bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acidosis downregulates platelet haemostatic functions and promotes neutrophil proinflammatory responses mediated by platelets
Authors: Etulain Julia , Negrotto Soledad , Carestia Agostina , Pozner Roberto , Romaniuk María , D’Atri Lina , Klement Giannoula , Schattner Mirta 
Published: December 2011

SummaryAcidosis is one of the hallmarks of tissue injury such as trauma, infection, inflammation, and tumour growth. Although platelets participate in the pathophysiology of all these processes, the impact of acidosis on platelet biology has not been studied outside of the quality control of laboratory aggregation assays or platelet transfusion optimization. Herein, we evaluate the effect of physiologically relevant changes in extracellular acidosis on the biological function of platelets, placing particular emphasis on haemostatic and secretory functions. Platelet haemostatic responses such as adhesion, spreading, activation of αIIbβ3 integrin, ATP release, aggregation, thromboxane B2 generation, clot retraction and procoagulant activity including phosphatidilserine exposure and microparticle formation, showed a statistically significant inhibition of thrombin-induced changes at pH of 7.0 and 6.5 compared to the physiological pH (7.4). The release of alpha granule content was differentially regulated by acidosis. At low pH, thrombin or collagen-induced secretion of vascular endothelial growth factor and endostatin were dramatically reduced. The release of von Willebrand factor and stromal derived factor-1α followed a similar, albeit less dramatic pattern. In contrast, the induction of CD40L was not changed by low pH, and P-selectin exposure was significantly increased. While the generation of mixed platelet-leukocyte aggregates and the increased chemotaxis of neutrophils mediated by platelets were further augmented under acidic conditions in a P-selectin dependent manner, the increased neutrophil survival was independent of P-selectin expression. In conclusion, our results indicate that extracellular acidosis downregulates most of the haemostatic platelet functions, and promotes those involved in amplifying the neutrophil-mediated inflammatory response.
Triplatin, a platelet aggregation inhibitor from the salivary gland of the triatomine vector of Chagas disease, binds to TXA2 but does notinteract with glycoprotein PVI
Authors: Ma Dongying , Assumpção Teresa C. F. , Li Yuan , Andersen John F. , Ribeiro José M.C. , Francischetti Ivo M.B. 
Published: December 2011

SummarySalivary glands from haematophagous animals express a notable diversity of negative modulators of platelet function. Triplatin is an inhibitor of collagen-induced platelet aggregation which has been described as an antagonist of glycoprotein VI (GPVI). Because triplatin displays sequence homology to members of the lipocalin family of proteins, we investigated whether triplatin mechanism of action could be explained by interaction with pro-haemostatic prostaglandins. Our results demonstrate that triplatin inhibits platelet aggregation induced by low doses of collagen, thromboxane A2 (TXA2) mimetic (U46619), and arachidonic acid (AA). On the other hand, it does not inhibit platelet aggregation by convulxin, PMA, or low-dose ADP. Isothermal titration calorimetry (ITC) revealed that triplatin binds AA, cTXA2, TXB2, U46619 or prostaglandin (PG)H2 mimetic (U51605). Consistent with its ligand specificity, triplatin induces relaxation of rat aorta contracted with U46619. Triplatin also interacts with PGF2a and PGJ2, but not with leukotrienes, AA or biogenic amines. Surface plasmon resonance experiments failed to demonstrate interaction of triplatin with GPVI; it also did to inhibit platelet adhesion to fibrillar or soluble collagen. Because triplatin displays sequence similarity to apolipoprotein D (ApoD) – a lipocalin associated with high-density lipoprotein, ApoD was tested as a putative TXA2-binding molecule. ITC failed to demonstrate binding of ApoD to all prostanoids described above, or to AA. Furthermore, ApoD was devoid of inhibitory properties towards platelets activation by AA, collagen, or U46619. In conclusion, triplatin mechanism of action has been elucidated without ambiguity as a novel TXA2- and PGF2α- binding protein. It conceivably blocks platelet aggregation and vasoconstriction, thus contributing to successful blood feeding at the vector-host interface.
Urokinase-Type Plasminogen Activator Downregulates Paraoxonase 1 Expression in Hepatocytes by Stimulating Peroxisome Proliferator–Activated Receptor-γ Nuclear Export
Authors: Khateeb Jasmin , Kiyan Yulia , Aviram Michael , Tkachuk Sergey , Dumler Inna , Fuhrman Bianca 
Published: December 2011

Objective—
The atherosclerotic lesion is characterized by lipid peroxide accumulation. Paraoxonase 1 (PON1) reduces atherosclerotic lesion oxidative stress, whereas urokinase-type plasminogen activator (uPA) increases oxidative stress in atherosclerotic lesions and contributes to the progression and complications of atherosclerosis. We hypothesized that uPA may promote oxidative stress in the arterial wall via modulation of PON1 activity. Because the liver is the main site for PON1 production, in the present study, we tested whether uPA influences PON1 expression in hepatocytes.

