bluuebunny/crossref_metadata_2025 huggingface dataset:
Tracing phenotypic reversibility of pancreatic β‐cells in vitro
Authors: Minami Kohtaro , Miyawaki Kazumasa , Hara Manami , Yamada Shuichi , Seino Susumu
Published: December 2010

Aims/Introduction:  Studies have suggested that pancreatic β‐cells undergo dedifferentiation during proliferation in vitro. However, due to limitations of the methodologies used, the question remains whether such dedifferentiated cells can redifferentiate into β‐cells.

Materials and Methods:  We have established a method for cell tracing in combination with fluorescence‐activated cell sorter (FACS). Using this method, mouse pancreatic β‐cells labeled with green fluorescent protein (GFP) under the control of the insulin promoter are collected by FACS. These β‐cells can be traced and characterized throughout the culture process, even when insulin becomes undetectable, because the cells are also marked with monomeric red fluorescent protein (mRFP) driven by the CAG promoter.

Results:  When cultured with fetal mouse pancreatic cells, FACS sorted β‐cells lost GFP expression, but retained mRFP expression. The cells also lost expressions of genes characteristic of the β‐cell phenotype, such as Pdx1 and glucokinase, indicating dedifferentiation. More than 30% of such dedifferentiated pancreatic β‐cells were detected in S or G2/M phase. Furthermore, these dedifferentiated cells redifferentiated into insulin‐expressing cells on cultivation with a MEK1/2 inhibitor.

Conclusions:  Our data provide direct evidence that pre‐existing β‐cells can undergo dedifferentiation and redifferentiation in vitro, their phenotype is reversible and that dedifferentiation in β‐cells is associated with progression of the cell cycle. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00051.x, 2010)
A Virtual Instrument for Automated Measurement of Arterial Compliance
Authors: Joseph Jayaraj , Jayashankar V.
Published: December 2010

Measurement of arterial distensibility is very important in cardiovascular diagnosis for early detection of coronary heart disease and possible prediction of future cardiac events. Conventionally, B-mode ultrasound imaging systems have been used along with expensive vessel wall tracking systems for estimation of arterial distension and calculation of various estimates of compliance. We present a simple instrument for noninvasive in vivo evaluation of arterial compliance using a single element ultrasound transducer. The measurement methodology is initially validated using a proof of concept pilot experiment using a commercial ultrasound pulser-receiver. A prototype system is then developed around a PXI chassis using LABVIEW software. The virtual instrument employs a dynamic threshold algorithm to identify the artery walls and then utilizes a correlation based tracking technique to estimate arterial distension. The end-diastolic echo signals are averaged to reduce error in the automated diameter measurement process. The instrument allows automated measurement of the various measures of arterial compliance with minimal operator intervention. The performance of the virtual instrument was first analyzed using simulated data sets to establish the maximum measurement accuracy achievable under different input signal to noise ratio (SNR) levels. The system could measure distension with accuracy better than 10 μm for positive SNR. The measurement error in diameter was less than 1%. The system was then thoroughly evaluated by the experiments conducted on phantom models of the carotid artery and the accuracy and resolution were found to meet the requirements of the application. Measurements performed on human volunteers indicate that the instrument can measure arterial distension with a precision better than 5%. The end-diastolic arterial diameter can be measured with a precision better than 2% and an accuracy of 1%. The measurement system could lead to the development of small, portable, and inexpensive equipment for estimation of arterial compliance suitable in mass screening of “at risk” patients. The automated compliance measurement algorithm implemented in the instrument requires minimal operator input. The instrument could pave the way for dedicated systems for arterial compliance evaluation targeted at the general medical practitioner who has little or no expertise in vascular ultrasonography.
Particle Size Effects on Slurry Erosion of 5117 steels
Authors: Abouel-Kasem A.
Published: December 2010

The effect of particles size and shape on erosion rates and erosion mechanisms of 5117 steels are investigated using slurry whirling-arm ring. Six different sized silica sand particles are used as erodent. These particles are characterized in terms of their average diameter, aspect ratio, and circularity factor. The measured average diameter varies from 112.7 μm to 516.4 μm. The wear tests are carried out at impact velocity of 15 m/s and 30 deg and 90 deg impact angles using a sand-water mixture of 1 wt % concentration. Analysis of erosion rates shows that there exists threshold energy of impacting particles at which a transition in erosion rate is noticed for sizes of 200 μm. It is also observed that the erosion rate increases with the increase in shape factors (aspect ratio and circularity factor). The surface morphology of the eroded surface at impact of 30 deg shows that below 200 μm, the erosion mechanism is indentation and material extrusion and above 200 μm, the erosion mechanism is ploughing.
Three-Dimensional Heat Transfer Analysis of Pin-Bushing System With Oscillatory Motion: Theory and Experiment
Authors: Wen Jun , Khonsari M. M. , Hua D. Y.
Published: December 2010

A three-dimensional computational thermal contact model is developed. The approach utilizes a combination of the transfer matrix and finite element methods. The frictional heat generated at the contact interface is instantaneously partitioned between the bushing and the shaft. Two methods to couple the heat and temperature at the contact interface are presented. One method automatically accounts for the heat division between contacting bodies by satisfying the heat equilibrium and temperature continuity at interactive surfaces. The other method introduces a fictitious layer between contacting bodies with a specified gap conductance to partition the frictional heat. Application of the model to the heat transfer analysis of journal bearing systems experiencing oscillatory motion is presented. Nonuniformly distributed frictional heat along the axial direction is considered. The model is capable of predicting the transient temperature field for journal bearings. It can also be used to determine the maximum contact temperature, which is difficult to be measured experimentally. Comparison of the simulated resulted along with experimental tests conducted in a laboratory is presented.
Micropatterned Treads for In Vivo Robotic Mobility
Authors: Sliker Levin J. , Wang Xin , Schoen Jonathan A. , Rentschler Mark E.
Published: December 2010

