bluuebunny/crossref_metadata_2025 huggingface dataset:
Renal Sympathetic Denervation for the Treatment of Refractory Hypertension
Authors: Leong Kui Toh Gerard , Walton Antony , Krum Henry
Published: January 2014

Resistant hypertension poses significant health concerns. There are strong demands for new and safe therapies to control resistant hypertension while addressing its common causes, specifically poor compliance to lifelong polypharmacy, lifestyle modifications, and physician inertia. The sympathetic nervous system plays a significant pathophysiological role in hypertension. Surgical sympathectomy for blood pressure reduction is an old but extremely efficacious therapeutic concept, now abandoned with the dawn of a safer contemporary pharmacology era. Recently, clinical studies have revealed promising results for safe and sustained blood pressure reduction with percutaneous renal sympathetic denervation. This is a novel, minimally invasive, device-based therapy, specifically targeting and ablating the renal artery nerves with radiofrequency waves without permanent implantation. There are also reported additional benefits in related comorbidities, such as impaired glucose metabolism, renal impairment, left ventricular hypertrophy, heart failure, and others. This review focuses on how selective renal sympathetic denervation works, its present and potential therapeutic indications, and its future directions.
Endothelin-1-induced vasoconstriction does not require intracellular Ca2+ waves in arteries from rats exposed to intermittent hypoxia
Authors: Osmond Jessica M. , Gonzalez Bosc Laura V. , Walker Benjimen R. , Kanagy Nancy L.
Published: January 2014

Sleep apnea is associated with cardiovascular disease, and patients with sleep apnea have elevated plasma endothelin (ET)-1 concentrations. Rats exposed to intermittent hypoxia (IH), a model of sleep apnea, also have increased plasma ET-1 concentrations and heightened constriction to ET-1 in mesenteric arteries without an increase in global vascular smooth muscle cell Ca2+ concentration ([Ca2+]). Because ET-1 has been shown to increase the occurrence of propagating Ca2+ waves, we hypothesized that ET-1 increases Ca2+ wave activity in mesenteric arteries, rather than global [Ca2+], to mediate enhanced vasoconstriction after IH exposure. Male Sprague-Dawley rats were exposed to sham or IH conditions for 7 h/day for 2 wk. Mesenteric arteries from sham- and IH-exposed rats were isolated, cannulated, and pressurized to 75 mmHg to measure ET-1-induced constriction as well as changes in global [Ca2+] and Ca2+ wave activity. A low concentration of ET-1 (1 nM) elicited similar vasoconstriction and global Ca2+ responses in the two groups. Conversely, ET-1 had no effect on Ca2+ wave activity in arteries from sham rats but significantly increased wave frequency in arteries from IH-exposed rats. The ET-1-induced increase in Ca2+ wave frequency in arteries from IH rats was dependent on phospholipase C and inositol 1,4,5-trisphosphate receptor activation, yet inhibition of phospholipase C and the inositol 1,4,5-trisphosphate receptor did not prevent ET-1-mediated vasoconstriction. These results suggest that although ET-1 elevates Ca2+ wave activity after IH exposure, increases in wave activity are not associated with increased vasoconstriction.
PKC activation increases Ca2+sensitivity of permeabilized lymphatic muscle via myosin light chain 20 phosphorylation-dependent and -independent mechanisms
Authors: Dougherty Patrick J. , Nepiyushchikh Zhanna V. , Chakraborty Sanjukta , Wang Wei , Davis Michael J. , Zawieja David C. , Muthuchamy Mariappan
Published: January 2014

The contractile activity of muscle cells lining the walls of collecting lymphatics is responsible for generating and regulating flow within the lymphatic system. Activation of PKC signaling contributes to the regulation of smooth muscle contraction by enhancing sensitivity of the contractile apparatus to Ca2+. It is currently unknown whether PKC signaling contributes to the regulation of lymphatic muscle contraction. We hypothesized that the activation of PKC signaling would increase the sensitivity of the lymphatic myofilament to Ca2+. To test this hypothesis, we determined the effects of PKC activation with phorbol esters [PMA or phorbol dibutyrate (PDBu)] on the contractile behavior of α-toxin-permeabilized rat mesenteric and cervical lymphatics or the thoracic duct. The addition of PMA or PDBu induced a significant increase in the contractile force of submaximally activated α-toxin-permeabilized lymphatic muscle independent of a change in intracellular Ca2+concentration, and the Ca2+-force relationship of lymphatic muscle was significantly left shifted, indicating greater myofilament Ca2+sensitivity. Phorbol esters increased the maximal rate of force development, whereas the rate of relaxation was reduced. Western blot and immunohistochemistry data indicated that the initial rapid increase in tension development after stimulation by PDBu was associated with myosin light chain (MLC)20phosphorylation; however, the later, steady-state Ca2+sensitization of permeabilized lymphatic muscle was not associated with increased phosphorylation of MLC20at Ser19, 17-kDa C-kinase-potentiated protein phosphatase-1 inhibitor at Thr38, or caldesmon at Ser789. Thus, these data indicate that PKC-dependent Ca2+sensitization of lymphatic muscle may involve MLC20phosphorylation-dependent and -independent mechanism(s).
Exploring the vascular smooth muscle receptor landscape in vivo: ultrasound Doppler versus near-infrared spectroscopy assessments
Authors: Ives Stephen J. , Fadel Paul J. , Brothers R. Matthew , Sander Mikael , Wray D. Walter
Published: January 2014

