bluuebunny/crossref_metadata_2025 huggingface dataset:
VEGF164differentially regulates neutrophil and T cell adhesion through ItgaL- and ItgaM-dependent mechanisms
Authors: Chidlow John H. , Glawe John D. , Alexander J. Steven , Kevil Christopher G.
Published: October 2010

Leukocyte recruitment to inflamed tissues is the cornerstone of inflammatory responses and the driving force behind the establishment of inflammatory bowel disease, consisting of Crohn's disease and ulcerative colitis. It has been reported that angiogenic cytokines contribute to this inflammatory response that facilitates the chronic nature of disease. We have previously reported (Goebel S, Huang M, Davis WC, Jennings M, Siahaan TJ, Alexander JS, Kevil CG. Am J Physiol Gastrointest Liver Physiol 290: G648–G654, 2006) that vascular endothelial growth factor (VEGF)-A can stimulate neutrophil adhesion to colon microvascular endothelial cells in a β2-integrin (Itgb2)-dependent manner. However, it is not known which of the specific leukocyte integrins are critical for VEGF-A-dependent neutrophil and T cell recruitment. Here we examine the differential importance of either α-integrin (Itga)L or ItgaM in governing neutrophil and T cell adhesion to VEGF-A-activated colonic endothelium. Using an in vitro parallel-plate flow chamber model, we found that genetic deficiency of ItgaM completely blunted neutrophil adhesion to VEGF-A-stimulated endothelium, whereas ItgaL deficiency only partly blocked neutrophil adhesion. Deficiency of ItgaM did significantly decrease neutrophil rolling, whereas deficiency of ItgaL did not. We found that genetic deficiency of either ItgaL or ItgaM did significantly blunt T cell adhesion to VEGF-A-stimulated colon endothelium. We also found that genetic deficiency of these Itgas significantly attenuated T cell rolling behavior. Lastly, we examined whether VEGF-A-mediated leukocyte recruitment occurred through different VEGF receptor (VEGFR) pathways and found that VEGFR2 activation regulates neutrophil recruitment, whereas both VEGFR1 and VEGFR2 modulate T cell recruitment. Together, these data identify differential molecular mechanisms of VEGF-A-mediated leukocyte recruitment.
Ca2+ clock malfunction in a canine model of pacing-induced heart failure
Authors: Shinohara Tetsuji , Park Hyung-Wook , Han Seongwook , Shen Mark J. , Maruyama Mitsunori , Kim Daehyeok , Chen Peng-Sheng , Lin Shien-Fong
Published: October 2010

The mechanisms of sinoatrial node (SAN) dysfunction in heart failure (HF) remain unclear. We hypothesized that impaired rhythmic spontaneous sarcoplasmic reticulum Ca2+ release (Ca2+ clock) plays an important role in SAN dysfunction in HF. HF was induced in canine hearts by rapid ventricular pacing. The location of pacemaking sites was determined in vivo using computerized electrical mapping in acute open-chest preparations (normal, n = 3; and HF, n = 4). Isoproterenol (Iso, 0.2 μg·kg−1·min−1) infusion increased heart rate and shifted the pacemaking site to the superior SAN in all normal hearts. However, in failing hearts, Iso did not induce superior shift of the pacemaking site despite heart rate acceleration. Simultaneous optical recording of intracellular Ca2+ and membrane potential was performed in Langendorff-perfused isolated right atrium (RA) preparations from normal ( n = 7) and failing hearts ( n = 6). Iso increased sinus rate, enhanced late diastolic Ca2+ elevation (LDCAE), and shifted the pacemaking sites to the superior SAN in all normal but in none of the HF RAs. Caffeine (2 ml, 20 mmol/l) caused LDCAE and increased heart rate in four normal RAs but in none of the three HF RAs. Iso induced ectopic beats from lower crista terminalis in five of six HF RAs. These ectopic beats were suppressed by ZD-7288, a specific pacemaker current ( If) blocker. We conclude that HF results in the suppression of Ca2+ clock, resulting in the unresponsiveness of superior SAN to Iso and caffeine. HF also increases the ectopic pacemaking activity by activating the If at the latent pacemaking sites in lower crista terminalis.
In vivo assessment of muscle fascicle length by extended field-of-view ultrasonography
Authors: Noorkoiv M. , Stavnsbo A. , Aagaard P. , Blazevich A. J.
Published: October 2010

The present study examined the reliability and validity of in vivo vastus lateralis (VL) fascicle length ( Lf) assessment by extended field-of-view ultrasonography (EFOV US). Intraexperimenter and intersession reliability of EFOV US were tested. Further, Lf measured from EFOV US images were compared to Lf measured from static US images (6-cm FOV) where out-of-field fascicle portions were trigonometrically estimated (linear extrapolation). Finally, spatial accuracy of the EFOV technique was assessed by comparing Lf measured on swine VL by EFOV US to actual measurements from digital photographs. The difference between repeated VL Lf measurements by the same experimenter was 2.1 ± 1.7% with an intraclass correlation (ICC) of 0.99 [95% confidence interval (CI) = 0.95–1.00]. In terms of intersession reliability, no difference ( P = 0.48) was observed between Lf measured on two different occasions, with ICC = 0.95 (CI = 0.80–0.99). The average absolute difference between Lf measured by EFOV US and using linear extrapolation was 12.6 ± 8.1% [ICC = 0.76 (CI = −0.20–0.94)]; EFOV Lf was always longer than extrapolated Lf. The relative error of measurement between Lf measured by EFOV US and by dissective assessment (digital photographs) in isolated swine VL was 0.84% ± 2.6% with an ICC of 0.99 (CI = 0.94–1.00). These results show that EFOV US is a reliable and valid method for the measurement of long muscle fascicle in vivo. Thus EFOV US analysis was proven more accurate for the assessment of skeletal muscle fascicle length than conventional extrapolation methods.
Intermittent electrical stimulation redistributes pressure and promotes tissue oxygenation in loaded muscles of individuals with spinal cord injury
Authors: Gyawali Selina , Solis Leandro , Chong Su Ling , Curtis Cara , Seres Peter , Kornelsen Isaak , Thompson Richard , Mushahwar Vivian K.
Published: October 2010

