bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thioredoxin-Interacting Protein Mediates Sustained VEGFR2 Signaling in Endothelial Cells Required for Angiogenesis
Authors: Park Shin-Young , Shi Xi , Pang Jinjiang , Yan Chen , Berk Bradford C. 
Published: February 2013

Objective—
Thioredoxin-interacting protein (TXNIP) is an α-arrestin protein whose function is important for the regulation of vascular endothelial growth factor receptor 2 (VEGFR2) signaling and endothelial cell survival. Because VEGFR2 is critical for angiogenesis, we explored the role of TXNIP in VEGF-induced angiogenesis.

Approach and Results—
TXNIP knockdown inhibited VEGF-induced endothelial cell tube formation and proliferation in cultured human umbilical vein endothelial cell. To elucidate the mechanism by which TXNIP altered VEGFR2 signaling in human umbilical vein endothelial cell, we studied phosphorylation of VEGFR2, phospholipase C gamma-1 (PLCγ1), endothelial NO synthase, and Akt (known as protein kinase B). TXNIP knockdown significantly decreased phosphorylation of VEGFR2 and PLCγ1 at times >5 minutes, but phosphorylation was unchanged at 2 minutes, as was Akt and endothelial NO synthase phosphorylation. Cell-surface biotinylation assay showed that TXNIP knockdown significantly attenuated VEGFR2 internalization. These results suggested that TXNIP was required for sustained VEGFR2 signaling, which is mediated largely by internalized VEGFR2. Rab5 knockdown to inhibit the trafficking and fusion of early endosomes significantly blocked VEGF-induced VEGFR2 internalization and phosphorylation of VEGFR2 and PLCγ1. Immunofluorescence and coimmunoprecipitation showed that TXNIP was part of a complex that included Rab5 and VEGFR2. Finally, TXNIP knockdown prevented the association of VEGFR2 and Rab5.

Conclusions—
Our results show that TXNIP is essential for VEGFR2 internalization in Rab5 positive endosomes, which is required for endothelial cell growth and angiogenesis.
Organ-Specific Protection Against Lipopolysaccharide-Induced Vascular Leak Is Dependent on the Endothelial Protein C Receptor
Authors: von Drygalski Annette , Furlan-Freguia Christian , Ruf Wolfram , Griffin John H. , Mosnier Laurent O. 
Published: February 2013

Objective—
To study the role of the endothelial protein C receptor (EPCR) in the modulation of susceptibility to inflammation-induced vascular leak in vivo.

Approach and Results—

Genetically modified mice with low, <10% EPCR expression (EPCR
low
) and control mice were challenged with lipopolysaccharides in a mouse model of endotoxemia. Infrared fluorescence and quantification of albumin-bound Evans Blue in tissues and intravascular plasma volumes were used to assess plasma extravasation. Pair-wise analysis of EPCR
low
and control mice matched for sex, age, and weight allowed determination of EPCR-dependent vascular leak. Kidney, lung, and brain were the organs with highest discriminative increased Evans Blue accumulation in EPCR
low
versus control mice in response to lipopolysaccharides. Histology of kidney and lung confirmed the EPCR-specific pathology. In addition to severe kidney injury in response to lipopolysaccharides, EPCR
low
and anti-EPCR–treated wild-type mice suffered from enhanced albuminuria and profound renal hemorrhage versus controls. Intravascular volume loss at the same extent of weight loss in EPCR
low
mice compared with control mice provided proof that plasma leak was the predominant cause of Evans Blue tissue accumulation.

Conclusions—
This study demonstrates an important protective role for EPCR in vivo against vascular leakage during inflammation and suggests that EPCR-dependent vascular protection is organ-specific.
MicroRNA-145 Restores Contractile Vascular Smooth Muscle Phenotype and Coronary Collateral Growth in the Metabolic Syndrome
Authors: Hutcheson Rebecca , Terry Russell , Chaplin Jennifer , Smith Erika , Musiyenko Alla , Russell James C. , Lincoln Thomas , Rocic Petra 
Published: February 2013

Objective—
Transient, repetitive occlusion stimulates coronary collateral growth (CCG) in normal animals. Vascular smooth muscle cells (VSMCs) switch to synthetic phenotype early in CCG, then return to contractile phenotype. CCG is impaired in the metabolic syndrome. We determined whether impaired CCG was attributable to aberrant VSMC phenotypic modulation by miR-145–mediated mechanisms, and whether restoration of physiological miR-145 levels in metabolic syndrome (JCR rat) improved CCG.