Ultrasound Doppler and near-infrared spectroscopy (NIRS) are routinely used for noninvasive monitoring of peripheral hemodynamics in both clinical and experimental settings. However, the comparative ability of these methodologies to detect changes in microvascular and whole limb hemodynamics during pharmacological manipulation of vascular smooth muscle receptors located at varied locations within the arterial tree is unknown. Thus, in 10 healthy subjects (25 ± 2 yr), changes in resting leg blood flow (ultrasound Doppler; femoral artery) and muscle oxygenation (oxyhemoglobin + oxymyoglobin; vastus lateralis) were simultaneously evaluated in response to intra-arterial infusions of phenylephrine (PE, 0.025–0.8 μg·kg−1·min−1), BHT-933 (2.5–40 μg·kg−1·min−1), and angiotensin II (ANG II, 0.5–8 ng·kg−1·min−1). All drugs elicited significant dose-dependent reductions in leg blood flow and oxyhemoglobin + oxymyoglobin. Significant relationships were found between ultrasound Doppler and NIRS changes across doses of PE ( r2 = 0.37 ± 0.08), BHT-933 ( r2 = 0.74 ± 0.06), and ANG II ( r2 = 0.68 ± 0.13), with the strongest relationships evident with agonists for receptors located preferentially “downstream” in the leg microcirculation (BHT-933 and ANG II). Analyses of drug potency revealed similar EC50 between ultrasound Doppler and NIRS measurements for PE (0.06 ± 0.02 vs. 0.10 ± 0.01), BHT-933 (5.0 ± 0.9 vs. 4.5 ± 1.3), and ANG II (1.4 ± 0.8 vs. 1.3 ± 0.3). These data provide evidence that both ultrasound Doppler and NIRS track pharmacologically induced changes in peripheral hemodynamics and are equally capable of determining drug potency. However, considerable disparity was observed between agonist infusions targeting different levels of the arterial tree, suggesting that receptor landscape is an important consideration for proper interpretation of hemodynamic monitoring with these methodologies.
Why are sex and gender important to basic physiology and translational and individualized medicine?
Authors: Miller Virginia M.
Published: January 2014

Sex refers to biological differences between men and women. Although sex is a fundamental aspect of human physiology that splits the population in two approximately equal halves, this essential biological variable is rarely considered in the design of basic physiological studies, in translating findings from basic science to clinical research, or in developing personalized medical strategies. Contrary to sex, gender refers to social and cultural factors related to being a man or a woman in a particular historical and cultural context. Unfortunately, gender is often used incorrectly by scientists and clinical investigators as synonymous with sex. This article clarifies the definition of sex and gender and reviews evidence showing how sex and gender interact with each other to influence etiology, presentation of disease, and treatment outcomes. In addition, strategies to improve the inclusion of female and male human beings in preclinical and clinical studies will be presented, and the importance of embedding concepts of sex and gender into postgraduate and medical curricula will be discussed. Also, provided is a list of resources for educators. In the history of medical concepts, physiologists have provided pivotal contributions to understanding health and disease processes. In the future, physiologists should provide the evidence for advancing personalized medicine and for reducing sex and gender disparities in health care.
Pulmonary vasoconstrictor influence of endothelin in exercising swine depends critically on phosphodiesterase 5 activity
Authors: Zhou Zhichao , de Beer Vincent J. , Wijs-Meijler Daphne de , Bender Shawn B. , Hoekstra Maaike , Laughlin M. Harold , Duncker Dirk J. , Merkus Daphne
Published: January 2014

Both phosphodiesterase 5 (PDE5) inhibition and endothelin (ET) receptor blockade have been shown to induce pulmonary vasodilation. However, little is known about the effect of combined blockade of these two vasoconstrictor pathways. Since nitric oxide (NO) exerts its pulmonary vasodilator influence via production of cyclic guanosine monophosphate (cGMP) as well as through inhibition of ET, we hypothesized that interaction between the respective signaling pathways precludes an additive vasodilator effect. We tested this hypothesis in chronically instrumented swine exercising on a treadmill by comparing the vasodilator effect of the PDE5 inhibitor EMD360527, the ETA/ETBantagonist tezosentan, and combined EMD360527 and tezosentan. In the systemic circulation, vasodilation by tezosentan and EMD360527 was additive, both at rest and during exercise, resulting in a 17 ± 2% drop in blood pressure. In the pulmonary circulation, both EMD360527 and tezosentan produced vasodilation. However, tezosentan produced no additional pulmonary vasodilation in the presence of EMD360527, either at rest or during exercise. Moreover, in isolated preconstricted porcine pulmonary small arteries (∼300 μm) EMD360527 (1 nM–10 μM) induced dose-dependent vasodilation, whereas tezosentan (1 nM–10 μM) failed to elicit vasodilation irrespective of the presence of EMD360527. However, both PDE5 inhibition and 8Br-cGMP, but not 8Br-cAMP, blunted pulmonary small artery contraction to ET and its precursor Big ET in vitro. In conclusion, in healthy swine, either at rest or during exercise, PDE5 inhibition and the associated increase in cGMP produce pulmonary vasodilation that is mediated in part through inhibition of the ET pathway, thereby precluding an additional vasodilator effect of ETA/ETBreceptor blockade in the presence of PDE5 inhibition.
IFN-γ-mediated reduction of large-conductance, Ca2+-activated, voltage-dependent K+ (BK) channel activity in airway epithelial cells leads to mucociliary dysfunction
Authors: Manzanares Dahis , Srinivasan Maria , Salathe Samuel T. , Ivonnet Pedro , Baumlin Nathalie , Dennis John S. , Conner Gregory E. , Salathe Matthias
Published: January 2014

