bluuebunny/crossref_metadata_2025 huggingface dataset:
2-Methoxyestradiol Analogue ENMD-1198 Reduces Breast Cancer-Induced Osteolysis and Tumor Burden BothIn VitroandIn Vivo
Authors: Snoeks Thomas J.A. , Mol Isabel M. , Que Ivo , Kaijzel Eric L. , Löwik Clemens W.G.M.
Published: March 2011

It has been estimated that 70% of advanced breast cancer patients will face the complication of bone metastases. Three processes are pivotal during bone metastatic growth of breast cancer, namely, tumor cell proliferation, angiogenesis, and osteolysis. During tumor-induced osteolysis, a number of cytokines and growth factors are released from the degraded bone matrix. These factors stimulate further tumor growth, tumor angiogenesis, and tumor-induced osteolysis. New therapies should target all relevant processes to halt this powerful feedback loop. Here, we characterized the new 2-methoxyestradiol analogue ENMD-1198 and showed that it is cytotoxic to tumor cells. Moreover, ENMD-1198 showed both antiangiogenic and vascular disruptive properties and was capable of protecting the bone against tumor-induced osteolysis. We confirmed the in vitro data with a series of in vivo experiments showing the beneficial effects of ENMD-1198 and ENMD-1198–based combination treatments of metastatic breast cancer in bone both on tumor progression and on survival with long-term ENMD-1198 treatment. We confirmed the in vivo relevance of the ENMD-1198 protective effect on bone both with X-ray radiographs and microcomputed tomography. In addition, we combined ENMD-1198 treatment with low-dose metronomic cyclophosphamide and the bisphosphonate risedronic acid, leading to a mild increase in treatment efficacy. Mol Cancer Ther; 10(5); 874–82. ©2011 AACR.
Meiotic Studies of a 38,XY/39,XXY Mosaic Boar
Authors: Pinton A. , Barasc H. , Raymond Letron I. , Bordedebat M. , Mary N. , Massip K. , Bonnet N. , Calgaro A. , Dudez A.M. , Feve K. , Riquet J. , Yerle M. , Ducos A.
Published: March 2011

Klinefelter’s syndrome (KS) is the most common sex chromosome abnormality identified in human males. This syndrome is generally associated with infertility. Men with KS may have a 47,XXY or a 46,XY/47,XXY karyotype. Studies carried out in humans and mice suggest that only XY cells are able to enter and complete meiosis. These cells could originate from the XY cells present in mosaic patients or from XXY cells that have lost one X chromosome. In pig, only 3 cases of pure 39,XXY have been reported until now, and no meiotic analysis was carried out. For the first time in pig species we report the analysis of a 38,XY/39,XXY boar and describe the origin of the supplementary X chromosome and the chromosomal constitutions of the germ and Sertoli cells.
Electroencephalographic Spectral and Coherence Analysis of Ketamine in Rats: Correlation with Behavioral Effects and Pharmacokinetics
Authors: Páleníček Tomáš , Fujáková Michaela , Brunovský Martin , Balíková Marie , Horáček Jiří , Gorman Ingmar , Tylš Filip , Tišlerová Barbora , Šoš Peter , Bubeníková-Valešová Věra , Höschl Cyril , Krajča Vladimír
Published: March 2011

Aims: This study was designed to evaluate the changes in EEG power spectra and EEG coherence in a ketamine model of psychosis in rats. Analyses of behavioral measurements – locomotion and sensorimotor gating – and the pharmacokinetics of ketamine and norketamine were also conducted. Methods: Ketamine and norketamine levels in rat sera and brains were analyzed by gas chromatography-mass spectrometry after ketamine 30 mg/kg (i.p.). Ketamine 9 and 30 mg/kg (i.p.) were used in the behavioral and EEG experiments. Locomotor effects in an open field test and deficits in prepulse inhibition of acoustic startle reaction (PPI ASR) were evaluated in the behavioral experiments. EEG signals were simultaneously recorded from 12 implanted active electrodes; subsequently, an EEG power spectral and coherence analysis was performed. Results: Ketamine had a rapid penetration into the brain; the peak concentrations of the drug were reached within 15 min after administration. Ketamine induced marked hyperlocomotion and deficits in the PPI ASR. EEG spectral analysis mainly showed increases in EEG power as well as coherence. These were most robust at 10–15 min after the administration and influenced all parts of the spectrum with ketamine 30 mg/kg. Conclusions: Ketamine at behaviorally active doses induces a robust increase in EEG power spectra and coherence. The maximum levels of change correlated with the kinetics of ketamine.
Male Fertility, Chromosome Abnormalities, and Nuclear Organization
Authors: Ioannou D. , Griffin D.K.
Published: March 2011

Numerous studies have implicated the role of gross genomic rearrangements in male infertility, e.g., constitutional aneuploidy, translocations, inversions, Y chromosome deletions, elevated sperm disomy, and DNA damage. The primary purpose of this paper is to review male fertility studies associated with such abnormalities. In addition, we speculate whether altered nuclear organization, another chromosomal/whole genome-associated phenomenon, is also concomitant with male factor infertility. Nuclear organization has been studied in a range of systems and implicated in several diseases. For many applications the measurement of the relative position of chromosome territories is sufficient to determine patterns of nuclear organization. Initial evidence has suggested that, unlike in the more usual ‘size-related’ or ‘gene density-related’ models, mammalian (including human) sperm heads display a highly organized pattern including a chromocenter with the centromeres located to the center of the nucleus and the telomeres near the periphery. More recent evidence, however, suggests there may be size- and gene density-related components to nuclear organization in sperm. It seems reasonable to hypothesize therefore that alterations in this pattern may be associated with male factor infertility. A small handful of studies have addressed this issue; however, to date it remains an exciting avenue for future research with possible implications for diagnosis and therapy.
Alterations in Phosphatidylinositol 3-Kinase Activity and PTEN Phosphatase in the Prefrontal Cortex of Depressed Suicide Victims
Authors: Karege Félicien , Perroud Nader , Burkhardt Sandra , Fernandez Rafael , Ballmann Eladia , La Harpe Romano , Malafosse Alain
Published: March 2011

