bluuebunny/crossref_metadata_2025 huggingface dataset:
Constitutive K-RasG12D Activation of ERK2 Specifically Regulates 3D Invasion of Human Pancreatic Cancer Cells via MMP-1
Authors: Botta Gregory P. , Reginato Mauricio J. , Reichert Maximilian , Rustgi Anil K. , Lelkes Peter I.
Published: December 2011

Pancreatic ductal adenocarcinomas (PDAC) are highly invasive and metastatic neoplasms commonly unresponsive to current drug therapy. Overwhelmingly, PDAC harbors early constitutive, oncogenic mutations in K-RasG12D that exist prior to invasion. Histologic and genetic analyses of human PDAC biopsies also exhibit increased expression of extracellular signal-regulated kinase (ERK) 1/2 and proinvasive matrix metalloproteinases (MMP), indicators of poor prognosis. However, the distinct molecular mechanisms necessary for K-Ras/ERK1/2 signaling and its influence on MMP-directed stromal invasion in primary human pancreatic ductal epithelial cells (PDEC) have yet to be elucidated in three-dimensions. Expression of oncogenic K-RasG12D alone in genetically defined PDECs reveals increased invadopodia and epithelial-to-mesenchymal transition markers, but only when cultured in a three-dimensional model incorporating a basement membrane analog. Activation of ERK2, but not ERK1, also occurs only in K-RasG12D–mutated PDECs cultured in three-dimensions and is a necessary intracellular signaling event for invasion based upon pharmacologic and short hairpin RNA (shRNA) inhibition. Increased active invasion of K-RasG12D PDECs through the basement membrane model is associated with a specific microarray gene expression signature and induction of MMP endopeptidases. Specifically, MMP-1 RNA, its secreted protein, and its proteolytic cleavage activity are amplified in K-RasG12D PDECs when assayed by real-time quantitative PCR, ELISA, and fluorescence resonance energy transfer (FRET). Importantly, shRNA silencing of MMP-1 mimics ERK2 inhibition and disrupts active, vertical PDEC invasion. ERK2 isoform and MMP-1 targeting are shown to be viable strategies to attenuate invasion of K-RasG12D–mutated human pancreatic cancer cells in a three-dimensional tumor microenvironment. Mol Cancer Res; 10(2); 183–96. ©2011 AACR.
Fetoscopic Laser Surgery for Twin-to-Twin Transfusion Syndrome after 26 Weeks of Gestation
Authors: Valsky Dan V. , Eixarch Elisenda , Martinez-Crespo Josep M. , Acosta Emilia-Ruthy , Lewi Liesbeth , Deprest Jan , Gratacós Eduard
Published: December 2011

Objective: To compare the outcomes of twin-to-twin transfusion syndrome (TTTS) cases treated with fetoscopic laser coagulation of vascular anastomoses before 25 + 6 weeks of gestation and between 26 and 28 weeks of gestation. Material and Methods: 28 consecutive cases of TTTS at Quintero stages II-IV treated with laser therapy between 26 + 0 and 28 + 6 weeks of gestation were compared with 324 cases treated between 15 + 0 and 25 + 6 weeks during a 3-year period in two centers. The following data were recorded and compared: duration of the fetoscopy, rate of complications (preterm labor before 28 weeks and before 32 weeks, chorioamnionitis, twin anemia-polycythemia syndrome and recurrent TTTS), gestational age at delivery and neonatal survival rate. Results: The study groups were similar as regards Quintero staging and the frequency of anterior placental location (50.0 vs. 47.8%, p = 0.85 in late and conventional laser, respectively). There were no significant differences in the duration of surgery (29 vs. 30, p = 0.27, respectively) and in the rates of any of the complications evaluated. Gestational age at delivery (33 vs. 33.3 weeks, p = 0.69) and neonatal survival of at least one fetus (92.3 vs. 88.6%, p = 0.24) were also similar. Conclusion: Fetoscopic laser coagulation for TTTS performed between 26 + 0 and 28 + 6 weeks of gestation was associated with similar outcomes as those observed in cases treated before 26 weeks.
Lack of Association between hOGG1 Ser326Cys Polymorphism and the Risk of Bladder Cancer: A Meta-Analysis
Authors: Li Dawei , Liu Hainan , Yan Lei , Tang Yueqing , Ren Juchao , Xu Zhonghua
Published: December 2011