Approach and Results—
CCG was stimulated by transient, repetitive left anterior descending artery occlusion and evaluated after 9 days by coronary blood flow measurements (microspheres). miR-145 was delivered to JCR VSMCs via adenoviral vector (miR-145-Adv). In JCR rats, miR-145 was decreased late in CCG (≈2-fold day 6; ≈4-fold day 9 versus SD), which correlated with decreased expression of smooth muscle-specific contractile proteins (≈5-fold day 6; ≈10-fold day 9 versus SD), indicative of VSMCs’ failure to return to the contractile phenotype late in CCG. miR-145 expression in JCR rats (miR-145-Adv) on days 6 to 9 of CCG completely restored VSMCs contractile phenotype and CCG (collateral/normal zone flow ratio was 0.93±0.09 JCR+miR-145-Adv versus 0.12±0.02 JCR versus 0.87±0.02 SD).

Conclusions—
Restoration of VSMC contractile phenotype through miR-145 delivery is a highly promising intervention for restoration of CCG in the metabolic syndrome.
Mechanism-Based Facilitated Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes
Authors: Lieu Deborah K. , Fu Ji-Dong , Chiamvimonvat Nipavan , Tung Kelvin Chan , McNerney Gregory P. , Huser Thomas , Keller Gordon , Kong Chi-Wing , Li Ronald A. 
Published: February 2013

Background—
Human embryonic stem cells (hESCs) can be efficiently and reproducibly directed into cardiomyocytes (CMs) using stage-specific induction protocols. However, their functional properties and suitability for clinical and other applications have not been evaluated.

Methods and Results—

Here we showed that CMs derived from multiple pluripotent human stem cell lines (hESC: H1, HES2) and types (induced pluripotent stem cell) using different in vitro differentiation protocols (embryoid body formation, endodermal induction, directed differentiation) commonly displayed immature, proarrhythmic action potential properties such as high degree of automaticity, depolarized resting membrane potential, Phase 4- depolarization, and delayed after-depolarization. Among the panoply of sarcolemmal ionic currents investigated (
I
Na
+
/
I
CaL
+
/
I
Kr
+
/
I
NCX
+
/
I
f
+
/
I
to
+
/
I
K1
−
/
I
Ks
−
), we pinpointed the lack of the Kir2.1-encoded inwardly rectifying K
+
current (
I
K1
) as the single mechanistic contributor to the observed immature electrophysiological properties in hESC-CMs. Forced expression of Kir2.1 in hESC-CMs led to robust expression of Ba
2+
-sensitive
I
K1
and, more importantly, completely ablated all the proarrhythmic action potential traits, rendering the electrophysiological phenotype indistinguishable from the adult counterparts. These results provided the first link of a complex developmentally arrested phenotype to a major effector gene, and importantly, further led us to develop a bio-mimetic culturing strategy for enhancing maturation.

Conclusions—
By providing the environmental cues that are missing in conventional culturing method, this approach did not require any genetic or pharmacological interventions. Our findings can facilitate clinical applications, drug discovery, and cardiotoxicity screening by improving the yield, safety, and efficacy of derived CMs.
Microembolism and Catheter Ablation I
Authors: Haines David E. , Stewart Mark T. , Ahlberg Sarah , Barka Noah D. , Condie Cathy , Fiedler Gary R. , Kirchhof Nicole A. , Halimi Franck , Deneke Thomas 
Published: February 2013

Background—
Cerebral diffusion-weighted MRI lesions have been observed after catheter ablation of atrial fibrillation. We hypothesized that conditions predisposing to microembolization could be identified using a porcine model of pulmonary vein ablation and an extracorporeal circulation loop.

