bluuebunny/crossref_metadata_2025 huggingface dataset:
Current Technique of Fluid Status Assessment
Authors: Frank Peacock W. , Soto Karina M.
Published: July 2010

Congest Heart Fail. 2010;16(4)(suppl 1):S45–S51. ©2010 Wiley Periodicals, Inc.

Early in the management of acute illness, it is critically important that volume status is accurately estimated. If inappropriate therapy is given because of errors in volume assessment, acute mortality rates are increased. Unfortunately, as the gold standard of radioisotopic volume measurement is costly and time‐consuming, in the acute care environment clinicians are forced to rely on less accurate measures. In this manuscript, the authors review the currently available techniques of volume assessment for patients presenting with acute illness. In addition to discussing the accuracy of the history, physical examination, and radiography, acoustic cardiography and bedside ultrasonography are presented.
RIFLE Criteria for Cardiac Surgery–Associated Acute Kidney Injury: Risk Factors and Outcomes
Authors: D’Onofrio Augusto , Cruz Dinna , Bolgan Irene , Auriemma Stefano , Cresce Giovanni D. , Fabbri Alessandro , Ronco Claudio
Published: July 2010

The aims of this study were to identify risk factors and evaluate the association with clinical outcomes of postoperative cardiac surgery–associated acute kidney injury (CSA‐AKI). Data from 2488 consecutive adult patients were analyzed. Patients were classified as having CSA‐AKI based on the risk, injury, failure, loss of kidney function, and end‐stage kidney disease (RIFLE) criteria using peak postoperative creatinine in the postoperative intensive care unit (ICU). Multiple stepwise logistic regression analysis was used to identify independent risk factors for CSA‐AKI. CSA‐AKI occurred in 584 patients (23.5%). CSA‐AKI patients had significantly longer aortic cross‐clamp and cardiopulmonary bypass times. Furthermore, CSA‐AKI patients had higher hospital mortality (5.5% vs 1.5%, P<.001) and significantly longer ICU and hospital stays. Independent risk factors for CSA‐AKI were age, peripheral vascular disease, hypertension, left ventricular ejection fraction, cardiopulmonary bypass time, and surgery on the thoracic aorta. In conclusion, patients who develop CSA‐AKI have a higher preoperative risk profile, more complex surgery, and worse clinical outcomes. Congest Heart Fail. 2010;16(4)(suppl 1):S32–S36. ©2010 Wiley Periodicals, Inc.
A Double‐Blind, Randomized, Placebo and Active‐Controlled Study of Nebicapone for the Treatment of Motor Fluctuations in Parkinson's Disease
Authors: Ferreira Joaquim J. , Rascol Olivier , Poewe Werner , Sampaio Cristina , Rocha José‐Francisco , Nunes Teresa , Almeida Luis , Soares‐da‐Silva Patrício ,   on behalf of the BIA‐3202‐202 Study Investigators
Published: July 2010

To determine the efficacy, safety and tolerability of nebicapone, a new catechol‐O‐methyltransferase inhibitor for the treatment of motor fluctuations in Parkinson's disease (PD), we conducted a multicenter, randomized, 8‐week double‐blind, placebo‐ and active‐controlled, parallel‐group study comparing nebicapone 50 mg, 100 mg, or 150 mg, entacapone 200 mg (active control) or placebo administered concomitantly with levodopa/carbidopa or levodopa/benserazide. Two hundred and fifty‐two PD patients with motor fluctuations treated with levodopa/carbidopa or levodopa/benserazide (4–8 daily doses) were enrolled and 250 patients were eligible for intention‐to‐treat (ITT) analysis on the basis of having at least one efficacy assessment. The primary endpoint was 8‐week change from baseline in absolute “Off” time duration noted in self‐scoring diaries. At 8 weeks of treatment the mean daily “Off” time decreased significantly compared to placebo for nebicapone 150 mg (−106 min; 95%CI: −192; −21) and entacapone 200 mg (−81 min; 95%CI: −142; −19). The decrease in “Off” time with nebicapone 50 mg or 100 mg did not reach statistical significance. Treatment‐emergent adverse events were reported by 32% to 49% of patients in any treatment group, with no observed dose relationship in the nebicapone groups. Clinically relevant elevations in aspartate transaminase (AST) and/or alanine transaminase (ALT) were observed in 4 of 46 patients with the nebicapone 150 mg dose. The results of this study show that nebicapone 150 mg is efficacious for the treatment of motor fluctuations in PD patients. However, the risk of increasing liver transaminases and its clinically relevance deserves further evaluation.
Education and support for dominant ideology*
Authors: BAER DOUGLAS E. , LAMBERT RONALD D.
Published: July 2010

Utilisant les résultats du sondage national sur la qualité de la vie de 1977, nous avons examiné les quatre hypothèses qui expliquent l'influence de l'instruction sur l'opinion publique au sujet de l'inégalitééconomique. Les hypothèses sont l'instruction, la socialisation, la reproduction, et l'investissement.

L'élément français‐anglais et les différences d'âge sont examinés également. Les résultats des analyses multivariées favorisent la socialisation ainsi qu'une des versions de l'hypothèse d'investissement. Les problèmes rencontrés au cours de l'étude du concept d'une idéologie dominante et son utilité dans l'analyse du processus de légitimation au Canada, sont discutés également.

