bluuebunny/crossref_metadata_2025_split huggingface dataset:
uPAR regulates pericellular proteolysis through a mechanism involving integrins and fMLF-receptors
Authors: Rinaldi Loredana , Rea Vincenza Elena Anna , Montuori Nunzia , Cosimato Vincenzo , Alfano Daniela , Ragno Pia 
Published: December 2012

SummaryThe expression of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR) can be regulated by several hormones, cytokines, and tumour promoters. uPAR is a glycosyl-phosphatidyl inositol (GPI)- linked cell-surface protein; however, it is capable to transduce signals inside the cell by interacting with other cell-surface proteins, such as integrins and G-protein coupled (GPC) receptors. We previously reported that uPAR cell-surface expression can be positively regulated by its ligand, uPA, independently of its proteolytic activity. We now demonstrate that uPAR overexpression induces or increases uPA secretion both in uPAR-negative and in uPAR-expressing cells. Accordingly, uPAR depletion impairs uPA expression in cells which constitutively express both uPA and its receptor. uPAR exerts its regulatory effect through the activation of the ERK mitogen-activated protein kinases (MAPKs), whereas the p-38 MAPK is not involved. Overexpression of truncated forms of uPAR, lacking the N-terminal domain (DI) and not able to interact with membrane co-receptors, failed to increase uPA expression. Inhibition of uPAR-integrin interaction by the specific P-25 peptide, as well as Gi-protein inhibition by cholera pertussin toxin or depletion of the GPC receptors for fMLF (fMLF-Rs) also impaired uPAR capability to regulate uPA expression. These findings demonstrate that uPAR, whose expression is regulated by uPA, can, in turn, regulate uPA expression through a mechanism involving its functional interaction with integrins and fMLF-Rs.
Platelet protein S directly inhibits procoagulant activity on platelets and microparticles
Authors: Stavenuiter Fabian , Davis Nicole , Duan Erning , Gale Andrew , Heeb Mary 
Published: December 2012

SummaryAnticoagulant plasma protein S (PS) is essential for maintaining haemostatic balance. About 2.5% of PS is stored in platelets and released upon platelet stimulation. So far, little is known about the functionality and importance of platelet (plt)PS. A platelet-associated protease cleaves plasma-derived (pd)PS and pltPS in the “thrombin-sensitive region”, abolishing activated protein C (APC) cofactor activity. However, we showed that cleaved PS retains APC-independent anticoagulant activities (“PS-direct”). To investigate whether pltPS or pdPS exert PS-direct on platelets or platelet-shed microparticles, thrombin and factor (F)Xa generation on unstimulated or stimulated washed platelets and microparticles were measured. Western blotting revealed that pltPS and pdPS bound to washed, stimulated platelets and microparticles, and that pltPS had slower electrophoretic mobility than pdPS. Platelet stimulation in the presence of inhibitory anti-PS antibodies resulted in 2.6 ± 1.6-fold (p<0.0004, n=20) more thrombin generation upon addition of FXa and prothrombin. PltPS exerted PSdirect that was similar to or greater than that of Zn2+-containing pdPS and much greater than that of Zn2+-deficient pdPS. Findings were confirmed using purified pltPS. Platelet-bound pltPS and microparticlebound pltPS had similar PS-direct. Finally, platelet stimulation in the presence of inhibitory anti-PS antibodies resulted in 1.5 ± 0.2-fold (p<0.0001, n=11) more FXa generation upon addition of TF/FVIIa and FX. Thus, pltPS inhibits both prothrombinase and extrinsic FXase activities. Neutralising antibodies against APC and TFPI had no effect on the PS-direct of pltPS or pdPS on platelets. This study indicates that pltPS may be an essential pool of PS that counterbalances procoagulant activities on platelets.
Obesity with insulin resistance increase thrombosis in wild-type and bone marrow-transplanted Zucker fatty rats
Authors: Vera Rodrigo Hernández , Vilahur Gemma , Badimon Lina 
Published: December 2012