Objective: In some but not all studies, hOGG1 Ser326Cys polymorphism has been reported to contribute to the risk of bladder cancer. To determine whether there is a significant association of hOGG1 Ser326Cys polymorphism with the susceptibility for bladder cancer, we performed a comprehensive meta-analysis. Methods: The electronic PubMed, Medline and Springer databases were searched for publications on the association between hOGG1 Ser326Cys polymorphism and bladder cancer through to May 20, 2011. Seven case-control studies were identified, including 2,474 cases and 2,408 controls. From these identified publications, crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of association using fixed- or random-effects models. Two investigators each extracted data and conducted the analysis independently. Results: Overall, no significant associations were found between hOGG1 Ser326Cys polymorphism and bladder cancer in codominant models (GG vs. CC: OR 1.11, 95% CI 0.74–1.66, p = 0.63; GC vs. CC: OR 1.07, 95% CI 0.80–1.41, p = 0.65). Similarly, no significant associations with bladder cancer were observed in the recessive model (GG vs. GC+CC: OR 1.05, 95% CI 0.65–1.70, p = 0.85), dominant model (GG+GC vs. CC: OR 1.07, 95% CI 0.87–1.32, p = 0.53) and allele model (G vs. C: OR 1.06, 95% CI 0.90–1.26, p = 0.49). In the stratified analyses by ethnicity, control sources, pathology, Hardy-Weinberg equilibrium, significant associations were still not observed. Conclusions: The overall current literature on hOGG1 Ser326Cys polymorphism and the risk of bladder cancer suggests no statistically significant association between the two. Additional primary studies may be necessary to provide evidence of any significant association between this specific polymorphism and bladder cancer.
Novel Therapeutic Approach for Neurodegenerative Pathologies: Multitarget Iron-Chelating Drugs Regulating Hypoxia-Inducible Factor 1 Signal Transduction Pathway
Authors: Weinreb Orly , Amit Tamar , Mandel Silvia , Youdim Moussa B.H.
Published: December 2011

Our novel multimodal brain-permeable iron-chelating compounds M30 and HLA20 were demonstrated to possess neuroprotective/neurorescue activities in vitro and in vivo against several insults applicable to various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Neuroprotection by iron chelators has been widely recognized with respect to their ability to prevent reactive oxygen species generation in the Fenton reaction by sequestering redox-active iron. An additional neuroprotective mechanism of iron-chelating compounds is associated with their ability to regulate the transcriptional activator hypoxia-inducible factor 1 (HIF-1). HIF-1 is a ‘master switch’ being an important physiological response mechanism, likely enhancing neuroprotective compensatory pathways involved in many physiological processes within the brain. This mini-review will discuss the multifunctional mechanisms of action of the drugs, M30 and HLA20 in preclinical models of neurodegeneration with a specific emphasis on their ability to activate the HIF-1 signal transduction pathway.
Exon Arrays Reveal Alternative Splicing Aberrations in Parkinson’s Disease Leukocytes
Authors: Soreq Lilach , Bergman Hagai , Israel Zvi , Soreq Hermona
Published: December 2011

