bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Disruption of the Prostaglandin E
2
E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice
Authors: Zhu Sen , Xue Rui , Zhao Pan , Fan Fen-Ling , Kong Xiaomu , Zheng Senfeng , Han Qifei , Zhu Yi , Wang Nanping , Yang Jichun , Guan Youfei 
Published: June 2011

Objective—

Restenosis after angioplasty remains a major clinical problem. Prostaglandin E
2
(PGE
2
) plays an important role in vascular homeostasis. The PGE
2
receptor E-prostanoid 2 (EP2) is involved in the proliferation and migration of various cell types. We aimed to determine the role of EP2 in the pathogenesis of neointimal formation after vascular injury.

Methods and Results—

Wire-mediated vascular injury was induced in the femoral arteries of male wild-type (EP2+/+) and EP2 gene-deficient (EP2−/−) mice. In EP2+/+ mice, EP2 mRNA expression was increased in injured vessels for at least 4 weeks after vascular injury. Neointimal hyperplasia was markedly accelerated in EP2−/− mice, which was associated with increased proliferation and migration of vascular smooth muscle cells (VSMCs) and increased cyclin D1 expression in the neointima layer. Platelet-derived growth factor-BB (PDGF-BB) treatment resulted in more significant cell proliferation and migration in VSMCs of EP2−/− mice than in those of EP2+/+ mice. Activation and overexpression of EP2 attenuated PDGF-BB–elicited cell proliferation and migration, induced G
1
→S-phase arrest and reduced PDGF-BB–stimulated extracellular signal–regulated kinase phosphorylation in EP2+/+ VSMCs.

Conclusion—
These findings reveal a novel role of the EP2 receptor in neointimal hyperplasia after arterial injury. The EP2 receptor may represent a potential therapeutic target for restenosis after angioplasty.
Thioredoxin-Interacting Protein Mediates TRX1 Translocation to the Plasma Membrane in Response to Tumor Necrosis Factor-α
Authors: World Cameron , Spindel Oded N. , Berk Bradford C. 
Published: June 2011

Objective—
Thioredoxin-interacting protein (TXNIP) promotes inflammation in endothelial cells (EC) by binding to thioredoxin-1 (TRX1) in a redox-dependent manner. Formation of the TXNIP-TRX1 complex relieves inhibition of the apoptosis signal–regulating kinase 1–c-Jun N-terminal kinase–vascular cell adhesion molecule-1 pathway. Because TXNIP is an α-arrestin with numerous protein-protein interacting domains, we hypothesized that TXNIP-TRX1 trafficking should alter function of EC exposed to reactive oxygen species (ROS).

Methods and Results—

In response to physiological levels of ROS (10 ng/mL tumor necrosis factor-α and 30 μmol/L H
2
O
2
), TXNIP-TRX1 translocated to the plasma membrane in human umbilical vein EC, with a peak at 30 minutes, as measured by immunofluorescence colocalization with vascular endothelial-cadherin, cell fractionation, and membrane sheet assay. TXNIP-mediated translocation of TRX1 to the membrane required TXNIP and TRX1 binding, as evidenced by inability of the ROS-insensitive TXNIP-Cys247Ser mutant to promote membrane localization. Vascular endothelial growth factor signaling required TXNIP, as shown by significant decreases in plasma membrane tyrosine phosphorylation and EC migration after TRX1 knockdown. Furthermore, TXNIP knockdown increased human umbilical vein EC apoptosis induced by tumor necrosis factor. Rescue with TXNIP-wild-type but not TXNIP-Cys247Ser prevented cell death.

Conclusion—
These findings suggest a novel role for the TXNIP-TRX1 complex to enable inflammation by promoting EC survival and vascular endothelial growth factor signaling under conditions of physiological oxidative stress.
Dietary Phosphate Modulates Atherogenesis and Insulin Resistance in Apolipoprotein E Knockout Mice—Brief Report
Authors: Ellam Timothy , Wilkie Martin , Chamberlain Janet , Crossman David , Eastell Richard , Francis Sheila , Chico Timothy J.A. 
Published: June 2011

Objective—
Epidemiological studies link higher serum phosphate and the phosphatonin fibroblast growth factor 23 with cardiovascular events and atheroma, and they link lower serum phosphate with insulin resistance and the metabolic syndrome. We investigated whether manipulating dietary phosphate influences atherogenesis or insulin sensitivity in mice.

