bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Acalabrutinib, A Selective Bruton Tyrosine Kinase Inhibitor, with Ibrutinib in Chronic Lymphocytic Leukemia Cells
Authors: Patel Viralkumar , Balakrishnan Kumudha , Bibikova Elena , Ayres Mary , Keating Michael J. , Wierda William G. , Gandhi Varsha
Published: December 2016

Purpose: Ibrutinib inhibits Bruton tyrosine kinase (BTK) by irreversibly binding to the Cys-481 residue in the enzyme. However, ibrutinib also inhibits several other enzymes that contain cysteine residues homologous to Cys-481 in BTK. Patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL) demonstrate a high overall response rate to ibrutinib with prolonged survival. Acalabrutinib, a selective BTK inhibitor developed to minimize off-target activity, has shown promising overall response rates in patients with relapsed/refractory CLL. A head-to-head comparison of ibrutinib and acalabrutinib in CLL cell cultures and healthy T cells is needed to understand preclinical biologic and molecular effects.

Experimental Design: Using samples from patients with CLL, we compared the effects of both BTK inhibitors on biologic activity, chemokine production, cell migration, BTK phosphorylation, and downstream signaling in primary CLL lymphocytes and on normal T-cell signaling to determine the effects on other kinases.

Results: Both BTK inhibitors induced modest cell death accompanied by cleavage of PARP and caspase-3. Production of CCL3 and CCL4 chemokines and pseudoemperipolesis were inhibited by both drugs to a similar degree. These drugs also showed similar inhibitory effects on the phosphorylation of BTK and downstream S6 and ERK kinases. In contrast, off-target effects on SRC-family kinases were more pronounced with ibrutinib than acalabrutinib in healthy T lymphocytes.

Conclusions: Both BTK inhibitors show similar biological and molecular profile in primary CLL cells but appear different on their effect on normal T cells. Clin Cancer Res; 23(14); 3734–43. ©2016 AACR.
Increased Proangiogenic Activity of Mobilized CD34
+
Progenitor Cells of Patients With Acute ST-Segment–Elevation Myocardial Infarction
Authors: Templin Christian , Volkmann Julia , Emmert Maximilian Y. , Mocharla Pavani , Müller Maja , Kraenkel Nicolle , Ghadri Jelena-R. , Meyer Martin , Styp-Rekowska Beata , Briand Sylvie , Klingenberg Roland , Jaguszewski Milosz , Matter Christian M. , Djonov Valentin , Mach Francois , Windecker Stephan , Hoerstrup Simon P. , Thum Thomas , Lüscher Thomas F. , Landmesser Ulf
Published: December 2016

Objective—

Proangiogenic effects of mobilized bone marrow–derived stem/progenitor cells are essential for cardiac repair after myocardial infarction. MicroRNAs (miRNA/miR) are key regulators of angiogenesis. We investigated the differential regulation of angio-miRs, that is, miRNAs regulating neovascularization, in mobilized CD34
+
progenitor cells obtained from patients with an acute ST-segment–elevation myocardial infarction (STEMI) as compared with those with stable coronary artery disease or healthy subjects.

Approach and Results—

CD34
+
progenitor cells were isolated from patients with STEMI (on day 0 and day 5), stable coronary artery disease, and healthy subjects (n=27). CD34
+
progenitor cells of patients with STEMI exhibited increased proangiogenic activity as compared with CD34
+
cells from the other groups. Using a polymerase chain reaction–based miRNA-array and real-time polymerase chain reaction validation, we identified a profound upregulation of 2 known angio-miRs, that are, miR-378 and let-7b, in CD34
+
cells of patients with STEMI. Especially, we demonstrate that miR-378 is a critical regulator of the proangiogenic capacity of CD34
+
progenitor cells and its stimulatory effects on endothelial cells in vitro and in vivo, whereas let-7b upregulation in CD34
+
cells failed to proof its effect on endothelial cells in vivo.