Using the Quality of Life (1977) national survey, we tested four hypotheses explaining the effects of education on people's beliefs about economic inequality. The hypotheses are enlightenment, socialization, reproduction, and investment. French‐English and age differences are also examined. Results of the multivariate analyses favour the socialization and one version of the investment hypotheses. Problems in thinking about the concept of dominant ideology and its utility in analyzing legitimation processes in Canada are discussed.
Psychological and cultural foundations of prejudice: The case of anti‐Semitism in Quebec
Authors: SNIDERMAN PAUL M. , NORTHRUP DAVID A. , FLETCHER JOSEPH F. , RUSSELL PETER H. , TETLOCK PHILIP E.
Published: July 2010

Cette communication documente l'existence de niveaux d'antisémitisme et d'ethnocentrisme systématiquement plus élevés au Québec qu'ailleurs au Canada, puis examine les facteurs socioculturels, psychologiques et politiques qui sous‐tendent ce phénomène. L'analyse des données de l'Enquěte sur la Charte des droits et libertés révèle que les facteurs socioculturels jouent le rǒle prépondérant. Plus particulièrement, la plus forte propension des Québécois à voir les Juifs d'un oeil défavorable est en grande partie attribuable à une plus grande valorisation de la conformité dans la culture québécoise. Ainsi, les Québécois diffèrent des autres canadiens non pas tant parce qu'ils souscrivent à tout l'éventail des préjugés antisémites, mais parce qu'ils acceptent les caractérisations négatives des Juifs sans se poser des questions. D'après les auteurs, l'antisémitisme au Québec ne s'explique ni par le nationalisme politique ni par des traits de personalité. La communication traite également de diverses questions concernant la méthodologie à employer pour mesurer l'antisémitisme.

Documenting consistently higher levels of anti‐Semitism and ethnocentrism in Quebec than elsewhere in Canada, this article investigates the sources of this prejudice in socio‐cultural, psychological and political factors. Analysis of survey data from the Charter of Rights Study show that socio‐cultural factors are most important. In particular, the greater readiness of Quebeckers to look unfavourably on Jews is largely a consequence of the high value placed upon conformity in Quebec culture. Quebeckers therefore differ from other Canadians not primarily in a willingness to subscribe to a full syndrome of anti‐Semitic sentiments, but in casually accepting negative characterizations of Jews. Anti‐Semitism in Quebec is found not to be related to nationalist political sentiments, nor is it substantially personality‐driven. A variety of methodological issues pertaining to the measurement of anti‐Semitism are also discussed.
The Massachusetts Court Clinic Program 1
Authors: Russell Donald Hayes , Devlin James M.
Published: July 2010

This article has been requested because Juvenile Judges are interested in the idea of Court Clinic services. They have their own ideas about their needs for such service, and how they would be served, Further, they would be interested in knowing how such a service can be established, how it must be implemented, what it is really like to have the service, and how the service should feel about the Court.
Clinical characteristics of patients with autoimmune hepatitis seropositive for anticentromere antibody
Authors: Himoto Takashi , Murota Masayuki , Yoneyama Hirohito , Deguchi Akihiro , Kurokochi Kazutaka , Senda Shoichi , Haba Reiji , Watanabe Seishiro , Nishioka Mikio , Masaki Tsutomu
Published: July 2010

Aim:  Recent studies have revealed that primary biliary cirrhosis patients with anticentromere antibody (ACA) commonly develop portal hypertension. However, the clinical characteristics of autoimmune hepatitis (AIH) remain uncertain. We investigated the clinical features of patients with AIH seropositive for ACA (ACA‐AIH), comparing them with those of patients with AIH seropositive for other immunofluorescent patterns of antinuclear antibodies (ANA) (other‐AIH).

Methods:  AIH was diagnosed on the basis of the scoring system proposed by the International Autoimmune Hepatitis Group. Seropositivity for ACA was determined by a discrete speckled pattern on HEp‐2 cells by an immunofluorescent technique. The severity of histological grading and staging was evaluated by the histological activity index (HAI) score.

Results:  Eight (17%) of 47 patients with AIH had ACA. No significant differences in age, sex, onset pattern of the disease, progression to hepatic failure and relapse rate were present between the ACA‐AIH and other‐AIH groups. The frequency of concurrent autoimmune diseases in ACA‐AIH was significantly higher than that in other‐AIH (75% vs 36%, P = 0.0406). Biochemical analysis revealed a significantly lower mean immunoglobulin G (IgG) level than that in other‐AIH (2176 ± 641 vs 3013 ± 923 mg/dL, P = 0.0150). However, there were no differences in serum alanine aminotransferase levels, titers of ANA, HAI scores or the positive rate of human leukocyte antigen (HLA)‐DR4 between the groups.

Conclusion:  These results suggest that the emergence of ACA is not a distinct entity of AIH, despite its clinical characteristics of a significantly higher frequency of concurrent autoimmune diseases and lower serum IgG levels.
A boreal forest grass with an open meadow photosynthetic strategy
Authors: Greenway Ken J. , Lieffers Victor J.
Published: July 2010

Calamagrostis canadensis is present in the understory of most boreal forest mixed-wood stands and can rapidly dominate an area once the overstory is removed. The nature of the photosynthetic response to light was studied by investigating the stomatal response to cycles of high and low fluence light, and by developing photosynthetic light response curves for sun- and shade-grown plants. Photosynthetic light response curves did not differ between sun- and shade-grown plants. However, higher stomatal conductances, at all light intensities, were found in shade-grown plants. Stomatal conductance tracked changes in light under intermittent high and low fluence light. Average rates of stomatal opening after a change from low to high light were greater than closing rates (23 vs. 17 mmol m−2 s−1/min). The faster opening response was negated by a 1 – to 2-min time lag between the onset of high light and the initiation of stomatal opening. Thus the time to reach 80% of maximal response did not differ between opening or closing. The photosynthetic system of C. canadensis is not particularly well adapted to intermittent light conditions. The poor performance in the understory of this apparently meadow-adapted photosynthetic system is offset by the gain in the ability to rapidly recolonize the site after disturbance. Key words: gas exchange, stomatal conductance, Calamagrostis canadensis, non-steady state photosynthesis, variable light.
White spruce resistance to white pine weevil related to bark resin canal density
Authors: Alfaro René I. , He Fangliang , Tomlin Elizabeth , Kiss G.
Published: July 2010