SummaryObesity induces metabolic and inflammatory alterations that contribute to the presentation of cardiovascular events. Although obesity is a risk factor for atherosclerosis and vascular disease, its role on thrombosis has not been directly explored. Therefore, we aimed to investigate the mechanisms by which obesity affects thrombosis. Thrombus formation was monitored by real-time intravital microscopy in Zucker Fatty rats (ZF) and lean controls (ZC). Crossed bone marrow (BM) transplants between ZF and ZC were performed. Intravital microscopy showed that ZF had significantly shorter occlusion times (OTs) than ZC, reflecting a three-fold higher thrombotic risk. Transplantation of ZC-BM to ZF recipients significantly reduced thrombosis, reducing their thrombotic risk to one third of that observed in non-transplanted ZF. Wild-type ZF showed increased platelet counts and increased platelet size compared to wild-type ZC and platelet number remained unaltered after transplantation. However, ZF-BM produced a significant increase in platelet size in ZC recipients. Thrombotic risk was found to be inversely correlated with both weight and insulin levels and directly correlated to HOMA-IR, while platelet number and size were directly correlated with weight. Thus, our data shows that obesity with insulin resistance significantly increases thrombosis and that alterations in BM-derived cells significantly contribute to this prothrombotic behaviour. Importantly, the reduction of insulin resistance was associated with reduced thrombotic risk even in the presence of obesity.
Toronto Hypertrophic Cardiomyopathy Genotype Score for Prediction of a Positive Genotype in Hypertrophic Cardiomyopathy
Authors: Gruner Christiane , Ivanov Joan , Care Melanie , Williams Lynne , Moravsky Gil , Yang Hua , Laczay Balint , Siminovitch Katherine , Woo Anna , Rakowski Harry 
Published: December 2012

Background—
Genotyping in hypertrophic cardiomyopathy has gained increasing attention in the past decade. Its major role is for family screening and rarely influences decision-making processes in any individual patient. It is associated with substantial costs, and cost-effectiveness can only be achieved in the presence of high-detection rates for disease-causing sarcomere protein gene mutations. Therefore, our aim was to develop a score based on clinical and echocardiographic variables that allows prediction of the probability of a positive genotype.

Methods and Results—

Clinical and echocardiographic variables were collected in 471 consecutive patients undergoing genetic testing at a tertiary referral center between July 2005 and November 2010. Logistic regression for a positive genotype was used to construct integer risk weights for each independent predictor variable. These were summed for each patient to create the Toronto hypertrophic cardiomyopathy genotype score. A positive genotype was found in 163 of 471 patients (35%). Independent predictors with associated-risk weights in parentheses were as follows: age at diagnosis 20 to 29 (−1), 30 to 39 (−2), 40 to 49 (−3), 50 to 59 (−4), 60 to 69 (−5), 70 to 79 (−6), ≥80 (−7); female sex (4); arterial hypertension (−4); positive family history for hypertrophic cardiomyopathy (6); morphology category (5); ratio of maximal wall thickness:posterior wall thickness <1.46 (0), 1.47 to 1.70 (1), 1.71 to 1.92 (2), 1.93 to 2.26 (3), ≥2.27 (4). The model had a receiver operator curve of 0.80 and Hosmer–Lemeshow goodness-of-fit
P
=0.22.

Conclusions—
The Toronto genotype score is an accurate tool to predict a positive genotype in a hypertrophic cardiomyopathy cohort at a tertiary referral center.
A Validated Risk Score to Predict Outcomes after Carotid Stenting
Authors: Hoke Matthias , Ljubuncic Elmir , Steinwender Clemens , Huber Kurt , Minar Erich , Koppensteiner Renate , Leisch Franz , Dick Petra , Kerschner Klaus , Schillinger Martin , Hofmann Robert , Niessner Alexander 
Published: December 2012

Background—
Periprocedural outcome has been extensively investigated in patients undergoing carotid artery stenting. However, risk factors contributing to long-term mortality have not been comprehensively assessed. We aimed to establish a validated clinical risk score for long-term mortality in patients after carotid artery stenting.

Methods and Results—

Two independent cohorts after successful carotid artery stenting (602 and 552 patients) were prospectively investigated. Multivariable Cox regression and bootstrap variable selection were used to select the best-fitting multivariable model. The mortality rate was 35% in the derivation and 39% in the validation cohort during a median follow-up of 6.5 and 7.4 years, respectively. The following variables were identified as most robust risk factors in the derivation cohort: age, heart failure, diabetes mellitus, relative lymphocyte count, prothrombin time, peripheral artery disease, and contralateral carotid occlusion. A weighted multimarker risk score yielded an area under the receiver operating characteristic curve of 0.79 in the derivation (
P
<0.001) and of 0.69 (
P
<0.001) in the validation cohort. In comparison, the best area under the receiver operating characteristic curves for single risk factors were 0.67 and 0.63, respectively. For optimal clinical use, a simplified risk score was also developed, which discriminated very well from very low to very high risk. The risk of all-cause mortality ranged from 8% for a score of 1 to 93% for a score of 7 (
P
<0.001) in the derivation and from 11% to 100% in the validation cohort (
P
<0.001).