Methods and Results—
HuH7 hepatocytes were incubated in culture with increasing concentrations of uPA. uPA decreased PON1 gene expression and activity in a dose-dependent manner and accordingly suppressed PON1 secretion from hepatocytes. This effect required uPA/uPA receptor interaction. uPA downregulated PON1 gene expression via inactivation of peroxisome proliferator–activated receptor-γ (PPARγ) activity, and this effect was dependent on uPA-mediated mitogen-activated protein kinase kinase activation. Mechanistic studies showed that uPA enhanced mitogen-activated protein kinase kinase–PPARγ interaction, resulting in PPARγ nuclear export to the cytosol.

Conclusion—
This study provides the first evidence that uPA interferes with PPARγ transcriptional activity in hepatocytes, resulting in downregulation of PON1 expression and its secretion to the medium. This may explain, at least in part, the prooxidative effect of uPA in the vascular wall.
The Proteoglycan Syndecan 4 Regulates Transient Receptor Potential Canonical 6 Channels via RhoA/Rho-associated Protein Kinase Signaling
Authors: Liu Ying , Echtermeyer Frank , Thilo Florian , Theilmeier Gregor , Schmidt Antje , Schülein Ralf , Jensen Boye L. , Loddenkemper Christoph , Jankowski Vera , Marcussen Niels , Gollasch Maik , Arendshorst William J. , Tepel Martin 
Published: December 2011

Objective—
Syndecan 4 (Sdc4) modulates signal transduction and regulates activity of protein channels. Sdc4 is essential for the regulation of cellular permeability. We hypothesized that Sdc4 may regulate transient receptor potential canonical 6 (TRPC6) channels, a determinant of glomerular permeability, in a RhoA/Rho-associated protein kinase-dependent manner.

Methods and Results—

Sdc4 knockout (Sdc4
−/−
) mice showed increased glomerular filtration rate and ameliorated albuminuria under baseline conditions and after bovine serum albumin overload (each
P
<0.05). Using reverse transcription–polymerase chain reaction and immunoblotting, Sdc4
−/−
mice showed reduced TRPC6 mRNA by 79% and TRPC6 protein by 82% (each
P
<0.05). Sdc4
−/−
mice showed an increased RhoA activity by 87% and increased phosphorylation of ezrin in glomeruli by 48% (each
P
<0.05). Sdc4 knockdown in cultured podocytes reduced TRPC6 gene expression and reduced the association of TRPC6 with plasma membrane and TRPC6-mediated calcium influx and currents. Sdc4 knockdown inactivated negative regulatory protein Rho GTPase activating protein by 33%, accompanied by a 41% increase in RhoA activity and increased phosphorylation of ezrin (
P
<0.05). Conversely, overexpression of Sdc4 reduced RhoA activity and increased TRPC6 protein and TRPC6-mediated calcium influx and currents.

Conclusion—
Our results establish a previously unknown function of Sdc4 for regulation of TRPC6 channels and support the role of Sdc4 for the regulation of glomerular permeability.
Angiotensin II-Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF) Trial
Authors: Goette Andreas , Schön Norbert , Kirchhof Paulus , Breithardt Günter , Fetsch Thomas , Häusler Karl Georg , Klein Helmut U. , Steinbeck Gerhard , Wegscheider Karl , Meinertz Thomas 
Published: December 2011

Background—
Unlike antiarrhythmic drugs, the safety and beneficial effects of angiotensin II receptor blockade (ARB) in patients with structural heart disease is well established. The clinical efficacy of ARBs to prevent atrial fibrillation (AF) so far only has been shown in patients with structural heart disease. Here, we report the primary outcome of the Angiotensin II-Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF) trial, which investigated the effect of olmesartan medoxomil compared with placebo on AF burden in patients with paroxysmal AF without structural heart disease.

