bluuebunny/crossref_metadata_2025 huggingface dataset:
CRYPTANALYSIS OF FRIDRICH'S CHAOTIC IMAGE ENCRYPTION
Authors: SOLAK ERCAN , ÇOKAL CAHIT , YILDIZ OLCAY TANER , BIYIKOĞLU TÜRKER
Published: May 2010

We cryptanalyze Fridrich's chaotic image encryption algorithm. We show that the algebraic weaknesses of the algorithm make it vulnerable against chosen-ciphertext attacks. We propose an attack that reveals the secret permutation that is used to shuffle the pixels of a round input. We demonstrate the effectiveness of our attack with examples and simulation results. We also show that our proposed attack can be generalized to other well-known chaotic image encryption algorithms.
ANALYSIS OF STOCHASTIC CYCLES IN THE CHEN SYSTEM
Authors: BASHKIRTSEVA IRINA , CHEN GUANRONG , RYASHKO LEV
Published: May 2010

We study the stochastically forced Chen system in its parameter zone under the transition to chaos via period-doubling bifurcations. We suggest a stochastic sensitivity function technique for the analysis of stochastic cycles. We show that this approach allows to construct the dispersion ellipses of random trajectories for any Poincaré sections, and these ellipses reflect the essential features of a spatial arrangement of random trajectories near deterministic cycles. For the Chen system, we demonstrate a growth of stochastic sensitivity of the forced cycles under transition to chaos.
GRAVITY EFFECTS ON EARTHQUAKE RESPONSE OF A FLEXURE BUILDING: A SHEAR BUILDING COMPARISON
Authors: TINGATINGA ERIC AUGUSTUS , KAWAKAMI HIDEJI , MOGI HIDENORI
Published: May 2010

An analytical building model including the nonlinear effects caused by gravity is presented in this paper. Governing equations are derived for both single-degree-of-freedom (SDOF) and multi-degree-of-freedom (MDOF) models with large displacements taken into account, and solutions are obtained by direct integration and modal analysis. The response of typical structures subjected to harmonic ground excitation was expressed in exact and approximate forms, compared with the response of an equivalent shear building. Numerical examples show that while gravity generally decreases the natural frequency of elastic SDOF systems with small displacement approximations, actual natural frequency increases with ground motion. The difference in the natural frequency and response of MDOF systems to the equivalent shear building is not only due to gravity, but also caused by the geometry of the structure. Exact solution shows that the frequency varies with ground motion amplitude.
EDGE-WEIGHTING OF GENE EXPRESSION GRAPHS
Authors: KERR GRAINNE , PERRIN DIMITRI , RUSKIN HEATHER J. , CRANE MARTIN
Published: May 2010

In recent years, considerable research efforts have been directed to micro-array technologies and their role in providing simultaneous information on expression profiles for thousands of genes. These data, when subjected to clustering and classification procedures, can assist in identifying patterns and providing insight on biological processes. To understand the properties of complex gene expression datasets, graphical representations can be used. Intuitively, the data can be represented in terms of a bipartite graph, with weighted edges corresponding to gene-sample node couples in the dataset. Biologically meaningful subgraphs can be sought, but performance can be influenced both by the search algorithm, and, by the graph-weighting scheme and both merit rigorous investigation. In this paper, we focus on edge-weighting schemes for bipartite graphical representation of gene expression. Two novel methods are presented: the first is based on empirical evidence; the second on a geometric distribution. The schemes are compared for several real datasets, assessing efficiency of performance based on four essential properties: robustness to noise and missing values, discrimination, parameter influence on scheme efficiency and reusability. Recommendations and limitations are briefly discussed.
A METHOD FOR FINDING AGGREGATED REPRESENTATIONS OF LINEAR DYNAMICAL SYSTEMS
Authors: GÖRNERUP OLOF , JACOBI MARTIN NILSSON
Published: May 2010

A central problem in the study of complex systems is to identify hierarchical and intertwined dynamics. A hierarchical level is defined as an aggregation of the system's variables such that the aggregation induces its own closed dynamics. In this paper, we present an algorithm that finds aggregations of linear dynamical systems, e.g. including Markov chains and diffusion processes on weighted and directed networks. The algorithm utilizes that a valid aggregation with n states correspond to a set of n eigenvectors of the dynamics matrix such that these respect the same permutation symmetry with n orbits. We exemplify the applicability of the algorithm by employing it to identify coarse grained representations of cellular automata.
R&D COLLABORATION IN THE LIFE SCIENCES: FINDING PARTNERS AND THE ROLE OF RESOURCE-BASED INDUCEMENTS AND OPPORTUNITIES
Authors: VAN DER VALK T. , MEEUS M. T. H. , MOORS E. H. M. , FABER J.
Published: May 2010

This paper addresses interorganisational collaboration by science-based firms active in the Dutch life sciences. More specifically, we focus on two aspects (1) processes of finding partners; and (2) resource-based inducements and opportunities guiding these processes. Overall, there appears to be an evolution from untargeted to targeted search as the firms become more established within the technological field. Unestablished firms largely depend on accepting invitations for collaboration offered to them by partners while more established firms are able to successfully initiate partnerships themselves. Considering more than one potential partner, e.g. actual partner selection, does not occur regularly, especially not in the case of partnerships initiated by the partner instead of the focal organisation. The use of a standardised list of preconditions to be considered in partner selection could be relevant here.
START-UP CREATION IN BIOTECHNOLOGY: LESSONS FROM THE CASE OF FOUR NEW VENTURES IN THE UPPER RHINE BIOVALLEY
Authors: BURETH ANTOINE , PÉNIN JULIEN , WOLFF SANDRINE
Published: May 2010