Examination of the bark from the uppermost lateral branches of white spruce, Picea glauca (Moench) Voss, indicated that trees resistant to attack by the white pine weevil, Pissodes strobi Peck, had significantly higher number and density of vertical resin canals per unit of bark area (mm2) than susceptible trees. The number and density of resin canals were also positively correlated with tree growth rate, an indicator of tree vigor. The density of the resin canals found near the periphery of the bark (outer resin canals) had higher correlation with resistance and growth than inner resin canals. Measurements of resin canals on the bark of lateral branches correlated well with measurements on the bark of the leader of the same tree, indicating that lateral samples could be used to screen white spruce for resistance to weevils. Key words: Picea glauca, Pissodes strobi, pest management, tree genetics.
Inflorescence and flower development in the Hedychieae (Zingiberaceae): Hedychium
Authors: Kirchoff Bruce K.
Published: July 2010

Flower organogenesis in Hedychium gardnerianum and Hedychium coronarium begins with the sequential formation of the sepals on a rounded–triangular apex. Growth in three regions of the apex, inside the sepals, produces three common petal – inner androecial primordia. Intercalary growth below and between these primordia produces a floral cup, the site of gynoecial formation. The common primordia separate to form petals and inner androecial members. After separation, the anterior inner androecial members fuse to form the labellum. The posterior member forms the polleniferous stamen. Up to this point in development, the flowers of H. coronarium are slightly ahead of those of H. gardnerianum. However, in H. gardnerianum, initiation of the two thecae of the stamen occurs immediately following the separation of the common primordia, while thecae formation in H. coronarium is slightly delayed. These results show that the relative timing of developmental events can vary even over a short developmental period. Formation of the outer androecium takes place at the apices of a triangle formed by the inner androecial members. The anterior outer androecial member aborts soon after formation, whereas the posterior outer androecial members form the two petaloid staminodes that are found on the lateral sides of the labellum in the mature flower. Key words: flower development, flower structure, inflorescence, stamen, Zingiberaceae, Hedychium.
Paleomagnetic evidence for multiple late Cenozoic glaciations in the Tintina Trench, west-central Yukon, CanadaThis article is a companion paper to Duk-Rodkin et al., also in this issue.
Authors: Barendregt René W. , Enkin Randolph J. , Duk-Rodkin Alejandra , Baker Judith
Published: July 2010

The Tintina Trench in west-central Yukon has preserved an extensive record of late Cenozoic preglacial, glacial, and interglacial deposits. These deposits comprise multiple sequences of tills, outwash, loesses, and paleosols. The sediments that were laid down directly by ice (tills) are of both local (montane) and regional (Cordilleran) provenance. The Tintina Trench area was impacted repeatedly by montane ice from the southern Ogilvie Mountains to the northwest (2500 m above sea level (asl)), and also repeatedly along its southern extent by Cordilleran ice from the Selwyn Mountains to the east (2759 m asl), the latter forming the continental divide in this region. We report here the magnetostratigraphy of three sections: Rock Creek (64°13′N, 139°07′W), West Fifteenmile River (64°29′N, 139°55′W), and East Fifteenmile River (64°23′N, 139°48′W). The majority of the units identified at these sections record late Pliocene to mid-Pleistocene glaciations, although relatively thin surficial sequences of late middle Pleistocene to late Pleistocene loesses and tills are present as well. Of the 11 units described in the Tintina Trench, seven have normal polarity, three have reversed polarity, and one has an undefined polarity. These units span about 3.0 million years. It appears that most of the polarity chrons and subchrons of the late Cenozoic are present and that the sequence of six reversals record at least 10 glaciations (three in the Brunhes Chron and seven in the Matuyama Chron), and 11 interglaciations (four in the Brunhes Chron and seven in the Matuyama Chron). The interglacials are recorded as either paleosols or unconformities between glacial or loess units having opposite polarity. While not all Matuyama Chron glacial and interglacial cycles recorded in marine isotopic records are seen on land, the terrestrial records found in the Tintina Trench have thus far proven to be the most complete in terms of the polarity record. While no absolute ages were obtained from the sediments in the trench, the extensive polarity sequence constrains the timing of glaciations to a considerably greater degree than was previously possible for this region. The magnetostratigraphy of the trench sites are compared with the glacial, glaciofluvial, and loessic deposits at the nearby Klondike River valley and Fort Selkirk sites, central Yukon, where tephras and basalts provide absolute ages, and stratigraphic units contain an extensive late Cenozoic climate proxy for northwestern North America (eastern Beringia). In this study, we present new paleomagnetic polarity data and establish a magneto-lithostratigraphy describing preglacial, glacial, and interglacial deposits in the Tintina Trench. These deposits are referred to as the West Tintina Trench Allogroup and provide a broad framework for establishing a paleoclimate record for the northern Canadian Cordillera.
Impact of growth environment and physiological state on metal immobilization byPseudomonas aeruginosaPAO1
Authors: Hunter Ryan C. , Phoenix Vernon R. , Saxena Anuradha , Beveridge Terry J.
Published: July 2010