Methods and Results—

Ablations of the pulmonary veins were performed in 18 swine with echo monitoring. The femoral artery and vein were cannulated and an extracorporeal circulation loop with 2 ultrasonic bubble detectors and a 73-μm filter were placed in series. Microemboli and microbubbles were compared between ablation with an irrigated radiofrequency system (Biosense-Webster) and a phased radiofrequency multielectrode system (pulmonary vein ablation catheter [PVAC], Medtronic, Inc, Carlsbad, CA) in unipolar and 3 blended unipolar/bipolar modes. Animal pathology was examined. The size and number of microbubbles observed during ablation ranged from 30 to 180 μm and 0 to 3253 bubbles per ablation. Microbubble volumes with PVAC (29.1 nL) were greater than with irrigated radiofrequency (0.4 nL;
P
=0.045), and greatest with type II or III microbubbles on transesophageal echocardiography. Ablation with the PVAC showed fewest microbubbles in the unipolar mode (
P
=0.012 versus bipolar). The most occurred during bipolar energy delivery with overlap of proximal and distal electrodes (median microbubble volume, 1744 nL; interquartile range, 737–4082 nL; maximum, 19 516 nL). No cerebral MRI lesions were seen, but 2 animals had renal embolization.

Conclusions—
Left atrial ablation with irrigated radiofrequency and PVAC catheters in swine is associated with microbubble and microembolus production. Avoiding overlap of electrodes 1 and 10 on PVAC should reduce the microembolic burden associated with this procedure.
Prognostic Value of Endocardial Voltage Mapping in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
Authors: Migliore Federico , Zorzi Alessandro , Silvano Maria , Bevilacqua Michela , Leoni Loira , Marra Martina Perazzolo , Elmaghawry Mohamed , Brugnaro Luca , Dal Lin Carlo , Bauce Barbara , Rigato Ilaria , Tarantini Giuseppe , Basso Cristina , Buja Gianfranco , Thiene Gaetano , Iliceto Sabino , Corrado Domenico 
Published: February 2013

Background—
Endocardial voltage mapping (EVM) identifies low-voltage right ventricular (RV) areas, which may represent the electroanatomic scar substrate of life-threatening tachyarrhythmias. We prospectively assessed the prognostic value of EVM in a consecutive series of patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D).

Methods and Results—

We studied 69 consecutive ARVC/D patients (47 males; median age 35 years [28–45]) who underwent electrophysiological study and both bipolar and unipolar EVM. The extent of confluent bipolar (<1.5 mV) and unipolar (<6.0 mV) low-voltage electrograms was estimated using the CARTO-incorporated area calculation software. Fifty-three patients (77%) showed ≥1 RV electroanatomic scars with an estimated burden of bipolar versus unipolar low-voltage areas of 24.8% (7.2–31.5) and 64.8% (39.8–95.3), respectively (
P
=0.009). In the remaining patients with normal bipolar EVM (n=16; 23%), the use of unipolar EVM unmasked ≥1 region of low-voltage electrogram affecting 26.2% (11.6–38.2) of RV wall. During a median follow-up of 41 (28–56) months, 19 (27.5%) patients experienced arrhythmic events, such as sudden death (n=1), appropriate implantable cardioverter defibrillator interventions (n=7), or sustained ventricular tachycardia (n=11). Univariate predictors of arrhythmic outcome included previous cardiac arrest or syncope (hazard ratio=3.4; 95% confidence interval, 1.4–8.8;
P
=0.03) and extent of bipolar low-voltage areas (hazard ratio=1.7 per 5%; 95% confidence interval, 1.5–2;
P
<0.001), whereas the only independent predictor was the bipolar low-voltage electrogram burden (hazard ratio=1.6 per 5%; 95% confidence interval, 1.2–1.9;
P
<0.001). Patients with normal bipolar EVM had an uneventful clinical course.

Conclusions—
The extent of bipolar RV endocardial low-voltage area was a powerful predictor of arrhythmic outcome in ARVC/D, independently of history and RV dilatation/dysfunction. A normal bipolar EVM characterized a low-risk subgroup of ARVC/D patients.
Temporal Pattern of Cytotoxic Edema in the Perihematomal Region After Intracerebral Hemorrhage
Authors: Li Na , Worthmann Hans , Heeren Meike , Schuppner Ramona , Deb-Chatterji Milani , Tryc Anita B. , Bueltmann Eva , Lanfermann Heinrich , Donnerstag Frank , Weissenborn Karin , Raab Peter 
Published: February 2013

Background and Purpose—
Knowledge about cytotoxic edema (CE) in intracerebral hemorrhage is still limited. We aimed to analyze its presence, temporal pattern, and prognostic meaning.

Methods—
Twenty-one patients with primary intracerebral hemorrhage underwent magnetic resonance imaging at days 1, 3, and 7 after symptom onset. CE was identified using diffusion-weighted imaging. Hematoma and perihematomal edema volumes were measured on fluid-attenuated inversion recovery images. National Institutes of Health Stroke Scale score was assessed at admission and with each magnetic resonance imaging. Clinical outcome was assessed by modified Rankin scale at 90 days.