This paper explores start-up creation in biotech through an in-depth analysis of four new ventures located in the Upper Rhine Biovalley. This analysis helps us discuss the role of several factors in the performance of a new biotech firm. The study specifically outlines three elements, namely: the importance of public science, without which new biotech firms cannot exist; the role of the patent system, which impacts the business model adopted by the firm; and the importance of collaborations, which we study through the concept of distributed entrepreneurship.
THE RELATIONSHIP BETWEEN AN INNOVATION ORIENTATION AND COMPETITIVE STRATEGY
Authors: DOBNI C. BROOKE
Published: May 2010

The strategy chosen in organizations is related to several factors including the organization's mission, objectives, resources, and its innovation orientation. Using a sample of Canadian organizations, this study examines the relationships between an organization's innovation orientation and the types of competitive strategies they pursue.

An innovation orientation describes how innovative an organization is and the results suggest that such an orientation provides a context for the implementation of proactive growth-based strategies. Organizations that possess high innovation orientations engage in value creation strategies such as market segmentation, developing new products/services for new markets, and product or service customisation. Those organizations possessing low innovation orientations generally practice less aggressive and internally focused strategies, de-emphasising such things as customer service, brand reputation, and co-operation based strategies such as joint ventures and alliances.
Activation of natural killer cells inhibits liver regeneration in toxin-induced liver injury model in mice via a tumor necrosis factor-α-dependent mechanism
Authors: Wei Hairong , Wei Haiming , Wang Hua , Tian Zhigang , Sun Rui
Published: May 2010

Liver lymphocytes are enriched in natural killer (NK) cells, and activation of NK cells by injection of polyinosinic-polycytidylic acid (poly I:C) inhibits liver regeneration in the partial hepatectomy model via production of IFN-γ. However, the role of NK cells in liver regeneration in a model of carbon tetrachloride (CCl4)-induced liver injury remains unknown. In this study, we investigated the effect of activation of NK cells induced by poly I:C on liver regeneration in the CCl4 model. Administration of poly I:C suppressed liver regeneration in CCl4-treated mice. Depletion of NK cells but not Kupffer cells or T cells restored liver regeneration in poly I:C/CCl4-treated mice. Poly I:C and CCl4 cotreatment synergistically induced accumulation of NK cells in the liver and NK cell production of IFN-γ and tumor necrosis factor (TNF)-α. Serum levels of these two cytokines were also synergistically induced after poly I:C and CCl4 treatment. Finally, blockage of TNF-α but not IFN-γ restored liver regeneration in poly I:C/CCl4-treated mice. Taken together, these findings suggest that poly I:C treatment inhibits liver regeneration in the CCl4-induced liver injury model via induction of NK cell production of TNF-α.
Luminal leptin inhibits l-glutamine transport in rat small intestine: involvement of ASCT2 and B0AT1
Authors: Ducroc Robert , Sakar Yassine , Fanjul Carmen , Barber Ana , Bado André , Lostao Maria Pilar
Published: May 2010

l-glutamine is the primary metabolic fuel for enterocytes. Glutamine from the diet is transported into the absorptive cells by two sodium-dependent neutral amino acid transporters present at the apical membrane: ASCT2/SLC1A5 and B0AT1/SLC6A19. We have demonstrated that leptin is secreted into the stomach lumen after a meal and modulates the transport of sugars after binding to its receptors located at the brush border of the enterocytes. The present study was designed to address the effect of luminal leptin on Na+-dependent glutamine (Gln) transport in rat intestine and identify the transporters involved. We found that 0.2 nM leptin inhibited uptake of Gln and phenylalanine (Phe) (substrate of B0AT1) using everted intestinal rings. In Ussing chambers, 10 mM Gln absorption followed as Na+-induced short-circuit current was inhibited by leptin in a dose-dependent manner (maximum inhibition at 10 nM; IC50 = ∼0.1 nM). Phe absorption was also decreased by leptin. Western blot analysis after 3-min incubation of the intestinal loops with 10 mM Gln, showed marked increase of ASCT2 and B0AT1 protein in the brush-border membrane that was reduced by rapid preincubation of the intestinal lumen with 1 nM leptin. Similarly, the increase in ASCT2 and B0AT1 gene expression induced by 60-min incubation of the intestine with 10 mM Gln was strongly reduced after a short preincubation period with leptin. Altogether these data demonstrate that, in rat, leptin controls the active Gln entry through reduction of both B0AT1 and ASCT2 proteins traffic to the apical plasma membrane and modulation of their gene expression.
Dantrolene mitigates caerulein-induced pancreatitis in vivo in mice
Authors: Orabi Abrahim I. , Shah Ahsan U. , Ahmad Mahwish U. , Choo-Wing Rayman , Parness Jerome , Jain Dhanpat , Bhandari Vineet , Husain Sohail Z.
Published: May 2010

