bluuebunny/crossref_metadata_2025 huggingface dataset:
A SYMPLECTIC HAMILTONIAN APPROACH FOR THERMAL BUCKLING OF CYLINDRICAL SHELLS
Authors: XU XINSHENG , CHU HONGJIE , LIM C. W.
Published: May 2010

The paper deals with the thermal buckling of cylindrical shells in a uniform temperature field based on the Hamiltonian principle in a symplectic space. In the system, the buckling problem is reduced to an eigenvalue problem which corresponds to the critical temperatures and buckling modes. Unlike the classical approach where a predetermined trial shape function satisfying the geometric boundary conditions is required at the outset, the symplectic eigenvalue approach is completely rational where solutions satisfying both geometric and natural boundary conditions are solved with complete reasoning. The results reveal distinct axisymmetric buckling and nonaxisymmetric buckling modes under thermal loads. Besides, the influence for different boundary conditions is discussed.
DIRECT VERSUS ITERATIVE MODEL UPDATING METHODS FOR MASS AND STIFFNESS MATRICES
Authors: YANG Y. B. , CHEN Y. J.
Published: May 2010

A comparative study is performed for the direct and iterative methods for updating the structural matrices based on measured data. The former was derived from the orthogonality constraints by replacing the modal vector of concern by the modal matrix in computing the correction matrices.1The iterative method used is the improved inverse eigensenstivity method.2Through the numerical studies, it was demonstrated that both methods yield good results. However, the direct updating method is found to be more suitable for engineering applications due to its ease in treating multi-modes and higher efficiency, especially for complicated structures.
A MULTIAGENT COORDINATION APPROACH TO ROBUST CONSENSUS CLUSTERING
Authors: AGOGINO ADRIAN , TUMER KAGAN
Published: May 2010

In many distributed modeling, control or information processing applications, clustering patterns that share certain similarities is the critical first step. However, many traditional clustering algorithms require centralized processing, reliable data collection and the availability of all the raw data in one place at one time. None of these requirement can be met in many complex real world problems. In this paper, we present an agent-based method for combining multiple base clusterings into a single unified "consensus" clustering that is robust against many types of failures and does not require spatial/temporal synchronization. In this approach, agents process clusterings coming from separate sources and pool them to produce a unified consensus. The first contribution of this work is to provide an adaptive method by which the agents update their selections to maximize an objective function based on the quality of the consensus clustering. The second contribution of this work is in providing intermediate agent-specific objective functions that significantly improve the quality of the consensus clustering process. Our results show that this agent-based method achieves comparable or better performance than traditional non-agent consensus clustering methods in fault-free conditions, and remains effective under a wide range of failure scenarios that paralyze the traditional methods.
GENERATING STRUCTURE SPECIFIC NETWORKS
Authors: HȦKANSSON N. , JONSSON A. , LENNARTSSON J. , LINDSTRÖM T. , WENNERGREN U.
Published: May 2010

Theoretical exploration of network structure significance requires a range of different networks for comparison. Here, we present a new method to construct networks in a spatial setting that uses spectral methods in combination with a probability distribution function. Nearly all previous algorithms for network construction have assumed randomized distribution of links or a distribution dependent on the degree of the nodes. We relax those assumptions. Our algorithm is capable of creating spectral networks along a gradient from random to highly clustered or diverse networks. Number of nodes and link density are specified from start and the structure is tuned by three parameters (γ, σ, κ). The structure is measured by fragmentation, degree assortativity, clustering and group betweenness of the networks. The parameter γ regulates the aggregation in the spatial node pattern and σ and κ regulates the probability of link forming.
COMPLEXITY, TIME AND MUSIC
Authors: BOON JEAN PIERRE
Published: May 2010

The concept of complexity as considered in terms of its algorithmic definition proposed by G. J. Chaitin and A. N. Kolmogorov is revisited for the dynamical complexity of music. When music pieces are cast in the form of time series of pitch variations, concepts of dynamical systems theory can be used to define new quantities such as the dimensionality as a measure of the global temporal dynamics of a music piece, and the Shanon entropy as an evaluation of its local dynamics. When these quantities are computed explicitly for sequences sampled in the music literature from the 18th to the 20th century, no indication is found of a systematic increase in complexity paralleling historically the evolution of classical western music, but the analysis suggests that the fractional nature of art might have an intrinsic value of more general significance.
TOWARDS THE QUANTIFICATION OF THE SEMANTIC INFORMATION ENCODED IN WRITTEN LANGUAGE
Authors: MONTEMURRO MARCELO A. , ZANETTE DAMIÁN H.
Published: May 2010

Written language is a complex communication signal capable of conveying information encoded in the form of ordered sequences of words. Beyond the local order ruled by grammar, semantic and thematic structures affect long-range patterns in word usage. Here, we show that a direct application of information theory quantifies the relationship between the statistical distribution of words and the semantic content of the text. We show that there is a characteristic scale, roughly around a few thousand words, which establishes the typical size of the most informative segments in written language. Moreover, we find that the words whose contributions to the overall information is larger, are the ones more closely associated with the main subjects and topics of the text. This scenario can be explained by a model of word usage that assumes that words are distributed along the text in domains of a characteristic size where their frequency is higher than elsewhere. Our conclusions are based on the analysis of a large database of written language, diverse in subjects and styles, and thus are likely to be applicable to general language sequences encoding complex information.
SOURCES OF SUCCESS IN ADVANCED MATERIALS INNOVATION: THE ROLE OF "CORE RESEARCHERS" IN UNIVERSITY–INDUSTRY COLLABORATION IN JAPAN
Authors: BABA YASUNORI , YARIME MASARU , SHICHIJO NAOHIRO
Published: May 2010