Results—

CE appeared in half of the patients within the first 24 hours. The apparent diffusion coefficient values decreased until day 3 and were significantly reversed from days 3 through 7 (
P
<0.01). Patients with CE showed significantly faster perihematomal edema growth from day 0 to 1 (
P
=0.036) than those without. Larger 3-day perihematomal edema volume (
P
=0.02) and presence of CE on day 3 (
P
=0.07) were associated with poor clinical outcome.

Conclusions—
CE is associated with stroke severity, perihematomal edema volume, and poor outcome. It is considered to indicate ongoing neuronal injury and, thus, might emerge as new treatment target.
Association of Molecular Markers With Perihematomal Edema and Clinical Outcome in Intracerebral Hemorrhage
Authors: Li Na , Liu Yan Fang , Ma Li , Worthmann Hans , Wang Yi Long , Wang Yong Jun , Gao Yi Pei , Raab Peter , Dengler Reinhard , Weissenborn Karin , Zhao Xing Quan 
Published: February 2013

Background and Purpose—
Perihematomal edema contributes to secondary brain injury in intracerebral hemorrhage (ICH). Increase of matrix metalloproteinases (MMPs) and growth factors is considerably involved in blood–brain barrier disruption and neuronal cell death in ICH models. We therefore hypothesized that increased levels of these molecular markers are associated with perihematomal edema and clinical outcome in ICH patients.

Methods—
Fifty-nine patients with spontaneous ICH admitted within 24 hours of symptom onset were prospectively investigated. Noncontrast CT was performed on admission for diagnosis of ICH and quantification of initial hematoma volume. MRI was performed on day 3 to evaluate perihematomal edema. Concentrations of MMP-3, MMP-9, as well as vascular endothelial growth factor and angiopoietin-1 on admission were determined by enzyme-linked immunosorbent assays. Clinical outcome was assessed by modified Rankin Scale at 90 days.

Results—

Increased MMP-3 levels were independently associated with perihematomal edema volume (
P
<0.05). Cytotoxic edema surrounding the hematoma was seen in 36 (61%) cases on 3-day MRI. Cytotoxic edema did not correlate with the level of any of the biomarkers studied. Levels of MMP-3 ≥12.4 ng/mL and MMP-9 ≥192.4 ng/mL but not vascular endothelial growth factor and angiopoietin-1 predicted poor clinical outcome at 90 days (modified Rankin Scale >3) independent of stroke severity and hematoma volume at baseline (odds ratio, 25.3,
P
=0.035; odds ratio, 68.9,
P
=0.023; respectively).

Conclusions—
MMPs 3 and 9 seem to be significantly involved in secondary brain injury and outcome after primary ICH in humans, and thus should be further evaluated as targets for therapeutic strategies in this devastating disorder.
Leukoaraiosis on Magnetic Resonance Imaging Correlates With Worse Outcomes After Spontaneous Intracerebral Hemorrhage
Authors: Caprio Fan Z. , Maas Matthew B. , Rosenberg Neil F. , Kosteva Adam R. , Bernstein Richard A. , Alberts Mark J. , Prabhakaran Shyam , Naidech Andrew M. 
Published: February 2013

Background and Purpose—
Leukoaraiosis (LA) is associated with dementia, ischemic stroke, and intracerebral hemorrhage (ICH), but there are few data on how LA might impact outcomes after acute ICH. We tested the hypothesis that the severity of LA on magnetic resonance imaging is related to worse functional outcomes after spontaneous ICH.

Methods—
We prospectively identified patients with spontaneous acute ICH. LA was identified on magnetic resonance imaging and its severity was graded using the Fazekas method to include a score for the deep white matter and periventricular regions. Outcomes were obtained at 14 days, 28 days, and 3 months with the modified Rankin Scale (mRS; a validated scale from 0 [no symptoms] to 6 [dead]) and analyzed with multivariate logistic regression.