Acute pancreatitis is a painful, inflammatory disorder for which adequate treatments are lacking. An early, critical step in its development is the aberrant signaling of Ca2+within the pancreatic acinar cell. This Ca2+release is modulated by the intracellular Ca2+channel the ryanodine receptor (RYR). We have previously shown that RYR inhibition reduces pathological intra-acinar protease activation, an early marker of pancreatitis. In this study, we examined whether pretreatment with the RYR inhibitor dantrolene attenuates the severity of caerulein-induced pancreatitis in mice. Immunofluorescent labeling for RYR from mouse pancreatic sections showed localization to the basolateral region of the acinar cell. After 1 h of caerulein hyperstimulation in vivo, dantrolene 1) reduced pancreatic trypsin activity by 59% ( P < 0.05) and 2) mitigated early ultrastructural derangements within the acinar cell. Eight hours after pancreatitis induction, dantrolene reduced pancreatic trypsin activity and serum amylase by 61 and 32%, respectively ( P < 0.05). At this later time point, overall histological severity of pancreatitis was reduced by 63% with dantrolene pretreatment ( P < 0.05). TUNEL-positive cells were reduced by 58% ( P < 0.05). These data suggest that the RYR plays an important role in mediating early acinar cell events during in vivo pancreatitis and contributes to disease severity. Blockade of Ca2+signals and particularly RYR-Ca2+may be useful as prophylactic treatment for this disease in high-risk settings for pancreatitis.
Role of the mediastinum in the mechanics of the canine diaphragm
Authors: De Troyer André , Cappello Matteo , Leduc Dimitri , Gevenois Pierre Alain
Published: May 2010

The objective of this study was to evaluate the role of the mediastinum in the mechanics of the canine diaphragm. Two sets of experiments were performed. In the first experiment on five animals, the mediastinum was severed from the sternum to the vena cava, and radiopaque markers were attached to muscle bundles in the midcostal region of the diaphragm. The three-dimensional location of the markers during relaxation at different lung volumes and during phrenic nerve stimulation at the same lung volumes was then measured using computed tomography. From these data, accurate measurements of muscle displacement and muscle length were obtained, and these measurements, together with the changes in airway opening pressure, were compared with those previously obtained in animals with an intact mediastinum. Severing the mediastinum per se appeared to have no influence on the pressure-generating capacity of the diaphragm or on the lung-volume dependence of this capacity. The great vessels and the esophagus in these animals, however, were left intact, so the possibility remained that these structures continued to impact on the diaphragm through their close attachments to the muscle. In the second experiment, therefore, loads were applied caudally to the central tendon to assess the force-displacement relationship of the entire mediastinum, and this relationship, combined with the known displacement of the diaphragm dome during phrenic nerve stimulation, was used to infer the force exerted by the mediastinum on the muscle during contraction. The results showed that this force is small compared with that developed by the diaphragm, except at very high lung volumes. It is concluded, therefore, that the mediastinum has only little influence on the mechanics of the canine diaphragm.
Mechanisms and modifiers of reflex induced cutaneous vasodilation and vasoconstriction in humans
Authors: Charkoudian Nisha
Published: May 2010

Human skin blood flow responses to body heating and cooling are essential to the normal processes of physiological thermoregulation. Large increases in skin blood flow provide the necessary augmentation of convective heat loss during environmental heat exposure and/or exercise, just as reflex cutaneous vasoconstriction is key to preventing excessive heat dissipation during cold exposure. In humans, reflex sympathetic innervation of the cutaneous circulation has two branches: a sympathetic noradrenergic vasoconstrictor system, and a non-noradrenergic active vasodilator system. Noradrenergic vasoconstrictor nerves are tonically active in normothermic environments and increase their activity during cold exposure, releasing both norepinephrine and cotransmitters (including neuropeptide Y) to decrease skin blood flow. The active vasodilator system in human skin does not exhibit resting tone and is only activated during increases in body temperature, such as those brought about by heat exposure or exercise. Active cutaneous vasodilation occurs via cholinergic nerve cotransmission and has been shown to include potential roles for nitric oxide, vasoactive intestinal peptide, prostaglandins, and substance P (and/or neurokinin-1 receptors). It has proven both interesting and challenging that no one substance has been identified as the sole mediator of active cutaneous vasodilation. The processes of reflex cutaneous vasodilation and vasoconstriction are both modified by acute factors, such as exercise and hydration, and more long-term factors, such as aging, reproductive hormones, and disease. This review will highlight some of the recent findings in these areas, as well as interesting areas of ongoing and future work.
Single trial detection of human vestibular evoked myogenic potentials is determined by signal-to-noise ratio
Authors: Todd Neil P. McAngus , Rosengren Sally M. , Govender Sendhil , Colebatch James G.
Published: May 2010

Vestibular reflexes in humans can be assessed by means of acoustically evoked responses of myogenic origin. For the vestibular-collic pathway this is termed the vestibular evoked myogenic potential (or VEMP) and for the vestibular-ocular pathway the ocular VEMP (or OVEMP). Usually VEMPs require an averaging process to obtain a clear response against the background myogenic activity, but depending on the combination of target reflex and stimulus mode, in some cases clear responses can be observed in single trials without averaging. We aimed to test whether this difference in detectability was simply related to signal-to-noise ratio (SNR), or a manifestation of some other difference in the reflex pathways. In four healthy subjects we recorded VEMPs and OVEMPs in response to 2-ms, 500-Hz sound pips and 10-ms, 100-Hz transmastoid vibrations at four intensity levels, and also determined thresholds. A plot of probability of detection P vs. SNR for all subjects and conditions fell onto a single sigmoid curve. When fitted by a logistic function after linearization a regression yielded an R 2 of 0.89 ( n = 64, p < 0.001), with parameter estimates of μ = 2.9 and σ = 2.0. Three patients with superior canal dehiscence, characterized by significantly lowered thresholds for sound-activated responses, exhibited a similar detection curve. We conclude that single trial detection of evoked myogenic potentials is a property mainly determined by SNR. Thus vestibular reflexes, differing in both their response magnitude and in their levels of myogenic activity by more than an order of magnitude, can be described by a single relationship when their magnitude is expressed relative to background activity, demonstrating the fundamental importance of the SNR.
Improvements in dynamic plantar flexor strength after resistance training are associated with increased voluntary activation and V-to-M ratio
Authors: Nordlund Ekblom M. M.
Published: May 2010