Methods and Results—

Apolipoprotein E knockout mice were fed an atherogenic diet with low (0.2%), standard (0.6%), or high (1.6%) phosphate content. Serum phosphate and fibroblast growth factor 23 significantly increased with increasing dietary phosphate intake, but lipid profile and blood pressure were unaffected. After 20 weeks, mice on the higher phosphate diet had significantly more atheroma at the aortic sinus (42±1.9% versus 30±1.5% for high versus low phosphate,
P
<0.01). Compared with standard and high-phosphate diet groups, mice on a low-phosphate diet had more adipose tissue and a 4-fold increase in insulin resistance measured by homeostatic model assessment (43.7±9.3 versus 8.9±0.7 for low versus high phosphate,
P
<0.005).

Conclusion—

A high-phosphate diet accelerates atherogenesis in apolipoprotein E
−/−
mice, whereas low phosphate intake induces insulin resistance. These data indicate for the first time that controlling dietary phosphate intake may influence development of both atherosclerosis and the metabolic syndrome.
Drug-Induced Torsade de Pointes Arrhythmias in the Chronic AV Block Dog Are Perpetuated by Focal Activity
Authors: Boulaksil Mohamed , Jungschleger Jerome G. , Antoons Gudrun , Houtman Marien J.C. , de Boer Teun P. , Wilders Ronald , Beekman Jet D. , Maessen Jos G. , van der Hulst Ferenc F. , van der Heyden Marcel A.G. , van Veen Toon A.B. , van Rijen Harold V.M. , de Bakker Jacques M.T. , Vos Marc A. 
Published: May 2011

Background—
The electrically remodeled canine heart after chronic AV block (CAVB) has a high susceptibility for drug-induced torsade de pointes (TdP) arrhythmias. Although focal mechanisms have been considered for initiation, there is still controversy about whether reentry is the dominant mechanism for perpetuation of TdP. In this animal model with known nonuniform prolongation of repolarization, the mechanism of perpetuation of TdP arrhythmia was explored.

Methods and Results—

Seventeen TdP-sensitive CAVB and 10 sinus rhythm (SR) dogs were studied. In 6 animals, 66 needle electrodes were evenly distributed transmurally to record 240 unipolar local electrograms simultaneously. Activation times and activation recovery intervals were determined before and during ibutilide-induced TdP. In 12 CAVB and 9 SR dogs, left ventricular (LV) and right ventricular (RV) epicardial electrograms were recorded with a 208-point multiterminal grid electrode allowing conduction velocity (CV) and ventricular effective refractory period (VERP) measurements. Biopsy specimens were processed for connexin43 (Cx43) expression and collagen content. Ventricular myocytes were isolated to determine sodium current (
I
Na
) density and cell dimensions. Computer simulations were used to assess the effects of changes therein. In CAVB, VERP and ARI were increased, whereas CV was unaltered in LV. Transversal but not longitudinal CV was increased in RV.
I
Na
was reduced by 37% in LV but unaltered in RV. LV and RV cell size were increased, but collagen and Cx43 content remained unchanged. Simulations showed increase in CV of RV as a consequence of increased cell size at normal
I
Na
. Ibutilide increased ARI, ERP, and maximal transmural dispersion of ERP (45±25 to 120±65 ms;
P
<0.05). Twenty-eight of 47 episodes of self-terminating TdP (43±72 beats) were analyzed. The majority (>90%) of beats were focal; reentry was observed only occasionally.

Conclusions—
Focal activity is the dominant mechanism involved in perpetuation of ibutilide-induced TdP in CAVB dogs based on detailed 3D mapping. This conclusion is in line with unaltered conduction and documented increase in VERP.
Follistatin-Like 1 in Chronic Systolic Heart Failure
Authors: El-Armouche Ali , Ouchi Noriyuki , Tanaka Komei , Doros Gheorghe , Wittköpper Katrin , Schulze Thomas , Eschenhagen Thomas , Walsh Kenneth , Sam Flora 
Published: May 2011

Background—
Follistatin-like 1 (FSTL1) is an extracellular glycoprotein found in human serum. Recent work suggests that FSTL1 is secreted in response to ischemic injuries and that its overexpression is protective in the heart and vasculature.