Conclusions—
A multimarker risk score outperformed the prognostic value of single risk factors for the prediction of long-term mortality.
The Quality and Impact of Risk Factor Control in Patients With Stable Claudication Presenting for Peripheral Vascular Interventions
Authors: Ardati Amer K. , Kaufman Samuel R. , Aronow Herbert D. , Nypaver Timothy J. , Bove Paul G. , Gurm Hitinder S. , Grossman P. Michael 
Published: December 2012

Background—
Peripheral arterial disease is a manifestation of systemic atherosclerosis and is predictive of future cardiovascular events. Clinical trial data have demonstrated that medical therapy can attenuate cardiovascular morbidity and mortality in patients with peripheral arterial disease. The utilization and impact of recommended medical therapy in a contemporary population of patients who undergo percutaneous interventions for lifestyle-limiting peripheral arterial disease is unknown.

Methods and Results—
Using the Blue Cross Blue Shield of Michigan Cardiovascular Consortium Peripheral Vascular Intervention (BMC2 PVI) database, we identified 1357 peripheral vascular intervention encounters between January 2007 and December 2009 for the purpose of treating claudication. Before the intervention, 85% of these patients used aspirin, 76% used statin, 65% abstained from smoking, and 47% did all 3. There was no difference in cardiovascular events among those taking an aspirin and a statin on admission and those who were not. However, in both an unadjusted and a multivariable analysis, the odds of an adverse peripheral vascular outcome (repeat peripheral intervention, amputation, or limb salvage surgery) within 6 months decreased by more than half in patients receiving aspirin and statin therapy before peripheral vascular intervention as compared with those who received neither (odds ratio, 0.45; 95% CI, 0.29–0.71).

Conclusions—
The fundamental elements of medical therapy in patients with lifestyle-limiting claudication are often underutilized before referral for revascularization. Appropriate medical therapy before percutaneous revascularization is associated with fewer peripheral vascular events at 6 months.
Hospital Case Volume and Appropriate Prescriptions at Hospital Discharge After Acute Myocardial Infarction
Authors: Schiele François , Capuano Frédéric , Loirat Philippe , Desplanques-Leperre Armelle , Derumeaux Geneviève , Thebaut Jean-François , Gardel Christine , Grenier Catherine 
Published: December 2012

Background—
In acute myocardial infarction, the relationship between volume and quality indicators (QIs) is poorly documented. Through a nationwide assessment of QIs at discharge repeated for 3 years, we aimed to quantify the relationship between volume and QIs in survivors after acute myocardial infarction.

Methods and Results—
Almost all healthcare centers in France participated. Medical records were randomly selected. Data collection was performed by an independent group. QIs for acute myocardial infarction were defined by an expert consensus group as appropriate prescription at discharge of aspirin, clopidogrel, β-blocker, statin, and an angiotensin-converting enzyme inhibitor in patients with left ventricular ejection fraction <0.40. A composite QI was calculated through the use of the all-or-none method. Volume was classified into 7 categories based on the number of admissions for acute myocardial infarctions in 2008 (centers with <10 acute myocardial infarctions were excluded). Odds ratios adjusted for age and sex with 95% confidence interval for volume categories were calculated by use of logistic regression for each QI. Temporal changes were tested in centers that participated in all 3 campaigns. A total of 46 390 records were examined: 18 159 in 2008, 12 837 in 2009, and 15 394 in 2010. Two hundred ninety-one centers were eligible for the temporal analysis. There was a significant increase between 2008 and 2009 in appropriate prescription of antiplatelet agents, β-blockers, angiotensin-converting enzyme inhibitor, statins at discharge, and the composite indicator. Similarly, a significant increase was observed between 2009 and 2010 in appropriate prescription of angiotensin-converting enzyme inhibitor and β-blockers and in the composite QI. Compared with a volume of >300, a significantly lower rate of all QIs was observed in centers with the lowest volume. Odds ratios progressively decreased with increasing volume. Despite a significant increase in the composite QI over the 3 years, a significant relationship persisted between volume and quality of care.

