bluuebunny/crossref_metadata_2025 huggingface dataset:
NONLINEAR DYNAMIC BEHAVIOR OF A ROTOR ACTIVE MAGNETIC BEARING
Authors: CHEN HONGKUI , HEGAZY USAMA H.
Published: January 2011

The nonlinear dynamic behavior of a rigid disc-rotor supported by active magnetic bearings (AMB) is investigated, without gyroscopic effects. The vibration of the rotor is modeled by a coupled second order nonlinear ordinary differential equations with quadratic and cubic nonlinearities. Their approximate solutions are sought applying the method of multiple scales in the case of primary resonance. The Newton–Raphson method and the pseudo-arclength path-following algorithm are used to obtain the frequency response curves. Choosing the Hopf bifurcations as the initial points and applying the shooting method and the pseudo-arclength path-following algorithm, the periodic solution branches are obtained. At the same time, the Floquet theory is used to determine the stability of the periodic solutions. A detailed bifurcation analysis of the dynamic (periodic and chaotic) solutions of the averaged equations is presented. The three types of primary Hopf bifurcations are found for the first time in the rotor-AMB system. It is shown that the limit cycles undergo cyclic fold, period doubling bifurcations, and intermittent chaotic attractor, whereas the chaotic attractors undergo explosive bifurcation and boundary crises. In the regime of multiple coexisting solutions, multiple stable equilibriums, periodic solutions and chaotic solutions are the most interesting phenomena observed.
PARAMETERIZED DYNAMICS FOR THE WEIERSTRASS ELLIPTIC FUNCTION OVER SQUARE PERIOD LATTICES
Authors: HAWKINS JANE , MCCLURE MARK
Published: January 2011

We iterate the Weierstrass elliptic ℘ function in order to understand the dependence of the dynamics on the underlying period lattice L. We focus on square lattices and use the holomorphic dependence on the classical invariants (g2, g3) = (g2, 0) to show that in parameter space (g2-space) one sees both quadratic-like attracting orbit behavior and prepole dynamics. In the case of prepole parameters all critical orbits terminate at poles and the Julia set of ℘L is the entire sphere. We show that both the Mandelbrot-like dynamics and the prepole parameters accumulate on prepole parameters of lower order providing results on the dynamics occurring in parameter space "between Mandelbrot sets".
ON THE DYNAMICS OF A NEW SIMPLE 2-D RATIONAL DISCRETE MAPPING
Authors: ELHADJ ZERAOULIA , SPROTT J. C.
Published: January 2011

This paper is devoted to the analysis of a new simple rational map of the plane. Its dynamics are described in some detail, along with some other dynamical phenomena. In particular, the map under consideration is the first simple rational map whose fraction has no vanishing denominator that gives chaotic attractors via a quasi-periodic route to chaos.
A UNIFIED APPROACH FOR DEVELOPING SOFTWARE RELIABILITY GROWTH MODEL USING INFINITE SERVER QUEUING MODEL
Authors: KAPUR P. K. , ANAND SAMEER , INOUE SHINJI , YAMADA SHIGERU
Published: January 2011

In the past 35 years numerous software reliability growth models (SRGMs) have been proposed under diverse testing and debugging (T&D) environments and applied successfully in many real life software projects but no SRGM can claim to be the best in general as the physical interpretation of the T&D is not general. Unified modeling approach proves to be very successful in this regard and provides an excellent platform for obtaining several existing SRGM following single methodology. It forms the main focus of this paper; here we propose a unification modeling approach applying the infinite server queuing theory based on the basic assumptions of an SRGM defining three level of complexity of faults. Our unification methodology can be used to obtain several existing and new SRGMs which consider testing a one stage process with no fault categorization, two/three stage process with random delay functions and hence categorize faults in two/three level complexity. We have also provided data analysis based on two actual T&D data set for some of the models discussed and proposed in the paper.
RELIABILITY AND SENSITIVITY ANALYSIS OF COHERENT SYSTEMS WITH NEGATIVELY CORRELATED COMPONENT FAILURES
Authors: FIONDELLA LANCE
Published: January 2011

Modeling correlated component failures poses a unique challenge for reliability researchers because it requires ingenuity to devise an approach free from the assumption that components fail in a statistically independent manner. Several studies have addressed this problem with models that introduce additional parameters to describe the correlated failure of components. However, these earlier techniques often require the correlations to be positive and almost always introduce an exponential number of correlation parameters. These restrictions limit the scalability of existing approaches for conducting sensitivity analysis on the correlation parameters, which could identify correlation reductions that would improve system reliability. This paper presents a technique for reliability and sensitivity analysis that requires only a quadratic number of correlation parameters, encompassing systems with both negative and positive component correlations. Unlike previous research, the proposed approach places no unnecessary restrictions on a system's correlation parameters. A series of examples illustrates the flexibility of the approach. The results quantitatively confirm that negative component correlation assists fault-tolerant systems to attain levels of reliability even higher than systems of statistically independent redundant components. Thus, the techniques introduced here offer a methodology to concisely measure the utility of negative component correlations on system reliability improvement.
Small GTPase Rab11b regulates degradation of surface membrane L-type Cav1.2 channels
Authors: Best Jabe M. , Foell Jason D. , Buss Courtney R. , Delisle Brian P. , Balijepalli Ravi C. , January Craig T. , Kamp Timothy J.
Published: January 2011