The aim of this study was to investigate if, and via what mechanisms, resistance training of the plantar flexor muscles affects voluntary activation during maximal voluntary eccentric and concentric muscle actions. Twenty healthy subjects were randomized into a resistance training group ( n = 9) or a passive control group ( n = 11). Training consisted of 15 sessions of unilateral mainly eccentric plantar flexor exercise over a 5-wk period. During pre- and posttraining testing, dynamic plantar flexor strength was measured and voluntary activation was calculated using the twitch interpolation technique. The soleus Hoffman reflex (H-reflex) was used to assess motoneurone excitability and presynaptic inhibition of Ia afferents, whereas the soleus V-wave was used to test for changes in both presynaptic inhibition of Ia afferents and supraspinal inputs to the motoneurone pool. H-reflexes, V-waves, supramaximal M-waves, and twitches were evoked as the foot was moved at 5°/s through an angle of 90° during passive ankle rotations (passive H-relexes and M-waves) and during maximal voluntary concentric and eccentric plantar flexions [maximal voluntary contraction (MVC) H-reflexes, M-waves, and V-waves]. Training induced significant improvements in plantar flexor strength and voluntary activation during both concentric and eccentric maximal voluntary actions. Soleus passive and MVC H-to-M ratios remained unchanged after training, whereas the soleus V-to-M ratio was increased during both concentric and eccentric contractions after training. No changes were found in the control group for any of the parameters. The enhanced voluntary strength could be attributed partly to an increase in voluntary activation induced by eccentric training. Since the passive and MVC H-to-M ratios remained unchanged, the increase in activation is probably not due to decreased presynaptic inhibition. The increased V-to-M ratio for both action types indicates that increased voluntary drive from supraspinal centers and/or modulation in afferents other than Ia afferents may have contributed to such an increase in voluntary activation.
AdCD40L Immunogene Therapy for Bladder Carcinoma—The First Phase I/IIa Trial
Authors: Malmström Per-Uno , Loskog Angelica S.I. , Lindqvist Camilla A. , Mangsbo Sara M. , Fransson Moa , Wanders Alkwin , Gårdmark Truls , Tötterman Thomas H.
Published: May 2010

Purpose: Immunotherapy with Bacillus Calmette-Guerin (BCG) instillation is recommended for high-risk, non–muscle invasive bladder cancer. Bacillus Calmette-Guerin is not effective in advanced tumors, and better alternatives are warranted. Immunostimulating gene therapy with adenoviral vectors expressing CD40 ligand (AdCD40L) has shown efficacy in tumor models. CD40 ligand stimulates systemic immunity and may be effective in local and invasive human disease.

Experimental Design: Patients with invasive bladder cancer scheduled for cystectomy or patients with Ta tumors were enrolled in a phase I/IIa trial. Patients were treated with three cycles of intrabladder Clorpactin WCS-90 prewash, followed by AdCD40L instillation 1 week apart. Safety, gene transfer, immune effects, and antitumor responses were monitored.

Results: All eight recruited patients were treated as scheduled, and therapy was well tolerated. The main adverse effect was transient local pain during prewash. Postoperatively, urinary tract infections and one case of late septicemia with elevated potassium were reported. No adverse events were ascribed to vector therapy. Gene transfer was detected in biopsies, and bladders were heavily infiltrated with T cells. The effector marker IFN-γ increased in biopsies, whereas levels of circulating T regulatory cells were reduced. Histologic evaluation indicated that AdCD40L therapy reduced the load of malignant cells.

Conclusions: To our knowledge, this is the first report on immunogene therapy in bladder cancer and the first using AdCD40L in vivo. Local AdCD40L gene therapy was safe, boosted immune activation, and should be further evaluated as a single or an adjuvant therapy for urothelial malignancies. Clin Cancer Res; 16(12); 3279–87. ©2010 AACR.
Mortality from Cancer among US Hemodialysis Patients, 1995–2005
Authors: Foley Robert N. , Roberts Tricia L. , Liu Jiannong , Gilbertson David T. , Arneson Thomas J. , Dunning Stephan , Collins Allan J.
Published: May 2010

Background/Aims: Concern has emerged that erythropoiesis-stimulating agents (ESAs) may decrease survival for cancer patients; many patients beginning dialysis have previous cancer diagnoses. As ESA doses have more than tripled in the USA since ESAs were introduced, we aimed to compare annual trends in cancer-specific mortality rates among incident maintenance hemodialysis patients. Methods: This national, retrospective, incident cohort study included 873,493 patients aged ≧20 years who initiated hemodialysis between 1995 and 2005. Cancer-specific mortality rates were adjusted for baseline characteristics, determined from the Centers for Medicare & Medicaid Services (CMS) Medical Evidence Report (form CMS-2728). Follow-up extended to December 31, 2006. Cause of death was ascertained from the Death Notification (form CMS-2746). Results: Crude first-year cancer-specific mortality rates, per 1,000 patient-years, 1995–2005, were as follows: 13.8, 13.7, 14.2, 14.9, 13.8, 15.4, 15.4, 16.5, 16.4, 15.8, 15.2. Mortality rates remained stable year to year within subsequent follow-up intervals; for the first and last annual cohorts, mortality rates by follow-up interval were: year 2, 9.1 and 8.7; year 3, 8.6 and 8.3; years 4–5, 7.9 and 6.8. Annual comparisons were similar after adjustment for patient characteristics at dialysis initiation. Conclusion: Cancer-specific mortality rates remained stable among US hemodialysis patients between 1995 and 2005.
Quantitative Analysis of Reduced Arm Swing Frequency in Essential Tremor
Authors: Benbir Gülçin , Ozekmekci Sibel , Oguz Semra , Kenangil Gulay , Ertan Sibel , Akalan Ekin
Published: May 2010