Methods and Results—

The ANTIPAF trial was a prospective, randomized, placebo-controlled, multicenter trial analyzing the AF burden (percentage of days with documented episodes of paroxysmal AF) during a 12-month follow-up as the primary study end point. Four hundred thirty patients with documented paroxysmal AF without structural heart disease were randomized to placebo or 40 mg olmesartan per day. Concomitant therapy with ARBs, angiotensin-converting enzyme inhibitors, and antiarrhythmic drugs was prohibited. Patients were followed using daily transtelephonic ECG (tele-ECG) recordings independent of symptoms. The intention-to-treat population of the trial encompassed 425 patients (placebo group, n=211; olmesartan group, n=214). A total of 87 818 tele-ECGs were analyzed in these patients during follow-up (placebo group, 44 888 ECGs; olmesartan group, 42 930 ECGs). Thus, a mean of 207 tele-ECGs were recorded per patient. The primary end point (AF burden) was not different between the 2 groups (
P
=0.770). Secondary outcome parameters, including quality of life, also were not different. In particular, time to first AF recurrence, time to persistent AF, and number of hospitalizations were not different between the 2 groups. The time to prescription of recovery medication (amiodarone) was the only parameter showing an intergroup difference, with earlier prescription of amiodarone in the placebo group (
P
=0.022).

Conclusions—
One year of ARB therapy per se does not reduce the number of AF episodes in patients with documented paroxysmal AF without structural heart disease.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00098137.
Connexin Gene Transfer Preserves Conduction Velocity and Prevents Atrial Fibrillation
Authors: Igarashi Tomonori , Finet J. Emanuel , Takeuchi Ayano , Fujino Yoshihisa , Strom Maria , Greener Ian D. , Rosenbaum David S. , Donahue J. Kevin 
Published: December 2011

Background—
Several lines of evidence have suggested that maintenance of atrial fibrillation (AF) depends on reentrant mechanisms. Maintenance of reentry necessitates a sufficiently short refractory period and/or delayed conduction, and AF has been associated with both alterations. Fibrosis, cellular dysfunction, and gap junction protein alterations occur in AF and cause conduction delay. We performed this study to test the hypothesis that gap junction protein overexpression would improve conduction and prevent AF.

Methods and Results—
Thirty Yorkshire swine were randomized into 2 groups (sinus rhythm and AF), and each group into 3 subgroups: sham-operated control, gene therapy with adenovirus expressing connexin (Cx) 40, and gene therapy with adenovirus expressing Cx43 (n=5 per subgroup). All animals had epicardial gene painting; the AF group had burst atrial pacing. All animals underwent terminal study 7 days after gene transfer. Sinus rhythm animals had strong transgene expression but no atrial conduction changes. In AF animals, controls had reduced and lateralized Cx43 expression, and Cx43 gene transfer restored expression and cellular location to sinus rhythm control levels. In the AF group, both Cx40 and Cx43 gene transfer improved conduction and reduced AF relative to controls.

Conclusions—
Connexin gene therapy preserved atrial conduction and prevented AF.
Towards a Consensus-Based Classification of Childhood Arterial Ischemic Stroke
Authors: Bernard Timothy J. , Manco-Johnson Marilyn J. , Lo Warren , MacKay Mark T. , Ganesan Vijeya , deVeber Gabrielle , Goldenberg Neil A. , Armstrong-Wells Jennifer , Dowling Michael M. , Roach E. Steve , Tripputi Mark , Fullerton Heather J. , Furie Karen L. , Benseler Susanne M. , Jordan Lori C. , Kirton Adam , Ichord Rebecca 
Published: December 2011

Background and Purpose—
The implementation of uniform nomenclature and classification in adult arterial ischemic stroke (AIS) has been critical for defining outcomes and recurrence risks according to etiology and in developing risk-stratified treatments. In contrast, current classification and nomenclature in childhood AIS are often overlapping or contradictory. Our purpose was to develop a comprehensive consensus-based classification system for childhood AIS.

Methods—
Using a modified-Delphi method, members of the International Pediatric Stroke Study (IPSS) developed the Childhood AIS Standardized Classification And Diagnostic Evaluation (CASCADE) criteria. Two groups of pediatric stroke specialists from the IPSS classified 7 test cases using 2 methods each: (1) classification typical of the individual clinician's current clinical practice; and (2) classification based on the CASCADE criteria. Group 1 underwent in-person training in the utilization of the CASCADE criteria. Group 2 classified the same cases via an online survey, including definitions but without training. Inter-rater reliability (IRR) was assessed via multi-rater unweighted κ-statistic.