This article aimed to identify the effect of university-industry collaborations on the innovative performance of firms operating in the advanced materials field, and it proposed an original classification of the research organization partners. The main contribution resides in the estimation of the role played by collaborations with differently experienced corporate researchers. In the advanced materials industry the most effective collaborations are driven by "core researchers," who have been involved in authoring scientific papers, in addition to applying sizeable patents. The results of the case study focusing on partner firms collaborating with "Pasteur scientists" such as Fujishima and Hashimoto of the University of Tokyo confirm the idea that core researchers have the quality to work as boundary spanners between science and technology, and that their becoming heavy-weighted project leaders pushed the firms' R&D towards commercialization.
SMALL WORLD CHARACTERISTICS OF INNOVATIVE SMART CARD NETWORKS
Authors: M'CHIRGUI ZOUHAÏER
Published: May 2010

The paper examines the evolving innovative network structure in the smart card industry between 1992 and 2006. The aim is to search for sub-groups within the main network which allowed better understanding of the global innovative network structure and the speed of the smart card innovation system. Based on a proprietary database covering inter-firm agreements in the smart card industry, our empirical results reveal the existence of small-world structures, widely thought to enhance creativity and knowledge diffusion, and the emergence of giant components of innovative networks. Three notable features of this small world structure were the presence of broker incumbents, the decrease of average degree, and the increase of average distance of the networks.
A COGNITIVE-RELATIONAL VIEW OF INNOVATION IN THE AGRI-FOOD INDUSTRY: THE FRESH-CUT BUSINESS
Authors: RUSSO SPENA TIZIANA , COLURCIO MARIA
Published: May 2010

The aim of our study is to analyse competitive dynamics in an emerging sector of the wider agri-food industry, namely the fresh-cut business (fruit and vegetable products that are minimally processed and ready to eat). Our work is based on case study research. We propose an interpretive model that we term the cognitive-relational framework. Our framework explains the development dynamics of the emergent fresh -cut business and outlines structural links among resources, relationships, and innovation processes, which are basic and critical elements for the continued growth of the traditional agri-food industry.

Our proposed cognitive-relational approach allowed us to understand how the studied firms radically transformed the ways they manage their business and develop new products. Using this approach, we now understand why these firms have become market leaders in this innovative sector of the food industry.
An investigation on institutionalization of websites of firms
Authors: Lee Kyootai , Mirchandani Dinesh , Zhang Xinde
Published: May 2010

Websites as an IT artifact have been utilized by companies for over a decade. The structure of websites may show isomorphic patterns, explainable by the conformity of firms to institutional pressures. However, there is insufficient evidence in prior literature to confirm the existence of such patterns. Following institutional theory, we examined website structures of firms. We selected industry sectors and firm reputation levels as institutional forms. Based on a sample of 28 Fortune 500 firms, we conducted content analysis using a descriptive taxonomy provided by Piccoli et al. (2004). The results revealed 1) that websites of firms are isomorphic within an industry sector, but polymorphic across industry sectors, and 2) websites of firms do not differ across reputation levels. These results are discussed in depth, and managerial implications are suggested.
Effect of purinergic receptor activation on Na+-K+pump activity, excitability, and function in depolarized skeletal muscle
Authors: Broch-Lips Martin , Pedersen Thomas Holm , Nielsen Ole Bækgaard
Published: May 2010

Activity-induced elevation of extracellular purines and pyrimidines has been associated with autocrine and paracrine signaling in many tissues. Here we investigate the effect of purinergic signaling for the excitability and contractility of depolarized skeletal muscle. Muscle excitability was experimentally depressed by elevating the extracellular K+from 4 to 10 mM, which reduced the tetanic force to 24 ± 2% of the force at 4 mM K+. Upon addition of 1 mM ATP, however, the force recovered to 65 ± 8% of the control force ( P < 0.001, n = 5). A similar recovery was seen with ADP, but not with UTP or adenosine. The ATP-induced force recovery could be inhibited by P2Y1receptor antagonists (3 μM SCH-202676 or 1 μM MRS-2500). A fourfold increase in M-wave area demonstrated that the ATP-induced force recovery was associated with restoration of muscle excitability ( P < 0.05, n = 4). Experiments using86Rb+as a tracer for K+showed that ATP also induced a twofold increase in the activity of muscle Na+-K+pumps. The force recovery and the stimulation of the Na+-K+pump activity by ATP were inhibited by 50 μM of the phospholipase C inhibitor U-73122. It is concluded that purinergic signaling can increase the Na+-K+pump activity and improve force and excitability of depolarized skeletal muscles. This novel purinergic regulation may be important for the maintenance of muscle excitability during intense exercise, where the extracellular K+can increase substantially.
Glial cell line-derived neurotrophic factor enhances neurogenin3 gene expression and β-cell proliferation in the developing mouse pancreas
Authors: Mwangi Simon M. , Usta Yousef , Raja Shreya M. , Anitha Mallappa , Chandrasekharan Bindu , Parsadanian Alexander , Sitaraman Shanthi V. , Srinivasan Shanthi
Published: May 2010