Effective mucociliary clearance (MCC) depends in part on adequate airway surface liquid (ASL) volume to maintain an appropriate periciliary fluid height that allows normal ciliary activity. Apically expressed large-conductance, Ca2+-activated, and voltage-dependent K+ (BK) channels provide an electrochemical gradient for Cl− secretion and thus play an important role for adequate airway hydration. Here we show that IFN-γ decreases ATP-mediated apical BK activation in normal human airway epithelial cells cultured at the air-liquid interface. IFN-γ decreased mRNA levels of KCNMA1 but did not affect total protein levels. Because IFN-γ upregulates dual oxidase (DUOX)2 and therefore H2O2 production, we hypothesized that BK inactivation could be mediated by BK oxidation. However, DUOX2 knockdown did not affect the IFN-γ effect on BK activity. IFN-γ changed mRNA levels of the BK β-modulatory proteins KCNMB2 (increased) and KCNMB4 (decreased) as well as leucine-rich repeat-containing protein (LRRC)26 (decreased). Mallotoxin, a BK opener only in the absence of LRRC26, showed that BK channels lost their association with LRRC26 after IFN-γ treatment. Finally, IFN-γ caused a decrease in ciliary beating frequency that was immediately rescued by apical fluid addition, suggesting that it was due to ASL volume depletion. These data were confirmed with direct ASL measurements using meniscus scanning. Overexpression of KCNMA1, the pore-forming subunit of BK, overcame the reduction of ASL volume induced by IFN-γ. Key experiments were repeated in cystic fibrosis cells and showed the same results. Therefore, IFN-γ induces mucociliary dysfunction through BK inactivation.
Enhanced lysis and accelerated establishment of viscoelastic properties of fibrin clots are associated with pulmonary embolism
Authors: Martinez Marissa R. , Cuker Adam , Mills Angela M. , Crichlow Amanda , Lightfoot Richard T. , Chernysh Irina N. , Nagaswami Chandrasekaran , Weisel John W. , Ischiropoulos Harry
Published: January 2014

The factors that contribute to pulmonary embolism (PE), a potentially fatal complication of deep vein thrombosis (DVT), remain poorly understood. Whereas fibrin clot structure and functional properties have been implicated in the pathology of venous thromboembolism and the risk for cardiovascular complications, their significance in PE remains uncertain. Therefore, we systematically compared and quantified clot formation and lysis time, plasminogen levels, viscoelastic properties, activated factor XIII cross-linking, and fibrin clot structure in isolated DVT and PE subjects. Clots made from plasma of PE subjects showed faster clot lysis times with no differences in lag time, rate of clot formation, or maximum absorbance of turbidity compared with DVT. Differences in lysis times were not due to alterations in plasminogen levels. Compared with DVT, clots derived from PE subjects showed accelerated establishment of viscoelastic properties, documented by a decrease in lag time and an increase in the rate of viscoelastic property formation. The rate and extent of fibrin cross-linking by activated factor XIII were similar between clots from DVT and PE subjects. Electron microscopy revealed that plasma fibrin clots from PE subjects exhibited lower fiber density compared with those from DVT subjects. These data suggest that clot structure and functional properties differ between DVT and PE subjects and provide insights into mechanisms that may regulate embolization.
Vitamin D treatment improves survival and infant lung structure after intra-amniotic endotoxin exposure in rats: potential role for the prevention of bronchopulmonary dysplasia
Authors: Mandell Erica , Seedorf Gregory , Gien Jason , Abman Steven H.
Published: January 2014

Vitamin D (vit D) has anti-inflammatory properties and modulates lung growth, but whether vit D can prevent lung injury after exposure to antenatal inflammation is unknown. We hypothesized that early and sustained vit D treatment could improve survival and preserve lung growth in an experimental model of bronchopulmonary dysplasia induced by antenatal exposure to endotoxin (ETX). Fetal rats (E20) were exposed to ETX (10 μg), ETX + Vit D (1 ng/ml), or saline (control) via intra-amniotic (IA) injections and delivered 2 days later. Newborn pups exposed to IA ETX received daily intraperitoneal injections of vit D (1 ng/g) or saline for 14 days. Vit D treatment improved oxygen saturations (78 vs. 87%; P < 0.001) and postnatal survival (84% vs. 57%; P < 0.001) after exposure to IA ETX compared with IA ETX alone. Postnatal vit D treatment improved alveolar and vascular growth at 14 days by 45% and 25%, respectively ( P < 0.05). Vit D increased fetal sheep pulmonary artery endothelial cell (PAEC) growth and tube formation by 64% and 44%, respectively ( P < 0.001), and prevented ETX-induced reductions of PAEC growth and tube formation. Vit D directly increased fetal alveolar type II cell (ATIIC) growth by 26% ( P < 0.001) and enhanced ATIIC growth in the presence of ETX-induced growth suppression by 73% ( P < 0.001). We conclude that antenatal vit D therapy improved oxygenation and survival in newborn rat pups and enhanced late lung structure after exposure to IA ETX in vivo, which may partly be due to direct effects on vascular and alveolar growth.
An Integrated Procedure for Bayesian Reliability Inference Using MCMC
Authors: Lin Jing
Published: January 2014

The recent proliferation of Markov chain Monte Carlo (MCMC) approaches has led to the use of the Bayesian inference in a wide variety of fields. To facilitate MCMC applications, this paper proposes an integrated procedure for Bayesian inference using MCMC methods, from a reliability perspective. The goal is to build a framework for related academic research and engineering applications to implement modern computational-based Bayesian approaches, especially for reliability inferences. The procedure developed here is a continuous improvement process with four stages (Plan, Do, Study, and Action) and 11 steps, including: (1) data preparation; (2) prior inspection and integration; (3) prior selection; (4) model selection; (5) posterior sampling; (6) MCMC convergence diagnostic; (7) Monte Carlo error diagnostic; (8) model improvement; (9) model comparison; (10) inference making; (11) data updating and inference improvement. The paper illustrates the proposed procedure using a case study.
Plasma Levels of Aminothiols, Nitrite, Nitrate, and Malondialdehyde in Myelodysplastic Syndromes in the Context of Clinical Outcomes and as a Consequence of Iron Overload
Authors: Pimková Kristýna , Chrastinová Leona , Suttnar Jiří , Štikarová Jana , Kotlín Roman , Čermák Jaroslav , Dyr Jan Evangelista
Published: January 2014