Background: Parkinson’s disease (PD) is the second most frequent neurodegenerative disease worldwide. Clinical diagnosis can only be made when the vast majority of the dopaminergic cell population has died. However, the cause(s) for sporadic PD is/are yet unclear. Transcript changes have recently been described in PD patients’ whole blood cells, but corresponding splicing patterns remained unknown. Objective: To search for alternative splicing aberrations in PD patients’ blood leukocytes. Methods: We applied exon microarrays to profile PD patients’ blood leukocyte mRNA. Exon level splicing analysis served as a basis for downstream classification and functional analyses. Results: Patients and carefully matched controls were classified by the splicing exon profiles of their leukocyte transcripts. Specifically, many exons were downregulated in PD patients compared to controls. Functional analysis highlighted aberrant splicing of PD-related transcripts and impaired NF-ĸB cascade and immune response. Conclusion: PD patient’s blood leukocytes exhibit alternative splicing of numerous transcripts. The aberrant alternative splicing in PD patients’ blood cells has potential implications for early diagnosis and future therapeutics.
Software Tool for Improved Prediction of Alzheimer’s Disease
Authors: Soininen Hilkka , Mattila Jussi , Koikkalainen Juha , van Gils Mark , Hviid Simonsen A. , Waldemar Gunhild , Rueckert Daniel , Thurfjell Lennart , Lötjönen Jyrki ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2011

Background: Diagnostic criteria of Alzheimer’s disease (AD) emphasize the integration of clinical data and biomarkers. In practice, collection and analysis of patient data vary greatly across different countries and clinics. Objective: The goal was to develop a versatile and objective clinical decision support system that could reduce diagnostic errors and highlight early predictors of AD. Methods: Novel data analysis methods were developed to derive composite disease indicators from heterogeneous patient data. Visualizations that communicate these findings were designed to help the interpretation. The methods were implemented with a software tool that is aimed for daily clinical practice. Results: With the tool, clinicians can analyze available patients as a whole, study them statistically against previously diagnosed cases, and characterize the patients with respect to having AD. The tool is able to work with virtually any patient measurement data, as long as they are stored in electronic format or manually entered into the system. For a subset of patients from the test cohort, the tool was able to predict conversion to AD at an accuracy of 93.6%. Conclusion: The software tool developed in this study provides objective information for early detection and prediction of AD based on interpretable visualizations of patient data.
Atypical Follicular Cells with Equivocal Features of Papillary Thyroid Carcinoma Is Not a Low-Risk Cytologic Diagnosis
Authors: Luu Martin H. , Fischer Andrew H. , Stockl Thomas J. , Pisharodi Latha , Owens Christopher L.
Published: December 2011

Objective: To determine whether or not significant differences in the risk of malignancy exist between subgroups of atypical follicular cells in The Bethesda System for Reporting Thyroid Cytology (TBSRTC) in patients who underwent surgical resection. Study Design: Between 2004 and 2009, consecutive thyroid fine-needle aspirates at our institutions with a cytologic diagnosis of ‘atypical follicular cells’ were retrieved and subclassified using the diagnosis and diagnostic comment as: (1) atypical follicular cells with equivocal features of papillary carcinoma [cannot exclude papillary thyroid carcinoma (PTC)] and (2) atypical follicular cells, other patterns. The risks of malignancy for excised nodules were calculated and comparisons were made between these subgroups. Categorical analysis was performed using a 2-tailed Fisher’s exact test, and p < 0.05 was considered statistically significant. Results: A total of 7,072 thyroid fine-needle aspiration cases were retrieved, with 1,542 (21.8%) having a histologic follow-up. There were 222 (3.1%) cases of ‘atypical follicular cells’, with 127 (57.2%) having a histologic correlation and 33 having confirmed malignancies. Atypical follicular cells, cannot exclude PTC, have a significantly higher risk of malignancy than atypical follicular cells, other patterns (45.8 vs. 13.9%, p < 0.01). Conclusions: Atypical follicular cells with equivocal features of papillary carcinoma is not a low-risk cytologic diagnosis.
The Bethesda Terminology for Reporting Thyroid Cytopathology: From Theory to Practice in Europe
Authors: Cochand-Priollet B. , Schmitt F.C. , Tötsch M. , Vielh P. ,   European Federation of Cytology Societies’ Scientific Committee
Published: December 2011