Despite revolutionary advances in many fields of medicine, there are no active mobile in vivo devices commercially available, or in use, today. Several research groups are actively looking at a number of mobility methods in a number of lumens but little commercial work has been done. While robotic surgery is available today, thanks to ex vivo robots, such as the da Vinci surgical system, these methods are very expensive, require heavy external equipment, and are still constrained by entry incisions. An alternative approach may be to place the robot completely inside the patient. Such devices may enable noninvasive imaging and diagnostics. These devices may be significantly less expensive than current minimally invasive methods, without extensive support equipment, which may allow them to be also used routinely in the emergency room (ER)/trauma sites and remote locations. This work explores micropatterned treads that may enable mobile capsule crawlers inside the body. Current research efforts into providing contact locomotion using micro-tread tracks are explored including initial drawbar force generation experimental results, dynamic finite element analysis with these tread designs, and in vivo porcine evaluation and comparison of two leading tread designs.
Effects of the Thermocompression Bonding on the Microstructure and Contact Resistance for the Ultrafine Pitch Chip-on-Glass Packaging With Nonconductive Film
Authors: Zhang Jianhua , Zhang Jinsong , Yang Lianqiao
Published: December 2010

Nonconductive film (NCF) is a challenging potential material to substitute the application of anisotropic conductive film in the ultrafine pitch chip-on-glass (COG) packaging. The NCF interconnection requires a high bonding temperature and pressure to form joints, and this causes new reliability concerns. This study investigated effects of the thermocompression bonding parameters on the microstructure and geometric size in the joints to a COG module packaged with NCF. The results revealed that the high temperature and pressure compressed the joints to become wider and shorter. A dual layer of intermetallic compounds consisting of AuSn2 (ε phase) and AuSn4 (η phase) was found in each joint. They were the two kinds of interphases with different melting points (AuSn2:309°C and AuSn4:257°C) during the interfacial reaction between Au and Sn. At the low temperature (below the melting point), the high pressure induced the residual inner stress to generate the cracks in the joints, and this also increased the contact resistance of the joints. The contact resistance increased with the pressure elevating at the same temperature and with the temperature degrading at the same pressure. In the COG packaging with NCF, a proper elevating of the bonding temperature could produce a stable direct connection with the low contact resistance.
Science 101: Building the Foundations for Real Understanding
Authors: Thanukos Anastasia , Scotchmoor Judith G. , Caldwell Roy , Lindberg David R.
Published: December 2010

Two online projects offer one-stop shopping for teaching evolution, as well as the nature and process of science.
Fracture of the extensor process of the distal phalanx in a bull and a cow
Authors: Taguchi K. , Nakamura S. , Hyakutake K.
Published: December 2010

Two cases of extensor process fracture of the distal phalanx in the forelimb in a Holstein bull and a lactating Holstein cow are described. Each animal showed acute onset of severe lameness with a gait characterised by lengthening of the cranial phase of the step in order to place more weight on the heel. Mild swelling and a localised pain response upon application of deep pressure above the coronet were also observed. A definitive diagnosis was made by radiography with complementary ultrasonography, which provided the best definition of the fracture fragment over the dorsal aspect of the distal interphalangeal joint. Applying a wooden block to a sound claw for three weeks was curative and provided a good prognosis in both cases.
Acute phase protein concentrations in dogs with nasal disease
Authors: Sheahan D. , Bell R. , Mellanby R. J. , Gow A. G. , Friend E. , Heller J. , Bence L. M. , Eckersall P. D.
Published: December 2010

The concentrations of C‐reactive protein (CRP), serum amyloid A, haptoglobin (Hp) and α1‐acid glycoprotein were measured in dogs with clinical signs of nasal disease and compared with those of healthy dogs in order to determine the expression of these proteins in cases of canine nasal disease. A significant difference (P<0.001) between the symptomatic group and the control group was found for both CRP and Hp. Among the animals with nasal disease, a significant intergroup difference (P<0.05) was found in the expression of Hp between dogs with aspergillosis and those with chronic rhinitis.
EFFECTS OF f(R) DARK ENERGY ON DISSIPATIVE ANISOTROPIC COLLAPSING FLUID
Authors: SHARIF M. , RIZWANA KAUSAR H.
Published: December 2010

The purpose of this paper is to study the effects of dark energy on dynamics of the collapsing fluid within the framework of metric f(R) gravity. The fluid distribution is assumed to be locally anisotropic and undergoing dissipation in the form of heat flow, null radiations and shear viscosity. For this purpose, we take general spherical symmetric spacetime. Dynamical equations are obtained and also some special solutions are found by considering shearing expansion-free evolution of the fluid. It is found that dark energy affects the mass of the collapsing matter and rate of collapse but does not affect the hydrostatic equilibrium.
DIRAC QUASINORMAL MODES OF CHARGED BRANEWORLD BLACK HOLE
Authors: LIN KAI , YANG NAN , LI JIN , CHEN SHANSHAN , YI XIUQIANG
Published: December 2010

We study the quasinormal modes (QNMs) of charged braneworld black hole, which carry two types of "charge". In this paper, the six-order Wentzel–Kramers–Brillouin (WKB) approximation is applied to calculate the quasinormal frequencies (QNF), and then two types of charges affecting the shape of potential function, and oscillation frequency increases with increasing β while the damping of QMNs is slower as β is smaller.
ON THE SUPERSYMMETRY OF SPIKY BRANES IN AdS4×ℂℙ3
Authors: KIM HYOJOONG , KIM NAKWOO
Published: December 2010