Background: Essential tremor (ET) has recently been accepted as a heterogeneous disorder which may be associated with synuclein pathology or a variety of other genetic disorders. Methods: We observed decreased arm swing frequency in 18 of 136 definite ET patients, and recorded the associated arm movements in 18 ET patients and 33 sex- and age-matched healthy controls. Results: The mean frequency of the right arm (p = 0.047), left arm (p = 0.025) and leg (p = 0.030), and the mean arm/leg frequency on the right side (p = 0.048) were significantly lower in ET patients. The mean frequencies for both arms and legs were significantly lower for the more affected side of the body (p = 0.034 and p = 0.036, respectively). Conclusion: We conclude that ET may be associated with decreased arm and leg swing frequencies, especially on the more affected side of the body.
Dissociation of Cardinal Motor Signs in Parkinson’s Disease Patients
Authors: Koh Seong-Beom , Kwon Do-Young , Seo Woo-Keun , Kim Ji Hyun , Kim Jong Hyun , Lee Seung-Hwan , Oh Kyungmi , Kim Byung-Jo , Park Kun-Woo
Published: May 2010

Most cardinal motor signs in Parkinson’s disease (PD) are more pronounced on one side than on the other. Unusually, one type of cardinal motor sign is found on one side while other motor signs are more pronounced on the contralateral side, the so-called dissociation of motor signs. The aims of this study were to determine the frequency of motor sign dissociation and to study the clinical characteristics of the dissociation group. To this end, clinical characteristics including the Unified Parkinson’s Disease Rating Scale, Mini-Mental State Examination, Non-Motor Symptom Questionnaire and Frontal Lobe Assessment Battery were analyzed for 411 patients during consecutive follow-up visits. Dissociation was noted in 29 (7.06%) of the 411 patients. Dissociation of tremor and rigidity-bradykinesia was the most common type of dissociation pattern (17/29). There were no significant differences in demographic factors and clinical profiles between the dissociation and control groups. We suspect that each cardinal motor sign is pathogenetically different. The presence of dissociation did not affect the natural history of PD.
Lithium: Still a Cornerstone in the Long-Term Treatment in Bipolar Disorder?
Authors: Nivoli Alessandra M.A. , Murru Andrea , Vieta Eduard
Published: May 2010

Background: Scientific literature considers lithium a key treatment for the acute and long-term management of bipolar disorder (BD). Despite its worldwide clinical use, the effectiveness of lithium has been questioned. The aim of this work is to critically review the available data on randomized controlled trials (RCTs) concerning long-term lithium treatment. Methods: A systematic search for long-term treatment RCTs with at least 6 months of follow-up was performed. Six RCTs enrolling 1,561 bipolar I and II patients of adult and pediatric age, randomizing 534 to lithium, were identified. All studies are controlled trials sponsored by industry, investigating new treatments for BD, with lithium as an active comparator, and therefore not specifically designed to study lithium efficacy or safety. Results: Results from earliest studies suggest a high effectiveness of lithium against both mania and depression, while more recent studies highlight lithium as more effective than placebo in mania and hypomania, without significant evidence in depression. Lithium does not achieve significant differences in efficacy when compared with divalproex; it seems less effective than lamotrigine in preventing depression and less effective than olanzapine in manic and mixed episodes. Conclusions: Despite a number of methodological issues (enriched designs, unbalanced samples, potential inclusion of lithium nonresponders in some studies), lithium appears to have a clear antimanic prophylactic activity and some efficacy in the prevention of depression. Lithium should still have a major role in the long-term treatment of BD.
Lithium’s Emerging Role in the Treatment of Refractory Major Depressive Episodes: Augmentation of Antidepressants
Authors: Bauer Michael , Adli Mazda , Bschor Tom , Pilhatsch Maximilian , Pfennig Andrea , Sasse Johanna , Schmid Rita , Lewitzka Ute
Published: May 2010

Background: The late onset of therapeutic response and a relatively large proportion of nonresponders to antidepressants remain major concerns in clinical practice. Therefore, there is a critical need for effective medication strategies that augment treatment with antidepressants. Methods: To review the available evidence on the use of lithium as an augmentation strategy to treat depressive episodes. Results: More than 30 open-label studies and 10 placebo-controlled double-blind trials have demonstrated substantial efficacy of lithium augmentation in the acute treatment of depressive episodes. Most of these studies were performed in unipolar depression and included all major classes of antidepressants, however mostly tricyclics. A meta-analysis including 10 randomized placebo-controlled trials has provided evidence that lithium augmentation has a statistically significant effect on the response rate compared to placebo with an odds ratio of 3.11, which corresponds to a number-needed-to-treat of 5. The meta-analysis revealed a mean response rate of 41.2% in the lithium group and 14.4% in the placebo group. One placebo-controlled trial in the continuation treatment phase showed that responders to acute-phase lithium augmentation should be maintained on the lithium-antidepressant combination for at least 12 months to prevent early relapses. Preliminary studies to assess genetic influences on response probability to lithium augmentation have suggested a predictive role of the –50T/C single nucleotide polymorphism of the GSK3β gene. Conclusion: Augmentation of antidepressants with lithium is currently the best-evidenced augmentation therapy in the treatment of depressed patients who do not respond to antidepressants.
Pharmacogenetics of Lithium Long-Term Treatment: Focus on Initiation and Adaptation Mechanisms
Authors: Serretti Alessandro , Drago Antonio
Published: May 2010