Glial cell line-derived neurotrophic factor (GDNF) is a factor produced by glial cells that is required for the development of the enteric nervous system. In transgenic mice that overexpress GDNF in the pancreas, GDNF has been shown to enhance β-cell mass and improve glucose control, but the transcriptional and cellular processes involved are not known. In this study we examined the influence of GDNF on the expression of neurogenin3 (Ngn3) and other transcription factors implicated in early β-cell development, as well as on β-cell proliferation during embryonic and early postnatal mouse pancreas development. Embryonic day 15.5 (E15.5) mouse pancreatic tissue when exposed to GDNF for 24 h showed higher Ngn3, pancreatic and duodenal homeobox gene 1 (Pdx1), neuroD1/β2, paired homeobox gene 4 (Pax4), and insulin mRNA expression than tissue exposed to vehicle only. Transgenic expression of GDNF in mouse pancreata was associated with increased numbers of Ngn3-expressing pancreatic cells and higher β-cell mass at embryonic day 18 (E18), as well as higher β-cell proliferation and Pdx1 expression in β-cells at E18 and postnatal day 1. In the HIT-T15 β-cell line, GDNF enhanced the expression of Pax6. This response was, however, blocked in the presence of Pdx1 small interfering RNA (siRNA). Chromatin immunoprecipitation studies using the HIT-T15 β-cell line demonstrated that GDNF can influence Pdx1 gene expression by enhancing the binding of Sox9 and neuroD1/β2to the Pdx1 promoter. Our data provide evidence of a mechanism by which GDNF influences β-cell development. GDNF could be a potential therapeutic target for the treatment and prevention of diabetes.
Norepinephrine modulates the zonally different hepatocyte proliferation through the regulation of transglutaminase activity
Authors: Ohtake Yosuke , Kobayashi Tomonori , Maruko Akiko , Oh-ishi Nao , Yamamoto Fumihiko , Katoh Shinsuke , Ohkubo Yasuhito
Published: May 2010

A neurotransmitter, norepinephrine (NE), amplifies the mitogenic effect of epidermal growth factor (EGF) in the liver by acting on the α1-adrenergic receptor coupled with G protein, Gαh. However, the molecular mechanism is not well understood. Gαhis known as a transglutaminase 2 (TG2), a cross-linking enzyme implicated in hepatocyte proliferation. We investigated the effect of NE on EGF-induced cell proliferation and TG2 activity using hepatocytes isolated in periportal and perivenous regions of the liver, which differ in proliferative capacity. Periportal hepatocytes (PPH) and perivenous hepatocytes (PVH) were isolated by the digitonin-collagenase perfusion technique. EGF or NE receptor binding was analyzed by Scatchard analysis. Changes in NE-induced DNA synthesis, EGF receptor (EGFR) dimerization and phosphorylation, and TG2 activity were measured. NE enhanced EGF-induced DNA synthesis, EGF-induced EGFR dimerization, and its phosphorylation in PVH but not in PPH. [3H]NE binding studies indicated that PVH was found to have a greater affinity and number of receptors than PPH. Furthermore, NE treatment decreased TG2 activity and increased phospholipase C activity in PVH although TG2 level showed no change. These results suggest that NE-induced amplification of EGF-induced DNA synthesis especially in PVH is caused by upregulation of EGFR activation through the switching of function from TG2 to Gαh.
Hemopoietic and angiogenetic progenitors in healthy athletes: different responses to endurance and maximal exercise
Authors: Bonsignore Maria R. , Morici Giuseppe , Riccioni Roberta , Huertas Alice , Petrucci Eleonora , Veca Mario , Mariani Gualtiero , Bonanno Anna , Chimenti Laura , Gioia Maria , Palange Paolo , Testa Ugo
Published: May 2010

The effects of endurance or maximal exercise on mobilization of bone marrow-derived hemopoietic and angiogenetic progenitors in healthy subjects are poorly defined. In 10 healthy amateur runners, we collected venous blood before, at the end of, and the day after a marathon race ( n = 9), and before and at the end of a 1.5-km field test ( n = 8), and measured hemopoietic and angiogenetic progenitors by flow cytometry and culture assays, as well as plasma or serum concentrations of several cytokines/growth factors. After the marathon, CD34+ cells were unchanged, whereas clonogenetic assays showed decreased number of colonies for both erythropoietic (BFU-E) and granulocyte-monocyte (CFU-GM) series, returning to baseline the morning post-race. Conversely, CD34+ cells, BFU-E, and CFU-GM increased after the field test. Angiogenetic progenitors, assessed as CD34+KDR+ and CD133+VE-cadherin+ cells or as adherent cells in culture expressing endothelial markers, increased after both endurance and maximal exercise but showed a different pattern between protocols. Interleukin-6 increased more after the marathon than after the field test, whereas hepatocyte growth factor and stem cell factor increased similarly in both protocols. Plasma levels of angiopoietin (Ang) 1 and 2 increased after both types of exercise, whereas the Ang-1-to-Ang-2 ratio or vascular endothelial growth factor-A were little affected. These data suggest that circulating hemopoietic progenitors may be utilized in peripheral tissues during prolonged endurance exercise. Endothelial progenitor mobilization after exercise in healthy trained subjects appears modulated by the type of exercise. Exercise-induced increase in growth factors suggests a physiological trophic effect of exercise on the bone marrow.
Visual Error Signals From the Pretectal Nucleus of the Optic Tract Guide Motor Learning for Smooth Pursuit
Authors: Ono Seiji , Mustari Michael J.
Published: May 2010