Deep tissue injury (DTI) is a severe form of pressure ulcer that originates at the bone-muscle interface. It results from mechanical damage and ischemic injury due to unrelieved pressure. Currently, there are no established clinical methods to detect the formation of DTI. Moreover, despite the many recommended methods for preventing pressure ulcers, none so far has significantly reduced the incidence of DTI. The goal of this study was to assess the effectiveness of a new electrical stimulation-based intervention, termed intermittent electrical stimulation (IES), in ameliorating the factors leading to DTI in individuals with compromised mobility and sensation. Specifically, we sought to determine whether IES-induced contractions in the gluteal muscles can 1) reduce pressure in tissue surrounding bony prominences susceptible to the development of DTI and 2) increase oxygenation in deep tissue. Experiments were conducted in individuals with spinal cord injury, and two paradigms of IES were utilized to induce contractions in the gluteus maximus muscles of the seated participants. Changes in surface pressure around the ischial tuberosities were assessed using a pressure-sensing mattress, and changes in deep tissue oxygenation were indirectly assessed using T2*-weighted magnetic resonance imaging (MRI) techniques. Both IES paradigms significantly reduced pressure around the bony prominences in the buttocks by an average of 10–26% ( P < 0.05). Furthermore, both IES paradigms induced significant increases in T2* signal intensity (SI), indicating significant increases in tissue oxygenation, which were sustained for the duration of each 10-min trial ( P < 0.05). Maximal increases in SI ranged from 2–3.3% (arbitrary units). Direct measurements of oxygenation in adult rats revealed that IES produces up to a 100% increase in tissue oxygenation. The results suggest that IES directly targets factors contributing to the development of DTI in people with reduced mobility and sensation and may therefore be an effective method for the prevention of deep pressure ulcers.
Voluntary Running Prevents Progressive Memory Decline and Increases Adult Hippocampal Neurogenesis and Growth Factor Expression after Whole-Brain Irradiation
Authors: Wong-Goodrich Sarah J.E. , Pfau Madeline L. , Flores Catherine T. , Fraser Jennifer A. , Williams Christina L. , Jones Lee W.
Published: October 2010

Whole-brain irradiation (WBI) therapy produces progressive learning and memory deficits in patients with primary or secondary brain tumors. Exercise enhances memory and adult hippocampal neurogenesis in the intact brain, so we hypothesized that exercise may be an effective treatment to alleviate consequences of WBI. Previous studies using animal models to address this issue have yielded mixed results and have not examined potential molecular mechanisms. We investigated the short- and long-term effects of WBI on spatial learning and memory retention and determined whether voluntary running after WBI aids recovery of brain and cognitive function. Forty adult female C57Bl/6 mice given a single dose of 5 Gy or sham WBI were trained 2.5 weeks and up to 4 months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting 1 month after sham or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdUrd) immunolabeling and enzyme-linked immunosorbent assay indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdUrd+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor-1, and occurred despite irradiation-induced elevations in hippocampal proinflammatory cytokines. WBI in adult mice produced a progressive memory decline consistent with what has been reported in cancer patients receiving WBI therapy. Our findings show that running can abrogate this memory decline and aid recovery of adult hippocampal plasticity, thus highlighting exercise as a potential therapeutic intervention. Cancer Res; 70(22); 9329–38. ©2010 AACR.
Dual Inhibition of PI3K and mTORC1/2 Signaling by NVP-BEZ235 as a New Therapeutic Strategy for Acute Myeloid Leukemia
Authors: Chapuis Nicolas , Tamburini Jerome , Green Alexa S. , Vignon Christine , Bardet Valerie , Neyret Aymeric , Pannetier Melanie , Willems Lise , Park Sophie , Macone Alexandre , Maira Sauveur-Michel , Ifrah Norbert , Dreyfus François , Herault Olivier , Lacombe Catherine , Mayeux Patrick , Bouscary Didier
Published: October 2010

Purpose: The growth and survival of acute myeloid leukemia (AML) cells are enhanced by the deregulation of signaling pathways such as phosphoinositide 3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR). Major efforts have thus been made to develop molecules targeting these activated pathways. The mTOR serine/threonine kinase belongs to two separate complexes: mTORC1 and mTORC2. The mTORC1 pathway is rapamycin sensitive and controls protein translation through the phosphorylation of 4E-BP1 in most models. In AML, however, the translation process is deregulated and rapamycin resistant. Furthermore, the activity of PI3K/Akt and mTOR is closely related, as mTORC2 activates the oncogenic kinase Akt. We therefore tested, in this study, the antileukemic activity of the dual PI3K/mTOR ATP-competitive inhibitor NVP-BEZ235 compound (Novartis).