Conclusions—

The present study demonstrates a significant upregulation of the angio-miRs miR-378 and let-7b in mobilized CD34
+
progenitor cells of patients with STEMI. The increased proangiogenic activity of these cells in patients with STEMI and the observation that in particular miR-378 regulates the angiogenic capacity of CD34
+
progenitor cells in vivo suggest that this unique miRNA expression pattern represents a novel endogenous repair mechanism activated in acute myocardial infarction.
Targeting Elastase for Molecular Imaging of Early Atherosclerotic Lesions
Authors: Glinzer Almut , Ma Xiaopeng , Prakash Jaya , Kimm Melanie A. , Lohöfer Fabian , Kosanke Katja , Pelisek Jaroslav , Thon Moritz P. , Vorlova Sandra , Heinze Katrin G. , Eckstein Hans-Henning , Gee Michael W. , Ntziachristos Vasilis , Zernecke Alma , Wildgruber Moritz
Published: December 2016

Objective—

Neutrophils accumulate in early atherosclerotic lesions and promote lesion growth. In this study, we evaluated an elastase-specific near-infrared imaging agent for molecular imaging using hybrid fluorescence molecular tomography/x-ray computed tomography.

Approach and Results—

Murine neutrophils were isolated from bone marrow and incubated with the neutrophil-targeted near-infrared imaging agent Neutrophil Elastase 680 FAST for proof of principle experiments, verifying that the elastase-targeted fluorescent agent is specifically cleaved and activated by neutrophil content after lysis or cell stimulation. For in vivo experiments, low-density lipoprotein receptor–deficient mice were placed on a Western-type diet and imaged after 4, 8, and 12 weeks by fluorescence molecular tomography/x-ray computed tomography. Although this agent remains silent on injection, it produces fluorescent signal after cleavage by neutrophil elastase. After hybrid fluorescence molecular tomography/x-ray computed tomography imaging, mice were euthanized for whole-body cryosectioning and histological analyses. The in vivo fluorescent signal in the area of the aortic arch was highest after 4 weeks of high-fat diet feeding and decreased at 8 and 12 weeks. Ex vivo whole-body cryoslicing confirmed the fluorescent signal to locate to the aortic arch and to originate from the atherosclerotic arterial wall. Histological analysis demonstrated the presence of neutrophils in atherosclerotic lesions.

Conclusions—

This study provides evidence that elastase-targeted imaging can be used for in vivo detection of early atherosclerosis. This imaging approach may harbor potential in the clinical setting for earlier diagnosis and treatment of atherosclerosis.
Adipocyte-Specific Deficiency of NADPH Oxidase 4 Delays the Onset of Insulin Resistance and Attenuates Adipose Tissue Inflammation in Obesity
Authors: Den Hartigh Laura J. , Omer Mohamed , Goodspeed Leela , Wang Shari , Wietecha Tomasz , O’Brien Kevin D. , Han Chang Yeop
Published: December 2016

Objective—

Obesity is associated with insulin resistance and adipose tissue inflammation. Reactive oxygen species (ROS) increase in adipose tissue during the development of obesity. We previously showed that in response to excess nutrients like glucose and palmitate, adipocytes generated ROS via NADPH oxidase (NOX) 4, the major adipocyte isoform, instead of using mitochondrial oxidation. However, the role of NOX4-derived ROS in the development of whole body insulin resistance, adipocyte inflammation, and recruitment of macrophages to adipose tissue during the development of obesity is unknown.

Approach and Results—

In this study, control C57BL/6 mice and mice in which NOX4 has been deleted specifically in adipocytes were fed a high-fat, high-sucrose diet. During the development of obesity in control mice, adipocyte NOX4 and pentose phosphate pathway activity were transiently increased. Primary adipocytes differentiated from mice with adipocytes deficient in NOX4 showed resistance against high glucose or palmitate-induced adipocyte inflammation. Mice with adipocytes deficient in NOX4 showed a delayed onset of insulin resistance during the development of obesity, with an initial reduction in adipose tissue inflammation that normalized with prolonged high-fat, high-sucrose feeding.