Background: Recent studies have reported alterations in protein kinase B (PKB)/Akt and in its downstream target, glycogen synthase kinase 3β, in depression and suicide. The aim of the present study was to investigate possible impairment of the upstream regulators, namely phosphatidylinositol 3-kinase (PI3K) and PTEN. Methods: The ventral prefrontal cortex (Brodmann’s area 11) of 24 suicide victims and 24 drug-free nonsuicide subjects was used. The antemortem diagnoses of major depression disorder were obtained from the institutional records or psychological autopsy, and toxicological analyses were performed. Protein levels of PI3K and PTEN were assayed using the immunoblot method, and the kinase activity of PI3K and Akt was determined by phosphorylation of specific substrates. Results: A decrease was observed in the enzymatic activity of PI3K [ANOVA: F(3, 44) = 9.20; p < 0.001] and Akt1 [ANOVA: F(3, 44) = 13.59; p < 0.001], without any change in protein levels, in both depressed suicide victims and depressed nonsuicide subjects (p < 0.01 and p < 0.002, respectively). PTEN protein levels were increased in the same groups [ANOVA: F(3, 44) = 10.5; p < 0.001]. No change was observed in nondepressed suicide victims. Conclusion: This study concludes that attenuation of kinase activity of PKB/Akt in depressed suicide victims may be due to the combined dysregulation of PTEN and PI3K resulting in insufficient phosphorylation of lipid second messengers. The effect is associated with major depression rather than with suicide per se. Given the cellular deficits reported in major depression, the study of enzymes involved in cell survival and neuroplasticity is particularly relevant to neurotrophic factor dysregulation in depression.
Possible Role of NF-ĸB Signals in Heat Stress-Associated Increase in Protein Content of Cultured C2C12 Cells
Authors: Ohno Yoshitaka , Yamada Sumio , Sugiura Takao , Ohira Yoshinobu , Yoshioka Toshitada , Goto Katsumasa
Published: March 2011

Heat stress is one of the hypertrophic stimuli on mammalian skeletal muscle. Nuclear factor-ĸB (NF-ĸB) signaling plays an important role in the regulation of skeletal muscle mass. However, the effects of heat stress on NF-ĸB signaling in skeletal muscle cells remain unclear. Effects of heat stress and/or administration of BAY11-7082, an inhibitor of NF-ĸB, on NF-ĸB signals and protein content of skeletal muscle were studied by using cell culture system. Differentiated mouse myoblasts (C2C12) were subjected to either (1) control (cultured at 37°C without BAY11-7082), (2) heat stress at 41°C for 60 min, (3) BAY11-7082 administration (1.25 µM) or (4) heat stress combined with BAY11-7082 administration. Heat shock protein 72 (HSP72) was upregulated by heat stress with or without administration of BAY11-7082. The increase in inhibitor of ĸBα (IĸBα), which regulates the phosphorylation of NF-ĸB, and the decrease in phosphorylated NF-ĸB were also induced by administration of BAY11-7082 and/or heat stress. Protein content in C2C12 cells was increased by the administration of BAY11-7082 with a semi-logarithm fashion. Significant increases in the protein content of C2C12 cells were observed 48 h following heating with or without administration of BAY11-7082. These observations suggest that heat stress might increase muscle protein through the downregulation of NF-ĸB signaling. Inhibition of NF-ĸB induced by application of heat stress might be one of the hypertrophic stimuli on skeletal muscle cells.
Sporadic Aneuploidy in PHA-Stimulated Lymphocytes of Trisomies 21, 18, and 13
Authors: Reish O. , Regev M. , Kanesky A. , Girafi S. , Mashevich M.
Published: March 2011

Following the observation detected in a previous study that X chromosome monosomy in Turner’s syndrome genotypes was associated with a sporadic loss and/or gain of other chromosomes, we studied here whether this instability is a consistent finding in constitutional autosomal trisomies. We used PHA-stimulated lymphocytes derived from 14 patients (10 patients with trisomy 21, 2 with trisomy 18, and 2 with trisomy 13). Fourteen healthy controls were compared. Fluorescence in situ hybridization, applied at interphase cells, was used to evaluate the level of aneuploidy for 3 randomly selected chromosomes (autosomes 8, 15, and 16) in each sample. For each tested chromosome, our results showed a significantly higher level of aneuploid cells in the samples from the patients than in those from controls, with no difference between the patient groups. The mean level of aneuploid cells (percentage) for all 3 tested autosomes was almost twice as high in the patient samples as in the control samples. The aneuploidy level was mainly due to monosomy, which was significantly higher in the samples from the patients than in those from controls for each one of the tested chromosomes, with no difference between the patient groups. The mean level of monosomic cells (percentage) for all 3 tested chromosomes was almost twice as high in the patient samples as in the control samples. Our study shows that various constitutional autosomal trisomies are associated with an increased frequency of non-chromosome specific aneuploidy and is a continuation of the previous study documenting sporadic aneuploidy in Turner’s sample cells. It is possible that primary aneuploid cells destabilize their own genome resulting in variable aneuploidy of other chromosomes. It is also possible that one or several common factor(s) is/are involved in both constitutional and sporadic aneuploidy.
The Role of Shugoshin in Meiotic Chromosome Segregation
Authors: Clift D. , Marston A.L.
Published: March 2011