Experimental Design: The activity of NVP-BEZ235 was tested in primary AML samples (n = 21) and human leukemic cell lines. The different signaling pathways were analyzed by Western blotting. The cap-dependent mRNA translation was studied by 7-methyl-GTP pull-down experiments, polysomal analysis, and [3H]leucine incorporation assays. The antileukemic activity of NVP-BEZ235 was tested by analyzing its effects on leukemic progenitor clonogenicity, blast cell proliferation, and survival.

Results: The NVP-BEZ235 compound was found to inhibit PI3K and mTORC1 signaling and also mTORC2 activity. Furthermore, NVP-BEZ235 fully inhibits the rapamycin-resistant phosphorylation of 4E-BP1, resulting in a marked inhibition of protein translation in AML cells. Hence, NVP-BEZ235 reduces the proliferation rate and induces an important apoptotic response in AML cells without affecting normal CD34+ survival.

Conclusions: Our results clearly show the antileukemic efficiency of the NVP-BEZ235 compound, which therefore represents a promising option for future AML therapies. Clin Cancer Res; 16(22); 5424–35. ©2010 AACR.
Mechanisms by which cleaved kininogen inhibits endothelial cell differentiation and signalling
Authors: Wu Yi , Liu Yuchuan , Colman Robert
Published: October 2010

We have shown that cleaved high-molecular-weight kininogen inhibits endoththelial cell tube and vacuole formation in a concentration-dependent manner and this correlates with its recognised anti-angiogenic activity. The antibody against the urokinase plasminogen activator receptor (uPAR) mimicked the inhibitory effect of cleaved kininogen (HKa) on apoptosis (HKa: 30% and uPAR antibody: 26%) and tube formation. In tumour angiogenesis, cancer cells release angiogenic stimulators, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), thus stimulating the transformation of endogenous pro-uPA to uPA. The proteolytic enzyme urokinase plasminogen activator (uPA) then binds to its receptor in a complex with its inhibitor PAI-1, which results in the internalisation of this complex, and activates extracellular signal-regulated kinase (ERK). Recycling of the uPAR regulates the migration of endothelial cells (ECs). ERK activation stimulates migration and proliferation and suppresses apoptosis of ECs. HKa disrupted the uPA-uPAR complex, inhibited ERK activation, and blocked the internalization of uPAR, eventually resulting in cell death and cell motility arrest. Both are critical steps in angiogenesis.
Urokinase-type plasminogen activator receptor is associated with the development of adipose tissue
Authors: Matsuno Hiroyuki , Kawashita Eri , Okada Kiyotaka , Suga Hidetaka , Ueshima Shigeru , Matsuo Osamu , Kanno Yosuke
Published: October 2010

Urokinase-type plasminogen activator receptor (uPAR) plays a role in cellular responses which include cellular adhesion, differentiation, proliferation and migration. The aim of this study was to clarify the role of uPAR on the development of adipose tissue. To clarify the role of uPAR on adipogenesis, we examined the effect of uPAR overexpression and uPAR deficiency on the adipocyte differentiation. Adipocyte differentiation was induced by incubation of 3T3-L1 cells with differentiation media containing insulin, dexamethasone, and 1-methyl-3-isobutylxanthin. uPAR overexpression by transfection of uPAR expression vector induced adipocyte differentiation. In addition, we examined the difference in adipocyte differentiation of mesenchymal stem cells from wild-type mice and uPAR knockout (uPAR-/-) mice. The uPAR deficiency attenuated differentiation media-induced adipocyte differentiation. Moreover, we found that the inhibition of phosphatidylinositol 3-kinase (PI3K) pathway attenuated uPAR overexpression-induced adipocyte differentiation, and uPAR overexpression induced the activation of Akt. We also found that an increase of the adipose tissue mass in uPAR-/- mice was less than that observed in wild-type mice. The present results suggest that uPAR plays a pivotal role in the development of adipose tissue through PI3K/Akt pathway.
Urokinase plasminogen activator independent early experimental thrombus resolution: MMP2 as an alternative mechanism
Authors: Sood Vikram , Luke Catherine E. , Baldwin Joseph , Miller Erin M. , Elfline Megan , Upchurch Gilbert R. , Wakefield Thomas W. , Henke Peter K.
Published: October 2010

Deep-vein thrombosis (DVT) resolution is thought to be primarily a urokinase plasminogen activator (uPA) -dependent mechanism, although observations suggest other non-fibrinolytic mechanisms may exist. We explored the role of matrix metalloproteinase (MMP) -2 and –9 in early DVT resolution in uPA-deficient mice. Male B6/SVEV (WT) and genetically matched uPA -/- mice underwent inferior vena cava (IVC) ligation to create stasis venous thrombi, with IVC and thrombus harvest. Thrombus size was similar between WT and uPA -/- mice at day 4, suggesting early non uPA-dependent resolution. Intrathrombus neutrophils and monocytes were reduced 3- and 3.5-fold in uPA -/- mice as compared with WT. By ELISA, tumour necrosis factor α and interleukin 1β were not altered, while interferon (IFN)γ was significantly elevated in uPA -/- mice. A compensatory increase in thrombus tPA was not observed, plasmin activity was reduced and PAI-1 was elevated 2.5-fold in uPA -/- mice. Active MMP2, but not MMP9, was elevated 3-fold in uPA-/- mice as compared with WT as well as MMP-14, an MMP2 activator. Collagen type IV and fibrinogen were reduced in uPA -/- mice thrombi as compared with WT. IFNγ induces MMP2, and blockade of IFNγ was associated with larger venous thrombi and reduced active MMP2, as compared with WT. Consistently, MMP2 -/- mice had larger VT as compared with WT controls, despite normal thrombus plasmin levels. Taken together, early experimental venous thrombus resolution is independent of uPA, and, in part, inflammatory cell influx. MMP2-dependent thrombolysis is an important compensatory mechanism of venous thrombus resolution, possibly by collagen type IV metabolism, and may represent an exploitable therapeutic avenue.
Prostanoid and TP-receptors in atherothrombosis: Is there a role for their antagonism?
Authors: Giannarelli Chiara , Zafar M. Urooj , Badimon Juan
Published: October 2010