Conclusions—

These findings imply that NOX4-derived ROS may play a role in the onset of insulin resistance and adipose tissue inflammation. As such, therapeutics targeting NOX4-mediated ROS production could be effective in preventing obesity-associated conditions, such as insulin resistance.
Body Mass Index and Mortality Among Adults Undergoing Cardiac Surgery
Authors: Mariscalco Giovanni , Wozniak Marcin J. , Dawson Alan G. , Serraino Giuseppe F. , Porter Richard , Nath Mintu , Klersy Catherine , Kumar Tracy , Murphy Gavin J.
Published: December 2016

Background:

In an apparent paradox, morbidity and mortality are lower in obese patients undergoing cardiac surgery, although the nature of this association is unclear. We sought to determine whether the obesity paradox observed in cardiac surgery is attributable to reverse epidemiology, bias, or confounding.

Methods:

Data from the National Adult Cardiac Surgery registry for all cardiac surgical procedures performed between April 2002 and March 2013 were extracted. A parallel systematic review and meta-analysis (MEDLINE, Embase, SCOPUS, Cochrane Library) through June 2015 were also accomplished. Exposure of interest was body mass index categorized into 6 groups according to the World Health Organization classification.

Results:

A total of 401 227 adult patients in the cohort study and 557 720 patients in the systematic review were included. A U-shaped association between mortality and body mass index classes was observed in both studies, with lower mortality in overweight (adjusted odds ratio, 0.79; 95% confidence interval, 0.76–0.83) and obese class I and II (odds ratio, 0.81; 95% confidence interval, 0.76–0.86; and odds ratio, 0.83; 95% confidence interval, 0.74–0.94) patients relative to normal-weight patients and increased mortality in underweight individuals (odds ratio, 1.51; 95% confidence interval, 1.41–1.62). In the cohort study, a U-shaped relationship was observed for stroke and low cardiac output syndrome but not for renal replacement therapy or deep sternal wound infection. Counter to the reverse epidemiology hypotheses, the protective effects of obesity were less in patients with severe chronic renal, lung, or cardiac disease and greater in older patients and in those with complications of obesity, including the metabolic syndrome and atherosclerosis. Adjustments for important confounders did not alter our results.

Conclusions:

Obesity is associated with lower risks after cardiac surgery, with consistent effects noted in multiple analyses attempting to address residual confounding and reverse causation.
Renal Dysfunction Is Associated With Poststroke Discharge Disposition and In-Hospital Mortality
Authors: El Husseini Nada , Fonarow Gregg C. , Smith Eric E. , Ju Christine , Schwamm Lee H. , Hernandez Adrian F. , Schulte Phillip J. , Xian Ying , Goldstein Larry B.
Published: December 2016

Background and Purpose—

Kidney disease is a frequent comorbidity in patients presenting with acute ischemic stroke. We evaluated whether the estimated glomerular filtration rate (eGFR) on admission is associated with poststroke in-hospital mortality or discharge disposition.

Methods—

In this cohort study, data from ischemic stroke patients in Get With The Guidelines–Stroke linked to fee-for-service Medicare data were analyzed. The Modification of Diet in Renal Disease study equation was used to calculate the eGFR (mL/min/1.73 m
2
). Dialysis was identified by
International Classification of Diseases, Ninth Revision
codes. Adjusted multivariable Cox proportional hazards models were used to determine the independent associations of eGFR with discharge disposition and in-hospital mortality. Adjusted individual models also examined whether the association of clinical and demographic factors with outcomes varied by eGFR level.