During meiosis, DNA replication is followed by 2 successive chromosome segregation events, resulting in the production of gametes with a haploid number of chromosomes from a diploid precursor cell. Faithful chromosome segregation in meiosis requires that sister chromatid cohesion is lost from chromosome arms during meiosis I, but retained at centromeric regions until meiosis II. Recent studies have begun to uncover the mechanisms underlying this stepwise loss of cohesion in meiosis and the role of a conserved protein, shugoshin, in regulating this process.
Aneuploidy in the Human Cleavage Stage Embryo
Authors: Mantzouratou A. , Delhanty J.D.A.
Published: March 2011

The cleavage stage embryo (days 1–3) stands out due to the high level of chromosomal anomalies, especially mosaicism that arises prior to global embryonic genome activation. Molecular cytogenetic studies show that an average of 60% of in vitro derived embryos have at least one aneuploid cell by the time they are 3 days old. However, comprehensive studies of the chromosome content of individual cells have revealed that 25% of these embryos have no aneuploid cells, a fact that sits well with the knowledge that at most 1 in 5 have the capacity to implant. The evidence is that extensive mosaicism, affecting several chromosomes, interferes with development to a greater extent than does uniform aneuploidy. Follow-up studies on embryos after pre-implantation genetic aneuploidy screening indicate that the frequency of meiotic errors varies according to the referral reason, with the highest frequency being recorded for the recurrent miscarriage category and the lowest in the repeated implantation failure group where younger women have a good response to ovarian stimulation. The exceptionally high incidence of pre- and post-zygotic chromosomal anomalies seen in early human embryos is thus the product of several mechanisms. Firstly, the error-prone cell cycle during the embryonic cleavage stage and secondly, parental susceptibility to meiotic and mitotic chromosomal instability together with their general genetic background.
Chromosome Abnormalities in the Human Oocyte
Authors: Fragouli E. , Wells D. , Delhanty J.D.A.
Published: March 2011

Aneuploidy is the most commonly occurring type of chromosome abnormality and the most significant clinically. It arises mostly due to segregation errors taking place during female meiosis and is also closely associated with advancing maternal age. Two main aneuploidy-causing mechanisms have been described: the first involves the non-disjunction of entire chromosomes and can take place during both meiotic divisions, whereas the second involves the premature division of a chromosome into its 2 sister chromatids, followed by their random segregation, upon completion of meiosis I. To elucidate the causal mechanisms of maternally derived aneuploidy and the manner with which they affect the 2 meiotic divisions, a large number of oocytes and their corresponding polar bodies have been examined. Various classical and molecular cytogenetic methods have been employed for this purpose, and valuable data have been obtained. Moreover, research into the gene expression patterns of oocytes according to maturity, maternal age, and chromosome status has provided a unique insight into the complex nature of the biological processes and genetic pathways regulating female meiosis. Findings obtained from the cytogenetic and molecular analysis of oocytes will be reviewed in this article.
Inositol Phospholipid Signaling and the Biology of Natural Killer Cells
Authors: Kerr William G. , Colucci Francesco
Published: March 2011

A family of phosphoinositide-3 kinase (PI3K) isoenzymes catalyzes the production of second messengers that recruit critical regulators of cell growth, survival, proliferation and motility. Conversely, 3′- (phosphatase and tensin homolog) and 5′-inositol polyphosphatases (SH2-containing inositol phosphatases 1/2, SHIP1/2) are recruited to sites of PI3K signaling at the plasma membrane to oppose or, in some cases, to modify and enhance PI3K signaling. A substantial and growing body of literature demonstrates that these enzymes which mediate interchange of phosphates on inositol phospholipid species at the plasma membrane have prominent roles in natural killer cell biology, including development, effector functions and trafficking. Here, we review the salient points of these recent papers with a special emphasis on the role of p110δ and SHIP1 in natural killer cells.
Vis-à-Vis in the NKC: Genetically Linked Natural Killer Cell Receptor/Ligand Pairs in the Natural Killer Gene Complex (NKC)
Authors: Vogler Isabel , Steinle Alexander
Published: March 2011

The natural killer gene complex (NKC) encodes several dozens of C-type lectin-like receptors that, in various ways, tune the reactivity of NK cells and other cytotoxic lymphocytes depending on the cellular environment. Among these are C-type lectin-like receptors such as NKG2D, CD94/NKG2A and the murine Ly49 receptors that bind to cell surface glycoproteins of the major histocompatibility complex (MHC) class I family and thereby facilitate detection of stressed cells or cells exhibiting aberrant MHC class I expression. In contrast, NKRP1 receptors including the prototypic NK1.1 do not engage ligands with an MHC class-I-like fold, but rather interact with the likewise C-type lectin-like CLEC2 glycoproteins. Notably, CLEC2 and NKRP1 molecules not only share the same fold, but are also genetically linked in the NKC. Recent research efforts began to systematically elucidate the expression and function of the numerous NKRP1 and CLEC2 family members in rodents and revealed previously unnoticed corresponding receptor/ligand pairs in humans. Here, we provide a snapshot of the current knowledge on receptors of the NKRP1 family and their genetically linked CLEC2 ligands in mouse and man.
New Insights into the Genetic Regulation of Homologue Disjunction in Mammalian Oocytes
Authors: Homer H.
Published: March 2011