Environmental growth conditions and cell physiology have the potential to influence bacterial surface–metal interactions in both planktonic and biofilm systems. Here, Pseudomonas aeruginosa was studied to determine the influence of these factors (pH, redox potential, and active respiration) on surface electrostatics and metal immobilization. Acid–base titrations revealed a decrease in ionizable ligands at pKa5 (putative carboxyls) in cells grown below pH 6.2 and in cells grown anaerobically relative to cells grown under oxic and circumneutral pH conditions. This observation correlates with Western immunoblotting assays that revealed a reduction in carboxylated B-band lipopolysaccharide in these cells. Furthermore, spectrophotometric analysis revealed a decrease in zinc, copper, and iron immobilization in these cells, suggesting that lipopolysaccharide modification in response to environmental stimuli influences metal binding. The effect of active versus inactive metabolism on metal adsorption was also examined using respiration inhibitors carbonyl cyanide m-chlorophenylhydrazone and sodium azide. Cells treated with these compounds bound more zinc, copper, and iron than untreated controls, suggesting proton extrusion through respiration competes with metal cations for reactive groups on the cell surface. Accumulation of gold did not show the same trend, and transmission electron microscopy studies confirmed it was not a surface-mediated process. These results suggest that variations in growth environment and cell physiology influence metal accumulation by bacterial cell surfaces and may help to explain discontinuous accumulation of metal observed throughout microbial communities.
Tetracycline-resistant coliforms in the effluent of the main sewage treatment plant in Hamilton, Ontario — do they have a common ancestral strain?
Authors: Sorger George J. , Quinn James S.
Published: July 2010

Sewage, a major source of bacterial contamination of the environment, can be an important health hazard. The presence of antibiotic-resistant bacteria in sewage can exacerbate this problem. The sources of antibiotic-resistant bacteria in sewage are, for this reason, worth identifying and addressing. The bacterial flora in the effluent of the Woodward Avenue Wastewater Treatment Plant (WAWTP) in Hamilton, Ontario, Canada, contains many antibiotic-resistant coliforms. Here we ask, are the antibiotic resistance genes in the coliforms in the effluent of WAWTP descended from a recent common ancestor strain? If so, the source could be identified and eliminated. If, on the other hand, the antibiotic resistance genes in the bacterial flora of the WAWTP have more than one origin, identification and elimination of the source(s) could be difficult. There was considerable diversity of antibiotic resistance patterns and antibiotic resistance genes among the effluent and influent coliform isolates of the WAWTP, suggesting multiple genetic ancestry. The patterns of horizontal transmissibility and sequence differences in the genes tetA and tetE among these coliform isolates also suggest that they have no one predominant ancestral strain. Using the same logic, the evidence presented here is not compatible with a single ancestral origin of the antibiotic resistance genes in the isolates described herein.
Genomic analysis of two ORF2 segments of new porcine astrovirus isolates and their close relationship with human astroviruses
Authors: Ulloa Juan Carlos , Gutiérrez María Fernanda
Published: July 2010

Porcine astrovirus (PAstV) has been poorly studied and has been associated mainly with gastroenteritis. Computational analysis has revealed the close relationship of PAstV with astroviruses of humans (HAstV) and cats (FAstV). In this study, 105 and 171 stool specimens were collected from piglets and children under 5 years of age, respectively, in different Colombian regions during a 1-year period. The stool samples were examined for astroviruses by ELISA and RT–PCR; 23.8% and 4% were found to be positive for PAstV and HAstV, respectively. Additional sequence analysis with partial sequences obtained from ORF2 identified at least 2 probable groups of PAstVs and possible recombination events between porcine and human astroviruses. This study provides preliminary evidence of the high presence of PAstVs in pigs and proposes the existence of multiple PAstV types that are evolutionarily closely related to HAstVs.
Characterization of clonal strains ofPseudomonas aeruginosaisolated from cystic fibrosis patients in Ontario, Canada
Authors: Beaudoin Trevor , Aaron Shawn D. , Giesbrecht-Lewis Tracy , Vandemheen Kathy , Mah Thien-Fah
Published: July 2010

Pseudomonas aeruginosa is an opportunistic pathogen that can form biofilms in the lungs and airways of cystic fibrosis (CF) patients, resulting in chronic endobronchial infection. Two clonal strains of P. aeruginosa, named type A and type B, have recently been identified and have been found to infect more than 20% of CF patients in Ontario, Canada. In this study, 4 type A and 4 type B isolates retrieved from 8 CF patients in Ontario, Canada, were characterized. All 8 isolates grew well in rich medium and formed biofilms in vitro. Antibiotic resistance profiles of bacteria grown in biofilms and planktonic culture were studied via minimal bactericidal concentration assays for tobramycin, gentamicin, and ciprofloxacin. Compared to laboratory strains of P. aeruginosa, all 8 isolates showed increased resistance to all antibiotics studied in both biofilm and planktonic assays. Gene expression analysis of mexX, representing the MexXY–OprM efflux pump, and mexA, representing MexAB–OprM, revealed that these genes were up-regulated in the 8 clinical isolates. These results suggest clonal type A and type B isolates of P. aeruginosa isolated from CF patients in Ontario, Canada, show a multidrug resistance pattern that can be partially explained as being due to the increased expression of common antibiotic efflux systems.
The solubilization of potassium-bearing rock powder by Aspergillus niger in small-scale batch fermentations
Authors: Lopes-Assad Maria L. , Avansini Simoni H. , Rosa Márcia M. , de Carvalho José R.P. , Ceccato-Antonini Sandra R.
Published: July 2010