Methods and Results—

We examined serum FSTL1 levels in patients with chronic heart failure with left ventricular (LV) ejection fraction <40% (n=86). The sample was separated into three tertiles of patients with low, medium, and high FSTL1 levels. Serum FSTL1 was increased 56% above age- and sex-matched healthy controls. Diabetes mellitus, brain natriuretic peptide level, left atrial size, LV posterior wall thickness, LV end-diastolic diameter, and LV mass were significant determinants of FSTL1 serum levels by bivariate analysis. After controlling for significant covariates, FSTL1 levels predicted LV hypertrophy (as measured by LV mass index) by multivariate linear regression analysis (
P
<0.001). Unadjusted survival analysis demonstrated increased mortality in patients with increasing FSTL1 levels (
P
=0.09). After adjusting for significant parameters, patients with increased FSTL1 remained at the highest risk of death (hazard ratio, 1.028; 95% CI, 0.98 to 1.78;
P
=0.26). To determine whether elevated FSTL1 levels may be derived from the myocardium, FSTL1 protein expression was measured in explanted failing (n=18) and nonfailing (n=7) human hearts. LV failing hearts showed 2.5-fold higher FSTL1 protein levels over nonfailing control hearts (
P
<0.05).

Conclusions—
Elevated serum FSTL1 in patients with heart failure was associated with LV hypertrophy. Further studies on the role of FSTL1 as a biomarker in chronic systolic heart failure are warranted.
Assessment of Nasal Fibroscopy to Explore Olfactory Cleft
Authors: Porez Florence , de Pommerol Marie Jullien , Krief Peggy , Conso Françoise , Stoll Dominique , de Gabory Ludovic 
Published: May 2011

ObjectiveTo assess whether flexible nasoendoscopy can be used to visualize all parts of the olfactory cleft (OC) without morbidity.Study DesignSingle‐center, prospective, observational study.SettingFrench tertiary referral center.Subjects and Methods100 consecutive patients were divided in 2 groups of 50. Group 1 underwent nasal fibroscopy without vasoconstriction or local anesthesia with an endosheath‐ protected endoscope. Group 2 was examined by a fiberscope without an endosheath after application of naphazoline Xylocaine. Each OC was divided in 16 items recorded as visualized or not. Four scores were compared between both groups: out of 16 (1 side), out of 32 (both sides), out of 12 concerning only the narrowest and highest bilateral spaces, and out of 4 to divide these specific areas in anterior, middle, and posterior parts. Length of procedure, pain, epistaxis, blood mark on the endosheath, sneezing, rhinorrhea, and causes of failure were recorded.ResultsThere was no significant difference between both groups concerning score out of 16 or 32. The visibility of the narrower and higher spaces was better in group 2: scores out of 12 were significantly different between the groups (P =. 025), as were scores out of 4 for the anterior and middle parts of the OC (P =. 02 and. 01 respectively). Morbidity was low without differences between the groups. Deviated nasal septum was the only cause of failure and increased the patients’ pain during the examination (P =. 045).ConclusionNasal fibroscopy could be used to explore the different portions of the OC efficiently and with low morbidity.
Tibial Fixation in Anterior Cruciate Ligament Reconstruction
Authors: De Wall Mathew , Scholes Corey J. , Patel Sandeep , Coolican Myles R.J. , Parker David A. 
Published: May 2011

Background: The use of hamstring tendons for anterior cruciate ligament reconstruction has increased in popularity over recent years. However, concerns with the stability of graft fixation on the tibial side remain. Centrally placed interference screw/sheath implants have demonstrated promising results in biomechanical studies. Hypothesis: Centrally placed, polyethylene screw and sheath implants will provide clinically equivalent fixation to the standard metal interference screw and supplemental staple fixation. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 113 consecutive patients undergoing isolated, unilateral, primary anterior cruciate ligament reconstruction with hamstring autografts were randomized to tibial fixation with metal interference screw and staples (RCI) or with a centrally placed polyethylene screw and sheath implant (INTRAFIX). Prospective assessment of subjective outcomes was performed using Lysholm, Mohtadi, and International Knee Documentation Committee (IKDC) scores. Results: At minimum 2-year follow-up, there were no significant differences between the 2 groups in terms of instrumented stability testing (KT-1000 arthrometer) or subjective assessment of knee outcomes (IKDC, Lysholm, Mohtadi). Both fixation methods demonstrated a significant, but not different, increase in outcomes scores from preoperative to postoperative evaluation. There were 7 failures (5 INTRAFIX, 2 RCI) caused by reinjury, but no statistically significant differences were observed between the 2 fixation methods. Conclusion: The centrally placed polyethylene screw and sheath provided equivalent clinical outcomes at minimum 2-year follow-up to standard tibial fixation with metal interference screw and staples.
Dynamic Ankle Control in Athletes With Ankle Instability During Sports Maneuvers
Authors: Lin Cheng-Feng , Chen Chin-Yang , Lin Chia-Wei 
Published: May 2011