Mammalian oocytes execute a unique meiotic programme involving 2 arrest stages and an unusually protracted preamble to chromosome segregation during the first meiotic division (meiosis I). How mammalian oocytes successfully navigate their exceptional meiotic journey has long been a question of immense interest. Understanding the minutiae of female mammalian meiosis I is not merely of academic interest as 80–90% of human aneuploidy is the consequence of errors arising at this particular stage of oocyte maturation, a stage with a peculiar vulnerability to aging. Recent evidence indicates that oocytes employ many of the same cast of proteins during meiosis I as somatic cells do during mitosis, often to execute similar tasks, but intriguingly, occasionally delegate them to unexpected and unprecedented roles. This is epitomised by the master cell-cycle regulon, the anaphase-promoting complex or cyclosome (APC/C), acting in concert with a critical APC/C-targeted surveillance mechanism, the spindle assembly checkpoint (SAC). Together, the APC/C and the SAC are among the most influential entities overseeing the fidelity of cell-cycle progression and the precision of chromosome segregation. Here I review the current status of pivotal elements underpinning homologue disjunction in mammalian oocytes including spindle assembly, critical biochemical anaphase-initiating events, APC/C activity and SAC signalling along with contemporary findings relevant to progressive oocyte SAC dysfunction as a model for age-related human aneuploidy.
Comparison of 7.0-T T2*-Magnetic Resonance Imaging of Cerebral Bleeds in Post-Mortem Brain Sections of Alzheimer Patients with Their Neuropathological Correlates
Authors: De Reuck J. , Auger F. , Cordonnier C. , Deramecourt V. , Durieux N. , Pasquier F. , Bordet R. , Maurage C.A. , Leys D.
Published: March 2011

Background: In view of the increasing recognition of cerebral microbleeds (MCBs) with MRI, there is a need to validate their detection in post-mortem brains in patients with cerebrovascular diseases and dementia. Materials and Methods: Out of 20 post-mortem brains of patients with Alzheimer dementia and with different cerebrovascular lesions, 45 large sections of the cerebral hemispheres, brainstem and cerebellum were submitted to a 7.0-T T2*-weighted MRI, and afterwards compared to the histological detection of haematomas, MCBs and mini-bleeds (MNBs). Results: The sensitivity, specificity, predictive positive value and predictive negative value of the T2* imaging to detect MCBs and MNBs were excellent for those in the cortico-subcortical regions. There was a significant overestimation of MNBs in the striatum due to iron deposits unrelated to old haemorrhages. Also in the deep white matter, 42% of MNBs were not detected, while 31% of T2* hyposignals were not due to MNBs but to vessels filled with post-mortem thrombi. Conclusions: When evaluating the ‘bleeding load’ with 7.0-T T2*-weighted MRI in post-mortem brain sections of patients with dementia and vascular risk factors, only quantification of small cerebral bleeds in the cortico-subcortical regions is reliable.
Where’s the Evidence?
Authors: Vieland Veronica J.
Published: March 2011

Science is in large part the art of careful measurement, and a fixed measurement scale is the sine qua non of this art. It is obvious to us that measurement devices lacking fixed units and constancy of scale across applications are problematic, yet we seem oddly laissez faire in our approach to measurement of one critically important quantity: statistical evidence. Here I reconsider problems with reliance on p values or maximum LOD scores as measures of evidence, from a measure-theoretic perspective. I argue that the lack of an absolute scale for evidence measurement is every bit as problematic for modern biological research as was lack of an absolute thermal scale in pre-thermodynamic physics. Indeed, the difficulty of establishing properly calibrated evidence measures is strikingly similar to the problem 19th century physicists faced in deriving an absolute scale for the measurement of temperature. I propose that the formal relationship between the two problems might enable us to apply the mathematical foundations of thermodynamics to establish an absolute scale for the measurement of evidence, in statistical applications and possibly other areas of mathematical modeling as well. Here I begin to sketch out what such an endeavor might look like.
Activity of the Two-Component Regulatory System CiaRH in Streptococcus pneumoniae R6
Authors: Halfmann Alexander , Schnorpfeil Anke , Müller Miriam , Marx Patrick , Günzler Ulrike , Hakenbeck Regine , Brückner Reinhold
Published: March 2011

The two-component regulatory system CiaRH of Streptococcus pneumoniae affects a variety of processes such as competence development, autolysis, bacteriocin production, host colonization, and virulence. While the targets of the regulator CiaR are known, the role of phosphorylation in CiaR regulation has not been defined. To address this issue, the presumed phosphorylation site of CiaR, aspartic acid at position 51, was replaced by alanine. The mutant CiaRD51A protein was no longer able to activate CiaR-dependent promoters, strongly suggesting that the phosphorylated form of CiaR is active in regulation. However, depending on the growth medium, inactivation of the kinase gene ciaH resulted in a subtle increase of CiaR-dependent promoter activities or in a strong reduction. Therefore, CiaH may act as a kinase or phosphatase and CiaR is apparently able to obtain its phosphate independently of CiaH. On the other hand, promoter measurements in cells with an intact CiaRH system demonstrated a high, nearly constitutive, expression level of the CiaR regulon independent from the growth medium. Thus, in contrast to many other two-component regulatory systems, CiaRH has apparently evolved to maintain high levels of gene expression under a variety of conditions rather than responding strongly to a signal.
KLOTHO Gene Polymorphism of G395A Is Associated with Kidney Stones
Authors: Telci Dilek , Dogan Ali Umman , Ozbek Emin , Polat Emre Can , Simsek Abdulmuttalip , Cakir Suleyman Sami , Yeloglu Hakki Okan , Sahin Fikrettin
Published: March 2011