Results—

Of 232 236 patients, 47.3% had an eGFR ≥60, 26.6% an eGFR 45 to 59, 16.8% an eGFR 30 to 44, 5.6% an eGFR 15 to 29, 0.7% an eGFR<15 without dialysis, and 2.8% were receiving dialysis. Of the total cohort, 11.8% died during the hospitalization or were discharged to hospice, and 38.6% were discharged home. After adjusting for other relevant variables, renal dysfunction was independently associated with an increased risk of in-hospital mortality that was highest among those with eGFR <15 without dialysis (odds ratio, 2.52; 95% confidence interval, 2.07–3.07). An eGFR 15 to 29 (odds ratio, 0.82; 95% confidence interval, 0.78–0.87), eGFR <15 (odds ratio, 0.72; 95% confidence interval, 0.61–0.86), and dialysis (odds ratio, 0.86; 95% confidence interval, 0.79–0.94) remained associated with lower odds of being discharged home. In addition, the associations of several clinical and demographic factors with outcomes varied by eGFR level.

Conclusions—

eGFR on admission is an important predictor of poststroke short-term outcomes.
Predictors and Clinical Impact of Incident Lacunes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy
Authors: Ling Yifeng , De Guio François , Duering Marco , Jouvent Eric , Hervé Dominique , Godin Ophélia , Dichgans Martin , Chabriat Hugues
Published: December 2016

Background and Purpose—

Previous studies in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy showed that accumulation of lacunes strongly relate to clinical severity. However, the potential predictors of incident lacunes and their clinical consequences over a short time frame have not been investigated. This study aimed to determine the predictors and clinical impact of such lesions in a large cohort of patients.

Methods—

Two hundred and six NOTCH3 mutation carriers (mean age, 49.5±10.6 years) were followed up over 3 years. Incident lacunes were identified using difference imaging from 3-dimensional T1 images. Clinical events and change in different clinical scores such as the Mattis Dementia Rating Scale, Modified Rankin Scale, Barthel index, and time to complete part A and part B of Trail Making Test were recorded. Associations were analyzed with multivariable logistic regression analysis and ANCOVA.

Results—

Over a mean period of 3.4±0.7 years, incident lacunes occurred in 51 of 206 patients. Both the number of lacunes (
P
<0.0001) and systolic blood pressure at baseline (
P
<0.01) were independent predictors of incident lacunes during follow-up. The results were still significant after excluding patients with systolic blood pressure >140 mm Hg. Incident lacunes were also associated with incident stroke and with change in time to complete Trail Making Test part B, initiation/perseveration subscale of the Mattis Dementia Rating Scale and Barthel Index over the study period.

Conclusions—

Systolic blood pressure and the number of prevalent lacunes are independent predictors of incident lacunes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. These lesions mainly impact executive performances and functional independence over 3 years.
Meshchera as a Point of Political Interaction between Muscovy and the Tatar World
Authors: Rakhimzianov Bulat R.
Published: December 2016

Meshchera (also known in the historiography as the Kasimov Khanate, in diplomatic sources as the Meshcherskiy iurt) played a special, very specific role in the relations between Muscovy and the Tatar Khanates during the fifteenth through sixteenth centuries. As a kind of specific frontier zone, it was situated within Muscovy and the Muscovite grand prince possessed authority over it, but at the same time, it became widely regarded as a Tatar iurt. For instance, in Crimean eyes, it was a iurt of the Girays and the Shirin clan. It became for some Crimean servitors a home-away-from-home, a colony of sorts, where they came to serve a Gireiid dynast and enjoy material support and opportunities for campaigning. Certain of Nur-Daulet’s (initially a Crimean, then a Kasimov khan) followers moved back and forth between Meshcherskii Gorodok (the capital of Meshchera) and the Crimea. This Tatar enclave, which served for Muscovite rulers as a pattern for other Tatar enclaves of this type (Kashira, Serpukhov, Zvenigorod, Romanov etc.), became an integral part of the steppe appanage system. Muscovite and Tatar political histories overlapped at this point. Although the Kasimov Khanate was not large in size, it figured very prominently in relations between Muscovy (Russia) and the steppe khanates, such as Kazan and the Crimean, as well as the Great and the Nogay Hordes. It, like other iurts of this sort, often acted as a bridge and arbiter of conflict between Orthodoxy Christians and Muslims. The existence of such Tatar enclaves within Muscovite territory influenced Muscovy’s status within the whole of the lands of the later Golden Horde.
The Moscow Olympics and the Role of the Security Services in Late Soviet Politics, 1975–1980
Authors: Young Simon
Published: December 2016