The role of oxidative stress in the initiation and progression of myelodysplastic syndromes (MDS) as a consequence of iron overload remains unclear. In this study we have simultaneously quantified plasma low-molecular-weight aminothiols, malondialdehyde, nitrite, and nitrate and have studied their correlation with serum iron/ferritin levels, patient treatment (chelation therapy), and clinical outcomes. We found significantly elevated plasma levels of total, oxidized, and reduced forms of cysteineP<0.001, homocysteineP<0.001, and cysteinylglycineP<0.006and significantly depressed levels of total and oxidized forms of glutathioneP<0.03and nitriteP<0.001in MDS patients compared to healthy donors. Moreover, total(P=0.032)and oxidized cysteinylglycine(P=0.029)and nitrite(P=0.021)differed significantly between the analyzed MDS subgroups with different clinical classifications. Malondialdehyde levels in plasma correlated moderately with both serum ferritin levels(r=0.78, P=0.001)and serum free iron levels(r=0.60, P=0.001)and were significantly higher in patients with iron overload. The other analyzed compounds lacked correlation with iron overload (represented by serum iron/ferritin levels). For the first time our results have revealed significant differences in the concentrations of plasma aminothiols in MDS patients, when compared to healthy donors. We found no correlation of these parameters with iron overload and suggest the role of oxidative stress in the development of MDS disease.
Risk Factors and Prevalence ofHelicobacter pyloriInfection in Persistent High Incidence Area of Gastric Carcinoma in Yangzhong City
Authors: Zhu Yangchun , Zhou Xiaoying , Wu Junbei , Su Jing , Zhang Guoxin
Published: January 2014

Aim. The aim of this study was to investigate the prevalence and risk factors ofH. pyloriinfection in areas with high prevalence of gastric cancer in Jiangsu Province, China.Methods. A prospective epidemiologic survey ofH. pyloriinfection was accomplished in a natural population of 5417 individuals in Yangzhong city. Questionnaires and 13C-urea breath test forH. pyloriinfection were performed.Results. Among 5417 subjects who completed questionnaires and 13C-urea breath test, 3435 (63.41%) wereH. pyloripositive. The prevalence reached a peak at the age of 30–39 years (90.82%). There was significant difference between sexes and women had a higher infection rate than men. The prevalence ofH. pyloriinfection was also associated with eating kipper food and fried food. No association betweenH. pyloriprevalence and smoking or drinking was found. Compared to healthy individuals, people with dyspeptic diseases (peptic ulcer, gastroenteritis) presented a high prevalence ofH. pyloriinfection. Using multivariate logistic regression analysis, age and history of peptic ulcer and gastroenteritis were the independent predictors forH. pyloriinfection.Conclusions. Yangzhong city had a high prevalence ofH. pyloriinfection and was related to several risk factors. The underlying mechanisms are needed to be further investigated.
Maps Preserving Schattenp-Norms of Convex Combinations
Authors: Kuo David Li-Wei , Tsai Ming-Cheng , Wong Ngai-Ching , Zhang Jun
Published: January 2014

We study mapsϕof positive operators of the Schattenp-classes (1<p<+∞), which preserve thep-norms of convex combinations, that is,  ∥tρ+(1-t)σ∥p=∥tϕ(ρ)+(1-t)ϕ(σ)∥p,  ∀ρ,σ∈𝒮p+(H)1,  t∈[0,1]. They are exactly those carrying the formϕ(ρ)=UρU*for a unitary or antiunitaryU. In the casep=2, we have the same conclusion whenever it just holds∥ρ+σ∥2=∥ϕ(ρ)+ϕ(σ)∥2for all the positive Hilbert-Schmidt class operatorsρ,σof norm1. Some examples are demonstrated.
Acute Supratentorial Ischemic Stroke: When Surgery Is Mandatory
Authors: Ronchetti Gabriele , Panciani Pier Paolo , Stefini Roberto , Spena Giannantonio , Fontanella Marco Maria
Published: January 2014

Acute occlusion of middle cerebral artery (MCA) leads to severe brain swelling and to a malignant, often fatal syndrome. The authors summarize the current knowledge about such a condition and review the main surgical issues involved. Decompressive hemicraniectomy keeps being a valid option in accurately selected patients.
Cellular Localization and Biochemical Characterization of a Chimeric Fluorescent Protein Fusion ofArabidopsisCellulose Synthase-Like A2 Inserted into Golgi Membrane
Authors: De Caroli Monica , Lenucci Marcello S. , Di Sansebastiano Gian-Pietro , Tunno Michela , Montefusco Anna , Dalessandro Giuseppe , Piro Gabriella
Published: January 2014