Objectives: A 2007 conference held at the National Cancer Institute, Bethesda, Md., USA, proposed a new terminology for classifying the results of thyroid fine-needle aspiration (FNA) – The Bethesda System for Reporting Thyroid Cytology (TBSRTC). The need to standardize thyroid FNA terminology was emphasized during the 35th European Congress of Cytology in 2009. An interobserver review study to assess the new terminology for analyzing the results of thyroid FNA was organized by the scientific committee of the European Federation of Cytology Societies. Study Design: Four experts in thyroid FNA examined and classified 116 FNAs according to the 6 levels of TBSRTC which are: nondiagnostic (ND); benign; atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS); follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN), with those of Hürthle cell type reported as follicular neoplasm, Hürthle cell type/suspicious for a follicular neoplasm, Hürthle cell type (FNHCT/SFNHCT); suspicious (SUS), and malignant. Results: The total consensus was 62.1%; the cytopathologists disagreed on 44 cases, including 8 cases of AUS/FLUS and 18 of FN/SFN; 59% of the cases had no consensus. They agreed on 73 and 80% of the cases classified as benign and malignant, respectively, and on 58.3% of the SUS cases. The percentage of no consensus for each expert was between 32 and 39%. Conclusions: Disagreement regarding the use of TBSRTC terminology for classifying the results of thyroid FNA mainly occurred in the most-often criticized categories of AUS/FLUS and FN/SFN.
Revisiting the molecular epidemiology of factor XI deficiency: Nine new mutations and an original large 4qTer deletion in western Brittany (France)
Authors: Guéguen Paul , Chauvin Angélique , Quémener-Redon Sylvia , Pan-Petesch Brigitte , Férec Claude , Abgrall Jean-François , Maréchal Cédric
Published: December 2011

Constitutional deficiency in factor XI (FXI) is a rare bleeding disorder in the general population, with the exception of Ashkenazi Jews. During the last decade, the detection of FXI-deficient patients has shifted from clinical screening identifying mostly severe bleeders to biological screening combining findings of prolonged activated partial thromboplastin time and FXI coagulation activity (FXI:C) below 50 U/dl. The goal of this study was to determine the molecular basis of FXI deficiency in western Brittany, France. Over the course of four years, we detected 98 FXI-deficient patients through biological screening, and 44 patients agreed to participate in this study corresponding to 25 index cases. We developed an efficient mutation detection strategy (combining direct sequencing and QFM-PCR to search for heterozygous rearrangements in a routine setting) that detected F11 mutations in 24 out of the 25 index cases. An unexpected allelic heterogeneity was found, with 14 different single point mutations being detected, among which nine are new. Moreover, a large heterozygous deletion of the entire F11 gene was detected, and was then further defined using a CGH array as a 4q34.2 telomeric deletion of 7 Mb containing 77 genes. We propose that the observed recurrent mutations may be considered as genetic tags of a population. This study highlights the importance of screening for large deletions in molecular studies of F11.
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

Acidosis 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

Salivary 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.
Inhibition of CaMKII Phosphorylation of RyR2 Prevents Induction of Atrial Fibrillation in FKBP12.6 Knockout Mice
Authors: Li Na , Wang Tiannan , Wang Wei , Cutler Michael J. , Wang Qiongling , Voigt Niels , Rosenbaum David S. , Dobrev Dobromir , Wehrens Xander H.T.
Published: December 2011

Rationale:

Abnormal calcium release from sarcoplasmic reticulum (SR) is considered an important trigger of atrial fibrillation (AF). Whereas increased Ca
2+
/calmodulin-dependent protein kinase II (CaMKII) activity has been proposed to contribute to SR leak and AF induction, downstream targets of CaMKII remain controversial.

Objective:

To test the hypothesis that inhibition of CaMKII-phosphorylated type-2 ryanodine receptors (RyR2) prevents AF initiation in FKBP12.6-deficient (−/−) mice.