Atherosclerosis and its clinical manifestations (i.e. myocardial infarction, stroke) are major causes of mortality and morbidity in Western countries. Endothelial dysfunction is considered the first step in the cascade leading up to coronary events. Increasing evidence suggests that direct inhibition of thromboxane A2/prostaglandin (TP)-receptors may not only have anti-platelet effects but also impact endothelial dysfunction as well as inflammatory component of atherosclerosis. While TP-receptor involvement in platelet function has received the greatest attention, more recent findings support the critical role of TP-receptor in other pathophysiological aspects of atherothrombosis. Prostanoids (i.e. TxA2, F2-isoprostanes, prostaglandins endoperoxides PGG2/PGH2) are known to promote the initiation and progression of atherosclerosis, not only via platelet activation, but through leukocyte-endothelial interactions and vasoconstriction. Dysfunctional endothelium, characterised by increased COX-activity, releases prostanoids that promote endothelial exposure to adhesion molecules and induce smooth muscle cell contraction. Plaque macrophages synthesise PGH2/PGG2 via COX-2; these potent prostanoids can trigger platelet activation and aggregation despite COX-1 inhibition by aspirin. TP-receptor inhibition has been reported to exert anti-atherosclerotic effects in pre-clinical model of disease. Reduction of plaque burden was associated with plaque stabilisation documented by the reduction in the content of macrophages, apoptotic cells, MMPs and endothelin-1, and the increase in smooth muscle cells content. TP-receptor blockade might have an anti-athero-sclerotic and plaque stabilisation effect. The possibility of combining anti-platelet activity with an anti-atherosclerotic effect via selective TP-receptor inhibitors could have important implications especially in clinical conditions associated with increased production of prostanoids, such as diabetes.
Endocytic receptor for pro-coagulant factor VIII: Relevance to inhibitor formation
Authors: Navarrete Ana-Maria , Dasgupta Suryasarathi , Teyssandier Maud , Repessé Yohann , Delignat Sandrine , André Sébastien , Bayry Jagadeesh , Kaveri Srinivas V. , Lacroix-Desmazes Sébastien
Published: October 2010

The immunogenicity of therapeutic factor VIII (FVIII) in patients with haemophilia A remains a critical issue in patient management. This review describes the immunological processes involved in the activation of the immune system against FVIII, with a particular focus on the role of endocytic receptors for the recognition of FVIII by antigen-presenting cells.
Predictive factors for concurrent deep-vein thrombosis and symptomatic venous thromboembolic recurrence in case of superficial venous thrombosis
Authors: Genty Celine , Sevestre Marie-Antoinette , Brisot Dominique , Lausecker Michel , Gillet Jean-Luc , Rolland Carole , Righini Marc , Leftheriotis Georges , Bosson Jean-Luc , Quere Isabelle , Galanaud Jean-Philippe ,   the OPTIMEV SFMV investigators
Published: October 2010

Superficial venous thrombosis (SVT) prognosis is debated and its management is highly variable. It was the objective of this study to assess predictive risk factors for concurrent deep-vein thrombosis (DVT) at presentation and for three-month adverse outcome. Using data from the prospective multicentre OPTIMEV study, we analysed SVT predictive factors associated with concurrent DVT and three-month adverse outcome. Out of 788 SVT included, 227 (28.8%) exhibited a concurrent DVT at presentation. Age >75years (odds ratio [OR]=2.9 [1.5–5.9]), active cancer (OR=2.6 [1.3–5.2]), inpatient status (OR=2.3 [1.2–4.4]) and SVT on non-varicose veins (OR=1.8 [1.1–2.7]) were significantly and independently associated with an increased risk of concurrent DVT. 39.4% of SVT on non-varicose veins presented a concurrent DVT. However, varicose vein status did not influence the three-month prognosis as rates of death, symptomatic venous thromboembolic (VTE) recurrence and major bleeding were equivalent in both non-varicose and varicose SVTs (1.4% vs. 1.1%; 3.4% vs. 2.8%; 0.7% vs. 0.3%). Only male gender (OR=3.5 [1.1–11.3]) and inpatient status (OR=4.5 [1.3–15.3]) were independent predictive factors for symptomatic VTE recurrence but the number of events was low (n=15, 3.0%). Three-month numbers of deaths (n=6, 1.2%) and of major bleedings (n=2, 0.4%) were even lower, precluding any relevant interpretation. In conclusion, SVT on non-varicose veins and some classical risk factors for DVT were predictive factors for concurrent DVT at presentation. As SVT remains mostly a clinical diagnosis, these data may help selecting patients deserving an ultrasound examination or needing anticoagulation while waiting for diagnostic tests. Larger studies are needed to evaluate predictive factors for adverse outcome.
New-onset atrial fibrillation and warfarin initiation: High risk periods and implications for new antithrombotic drugs
Authors: Lopes Renato D. , Hylek Elaine M. , Garcia David A.
Published: October 2010