L-type Ca2+ channels (LTCCs) play a critical role in Ca2+-dependent signaling processes in a variety of cell types. The number of functional LTCCs at the plasma membrane strongly influences the strength and duration of Ca2+ signals. Recent studies demonstrated that endosomal trafficking provides a mechanism for dynamic changes in LTCC surface membrane density. The purpose of the current study was to determine whether the small GTPase Rab11b, a known regulator of endosomal recycling, impacts plasmalemmal expression of Cav1.2 LTCCs. Disruption of endogenous Rab11b function with a dominant negative Rab11b S25N mutant led to a significant 64% increase in peak L-type Ba2+ current ( IBa,L) in human embryonic kidney (HEK)293 cells. Short-hairpin RNA (shRNA)-mediated knockdown of Rab11b also significantly increased peak IBa,L by 66% compared when with cells transfected with control shRNA, whereas knockdown of Rab11a did not impact IBa,L. Rab11b S25N led to a 1.7-fold increase in plasma membrane density of hemagglutinin epitope-tagged Cav1.2 expressed in HEK293 cells. Cell surface biotinylation experiments demonstrated that Rab11b S25N does not significantly impact anterograde trafficking of LTCCs to the surface membrane but rather slows degradation of plasmalemmal Cav1.2 channels. We further demonstrated Rab11b expression in ventricular myocardium and showed that Rab11b S25N significantly increases peak IBa,L by 98% in neonatal mouse cardiac myocytes. These findings reveal a novel role for Rab11b in limiting, rather than promoting, the plasma membrane expression of Cav1.2 LTCCs in contrast to its effects on other ion channels including human ether-a-go-go-related gene (hERG) K+ channels and cystic fibrosis transmembrane conductance regulator. This suggests Rab11b differentially regulates the trafficking of distinct cargo and extends our understanding of how endosomal transport impacts the functional expression of LTCCs.
Metabolic and functional differences between brain and spinal cord mitochondria underlie different predisposition to pathology
Authors: Panov Alexander V. , Kubalik Nataliya , Zinchenko Natalia , Ridings Daisy M. , Radoff David A. , Hemendinger Richelle , Brooks Benjamin R. , Bonkovsky Herbert L.
Published: January 2011

Mitochondrial dysfunctions contribute to neurodegeneration, the locations of which vary among neurodegenerative diseases. To begin to understand what mechanisms may underlie higher vulnerability of the spinal cord motor neurons in amyotrophic lateral sclerosis, compared with brain mitochondria, we studied three major functions of rat brain mitochondria (BM) and spinal cord mitochondria (SCM) mitochondria: oxidative phosphorylation, Ca2+sequestration, and production of reactive oxygen species (ROS), using a new metabolic paradigm (Panov et al., J. Biol. Chem. 284: 14448–14456, 2009). We present data that SCM share some unique metabolic properties of the BM. However, SCM also have several distinctions from the BM: 1) With the exception of succinate, SCM show significantly lower rates of respiration with all substrates studied; 2) immunoblotting analysis showed that this may be due to 30–40% lower contents of respiratory enzymes and porin; 3) compared with BM, SCM sequestered 40–50% less Ca2+, and the total tissue calcium content was 8 times higher in the spinal cord; 4) normalization for mitochondria from 1 g of tissue showed that BM can sequester several times more Ca2+than was available in the brain tissue, whereas SCM had the capacity to sequester only 10–20% of the total tissue Ca2+; and 5) with succinate and succinate-containing substrate mixtures, SCM showed significantly higher state 4 respiration than BM and generated more ROS associated with the reverse electron transport. We conclude that SCM have an intrinsically higher risk of oxidative damage and overload with calcium than BM, and thus spinal cord may be more vulnerable under some pathologic conditions. (250)
Factors that render the kidney susceptible to tissue hypoxia in hypoxemia
Authors: Evans Roger G. , Goddard Duncan , Eppel Gabriela A. , O'Connor Paul M.
Published: January 2011

To better understand what makes the kidney susceptible to tissue hypoxia, we compared, in the rabbit kidney and hindlimb, the ability of feedback mechanisms governing oxygen consumption (V̇o2) and oxygen delivery (Do2) to attenuate tissue hypoxia during hypoxemia. In the kidney (cortex and medulla) and hindlimb (biceps femoris muscle), we determined responses of whole organ blood flow and V̇o2, and local perfusion and tissue Po2, to reductions in Do2mediated by graded systemic hypoxemia. Progressive hypoxemia reduced tissue Po2similarly in the renal cortex, renal medulla, and biceps femoris. Falls in tissue Po2could be detected when arterial oxygen content was reduced by as little as 4–8%. V̇o2remained stable during progressive hypoxemia, only tending to fall once arterial oxygen content was reduced by 55% for the kidney or 42% for the hindlimb. Even then, the fall in renal V̇o2could be accounted for by reduced oxygen demand for sodium transport rather than limited oxygen availability. Hindlimb blood flow and local biceps femoris perfusion increased progressively during graded hypoxia. In contrast, neither total renal blood flow nor cortical or medullary perfusion was altered by hypoxemia. Our data suggest that the absence in the kidney of hyperemic responses to hypoxia, and the insensitivity of renal V̇o2to limited oxygen availability, contribute to kidney hypoxia during hypoxemia. The susceptibility of the kidney to tissue hypoxia, even in relatively mild hypoxemia, may have important implications for the progression of kidney disease, particularly in patients at high altitude or with chronic obstructive pulmonary disease.
Immortalized neurons for the study of hypothalamic function
Authors: Dalvi Prasad S. , Nazarians-Armavil Anaies , Tung Stephanie , Belsham Denise D.
Published: January 2011