Smooth pursuit (SP) eye movements are used to maintain the image of a moving object on or near the fovea. Visual motion signals aid in driving SP and are necessary for its adaptation. The sources of visual error signals that support SP adaptation are incompletely understood but could involve neurons in cortical and brain stem areas with direction selective visual motion responses. Here we focus on the pretectal nucleus of the optic tract (NOT), which encodes retinal error information during SP. The aim of this study was to characterize the role of the NOT in SP adaptation. SP adaptation is typically produced using a double step of velocity ramp (double-step paradigm), where target speed either increases or decreases 100 ms after the beginning of a trial. In our study, we delivered a brief (200 ms) train of microelectrical stimulation (ES) in the left NOT to introduce directional error signals at the point in time where a second target speed would appear in a double-step paradigm. The target was extinguished coincidentally with the onset of the ES train. Initial eye acceleration (1st 100 ms) showed significant increases after 100 trials, which included left NOT stimulation during ongoing pursuit in an ipsiversive (leftward) direction. In contrast, initial eye acceleration showed significant decreases after repeated left NOT stimulation during contraversive (rightward) SP. Control studies performed using the same periodicity of NOT stimulation as in the preceding text but without accompanying SP did not induce changes in eye acceleration. In contrast, ES of the NOT paired with active SP produced gradual changes in eye acceleration similar to that observed in double-step paradigm. Therefore our findings support the suggestion that the NOT is an important source of visual error information for guiding motor learning during horizontal SP.
The Relationship between Birthweight and Longitudinal Changes of Blood Pressure Is Modulated by Beta-Adrenergic Receptor Genes: The Bogalusa Heart Study
Authors: Chen Wei , Srinivasan Sathanur R. , Hallman D. Michael , Berenson Gerald S.
Published: May 2010

This study examines the genetic influence ofβ-adrenergic receptor gene polymorphisms (β2-AR Arg16Gly andβ3-AR Trp64Arg) on the relationship of birthweight to longitudinal changes of blood pressure (BP) from childhood to adulthood in 224 black and 515 white adults, aged 21–47 years, enrolled in the Bogalusa Heart Study. Blacks showed significantly lower birthweight and frequencies ofβ2-AR Gly16 andβ3-AR Trp64 alleles and higher BP levels and age-related trends than whites. In multivariable regression analyses using race-adjusted BP and birthweight, low birthweight was associated with greater increase in age-related trend of systolic BP (standardized regression coefficientβ=−0.09,P=.002) and diastolic BP (β=−0.07,P=.037) in the combined sample of blacks and whites, adjusting for the first BP measurement in childhood, sex, age, and gestational age. Adjustment for the current body mass index strengthened the birthweight-BP association. Importantly, the strength of the association, measured as regression coefficients, was modulated by the combination ofβ2-AR andβ3-AR genotypes for systolic (P=.042for interaction) and diastolic BP age-related trend (P=.039for interaction), with blacks and whites showing a similar trend in the interaction. These findings indicate that the intrauterine programming of BP regulation later in life depends onβ-AR genotypes.
Three-Component Forward Modeling for Transient Electromagnetic Method
Authors: Xiong Bin
Published: May 2010

In general, the time derivative of vertical magnetic field is considered only in the data interpretation of transient electromagnetic (TEM) method. However, to survey in the complex geology structures, this conventional technique has begun gradually to be unsatisfied with the demand of field exploration. To improve the integrated interpretation precision of TEM, it is necessary to study the three-component forward modeling and inversion. In this paper, a three-component forward algorithm for 2.5D TEM based on the independent electric and magnetic field has been developed. The main advantage of the new scheme is that it can reduce the size of the global system matrix to the utmost extent, that is to say, the present is only one fourth of the conventional algorithm. In order to illustrate the feasibility and usefulness of the present algorithm, several typical geoelectric models of the TEM responses produced by loop sources at air-earth interface are presented. The results of the numerical experiments show that the computation speed of the present scheme is increased obviously and three-component interpretation can get the most out of the collected data, from which we can easily analyze or interpret the space characteristic of the abnormity object more comprehensively.
Enteral Feeding of Neonates with Congenital Heart Disease
Authors: Natarajan Girija , Reddy Anne Sreedhar , Aggarwal Sanjeev
Published: May 2010

Background: Despite their putative impact on post-operative outcomes, there is paucity of data on enteral feeding practices of neonates with congenital heart disease (CHD). Objectives: To examine feeding patterns among neonates with CHD before and after surgical repair and determine the incidence of and to identify risk factors associated with feeding-related morbidities. Methods: Retrospective data review of neonates with CHD who underwent surgical repair within the first month of life. SPSS software (version 17) was used for analyses and p < 0.05 taken as significant. Results: The median (range) gestational age of our cohort (n = 67) was 39 weeks (32–41) and birth weight 3,100 g (1,615–4,280). Ductal-dependent lesions were diagnosed in 52 infants (77.6%). Prior to surgery, feedings were initiated in 62 infants (92.5%) at a median age of 2.5 days (1–18); 100 ml/kg daily intake was achieved in 47 infants (70.1%) at 5 days (1–20) and full feeds in 22 infants (32.8%). Postoperative enteral feeds were started 3 days (1–20) after surgery in 66 infants (98.5%) and intake of 100 ml/kg/day was reached in 64 infants at 5 postoperative days (1–29). Four infants (5.9%) died; 27 (40.3%) were on at least partial gavage feedings at the time of discharge home. NEC was diagnosed in 2 infants. On regression analysis, cardiopulmonary bypass (p = 0.024) and age at which full feeds were attained prior to surgery (p = 0.039) were significantly associated with death and/or gavage at discharge. Conclusions: The majority of infants with CHD achieve moderate enteral intake prior to surgery, even while on prostaglandins. Despite this and the early initiation of postoperative enteral feeds, many infants need gavage feeds at discharge. Evidence-based feeding strategies for this high-risk population are critical to improving outcomes.
Changes in Survival and Neonatal Morbidity in Infants with a Birth Weight of 750 g or Less
Authors: Claas M.J. , Bruinse H.W. , van der Heide-Jalving M. , Termote J.U.M. , de Vries L.S.
Published: May 2010