The fungus Aspergillus niger was cultivated in culture medium with an alkaline ultramafic rock powder to evaluate the solubilization of potassium for biofertilizer production. The assays were carried out with 2 strains (CCT4355 and CCT911) in small-scale batch fermentations using 125, 500, 1000, and 2000 mL Erlenmeyer flasks, with a nominal volume of 40%, and rock powder at 0.4%, shaken at 160 r/min, incubated at 30 °C, and sampled every 7 days for 35 days. The amount of soluble K+, the pH of the culture medium, and the acidity were determined. Both strains solubilized K+ from the rock powder to the same extent (approximately 62%–70% after 35 days) in the 125 mL flasks; however, the percent solubilization decreased at higher volumetric scales. The results also indicated a difference in strain sensitivity to the increase in volumetric scales in batch fermentation. When filter-sterilized air was injected into the medium, the K+ percent solubilization obtained after 4 days of cultivation was similar to that obtained after a 28 day period. The acid production by the fungus may be a mechanism of rock solubilization, in spite of the elevation in pH values probably caused by the increasing hydrolysis of the silicates. Both strains of A. niger are recommended for solubilizing potassium from ultramafic rocks, but it is necessary to optimize the oxygen transfer, which seemed to affect the rock solubilization at higher volumetric scales.
Diazoxide potentiates mesenchymal stem cell survival via NF-κB-dependent miR-146a expression by targeting Fas
Authors: Suzuki Yoko , Kim Ha Won , Ashraf Muhammad , Haider Husnain Kh
Published: July 2010

We have previously reported that preconditioning of bone marrow-derived mesenchymal stem cells (MSCs) with diazoxide (DZ) significantly improved cell survival via NF-κB signaling. Since micro-RNAs (miRNAs) are critical regulators of a wide variety of biological events, including apoptosis, proliferation, and differentiation, it is likely that DZ-induced survival is mediated by miRNAs. Here we show that miR-146a expressed during preconditioning with DZ is a key regulator of stem cell survival. Treatment of MSCs with DZ (200 μM) markedly increased miR-146a expression and promoted cell survival, as evaluated by lactate dehydrogenase release and transferase-mediated dUTP nick-end labeling staining. Interestingly, blocking NF-κB by IKK-γ NEMO binding domain inhibitor peptide did not induce miR-146a expression, indicating NF-κB regulates miR-146a expression. Moreover, blockade of miR-146a expression by antisense miR-146a inhibitor abolished DZ-induced cytoprotective effects, suggesting a critical role of miR-146a in MSC survival. Computational analysis found a consensus putative target site of miR-146a relevant to apoptosis in the 3′ untranslated region of Fas mRNA. The role of Fas as a target gene was substantiated by abrogation of miR-146a, which markedly increased Fas protein expression. This was verified by luciferase reporter assay, which showed that forced expression of miR-146a downregulated Fas expression via targeting its 3′-UTR of this gene. Taken together, these data demonstrated that cytoprotection afforded by preconditioning of MSCs with DZ was regulated by miR-146a induction, which may be a novel therapeutic target in cardiac ischemic diseases.
Voltage-Gated Na+ Channel SCN5A Is a Key Regulator of a Gene Transcriptional Network That Controls Colon Cancer Invasion
Authors: House Carrie D. , Vaske Charles J. , Schwartz Arnold M. , Obias Vincent , Frank Bryan , Luu Truong , Sarvazyan Narine , Irby Rosalyn , Strausberg Robert L. , Hales Tim G. , Stuart Joshua M. , Lee Norman H.
Published: July 2010

Voltage-gated Na+ channels (VGSC) have been implicated in the metastatic potential of human breast, prostate, and lung cancer cells. Specifically, the SCN5A gene encoding the VGSC isotype Nav1.5 has been defined as a key driver of human cancer cell invasion. In this study, we examined the expression and function of VGSCs in a panel of colon cancer cell lines by electrophysiologic recordings. Na+ channel activity and invasive potential were inhibited pharmacologically by tetrodotoxin or genetically by small interfering RNAs (siRNA) specifically targeting SCN5A. Clinical relevance was established by immunohistochemistry of patient biopsies, with strong Nav1.5 protein staining found in colon cancer specimens but little to no staining in matched-paired normal colon tissues. We explored the mechanism of VGSC-mediated invasive potential on the basis of reported links between VGSC activity and gene expression in excitable cells. Probabilistic modeling of loss-of-function screens and microarray data established an unequivocal role of VGSC SCN5A as a high level regulator of a colon cancer invasion network, involving genes that encompass Wnt signaling, cell migration, ectoderm development, response to biotic stimulus, steroid metabolic process, and cell cycle control. siRNA-mediated knockdown of predicted downstream network components caused a loss of invasive behavior, demonstrating network connectivity and its function in driving colon cancer invasion. Cancer Res; 70(17); 6957–67. ©2010 AACR.
System-Level Analysis of Neuroblastoma Tumor–Initiating Cells Implicates AURKB as a Novel Drug Target for Neuroblastoma
Authors: Morozova Olena , Vojvodic Milijana , Grinshtein Natalie , Hansford Loen M. , Blakely Kim M. , Maslova Alexandra , Hirst Martin , Cezard Timothee , Morin Ryan D. , Moore Richard , Smith Kristen M. , Miller Freda , Taylor Paul , Thiessen Nina , Varhol Richard , Zhao Yongjun , Jones Steven , Moffat Jason , Kislinger Thomas , Moran Michael F. , Kaplan David R. , Marra Marco A.
Published: July 2010

Purpose: Neuroblastoma (NB) is an aggressive tumor of the developing peripheral nervous system that remains difficult to cure in the advanced stages. The poor prognosis for high-risk NB patients is associated with common disease recurrences that fail to respond to available therapies. NB tumor-initiating cells (TICs), isolated from metastases and primary tumors, may escape treatment and contribute to tumor relapse. New therapies that target the TICs may therefore prevent or treat tumor recurrences.