Conclusions—
Analysis of QIs at discharge demonstrates the existence of a relationship between volume and appropriate prescriptions at discharge. Centers with the highest volume perform better on quality measures than centers with lower volumes. Temporal analysis over 3 consecutive years confirms this relationship and shows that it persists despite improvement in QIs between 2008 and 2010.
Remodeling of the Axon Initial Segment After Focal Cortical and White Matter Stroke
Authors: Hinman Jason D. , Rasband Matthew N. , Carmichael S. Thomas 
Published: December 2012

Background and Purpose—
Recovery from stroke requires neuroplasticity within surviving adjacent cortex. The axon initial segment (AIS) is the site of action potential initiation and a focal point for tuning of neuronal excitability. Remodeling of the AIS may be important to neuroplasticity after stroke.

Methods—
Focal cortical stroke in forelimb motor cortex was induced by photothrombosis and compared with sham controls. White matter stroke was produced through stereotactic injection of a vasoconstrictor together with biotinylated dextran amine to retrogradely label injured cortical neurons. AIS length, morphology and number were measured using immunofluorescence and confocal microscopy 2 weeks after stroke.

Results—
Within the peri-infarct cortex and after white matter stroke, AIS length decreases. This shortening is accompanied by altered AIS morphology. In peri-infarct cortex, the decrease in AIS length after stroke occurs from the distal end of the AIS, resulting in a Nav1.6. γ-aminobutyric acid type A receptor-α2 subunit staining at axoaxonic synapses along the AIS is significantly decreased. In addition, a significant increase in small, immature initial segments is present in layers 2/3 of peri-infarct cortex, reflecting maturation of axonal sprouting and new initial segments from surviving neurons.

Conclusions—
Stroke alters the compartmental morphology of surviving adjacent neurons in peri-infarct cortex and in neurons whose distal axons are injured by white matter stroke. With a key role in modulation of neuronal excitability, these changes at the AIS may contribute to altered neuronal excitability after injury and prove crucial to increasing neuroplasticity in surviving tissue affected by stroke.
Characteristics of Ischemic Brain Lesions After Stenting or Endarterectomy for Symptomatic Carotid Artery Stenosis
Authors: Gensicke Henrik , Zumbrunn Thomas , Jongen Lisa M. , Nederkoorn Paul J. , Macdonald Sumaira , Gaines Peter A. , Lyrer Philippe A. , Wetzel Stephan G. , van der Lugt Aad , Mali Willem P. Th. M. , Brown Martin M. , van der Worp H. Bart , Engelter Stefan T. , Bonati Leo H. 
Published: December 2012

Background and Purpose—
In a substudy of the International Carotid Stenting Study (ICSS), more patients had new ischemic brain lesions on diffusion-weighted magnetic resonance imaging (MRI) after stenting (CAS) than after endarterectomy (CEA). In the present analysis, we compared characteristics of diffusion-weighted MRI lesions.

Methods—
Number, individual and total volumes, and location of new diffusion-weighted MRI lesions were compared in patients with symptomatic carotid stenosis randomized to CAS (n=124) or CEA (n=107) in the ICSS-MRI substudy.

Results—

CAS patients had higher lesion numbers than CEA patients (1 lesion, 15% vs 8%; 2–5 lesions, 19% vs 5%; >5 lesions, 16% vs 4%). The overall risk ratio for the expected lesion count with CAS versus CEA was 8.8 (95% confidence interval, 4.4–17.5;
P
<0.0001) and significantly increased among patients with lower blood pressure at randomization, diabetes mellitus, stroke as the qualifying event, left-side stenosis, and if patients were treated at centers routinely using filter-type protection devices during CAS. Individual lesions were smaller in the CAS group than in the CEA group (
P
<0.0001). Total lesion volume per patient did not differ significantly. Lesions in the CAS group were more likely to occur in cortical areas and subjacent white matter supplied by leptomeningeal arteries than lesions in the CEA group (odds ratio, 4.2; 95% confidence interval, 1.7–10.2;
P
=0.002).

Conclusions—
Compared with patients undergoing CEA, patients treated with CAS had higher numbers of periprocedural ischemic brain lesions, and lesions were smaller and more likely to occur in cortical areas and subjacent white matter. These findings may reflect differences in underlying mechanisms of cerebral ischemia.