Atrial fibrillation is a common condition that increases the risk of stroke in many patients. Although warfarin has been shown to reduce the risk of stroke, many patients who might benefit from anticoagulation do not receive this therapy. Fear of bleeding is the most often cited reason. Several new anticoagulant medications are being studied to determine their efficacy and safety relative to warfarin. Unlike earlier trials that established the superiority of warfarin over placebo, recent trials in atrial fibrillation have enrolled a disproportionate number of patients already taking warfarin. This review suggests that the risk of both haemorrhage and stroke are highest when atrial fibrillation is newly diagnosed and during the initiation of anticoagulant medication. Randomised controlled trials designed to evaluate the safety and efficacy of new anti-thrombotic agents should include substantial numbers of patients without prior exposure to anticoagulation since these individuals are at the highest risk for bleeding and thromboembolism.
Multiple Genetic Loci Influence Serum Urate Levels and Their Relationship With Gout and Cardiovascular Disease Risk Factors
Authors: Yang Qiong , Köttgen Anna , Dehghan Abbas , Smith Albert V. , Glazer Nicole L. , Chen Ming-Huei , Chasman Daniel I. , Aspelund Thor , Eiriksdottir Gudny , Harris Tamara B. , Launer Lenore , Nalls Michael , Hernandez Dena , Arking Dan E. , Boerwinkle Eric , Grove Megan L. , Li Man , Linda Kao W.H. , Chonchol Michel , Haritunians Talin , Li Guo , Lumley Thomas , Psaty Bruce M. , Shlipak Michael , Hwang Shih-Jen , Larson Martin G. , O'Donnell Christopher J. , Upadhyay Ashish , van Duijn Cornelia M. , Hofman Albert , Rivadeneira Fernando , Stricker Bruno , Uitterlinden Andre G. , Paré Guillaume , Parker Alex N. , Ridker Paul M. , Siscovick David S. , Gudnason Vilmundur , Witteman Jacqueline C. , Fox Caroline S. , Coresh Josef
Published: October 2010

Background—

Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD).

Methods and Results—

Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (
P
=4×10
−8
to 2×10
−242
in
SLC22A11, GCKR, R3HDM2-INHBC
region,
RREB1, PDZK1
,
SLC2A9, ABCG2
, and
SLC17A1
). Only 2 loci (
SLC2A9, ABCG2
) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L;
P
=3×10
−39
) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study.

Conclusions—

The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.
Familial Aggregation of Left Ventricular Geometry and Association With Parental Heart Failure
Authors: Lam Carolyn S.P. , Liu Xuan , Yang Qiong , Larson Martin G. , Pencina Michael J. , Aragam Jayashri , Redfield Margaret M. , Benjamin Emelia J. , Vasan Ramachandran S.
Published: October 2010

Background—

Data regarding the familial aggregation of left ventricular (LV) geometry and its relations to parental heart failure (HF) are limited.

Methods and Results—

We evaluated concordance of LV geometry within 1093 nuclear families in 5758 participants of the original (parents) (n=2351) and offspring (n=3407) cohorts of the Framingham Heart Study undergoing routine echocardiography in mid- to late adulthood. LV geometry was categorized based on cohort- and sex-specific 80th percentile cutoffs of LV mass and relative wall thickness (RWT) into normal (both <80th percentile), concentric remodeling (LV mass <80th percentile; RWT >80th percentile), concentric hypertrophy (both >80th percentile), and eccentric hypertrophy (LV mass >80th percentile; RWT <80th percentile). Within nuclear families, LV geometry was concordant among related pairs (parent-child, sibling-sibling) (
P
=0.0015) but not among unrelated spousal pairs (
P
=0.60), a finding that remained unchanged after adjusting for clinical covariates known to influence LV remodeling (age, systolic blood pressure, body mass index), excluding individuals with prevalent HF and myocardial infarction, and varying the thresholds for defining LV geometry. The prevalence of abnormal LV geometry was higher in family members of affected individuals, with recurrence risks of 1.4 for concentric remodeling (95% CI, 1.2 to 1.7) and eccentric hypertrophy (95% CI, 1.1 to 1.8) and 3.9 (95% CI, 3.2 to 4.6) for concentric hypertrophy. In a subset of 1497 offspring, we observed an association between parental HF (n=458) and eccentric hypertrophy in offspring (
P
<0.0001).

Conclusions—

Our investigation of a 2-generational community-based sample demonstrates familial aggregation of LV geometry, with the greatest recurrence risk for concentric LV geometry, and establishes an association between eccentric LV geometry and parental HF.
BAG3 and Hsc70 Interact With Actin Capping Protein CapZ to Maintain Myofibrillar Integrity Under Mechanical Stress
Authors: Hishiya Akinori , Kitazawa Toshio , Takayama Shinichi
Published: October 2010

Rationale:

A homozygous disruption or genetic mutation of the
bag
3 gene, a member of the Bcl-2–associated athanogene (BAG) family proteins, causes cardiomyopathy and myofibrillar myopathy that is characterized by myofibril and Z-disc disruption. However, the detailed disease mechanism is not yet fully understood.