Bipolar disorder is a common disease with a high impact in terms of personal suffering and socioeconomic burden. The disentanglement of the molecular deregulations that cause this disorder is pivotal to the understanding of its etiology. This will hopefully cast the engineering of new and more favorable treatments. New insights in the molecular aspects of bipolar disorder may be brought by the understanding of the pharmacodynamics of lithium, the first-line treatment for this disease. The mechanisms by which lithium exerts its activity in the central nervous system are not fully clarified: it is hypothesized that lithium may drive acute molecular events whose activation over time triggers long-lasting modifications in critical neuronal nets. These events are associated with long-lasting changes in the expression profile of genes in neurons that are embedded in these crucial nets. The molecular events that are acutely and chronically triggered by lithium will be reviewed here and matched with the evidence that arises from the pharmacogenetics investigations. Moreover, the pharmacogenetics reports that are not strictly associated with the mechanisms that are thought to be acutely and chronically elicited by lithium will be included in the final part of the paper.
Smoking Cessation Interventions Offered to French Adult Light Smokers: A Heterogeneous Population with Specific Needs
Authors: Baha Monique Y. , Le Faou Anne-Laurence
Published: May 2010

Aims: We addressed the understudied topic of cessation interventions for adult light smokers (≤10 cigarettes daily). We identified cessation aids offered in French cessation services and their impact on cessation outcomes at 1-month follow-up. Methods: We retrospectively analyzed data from 36,594 smokers in cessation services nationwide. Smokers could be offered pharmacotherapy as well as cognitive behavioral therapy (CBT). Bivariate methods and multivariate logistic regression analyses were used. Results: Light smokers were 1.23 times more likely to drop out than heavy smokers. 13.3% were abstinent at follow-up versus 14.5% for heavy smokers (p = 0.013). Light smokers were offered pharmacotherapy less often than heavy smokers. Yet, among light smokers, varenicline doubled the odds of abstinence as did nicotine patch. CBT improved abstinence only when combined with nicotine patch. Intervention outcomes differed according to various profiles: light smokers self-referred or with several previous quit attempts achieved better outcomes than those not interested in quitting or referred through hospitalization. Conclusion: Light smokers’ poor intervention outcomes might partly be explained by inadequate treatment plans in French cessation services. Our results reveal that pharmacotherapy is effective and that tailored CBT should be offered according to the variety of profiles among light smokers.
The Physical Ability of Japanese Female Elderly with Cerebrovascular Disease Correlates with the Telomere Length and Subtelomeric Methylation Status in Their Peripheral Blood Leukocytes
Authors: Maeda Toyoki , Oyama Jun-ichi , Higuchi Yoshihiro , Nishiyama Yasuhiro , Kudo Yoshihiro , Yamori Tomoko , Nakazono Takashi , Arima Takahiro , Mimori Koshi , Makino Naoki
Published: May 2010

Background: The telomere length and subtelomeric methylated status of peripheral blood leukocytes have been reported to be correlated with many kinds of pathophysiological conditions. However, the correlation between the telomeric parameters and patients’ physical ability is not known. Objective: This study aims to study how telomeric parameters, including telomere length and the subtelomeric methylation status of peripheral blood leukocytes, are associated with the physical inability of patients with cerebrovascular disease and its improvement by inpatient rehabilitation. Methods: The physical ability of female patients with cerebrovascular disease admitted in the chronic disease ward of Kyushu University Hospital was assessed using the Barthel index, and the telomeric parameters in their peripheral blood leukocytes were determined by Southern blotting with methylation-sensitive and -insensitive isoschizomers. Results: The patients revealed a significant correlation between Barthel score and the mean telomere length and expression of long telomeres (>9.4 kb). Improvement of the Barthel index of patients during admission was correlated not to telomere length, but to subtelomeric hypermethylation of long telomeres. Conclusions: The physical ability of patients was positively correlated with the lengths of their somatic telomeres, and the recovery potential of physical ability was associated with the subtelomeric hypermethylated status stabilizing long telomeric structure.
Biomarkers of the Osteoprotegerin Pathway
Authors: Lieb Wolfgang , Gona Philimon , Larson Martin G. , Massaro Joseph M. , Lipinska Izabella , Keaney John F. , Rong Jian , Corey Diane , Hoffmann Udo , Fox Caroline S. , Vasan Ramachandran S. , Benjamin Emelia J. , O'Donnell Christopher J. , Kathiresan Sekar
Published: May 2010

Objective—

Experimental evidence identified the osteoprotegerin (OPG)/receptor activator of nuclear factor–κB (RANK)/RANK ligand (RANKL) pathway as a candidate system modulating vascular remodeling and cardiovascular disease (CVD).

Methods and Results—

Serum concentrations of OPG and RANKL were measured in 3250 Framingham Study participants (54% women, 61±9 years). During a mean follow-up of 4.6 years, 143 (of 3084 free of CVD at baseline) participants developed a first CVD event, and 235 died. In multivariable models, OPG was associated with increased hazards for incident CVD and mortality (hazard ratio, 1.27; 95% CI, 1.04 to 1.54; and hazard ratio, 1.25; 95% CI, 1.07 to 1.47, per 1-SD increment in log-OPG, respectively). Log-OPG was positively related to multiple CVD risk factors, including age, smoking, diabetes, systolic blood pressure, and prevalent CVD. In a subsample (n=1264), the prevalence of coronary artery calcification, measured by computed tomography, increased nonsignificantly with OPG quartiles. RANKL concentrations displayed inverse associations with multiple CVD risk factors, including smoking, diabetes, and antihypertensive treatment, and were not related to coronary artery calcification or incident CVD or mortality.