Background/Aims: KLOTHO, a type-1 transmembrane protein with glucurodinase activity, is expressed in tissues responsible for calcium homeostasis such as the kidney, parathyroid gland and the epithelium of the choroid plexus in the brain. Given the emerging evidence indicating a novel regulatory function for KLOTHO protein in renal calcium and phosphate homeostasis, the present study aims to investigate the association between KLOTHO genetic polymorphisms and kidney stone (KS). Methods:KLOTHO gene polymorphisms G395A in the promoter region, F252V in exon 2, and C1818T in exon 4 were investigated in 108 patients with renal calcium stone formation and 51 age-matched healthy volunteers with no history of renal stone formation, using polymerase chain reaction. Results: GG genotype of G395A KLOTHO polymorphism had approximately 2-fold increased KS risk compared with the homozygous genotype AA and heterozygote GA (OR 1.849, 95% CI 1.016–3.364, p = 0.044). We also found that non-A allele carriers had significantly higher KS risk associated with the KS clinical characteristics including hypercalcemia, hypophosphatemia and phosphaturia. Conclusion: Our findings suggested that the G395A polymorphism of KLOTHO gene is associated with the KSs and may act as a risk factor for the development of KS disease.
Alfred Vulpian and Jean-Martin Charcot in Each Other’s Shadow? From Castor and Pollux at La Salpêtrière to Neurology Forever
Authors: Bogousslavsky Julien , Walusinski Olivier , Moulin Thierry
Published: March 2011

While Alfred Vulpian (1826–1887) is not completely forgotten, he cannot match the uninterrupted celebrity which Jean-Martin Charcot (1825–1893) still enjoys today. After becoming interne (residents) at the same institute in 1848, both were involved in shaping the cradle of what would become modern neurology. Both started work as chiefs at a La Salpêtrière service on January 1, 1862, making common rounds and studies, with several common publications. While their friendship remained ‘for life’, as stated by Charcot at Vulpian’s funeral, their career paths differed. Vulpian progressed quicker and higher, being appointed full professor and elected at the Académie Nationale de Médecine and the Académie des Sciences several years before Charcot, as well as becoming dean of the Paris Faculty of Medicine. These positions also enabled him to support his friend Charcot in getting appointed full clinical professor and becoming the first holder of the chair of Clinique des Maladies du Système Nerveux in 1882. Before studying medicine, Vulpian had worked in physiology with Pierre Flourens, and his career always remained balanced between physiology and neurology, with remarkable papers. He introduced Charcot to optic microscopy during their La Salpêtrière years, indirectly helping him to become his successor to the chair of pathological anatomy in 1872. While Vulpian succeeded so well in local medical affairs, Charcot spent his time building up a huge clinical service and a teaching ‘school’ at La Salpêtrière, which he never left for over 31 years until his death. This ‘school’ progressively became synonymous with clinical neurology itself and perpetuated the master’s memory for decades. Vulpian never had such support, although Jules Déjerine was his pupil and Joseph Babinski was his interne before becoming Charcot’s chef de clinique (chief of staff) in 1885. This unusual switch in Parisian medicine contributed to Charcot’s unaltered celebrity over more than a century, while Vulpian was progressively relegated to the studies of historians. However, Vulpian and Charcot remain inseparable in the memory of a lifelong friendship which gave birth to neurology.
Stent Thrombogenicity Early in High-Risk Interventional Settings Is Driven by Stent Design and Deployment and Protected by Polymer-Drug Coatings
Authors: Kolandaivelu Kumaran , Swaminathan Rajesh , Gibson William J. , Kolachalama Vijaya B. , Nguyen-Ehrenreich Kim-Lien , Giddings Virginia L. , Coleman Leslie , Wong Gee K. , Edelman Elazer R.
Published: March 2011

Background—

Stent thrombosis is a lethal complication of endovascular intervention. Concern has been raised about the inherent risk associated with specific stent designs and drug-eluting coatings, yet clinical and animal support is equivocal.

Methods and Results—

We examined whether drug-eluting coatings are inherently thrombogenic and if the response to these materials was determined to a greater degree by stent design and deployment with custom-built stents. Drug/polymer coatings uniformly reduce rather than increase thrombogenicity relative to matched bare metal counterparts (0.65-fold;
P
=0.011). Thick-strutted (162 μm) stents were 1.5-fold more thrombogenic than otherwise identical thin-strutted (81 μm) devices in ex vivo flow loops (
P
<0.001), commensurate with 1.6-fold greater thrombus coverage 3 days after implantation in porcine coronary arteries (
P
=0.004). When bare metal stents were deployed in malapposed or overlapping configurations, thrombogenicity increased compared with apposed, length-matched controls (1.58-fold,
P
=0.001; and 2.32-fold,
P
<0.001). The thrombogenicity of polymer-coated stents with thin struts was lowest in all configurations and remained insensitive to incomplete deployment. Computational modeling–based predictions of stent-induced flow derangements correlated with spatial distribution of formed clots.

Conclusions—

Contrary to popular perception, drug/polymer coatings do not inherently increase acute stent clotting; they reduce thrombosis. However, strut dimensions and positioning relative to the vessel wall are critical factors in modulating stent thrombogenicity. Optimal stent geometries and surfaces, as demonstrated with thin stent struts, help reduce the potential for thrombosis despite complex stent configurations and variability in deployment.
Cardiorespiratory Fitness and Classification of Risk of Cardiovascular Disease Mortality
Authors: Gupta Sachin , Rohatgi Anand , Ayers Colby R. , Willis Benjamin L. , Haskell William L. , Khera Amit , Drazner Mark H. , de Lemos James A. , Berry Jarett D.
Published: March 2011

Background—

Cardiorespiratory fitness (fitness) is associated with cardiovascular disease (CVD) mortality. However, the extent to which fitness improves risk classification when added to traditional risk factors is unclear.