Background: Ankle sprain is a common sports injury. While the effects of static constraints in stabilizing the ankle joint are relatively well understood, those of dynamic constraints are less clear and require further investigation. Purpose: This study was undertaken to evaluate the dynamic stability of the ankle joint during the landing phase of running and stop-jump maneuvers in athletes with and without chronic ankle instability (CAI). Study Design: Controlled laboratory study. Methods: Fifteen athletes with CAI and 15 age-matched athletes without CAI performed running and stop-jump landing tasks. The dynamic ankle joint stiffness, tibialis anterior (TA)/peroneus longus (PL) and TA/gastrocnemius lateralis (GL) co-contraction indices, ankle joint angle, and root-mean-square (RMS) of the TA, PL, and GL electromyographic signals were measured during each task. Results: During running, the CAI group exhibited a greater ankle inversion angle than the control group in the pre-landing phase ( P = .012-.042) and a lower dynamic ankle joint stiffness in the post-landing phase (CAI: 0.109 ± 0.039 N·m/deg; control: 0.150 ± 0.068 N·m/deg; P = .048). In the stop-jump landing task, athletes with CAI had a significantly lower TA/PL co-contraction index during the pre-landing phase (CAI: 49.1 ± 19; control: 64.8 ± 16; P = .009). In addition, the CAI group exhibited a greater ankle inversion ( P = .049), a lower peak eversion ( P = .04), and a smaller RMS of the PL electromyographic signal in the post-landing phase (CAI: 0.73 ± 0.32; control: 0.51 ± 0.22; P = .04). Conclusion: Athletes with CAI had a relatively inverted ankle, reduced muscle co-contraction, and a lower dynamic stiffness in the ankle joint during the landing phase of sports maneuvers and this may jeopardize the stability of the ankle. Clinical Relevance: Sports training or rehabilitation programs should differentiate between the pre-landing and post-landing phases of sports maneuvers, and should educate athletes to land with an appropriate ankle position and muscle recruitment.
Integrated contour detection and pose estimation for fluoroscopic analysis of knee implants
Authors: Prins A H , Kaptein B L , Stoel B C , Nelissen R G H H , Reiber J H C , Valstar E R 
Published: June 2011

With fluoroscopic analysis of knee implant kinematics the implant contour must be detected in each image frame, followed by estimation of the implant pose. With a large number of possibly low-quality images, the contour detection is a time-consuming bottleneck. The present paper proposes an automated contour detection method, which is integrated in the pose estimation. In a phantom experiment the automated method was compared with a standard method, which uses manual selection of correct contour parts. Both methods demonstrated comparable precision, with a minor difference in the Y-position (0.08 mm versus 0.06 mm). The precision of each method was so small (below 0.2 mm and 0.3°) that both are sufficiently accurate for clinical research purposes. The efficiency of both methods was assessed on six clinical datasets. With the automated method the observer spent 1.5 min per image, significantly less than 3.9 min with the standard method. A Bland–Altman analysis between the methods demonstrated no discernible trends in the relative femoral poses. The threefold increase in efficiency demonstrates that a pose estimation approach with integrated contour detection is more intuitive than a standard method. It eliminates most of the manual work in fluoroscopic analysis, with sufficient precision for clinical research purposes.
Loss of p19Arf in a Rag1−/− B-cell precursor population initiates acute B-lymphoblastic leukemia
Authors: Hauer Julia , Mullighan Charles , Morillon Estelle , Wang Gary , Bruneau Julie , Brousse Nicole , Lelorc'h Marc , Romana Serge , Boudil Amine , Tiedau Daniela , Kracker Sven , Bushmann Frederic D. , Borkhardt Arndt , Fischer Alain , Hacein-Bey-Abina Salima , Cavazzana-Calvo Marina 
Published: May 2011

Abstract
In human B-acute lymphoblastic leukemia (B-ALL), RAG1-induced genomic alterations are important for disease progression. However, given that biallelic loss of the RAG1 locus is observed in a subset of cases, RAG1's role in the development of B-ALL remains unclear. We chose a p19Arf−/−Rag1−/− mouse model to confirm the previously published results concerning the contribution of CDKN2A (p19ARF /INK4a) and RAG1 copy number alterations in precursor B cells to the initiation and/or progression to B-acute lymphoblastic leukemia (B-ALL). In this murine model, we identified a new, Rag1-independent leukemia-initiating mechanism originating from a Sca1+CD19+ precursor cell population and showed that Notch1 expression accelerates the cells' self-renewal capacity in vitro. In human RAG1-deficient BM, a similar CD34+CD19+ population expressed p19ARF. These findings suggest that combined loss of p19Arf and Rag1 results in B-cell precursor leukemia in mice and may contribute to the progression of precursor B-ALL in humans.
New mechanism of X-linked anhidrotic ectodermal dysplasia with immunodeficiency: impairment of ubiquitin binding despite normal folding of NEMO protein
Authors: Hubeau Marjorie , Ngadjeua Flora , Puel Anne , Israel Laura , Feinberg Jacqueline , Chrabieh Maya , Belani Kiran , Bodemer Christine , Fabre Isabelle , Plebani Alessandro , Boisson-Dupuis Stéphanie , Picard Capucine , Fischer Alain , Israel Alain , Abel Laurent , Veron Michel , Casanova Jean-Laurent , Agou Fabrice , Bustamante Jacinta 
Published: May 2011