Background: Improvement in perinatal and neonatal care has resulted in increased survival of extremely low birth weight (ELBW) infants. Objectives: To describe survival and neonatal morbidity in a cohort of ELBW infants, to compare two consecutive 5-year periods, and compare appropriate (AGA) with small for gestational age (SGA) infants (AGA ≧p10, and SGA <p10). Methods: Retrospective cohort study of 179 live-born infants with a birth weight (BW) of ≤750 g and gestation of ≧24 weeks, born in 1996–2000 (cohort I, n = 94) and 2001–2005 (cohort II, n = 85) in theWilhelmina Children’s Hospital Utrecht, the Netherlands. Results: During NICU stay (n = 146) 62.3% experienced infant respiratory distress syndrome (IRDS), 46.6% bronchopulmonary dysplasia, 50.7% septicemia, 34.2% periventricular leukomalacia grade I and 24.7% intraventricular hemorrhage grade I/II. IRDS grade III/IV occurred significantly more often in cohort I (p = 0.042), whereas septicemia and hyperbilirubinemia occurred more in cohort II (p = 0.045 and p = 0.001). In AGA infants mean gestation was significantly shorter (p < 0.001), and IRDS grade III/IV (p = 0.015), mechanical ventilation (p = 0.045) and patent ductus arteriosus (p = 0.003) were significantly more prevalent. Overall survival was 62%, and survival in the NICU increased from 65.8% (cohort I) to 88.1% (cohort II, p = 0.002). Survival of AGA and SGA infants did not differ, but increased with time (71.4 to 75.9% and 61.4 to 97.4%, respectively). Conclusions: Mortality of infants with a BW of ≤750 g is high, but decreased over time, especially in SGA infants. Considerable neonatal morbidity was present, especially in AGA infants, most likely due to their significantly shorter gestation.
Taxol, a Microtubule Stabilizer, Improves Cardiac Contractile Function during Ischemia in vitro
Authors: Xiao Junjie , Zhao Hong , Liang Dandan , Liu Ying , Zhang Hong , Liu Yi , Li Jun , Peng Luying , Zhou Zhaonian , Chen Yi-Han
Published: May 2010

Ischemic heart disease is one of the leading causes of heart failure, and microtubule disruption has been implicated in the response to ischemia in cardiac myocytes. The present study was designed to explore the effects of taxol, a microtubule stabilizer, on cardiac contractile function during ischemia. Heart rate, left ventricular developed pressure, left ventricular end-diastolic pressure, maximal time derivatives of pressure and work index were analyzed in isolated rat or rabbit hearts during ischemia. In addition, intracellular calcium concentrations ([Ca2+]i) and Ca2+ transients were examined by Fura-2-AM and Fluo-3-AM, respectively. Reactive oxygen species (ROS) and oxidative enzyme activities were measured with fluorometric or spectrophotometric techniques. It was found that taxol could improve the cardiac contractile function during ischemia. This effect was identified based on a blunting of the decrease in heart rate, left ventricular developed pressure, maximal time derivatives of pressure and work index during ischemia, which might be related to the preservation of calcium homeostasis and ROS levels. The preservation of calcium homeostasis included a decrease in the rise of [Ca2+]i and maintenance of the amplitude and decay time of Ca2+ transients. The reduction in ROS levels was associated with increased activity of mitochondrial electron transport chain complex I and complex III. In conclusion, taxol could effectively improve the cardiac contractile function during ischemia by preserving calcium homeostasis and ROS levels. This study presents evidence that taxol could represent a novel approach to drug development for heart failure.
Bone Conduction Thresholds and Skull Vibration Measured on the Teeth during Stimulation at Different Sites on the Human Head
Authors: Ito T. , Röösli C. , Kim C.J. , Sim J.H. , Huber A.M. , Probst R.
Published: May 2010

Vibratory auditory stimulation or bone conduction (BC) reaches the inner ear through both osseous and non-osseous structures of the head, but the contribution of the different pathways of BC is still unclear. In this study, BC thresholds in response to stimulation at several different locations including the eye were assessed, while the magnitudes of skull bone vibrations were measured on the front teeth in human subjects with either normal hearing on both sides or unilateral deafness with normal hearing on the other side. The BC thresholds with stimulation at the ipsilateral mastoid and ipsilateral temporal region were lower than the BC thresholds with stimulation at the other sites, as reported by previous works. The lower thresholds with stimulation at the ipsilateral mastoid and ipsilateral temporal region matched higher amplitudes of skull bone vibrations measured on the teeth, but only at frequencies below 1 kHz. With stimulation at the eye, the thresholds were significantly higher than those with stimulation at the bony sites in the frequency range of 0.25–4 kHz. While skull bone vibrations as measured on the teeth during stimulation at the eye were low for low frequencies, significant bone vibrations were measured at 3 and 4 kHz, indicating different pathways for BC for either the soft tissue or bony site stimulation. This finding contradicts a straightforward relationship between vibrations of the skull bones and BC hearing thresholds.
Sixty Years of Lithium Responders
Authors: Grof Paul
Published: May 2010