We study supersymmetric D-brane configurations in AdS4×ℂℙ3 background, which is dual to the D = 3, [Formula: see text] Chern–Simons-matter theory discovered by Aharony et al. In particular, we consider D2 and D6-branes with fundamental strings attached to them. D2-branes are wrapped on ℂℙ1 ⊂ ℂℙ3 and dual to a symmetric product of Wilson lines, while D6-branes wrapping the entire ℂℙ3 correspond to baryonic vertices. We perform the κ-symmetry analysis to construct the BPS equations and find explicit solutions of the world-volume D-brane action. When one turns on the electric field, D2 and D6-brane configurations preserve 4 and 2 supercharges respectively.
Lymphocyte enzymatic antioxidant responses to oxidative stress following high-intensity interval exercise
Authors: Fisher G. , Schwartz D. D. , Quindry J. , Barberio M. D. , Foster E. B. , Jones K. W. , Pascoe D. D.
Published: December 2010

The purposes of this study were to 1) examine the immune and oxidative stress responses following high-intensity interval training (HIIT); 2) determine changes in antioxidant enzyme gene expression and enzyme activity in lymphocytes following HIIT; and 3) assess pre-HIIT, 3-h post-HIIT, and 24-h post-HIIT lymphocyte cell viability following hydrogen peroxide exposure in vitro. Eight recreationally active males completed three identical HIIT protocols. Blood samples were obtained at preexercise, immediately postexercise, 3 h postexercise, and 24 h postexercise. Total number of circulating leukocytes, lymphocytes, and neutrophils, as well as lymphocyte antioxidant enzyme activities, gene expression, cell viability (CV), and plasma thiobarbituric acid-reactive substance (TBARS) levels, were measured. Analytes were compared using a three (day) × four (time) ANOVA with repeated measures on both day and time. The a priori significance level for all analyses was P < 0.05. Significant increases in superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities were observed in lymphocytes following HIIT. No significant increases in lymphocyte SOD, CAT, or GPX gene expression were found. A significant increase in TBARS was found immediately post-HIIT on days 1 and 2. Lymphocyte CV in vitro significantly increased on days 2 and 3 compared with day 1. Additionally, there was a significant decrease in CV at 3 h compared with pre- and 24 h postexercise. These findings indicate lymphocytes respond to oxidative stress by increasing antioxidant enzyme activity. Additionally, HIIT causes oxidative stress but did not induce a significant postexercise lymphocytopenia. Analyses in vitro suggest that lymphocytes may become more resistant to subsequent episodes of oxidative stress. Furthermore, the analysis in vitro confirms that lymphocytes are more vulnerable to cytotoxic molecules during recovery from exercise.
Neuromuscular electrical stimulation training induces atypical adaptations of the human skeletal muscle phenotype: a functional and proteomic analysis
Authors: Gondin Julien , Brocca Lorenza , Bellinzona Elena , D'Antona Giuseppe , Maffiuletti Nicola A. , Miotti Danilo , Pellegrino Maria A. , Bottinelli Roberto
Published: December 2010

The aim of the present study was to define the chronic effects of neuromuscular electrical stimulation (NMES) on the neuromuscular properties of human skeletal muscle. Eight young healthy male subjects were subjected to 25 sessions of isometric NMES of the quadriceps muscle over an 8-wk period. Needle biopsies were taken from the vastus lateralis muscle before and after training. The training status, myosin heavy chain (MHC) isoform distribution, and global protein pattern, as assessed by proteomic analysis, widely varied among subjects at baseline and prompted the identification of two subgroups: an “active” (ACT) group, which performed regular exercise and had a slower MHC profile, and a sedentary (SED) group, which did not perform any exercise and had a faster MHC profile. Maximum voluntary force and neural activation significantly increased after NMES in both groups (+∼30% and +∼10%, respectively). Both type 1 and 2 fibers showed significant muscle hypertrophy. After NMES, both groups showed a significant shift from MHC-2X toward MHC-2A and MHC-1, i.e., a fast-to-slow transition. Proteomic maps showing ∼500 spots were obtained before and after training in both groups. Differentially expressed proteins were identified and grouped into functional categories. The most relevant changes regarded 1) myofibrillar proteins, whose changes were consistent with a fast-to-slow phenotype shift and with a strengthening of the cytoskeleton; 2) energy production systems, whose changes indicated a glycolytic-to-oxidative shift in the metabolic profile; and 3) antioxidant defense systems, whose changes indicated an enhancement of intracellular defenses against reactive oxygen species. The adaptations in the protein pattern of the ACT and SED groups were different but were, in both groups, typical of both resistance (i.e., strength gains and hypertrophy) and endurance (i.e., a fast-to-slow shift in MHC and metabolic profile) training. These training-induced adaptations can be ascribed to the peculiar motor unit recruitment pattern associated with NMES.
The Integrin αvβ3-5 Ligand MFG-E8 Is a p63/p73 Target Gene in Triple-Negative Breast Cancers but Exhibits Suppressive Functions in ER+ and erbB2+ Breast Cancers
Authors: Yang Chuanwei , Hayashida Tetsu , Forster Nicole , Li Cuiqi , Shen Dejun , Maheswaran Shyamala , Chen Li , Anderson Karen S. , Ellisen Leif W. , Sgroi Dennis , Schmidt Emmett V.
Published: December 2010