Experimental Design: We undertook a system-level characterization of NB TICs to identify potential drug targets against recurrent NB. We used next-generation RNA sequencing and/or human exon arrays to profile the transcriptomes of 11 NB TIC lines from six NB patients, revealing genes that are highly expressed in the TICs compared with normal neural crest-like cells and unrelated cancer tissues. We used gel-free two-dimensional liquid chromatography coupled to shotgun tandem mass spectrometry to confirm the presence of proteins corresponding to the most abundant TIC-enriched transcripts, thereby providing validation to the gene expression result.

Results: Our study revealed that genes in the BRCA1 signaling pathway are frequently misexpressed in NB TICs and implicated Aurora B kinase as a potential drug target for NB therapy. Treatment with a selective AURKB inhibitor was cytotoxic to NB TICs but not to the normal neural crest-like cells.

Conclusion: This work provides the first high-resolution system-level analysis of the transcriptomes of 11 primary human NB TICs and identifies a set of candidate NB TIC-enriched transcripts for further development as therapeutic targets. Clin Cancer Res; 16(18); 4572–82. ©2010 AACR.
Personalized Tamoxifen: A Step Closer but Miles To Go
Authors: Bardia Aditya , Stearns Vered
Published: July 2010

Genetic variants in CYP2D6 lead to reduced conversion of tamoxifen to the active metabolite endoxifen. However, the role of the CYP2D6 genotype in predicting tamoxifen-associated outcomes remains controversial. Accurate assignment of the CYP2D6 genotype in archival tissues is crucial for future studies attempting to determine risk prediction of outcomes in tamoxifen-treated individuals. Clin Cancer Res; 16(17); 4308–10. ©2010 AACR.
Acute Humanin Therapy Attenuates Myocardial Ischemia and Reperfusion Injury in Mice
Authors: Muzumdar Radhika H. , Huffman Derek M. , Calvert John W. , Jha Saurabh , Weinberg Yoni , Cui Lingguang , Nemkal Anjana , Atzmon Gil , Klein Laura , Gundewar Susheel , Ji Sang Yong , Lavu Madhav , Predmore Benjamin L. , Lefer David J.
Published: July 2010

Objective—

Humanin (HN), an endogenous antiapoptotic peptide, has previously been shown to protect against Alzheimer’s disease and a variety of cellular insults. We evaluated the effects of a potent analog of HN (HNG) in an in vivo murine model of myocardial ischemia and reperfusion.

Methods and Results—

Male C57BL6/J mice (8 to 10 week old) were subjected to 45 minutes of left coronary artery occlusion followed by a 24-hour reperfusion. HNG or vehicle was administered IP 1 hour prior or at the time of reperfusion. The extent of myocardial infarction per area-at-risk was evaluated at 24 hours using Evans Blue dye and 2-3-5-triphenyl tetrazolium chloride staining. Left ventricular function was evaluated at 1 week after ischemia using high-resolution, 2D echocardiography (VisualSonics Vevo 770). Myocardial cell signaling pathways and apoptotic markers were assessed at various time points (0 to 24 hours) following reperfusion. Cardiomyocyte survival and apoptosis in response to HNG were assessed in vitro. HNG reduced infarct size relative to the area-at-risk in a dose-dependent fashion, with a maximal reduction at the dose of 2 mg/kg. HNG therapy enhanced left ventricular ejection fraction and preserved postischemic left ventricular dimensions (end-diastolic and end-systolic), resulting in improved cardiac function. Treatment with HNG significantly increased phosphorylation of AMPK and phosphorylation of endothelial nitric oxide synthase in the heart and attenuated Bcl-2-associated X protein and B-cell lymphoma-2 levels following myocardial ischemia and reperfusion. HNG improved cardiomyocyte survival and decreased apoptosis in response to daunorubicin in vitro.

Conclusion—

These data show that HNG provides cardioprotection in a mouse model of myocardial ischemia and reperfusion potentially through activation of AMPK-endothelial nitric oxide synthase-mediated signaling and regulation of apoptotic factors. HNG may represent a novel agent for the treatment of acute myocardial infarction.
Plasma MicroRNA Profiling Reveals Loss of Endothelial MiR-126 and Other MicroRNAs in Type 2 Diabetes
Authors: Zampetaki Anna , Kiechl Stefan , Drozdov Ignat , Willeit Peter , Mayr Ursula , Prokopi Marianna , Mayr Agnes , Weger Siegfried , Oberhollenzer Friedrich , Bonora Enzo , Shah Ajay , Willeit Johann , Mayr Manuel
Published: July 2010

Rationale:

MicroRNAs (miRNAs) have been implicated in the epigenetic regulation of key metabolic, inflammatory, and antiangiogenic pathways in type 2 diabetes (DM) and may contribute to common disease complications.

Objective:

In this study, we explore plasma miRNA profiles in patients with DM.