It has been 60 years since Cade first described patients who responded to antimanic lithium treatment. Two decades later, responders to lithium stabilization emerged in larger numbers. The responses of many severely ill bipolar patients to lithium were striking and called for an explanation. Remarkable reactions to a simple ion generated hope for an uncomplicated laboratory test of response and an extensive search for suitable biological markers ensued. But despite promising reports, particularly from molecular genetics, we are still waiting for a biological elucidation of the stabilizing effects of lithium. The most useful predictor of lithium stabilization has to date been the patient’s clinical profile, based on a comprehensive clinical assessment: complete remissions and other characteristics of episodic clinical course, bipolar family history, low psychiatric comorbidity and a characteristic presenting psychopathology. In brief, the responders approximate the classical Kraepelinian description of a manic-depressive patient. But the most intriguing findings have recently emerged from prospective observations of the next generation: the children of lithium responders, their counterparts coming from parents who did not respond to lithium and controls. Overall, they indicate that parents and offspring suffer from a comparable brain dysfunction that manifests clinically in distinct stages. If the child’s predicament starts early in childhood, it presents with varied, nonaffective or subclinical manifestations that are usually nonresponsive to standard treatments prescribed according to the symptoms. The next stage then unfolds in adolescence, first with depressive and later with activated episodes. The observations have a potential to markedly enrich the prevailing understanding and management of mood disorders.
The New Lithium Clinic
Authors: Osher Yamima , Bersudsky Yuly , Belmaker R.H.
Published: May 2010

Until the early 1950s, no effective pharmacological treatment existed for bipolar affective disorder. By the early 1960s, specialty clinics were being set up to dispense lithium carbonate to bipolar patients. By the late 1980s, a new body of knowledge was influencing the perception of bipolar disorder and how the disease should be treated. The authors’ lithium clinic from 1974 has grown and evolved from a lithium blood level monitoring model into a comprehensive care model with polypharmacy, psychoeducation, rehabilitation, cognitive therapy, social rhythm therapy, and employment counseling as well as a staff of 2 part-time psychiatrists and 1 clinical psychologist. This service delivery model may benefit both treatment and research in bipolar disorder. The evolution of psychopharmacological and psychosocial knowledge in treating bipolar illness has been integrated into our clinic. Case vignettes are presented to illustrate these points. The comparative cost of this model is discussed.
Lithium Reduces Pathological Aggression and Suicidality: A Mini-Review
Authors: Müller-Oerlinghausen Bruno , Lewitzka Ute
Published: May 2010

From a practical point of view, the well-proven antisuicidal and anti-aggressive effects of lithium are of utmost importance for a rational, safe and economical treatment of patients with affective disorders. Regular lithium long-term treatment reduces the otherwise 2- to 3-fold increased mortality of untreated patients with severe affective disorders down to the level of the general population. This is mainly due to the reduced suicide risk. Many international studies have confirmed this fascinating property of lithium which so far has not been demonstrated with comparable evidence for any other psychotropic compound. The antisuicidal effects of lithium might possibly be related to its anti-aggressive effects which have been shown in various species, populations and settings, such as animals, inhabitants of nursing homes for the elderly, mentally handicapped subjects, children and adolescents with hyperactive, hostile and aggressive behavior, and particularly in hyperaggressive inmates of correction units and prisons.
Novel Insights into Lithium’s Mechanism of Action: Neurotrophic and Neuroprotective Effects
Authors: Quiroz Jorge A. , Machado-Vieira Rodrigo , Zarate, Jr. Carlos A. , Manji Husseini K.
Published: May 2010

The monovalent cation lithium partially exerts its effects by activating neurotrophic and neuroprotective cellular cascades. Here, we discuss the effects of lithium on oxidative stress, programmed cell death (apoptosis), inflammation, glial dysfunction, neurotrophic factor functioning, excitotoxicity, and mitochondrial stability. In particular, we review evidence demonstrating the action of lithium on cyclic adenosine monophosphate (cAMP)-mediated signal transduction, cAMP response element binding activation, increased expression of brain-derived neurotrophic factor, the phosphatidylinositide cascade, protein kinase C inhibition, glycogen synthase kinase 3 inhibition, and B-cell lymphoma 2 expression. Notably, we also review data from clinical studies demonstrating neurotrophic effects of lithium. We expect that a better understanding of the clinically relevant pathophysiological targets of lithium will lead to improved treatments for those who suffer from mood as well as neurodegenerative disorders.
Pathogen-Mediated Inflammatory Atherosclerosis Is Mediated in Part via Toll-Like Receptor 2-Induced Inflammatory Responses
Authors: Hayashi Chie , Madrigal Andres G. , Liu Xinyan , Ukai Takashi , Goswami Sulip , Gudino Cynthia V. , Gibson, III Frank C. , Genco Caroline A.
Published: May 2010