The hypothalamus is a vital part of the central nervous system: it harbors control systems implicated in regulation of a wide range of homeostatic processes, including energy balance and reproduction. Structurally, the hypothalamus is a complex neuroendocrine tissue composed of a multitude of unique neuronal cell types that express a number of neuromodulators, including hormones, classical neurotransmitters, and specific neuropeptides that play a critical role in mediating hypothalamic function. However, neuropeptide and receptor gene expression, second messenger activation, and electrophysiological and secretory properties of these hypothalamic neurons are not yet fully defined, primarily because the heterogeneity and complex neuronal architecture of the neuroendocrine hypothalamus make such studies challenging to perform in vivo. To circumvent this problem, our research group recently generated embryonic- and adult-derived hypothalamic neuronal cell models by utilizing the novel molecular techniques of ciliary neurotrophic factor-induced neurogenesis and SV40 T antigen transfer to primary hypothalamic neuronal cell cultures. Significant research with these cell lines has demonstrated their value as a potential tool for use in molecular genetic analysis of hypothalamic neuronal function. Insights gained from hypothalamic immortalized cells used in conjunction with in vivo models will enhance our understanding of hypothalamic functions such as neurogenesis, neuronal plasticity, glucose sensing, energy homeostasis, circadian rhythms, and reproduction. This review discusses the generation and use of hypothalamic cell models to study mechanisms underlying the function of individual hypothalamic neurons and to gain a more complete understanding of the overall physiology of the hypothalamus.
Self-organized patterns of airway narrowing
Authors: Winkler Tilo , Venegas Jose G.
Published: January 2011

The behavior of respiratory diseases such as asthma and COPD may involve complicated interactions among multiple factors. Theoretical and experimental data suggest that interdependence among the airways of the bronchial tree leads to the emergence of self-organized patterns of airway narrowing, ventilation defects, and other phenomena when a tipping point is passed. Additionally, evidence from several studies shows that the behavior of an isolated airway is different from an identical airway embedded in the bronchial tree so that experimental results of isolated elements such as airways, airway smooth muscle, or inflammatory pathways may not explain the whole organ behavior. However, there may be factors in the isolated elements that can dramatically change the complex system's behavior. More effective strategies for prevention or recovery from a disease, such as asthma, will depend on our progress in identifying and understanding the essential parts of the self-organized behavior that is involved.
Comparison of the Rate of Convergence among Picard, Mann, Ishikawa, and Noor Iterations Applied to Quasicontractive Maps
Authors: Rhoades BE , Xue Zhiqun
Published: January 2011

We provide sufficient conditions for Picard iteration to converge faster than Krasnoselskij, Mann, Ishikawa, or Noor iteration for quasicontractive operators. We also compare the rates of convergence between Krasnoselskij and Mann iterations for Zamfirescu operators.
Different Learning Curves for Axillary Brachial Plexus Block: Ultrasound Guidance versus Nerve Stimulation
Authors: Luyet C. , Schüpfer G. , Wipfli M. , Greif R. , Luginbühl M. , Eichenberger U.
Published: January 2011

Little is known about the learning of the skills needed to perform ultrasound- or nerve stimulator-guided peripheral nerve blocks. The aim of this study was to compare the learning curves of residents trained in ultrasound guidance versus residents trained in nerve stimulation for axillary brachial plexus block. Ten residents with no previous experience with using ultrasound received ultrasound training and another ten residents with no previous experience with using nerve stimulation received nerve stimulation training. The novices' learning curves were generated by retrospective data analysis out of our electronic anaesthesia database. Individual success rates were pooled, and the institutional learning curve was calculated using a bootstrapping technique in combination with a Monte Carlo simulation procedure. The skills required to perform successful ultrasound-guided axillary brachial plexus block can be learnt faster and lead to a higher final success rate compared to nerve stimulator-guided axillary brachial plexus block.
Global Stability of a Rational Difference Equation
Authors: Tang Guo-Mei , Hu Lin-Xia , Ma Gang
Published: January 2011

We consider the higher‐order nonlinear difference equation xn+1 = (p + qxn−k)/(1 + xn + rxn−k), n = 0, 1, … with the parameters, and the initial conditions x−k, …, x0 are nonnegative real numbers. We investigate the periodic character, invariant intervals, and the global asymptotic stability of all positive solutions of the above‐mentioned equation. In particular, our results solve the open problem introduced by Kulenović and Ladas in their monograph (see Kulenović and Ladas, 2002).
Urban Surface Temperature Reduction via the Urban Aerosol Direct Effect: A Remote Sensing and WRF Model Sensitivity Study
Authors: Jin Menglin , Shepherd J. Marshall , Zheng Weizhong
Published: January 2011

The aerosol direct effect, namely, scattering and absorption of sunlight in the atmosphere, can lower surface temperature by reducing surface insolation. By combining National Aeronautics and Space Administration (NASA) AERONET (AErosol RObotic NETwork) observations in large cities with Weather Research and Forecasting (WRF) model simulations, we find that the aerosol direct reduction of surface insolation ranges from 40–100Wm−2, depending on aerosol loading and land‐atmosphere conditions. To elucidate the maximum possible effect, values are calculated using a radiative transfer model based on the top quartile of the multiyear instantaneous aerosol data observed by AERONET sites. As a result, surface skin temperature can be reduced by 1°C‐2°C while 2‐m surface air temperature reductions are generally on the order of 0.5°C–1°C.
On q‐Operators and Summation of Some q‐Series
Authors: Guesmi Sana , Fitouhi Ahmed
Published: January 2011