Objective:

bag3
−/−
mice exhibit differences in the extent of muscle degeneration between muscle groups with muscles experiencing the most usage degenerating at an accelerated rate. Usage-dependent muscle degeneration suggests a role for BAG3 in supporting cytoskeletal connections between the Z-disc and myofibrils under mechanical stress. The mechanism by which myofibrillar structure is maintained under mechanical stress remains unclear. The purpose of the study is to clarify the detailed molecular mechanism of BAG3-mediated muscle maintenance under mechanical stress.

Methods and Results:

To address the question of whether
bag3
gene knockdown induces myofibrillar disorganization caused by mechanical stress, in vitro mechanical stretch experiments using rat neonatal cardiomyocytes and a short hairpin RNA–mediated gene knockdown system of the
bag3
gene were performed. As expected, mechanical stretch rapidly disrupts myofibril structures in
bag3
knockdown cardiomyocytes. BAG3 regulates the structural stability of F-actin through the actin capping protein, CapZβ1, by promoting association between Hsc70 and CapZβ1. BAG3 facilitates the distribution of CapZβ1 to the proper location, and dysfunction of BAG3 induces CapZ ubiquitin–proteasome–mediated degradation. Inhibition of CapZβ1 function by overexpressing CapZβ2 increased myofibril vulnerability and fragmentation under mechanical stress. On the other hand, overexpression of CapZβ1 inhibits myofibrillar disruption in
bag3
knockdown cells under mechanical stress. As a result, heart muscle isolated from
bag3
−/−
mice exhibited myofibrillar degeneration and lost contractile activity after caffeine contraction.

Conclusions:

These results suggest novel roles for BAG3 and Hsc70 in stabilizing myofibril structure and inhibiting myofibrillar degeneration in response to mechanical stress. These proteins are possible targets for further research to identify therapies for myofibrillar myopathy or other degenerative diseases.
Prevention With Low-Dose Aspirin Plus Dipyridamole in Patients With Disabling Stroke
Authors: Dippel Diederik W.J. , Maasland Lisette , Halkes Patricia , Kappelle L. Jaap , Koudstaal Peter J. , Algra Ale
Published: October 2010

Background and Purpose—

The combination of low-dose aspirin and dipyridamole is more effective than aspirin alone in reducing the risk of recurrent stroke and other major cardiovascular events in patients with a recent transient ischemic attack or minor stroke. It is unknown whether this also applies to patients with a disabling stroke.

Methods—

We reanalyzed the data of 5700 patients from ESPRIT and ESPS-2 to study the effect of aspirin and dipyridamole according to modified Rankin scale (mRS) score at baseline. Primary outcome was vascular events (stroke, myocardial infarction, or vascular death). We used proportional hazards regression to estimate the treatment effect across mRS strata at baseline, and we tested for interactions with treatment.

Results—

In total, 426 patients (7.5%) had mRS score of 4 or 5 at baseline. The risk of an outcome event increased with mRS score. The relative risk associated with the combination of aspirin and dipyridamole compared to aspirin alone in patients with mRS score 0 to 5 was 0.79 (95% confidence interval, 0.69–0.91). The relative risk according to mRS subcategory score 0 to 4 at baseline varied between 0.73 and 0.96 for vascular events and between 0.62 and 0.96 for stroke. The number of patients with mRS score 5 was too small for reliable estimates, but the data suggest a beneficial effect. There was no evidence of interaction between treatment effect and mRS score at baseline.

Conclusion—

The beneficial effect of the combination of low-dose aspirin and dipyridamole was present in all subcategories of the mRS score.
From Electioneering to Governing: Obama’s Transition as Legitimation Ritual
Authors: Wiese Leek Danielle , Gronbeck Bruce E.
Published: October 2010

This essay reviews Barack Obama’s 2008-2009 transition from president-elect to president. Not only must the new and old presidents coordinate practical, bureaucratic matters, but in the United States, the president-elect is put through an 11-week legitimation ritual. As his status is transformed from campaigner to president, his words and actions in various situations are viewed as tests of strengths, weaknesses, vision, prudence, negotiative skill, humanity, fiber, and resolve. Not only is he tested but his words and actions are read by the press, commentators, and bloggers as signs of good or bad fortune for the country, just as the augurs of old read natural signs before momentous events. In general, Obama passed the tests and for the most part, an era of good fortune was predicted.
The Effects of Aural Versus Notated Instructional Materials on Achievement and Self-Efficacy in Jazz Improvisation
Authors: Watson Kevin E.
Published: October 2010

The purpose of the present study was to investigate the effects of aural versus notated pedagogical materials on achievement and self-efficacy in instrumental jazz improvisation performance. A secondary purpose of this study was to investigate how achievement and self-efficacy may be related to selected experience variables. The sample for the study consisted of collegiate instrumentalists ( N = 62) enrolled as music majors at one of six Midwestern universities. All study participants received identical instructional materials but were assigned to one of two differing instructional modalities. Participants engaged in three 70-minute instructional treatment sessions over 4 days and completed pre- and postinstruction improvisation performances that were evaluated by four expert judges using the researcher-constructed Jazz Improvisation Performance Achievement Measure. Self-efficacy was measured using the researcher-constructed Jazz Improvisation Self-Efficacy Scale. Results indicated a significant ( p < .05) interaction effect for pre- to postinstruction and instructional method, with the aural instruction group demonstrating significantly greater gains than the notation group. Posttreatment achievement scores indicated nonsignificant correlations with experience variables. Participants’ self-efficacy for jazz improvisation increased significantly ( p < .001) following exposure to improvisation instruction; however, no interaction effect was found for instruction and mode of instruction.
A Classroom-Based Study of Small-Group Planned Improvisation With Fifth-Grade Children
Authors: Beegle Amy C.
Published: October 2010