Results—

Higher Fazekas total (periventricular plus deep white matter) score correlated with higher mRS score at 14 days (
P
=0.02) and 3 months (
P
=0.02). This relationship was driven by the periventricular score, for which higher score (more severe disease) correlated with higher National Institute of Health Stroke Scale at 14 days (
P
=0.03), and higher mRS score at 14 days (
P
<0.001), 28 days (
P
=0.004), and 3 months (
P
=0.005). A higher (more severe) Fazekas periventricular score was associated with dependence or death at 3 months (odds ratio, 1.8 per point; 95% confidence interval, 1.02–3.1;
P
=0.04) after correction for the ICH score.

Conclusions—
Increased LA is an independent predictor of worse functional outcomes in patients after spontaneous ICH. The pathophysiology associating LA with worse outcomes requires further study. These data may improve prognostication and selection for clinical trials.
A Mixed Approach to the Work-Motherhood Relation: An Application of Fuzzy Set Qualitative Comparative Analysis and Generalized Linear Models
Authors: Dotti Sani Giulia Maria , Quaranta Mario 
Published: February 2013

Abstract
Female labor force participation and total fertility rates have been negatively correlated until the early ’80s. By the end of that decade, however, the relationship changed sign. Scholars have suggested a close link between individual reproductive behavior, labor market participation and institutional contexts, but we still lack clear evidence of the underlying micro-level mechanism. We propose the use of complementary techniques, fuzzy set Qualitative Comparative Analysis and Generalized Linear Models, as the different assumptions underlying the two, combinatory vs. additive, may lead to new insights on how the combination of institutional features can produce different outcomes in terms of the work-motherhood relationship.
Not Asking for Much: Public Opinion and Redistribution from the Rich
Authors: Weakliem David , Biggert Robert 
Published: February 2013

Abstract
The logic of self-interest suggests that most people will favor imposing heavy taxes on the rich and distributing the proceeds among the general population, but in reality this is not a popular position. A number of explanations have been suggested, but there has been little systematic research. This paper reviews a wide range of survey data with the goal of identifying more or less promising explanations. Three receive clear support: most people underestimate the earnings of those at the top, believe that the chance of earning high incomes contributes to economic growth, and have little faith in the government’s ability to redistribute wealth. One can be rejected: that people tend to overestimate their own economic standing. Others receive mixed or moderate support. The paper concludes by discussing how public opinion may help to account for national differences in the concentration of wealth and income.
Business and Social Responsibility in the Arab World: the Zakat vs. CSR models in Syria and Dubai
Authors: Selvik Kjetil 
Published: February 2013

Abstract
The article explores the promotion and reception of Corporate Social Responsibility (CSR) in the Arab world, taking Syria and Dubai as “most different” case studies. It observes that government-connected organizations have taken the lead in promoting CSR but are facing difficulties in rooting the concept beyond the ranks of crony capitalists. It argues that businessmen remain attached to an Islamic framework of social responsibility that contrasts with CSR as currently promoted. Extracting key themes in the businessmen’s approach and comparing them with the UN Global Compact the article proposes an ideal-typical comparison of what it calls the Zakat and the CSR models. It discusses their relative utility as symbolic resource for the different actors.
A Polygon-Based Line-Integral Method for Calculating Vorticity, Divergence, and Deformation from Nonuniform Observations
Authors: Helms Charles N. , Hart Robert E. 
Published: February 2013

AbstractTraditional observational analysis of derivative-based variables (e.g., vorticity) usually relies on interpolating observations and evaluating spatial derivatives either on a Cartesian grid or on a spherical grid. Great care must be taken in selecting the domain and the interpolation scheme to properly represent the features. There exist a number of alternative methods of calculating such variables by evaluating line integrals on triangular regions according to Green’s theorem. Since these methods rely on only three observations to perform calculations, they are overly sensitive to observations dominated by local phenomena as well as instrument noise. A few studies have attempted to minimize the impact of nonrepresentative or noisy observations by using higher-order polygons, but they have been limited to fitting regular polygons to near-regularly gridded data. The current study describes a new approach to calculating these fields by constructing higher-order polygons from a triangle tessellation and then applying Green’s theorem. Since the polygons are constructed using an automated triangle tessellation, the polygon construction process can proceed without the need for uniformly spaced data. The triangle tessellation employed here is unique for a given set of points, generating easily reproducible results. In addition, this method reduces the impact of noise associated with individual observations with only a minor loss in the length of the resolvable scale. An error analysis of the proposed method shows a large decrease in errors in comparison with purely triangle-based calculations. These improvements are present with a variety of data distributions (random and along research aircraft flight paths) and kinematic variables (vorticity, divergence, and deformation).