Methods and Results—

Fitness was measured by the Balke protocol in 66 371 subjects without prior CVD enrolled in the Cooper Center Longitudinal Study between 1970 and 2006; follow-up was extended through 2006. Cox proportional hazards models were used to estimate the risk of CVD mortality with a traditional risk factor model (age, sex, systolic blood pressure, diabetes mellitus, total cholesterol, and smoking) with and without the addition of fitness. The net reclassification improvement and integrated discrimination improvement were calculated at 10 and 25 years. Ten-year risk estimates for CVD mortality were categorized as <1%, 1% to <5%, and ≥5%, and 25-year risk estimates were categorized as <8%, 8% to 30%, and ≥30%. During a median follow-up period of 16 years, there were 1621 CVD deaths. The addition of fitness to the traditional risk factor model resulted in reclassification of 10.7% of the men, with significant net reclassification improvement at both 10 years (net reclassification improvement=0.121) and 25 years (net reclassification improvement=0.041) (
P
<0.001 for both). The integrated discrimination improvement was 0.010 at 10 years (
P
<0.001), and the relative integrated discrimination improvement was 29%. Similar findings were observed for women at 25 years.

Conclusions—

A single measurement of fitness significantly improves classification of both short-term (10-year) and long-term (25-year) risk for CVD mortality when added to traditional risk factors.
Association of DASH Diet With Cardiovascular Risk Factors in Youth With Diabetes Mellitus
Authors: Liese Angela D. , Bortsov Andrey , Günther Anke L.B. , Dabelea Dana , Reynolds Kristi , Standiford Debra A. , Liu Lenna , Williams Desmond E. , Mayer-Davis Elizabeth J. , D'Agostino Ralph B. , Bell Ronny , Marcovina Santica
Published: March 2011

Background—

We have shown that adherence to the Dietary Approaches to Stop Hypertension (DASH) diet is related to blood pressure in youth with type 1 and type 2 diabetes mellitus. We explored the impact of the DASH diet on other cardiovascular disease risk factors.

Methods and Results—

Between 2001 and 2005, data on total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, low-density lipoprotein particle density, apolipoprotein B, body mass index, waist circumference, and adipocytokines were ascertained in 2130 youth aged 10 to 22 years with physician-diagnosed diabetes mellitus. Dietary intake was assessed by food frequency questionnaire, categorized into the DASH food groups, and assigned an adherence score. Among youth with type 1 diabetes mellitus, higher adherence to the DASH diet was significantly and inversely associated with low-density lipoprotein/high-density lipoprotein ratio and A
1c
in multivariable-adjusted models. Youth in the highest adherence tertile had an estimated 0.07 lower low-density lipoprotein/high-density lipoprotein ratio and 0.2 lower A
1c
levels than those in the lowest tertile adjusted for confounders. No significant associations were observed with triglycerides, low-density lipoprotein particle density, adipocytokines, apolipoprotein B, body mass index
Z
score, or waist circumference. Among youth with type 2 diabetes mellitus, associations were observed with low-density lipoprotein particle density and body mass index
Z
score.

Conclusions—

The DASH dietary pattern may be beneficial in the prevention and management of cardiovascular disease risk in youth with diabetes mellitus.
Do Postmarketing Surveillance Studies Represent Real-World Populations?
Authors: Yeh Robert W. , Kennedy Kevin , Spertus John A. , Parikh Sahil A. , Sakhuja Rahul , Anderson H. Vernon , White Christopher J. , Rosenfield Kenneth
Published: March 2011

Background—

To evaluate outcomes after carotid artery stenting in larger real-world populations, the Food and Drug Administration mandated that companies conduct postmarketing surveillance (PMS) studies of approved stent systems. Whether PMS studies are representative of carotid artery stenting in routine clinical practice has not been established.

Methods and Results—

Within the National Cardiovascular Database Registry–Carotid Artery Revascularization and Endarterectomy (NCDR CARE) Registry, we compared patient and procedural characteristics, in-hospital outcomes, and subsequent all-cause mortality after carotid artery stenting in PMS study participants and nonparticipants. We conducted both crude and propensity score–adjusted comparisons for all outcomes between groups. Compared with nonparticipants, participants in PMS studies had lower rates of symptomatic carotid artery disease within the preceding 6 months, prior stroke, and acute evolving stroke at baseline. The PMS study participants had lower unadjusted rates of combined in-hospital death, stroke, or myocardial infarction (2.3% versus 4.1%;
P
<0.001), driven by lower rates of stroke (1.7% versus 2.7%;
P
=0.005) and death (0.3% versus 1.4%;
P
<0.001). Differences in survival persisted after propensity score adjustment (odds ratio, 0.44; 95% confidence interval, 0.21 to 0.95;
P
=0.04 for in-hospital mortality; and hazard ratio, 0.80; 95% confidence interval, 0.66 to 0.97;
P
=0.02 for 2-year mortality). Baseline differences in neurological history explained the largest proportion of the difference in outcomes between groups.