The purpose of this study was to examine and describe children’s music improvisations and the interactions that transpired within their four-person groups during regular weekly music classes as they planned and performed music improvisations in response to three different prompts: a poem, a painting, and a musical composition. Participants were two classes of fifth-grade children at the elementary school where the researcher was the general music teacher. Sixteen children in four focus groups were chosen for closer observation and a series of interviews. Data were gathered over a 12-week period, utilizing audio- and video-recorded observations, daily field notes, and interviews following students’ viewing of their own performances on video. The findings of this study demonstrate that (a) all children utilized a similar planning process, and social roles and relationships were often correlated to musical roles and relationships; (b) children’s music products differed based on the nature of the prompt, and children viewed prompts along a continuum of providing freedom of expression; and (c) children evidenced three specific strategies and expressed three valued considerations for planning and evaluating improvisation performances.
Musicians’ Preferences for Tempo and Pitch Levels in Recorded Orchestral Music
Authors: Geringer John M.
Published: October 2010

This study was designed to ascertain musicians’ tempo and pitch level preferences when listening to orchestral music. Ninety graduate and undergraduate music major students were assigned randomly to one of three groups. Participants listened individually to recorded symphonic excerpts, 5 with relatively fast and 5 with relatively slow tempos. Listeners in the tempo group modulated a dial to adjust tempos to their preferred levels for each of the 10 excerpts (pitch was unchanged). Similarly, pitch group participants turned the dial to modify pitch to preferred levels (tempo was unchanged). For the combination tempo/pitch group, turning the dial produced changes in both pitch and tempo concomitantly.The range of modulation for all groups encompassed ±18% relative to the original recording. Listeners preferred increased levels of tempo, pitch, and tempo/pitch combined for the relatively slow excerpts. For fast tempo examples, however, listeners preferred decreased tempos, little change in pitch, and slightly decreased tempo/pitch combined relative to original levels. Deviations from original recordings were greater for the tempo change group compared to pitch and tempo/pitch groups.
The Influence of Prior Relationship on Perceptions of Stalking in the United Kingdom and Australia
Authors: Scott Adrian J. , Lloyd Rebecca , Gavin Jeff
Published: October 2010

Research in the United Kingdom and Australia has produced inconsistent findings regarding the influence of the prior relationship between the perpetrator and the target on perceptions of stalking. It is unclear whether these inconsistencies represent a genuine cross-cultural difference. The current study investigates the influence of prior relationship and the nationality of participants on perceptions of stalking with a combined sample of 315 university students from the United Kingdom and Australia. Overall, perceptions failed to reflect the reality that ex-partner stalkers pose a greater threat than stranger or acquaintance stalkers. Participants were more likely to believe that behavior constituted stalking, necessitated police intervention, caused fear or apprehension, and caused mental or physical harm when the perpetrator was depicted as a stranger rather than an acquaintance or ex-partner. The direction of findings was consistent in the United Kingdom and Australia, although Australian participants perceived the perpetrator’s behavior to be more severe than did participants from the United Kingdom.
Social Psychological Influences on the Popularity of Amber Alerts
Authors: Sicafuse Lorie L. , Miller Monica K.
Published: October 2010

The AMBER Alert system enjoys widespread public support. Yet evidence suggests that the system may be ineffective and have unintended consequences. Because AMBER Alerts are illusory means of controlling crime, they may be conceptualized as “crime control theater” (CCT) and thus are indicative of a problematic social tendency to address complex issues through simple solutions. This article utilizes principles of social cognition, attitudes, social norms, and symbolic interaction to predict that the AMBER Alert system will persevere despite its disadvantages. This analysis can help account for the popularity of other forms of CCT. It also highlights the need for future research aimed at elucidating the processes responsible for the acceptance of policies that are mere theater.
DIF Testing for Ordinal Items With Poly-SIBTEST, the Mantel and GMH Tests, and IRT-LR-DIF When the Latent Distribution Is Nonnormal for Both Groups
Authors: Woods Carol M.
Published: October 2010

Differential item functioning (DIF) occurs when an item on a test, questionnaire, or interview has different measurement properties for one group of people versus another. One way to test items with ordinal response scales for DIF is likelihood ratio (LR) testing using item response theory (IRT), or IRT-LR-DIF. Despite the various advantages of IRT-LR-DIF, one disadvantage is that the latent variable is usually assumed to be normally distributed. If this normality assumption is violated, nonparametric alternatives such as the Mantel test, generalized Mantel—Haenszel (GMH) test, and poly-SIBTEST may be preferable. Simulations were carried out to compare IRT-LR-DIF to poly-SIBTEST and the GMH and Mantel tests when the latent density is nonnormal for both groups but presumed normal for IRT-LR-DIF. Results indicated that latent nonnormality detrimentally affected all three procedures, but IRT-LR-DIF was surprisingly more robust to latent nonnormality than all of the nonparametric approaches.
Troponin as a Biomarker of Cardiac Toxicity
Authors: Reagan William J.
Published: October 2010