Using Jackson′s q‐derivative and the q‐Stirling numbers, we establish some transformation theorems leading to the values of some
convergent q‐series.
The Consequence of Immune Suppressive Cells in the Use of Therapeutic Cancer Vaccines and Their Importance in Immune Monitoring
Authors: Vergati Matteo , Schlom Jeffrey , Tsang Kwong Y.
Published: January 2011

Evaluating the number, phenotypic characteristics, and function of immunosuppressive cells in the tumor microenvironment and peripheral blood could elucidate the antitumor immune response and provide information to evaluate the efficacy of cancer vaccines. Further studies are needed to evaluate the correlation between changes in immunosuppressive cells and clinical outcomes of patients in cancer vaccine clinical trials. This paper focuses on the role of T‐regulatory cells, myeloid‐derived suppressor cells, and tumor‐associated macrophages in cancer and cancer immunotherapy and their role in immune monitoring.
Glucose Tolerance and Left Ventricular Pressure‐Volume Relationships in Frequently Used Mouse Strains
Authors: Oosterlinck Wouter , Vanderper Annelies , Flameng Willem , Herijgers Paul
Published: January 2011

We investigated glucose tolerance and left ventricular contractile performance in 4 frequently used mouse strains (Swiss, C57BL/6J, DBA2, and BalbC) at 24 weeks. Glucose tolerance was tested by measuring blood glucose levels in time after intraperitoneal glucose injection (2 mg/g body weight). Left ventricular contractility was assessed by pressure‐conductance analysis. Peak glucose levels and glucose area under the curve were higher (all P < .05) in C57BL/6J (418 ± 65 mg/dL and 813 ± 100 mg·h/dL) versus Swiss (237 ± 66 mg/dL and 470 ± 126 mg·h/dL), DBA2 (113 ± 20 mg/dL and 304 ± 49 mg·h/dL, P < .01), and BalbC mice (174 ± 55 mg/dL and 416 ± 70 mg·h/dL). Cardiac output was higher (all P < .05) in Swiss (14038 ± 4530 μL/min) versus C57BL/6J (10405 ± 2683 μL/min), DBA2 (10438 ± 3251 μL/min), and BalbC mice (8466 ± 3013 μL/min). Load‐independent left ventricular contractility assessed as recruitable stroke work (PRSW) was comparable in all strains. In conclusion, glucose tolerance and load‐dependent left ventricular performance parameters were different between 4 mice background strains, but PRSW was comparable.
A Novel Aerosol Method for the Production of Hydrogel Particles
Authors: Guzman-Villanueva Diana , Smyth Hugh D. C. , Herrera-Ruiz Dea , El-Sherbiny Ibrahim M.
Published: January 2011

A novel method of generating hydrogel particles for various applications including drug delivery purposes was developed. This method is based on the production of hydrogel particles from sprayed polymeric nano/microdroplets obtained by a nebulization process that is immediately followed by gelation in a crosslinking fluid. In this study, particle synthesis parameters such as type of nebulizer, type of crosslinker, air pressure, and polymer concentration were investigated for their impact on the mean particle size, swelling behavior, and morphology of the developed particles. Spherical alginate-based hydrogel particles with a mean particle size in the range from 842 to 886 nm were obtained. Using statistical analysis of the factorial design of experiment it was found that the main factors influencing the size and swelling values of the particles are the alginate concentration and the air pressure. Thus, it was demonstrated that the method described in the current study is promising for the generation of hydrogel particles and it constitutes a relatively simple and low-cost system.
Successful Treatment of a Severe Case of Fournier's Gangrene Complicating a Perianal Abscess
Authors: Papaconstantinou Ioannis , Yiallourou Anneza I. , Dafnios Nicolaos , Grapsa Irini , Polymeneas George , Voros Dionysios
Published: January 2011

A 67-year-old male patient with diabetes mellitus and nephritic syndrome under cortisone treatment was admitted to our hospital with fever and severe perianal pain. Upon physical examination, a perianal abscess was identified. Furthermore, the scrotum was gangrenous with extensive cellulitis of the perineum and left lower abdominal wall. Crepitations between the skin and fascia were palpable. A diagnosis of Fournier's gangrene was made. He was treated with immediate extensive surgical debridement under general anesthesia. The patient received broad-spectrum antibiotics, and repeated extensive debridements were performed until healthy granulation was present in the wound. Due to the fact that his left testicle was severely exposed, it was transpositioned into a subcutaneous pocket in the inner side of the left thigh. He was finally discharged on the 57th postoperative day. Fournier's gangrene is characterized by high mortality rates, ranging from 15% to 50% and is an acute surgical emergency. The mainstay of treatment should be open drainage and early aggressive surgical debridement of all necrotic tissue, followed by broad-spectrum antibiotics therapy.
The Role of P‐Glycoprotein in Transport of Danshensu across the Blood‐Brain Barrier
Authors: Yu Peng-Fei , Wang Wen-Yan , Eerdun Gaowa , Wang Tian , Zhang Lei-Ming , Li Chong , Fu Feng-Hua
Published: January 2011