Cellulose synthase-like(Csl) genes are believed to encode enzymes for the synthesis of cell wall matrix polysaccharides. The subfamily ofCslAis putatively involved in the biosynthesis ofβ-mannans. Here we report a study on the cellular localization and the enzyme activity of anArabidopsisCslA family member, AtCslA2. We show that the fluorescent protein fusion AtCslA2-GFP, transiently expressed in tobacco leaf protoplasts, is synthesized in the ER and it accumulates in the Golgi stacks. The chimera is inserted in the Golgi membrane and is functional since membrane preparations obtained by transformed protoplasts carry out thein vitrosynthesis of a14C-mannan starting from GDP-d-[U-14C]mannose as substrate. The enzyme specific activity is increased by approximately 38% in the transformed protoplasts with respect to wild-type. Preliminary tests with proteinase K, biochemical data, and TM domain predictions suggest that the catalytic site of AtCslA2 faces the Golgi lumen.
VEGF-Mediated Angiogenesis Links EMT-Induced Cancer Stemness to Tumor Initiation
Authors: Fantozzi Anna , Gruber Dorothea C. , Pisarsky Laura , Heck Chantal , Kunita Akiko , Yilmaz Mahmut , Meyer-Schaller Nathalie , Cornille Karen , Hopfer Ulrike , Bentires-Alj Mohamed , Christofori Gerhard
Published: January 2014

An epithelial–mesenchymal transition (EMT) underlies malignant tumor progression and metastatic spread by enabling cancer cells to depart from the primary tumor, invade surrounding tissue, and disseminate to distant organs. EMT also enriches for cancer stem cells (CSC) and increases the capacity of cancer cells to initiate and propagate tumors upon transplantation into immune-deficient mice, a major hallmark of CSCs. However, the molecular mechanisms promoting the tumorigenicity of cancer cells undergoing an EMT and of CSCs have remained widely elusive. We here report that EMT confers efficient tumorigenicity to murine breast cancer cells by the upregulated expression of the proangiogenic factor VEGF-A and by increased tumor angiogenesis. On the basis of these data, we propose a novel interpretation of the features of CSCs with EMT-induced, VEGF-A–mediated angiogenesis as the connecting mechanism between cancer cell stemness and tumor initiation. Cancer Res; 74(5); 1566–75. ©2014 AACR.
Future Opportunities in Cancer Nanotechnology—NCI Strategic Workshop Report
Authors: Grodzinski Piotr , Farrell Dorothy
Published: January 2014

There has been significant progress in utilizing nanotechnology in several areas of cancer care, including in vitro diagnostics, imaging, and therapy. The National Cancer Institute, which currently supports an array of research activities in cancer nanotechnology, convened a strategic workshop to explore the most promising directions and areas for future resource investment. The major discussion points as well as the opportunities identified are presented herein. Cancer Res; 74(5); 1307–10. ©2014 AACR.
Role of CHD5 in Human Cancers: 10 Years Later
Authors: Kolla Venkatadri , Zhuang Tiangang , Higashi Mayumi , Naraparaju Koumudi , Brodeur Garrett M.
Published: January 2014

CHD5 was first identified because of its location on 1p36 in a region of frequent deletion in neuroblastomas. CHD5 (chromodomain–helicase–DNA–binding-5) is the fifth member of a family of chromatin remodeling proteins, and it probably functions by forming a nucleosome remodeling and deacetylation (NuRD) complex that regulates transcription of particular genes. CHD5 is preferentially expressed in the nervous system and testis. On the basis of its position, pattern of expression, and function in neuroblastoma cells and xenografts, CHD5 was identified as a tumor suppressor gene (TSG). Evidence soon emerged that CHD5 also functioned as a TSG in gliomas and a variety of other tumor types, including breast, colon, lung, ovary, and prostate cancers. Although one copy of CHD5 is deleted frequently, inactivating mutations of the remaining allele are rare. However, DNA methylation of the CHD5 promoter is found frequently, and this epigenetic mechanism leads to biallelic inactivation. Furthermore, low CHD5 expression is strongly associated with unfavorable clinical and biologic features as well as outcome in neuroblastomas and many other tumor types. Thus, based on its likely involvement as a TSG in neuroblastomas, gliomas, and many common adult tumors, CHD5 may play an important developmental role in many other tissues besides the nervous system and testis. Cancer Res; 74(3); 652–8. ©2014 AACR.
KIF3a Promotes Proliferation and Invasion via Wnt Signaling in Advanced Prostate Cancer
Authors: Liu Zun , Rebowe Ryan E. , Wang Zemin , Li Yingchun , Wang Zehua , DePaolo John S. , Guo Jianhui , Qian Chiping , Liu Wanguo
Published: January 2014

Aberrant activation of the Wnt/β-catenin signaling pathway is a critical event in advanced prostate cancer, but the genetic alterations that activate the Wnt signaling pathway in many other cancers are rarely observed in prostate cancer. Other molecular mechanisms that regulate the Wnt signaling pathway in prostate cancer remain to be identified. Here, it is demonstrated that KIF3a, a subunit of kinesin-II motor protein, functions as an agonist of the Wnt signaling pathway in prostate cancer. KIF3a is upregulated in the majority of human prostate cancer cell lines and primary tumor biopsies. The expression levels of KIF3a correlate with a higher Gleason score, tumor–node–metastasis stage, and metastatic status of prostate cancer. Moreover, exogenous expression of KIF3a promoted cell growth in the benign prostate cells, whereas silencing KIF3a in cancer cells decreased cell proliferation, anchorage-independent cell growth, and cell migration/invasion. Mechanistically, KIF3a increases CK1-dependent DVL2 phosphorylation and β-catenin activation in prostate cancer cells, leading to transactivation of the Wnt-signaling target genes such as cyclin D1, HEF1, and MMP9. These findings support the notion that upregulation of KIF3a is causal of aberrant activation of Wnt signaling in advanced prostate cancer through the KIF3a–DVL2–β-catenin axis.