Historians’ understanding of the involvement of the Soviet security services in the orchestration of the Moscow Olympics has heretofore been based on unsubstantiated rumours and anecdotes. Using previously unavailable sources, this article reveals for the first time how the ussr’s coercive apparatus was mobilized to both neutralize perceived threats to Soviet national security produced by the Olympiad and assist the cpsu in using it to promote Soviet socialism in the outside world during the Brezhnev era. The implications of this episode for our understanding of the kgb’s role in late Soviet politics are then considered, and compared with those which arise from a brief reading of the existing literature on the subject.
Epistemological Disjunctivism and the Random Demon Hypothesis
Authors: Lockhart Thomas
Published: December 2016

According to epistemological disjunctivism I can claim to know facts about the world around me on the basis of my perceptual experience. My possession of such knowledge is incompatible with a number of familiar skeptical scenarios (for example, that I am currently being deceived by an evil demon). So a paradigmatic epistemological disjunctivist perceptual experience should allow me to rule out such incompatible skeptical scenarios. In this paper, I consider skeptical scenarios which both cast doubt on my conviction that I can trust my purported perceptual experiences and appear to be compatible with my enjoying a veridical perceptual experience of my environment. Such skeptical scenarios draw attention to a significant difference between McDowell’s epistemological disjunctivism and Pritchard’s. McDowellian epistemological disjunctivism has the resources to rule out such skeptical scenarios but Pritchard’s does not. This is because the Pritchardian epistemological disjunctivist does not, unlike McDowell, insist on the idea that perception is a fallible capacity, self-consciously exercised and possessed, for knowledge.
Studying Russia’s Authoritarian Turn
Authors: Smyth Regina
Published: December 2016

Between 2011 and 2016, the Kremlin altered its strategy to maintain elite coherence and shore up social support. The papers presented in this volume argue that these changes in formal rules, informal practices, state policy, and ideational narratives constituted a second authoritarian turn since 2000. In comparison to the first regime shift in the mid-2000s this strategic change combined tactics designed redefine the Kremlin’s core support and construct electoral majorities that could deliver victories in the 2016 national parliamentary election and the 2018 presidential election. While the outcome of the 2016 election suggests overwhelming regime success, these papers raise important questions about the long-term efficacies of these strategies, their unintended consequences, and the contradictions that are evident in social attitudes. In the context of the growing literature on contemporary autocracy, these papers present a strong case for increased focus on social attitudes and behaviors as well as the ideational and informal elements of the state’s mechanisms to maintain regime stability.
Navalny’s Gamesters: Protest, Opposition Innovation, and Authoritarian Stability in Russia
Authors: Smyth Regina , V. Soboleva Irina
Published: December 2016

This paper explores the legacy of the For Fair Elections (ffe) protest movement in 2011–2012 for electoral competition in Russia. We argue that through strategic innovation, oppositions in authoritarian countries can challenge the autocratic state on multiple fronts by transferring resources from street protests to the electoral arena. Our empirical focus is on Alexei Navalny’s campaign for Moscow mayor in late summer 2013. The successful mass mobilization in the movement enabled the campaign to implement a model of electoral innovation based on ideational frames, resources, and tactics drawn from the protest movement. Voter response was stronger than expected, demonstrating the persistence of voter opposition in the face of genuine electoral choice. Relying on press reports, blogs, campaign materials and interviews with activists, we investigate the campaign’s strategy and show why it presented a particular challenge to the regime. Our conclusion underscores the state’s advantage in countering elite opposition innovation, but also highlights how effective opposition innovation can lead to significant changes in strategies to maintain regime stability.
Russian Media in the Digital Age: Propaganda Rewired
Authors: Oates Sarah
Published: December 2016