Danshensu (3‐(3, 4‐dihydroxyphenyl) lactic acid), a water‐soluble active component isolated from the root of Salvia miltiorrhiza Bunge, is widely used for the treatment of cerebrovascular diseases. The present study aims to investigate the role of P‐glycoprotein in transport of Danshensu across the blood‐brain barrier. Sprague‐Dawley rats were pretreated with verapamil at a dose of 20 mg kg−1 (verapamil group) or the same volume of normal saline (control group). Ninety minutes later, the animals were administrated with Danshensu (15 mg kg−1) by intravenous injection. At 15 min, 30 min, and 60 min after Danshensu administration, the levels of Danshensu in the blood and brain were detected by high‐performance liquid chromatography‐electrospray ionization tandem mass spectrometry (LC‐ESI‐MS/MS). The results showed that Danshensu concentrations in the brain of the rats pretreated with verapamil were significantly increased. In addition, the brain‐plasma ratios of the group pretreated with verapamil were much higher than that of the control group. There was no difference in Danshensu level in plasma between the verapamil group and control group. The findings indicated that Danshensu can pass the blood‐brain barrier, and P‐glycoprotein plays an important role in Danshensu transportation in brain.
A Sequential Model of Host Cell Killing and Phagocytosis byEntamoeba histolytica
Authors: Sateriale Adam , Huston Christopher D.
Published: January 2011

The protozoan parasiteEntamoeba histolyticais responsible for invasive intestinal and extraintestinal amebiasis. The virulence ofEntamoeba histolyticais strongly correlated with the parasite's capacity to effectively kill and phagocytose host cells. The process by which host cells are killed and phagocytosed follows a sequential model of adherence, cell killing, initiation of phagocytosis, and engulfment. This paper presents recent advances in the cytolytic and phagocytic processes ofEntamoeba histolyticain context of the sequential model.
Critical Concerns for Oral Communication Education in Alabama and Beyond
Authors: Emanuel Richard
Published: January 2011

An examination of oral communication education in Alabama (USA) identified four critical concerns. (1) Today's college students are not getting adequate oral communication education. (2) Oral communication education is being relegated to a “module” in another discipline-specific course. (3) When an oral communication course is included in the general education curriculum, that course tends to be narrow rather than broad in scope. (4) An increasing number of college faculty who teach oral communication courses do not have a graduate degree in the discipline. These concerns may be indicative of similar issues affecting oral communication education throughout the United States and beyond. Solutions to each concern are offered, and suggestions are provided about how decision-making bodies like state departments of education, regional accrediting agencies, the National Communication Association, and the like can address these concerns. This paper first examines the essential role of oral communication before identifying four critical concerns and offering suggested solutions for oral communication education in Alabama. These concerns may be indicative of similar issues affecting oral communication regionally, nationally, and even internationally. If so, then the suggested solutions offered herein may provide direction. If not, then being proactive rather than reactive may prevent some or all of these concerns from becoming reality.
Intragenic Rearrangement and Altered RNA Splicing of the Androgen Receptor in a Cell-Based Model of Prostate Cancer Progression
Authors: Li Yingming , Alsagabi Majid , Fan Danhua , Bova G. Steven , Tewfik Ahmed H. , Dehm Scott M.
Published: January 2011

Androgen depletion for advanced prostate cancer (PCa) targets activity of the androgen receptor (AR), a steroid receptor transcription factor required for PCa growth. The emergence of lethal castration-resistant PCa (CRPCa) is marked by aberrant reactivation of the AR despite ongoing androgen depletion. Recently, alternative splicing has been described as a mechanism giving rise to COOH-terminally truncated, constitutively active AR isoforms that can support the CRPCa phenotype. However, the pathologic origin of these truncated AR isoforms is unknown. The goal of this study was to investigate alterations in AR expression arising in a cell-based model of PCa progression driven by truncated AR isoform activity. We show that stable, high-level expression of truncated AR isoforms in 22Rv1 CRPCa cells is associated with intragenic rearrangement of an approximately 35-kb AR genomic segment harboring a cluster of previously described alternative AR exons. Analysis of genomic data from clinical specimens indicated that related AR intragenic copy number alterations occurred in CRPCa in the context of AR amplification. Cloning of the break fusion junction in 22Rv1 cells revealed long interspersed nuclear elements (LINE-1) flanking the rearranged segment and a DNA repair signature consistent with microhomology-mediated, break-induced replication. This rearrangement served as a marker for the emergence of a rare subpopulation of CRPCa cells expressing high levels of truncated AR isoforms during PCa progression in vitro. Together, these data provide the first report of AR intragenic rearrangements in CRPCa and an association with pathologic expression of truncated AR isoforms in a cell-based model of PCa progression. Cancer Res; 71(6); 2108–17. ©2011 AACR.
Genome-Wide Analysis of Alternative Splicing in Medulloblastoma Identifies Splicing Patterns Characteristic of Normal Cerebellar Development
Authors: Menghi Francesca , Jacques Thomas S. , Barenco Martino , Schwalbe Ed C. , Clifford Steven C. , Hubank Mike , Ham Jonathan
Published: January 2011