Results—
In Group 1 (with training), IRR was improved using CASCADE criteria (κ=0.78, 95% CI=[0.49, 0.94]), compared with typical clinical practice (κ=0.40, 95% CI=[0.11, 0.60]). In Group 2 (without training), IRR was lower than among trained raters (κ=0.61, 95% CI=[0.29, 0.77]), but higher than current practice (κ=0.23, 95% CI=[0.03, 0.36]).

Conclusions—
A new, consensus-based classification system for childhood AIS, the CASCADE criteria, can be used to classify cases with good IRR. These preliminary findings suggest that the CASCADE criteria may be particularity useful in the setting of prospective multicenter studies in childhood-onset AIS, where standardized training of investigators is feasible.
The Safety of Intravenous Thrombolysis for Ischemic Stroke in Patients With Pre-Existing Cerebral Aneurysms
Authors: Edwards Nancy J. , Kamel Hooman , Josephson S. Andrew 
Published: December 2011

Background and Purpose—
Unruptured cerebral aneurysms are currently considered a contraindication to intravenous tissue-type plasminogen activator for acute ischemic stroke. This is due to a theoretical increase in the risk of hemorrhage from aneurysm rupture, although it is unknown whether this risk is a significant one. We sought to determine the safety of intravenous tissue-type plasminogen activator administration in a cohort of patients with pre-existing aneurysms.

Methods—
We reviewed the medical records of patients treated for acute ischemic stroke with intravenous tissue-type plasminogen activator during an 11-year period at 2 academic medical centers. We identified a subset of patients with unruptured cerebral aneurysms present on prethrombolysis vascular imaging. Our outcomes of interest were any intracranial hemorrhage, symptomatic intracranial hemorrhage, and subarachnoid hemorrhage. Fisher exact test was used to compare the rates of hemorrhage among patients with and without aneurysms.

Results—
We identified 236 eligible patients, of whom 22 had unruptured cerebral aneurysms. The rate of intracranial hemorrhage among patients with aneurysms (14%; 95% CI, 3%–35%) did not significantly differ from the rate among patients without aneurysms (19%; 95% CI, 14%–25%). None of the patients with aneurysms developed symptomatic intracranial hemorrhage (0%; 95% CI, 0%–15%) compared with 10 of 214 patients without aneurysms (5%; 95% CI, 2%–8%). Similar proportions of patients developed subarachnoid hemorrhage (5%; 95% CI, 0%–23% versus 6%; 95% CI, 3%–10%).

Conclusions—
Our findings suggest that intravenous tissue-type plasminogen activator for acute ischemic stroke is safe to administer in patients with pre-existing cerebral aneurysms because the risk of aneurysm rupture and symptomatic intracranial hemorrhage is low.
Effect of Antihypertensive Therapy on Incident Stroke in Cohorts With Prehypertensive Blood Pressure Levels
Authors: Sipahi Ilke , Swaminathan Aparna , Natesan Viswanath , Debanne Sara M. , Simon Daniel I. , Fang James C. 
Published: December 2011

Background and Purpose—
Compared with normotensive individuals, there is a higher incidence of stroke in patients with hypertensive, as well as prehypertensive, blood pressure levels (ie, 120–139/80–89 mm Hg). Although several studies have shown that blood pressure reduction in hypertensive patients reduces the incidence of cardiovascular events, including stroke, it is still unknown whether treatment of prehypertensive blood pressure levels has a similar effect. We sought to determine whether reduction in blood pressure in the prehypertensive range reduces the incidence of stroke by performing a meta-analysis of randomized trials comparing an antihypertensive drug against placebo in cohorts with prehypertensive baseline blood pressure levels.

Methods—
Randomized controlled trials performed with the 95 different antihypertensive agents available in the market were identified using MEDLINE, returning a total of 2852 results. Exclusion criteria included: average blood pressure of ≥140/90 mm Hg at baseline, crossover studies, and lack of a control group receiving placebo.

Results—

A total of 16 trials involving 70 664 patients were included. Patients randomized to the active treatment arm had a statistically significant 22% reduction in the risk of stroke compared with placebo, with little heterogeneity among the trials (I
2
, 18.0%; RR, 0.78 [95% CI, 0.71–0.86];
P
<0.000001). To prevent 1 stroke, 169 patients had to be treated with a blood-pressure-lowering medication for an average of 4.3 years.