Methods and Results:

Total RNA was extracted from plasma samples of the prospective population-based Bruneck study. A total of 13 candidate miRNAs identified by microarray screening and miRNA network inference were quantified by quantitative PCR in all diabetic patients of the Bruneck study and age- and sex-matched controls (1995 evaluation, n=80 each). Quantitative PCR assessment revealed lower plasma levels of miR-20b, miR-21, miR-24, miR-15a, miR-126, miR-191, miR-197, miR-223, miR-320, and miR-486 in prevalent DM, but a modest increase of miR-28-3p. Findings emerged as robust in multivariable analysis and were independent of the standardization procedure applied. For endothelial miR-126, results were confirmed in the entire Bruneck cohort (n=822) in univariate (odds ratio [95% confidence interval], 0.38 [0.26 to 0.55];
P
=2.72×10
−7
) and multivariate analyses (0.57 [0.37 to 0.86];
P
=0.0082). Importantly, reduced miR-15a, miR-29b, miR-126, miR-223, and elevated miR-28-3p levels antedated the manifestation of disease. Most differences in miRNA levels were replicated in plasma obtained from hyperglycemic Lep
ob
mice. High glucose concentrations reduced the miR-126 content of endothelial apoptotic bodies. Similarly in patients with DM, the reduction of miR-126 was confined to circulating vesicles in plasma.

Conclusions:

We reveal a plasma miRNA signature for DM that includes loss of endothelial miR-126. These findings might explain the impaired peripheral angiogenic signaling in patients with DM.
Monitoring Cerebral Blood Flow Pressure Autoregulation in Pediatric Patients During Cardiac Surgery
Authors: Brady Ken M. , Mytar Jennifer O. , Lee Jennifer K. , Cameron Duke E. , Vricella Luca A. , Thompson W. Reid , Hogue Charles W. , Easley R. Blaine
Published: July 2010

Background and Purpose—

The limits of cerebral blood flow-pressure autoregulation have not been adequately defined for pediatric patients. Mean arterial blood pressure below these limits might contribute to brain injury during cardiac surgery. The purpose of this pilot study was to assess a novel method of determining the lower limits of pressure autoregulation in pediatric patients supported with cardiopulmonary bypass.

Methods—

A prospective, observational pilot study was conducted in children (n=54) undergoing cardiac surgery with cardiopulmonary bypass for correction of congenital heart defects. Cerebral oximetry index (COx) was calculated as a moving, linear correlation coefficient between slow waves of arterial blood pressure and cerebral oximetry measured with near-infrared spectroscopy. An autoregulation curve was constructed for each patient with averaged COx values sorted by arterial blood pressure.

Results—

Hypotension was associated with increased values of COx (
P
<0.0001). For 77% of patients, an individual estimate of lower limits of pressure autoregulation could be determined using a threshold COx value of 0.4. The mean lower limits of pressure autoregulation for the cohort using this method was 42±7 mm Hg.

Conclusions—

This pilot study of COx monitoring in pediatric patients demonstrates an association between hypotension during cardiopulmonary bypass and impairment of autoregulation. The COx may be useful to identify arterial blood pressure-dependent limits of cerebral autoregulation during cardiopulmonary bypass. Larger trials with neurological outcomes are indicated.
A Computerized In-Hospital Alert System for Thrombolysis in Acute Stroke
Authors: Heo Ji Hoe , Kim Young Dae , Nam Hyo Suk , Hong Keun-sik , Ahn Seong Hwan , Cho Hyun Ji , Choi Hye-Yeon , Han Sang Won , Cha Myoung-Jin , Hong Ji Man , Kim Gyeong-Moon , Kim Gyu Sik , Kim Hye Jin , Kim Seo Hyun , Kim Yong-Jae , Kwon Sun Uck , Lee Byung-Chul , Lee Jun Hong , Lee Kwang Ho , Oh Mi Sun
Published: July 2010

Background and Purpose—

An effective stroke code system that can expedite rapid thrombolytic treatment requires effective notification/communication and an organized team approach. We developed a stroke code program based on the computerized physician order entry (CPOE) system and investigated whether implementation of this CPOE-based program is useful for reducing the time from arrival at emergency departments (ED) to evaluation steps and the initiation of thrombolytic treatment in various hospital settings.

Methods—

The CPOE-based program was implemented by 10 hospitals. Time intervals from arrival at the ED to blood tests, computed tomography scanning, and thrombolytic treatment during the 1-year period before and the 1-year period after the program implementation were compared.

Results—

Time intervals from ED arrival to evaluation steps were significantly reduced after implementation of the CPOE-based program. Times from ED arrival to CT scan, complete blood counts, and prothrombin time testing were reduced by 7.7 minutes, 5.6 minutes, and 26.8 minutes, respectively (
P
<0.001). The time from ED arrival to intravenous thrombolysis was reduced from 71.7±33.6 minutes to 56.6±26.9 minutes (
P
<0.001). The number of patients who were treated with thrombolysis increased from 3.4% (199/5798 patients) before the CPOE-based program to 5.8% (312/5405 patients) afterward (
P
<0.001). The CPOE implementation also improved the inverse relationship between onset-to-door time and door-to-needle time.

Conclusions—

The CPOE-based stroke code could be successfully implemented to reduce in-hospital time delay in thrombolytic therapy in various hospital settings. CPOE may be used as an efficient tool to facilitate in-hospital notification/communication and an organized team approach.
Current Practice Versus Willingness to Enroll in Clinical Trials
Authors: El Khoury Ramy , Fisher Marc , Savitz Sean I.
Published: July 2010

Background and Purpose—

Clinical trials are assessing the efficacy of fibrinolysis in extended time windows for acute ischemic stroke.

Methods—

An Internet-based survey was sent to 400 US vascular neurologists affiliated with a university to assess whether there are consensus opinions on how they treat patients beyond 3 hours from symptom onset and which patients they are willing to enroll into clinical trials of fibrinolysis for acute ischemic stroke.