The progression from preinvasive lesion to invasive carcinoma is a critical step contributing to breast cancer lethality. We identified downregulation of milk fat globule-EGF factor 8 (MFG-E8) as a contributor to breast cancer progression using microarray analysis of laser capture microdissected (LCM) tissues. We first identified MFG-E8 downregulation in invasive lesions in transgenic mammary tumor models, which were confirmed in LCM-isolated human invasive ductal carcinomas compared with patient-matched normal tissues. In situ analyses of MFG-E8 expression in estrogen receptor (ER) positive cases confirmed its downregulation during breast cancer progression and small inhibitory MFG-E8 RNAs accelerated ER+ breast cancer cell proliferation. MFG-E8 also decreased in erbB2+ human cancers and erbB2 transgenic mice lacking MFG-E8 showed accelerated tumor formation. In contrast, MFG-E8 expression was present at high levels in triple-negative (ER−, PgR−, erbB2−) breast cancers, cell lines, and patient sera. Knockdown, chromatin immunoprecipitation, and reporter assays all showed that p63 regulates MFG-E8 expression, and MFG-E8 knockdowns sensitized triple-negative breast cancers to cisplatin treatment. Taken together, our results show that MFG-E8 is expressed in triple-negative breast cancers as a target gene of the p63 pathway, but may serve a suppressive function in ER+ and erbB2+ breast cancers. Its potential use as a serum biomarker that contributes to the pathogenesis of triple-negative breast cancers urges continued evaluation of its differential functions. Cancer Res; 71(3); 937–45. ©2010 AACR.
Dynamic Mathematical Modeling of IL13-Induced Signaling in Hodgkin and Primary Mediastinal B-Cell Lymphoma Allows Prediction of Therapeutic Targets
Authors: Raia Valentina , Schilling Marcel , Böhm Martin , Hahn Bettina , Kowarsch Andreas , Raue Andreas , Sticht Carsten , Bohl Sebastian , Saile Maria , Möller Peter , Gretz Norbert , Timmer Jens , Theis Fabian , Lehmann Wolf-Dieter , Lichter Peter , Klingmüller Ursula
Published: December 2010

Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) share a frequent constitutive activation of JAK (Janus kinase)/STAT signaling pathway. Because of complex, nonlinear relations within the pathway, key dynamic properties remained to be identified to predict possible strategies for intervention. We report the development of dynamic pathway models based on quantitative data collected on signaling components of JAK/STAT pathway in two lymphoma-derived cell lines, MedB-1 and L1236, representative of PMBL and cHL, respectively. We show that the amounts of STAT5 and STAT6 are higher whereas those of SHP1 are lower in the two lymphoma cell lines than in normal B cells. Distinctively, L1236 cells harbor more JAK2 and less SHP1 molecules per cell than MedB-1 or control cells. In both lymphoma cell lines, we observe interleukin-13 (IL13)-induced activation of IL4 receptor α, JAK2, and STAT5, but not of STAT6. Genome-wide, 11 early and 16 sustained genes are upregulated by IL13 in both lymphoma cell lines. Specifically, the known STAT-inducible negative regulators CISH and SOCS3 are upregulated within 2 hours in MedB-1 but not in L1236 cells. On the basis of this detailed quantitative information, we established two mathematical models, MedB-1 and L1236 model, able to describe the respective experimental data. Most of the model parameters are identifiable and therefore the models are predictive. Sensitivity analysis of the model identifies six possible therapeutic targets able to reduce gene expression levels in L1236 cells and three in MedB-1. We experimentally confirm reduction in target gene expression in response to inhibition of STAT5 phosphorylation, thereby validating one of the predicted targets. Cancer Res; 71(3); 693–704. ©2010 AACR.
Pharmacokinetically Guided Phase 1 Trial of the IGF-1 Receptor Antagonist RG1507 in Children with Recurrent or Refractory Solid Tumors
Authors: Bagatell R. , Herzog C.E. , Trippett T.M , Grippo J.F. , Cirrincione-Dall G. , Fox E. , Macy M. , Bish J. , Whitcomb P. , Aikin A. , Wright G. , Yurasov S. , Balis F.M. , Gore L.
Published: December 2010

Purpose: This pediatric phase I study was designed to identify the doses of RG1507, a monoclonal antibody against the Type 1 Insulin-like Growth Factor Receptor (IGF1R), that achieves exposures equivalent to those achieved in adults at recommended doses.

Experimental Design: Children with relapsed or refractory solid tumors were treated using the same doses and administration schedules of RG1507 (3 and 9 mg/kg/wk, and 16 mg/kg every 3 weeks [q3W]) as those studied in adults. Detailed pharmacokinetic (PK) sampling was performed after the first dose; selected peak and trough levels were subsequently obtained. Target exposures were ≥85% of mean areas under concentration x time curves (AUCs) in adults at doses of 9 mg/kg/wk and 16 mg/kg q3W. A maximum tolerated dose could be identified if dose-limiting toxicities (DLT) occurred.

Results: Thirty-one evaluable patients aged 3–17 years were enrolled at 3 mg/kg/wk (n = 3), 9 mg/kg/wk (n = 18), or 16 mg/kg q3W (n = 10). There were no DLTs. At 9 mg/kg/wk the mean AUC0–7d (21,000 μg h/mL) exceeded the target (16,000 μg h/mL). At 16 mg/kg q3W, the mean AUC021d (70,000 μg h/mL) exceeded the target (59,400 μg h/mL). Clearance normalized to body weight was age dependent. There were no objective responses. Seven patients had stable disease for >12 weeks, including two patients with osteosarcoma with stable disease for 52+ and 78+ weeks.