Implications: Inactivation of KIF3a may improve survival of patients with advanced prostate cancer in which Wnt signaling is activated. Mol Cancer Res; 12(4); 491–503. ©2014 AACR.
Prevalence, Significance, and Management of Aortic Insufficiency in Continuous Flow Left Ventricular Assist Device Recipients
Authors: Jorde Ulrich P. , Uriel Nir , Nahumi Nadav , Bejar David , Gonzalez-Costello Jose , Thomas Sunu S. , Han Jason , Morrison Kerry A. , Jones Sophie , Kodali Susheel , Hahn Rebecca T. , Shames Sofia , Yuzefpolskaya Melana , Colombo Paolo , Takayama Hiroo , Naka Yoshifumi
Published: January 2014

Background—

Aortic insufficiency (AI) is increasingly recognized as a complication of continuous flow left ventricular assist device support; however, its long-term prevalence, clinical significance, and efficacy of potential interventions are not well known.

Methods and Results—

We studied the prevalence and management of AI in 232 patients with continuous flow left ventricular assist device at our institution. Patients with aortic valve (AV) surgery before left ventricular assist device implantation were excluded from analysis. To examine the prevalence of de novo AI, patients without preoperative AI were divided into a retrospective and a prospective cohort based on whether a dedicated speed optimization study had been performed at the time of discharge. Forty-three patients underwent AV repair at the time of implant, and 3 subsequently developed greater than mild AI. In patients without surgical AV manipulation and no AI at the time of implant, Kaplan–Meier analysis revealed that freedom from greater than mild de novo AI at 1 year was 77.6±4.2%, and that at least moderate AI is expected to develop in 37.6±13.3% after 3 years. Nonopening of the AV was strongly associated with de novo AI development in patients without prospective discharge speed optimization. Seven of 21 patients with at least moderate AI developed symptomatic heart failure requiring surgical intervention.

Conclusions—

AI is common in patients with continuous flow left ventricular assist devices and may lead to clinical decompensation requiring surgical correction. The prevalence of AI is substantially less in patients whose AV opens, and optimized loading conditions may reduce AI prevalence in those patients in whom AV opening cannot be achieved.
Soluble Adenylyl Cyclase in Vascular Endothelium
Authors: Schmitz Boris , Nedele Johanna , Guske Katrin , Maase Martina , Lenders Malte , Schelleckes Michael , Kusche-Vihrog Kristina , Brand Stefan-Martin , Brand Eva
Published: January 2014

The Ca
2+
- and bicarbonate-activated soluble adenylyl cyclase (sAC) has been identified recently as an important mediator of aldosterone signaling in the kidney. Nuclear sAC has been reported to stimulate cAMP response element–binding protein 1 phosphorylation via protein kinase A, suggesting an alternative cAMP pathway in the nucleus. In this study, we analyzed the sAC as a potential modulator of endothelial stiffness in the vascular endothelium. We determined the contribution of sAC to cAMP response element–mediated transcriptional activation in vascular endothelial cells and kidney collecting duct cells. Inhibition of sAC by the specific inhibitor KH7 significantly reduced cAMP response element–mediated promoter activity and affected cAMP response element–binding protein 1 phosphorylation. Furthermore, KH7 and anti-sAC small interfering RNA significantly decreased mRNA and protein levels of epithelial sodium channel-α and Na
+
/K
+
-ATPase-α. Using atomic force microscopy, a nano-technique that measures stiffness and deformability of living cells, we detected significant endothelial cell softening after sAC inhibition. Our results suggest that the sAC is a regulator of gene expression involved in aldosterone signaling and an important regulator of endothelial stiffness. Additional studies are warranted to investigate the protective action of sAC inhibitors in humans for potential clinical use.
Vitamin D Therapy to Reduce Blood Pressure and Left Ventricular Hypertrophy in Resistant Hypertension
Authors: Witham Miles D. , Ireland Sheila , Houston J. Graeme , Gandy Stephen J. , Waugh Shelley , MacDonald Thomas M. , Mackenzie Isla S. , Struthers Allan D.
Published: January 2014

Low 25-hydroxyvitamin D levels are associated with higher prevalent blood pressure. We tested whether high-dose intermittent oral vitamin D therapy could reduce blood pressure and left ventricular mass in patients with hypertension resistant to conventional treatment. We conducted a parallel-group, double-blind, randomized placebo-controlled trial. Patients with supine office blood pressure >140/90 mm Hg on ≥3 antihypertensive agents received 100 000 U oral vitamin D3 or matching placebo every 2 months. Office and 24-hour ambulatory blood pressure, glucose, and cholesterol were measured at baseline, 2, 4, and 6 months; left ventricular mass index was measured by cardiac MRI on a subgroup at baseline and 6 months. The primary outcome was mean 24-hour ambulatory blood pressure at 6 months. A total of 68 participants were randomized, 34 in each group. Mean age was 63 (SD 11) years, mean baseline office blood pressure was 154/84 (13/10) mm Hg, and mean baseline 25-hydroxyvitamin D level was 42 (16) nmol/L. Treatment with vitamin D did not reduce 24-hour ambulatory blood pressure (adjusted treatment effects: systolic, +3 mm Hg; 95% confidence interval, –4 to +11;
P
=0.33; diastolic, –2 mm Hg; 95% confidence interval, –6 to +2;
P
=0.29); similar results were seen for office blood pressure. Left ventricular mass index was measured in a subgroup (n=25); no reduction was seen with vitamin D treatment (adjusted treatment effect, +4 g/m
2
; 95% confidence interval, 0 to +7;
P
=0.04). There was no significant change in cholesterol or glucose levels. Thus, 6 months of intermittent, high-dose oral vitamin D3 did not reduce blood pressure or left ventricular mass in patients with resistant hypertension.
Role for Germline Mutations and a Rare Coding Single Nucleotide Polymorphism Within the KCNJ5 Potassium Channel in a Large Cohort of Sporadic Cases of Primary Aldosteronism
Authors: Murthy Meena , Xu Shengxin , Massimo Gianmichele , Wolley Martin , Gordon Richard D. , Stowasser Michael , O’Shaughnessy Kevin M.
Published: January 2014