Methods and Results:

Mice lacking RyR2-stabilizing subunit FKBP12.6 had a higher incidence of spontaneous and pacing-induced AF compared with wild-type mice. Atrial myocytes from FKBP12.6−/− mice exhibited spontaneous Ca
2+
waves (SCaWs) leading to Na
+
/Ca
2+
-exchanger activation and delayed afterdepolarizations (DADs). Mutation S2814A in RyR2, which inhibits CaMKII phosphorylation, reduced Ca
2+
spark frequency, SR Ca
2+
leak, and DADs in atrial myocytes from FKBP12.6−/−:S2814A mice compared with FKBP12.6−/− mice. Moreover, FKBP12.6−/−:S2814A mice exhibited a reduced susceptibility to inducible AF, whereas FKBP12.6−/−:S2808A mice were not protected from AF.

Conclusions:

FKBP12.6 mice exhibit AF caused by SR Ca
2+
leak, Na
+
/Ca
2+
-exchanger activation, and DADs, which promote triggered activity. Genetic inhibition of RyR2-S2814 phosphorylation prevents AF induction in FKBP12.6−/− mice by suppressing SR Ca
2+
leak and DADs. These results suggest suppression of RyR2-S2814 phosphorylation as a potential anti-AF therapeutic target.
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

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 (>500 nm) than between IN concentration and the large aerosol concentration or temperature alone.
Effects of the PDO Phase on the Tropical Belt Width
Authors: Grassi Barbara , Redaelli Gianluca , Canziani Pablo Osvaldo , Visconti Guido
Published: December 2011

Recent studies have shown that the tropical belt (TB) has progressively expanded since at least the late 1970s. This trend has been largely attributed to the radiative forcing due to greenhouse gas (GHG) increase and stratospheric ozone depletion, even if an influence of sea surface temperature (SST) anomalies has been also suggested. The impact of the Pacific decadal oscillation (PDO) on the TB width is investigated in this work. The study is performed by using both Atmospheric Model Intercomparison Project (AMIP) and idealized simulations, produced by the NCAR Community Atmosphere Model, version 3 (CAM3) GCM and reanalysis data [40-yr European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis (ERA-40), ERA-Interim, and Modern-Era Retrospective Analysis for Research and Applications (MERRA)]. Reanalyses show that a switch of the PDO from a positive to a negative phase can lead to a significant TB expansion during the equinoxes. This effect, indicating a possible PDO contribution to the widening that characterized the TB width during the last decades, is not correctly reproduced by model simulations. Deficiencies in the sensitivity of model-simulated convective processes to SST anomalies are suggested as a possible cause of the TB widening underestimation.
Regimes of Diurnal Variation of Summer Rainfall over Subtropical East Asia
Authors: Yuan Weihua , Yu Rucong , Zhang Minghua , Lin Wuyin , Chen Haoming , Li Jian
Published: December 2011

Using hourly rain gauge records and Tropical Rainfall Measuring Mission 3B42 from 1998 to 2006, the authors present an analysis of the diurnal characteristics of summer rainfall over subtropical East Asia. The study shows that there are four different regimes of distinct diurnal variation of rainfall in both the rain gauge and the satellite data. They are located over the Tibetan Plateau with late-afternoon and midnight peaks, in the western China plain with midnight to early-morning peaks, in the eastern China plain with double peaks in late afternoon and early morning, and over the East China Sea with an early-morning peak. No propagation of diurnal phases is found from the land to the ocean across the coastlines. The different diurnal regimes are highly correlated with the inhomogeneous underlying surface, such as the plateau, plain, and ocean, with physical mechanisms consistent with the large-scale “mountain–valley” and “land–sea” breezes and convective instability. These diurnal characteristics over subtropical East Asia can be used as diagnostic metrics to evaluate the physical parameterization and hydrological cycle of climate models over East Asia.
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.
Synoptic Conditions Associated with Propagating and Nonpropagating Cloud/Rainfall Episodes during the Warm Season over the East Asian Continent
Authors: Wang Chung-Chieh , Chen George Tai-Jen , Huang Hsiao-Ling , Carbone Richard E. , Chang Sau-Wa
Published: December 2011