Conclusions: The recommended doses of RG1507 in children with solid tumors are 9 mg/kg/wk and 16 mg/kg q3W. This flexible design is well suited for trials of agents associated with limited toxicity. Clin Cancer Res; 17(3); 611–9. ©2010 AACR.
Transthyretin-Related Hereditary Amyloidosis in a Chinese Family with TTR Y114C Mutation
Authors: Zhang Yu , Deng Yu-Lei , Ma Jian-Fang , Zheng Lan , Hong Zhen , Wang Zhi-Quan , Sheng Cheng-Yu , Xiao Qin , Cao Li , Chen Sheng-Di
Published: December 2010

Background: Transthyretin-related hereditary amyloidosis is an autosomal dominant inherited disease caused by mutations in the transthyretin (TTR) gene. Corresponding to the various transthyretin gene mutations and a wide range of geographical distribution, transthyretin-related hereditary amyloidosis presents diverse characteristics in genotype-phenotype correlation. Objective/Method: Here, we identify the clinical characteristics of a Chinese family affected by transthyretin-related hereditary amyloidosis with TTR Tyr114Cys mutation. Results/Conclusion: The pathogenic mechanism studies showed that the protein encoded by TTR Tyr114Cys is more easily depolymerized to form amyloid fibrils. Moreover, the cytotoxicity of the TTR Tyr114Cys may be attributed to its ability to persistently activate the extracellular-signal-regulated kinase 1/2 pathway.
Endothelial Cell EphrinB2-Dependent Activation of Monocytes in Arteriosclerosis
Authors: Braun Jennifer , Hoffmann Sabrina C. , Feldner Anja , Ludwig Thomas , Henning Rob , Hecker Markus , Korff Thomas
Published: December 2010

Objective—

The expression of ephrinB2 in endothelial cells delineates their arterial phenotype and is a prerequisite for the development of the embryonic vasculature. Whereas the role of ephrinB2 in the microcirculation has been studied extensively, its expression and function in adult arteries is hardly understood.

Methods and Results—

Our analyses showed that in mouse arteries, ephrinB2 is located on the luminal surface of endothelial cells and may physically interact with monocyte EphB receptors. Moreover, transdifferentiation of human monocytes into macrophages was associated with an increase in EphB2 expression, and exposing monocytes to immobilized ephrinB2 resulted in phosphorylation of the receptor followed by an increased expression of proinflammatory chemokines such as interleukin-8 and monocyte chemotactic protein-1/CCL2. Relating to the (patho)physiological relevance of these findings, immunofluorescence analyses revealed that ephrinB2 is most abundantly expressed in endothelial cells at arteriosclerosis predilection sites of the mouse aorta. Subsequent analyses indicated that monocyte adhesion to aortic segments abundantly expressing ephrinB2 is strongly enhanced and that endothelial cell ephrinB2 forward signaling is sufficient to upregulate cytokine expression in monocytes.

Conclusion—

These observations suggest a hitherto unknown link between vascular ephrinB2 expression and the proinflammatory activation of monocytes that may contribute to the pathogenesis of arteriosclerosis.
Protease-Activated Receptor Signaling in Platelets Activates Cytosolic Phospholipase A2αDifferently for Cyclooxygenase-1 and 12-Lipoxygenase Catalysis
Authors: Holinstat Michael , Boutaud Olivier , Apopa Patrick L. , Vesci Joanne , Bala Manju , Oates John A. , Hamm Heidi E.
Published: December 2010

Objective—

The rate-limiting step in the biosynthesis of thromboxane A2(TxA2) and 12-hydroxyeicosatetraenoic acid (12-HETE) by platelets is activation of cytosolic phospholipase A2α(cPLA2α), which releases arachidonic acid, which is the substrate for cyclooxygenase-1 (COX-1) and 12-lipoxygenase. We evaluated signaling via the human platelet thrombin receptors, protease-activated receptor (PAR) 1 and PAR4, to the activation of cPLA2α, which provides a substrate for the biosynthesis of TxA2and 12-HETE.

Methods and Results—

Stimulating washed human platelets resulted in delayed biosynthesis of 12-HETE, which continues after maximal formation of TxA2is completed, suggesting that 12-HETE is not formed by the same pool of arachidonic acid that provides a substrate to COX-1. PAR1-induced formation of TxA2was inhibited by the phosphatidylinositol kinase inhibitor LY294002, whereas this inhibitor did not block 12-HETE biosynthesis. Both 1-butanol and propranolol also blocked TxA2biosynthesis but did not inhibit 12-HETE formation.

Conclusion—

The concerted evidence indicates that the platelet thrombin receptors signal activation of cPLA2αcoupled to COX-1 by a pathway different from that signaling activation of the cPLA2αcoupled to 12-lipoxygenase.
β-Catenin Mediates Mechanically Regulated, Transforming Growth Factor-β1–Induced Myofibroblast Differentiation of Aortic Valve Interstitial Cells
Authors: Chen Jan-Hung , Chen Wen Li Kelly , Sider Krista L. , Yip Cindy Ying Yin , Simmons Craig A.
Published: December 2010

Objective—

In calcific aortic valve disease, myofibroblasts and activation of the transforming growth factor-β1 (TGF-β1) and Wnt/β-catenin pathways are observed in the fibrosa, the stiffer layer of the leaflet, but their association is unknown. We elucidated the roles of β-catenin and extracellular matrix stiffness in TGF-β1-induced myofibroblast differentiation of valve interstitial cells (VICs).

Methods and Results—

TGF-β1 induced rapid β-catenin nuclear translocation in primary porcine aortic VICs in vitro through TGF-β receptor I kinase. Degrading β-catenin pharmacologically or silencing it with small interfering RNA inhibited TGF-β1-induced myofibroblast differentiation without altering Smad2/3 activity. Conversely, increasing β-catenin availability with Wnt3A alone did not induce differentiation. However, combining TGF-β1 and Wnt3A caused greater myofibroblast differentiation than TGF-β1 treatment alone. Notably, in VICs grown on collagen-coated PA gels with physiological stiffnesses, TGF-β1-induced β-catenin nuclear translocation and myofibroblast differentiation occurred only on matrices with fibrosa-like stiffness, but not ventricularis-like stiffness. In diseased aortic valves from pigs fed an atherogenic diet, myofibroblasts colocalized with increased protein expression of Wnt3A, β-catenin, TGF-β1, and phosphorylated Smad2/3 in the fibrosa.