Primary aldosteronism (autonomous aldosterone production with suppressed renin) plays an important pathophysiological role in what has been previously labeled as essential hypertension. Besides the recently described germline mutations in the KCNJ5 potassium channel associated with familial primary aldosteronism, somatic mutations in the same channel have been identified within aldosterone-producing adenomas. In this study, we have resequenced the flanking and coding region of KCNJ5 in peripheral blood DNA from 251 white subjects with primary aldosteronism to look for rare variants that might be important for the pathophysiology of sporadic primary aldosteronism. We have identified 3 heterozygous missense mutations (R52H, E246K, and G247R) in the cohort and found that 12 (5% of the cohort) were carriers for the rare nonsynonymous single nucleotide polymorphism rs7102584 causing E282Q substitution of KCNJ5. By expressing the channels in Xenopus oocytes and human adrenal H295R cells, we have shown that the R52H, E246K, and E282Q substitutions are functional, but the G247R mutation is indistinguishable from wild type. Although the functional substitutions are remote from the selectivity filter, they affect the inward-rectification, the ability of the KCNJ5 channels to conduct Na
+
currents and ATII-induced aldosterone release from the H295R cell line. Together these data suggest that germline variation in the
KCNJ5
gene has a role to play in the common sporadic form as well as the much rarer syndromic forms of primary aldosteronism.
Cardiorespiratory Fitness in Breast Cancer Patients: A Call for Normative Values
Authors: Peel Amanda B. , Thomas Samantha M. , Dittus Kim , Jones Lee W. , Lakoski Susan G.
Published: January 2014

Background

There is emerging evidence that adjuvant treatments for breast cancer negatively impact cardiorespiratory fitness (
CRF
) or
vo
2max
, a key predictor of cardiovascular risk. Although a number of studies have measured
CRF
in breast cancer patients, there is currently limited data regarding expected
CRF
values in this patient population. Given that
CRF
is a poor prognostic sign and recently highlighted as a key measure to standardize by the
A
merican
H
eart
A
ssociation, we sought to review the available literature on
CRF
among breast cancer patients.

Methods and Results

We identified 27 clinical trials and observational studies measuring
vo
2max
in the pre– and post–adjuvant treatment setting for breast cancer. We compared
vo
2max
before to
vo
2max
after adjuvant therapy and compared
vo
2max
in female breast cancer patients with
vo
2max
in healthy controls.

Conclusions

We found that
CRF
was substantially lower in women with a history of breast cancer compared with healthy women and this was most pronounced among breast cancer patients in the post‐adjuvant setting. We conclude that knowledge of normative
CRF
values is critical to tailor appropriately timed exercise interventions in breast cancer patients susceptible to low
CRF
and subsequent cardiovascular risk.
Тысячная книга 1550 г. и Дворовая тетрадь 50-х гг. XVI века как источники по изучению Государева двора в России середины XVI в
Authors: Корзинин Александр Л.
Published: January 2014

This article is devoted to the critical observation of the main sources for investigating the court of Tsar Ivan IV (the Terrible) during the 1550s. The author outlines the important moments for studying the Russian ruling elite, which makes it necessary to investigate the purposes, timing and staff included in the Tysiachnaia Kniga and Dvorovaia Tetrad’ of 1550.
Вечный спор о Петре Великом: благо или зло для России?
Authors: Анисимов Евгений В.
Published: January 2014

This article is devoted to the evaluation of the first Russian Emperor, Peter I. According to the author, Russia became a European Power thanks largely to his efforts. But, at the same time, we cannot reject other points of view about Peter I. Therefore, the author appears both as a “Westerner” who justifies and defends Peter and as a conservative patriot who condemns Peter and his politics. Both views have their place because they reflect the complex and ambiguous role of Peter the Great in Russian history.
Trends in Monthly Tropopause Characteristics Observed over Taipei, Taiwan*
Authors: Raman M. Roja , Chen Wei-Nai
Published: January 2014

This study presents monthly trends in the cold-point tropopause (CPT), calculated using three decades of radiosonde data from 1981 to 2010 over Taipei, Taiwan (25°01′N, 121°27′E). Multivariate regression analysis has been used to suppress the effect of natural variations, such as quasi-biennial oscillation (QBO), ENSO, solar cycle, and volcanic eruptions. From the continuous time series, statistically insignificant heating and a decrease in the height of CPT are observed. However, the trends estimated using individual monthly time series revealed new features with statistically significant increasing trends in CPT temperature at a rate of approximately 0.03°C yr−1 and statistically significant decreasing trends in CPT height at a rate of approximately 4.7 m yr−1 during summer months. An enhanced heating rate in the upper troposphere along with a suppressed cooling rate in the lower stratosphere observed over Taipei might have caused the tropopause heating trend during summer. The possible relationship between tropopause trends and lower-stratospheric ozone is also examined. The seasonal and spatial variations in trends estimated using NCEP–Climate Forecast System Reanalysis (CFSR) data reveal the spatial heterogeneity in CPT temperature trends. Initial inspection of monthly trends in tropopause characteristics suggests that the estimation of tropopause trends using the continuous time series may not exactly represent the long-term variability of individual months or seasons.
How Does the East Asian Summer Monsoon Behave in the Decaying Phase of El Niño during Different PDO Phases?
Authors: Feng Juan , Wang Lin , Chen Wen
Published: January 2014

Modulation of the Pacific decadal oscillation (PDO) on the behavior of the East Asian summer monsoon (EASM) in El Niño decaying years has been studied. When El Niño is in phase with the PDO (El Niño/high PDO), the low-level atmospheric anomalies are characterized by an anticyclone around the Philippines and a cyclone around Japan, inducing an anomalous tripolar rainfall pattern in China. In this case, the western Pacific subtropical high (WPSH) experiences a one-time slightly northward shift in July and then stays stationary from July to August. The corresponding anomalous tripolar rainfall pattern has weak subseasonal variations. When El Niño is out of phase with the PDO (El Niño/low PDO), however, the anomalous Philippines anticyclone has a much larger spatial domain, thereby causing an anomalous dipole rainfall pattern. Accordingly, WPSH experiences clearly two northward shifts. Therefore, the related dipole rainfall pattern has large subseasonal variations. One pronounced feature is that the positive rainfall anomalies shift northward from southern China in June to central China in July and finally to northern China in August.