Abstract
Nuclear factor-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase complex, is a critical component of the NF-κB pathway. Hypomorphic mutations in the X-linked human NEMO gene cause various forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). All known X-linked EDA-ID–causing mutations impair NEMO protein expression, folding, or both. We describe here 2 EDA-ID–causing missense mutations that affect the same residue in the CC2-LZ domain (D311N and D311G) that do not impair NEMO production or folding. Structural studies based on pull-down experiments showed a defect in noncovalent interaction with K63-linked and linear polyubiquitin chains for these mutant proteins. Functional studies on the patients' cells showed an impairment of the classic NF-κB signaling pathways after activation of 2 NEMO ubiquitin-binding–dependent receptors, the TNF and IL-1β receptors, and in the CD40-dependent NF-κB pathway. We report the first human NEMO mutations responsible for X-linked EDA-ID found to affect the polyubiquitin binding of NEMO rather than its expression and folding. These experiments demonstrate that the binding of human NEMO to polyubiquitin is essential for NF-κB activation. They also demonstrate that the normal expression and folding of NEMO do not exclude a pathogenic role for NEMO mutations in patients with EDA-ID.
Stromal cell–derived factor-1 and hematopoietic cell homing in an adult zebrafish model of hematopoietic cell transplantation
Authors: Glass Tiffany J. , Lund Troy C. , Patrinostro Xiaobai , Tolar Jakub , Bowman Teresa V. , Zon Leonard I. , Blazar Bruce R. 
Published: May 2011

Abstract
In mammals, stromal cell–derived factor-1 (SDF-1) promotes hematopoietic cell mobilization and migration. Although the zebrafish, Danio rerio, is an emerging model for studying hematopoietic cell transplantation (HCT), the role of SDF-1 in the adult zebrafish has yet to be determined. We sought to characterize sdf-1 expression and function in the adult zebrafish in the context of HCT. In situ hybridization of adult zebrafish organs shows sdf-1 expression in kidney tubules, gills, and skin. Radiation up-regulates sdf-1 expression in kidney to nearly 4-fold after 40 Gy. Assays indicate that zebrafish hematopoietic cells migrate toward sdf-1, with a migration ratio approaching 1.5 in vitro. A sdf-1a:DsRed2 transgenic zebrafish allows in vivo detection of sdf-1a expression in the adult zebrafish. Matings with transgenic reporters localized sdf-1a expression to the putative hematopoietic cell niche in proximal and distal renal tubules and collecting ducts. Importantly, transplant of hematopoietic cells into myelosuppressed recipients indicated migration of hematopoietic cells to sdf-1a–expressing sites in the kidney and skin. We conclude that sdf-1 expression and function in the adult zebrafish have important similarities to mammals, and this sdf-1 transgenic vertebrate will be useful in characterizing the hematopoietic cell niche and its interactions with hematopoietic cells.
Quantitative immunofluorescence mapping reveals little functional coclustering of proteins within platelet α-granules
Authors: Kamykowski Jeffrey , Carlton Peter , Sehgal Siddharth , Storrie Brian 
Published: May 2011

Abstract
Platelets are small anucleate blood cells that aggregate to seal leaks at sites of vascular injury and are important in the pathology of atherosclerosis, acute coronary syndromes, rheumatoid arthritis, cancer, and the regulation of angiogenesis. In all cases, platelet aggregation requires release of stored proteins from α-granules. However, how proteins with potentially antagonistic functions are packaged within α-granules is controversial. One possibility is the packaging of functional agonists and antagonists into different α-granule populations. By quantitative immunofluorescence colocalization, we found that pair-wise comparisons of 15 angiogenic-relevant α-granule proteins displayed little, if any, pattern of functional coclustering. Rather, the data suggested a Gaussian distribution indicative of stochastic protein delivery to individual granules. The apparent physiologic paradox raised by these data may be explained through alternate mechanisms, such as differential content release through incomplete granule fusion or dampened and balanced regulatory networks brought about by the corelease of antagonistic factors.