Conclusion—

Myofibroblast differentiation of VICs involves matrix stiffness–dependent crosstalk between TGF-β1 and Wnt signaling pathways and may explain in part why the stiffer fibrosa is more susceptible to disease.
Mutations in the Sarcomere Gene
MYH7
in Ebstein Anomaly
Authors: Postma Alex V. , van Engelen Klaartje , van de Meerakker Judith , Rahman Thahira , Probst Susanne , Baars Marieke J.H. , Bauer Ulrike , Pickardt Thomas , Sperling Silke R. , Berger Felix , Moorman Antoon F.M. , Mulder Barbara J.M. , Thierfelder Ludwig , Keavney Bernard , Goodship Judith , Klaassen Sabine
Published: December 2010

Background—

Ebstein anomaly is a rare congenital heart malformation characterized by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. An association between Ebstein anomaly with left ventricular noncompaction (LVNC) and mutations in
MYH7
encoding β-myosin heavy chain has been shown; in this report, we have screened for
MYH7
mutations in a cohort of probands with Ebstein anomaly in a large population-based study.

Methods and Results—

Mutational analysis in a cohort of 141 unrelated probands with Ebstein anomaly was performed by next-generation sequencing and direct DNA sequencing of
MYH7
. Heterozygous mutations were identified in 8 of 141 samples (6%). Seven distinct mutations were found; 5 were novel and 2 were known to cause hypertrophic cardiomyopathy. All mutations except for 1 3-bp deletion were missense mutations; 1 was a de novo change. Mutation-positive probands and family members showed various congenital heart malformations as well as LVNC. Among 8 mutation-positive probands, 6 had LVNC, whereas among 133 mutation-negative probands, none had LVNC. The frequency of
MYH7
mutations was significantly different between probands with and without LVNC accompanying Ebstein anomaly (
P
<0.0001). LVNC segregated with the
MYH7
mutation in the pedigrees of 3 of the probands, 1 of which also included another individual with Ebstein anomaly.

Conclusions—

Ebstein anomaly is a congenital heart malformation that is associated with mutations in
MYH7
.
MYH7
mutations are predominantly found in Ebstein anomaly associated with LVNC and may warrant genetic testing and family evaluation in this subset of patients.
Extracellular Signal-Regulated Kinases 1 and 2 Regulate the Balance Between Eccentric and Concentric Cardiac Growth
Authors: Kehat Izhak , Davis Jennifer , Tiburcy Malte , Accornero Federica , Saba-El-Leil Marc K. , Maillet Marjorie , York Allen J. , Lorenz John N. , Zimmermann Wolfram H. , Meloche Sylvain , Molkentin Jeffery D.
Published: December 2010

Rationale:

An increase in cardiac afterload typically produces concentric hypertrophy characterized by an increase in cardiomyocyte width, whereas volume overload or exercise results in eccentric growth characterized by cellular elongation and addition of sarcomeres in series. The signaling pathways that control eccentric versus concentric heart growth are not well understood.

Objective:

To determine the role of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in regulating the cardiac hypertrophic response.

Methods and Results:

Here, we used mice lacking all ERK1/2 protein in the heart (Erk1
−/−
Erk2
fl/fl-Cre
) and mice expressing activated mitogen-activated protein kinase kinase (Mek)1 in the heart to induce ERK1/2 signaling, as well as mechanistic experiments in cultured myocytes to assess cellular growth characteristics associated with this signaling pathway. Although genetic deletion of all ERK1/2 from the mouse heart did not block the cardiac hypertrophic response per se, meaning that the heart still increased in weight with both aging and pathological stress stimulation, it did dramatically alter how the heart grew. For example, adult myocytes from hearts of Erk1
−/−
Erk2
fl/fl-Cre
mice showed preferential eccentric growth (lengthening), whereas myocytes from Mek1 transgenic hearts showed concentric growth (width increase). Isolated adult myocytes acutely inhibited for ERK1/2 signaling by adenoviral gene transfer showed spontaneous lengthening, whereas infection with an activated Mek1 adenovirus promoted constitutive ERK1/2 signaling and increased myocyte thickness. A similar effect was observed in engineered heart tissue under cyclic stretching, where ERK1/2 inhibition led to preferential lengthening.

Conclusions:

Taken together, these data demonstrate that the ERK1/2 signaling pathway uniquely regulates the balance between eccentric and concentric growth of the heart.
Guidelines for the Primary Prevention of Stroke
Authors: Goldstein Larry B. , Bushnell Cheryl D. , Adams Robert J. , Appel Lawrence J. , Braun Lynne T. , Chaturvedi Seemant , Creager Mark A. , Culebras Antonio , Eckel Robert H. , Hart Robert G. , Hinchey Judith A. , Howard Virginia J. , Jauch Edward C. , Levine Steven R. , Meschia James F. , Moore Wesley S. , Nixon J.V. (Ian) , Pearson Thomas A.
Published: December 2010

Background and Purpose—

This guideline provides an overview of the evidence on established and emerging risk factors for stroke to provide evidence-based recommendations for the reduction of risk of a first stroke.