The different El Niño–EASM relationships are caused by the influences of PDO on the decaying speed of El Niño. During the high PDO phase, El Niño decays slowly and has a strong anchor in the north Indian Ocean warming, which is responsible for the anomalous EASM. Comparatively, during the low PDO phase, El Niño decays rapidly and La Niña develops in summer, which induces different EASM anomalies from that during the high PDO phase. Additionally, PDO changes El Niño behaviors mainly via modifying the background tropical winds.
The Regional Climate Impact of a Realistic Future Deforestation Scenario in the Congo Basin
Authors: Akkermans Tom , Thiery Wim , Van Lipzig Nicole P. M.
Published: January 2014

The demand for agricultural land in the Congo basin is expected to yield substantial deforestation over the coming decades. Although several studies exist on the climatological impact of deforestation in the Congo basin, deforestation scenarios that are implemented in climate models are generally crude. This study aims to refine current impact assessments by removing the primary forest according to an existing spatially explicit scenario, and replacing it by successional vegetation typically observed for the Congo basin. This is done within the Consortium for Small-Scale Modeling (COSMO) model in climate mode (COSMO-CLM), a regional climate model at 25-km grid spacing coupled to a state-of-the-art soil–vegetation–atmosphere transfer scheme (Community Land Model). An evaluation of the model shows good performance compared to in situ and satellite observations. Model integrations indicate that the deforestation, expected for the middle of the twenty-first century, induces a warming of about 0.7°C. This is about half the greenhouse gas–induced surface warming in this region, given an intermediate emission scenario (A1B) with COSMO-CLM driven by the ECHAM5 global climate model. This shows the necessity of taking into account deforestation to obtain realistic future climate projections. The deforestation-induced warming can be attributed to reduced evaporation, but this effect is mitigated by increased albedo and increased sensible heat loss to the atmosphere. Precipitation is also affected: as a consequence of surface warming resulting from deforestation, a regional heat low develops over the rain forest region. Resulting low-level convergence causes a redistribution of moisture in the boundary layer and a stabilization of the atmospheric column, thereby reducing convection intensity and hence precipitation by 5%–10% in the region of the heat low.
Stratocumulus Clouds in Southeastern Pacific Simulated by Eight CMIP5–CFMIP Global Climate Models
Authors: Lin Jia-Lin , Qian Taotao , Shinoda Toshiaki
Published: January 2014

This study examines the stratocumulus clouds and associated cloud feedback in the southeast Pacific (SEP) simulated by eight global climate models participating in phase 5 of the Coupled Model Intercomparison Project (CMIP5) and Cloud Feedback Model Intercomparison Project (CFMIP) using long-term observations of clouds, radiative fluxes, cloud radiative forcing (CRF), sea surface temperature (SST), and large-scale atmosphere environment. The results show that the state-of-the-art global climate models still have significant difficulty in simulating the SEP stratocumulus clouds and associated cloud feedback. Comparing with observations, the models tend to simulate significantly less cloud cover, higher cloud top, and a variety of unrealistic cloud albedo. The insufficient cloud cover leads to overly weak shortwave CRF and net CRF. Only two of the eight models capture the observed positive cloud feedback at subannual to decadal time scales. The cloud and radiation biases in the models are associated with 1) model biases in large-scale temperature structure including the lack of temperature inversion, insufficient lower troposphere stability (LTS), and insufficient reduction of LTS with local SST warming, and 2) improper model physics, especially insufficient increase of low cloud cover associated with larger LTS. The two models that arguably do best at simulating the stratocumulus clouds and associated cloud feedback are the only ones using cloud-top radiative cooling to drive boundary layer turbulence.
A Robust Estimation Method for Correcting Dynamic Draft Error in PPK GPS Elevation Using ADCP Tilt Data
Authors: Matte Pascal , Secretan Yves , Morin Jean
Published: January 2014

Measuring temporal and spatial variations in water level with high resolution and accuracy can provide fundamental insights into the hydrodynamics of marine and riverine systems. Real-time kinematic global positioning systems (RTK GPS), and by extension postprocessed kinematic (PPK) positioning, have provided the opportunity to achieve this goal, by allowing fast and straightforward measurements with subdecimeter accuracy. However, boat-mounted GPS are subject to movements of the water surface (e.g., waves, long-period heaves) as well as to the effects of dynamic draft. The latter contaminate the records and need to be separated and removed from the data. A method is proposed to postcorrect the elevation data using tilt information measured by an attitude sensor—in this case, an acoustic Doppler current profiler (ADCP) equipped with internal pitch and roll sensors. The technique uses iteratively reweighted least squares (IRLS) regressions to determine the position of the center of rotation (COR) of the boat that leads to optimal corrections. The COR is also allowed to change in time by performing the IRLS analyses on data subsamples, thus accounting for changes in weight distribution, for example, due to personnel movements. An example of application is presented using data collected in the Saint Lawrence fluvial estuary. The corrections exhibit significant reductions associated with the boat motion while keeping subtle variations in water levels likely related to local hydrodynamics.