This article reflects on the role of media in the Russian Federation through the concept of “rewired propaganda.” The approach highlights how the Russian regime copes with challenges to its information hegemony in the digital age. The study employs two critical case studies to examine the Russian political communication sphere: the 2011–12 election protests and the downing of Malaysia Airlines Flight 17 by a Russian missile in 2014. The article argues that a key vector of analysis is understanding strategic narrative as the critical measurement of media control. The findings suggests that it is not so much who owns or controls the media that is key to understanding information control; rather, it is knowing who is constructing and disseminating the most compelling national narrative that holds the key to power in Russia. This focus on rewired propaganda and recasting of the debate will permit an analysis of the role of the media in the post-Soviet state even as the overall media environment has shifted with the advent of the digital age. On balance, the two case studies demonstrate that Russian elites have continued to adapt to growing challenges, showing an ability to use many facets of communication to consolidate an information dominance over citizens.
A novel mechanism regulating human platelet activation by MMP-2–mediated PAR1 biased signaling
Authors: Sebastiano Manuela , Momi Stefania , Falcinelli Emanuela , Bury Loredana , Hoylaerts Marc F. , Gresele Paolo
Published: December 2016

Key Points

Active MMP-2 enhances platelet activation by cleaving PAR1 at an extracellular site different from the thrombin cleavage site. The novel PAR1-tethered ligand exposed by MMP-2 selectively stimulates PAR1-dependent Gq and G12/13 pathway activation.
How I treat anemia in pregnancy: iron, cobalamin, and folate
Authors: Achebe Maureen M. , Gafter-Gvili Anat
Published: December 2016

Anemia of pregnancy, an important risk factor for fetal and maternal morbidity, is considered a global health problem, affecting almost 50% of pregnant women. In this article, diagnosis and management of iron, cobalamin, and folate deficiencies, the most frequent causes of anemia in pregnancy, are discussed. Three clinical cases are considered. Iron deficiency is the most common cause. Laboratory tests defining iron deficiency, the recognition of developmental delays and cognitive abnormalities in iron-deficient neonates, and literature addressing the efficacy and safety of IV iron in pregnancy are reviewed. An algorithm is proposed to help clinicians diagnose and treat iron deficiency, recommending oral iron in the first trimester and IV iron later. Association of folate deficiency with neural tube defects and impact of fortification programs are discussed. With increased obesity and bariatric surgery rates, prevalence of cobalamin deficiency in pregnancy is rising. Low maternal cobalamin may be associated with fetal growth retardation, fetal insulin resistance, and excess adiposity. The importance of treating cobalamin deficiency in pregnancy is considered. A case of malarial anemia emphasizes the complex relationship between iron deficiency, iron treatment, and malaria infection in endemic areas; the heightened impact of combined etiologies on anemia severity is highlighted.
Abnormal joint and bone wound healing in hemophilia mice is improved by extending factor IX activity after hemarthrosis
Authors: Sun Junjiang , Hua Baolai , Livingston Eric W. , Taves Sarah , Johansen Peter B. , Hoffman Maureane , Ezban Mirella , Monroe Dougald M. , Bateman Ted A. , Monahan Paul E.
Published: December 2016