Studies in humans have established that polymorphisms in genes encoding the innate immune Toll-like receptors (TLRs) are associated with inflammatory atherosclerosis. In hyperlipidemic mice, TLR2 and TLR4 have been reported to contribute to atherosclerosis progression. Human and mouse studies support a role for the oral pathogen Porphyromonas gingivalis in atherosclerosis, although the mechanisms by which this pathogen stimulates inflammatory atherosclerosis via innate immune system activation is not known. Using a genetically defined apolipoprotien E-deficient (ApoE–/–) mouse model we demonstrate that pathogen-mediated inflammatory atherosclerosis occurs via both TLR2-dependent and TLR2-independent mechanisms. P. gingivalis infection in mice possessing functional TLR2 induced the accumulation of macrophages as well as inflammatory mediators including CD40, IFN-γ and the pro-inflammatory cytokines IL-1β, IL-6 and tumor necrosis factor-α in atherosclerotic lesions. The expression of these inflammatory mediators was reduced in atherosclerotic lesions from P. gingivalis-infected TLR2-deficient (TLR2–/–) mice. These studies provide a mechanistic link between an innate immune receptor and pathogen-accelerated atherosclerosis by a clinically and biologically relevant bacterial pathogen.
Ablation of the Transcription Factor Nrf2 Promotes Ischemia-Induced Neovascularization by Enhancing the Inflammatory Response
Authors: Ichihara Sahoko , Yamada Yoshiji , Liu Fang , Murohara Toyoaki , Itoh Ken , Yamamoto Masayuki , Ichihara Gaku
Published: May 2010

Objective—

To investigate the potential role of nuclear factor–erythroid 2–related factor 2 (Nrf2) in neovascularization with a murine surgical model of ischemia.

Methods and Results—

The transcription factor Nrf2 protects against oxidative stress by increasing the transcription of genes, including those for several antioxidant enzymes that contain an antioxidant response element. Ischemia was induced by femoral artery ligation in Nrf2-deficient (Nrf2
−/−
) and wild-type mice. Ischemia-induced neovascularization was enhanced in Nrf2
−/−
mice compared with that in wild-type mice. The expression of Nrf2 target genes for heme oxygenase 1 and thioredoxin 1 and the concentration of total glutathione in the ischemic hindlimb were reduced for Nrf2
−/−
mice compared with wild-type mice. The infiltration of inflammatory cells and the abundance of adhesion molecule mRNA were greater in the ischemic hindlimb of Nrf2
−/−
mice than in wild-type mice. The expression of monocyte chemoattractant protein-1, tumor necrosis factor-α, cyclooxygenase 2, and angiogenic factors in the ischemic hindlimb was also greater for Nrf2
−/−
mice than for wild-type mice.

Conclusion—

The ablation of Nrf2 promoted ischemia-induced neovascularization. This effect likely resulted from impaired antioxidant defense and increased accumulation of reactive oxygen species in endothelial cells; consequently, there was an enhanced inflammatory response.
Vasoprotective and Atheroprotective Effects of Angiotensin (1-7) in Apolipoprotein E–Deficient Mice
Authors: Tesanovic Sonja , Vinh Antony , Gaspari Tracey A. , Casley David , Widdop Robert E.
Published: May 2010

Objective—To evaluate the effectiveness of long-term angiotensin (Ang) (1-7) treatment to inhibit the progression of atherosclerosis in apolipoprotein E-deficient (ApoE−/−) mice.

Methods and Results—Ang (1-7) is a heptapeptide fragment that has been proposed to counterregulate the Ang II proatherogenic effects. The effect of long-term 4-week Ang (1-7) treatment on both inhibition of atherosclerotic lesion development and improvement of endothelial function was examined in apolipoprotein E−/−mice that had been fed an atherogenic high-fat (21%) diet for 16 weeks. Chronic Ang (1-7) treatment significantly improved endothelial function, an effect reversed with either angiotensin type 2 (AT2) orMasreceptor blockade. In these vessels, Ang (1-7) treatment significantly decreased superoxide production and increased endothelial nitric oxide synthase immunoreactivity when compared with vehicle treatment. These effects were blocked by both AT2andMasreceptor antagonists. Lesion development, assessed as both fatty deposits (oil red O) and intima to media ratio, was also significantly decreased with Ang (1-7) treatment compared with respective controls. Cotreatment with either AT2orMasreceptor antagonists reversed Ang (1-7)–mediated reduction in lesion development.

Conclusion—Long-term Ang (1-7) treatment caused both vasoprotection, via improvement in endothelial function, and atheroprotection, with a reduction in lesion progression in a model of atherosclerosis. These effects appear to be mediated by the restoration of nitric oxide bioavailability and involve a complex interaction of bothMasand AT2receptors.
Cholesterol Efflux Potential and Antiinflammatory Properties of High-Density Lipoprotein After Treatment With Niacin or Anacetrapib
Authors: Yvan-Charvet Laurent , Kling Jelena , Pagler Tamara , Li Hongna , Hubbard Brian , Fisher Tim , Sparrow Carl P. , Taggart Andrew K. , Tall Alan R.
Published: May 2010

Objective—

To examine the effects of treatments with niacin or anacetrapib (an inhibitor of cholesteryl ester transfer protein) on the ability of high-density lipoprotein (HDL) to promote net cholesterol efflux and reduce toll-like receptor–mediated inflammation in macrophages.