Alternative splicing is an important mechanism for the generation of protein diversity at a post-transcriptional level. Modifications in the splicing patterns of several genes have been shown to contribute to the malignant transformation of different tissue types. In this study, we used the Affymetrix Exon arrays to investigate patterns of differential splicing between pediatric medulloblastomas and normal cerebellum on a genome-wide scale. Of the 1,262 genes identified as potentially generating tumor-associated splice forms, we selected 14 examples of differential splicing of known cassette exons and successfully validated 11 of them by reverse transcriptase PCR. The pattern of differential splicing of three validated events was characteristic for the molecular subset of sonic hedgehog (Shh)-driven medulloblastomas, suggesting that their unique gene signature includes the expression of distinctive transcript variants. Generally, we observed that tumor and normal fetal cerebellar samples shared significantly lower exon inclusion rates than normal adult cerebellum. We investigated whether tumor-associated splice forms were expressed in primary cultures of Shh-dependent mouse cerebellar granule cell precursors (GCP) and found that Shh caused a decrease in the cassette exon inclusion rate of five of the seven tested genes. Furthermore, we observed a significant increase in exon inclusion between postnatal days 7 and 14 of mouse cerebellar development, at the time when GCPs mature into postmitotic neurons. We conclude that inappropriate splicing frequently occurs in human medulloblastomas and may be linked to the activation of developmental signaling pathways and a failure of cerebellar precursor cells to differentiate. Cancer Res; 71(6); 2045–55. ©2011 AACR.
Zyxin Is a Critical Regulator of the Apoptotic HIPK2-p53 Signaling Axis
Authors: Crone Johanna , Glas Carolina , Schultheiss Kathrin , Moehlenbrink Jutta , Krieghoff-Henning Eva , Hofmann Thomas G.
Published: January 2011

HIPK2 activates the apoptotic arm of the DNA damage response by phosphorylating tumor suppressor p53 at serine 46. Unstressed cells keep HIPK2 levels low through targeted polyubiquitination and subsequent proteasomal degradation. Here we identify the LIM domain protein Zyxin as a novel regulator of the HIPK2-p53 signaling axis in response to DNA damage. Remarkably, depletion of endogenous Zyxin, which colocalizes with HIPK2 at the cytoskeleton and in the cell nucleus, stimulates proteasome-dependent HIPK2 degradation. In contrast, ectopic expression of Zyxin stabilizes HIPK2, even upon enforced expression of its ubiquitin ligase Siah-1. Consistently, Zyxin physically interacts with Siah-1, and knock-down of Siah-1 rescues HIPK2 expression in Zyxin-depleted cancer cells. Mechanistically, our data suggest that Zyxin regulates Siah-1 activity through interference with Siah-1 dimerization. Furthermore, we show that endogenous Zyxin coaccumulates with HIPK2 in response to DNA damage in cancer cells, and that depletion of endogenous Zyxin results in reduced HIPK2 protein levels and compromises DNA damage-induced p53 Ser46 phosphorylation and caspase activation. These findings suggest an unforeseen role for Zyxin in DNA damage-induced cell fate control through modulating the HIPK2-p53 signaling axis. Cancer Res; 71(6); 2350–9. ©2011 AACR.
Rebiopsy of Lung Cancer Patients with Acquired Resistance to EGFR Inhibitors and Enhanced Detection of the T790M Mutation Using a Locked Nucleic Acid-Based Assay
Authors: Arcila Maria E. , Oxnard Geoffrey R. , Nafa Khedoudja , Riely Gregory J. , Solomon Stephen B. , Zakowski Maureen F. , Kris Mark G. , Pao William , Miller Vincent A. , Ladanyi Marc
Published: January 2011

Background: The epidermal growth factor receptor (EGFR) mutation T790M is reported in approximately 50% of lung cancers with acquired resistance to EGFR inhibitors and is a potential prognostic and predictive biomarker. Its assessment can be challenging due to limited tissue availability and underdetection at low mutant allele levels. Here, we sought to determine the feasibility of tumor rebiopsy and to more accurately assess the prevalence of the T790M using a highly sensitive locked nucleic acid (LNA) PCR/sequencing assay. MET amplification was also analyzed.

Methods: Patients with acquired resistance were rebiopsied and samples were studied for sensitizing EGFR mutations. Positive cases were evaluated for T790M using standard PCR-based methods and a subset were re-evaluated with an LNA-PCR/sequencing method with an analytical sensitivity of approximately 0.1%. MET amplification was assessed by FISH.

Results: Of 121 patients undergoing tissue sampling, 104 (86%) were successfully analyzed for sensitizing EGFR mutations. Most failures were related to low tumor content. All patients (61/61) with matched pretreatment and resistance specimens showed concordance for the original sensitizing EGFR mutation. Standard T790M mutation analysis on 99 patients detected 51(51%) mutants. Retesting of 30 negative patients by the LNA-based method detected 11 additional mutants for an estimated prevalence of 68%. MET was amplified in 11% of cases (4/37).

Conclusions: The re-biopsy of lung cancer patients with acquired resistance is feasible and provides sufficient material for mutation analysis in most patients. Using high sensitivity methods, the T790M is detected in up to 68% of these patients. Clin Cancer Res; 17(5); 1169–80. ©2011 AACR.
Overexpression of miR-200c Induces Chemoresistance in Esophageal Cancers Mediated Through Activation of the Akt Signaling Pathway
Authors: Hamano Rie , Miyata Hiroshi , Yamasaki Makoto , Kurokawa Yukinori , Hara Johji , Moon Jeong ho , Nakajima Kiyokazu , Takiguchi Shuji , Fujiwara Yoshiyuki , Mori Masaki , Doki Yuichiro
Published: January 2011

Purpose: To determine the relationship between resistance to chemotherapy and microRNA (miRNA) expression in esophageal cancer, we focused on miRNAs known to be associated with maintenance of stem cell function.