Conclusions—

Participants in PMS studies for carotid artery stenting have different clinical and procedural characteristics and lower mortality compared with nonparticipants. Extrapolating results from PMS studies of carotid artery stenting to larger real-world settings should be done only with great caution.
Control of Blood Pressure, Appetite, and Glucose by Leptin in Mice Lacking Leptin Receptors in Proopiomelanocortin Neurons
Authors: do Carmo Jussara M. , da Silva Alexandre A. , Cai Zhengwei , Lin Shuying , Dubinion John H. , Hall John E.
Published: March 2011

Although the central nervous system melanocortin system is an important regulator of energy balance, the role of proopiomelanocortin (POMC) neurons in mediating the chronic effects of leptin on appetite, blood pressure, and glucose regulation is unknown. Using Cre/loxP technology we tested whether leptin receptor deletion in POMC neurons (LepR
flox/flox
/POMC-Cre mice) attenuates the chronic effects of leptin to increase mean arterial pressure (MAP), enhance glucose use and oxygen consumption, and reduce appetite. LepR
flox/flox
/POMC-Cre, wild-type, LepR
flox/flox
, and POMC-Cre mice were instrumented for MAP and heart rate measurement by telemetry and venous catheters for infusions. LepR
flox/flox
/POMC-Cre mice were heavier, hyperglycemic, hyperinsulinemic, and hyperleptinemic compared with wild-type, LepR
flox/flox
, and POMC-Cre mice. Despite exhibiting features of metabolic syndrome, LepR
flox/flox
/POMC-Cre mice had normal MAP and heart rate compared with LepR
flox/flox
but lower MAP and heart rate compared with wild-type mice. After a 5-day control period, leptin was infused (2 μg/kg per minute, IV) for 7 days. In control mice, leptin increased MAP by ≈5 mm Hg despite decreasing food intake by ≈35%. In contrast, leptin infusion in LepR
flox/flox
/POMC-Cre mice reduced MAP by ≈3 mm Hg and food intake by ≈28%. Leptin significantly decreased insulin and glucose levels in control mice but not in LepR
flox/flox
/POMC-Cre mice. Leptin increased oxygen consumption in LepR
flox/flox
/POMC-Cre and wild-type mice. Activation of POMC neurons is necessary for the chronic effects of leptin to raise MAP and reduce insulin and glucose levels, whereas leptin receptors in other areas of the brain other than POMC neurons appear to play a key role in mediating the chronic effects of leptin on appetite and oxygen consumption.
Angiotensin II Binding to Angiotensin I–Converting Enzyme Triggers Calcium Signaling
Authors: Guimarães Paola B. , Alvarenga Érika C. , Siqueira Paula D. , Paredes-Gamero Edgar J. , Sabatini Regiane A. , Morais Rafael L.T. , Reis Rosana I. , Santos Edson L. , Teixeira Luis G.D. , Casarini Dulce E. , Martin Renan P. , Shimuta Suma I. , Carmona Adriana K. , Nakaie Clovis R. , Jasiulionis Miriam G. , Ferreira Alice T. , Pesquero Jorge L. , Oliveira Suzana M. , Bader Michael , Costa-Neto Claudio M. , Pesquero João B.
Published: March 2011

Angiotensin (Ang) I–converting enzyme (ACE) is involved in the control of blood pressure by catalyzing the conversion of Ang I into the vasoconstrictor Ang II and degrading the vasodilator peptide bradykinin. Human ACE also functions as a signal transduction molecule, and the binding of ACE substrates or its inhibitors initiates a series of events. In this study, we examined whether Ang II could bind to ACE generating calcium signaling. Chinese hamster ovary cells transfected with an ACE expression vector reveal that Ang II is able to bind with high affinity to ACE in the absence of the Ang II type 1 and type 2 receptors and to activate intracellular signaling pathways, such as inositol 1,4,5-trisphosphate and calcium. These effects could be blocked by the ACE inhibitor, lisinopril. Calcium mobilization was specific for Ang II, because other ACE substrates or products, namely Ang 1-7, bradykinin, bradykinin 1-5, and
N
-acetyl-seryl-aspartyl-lysyl-proline, did not trigger this signaling pathway. Moreover, in Tm5, a mouse melanoma cell line endogenously expressing ACE but not Ang II type 1 or type 2 receptors, Ang II increased intracellular calcium and reactive oxygen species. In conclusion, we describe for the first time that Ang II can interact with ACE and evoke calcium and other signaling molecules in cells expressing only ACE. These findings uncover a new mechanism of Ang II action and have implications for the understanding of the renin-Ang system.
Multiplicative Gain Modulation Arises Through Unsupervised Learning in a Predictive Coding Model of Cortical Function
Authors: De Meyer Kris , Spratling Michael W.
Published: March 2011

The combination of two or more population-coded signals in a neural model of predictive coding can give rise to multiplicative gain modulation in the response properties of individual neurons. Synaptic weights generating these multiplicative response properties can be learned using an unsupervised, Hebbian learning rule. The behavior of the model is compared to empirical data on gaze-dependent gain modulation of cortical cells and found to be in good agreement with a range of physiological observations. Furthermore, it is demonstrated that the model can learn to represent a set of basis functions. This letter thus connects an often-observed neurophysiological phenomenon and important neurocomputational principle (gain modulation) with an influential theory of brain operation (predictive coding).
Model Estimates of the Land and Ocean Contributions to Biospheric Carbon and Water Fluxes Using MODIS Satellite Data
Authors: Alton Paul B. , Bodin Per E.
Published: March 2011