Methods and Results—

A total of 18 patients received niacin, 2 g/d, for 4 weeks; 20 patients received anacetrapib, 300 mg/d, for 8 weeks; and 2 groups (n=4 and n=5 patients) received placebo. HDL samples were isolated by polyethylene glycol precipitation or ultracentrifugation, tested for the ability to promote cholesterol efflux in cholesterol-loaded THP-I or mouse peritoneal macrophages, or used to pretreat macrophages, followed by lipopolysaccharide exposure. HDL cholesterol levels were increased by 30% in response to niacin and by approximately 100% in response to anacetrapib. Niacin treatment increased HDL-mediated net cholesterol efflux from foam cells, primarily by increasing HDL concentration, whereas anacetrapib treatment increased cholesterol efflux by both increasing HDL concentration and causing increased efflux at matched HDL concentrations. The increased efflux potential of anacetrapib-HDL was more prominent at higher HDL cholesterol concentrations (>12 μg/mL), which was associated with an increased content of lecithin–cholesterol acyltransferase (LCAT) and apolipoprotein E and completely dependent on the expression of ATP binding cassette transporters (ABCA1 and ABCG1). Potent antiinflammatory effects of HDL were observed at low HDL concentrations (3 to 20 μg/mL) and were partly dependent on the expression of ABCA1 and ABCG1. All HDL preparations showed similar antiinflammatory effects, proportionate to the HDL cholesterol concentration.

Conclusion—

Niacin treatment caused a moderate increase in the ability of HDL to promote net cholesterol efflux, whereas inhibition of cholesteryl ester transfer protein via anacetrapib led to a more dramatic increase in association with enhanced particle functionality at higher HDL concentrations. All HDLs exhibited potent ability to suppress macrophage toll-like receptor 4–mediated inflammatory responses, in a process partly dependent on cholesterol efflux via ABCA1 and ABCG1.
Increased Cell and Matrix Accumulation During Atherogenesis in Mice With Vessel Wall–Specific Deletion of Discoidin Domain Receptor 1
Authors: Franco Christopher , Ahmad Pamela J. , Hou Guangpei , Wong Eric , Bendeck Michelle P.
Published: May 2010

Rationale
:

Discoidin domain receptor (DDR)1 is a collagen receptor expressed on both smooth muscle cells (SMCs) and macrophages, where it plays important roles regulating cell and matrix accumulation during atherogenesis. Systemic deletion of DDR1 resulted in attenuated plaque growth but accelerated matrix accumulation in LDLR-deficient mice. Deletion of DDR1 solely on bone marrow–derived cells resulted in decreased macrophage accumulation and plaque growth but no change in matrix accumulation.

Objective
:

These findings led us to hypothesize that accelerated matrix accumulation was attributable to the increased synthetic ability of
Ddr1
−/−
resident vascular wall SMCs.

Methods and Results
:

We used bone marrow transplantation to generate chimeric mice and investigate the role of SMC DDR1 during atherogenesis. Mice with deficiency of DDR1 in vessel wall–derived cells (
Ddr1
+/+→−/−
) or control mice (
Ddr1
+/+→+/+
) were fed an atherogenic diet for 12 weeks. We observed a 3.8-fold increase in the size of aortic sinus plaques in
Ddr1
+/+→−/−
compared to
Ddr1
+/+→+/+
mice. This was attributed to pronounced accumulation of collagen, elastin, proteoglycans, and fibronectin and resulted in a thickened fibrous cap. The enhanced matrix accumulation decreased the proportion of plaque area occupied by cells but was associated with a shift in the cellular composition of the lesions toward increased numbers of vessel wall–derived SMCs compared to bone marrow–derived macrophages. In vitro studies confirmed that
Ddr1
−/−
SMCs expressed more matrix, proliferated more, and migrated farther than
Ddr1
+/+
SMCs.

Conclusions
:

DDR1 expression on resident vessel wall SMCs limits proliferation, migration and matrix accumulation during atherogenesis.
Mechanistic Links Between Na
+
Channel (SCN5A) Mutations and Impaired Cardiac Pacemaking in Sick Sinus Syndrome
Authors: Butters Timothy D. , Aslanidi Oleg V. , Inada Shin , Boyett Mark R. , Hancox Jules C. , Lei Ming , Zhang Henggui
Published: May 2010

Rationale
:

Familial sick sinus syndrome (SSS) has been linked to loss-of-function mutations of the SCN5A gene, which result in decreased inward Na
+
current,
I
Na
. However, the functional role of
I
Na
in cardiac pacemaking is controversial, and mechanistic links between mutations and sinus node dysfunction in SSS are unclear.

Objective
:

To determine mechanisms by which the SCN5A mutations impair cardiac pacemaking.

Methods and Results
:

Action potential (AP) models for rabbit sinoatrial node (SAN) cells were modified to incorporate experimentally reported
I
Na
changes induced by 2 groups of SCN5A gene mutations (affecting the activation and inactivation of
I
Na
, respectively). The cell models were incorporated into an anatomically detailed 2D model of the intact SAN-atrium. Effects of the mutations and vagal nerve activity on cardiac pacemaking at the single-cell and tissue levels were studied. Multielectrode extracellular potential recordings of activation pattern from intact SAN-atrium preparations were performed to test predictions of the models. At the single-cell level, the mutations slowed down pacemaking rates in peripheral, but not in central SAN cells that control the heart rhythm. However, in tissue simulations, the mutations not only slowed down pacemaking, but also compromised AP conduction across the SAN-atrium, leading to a possible SAN exit block or sinus arrest, the major features of SSS. Simulated vagal nerve activity amplified the bradycardiac effects of the mutations. Two groups of SCN5A mutations showed subtle differences in impairing the ability of the SAN to drive the surrounding atrium, primarily attributable to their differential effects on atrial excitability and conduction safety. Experimental data with tetrodotoxin and carbachol confirmed the simulation outcomes.

Conclusions
:

Our study substantiates the causative link between SCN5A gene mutations and SSS and illustrates mechanisms by which the mutations impair the driving ability of the SAN.