Using European Centre for Medium-Range Weather Forecasts (ECMWF) analyses, this study identifies common synoptic flow patterns associated with propagating (long lived) and nonpropagating (short lived) precipitation/cloud episodes in the warm season over East Asia (25°–40°N, 95°–125°E). Among 123 initial cases during May–July 1997–2003, 86 were classified into three categories (propagating cases with strong and weak forcing, and nonpropagating ones with strong inhibition) consisting of 10 types based on their 500-hPa flow patterns. For each type, composites at various levels when episodes moved across 100°, 105°, 110°, 115°, and 120°E were made and discussed to elucidate the influence of synoptic conditions.

For propagating episodes with strong 500-hPa forcing (46 cases), four types were identified. In their composites, favorable positive vorticity advection forcing from an approaching trough/short wave exists aloft, and concurrent development of southwest vortex and front/wind-shift line at low levels leads to enhanced southwesterly flow to provide vertical shear and moisture. For nonpropagating episodes with strong inhibition (25 cases), three types dominated by synoptic-scale subsidence from either negative vorticity advection or the subtropical high were identified. Thus, episodes weaken shortly after they move out from the Tibetan Plateau. There are also propagating episodes but with weak forcing (15 cases), for which another three types were found. The differences in their composites from nonpropagating types are mainly at low levels, where the southerly flow is stronger and can penetrate deeper inland. As stability conditions are similar for all type of episodes, the results suggest an important role of stronger low-level southwesterly winds in providing moisture and vertical wind shear to sustain episodes and their propagation.
Cholesterol Curves to Identify Population Norms by Age and Sex in Healthy Weight Children
Authors: Skinner Asheley Cockrell , Steiner Michael J. , Chung Arlene E. , Perrin Eliana M.
Published: December 2011

Objective. Develop clinically applicable charts of lipid values illustrating fluctuations throughout childhood and by sex among healthy weight children. Methods. The National Health and Nutrition Examination Survey (1999-2008) was used to estimate total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides by age and sex in healthy weight children age 3 to 17 years. Using LMS procedures, the authors created smoothed curves demonstrating population-based 50th percentile for age and the 75th and 95th percentiles. Results. The curves were based on 7681 children meeting inclusion criteria. Total cholesterol, HDL, and LDL demonstrated peaks at approximately 8 to 12 years for boys. Similar peaks were evident for girls at slightly younger ages, approximately 7 to 11 years. Triglycerides showed peaks for girls, but values were similar across ages for boys. Conclusions. The use of fixed lipid value cutoffs in established guidelines regardless of age or sex likely mislabels many children as abnormal. The authors’ charts may allow for a more nuanced interpretation based on population norms.
Echoing Silence: Backwardness, Governmentality and Voice in Contemporary India
Authors: McDowell Andrew
Published: December 2011

I examine the conceptual trajectory of ‘backwardness’ in policy, politics and rural life to understand the term’s many uses in India. I examine links forged between backwardness and governance in colonial and post-colonial commissions and committees charged with assessing and affecting Indian democracy. Multiple commissions add confusion and ambiguity, setting a variable tone of backwardness in contemporary policies, citizens’ experience and claims-making. I examine the multiple voices that backwardness fosters and silences, engaging debates about mass politics, subjectivity, development and governance.
Force in Our Times
Authors: Jervis Robert
Published: December 2011

Recent world politics displays two seemingly contradictory trends: on the one hand, the incidence of international and even civil war shows a very great decline, but on the other hand the US, and to a lesser extent Britain and France, have been involved in many military adventures since the end of the Cold War. The causes are numerous, but among them is the unipolar structure of world politics, which presents the US with different kinds of threats and new opportunities. Central also is the existence of a security community among the leading states. A number of forces and events could undermine it, but they seem unlikely to occur. Even in this better world, however, recessed violence will still play a significant role, and force, like other forms of power, is most potent and useful when it remains far in the background.