Methods—

Writing group members were nominated by the committee chair on the basis of their previous work in relevant topic areas and were approved by the American Heart Association (AHA) Stroke Council Scientific Statement Oversight Committee and the AHA Manuscript Oversight Committee. The writing group used systematic literature reviews (covering the time since the last review was published in 2006 up to April 2009), reference to previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and when appropriate, formulate recommendations using standard AHA criteria (
Tables 1
and
2
). All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. The guideline underwent extensive peer review by the Stroke Council leadership and the AHA scientific statements oversight committees before consideration and approval by the AHA Science Advisory and Coordinating Committee.

Results—

Schemes for assessing a person's risk of a first stroke were evaluated. Risk factors or risk markers for a first stroke were classified according to potential for modification (nonmodifiable, modifiable, or potentially modifiable) and strength of evidence (well documented or less well documented). Nonmodifiable risk factors include age, sex, low birth weight, race/ethnicity, and genetic predisposition. Well-documented and modifiable risk factors include hypertension, exposure to cigarette smoke, diabetes, atrial fibrillation and certain other cardiac conditions, dyslipidemia, carotid artery stenosis, sickle cell disease, postmenopausal hormone therapy, poor diet, physical inactivity, and obesity and body fat distribution. Less well-documented or potentially modifiable risk factors include the metabolic syndrome, excessive alcohol consumption, drug abuse, use of oral contraceptives, sleep-disordered breathing, migraine, hyperhomocysteinemia, elevated lipoprotein(a), hypercoagulability, inflammation, and infection. Data on the use of aspirin for primary stroke prevention are reviewed.

Conclusion—

Extensive evidence identifies a variety of specific factors that increase the risk of a first stroke and that provide strategies for reducing that risk.
EPITHET
Authors: Nagakane Yoshinari , Christensen Soren , Brekenfeld Caspar , Ma Henry , Churilov Leonid , Parsons Mark W. , Levi Christopher R. , Butcher Kenneth S. , Peeters Andre , Barber P. Alan , Bladin Christopher F. , De Silva Deidre A. , Fink John , Kimber Thomas E. , Schultz David W. , Muir Keith W. , Tress Brian M. , Desmond Patricia M. , Davis Stephen M. , Donnan Geoffrey A.
Published: December 2010

Background and Purpose—

The Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) was a prospective, randomized, double-blinded, placebo-controlled, phase II trial of alteplase between 3 and 6 hours after stroke onset. The primary outcome of infarct growth attenuation on MRI with alteplase in mismatch patients was negative when mismatch volumes were assessed volumetrically, without coregistration, which underestimates mismatch volumes. We hypothesized that assessing the extent of mismatch by coregistration of perfusion and diffusion MRI maps may more accurately allow the effects of alteplase vs placebo to be evaluated.

Methods—

Patients were classified as having mismatch if perfusion-weighted imaging divided by coregistered diffusion-weighted imaging volume ratio was >1.2 and total coregistered mismatch volume was ≥10 mL. The primary outcome was a comparison of infarct growth in alteplase vs placebo patients with coregistered mismatch.

Results—

Of 99 patients with baseline diffusion-weighted imaging and perfusion-weighted imaging, coregistration of both images was possible in 95 patients. Coregistered mismatch was present in 93% (88/95) compared to 85% (81/95) with standard volumetric mismatch. In the coregistered mismatch patients, of whom 45 received alteplase and 43 received placebo, the primary outcome measure of geometric mean infarct growth was significantly attenuated by a ratio of 0.58 with alteplase compared to placebo (1.02 vs 1.77; 95% CI, 0.33–0.99;
P
=0.0459).

Conclusions—

When using coregistration techniques to determine the presence of mismatch at study entry, alteplase significantly attenuated infarct growth. This highlights the necessity for a randomized, placebo-controlled, phase III clinical trial of alteplase using penumbral selection beyond 3 hours.
Association of Circulating Inflammatory Markers With Recurrent Vascular Events After Stroke
Authors: Whiteley William , Jackson Caroline , Lewis Steff , Lowe Gordon , Rumley Ann , Sandercock Peter , Wardlaw Joanna , Dennis Martin , Sudlow Cathie
Published: December 2010

Background and Purpose—

Inflammatory markers may be associated with recurrent vascular events after stroke. We aimed to determine the association between IL-6, C-reactive protein, fibrinogen and white cell count, with recurrent vascular events after stroke, and to compare the association between circulating inflammatory markers with the risk of death from vascular vs nonvascular causes.

Methods—

We prospectively recruited patients with acute stroke (n=817) and followed them for up to 4 years for the occurrence of fatal or nonfatal recurrent stroke, myocardial infarction or fatal vascular events, and death from any cause (n=159).

Results—

The delay to assessment was a median of 10 days. The adjusted incidence of the outcome cluster recurrent stroke, myocardial infarction or vascular death after stroke was significantly higher with higher levels of IL-6 (75
th
to 25
th
percentile hazard ratio, 1.56; 95% CI, 1.37–1.77), C-reactive protein (75
th
to 25
th
percentile hazard ratio, 1.08; 95% CI, 1.04–1.11), and fibrinogen (75
th
to 25
th
percentile hazard ratio, 1.45; 95% CI, 1.24–1.72). The associations between inflammatory markers and death were stronger than with recurrent vascular events. The associations of inflammatory markers with vascular and nonvascular deaths were similar.

Conclusions—

Although inflammatory markers were associated with an increased risk of recurrent vascular events and vascular death after stroke, they were also associated with nonvascular causes of death, suggesting that inflammatory markers do not play a causal role specifically in the generation of recurrent vascular events after stroke. Future studies of the prediction of recurrent vascular events after stroke should concentrate on clinical variables or different blood markers.
Genetic Variation in
LPAL2
,
LPA
, and
PLG
Predicts Plasma Lipoprotein(a) Level and Carotid Artery Disease Risk
Authors: Ronald James , Rajagopalan Ramakrishnan , Cerrato Felecia , Nord Alex S. , Hatsukami Thomas , Kohler Ted , Marcovina Santica , Heagerty Patrick , Jarvik Gail P.
Published: December 2010

Background and Purpose—

Lipoprotein(a) [Lp(a)] level is an established risk factor for coronary artery disease and has been implicated in carotid artery disease (CAAD). The relationship between genetic variation in the
LPA
gene region and CAAD risk remains unknown.