Experimental Design: Using 98 formalin-fixed, paraffin-embedded samples obtained from patients with esophageal cancer who had received preoperative chemotherapy followed by surgery, we measured expression levels of several miRNAs that are considered to be involved in the regulation of stem cell function (e.g., let-7a, let-7g, miR-21, miR-134, miR-145, miR-155, miR-200c, miR-203, and miR-296) by real-time reverse transcriptase PCR. Then, we examined the relationship between miRNA expression and prognosis or response to chemotherapy. To investigate the mechanism of miRNA-induced chemoresistance, in vitro assays were carried out using esophageal cancer cells.

Results: Analyses of the 9 miRNAs expression showed that overexpression of miR-200c (P = 0.037), underexpression of miR-145 (P = 0.023), and overexpression of miR-21 (P = 0.048) correlated significantly with shortened overall duration of survival. In particular, miR-200c expression correlated significantly with response to chemotherapy (P = 0.009 for clinical response; P = 0.007 for pathologic response). In vitro assay showed significantly increased miR-200c expression in cisplatin-resistant cells compared with their parent cells (∼1.7-fold). In anti-miR-200c–transfected cells, chemosensitivity to cisplatin and apoptosis after exposure to cisplatin was found to increase as compared with the negative control. Western blotting showed that knockdown of miR-200c expression was associated with increased expression of PPP2R1B, a subunit of protein phosphatase 2A, which resulted in reduced expression of phospho-Akt.

Conclusions: Results of this study emphasized the involvement of miR-200c in resistance to chemotherapy among esophageal cancers and that this effect was mediated through the Akt pathway. Clin Cancer Res; 17(9); 3029–38. ©2011 AACR.
Modulators of Arginine Metabolism Do Not Impact on Peripheral T-Cell Tolerance and Disease Progression in a Model of Spontaneous Prostate Cancer
Authors: Rigamonti Nicolò , Capuano Giusy , Ricupito Alessia , Jachetti Elena , Grioni Matteo , Generoso Luca , Freschi Massimo , Bellone Matteo
Published: January 2011

Purpose: Chronic inflammation, recruitment of myeloid-derived cells, and perturbation of the arginine metabolism have been all proposed as mechanisms favoring prostate carcinogenesis and tumor immunoescape. Objective of this study was to evaluate whether accumulation of CD11b+Gr1+ cells, also defined myeloid-derived suppressor cells, occur in mice affected by transplantable or spontaneous prostate cancer (PC). We also investigated whether N(G) nitro-l-arginine methyl ester (l-NAME) and sildenafil, both modulators of the arginine metabolism, restrain tumor growth and restore tumor-specific immunity.

Experimental Design: Wild-type C57BL/6 mice bearing TRAMP-C1 PC and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were treated with vehicle, l-NAME or sildenafil, and evaluated for CD11b+ cells accumulation in the blood, several organs, and the tumor mass and for disease progression.

Results: CD11b+Gr1high, CD11b+Gr1int, and CD11b+Gr1− cells differently accumulated in different organs and especially in the tumor of the two mouse models. l-NAME and sildenafil impaired the immunosuppressive function of CD11b+ cells in both models and restrained TRAMP-C1 growth, but they neither break tumor-specific immune tolerance nor limit tumor progression in TRAMP mice.

Conclusions: Collectively, our results emphasize substantial differences in tumor-induced alteration of myelopoiesis and sensitivity to modulators of the arginine metabolism between a transplantable and a spontaneous model of PC. They also suggest that perturbation of the arginine metabolism is dispensable for PC progression and the associated T-cell tolerance. Clin Cancer Res; 17(5); 1012–23. ©2011 AACR.
Anticholinergic Drugs and Their Effects on Delirium and Mortality in the Elderly
Authors: Luukkanen M.J. , Uusvaara J. , Laurila J.V. , Strandberg T.E. , Raivio M.M. , Tilvis R.S. , Pitkälä K.H.
Published: January 2011

Aim: To investigate the use of drugs with anticholinergic properties (DAPs) and their associations with delirium and mortality among elderly patients with comorbidities. Methods: 425 patients (≧70 years of age) in geriatric wards and nursing homes were assessed. The use of DAPs was retrieved from their medical records. Delirium was diagnosed according to the DSM-IV criteria. Results: Of the 341 patients (80.2%) treated with multiple DAPs (≧2), 92 patients (27.0%) suffered from delirium, whereas 14 of 84 patients (16.7%) without DAP treatment had delirium (p = 0.050). In a logistic regression analysis with age, gender, and Charlson Comorbidity Index as covariates, DAP treatment did not predict delirium (odds ratio 1.67, 95% confidence interval 0.87–3.21). The 2-year mortality was 49.3% (n = 168) in DAP users and 35.7% (n = 30) in non-users, respectively (p = 0.026). In the Cox proportional hazard model adjusted for age, gender, and comorbidity, DAPs did not predict mortality (hazard ratio 1.12, 95% confidence interval 0.75–1.68). Conclusion: The use of DAPs is very frequent among frail inpatients with comorbidities, but their use has no independent prognostic significance.
Multicentric Reticulohistiocytosis with Dermatomyositis-Like Features: A More Common Disease Presentation than Previously Thought
Authors: Fett Nicole , Liu Rosemarie H.
Published: January 2011

Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans histiocytosis that presents with erosive arthritis and skin nodules. Approximately 25% of patients with MRH have an associated malignancy. Dermatomyositis is an inflammatory autoimmune condition that has also been associated with malignancy. To date, 7 cases of MRH have been reported to present with cutaneous features of dermatomyositis. We describe an eighth patient with MRH who presented with dermatomyositis-like features (V-neck erythema, shawl sign, Gottron’s papules and periungual erythema), who developed metastatic breast cancer 1 year after diagnosis. We hypothesized that clinical overlap between MRH and dermatomyositis was not as uncommon as review of the literature suggested. Careful review of the physical exam findings and photographs of the 234 papers reporting MRH revealed 27 cases of MRH with dermatomyositis-like features. Of these 27 cases, 7 (26%) were associated with a malignancy. Skin biopsies of the cutaneous features mimicking dermatomyositis revealed pathologic features of MRH. This is a descriptive analysis of published case reports. Based on a review of published case reports, MRH presenting with dermatomyositis-like features is likely fairly common. Histological examination of skin biopsies allows for disease differentiation. Differentiating MRH from dermatomyositis is important for management decisions and comorbidity screening.
Jean-Martin Charcot at the Birth of Russian Neurology
Authors: Vein Alla A.
Published: January 2011

Russian neurology was virtually nonexistent in the middle of the 19th century which made a traineeship abroad an absolute necessity. Charcot and his school did not just offer professional training, but created the best minds, which would determine the direction of neurology and psychiatry in Russia for many decades. After returning home, young Russian doctors not only implemented everything they had learned in Western Europe, but proceeded to make their own original contributions. The most talented pupils of Charcot, including such prominent names as Kozhevnikov, Korsakov, Minor, Bekhterev and Darkshevich, became the founders of neurological schools in Russia. They laid the basis for the further development of neurology and psychiatry. Remarkably, though trained by the same teachers, each of these future ‘founding fathers’ of these neurological and psychiatric schools followed his own individual path which resulted in an undeniable diversity in Russian neurology and psychiatry during the period of their formation.
Assessment of Catheter Tip Contact Force Resulting in Cardiac Perforation in Swine Atria Using Force Sensing Technology
Authors: Perna Francesco , Heist E. Kevin , Danik Stephan B. , Barrett Conor D. , Ruskin Jeremy N. , Mansour Moussa
Published: January 2011

Background—

Force sensing is a recently developed technology that allows the determination of the contact force (CF) at the tip of the catheter during electrophysiology procedures. Previous studies suggested that the optimal CF for adequate catheter contact ranges between 10 and 40 g. The aim of this study was to determine the CF needed to cause perforation in the swine atria.

Methods and Results—

Pericardial access was obtained at the beginning of the study in a swine model to drain pericardial effusions. Electroanatomic maps of the right atrium (RA) and left atrium (LA) were constructed. Ablation was performed using an irrigated-tip radiofrequency catheter equipped with force-sensing technology (30 W, 30 mL/min, for 30 seconds). Perforations of the LA and RA wall were intentionally performed in different locations with and without radiofrequency ablation. CF values preceding each perforation were recorded. A total of 111 cardiac perforations were achieved in 7 pigs. The overall average CF resulting in perforation was 175.8±60.4 g (range, 77 to 376 g). This was significantly lower after 30 seconds of radiofrequency delivery: 151.8±49.9 g versus 197±61.3 g (
P
=0.00005). The average value of CF resulting in perforation was not statistically different between the RA and the LA (169.6±61.6 g versus 181.7±59.3 g) (
P
=0.29).

Conclusions—

Perforation of the atrial wall in a swine model can occur over a wide range of CF values. Perforation can occur with a CF as low as 77 g. Ablation reduces the perforating force by 23%.
Oxidation-Specific Epitopes Are Danger-Associated Molecular Patterns Recognized by Pattern Recognition Receptors of Innate Immunity
Authors: Miller Yury I. , Choi Soo-Ho , Wiesner Philipp , Fang Longhou , Harkewicz Richard , Hartvigsen Karsten , Boullier Agnès , Gonen Ayelet , Diehl Cody J. , Que Xuchu , Montano Erica , Shaw Peter X. , Tsimikas Sotirios , Binder Christoph J. , Witztum Joseph L.
Published: January 2011

Oxidation reactions are vital parts of metabolism and signal transduction. However, they also produce reactive oxygen species, which damage lipids, proteins and DNA, generating “oxidation-specific” epitopes. In this review, we discuss the hypothesis that such common oxidation-specific epitopes are a major target of innate immunity, recognized by a variety of “pattern recognition receptors” (PRRs). By analogy with microbial “pathogen-associated molecular patterns” (PAMPs), we postulate that host-derived, oxidation-specific epitopes can be considered to represent “danger (or damage)-associated molecular patterns” (DAMPs). We also argue that oxidation-specific epitopes present on apoptotic cells and their cellular debris provided the primary evolutionary pressure for the selection of such PRRs. Furthermore, because many PAMPs on microbes share molecular identity and/or mimicry with oxidation-specific epitopes, such PAMPs provide a strong secondary selecting pressure for the same set of oxidation-specific PRRs as well. Because lipid peroxidation is ubiquitous and a major component of the inflammatory state associated with atherosclerosis, the understanding that oxidation-specific epitopes are DAMPs, and thus the target of multiple arcs of innate immunity, provides novel insights into the pathogenesis of atherosclerosis. As examples, we show that both cellular and soluble PRRs, such as CD36, toll-like receptor-4, natural antibodies, and C-reactive protein recognize common oxidation-specific DAMPs, such as oxidized phospholipids and oxidized cholesteryl esters, and mediate a variety of immune responses, from expression of proinflammatory genes to excessive intracellular lipoprotein accumulation to atheroprotective humoral immunity. These insights may lead to improved understanding of inflammation and atherogenesis and suggest new approaches to diagnosis and therapy.