Conclusion—

Our prospective data reinforce OPG as marker for CVD risk factor burden and predictor for CVD and mortality in the community.
Deficient CD4
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CD25
+
T Regulatory Cell Function in Patients With Abdominal Aortic Aneurysms
Authors: Yin Mingdi , Zhang Jian , Wang Yong , Wang Shaoye , Böckler Dittmar , Duan Zhiquan , Xin Shijie
Published: May 2010

Objective—

Increasing evidence shows that autoimmune response contributes importantly to pathogenesis of abdominal aortic aneurysm (AAA). This work was aimed to assess the possibly altered function of peripheral CD4
+
CD25
+
T regulatory cells (Tregs) that might breakdown immunologic self-tolerance in AAA patients.

Methods and Results—

Peripheral blood from 22 AAA patients, 11 patients with abdominal aortic atherosclerotic occlusive disease (AOD), and 32 healthy controls (HCs) was analyzed to determine the percentage of CD4
+
CD25
+
Tregs in the total CD4
+
T-cell population and FOXP3 expression by means of flow cytometry. The frequencies of the CD4
+
CD25
+
Treg population were not significantly different between groups (AAA, 5.69±0.99%; AOD, 5.52±1.13%; HC, 5.88±1.55%;
P
>0.05). However, the frequency of CD4
+
CD25
+
FOXP3
+
T cells in AAA patients (2.45±0.57%) was significantly lower than that in AOD group (3.41±0.72%;
P
<0.01) or in HCs (3.69±0.82%;
P
<0.01). A comparison of FOXP3 mRNA and protein expression revealed significantly lower levels in CD4
+
CD25
+
Tregs from AAA group than either of other 2 groups (
P
<0.01). Suppressive function assay showed that freshly isolated CD4
+
CD25
+
Tregs from patients with AAA exhibited significantly less suppressive activity than those from AOD patients or HCs (
P
<0.01). Mixing cultures with CD4
+
CD25
+
T cells and CD4
+
CD25
−
T cells from AAA patients and HCs demonstrated that the primary regulatory defect is due to a dysfunction of CD4
+
CD25
+
Tregs, and not a resistance of CD4
+
CD25
−
responder T cells to suppression in AAA patients.

Conclusion—

Our data demonstrate a reduced level of FOXP3 expression in peripheral CD4
+
CD25
+
Tregs and decreased frequency of CD4
+
CD25
+
FOXP3
+
T cells in a cohort of AAA patients enrolled in the study, which leads to a functional deficiency of CD4
+
CD25
+
Tregs as a whole. This indicates an impaired immunoregulation by Tregs that may contribute to AAA pathogenesis.
Increased Secretion of Lipoproteins in Transgenic Mice Expressing Human D374Y
PCSK9
Under Physiological Genetic Control
Authors: Herbert Bronwen , Patel Dilipkumar , Waddington Simon N. , Eden Emily R. , McAleenan Alexandra , Sun Xi-Ming , Soutar Anne K.
Published: May 2010

Objective—

To produce transgenic mice expressing the D374Y variant of the human proprotein convertase subtilisin/kexin type 9 (
PCSK9
) gene at physiological levels to investigate the mechanisms causing hypercholesterolemia and accelerated atherosclerosis.

Methods and Results—

A bacterial artificial chromosome containing
PCSK9
and its flanking regions was modified to introduce the D374Y mutation and a C-terminal myc
2
tag. Transgenic mice that expressed 1 copy of the mutant or wild-type (WT)
PCSK9
bacterial artificial chromosome were produced. Human PCSK9 mRNA was expressed at levels comparable to endogenous
pcsk9
and with the same tissue specificity. The expression of D374Y or WT human PCSK9 increased the serum cholesterol level and reduced hepatic low-density lipoprotein receptor protein levels in the transgenic mice compared with bacterial artificial chromosome–negative controls; however, the effects were more marked in D374Y mice. The effect of a high-cholesterol diet on increasing serum cholesterol level was greater in D374Y mice, and atherosclerotic plaques after 15 weeks were more extensive in mice expressing D374Y than in WT PCSK9. D374Y mice secreted more triglyceride-rich lipoproteins into the circulation than WT mice.

Conclusion—

The expression of human D374Y PCSK9 at physiological levels produced a phenotype that closely matched that found in heterozygous D374Y patients and suggested that reduced low-density lipoprotein receptor activity is not the sole cause of their hypercholesterolemia.
Glucagon-Like Peptide 1 Prevents Reactive Oxygen Species–Induced Endothelial Cell Senescence Through the Activation of Protein Kinase A
Authors: Oeseburg Hisko , de Boer Rudolf A. , Buikema Hendrik , van der Harst Pim , van Gilst Wiek H. , Silljé Herman H.W.
Published: May 2010

Objective—

Endothelial cell senescence is an important contributor to vascular aging and is increased under diabetic conditions. Here we investigated whether the antidiabetic hormone glucagon-like peptide 1 (GLP-1) could prevent oxidative stress–induced cellular senescence in endothelial cells.

Methods and Results—

In Zucker diabetic fatty rats, a significant 2-fold higher level of vascular senescence was observed compared with control lean rats. Dipeptidyl-peptidase 4 (DPP-4) inhibition significantly increased GLP-1 levels in these animals and reduced senescence almost to lean animal levels. In vitro studies with human umbilical vein endothelial cells showed that GLP-1 had a direct protective effect on oxidative stress (H
2
O
2
)–induced senescence and was able to attenuate oxidative stress–induced DNA damage and cellular senescence. The GLP-1 analogue exendin-4 provided similar results, whereas exendin fragment 9–39, a GLP-1 receptor antagonist, abolished this effect. Intracellular signaling by the phosphoinositide 3-kinase (PI3K)/Akt survival pathway did not appear to be involved. Further analysis revealed that GLP-1 activates the cAMP response element-binding (CREB) transcription factor in a cAMP/protein kinase A (PKA)–dependent manner, and inhibition of the cAMP/PKA pathway abolished the GLP-1 protective effect. Expression analysis revealed that GLP-1 can induce the oxidative defense genes
HO-1
and
NQO1
.