Cardiac troponin (cTn) is a sensitive and specific biomarker for assessing cardiac damage and should be utilized in drug safety assessment. Lactate dehydrogenase and creatine kinase isoenzyme analyses have historically been used in pre-clinical toxicity testing to assess cardiac injury, but since these assays are less sensitive and specific than cTn, isoenzyme analyses, as determined by the manual electrophoretic technique, are no longer warranted. Commercial cTn assays developed for humans do not have the same immunoreactivity and functional sensitivity in the common pre-clinical testing species, so it is important to show that the assay that is chosen is appropriate for the pre-clinical species being assessed. The kinetics of the cTn response depends on the dose and frequency of test article administration as well as the mechanism of the cardiac injury induced by the test article. Cardiac troponin should be used in the assessment of classes of compound that have previously been shown to induce cardiac necrosis or if cardiac necrosis is identified histologically with a novel compound. Next generation high sensitivity cTn assays are being developed and the low levels of cTn detected with these assays may be an early sign of possibly reversible damage to the heart.
Hematopoietic Proliferative Lesions in the Spleen of rasH2 Transgenic Mice Treated with MNU
Authors: Long Gerald G. , Goodman Dawn G. , Credille Kelly M. , Mann Peter C. , Wilson Jonathan M. , Cardy Richard
Published: October 2010

In this study, rasH2-Tg mice treated with N-methyl-N-nitrosurea (MNU) developed exuberant hematoproliferative changes in the spleen that included dysplasia and features of neoplasia. Hematoproliferative change was characterized as exuberant proliferation of hematopoietic cells within the spleen that distorted but did not displace normal splenic morphologic features. The hematopoietic cells were of mixed lineage, but one type, often erythroid, predominated. Cellular atypia was present in all mice with hematoproliferative change, and dysplasia was present in five of eight examined. Hematoproliferative neoplasia was characterized by similar cytologic features but also resulted in displacement/disruption of normal splenic architecture and increased numbers of unidentified blast cells. One case was differentiated toward myeloid proliferation, suggesting granulocytic leukemia. Affected mice had other neoplasms, such as lymphoma and anemia. These proliferative and dysplastic lesions of the spleen in rasH2-Tg mice treated with MNU require additional characterization to definitively differentiate them from the reactive hematopoiesis that can occur in response to inflammatory, neoplastic, or hematopoietic insults in mice.
We’re All in This Together: Identifying Meaningful Outcomes for K-6 Students of Teacher Candidates
Authors: Fisher Mary , Ociepka Anne
Published: October 2010

Connecting K—6 student outcomes with teacher preparation programs remains a critical need for the field. Even while educators have begun to sort through and document outcomes for teacher interns relative to national standards, the task of connecting performance to K—6 student outcomes has been little documented. In this interview study, the authors identify what mentor teachers associated with one urban teacher preparation program believe are positive student and associated mentor outcomes that result from student teacher participation in their elementary classrooms. The authors conduct a content analysis of individual interviews with 16 student teacher mentors, and use data from a teacher candidate focus group that addressed a subset of the teacher interview questions to triangulate this analysis. The authors discuss their findings in light of implications of the findings for teacher educators and how findings can be used for in-depth, follow-up studies.
Assessing the Strengths of Young Children at Risk: Examining Use of the Preschool Behavioral and Emotional Rating Scale With a Head Start Population
Authors: Griffith Annette K. , Duppong Hurley Kristin , Trout Alexandra L. , Synhorst Lori , Epstein Michael H. , Allen Elizabeth
Published: October 2010

Over the past decade, there has been an increased need for the development and use of psychometrically acceptable measures to assess the behavioral and emotional strengths of young children served in statewide preschool and Head Start programs. One measure developed to address this need is the Preschool Behavioral and Emotional Rating Scale (PreBERS), which is a strength-based instrument designed to evaluate the behavioral and emotional strengths of preschool children aged 3 to 5 years old. In a previous study with a nationally representative sample, researchers found that (a) the items of the PreBERS can best be described by a four-factor structure model (Emotional Regulation, School Readiness, Social Confidence, and Family Involvement), (b) the subscales and total measure have highly acceptable levels of internal consistency, and (c) differences were obtained for levels of strength for preschool children with and without disabilities. The findings of this investigation replicate these previous results with a national sample of children ( N = 962) enrolled in Head Start programs. Confirmatory factor analysis and analyses of internal consistency and criterion validity provide support for the use of the PreBERS with children served in Head Start programs. Study limitations and implications are addressed.
Organization and institutionalization of Russia’s political parties in 1905—1917 and 1993—2007: Similarities and differences from two occidentalist periods
Authors: Perepechko Alexander S. , ZumBrunnen Craig , Kolossov Vladimir A.
Published: October 2010

In this article, we use logit models to examine the role of the major characteristics of a political party's organization, (1) legitimation, (2) penetration/diffusion, (3) charisma, (4) ideology and (5) centralization/decentralization, in the institutionalization of parties in both pre-Soviet and post-Soviet Russian national parliamentary elections. The article begins by situating this research in the context of the theoretical and empirical literature on party origins, organizational development and institutionalization, in general, and party formation theories in post-communist countries, specifically. The impact of organizational features on electoral success or failure is analysed for 24 parties. The models correctly predicted both the successful and failed parties in the 2007 Russian Duma election and offer reasons for the apparent floating party system in Russia.