through a close reading and translation of the Arabic texts, the study presents a careful identification of the variants of lyricism in Ibn al-Mu‘tazz’s repertory of the ardiyyah genre.
Die Finanzbeziehungen zwischen Alexander von Humboldt und den Mendelssohns
Authors: Panwitz Sebastian
Published: March 2011

The continuous substantial and flexible material support of the bankers Joseph and Alexander Mendelssohn were of essential importance for Alexander von Humboldt's outstanding scientific expeditions and his work as a publicist, coordinator and supporter of fellow scientist and scientific projects in Berlin for decades. New sources present this support of Humboldt by the Mendelssohns in all its depth and variety. At the same time, the enduring funding of one of Prussia's most important Bildungsbürger clearly illustrates that the business policy of the Mendelssohn bankers was based on a canon of values in which the acceptance of responsibility in different fields of society were of equal importance as pure economic success.
Maritime Enforcement of United Nations Security Council Resolutions: Use of Force and Coercive Measures
Authors: Keyuan ZOU
Published: March 2011

The Charter of the United Nations designates the United Nations Security Council (UNSC) as one of the principal organs of the United Nations, assuming the “primary responsibility for the maintenance of international peace and security”. It has the power to determine the existence of any threat to the peace, breach of the peace, or act of aggression, to make recommendations, and decide what measures should be taken to maintain or restore international peace and security. This article addresses a number of issues concerning how the UNSC Resolutions are enforced at sea in accordance with applicable international law and makes special reference to the circumstances in East Asia, particularly the Korean Peninsula.
Establishment of the Outer Limits of the Continental Shelf: Is Crossing Boundaries Trespassing?
Authors: Kunoy Bjørn
Published: March 2011

This article examines whether State A may cross a continental shelf boundary in order to utilize a feature of the physical continental margin that is situated within the dominion of State B for the purpose of establishing the outer limits of its continental shelf. Given that a continental shelf boundary delimits, mutatis mutandis, the spatial powers of States, as a land boundary, in conjunction with the international framework as set out in the Law of the Sea Convention, it is concluded that it is not consistent with the Law of the Sea Convention for coastal State A to base its entitlement to the outer continental shelf on a generative feature that is located on a feature of the physical continental margin that is situated within the dominion of coastal State B.
Sir Hersch Lauterpacht and Poland’s Judges at the International Court: Judge Bohdan Winiarski
Authors: Skubiszewski Krzysztof
Published: March 2011

In a conference devoted to Sir Hersch Lauterpacht one would be remiss to neglect all the other important judges of Polish origin, whose work and ideas influenced and were influenced by those of Sir Hersch Lauterpacht. The present article outlines the main ideas and contributions of Judge Bohdan Winiarski in an era of great turbulence but also of great strides in the evolution of the system of public international law.
Conceptual History and the Philosophy of the Later Wittgenstein: A Critique of Quentin Skinner’s Contextualist Method
Authors: Burns Anthony
Published: March 2011

Although first published in 1969, the methodological views advanced in Quentin Skinner’s “Meaning and Understanding in the History of Ideas” remain relevant today. In his article Skinner suggests that it would be inappropriate to even attempt to write the history of any idea or concept. In support of this view, Skinner advances two arguments, one derived from the philosophy of the later Wittgenstein and the other from that of J. L. Austin.In this paper I focus on the first of these arguments. I claim that the conclusion which Skinner draws from this particular argument does not necessarily follow and that an alternative assessment of the methodological significance of Wittgenstein’s philosophy for historians of ideas is possible. On this alternative view, far from ruling out conceptual history, an appeal to the view of meaning set out in Wittgenstein’s Philosophical Investigations leads to a quite different conclusion, namely that the writing of such a history is arguably a necessary precondition for the elucidation of the meaning of a number of the core concepts in the canon of the history of political thought.Skinner’s views have changed somewhat since 1969. Indeed, from the mid 1970s onwards he came to relax the strict opposition to the idea of conceptual history to which he was then committed. The paper concludes by noting that this evolution in Skinner’s thinking has made him much more sympathetic than anybody reading “Meaning and Understanding in the History of Ideas” would have imagined to the research project of the Begriffgeschichte School of conceptual history.
The Turkish Validity and Reliability of the Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms Scales
Authors: Kutlu Adalet , Yılmaz Emel , Çeçen Dilek , Eser Erhan , Özbakkaloğlu Alper
Published: March 2011

The aim of the study was to test Turkish validity and reliability of Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms (VEINES-QoL/Sym) in patients with chronic venous insufficiency (CVI). A total of 118 patients with CVI hospitalized in 3 different hospitals were enrolled in this study. VEINES-QoL/Sym, translated to Turkish with a standard methodology, was applied to the patients and was evaluated for acceptability, reliability, validity, and responsiveness. Cronbach α (including if item deleted) values were used for the reliability analysis. Construct and criterion validity approaches were used for validity analysis. Cronbach α values are .86 for the VEINES-QOL and .81 for the VEINES-Sym. No problematic items were observed for the scale. The VEINES-QoL/Sym was significantly sensitive to clinical, etiology, anatomy, and pathophysiology (CEAP) classification, indicating good criterion validity. Significant correlation was found between scores of SF-36 and VEINESQoL (r = .43-.66). Turkish version of the VEINES-QOL/Sym was found reliable and valid for Turkish patients with CVI.
Medication Use Pattern and Predictors of Optimal Therapy at Discharge in 8176 Patients With Acute Coronary Syndrome From 6 Middle Eastern Countries: Data From the Gulf Registry of Acute Coronary Events
Authors: Al-Zakwani Ibrahim , Zubaid Mohammad , Panduranga Prashanth , Rashed Wafa , Sulaiman Kadhim , Almahmeed Wael , Al-Motarreb Ahmed , Al Suwaidi Jassim , Amin Haitham
Published: March 2011