Conclusion—

Dipeptidyl-peptidase 4 inhibition protects against vascular senescence in a diabetic rat model. In vitro studies with human umbilical vein endothelial cells showed that reactive oxygen species–induced senescence was attenuated by GLP-1 in a receptor-dependent manner involving downstream PKA signaling and induction of antioxidant genes.
Echocardiography Can Identify Patients With Increased Pulmonary Vascular Resistance by Assessing Pressure Reflection in the Pulmonary Circulation
Authors: Bech-Hanssen Odd , Lindgren Fredrik , Selimovic Nedim , Rundqvist Bengt
Published: May 2010

Background—

Pulmonary hypertension is a frequent finding in patients with cardiopulmonary disorders. It is important to recognize pulmonary hypertension due to increased pulmonary vascular resistance (PVR), as this affects treatment and prognosis. Patients with increased PVR have an increased pulmonary pressure reflection. We hypothesized that pressure reflection can be described by echocardiography and that variables related to pressure reflection can identify patients with increased PVR.

Methods and Results—

The study comprised 98 patients investigated within 24 hours of right heart catheterization and 20 control subjects. The pressure reflection variables were obtained by pulsed Doppler in the pulmonary artery and continuous Doppler of tricuspid regurgitation. We selected 3 variables related to pressure reflection: the interval from valve opening to peak velocity in the pulmonary artery (AcT, ms), the interval between pulmonary artery peak velocity and peak tricuspid velocity (tPV-PP, ms), and the right ventricular pressure increase after peak velocity in the pulmonary artery (augmented pressure, AP, mm Hg). The correlation between simultaneous catheter- and echocardiography-determined AP was strong (n=19,
R
=0.83). The AcT, tPV-PP, and AP in patients with a PVR of >3 Woods units (n=71) was (mean±SD) 77±16 ms, 119±36 ms, and 22±12 mm Hg, respectively, and differed from patients with a PVR of ≤3 Woods units (n=27,
P
<0.0001), 111±32 ms, 39±54 ms, and 3±4 mm Hg, and from controls, 153±32 ms, −19±45 ms, and 0 mm Hg, respectively (
P
<0.0001). The AcT, tPV-PP, and AP values were not correlated with capillary wedge pressure (
R
=0.08–0.16). The areas under the receiver operator characteristic curve (95%CI) for AcT, tPV-PP, and AP were 0.87 (0.82 to 0.95), 0.94 (0.89 to 0.99), and 0.98 (0.95 to 1.0), respectively.

Conclusions—

In this study, we describe a novel echocardiography method for assessing pressure reflection in the pulmonary circulation. This method can be used to identify patients with pulmonary hypertension due to increased PVR.
Inhibition of TRPC6 Channel Activity Contributes to the Antihypertrophic Effects of Natriuretic Peptides-Guanylyl Cyclase-A Signaling in the Heart
Authors: Kinoshita Hideyuki , Kuwahara Koichiro , Nishida Motohiro , Jian Zhong , Rong Xianglu , Kiyonaka Shigeki , Kuwabara Yoshihiro , Kurose Hitoshi , Inoue Ryuji , Mori Yasuo , Li Yuhao , Nakagawa Yasuaki , Usami Satoru , Fujiwara Masataka , Yamada Yuko , Minami Takeya , Ueshima Kenji , Nakao Kazuwa
Published: May 2010

Rationale
:

Atrial and brain natriuretic peptides (ANP and BNP, respectively) exert antihypertrophic effects in the heart via their common receptor, guanylyl cyclase (GC)-A, which catalyzes the synthesis of cGMP, leading to activation of protein kinase (PK)G. Still, much of the network of molecular mediators via which ANP/BNP-GC-A signaling inhibit cardiac hypertrophy remains to be characterized.

Objective
:

We investigated the effect of ANP-GC-A signaling on transient receptor potential subfamily C (TRPC)6, a receptor-operated Ca
2+
channel known to positively regulate prohypertrophic calcineurin–nuclear factor of activated T cells (NFAT) signaling.

Methods and Results
:

In cardiac myocytes, ANP induced phosphorylation of TRPC6 at threonine 69, the PKG phosphorylation site, and significantly inhibited agonist-evoked NFAT activation and Ca
2+
influx, whereas in HEK293 cells, it dramatically inhibited agonist-evoked TRPC6 channel activity. These inhibitory effects of ANP were abolished in the presence of specific PKG inhibitors or by substituting an alanine for threonine 69 in TRPC6. In model mice lacking GC-A, the calcineurin-NFAT pathway is constitutively activated, and BTP2, a selective TRPC channel blocker, significantly attenuated the cardiac hypertrophy otherwise seen. Conversely, overexpression of TRPC6 in mice lacking GC-A exacerbated cardiac hypertrophy. BTP2 also significantly inhibited angiotensin II–induced cardiac hypertrophy in mice.

Conclusions
:

Collectively, these findings suggest that TRPC6 is a critical target of antihypertrophic effects elicited via the cardiac ANP/BNP-GC-A pathway and suggest TRPC6 blockade could be an effective therapeutic strategy for preventing pathological cardiac remodeling.