Conclusions—
The risk of stroke is significantly reduced with antihypertensive therapy in cohorts with prehypertensive blood pressure levels. These findings can have important clinical implications.
Swallowing Screens After Acute Stroke
Authors: Schepp Sara K. , Tirschwell David L. , Miller Robert M. , Longstreth W.T. 
Published: December 2011

Background and Purpose—
Swallowing screens after acute stroke identify those patients who do not need a formal swallowing evaluation and who can safely take food and medications by mouth. We conducted a systematic review to identify swallowing screening protocols that met basic requirements for reliability, validity, and feasibility.

Methods—
We searched MEDLINE and supplemented results with references identified through other databases, journal tables of contents, and bibliographies. All relevant references were reviewed and evaluated with specific criteria.

Results—
Of 35 protocols identified, 4 met basic quality criteria. These 4 had high sensitivities of ≥87% and high negative predictive values of ≥91% when a formal swallowing evaluation was used as the gold standard. Two protocols had greater sample sizes and more extensive reliability testing than the others.

Conclusions—
We identified only 4 swallowing screening protocols for patients with acute stroke that met basic criteria. Cost-effectiveness of screening, including costs associated with false-positive results and impact of screening on morbidity, mortality, and length of hospital stay, requires elucidation.
Ice in Clouds Experiment–Layer Clouds. Part II: Testing Characteristics of Heterogeneous Ice Formation in Lee Wave Clouds
Authors: Field P. R. , Heymsfield A. J. , Shipway B. J. , DeMott P. J. , Pratt K. A. , Rogers D. C. , Stith J. , Prather K. A. 
Published: December 2011

Abstract
Heterogeneous ice nucleation is a source of uncertainty in models that represent ice clouds. The primary goal of the Ice in Clouds Experiment–Layer Clouds (ICE-L) field campaign was to determine if a link can be demonstrated between ice concentrations and the physical and chemical characteristics of the ambient aerosol. This study combines a 1D kinematic framework with lee wave cloud observations to infer ice nuclei (IN) concentrations that were compared to IN observations from the same flights. About 30 cloud penetrations from six flights were modeled. The temperature range of the observations was −16° to −32°C. Of the three simplified ice nucleation representations tested (deposition, evaporation freezing, and condensation/immersion droplet freezing), condensation/immersion freezing reproduced the lee wave cloud observations best. IN concentrations derived from the modeling ranged from 0.1 to 13 L−1 compared to 0.4 to 6 L−1 from an IN counter. A better correlation was found between temperature and the ratio of IN concentration to the concentration of large aerosol (&gt;500 nm) than between IN concentration and the large aerosol concentration or temperature alone.
Climate Sensitivity of the Community Climate System Model, Version 4
Authors: Bitz C. M. , Shell K. M. , Gent P. R. , Bailey D. A. , Danabasoglu G. , Armour K. C. , Holland M. M. , Kiehl J. T. 
Published: December 2011

Equilibrium climate sensitivity of the Community Climate System Model, version 4 (CCSM4) is 3.20°C for 1° horizontal resolution in each component. This is about a half degree Celsius higher than in the previous version (CCSM3). The transient climate sensitivity of CCSM4 at 1° resolution is 1.72°C, which is about 0.2°C higher than in CCSM3. These higher climate sensitivities in CCSM4 cannot be explained by the change to a preindustrial baseline climate. This study uses the radiative kernel technique to show that, from CCSM3 to CCSM4, the global mean lapse-rate feedback declines in magnitude and the shortwave cloud feedback increases. These two warming effects are partially canceled by cooling because of slight decreases in the global mean water vapor feedback and longwave cloud feedback from CCSM3 to CCSM4. A new formulation of the mixed layer, slab-ocean model in CCSM4 attempts to reproduce the SST and sea ice climatology from an integration with a full-depth ocean, and it is integrated with a dynamic sea ice model. These new features allow an isolation of the influence of ocean dynamical changes on the climate response when comparing integrations with the slab ocean and full-depth ocean. The transient climate response of the full-depth ocean version is 0.54 of the equilibrium climate sensitivity when estimated with the new slab-ocean model version for both CCSM3 and CCSM4. The authors argue the ratio is the same in both versions because they have about the same zonal mean pattern of change in ocean surface heat flux, which broadly resembles the zonal mean pattern of net feedback strength.