Land and ocean are often treated separately in modeling studies despite their close links through the carbon, water, and energy cycles. However, biospheric models, particularly when used in conjunction with recent satellite datasets, provide a new, fully coupled, global perspective. The current investigation uses a new version of the Grid Enabled Integrated Earth system (GENIE-SF) to compare both the magnitude and the seasonal and zonal variation in water flux [evaporation E and precipitation (PPT)] and carbon flux [net primary productivity (NPP)] above land and ocean. GENIE-SF contains state-of-the-art representations of photosynthesis and is driven by the phenological cycles of leaf area index (LAI) and marine chlorophyll concentration, both recorded with the Moderate Resolution Imaging Spectroradiometer (MODIS) satellite sensors. The current study reveals the striking uniformity of the ocean–atmosphere carbon and water flux exchange, both temporally and spatially, compared to the corresponding land–atmosphere exchange. Although biospheric annual NPP (108 ± 27 GtC yr−1) is split almost equally between land (52% ± 9%) and ocean (48% ± 9%), the oceanic contribution to biospheric annual E exceeds that of the land by a factor of 6.7 ± 1.7. Simulations conducted over a 50-yr period (1951–2000) suggest that a 16% increase in land NPP, owing mainly to CO2 fertilization, may be partially offset by a decline in marine productivity.
YouTube-ification of Political Talk: An Examination of Persuasion Appeals in Viral Video
Authors: English Kristin , Sweetser Kaye D. , Ancu Monica
Published: March 2011

In 2008, U.S. Internet users watched 14 billion videos on YouTube. During the 2008 presidential campaign, voters rated watching YouTube political videos as one of the top three most popular online political activities. But to what degree are YouTube political videos influential of viewers’ perceptions, and to what degree does the source of the video make an impact? Similar to all other new forms of online communication, the effects of YouTube clips on consumers of political information, and the credibility of these messages, have yet to be understood. This study takes a step into that direction through a three-cell posttest-only experimental design that exposed participants to three YouTube clips about health care, each clip containing a different persuasive appeal (source or ethos, logic or logos, and emotion or pathos). Results revealed that the ethos appeal ranked as the most credible appeal, followed by logos and pathos, a somewhat promising finding that users resist being swayed by emotion or hard numbers and pay attention to message source. No relationship was found between the appeals and political information efficacy or the political cynicism of participants.
Impact of Metabolic Syndrome on Clinical Outcomes After Drug-Eluting Stent Implantation in Patients With Coronary Artery Disease
Authors: Bin Hu  , Yujie Zhou  , Yuyang Liu  , Dongmei Shi  , Yingxin Zhao  , Dean Jia  , Shiwei Yang  , Zhe Fang  , Bin Nie
Published: March 2011

Metabolic syndrome (MetS) is regarded as a risk factor for coronary artery disease (CAD). However, the influence of MetS on morbidity and mortality after drug-eluting stent (DES) implantation in Chinese patients with CAD remains unknown. We evaluated the impact of MetS on the clinical outcome of 1224 patients following DES implantation. After a mean follow-up of 35.4 months, patients with MetS had a significantly higher incidence of all-cause death and major adverse cardiovascular events (MACE) compared with patients without MetS (P < .001). Analyses of individual MetS components showed that dysglycemia at the time of DES implantation predicted increased all-cause mortality, while the presence of hypertension and dysglycemia predicted increased incidence of MACE.
The Study of Religion in the University: Beyond Scientific and Humanistic Approaches
Authors: Stoever William K.B.
Published: March 2011

This essay considers an exchange between ‘‘new secular’’ theologians in the US and a Canadian proponent of the scientific study of religion, about humanistic and scientific values in the academic study of religion, in relation to the character of contemporary universities and the scope of the humanities. It suggests that the humanistic study of religion is culturally normal in North American higher education and educationally important, but is limited as a program for the study of religion as social reality. The essay argues that systematic, integrated study of religions, incorporating contemporary knowledge about human behavior, is necessary for understanding actions of religious people in social and historical circumstances. To this end it proposes an integrated causal model, drawing on Michael Pye’s concept of Religionswissenschaft and Talcott Parsons’s general action theory.
The Long-Term Sustainability of Different Item Response Theory Scaling Methods
Authors: Keller Lisa A. , Keller Robert R.
Published: March 2011

This article investigates the accuracy of examinee classification into performance categories and the estimation of the theta parameter for several item response theory (IRT) scaling techniques when applied to six administrations of a test. Previous research has investigated only two administrations; however, many testing programs equate tests across multiple administrations. As such, this article seeks to examine the long-term sustainability of IRT scaling methods. Three different types of shifts in the ability distribution were examined: no change, a mean shift, and a change in skewness. Haebara, Stocking and Lord, mean—sigma, mean—mean, and fixed common item parameter (FCIP) scaling were compared relative to bias, root mean square error, and classification of examinees into performance categories. Results indicate that FCIP may be the most suitable for complex changes in examinee performance, whereas the methods performed quite similarly for simple changes.
Constrained Maximum Likelihood Estimation for Two-Level Mean and Covariance Structure Models
Authors: Bentler Peter M. , Liang Jiajuan , Tang Man-Lai , Yuan Ke-Hai
Published: March 2011

Maximum likelihood is commonly used for the estimation of model parameters in the analysis of two-level structural equation models. Constraints on model parameters could be encountered in some situations such as equal factor loadings for different factors. Linear constraints are the most common ones and they are relatively easy to handle in maximum likelihood analysis. Nonlinear constraints could be encountered in complicated applications. The authors develop an EM-type algorithm for estimating model parameters with both linear and nonlinear constraints. The empirical performance of the algorithm is demonstrated by a Monte Carlo study. Application of the algorithm for linear constraints is illustrated by setting up a two-level mean and covariance structure model for a real two-level data set and running an EQS program.