Clinical Trial Registration—

URL:
http://www.isrctn.org
. Unique identifier: ISRCTN25337470.
Self-Report of Stroke, Transient Ischemic Attack, or Stroke Symptoms and Risk of Future Stroke in the Reasons for Geographic And Racial Differences in Stroke (REGARDS) Study
Authors: Judd Suzanne E. , Kleindorfer Dawn O. , McClure Leslie A. , Rhodes J. David , Howard George , Cushman Mary , Howard Virginia J. 
Published: December 2012

Background and Purpose—
History of stroke and transient ischemic attack (TIA) are documented risk factors for subsequent stroke and all-cause mortality. Recent reports suggest increased risk among those reporting stroke symptoms absent stroke or TIA. However, the relative magnitude of increased stroke risk has not been described across the symptomatic spectrum: (1) asymptomatic, (2) stroke symptoms (SS) only, (3) TIA, (4) distant stroke (DS), and (5) recent stroke (RS).

Methods—
Between 2003 and 2007, the REasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30 239 black and white Americans ≥45 years of age. DS and RS were defined as self-report of physician diagnosis of stroke >5 or <5 years before baseline, respectively. SS was defined as a history of any of 6 sudden onset stroke symptoms absent TIA/stroke diagnosis. Kaplan-Meier and proportional hazards analysis were used to contrast stroke risk differences.

Results—
Over 5.0±1.72 years of follow-up, 737 strokes were validated. Compared with asymptomatic persons, those with SS, TIA, DS, and RS all had increased risk of future stroke. After adjustment for age, race, sex, income, education, alcohol intake, current smoking, and a history of diabetes mellitus, hypertension, myocardial infarction, atrial fibrillation, and dyslipidemia, there was 1.20-fold (not statistically significant) increased stroke risk for SS (95% CI, 0.96–1.51), 1.73-fold for TIA (95% CI, 1.27–2.36), 2.23-fold for DS (95% CI, 1.61– 3.09), and 2.85-fold for RS (95% CI, 2.16–3.76).

Conclusions—
Results suggest a spectrum of risk from stroke symptoms to TIA, DS, and RS, and imply a need for establishing these categories in health screenings to manage risk for future stroke, reinforcing the clinical importance of stroke history including the presence of stroke symptoms.
On a Natural Environment for Glaciogenic Cloud Seeding
Authors: Morrison Anthony E. , Siems Steven T. , Manton Michael J. 
Published: December 2012

AbstractA “climatology” of supercooled cloud tops is presented for southeastern Australia and the western United States, where historic glaciogenic cloud-seeding trials have been located. The climatology finds that supercooled cloud tops are common over the mountainous region of southeastern Australia and Tasmania (SEAT). Regions where cloud-seeding trials reported positive results coincide with a higher likelihood of observing supercooled cloud tops. Maximum absolute frequencies (AFs) occur ∼40% of the time during winter. There is a relationship between the underlying orography and the likelihood of observing supercooled liquid water (SLW)-topped clouds. Regions of the United States that have been the subject of cloud-seeding trials show lower AFs of SLW-topped clouds. The maximum is located over the Sierra Nevada and occurs ∼20% of the time during winter (Sierra Cooperative Pilot Project). These sites are on mountains with peaks higher than any found in SEAT (>3000 m). For the Sierra Nevada, the AF of SLW-topped clouds decreases as the elevation increases, with glaciation occurring at the higher elevations. The remote sensing of supercooled cloud tops is not proof of a region’s amenability for glaciogenic cloud seeding. This study simply highlights the significant environmental differences between historical cloud-seeding regions in the United States and Australia, suggesting that it is not reasonable to extrapolate results from one region to another. Without in situ cloud microphysical measurements, in-depth knowledge of the timing and duration of potentially seedable events, or knowledge of the synoptic forcing of such events, it is not possible to categorize a region’s potential for precipitation augmentation operations.
Improvement of Multimodel Ensemble Seasonal Prediction Skills over East Asian Summer Monsoon Region Using a Climate Filter Concept
Authors: Lee Doo Young , Ahn Joong-Bae , Ashok Karumuri 
Published: December 2012

AbstractThe authors propose the use of a “climate filter” concept to enhance prediction skill of a multimodel ensemble (MME) suite for the East Asian summer monsoon (EASM) precipitation and temperature at 850 hPa. The method envisages grading models on the basis of the degree of reproducibility of the association of EASM variability with a few relevant climate drivers with the respective model hindcasts for the period 1981–2003. The analysis identifies the previous winter Niño-3.4 and spring North Atlantic Oscillation indices as the most suitable climate drivers in designing a climate filter for evaluating models that replicate the observed teleconnections to EASM well. The results show that the hindcast skills of a new MME with the better-performing models are significantly higher than those from the nonperforming models or from an all-inclusive operational MME.