Methods—

We genotyped single nucleotide polymorphisms (SNPs) in the
LPAL2
,
LPA
, and
PLG
regions in 530 individuals with severe CAAD and 770 controls and kringle IV type 2 (KIV2) repeat length in a subset of 90 individuals.

Results—

Nine SNPs collectively accounted for 30% of the variance in Lp(a) level. Six SNPs were associated with Lp(a) level after accounting for KIV2 copy number, and the dominant KIV2 allele combined with these markers explained 60% of the variance in Lp(a) level. Five SNPs, including rs10455872, which had an odds ratio of 2.1 per minor allele and haplotypes formed by rs10455872, rs6919346, and rs3123629, were significant predictors of CAAD. After accounting for Lp(a) level, all evidence of CAAD–genotype association in the
LPA
region was eliminated.

Conclusions—

LPA
region SNPs capture some but not all of the effect of KIV2 repeat length on Lp(a) level. There are associations between
LPA
region SNPs and CAAD that appear to be attributable to effects on Lp(a) level.
Diagnosing a Patent Foramen Ovale in Children
Authors: Hubail Zakariya , Lemler Matthew , Ramaciotti Claudio , Moore Jay , Ikemba Catherine
Published: December 2010

Background and Purpose—

Transesophageal echocardiography (TEE) is the gold standard for the diagnosis of a patent foramen ovale in adults. In children, acoustic windows on transthoracic echocardiography (TTE) are better than in adults; thus, an invasive TEE may not be necessary. Our goal was to assess the validity of TTE with agitated saline injection for the diagnosis of a patent foramen ovale in children using TEE as the gold standard.

Methods—

Fifty consecutive pediatric patients >1 year of age referred for TEE were prospectively enrolled. Imaging included 2-dimensional, color Doppler, and agitated saline contrast injections with and without Valsalva by TTE followed by TEE. Interpreters of the TTE were blinded to TEE results. Studies were categorized as “inconclusive” if the TTE images were inadequate for definitive diagnosis by the blinded interpreter.

Results—

TTE results were considered conclusive in 43 of 50 (86%) patients. Among the 43 conclusive studies, the 2 modalities disagreed in 1 patient. TTE had a positive predictive value of 100%, negative predictive value 97%, sensitivity of 88%, and specificity of 100% for detecting a patent foramen ovale.

Conclusions—

TTE with agitated saline injection is diagnostic for the assessment of atrial septal integrity in the majority of children.
Risk of Stroke in Patients Hospitalized for Isolated Vertigo
Authors: Lee Ching-Chih , Su Yu-Chieh , Ho Hsu-Chieh , Hung Shih-Kai , Lee Moon-Sing , Chou Pesus , Huang Yung-Sung
Published: December 2010

Background and Purpose—

Vertigo is a common presenting symptom in ambulatory care settings, and stroke is its leading and most challenging concern. This study aimed to determine the risk of stroke in vertigo patients in a 4-year follow-up after hospitalization for acute isolated vertigo.

Methods—

The study cohorts consisted of all patients hospitalized with a principal diagnosis of vertigo (n=3021), whereas patients hospitalized for an appendectomy in 2004 (n=3021) comprised the control group and surrogate for the general population. Cox proportional hazard model was performed as a means of comparing the 4-year stroke-free survival rate between the 2 cohorts after adjusting for possible confounding and risk factors. Among vertigo patients, there was further stratification for risk factors to identify the group at high risk for stroke.

Results—

Of the 243 stroke patients, 185 (6.1%) were from the study cohort and 58 (1.9%) were from the control group. Comparing the 2 groups, patients with vertigo symptoms had a 3.01-times (95% CI, 2.20–4.11;
P
<0.001) higher risk for stroke after adjusting for patient characteristics, comorbidities, geographic region, urbanization level of residence, and socioeconomic status. Vertigo patients with ≥3 risk factors had a 5.51-fold higher risk for stroke (95% CI, 3.10–9.79;
P
<0.001) than those without risk factors.

Conclusions—

Vertigo patients are at higher risk for stroke than the general population. They should have a comprehensive neurological examination, vascular risk factors survey, and regular follow-up for several years after hospital discharge after treatment of isolated vertigo.
Temporal and Spatial Variations of NOx and Ozone Concentrations in Seoul during the Solar Eclipse of 22 July 2009
Authors: Kwak Kyung-Hwan , Ryu Young-Hee , Baik Jong-Jin
Published: December 2010

The temporal and spatial variations of NO, NO2, and O3 concentrations in Seoul, South Korea, during the solar eclipse of 22 July 2009 are investigated by analyzing data measured at 25 environmental monitoring stations. The NO2 concentration increases and the NO and O3 concentrations decrease because the efficiency of NO2 photolysis decreases during the solar eclipse. About an hour after the maximum obscuration, the reduction in the average O3 concentration over Seoul is estimated to be 45%. The maximum reduction in the O3 concentration downwind of the NOx source area is higher and occurs later than that in the downtown region. Deviations from the NO–NO2–O3 photostationary state in the downwind region are larger than those in the downtown region. This result implies that, in addition to the photochemical effect, the effect of transport by winds increases the reduction potential of the O3 concentration in the downwind region during the solar eclipse.