We evaluated the use of quadruple evidence-based medication (EBM) combination consisting of antiplatelet therapy, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, β-blocker, and lipid-lowering agent concurrently at discharge among patients (n = 8154) with acute coronary syndrome (ACS) in 6 Middle Eastern countries. In all, 49% of the patients received the quadruple EBM combination concurrently at discharge. An adjusted model demonstrated that old age, diabetes mellitus, hyperlipidemia, hypertension, ST-segment elevation myocardial infarction, cardiac catheterization, as well as cardiologists as care providers and hospitals with cardiac catheterization facilities were all positively correlated with the use of the quadruple EBM combination. However, patients with cardiogenic shock, renal impairment, higher risk score, congestive heart failure, recurrent ischemia, and those admitted to academic hospitals were negatively correlated with the use of the quadruple EBM combination. Guideline adherence to the concurrent use of quadruple EBM combination in patients with ACS at discharge was suboptimal with wide disparity among the 6 countries.
Assessing the Long-Term Outcomes of Minor Lower Limb Amputations: A 5-Year Study
Authors: Mohammed Mohsin Uzzaman  , Jukaku Saud , Kambal Amir , Syed Tahir Hussain
Published: March 2011

Our aim was to assess the long-term outcome for minor forefoot amputations. A retrospective study of 126 patients who had such amputations between 1999 and 2004 was performed. Patients were divided into 2 groups, diabetic (group A: 79 patients) and nondiabetic (group B: 47 patients). Angiograms were requested in 45 patients in group A compared with 31 patients in group B (P = ·77). In group A, 11 patients underwent further ipsilateral amputations compared with 30 patients in group B (P = ·02.). The 2 groups were equally likely to have vascular reconstruction (35% vs 37%). The overall 5-year mortality was 27%, with 58% of deaths occurring within the first year. This study shows that foot amputees have high mortality and reintervention rates. Adequate utilization of vascular services, extra vigilance in the prevention of complications, and risk factor modifications are required to improve postoperative outcomes.
Angioplasty for Treatment of Isolated Below-the-Knee Arterial Stenosis in Patients With Critical Limb Ischemia
Authors: Mendiz Oscar A. , Fava Carlos M. , Valdivieso León R. , Lev Gustavo A. , Villagra Lorena G.
Published: March 2011

Objective: To report our experience in patients with critical limb ischemia (CLI) due to isolated below-the-knee (BTK) arterial lesions. Methods: Between 1992 and 2009, we performed 2747 peripheral angioplasties, while 2.8% (78 of 2747) were only BTK and were included in the present study. Results: Mean age was 70.2 ± 11 years, 58.4% had diabetic, 85.7% were smokers, and 20.8% had chronic renal failure. Baseline Rutherford class: 50 patients with class IV and 27 with class V to VI. Angiographic and clinical success were 97.4% and 90.91%, respectively. At 30 days, there were no deaths, 2 patients had acute vessel closure and 2 major amputation. At long-term follow-up (22.4 ± 9.6 months), there were 7 unrelated deaths (10%), 5 amputations (7.1%), 3 reinterventions (4.2%), while 16 patients remained symptomatic. Overall amputation and amputation plus claudication-free survival were 90% and 70%, respectively. Conclusion: Endovascular treatment of BTK lesions represents a safe and effective treatment option to patients with CLI.
Statin Myopathy: Significant Problem With Minimal Awareness by Clinicians and no Emphasis by Clinical Investigators
Authors: Whayne Thomas F.
Published: March 2011

High cardiovascular risk patients need reduction of low-density-lipoprotein cholesterol (LDL-C) to <70 mg/dL (1.8 mmol/L). Statins are optimal treatment but myopathy can be a limitation to their use. The incidence of statin-related myopathy is difficult to determine but up to 10.5% appears an appropriate estimate. Short-term trials report lower incidence than long-term trials. Statin-related myopathy may be influenced by genetics and tends to be dose-dependent. Ezetimibe can contribute to LDL-C reduction allowing a lower dose of statin to be used. Another approach is to administer rosuvastatin twice weekly. Statins have been shown to interfere with the cellular role of coenzyme Q10. Coenzyme Q10 supplementation may decrease or prevent statin myopathy, but this has not been proven. The occurrence of the most serious complication of myopathy—rhabdomyolysis—is very rare, but awareness of the problem, risks, and prevention are essential.
Cardio-Ankle Vascular Index Could Reflect Plaque Burden in the Coronary Artery
Authors: Horinaka Shigeo , Yabe Akihisa , Yagi Hiroshi , Ishimura Kimihiko , Hara Hitoshi , Iemura Tomomi , Ishimitsu Toshihiko
Published: March 2011

Cardio-ankle vascular index (CAVI) using the volume plethysmographic method is a noninvasive atherosclerotic indicator which is not influenced by blood pressure. Coronary intravascular ultrasound (IVUS) is a reliable technique to measure progression of atherosclerosis. The association between CAVI and IVUS has not been reported. The aim of this study was to evaluate the association between CAVI and the plaque burden measured by IVUS in the left main coronary artery (LMCA) in patients with coronary heart disease and normal LMCA. Cardio-ankle vascular index was significantly correlated with percentage plaque area (r = .649, P < .0001) measured by IVUS in the most diseased segment of LMCA. Cardio-ankle vascular index remained significant among cardiovascular disease risk factors included in the multiple regression analysis predicting percentage plaque area. Cardio-ankle vascular index was a good atherosclerotic indicator and associated with the plaque burden in nonculprit and angiographically normal LMCA.