Results—

We received 161 responses; 81% were male. Ninety-three percent of respondents treat patients with intravenous tissue plasminogen activator beyond 3 hours. More than 80% were treated beyond 3 hours with intra-arterial therapy (IAT). When asked if IAT improves stroke outcome, >50% selected the choice of “yes for middle cerebral artery and basilar occlusions” and only 2% selected the choice that “IAT does not improve outcome.” Over half believe that imaging could be used to approximate the penumbra but with improvements to better identify salvageable tissue. Eighty-seven percent were willing to enroll patients into a placebo-controlled intravenous thrombolysis beyond 3 hours. For IAT trials, >80% would randomize beyond 3 hours with or without prior intravenous treatment.

Conclusions—

Vascular neurologists have been treating acute ischemic stroke beyond 3 hours with intravenous tissue plasminogen activator even before the American Heart Association guidelines supported extending the therapeutic window. There is a paradox among the respondents willing to enroll patients into trials involving IAT given that a majority is offering IAT as part of their practice. These results suggest that clinical practice may impair enrollment into trials testing reperfusion therapies for acute ischemic stroke.
Comparison of Recovery Patterns and Prognostic Indicators for Ischemic and Hemorrhagic Stroke in China
Authors: Wei Jade W. , Heeley Emma L. , Wang Ji-Guang , Huang Yining , Wong Lawrence K.S. , Li Zhengyi , Heritier Stephane , Arima Hisatomi , Anderson Craig S.
Published: July 2010

Background and Purpose—

Limited data exist on the comparative recovery patterns and outcomes of patients with ischemic stroke and intracerebral hemorrhage in China.

Methods—

Data on baseline characteristics and outcomes of 6354 patients at 3 and 12 months poststroke are from ChinaQUEST (QUality Evaluation of Stroke Care and Treatment), a multicenter, prospective, 62-hospital registry study in China. Logistic regression was used to determine factors associated with a poor outcome defined by death/dependency (modified Rankin Scale score of 3 to 5) on follow-up. Generalized estimating equations were used to assess variations in recovery pattern by stroke type.

Results—

Baseline severity and rate of functional recovery in the early phase were significantly greater for intracerebral hemorrhage. However, patients with ischemic stroke were on average twice as likely to experience a good outcome (modified Rankin Scale score <3) by 12 months poststroke (OR: 1.98, CI: 1.76 to 2.24). In patients with ischemic stroke, diabetes and atrial fibrillation were strongly associated with a poor outcome at 12 months poststroke even after adjustment for confounding factors such as age, prior stroke/dependency, time to presentation, and stroke severity, whereas use of antiplatelets and lipid-lowering therapy after stroke were associated with improved outcome. For patients with intracerebral hemorrhage, low education and atrial fibrillation were associated with a poor outcome after adjustment for potential confounders and antihypertensive use was strongly associated with improved outcome.

Conclusions—

Patients with intracerebral hemorrhage and ischemic stroke have different recovery patterns in China. However, they share similar prognostic factors and in the use of evidence-based secondary prevention therapies to maximize chances of a good outcome.
Basic Rights and Cosmopolitan Justice from an Enlightened Localist Perspective
Authors: Ypi Lea
Published: July 2010

This article links a normative analysis of basic rights to an important debate between cosmopolitans and localists on the moral standing of particular political communities. Cosmopolitan scholars often defend the universality of basic rights by appealing to the importance of satisfying the vital needs of every human being. For its part, the localist critique of cosmopolitanism defends compatriot favoritism and emphasizes the role of particularist attachments that are thought to cultivate solidarity, reciprocity, and legitimacy. I move beyond this dualism and adopt an “enlightened localist” approach that justifies basic rights from a universal-cosmopolitan perspective even as it attends to local commitments when faced with corresponding issues of agency and the distribution of responsibility. I distinguish different cosmopolitan accounts in favor of basic rights and argue that one of them successfully defends the validity of basic rights from a universal perspective. But such an account cannot resolve the problem of agency in the global sphere: it cannot specify how transnational obligations corresponding to these basic rights should be allocated. In short, while the normative justification of basic rights is persuasive, the distribution of responsibilities that would render such rights institutionally effective rests on shaky grounds. I conclude by showing that cosmopolitan responsibilities corresponding to basic rights are more appropriately discharged by local communities as the most relevant agents of global justice - if such localism proceeds from an “enlightened” perspective.
Enlightened Localism in Contemporary China: Political Change in Property-Rights Institutions of Township and Village Enterprises
Authors: Wang Junmin
Published: July 2010

I examine the dynamic and interactive relationships between local governments and local economic elites as they attempted to privatize China’s township and village enterprises (TVEs) in the late 1990s. To pursue financial interests shared with the local economic elite, local governments informally privatized public TVEs and thereby compromised their role as political agents of the central government. This institutional change in property rights demonstrates a Chinese pattern of “enlightened localism” (Gregg 2003) by which the local political and economic actors develop a pragmatic way of coping with ambiguous legal issues. The deployment of enlightened localism in the TVE sector shows that China’s policies of economic decentralization unintentionally have led to a decentralization of political control.
Integration of the Ainu Minority in Japan: Enlightened Localism Combined with Universalism
Authors: Hasegawa Ko
Published: July 2010

I examine the significance of enlightened localism for problems associated with the social integration of minorities, with special reference to the Ainu people in Japan. From the standpoint of multicultural coexistence in a liberal spirit, I show how the Ainu might be better integrated into mainstream Japanese society by taking into account the perspective of enlightened localism. I propose the idea of polymorphic integration as a golden mean between group rights and individual rights. It offers a pragmatic way toward a cultural respect and concern for the Ainu based on a right to cultural integrity and embedded in the basically liberal yet inadequately race-sensitive legal system in Japan today.