Key Points

Joint and bone healing abnormalities are demonstrated in hemophilic mice that are not solely because of the amount of blood in their joints. Following initial hemostasis, extended FIX activity is needed in the week after hemarthrosis to normalize osteochondral healing.
Comparison of a teratogenic transcriptome-based predictive test based on human embryonic versus inducible pluripotent stem cells
Authors: Shinde Vaibhav , Perumal Srinivasan Sureshkumar , Henry Margit , Rotshteyn Tamara , Hescheler Jürgen , Rahnenführer Jörg , Grinberg Marianna , Meisig Johannes , Blüthgen Nils , Waldmann Tanja , Leist Marcel , Hengstler Jan Georg , Sachinidis Agapios
Published: December 2016

Background

Human embryonic stem cells (hESCs) partially recapitulate early embryonic three germ layer development, allowing testing of potential teratogenic hazards. Because use of hESCs is ethically debated, we investigated the potential for human induced pluripotent stem cells (hiPSCs) to replace hESCs in such tests.

Methods

Three cell lines, comprising hiPSCs (foreskin and IMR90) and hESCs (H9) were differentiated for 14 days. Their transcriptome profiles were obtained on day 0 and day 14 and analyzed by comprehensive bioinformatics tools.

Results

The transcriptomes on day 14 showed that more than 70% of the “developmental genes” (regulated genes with > 2-fold change on day 14 compared to day 0) exhibited variability among cell lines. The developmental genes belonging to all three cell lines captured biological processes and KEGG pathways related to all three germ layer embryonic development. In addition, transcriptome profiles were obtained after 14 days of exposure to teratogenic valproic acid (VPA) during differentiation. Although the differentially regulated genes between treated and untreated samples showed more than 90% variability among cell lines, VPA clearly antagonized the expression of developmental genes in all cell lines: suppressing upregulated developmental genes, while inducing downregulated ones. To quantify VPA-disturbed development based on developmental genes, we estimated the “developmental potency” (D
p
) and “developmental index” (D
i
).

Conclusions

Despite differences in genes deregulated by VPA, uniform D
i
values were obtained for all three cell lines. Given that the D
i
values for VPA were similar for hESCs and hiPSCs, D
i
can be used for robust hazard identification, irrespective of whether hESCs or hiPSCs are used in the test systems.
IL-10 distinguishes a unique population of activated, effector-like CD8+ T cells in murine acute liver inflammation
Authors: Rood Julia E , Canna Scott W , Weaver Lehn K , Tobias John W , Behrens Edward M
Published: December 2016

Immune-mediated liver injury is a central feature of hyperinflammatory diseases, such as hemophagocytic syndromes, yet the immunologic mechanisms underlying those processes are incompletely understood. In this study, we used the toll-like receptor 9 (TLR9)–mediated model of a hemophagocytic syndrome known as macrophage activation syndrome (MAS) to dissect the predominant immune cell populations infiltrating the liver during inflammation. We identified CD8+ T cells that unexpectedly produce interleukin-10 (IL-10) in addition to interferon-γ (IFN-γ) as a major hepatic population induced by TLR9 stimulation. Despite their ability to produce this anti-inflammatory cytokine, IL-10+ hepatic CD8+ T cells in TLR9–MAS mice did not resemble CD8+ T suppressor cells. Instead, the induction of these cells occurred independently of antigen stimulation and was partially dependent on IFN-γ. IL-10+ hepatic CD8+ T cells demonstrated an activated phenotype and high turnover rate, consistent with an effector-like identity. Transcriptional analysis of this population confirmed a gene signature of effector CD8+ T cells yet suggested responsiveness to liver injury–associated growth factors. Together, these findings suggest that IL-10+ CD8+ T cells induced by systemic inflammation to infiltrate the liver have initiated an inflammatory, rather than regulatory, program and may thus have a pathogenic role in severe, acute hepatitis.
Inducible targeting of CNS astrocytes in Aldh1l1-CreERT2 BAC transgenic mice
Authors: Winchenbach Jan , Düking Tim , Berghoff Stefan A. , Stumpf Sina K. , Hülsmann Swen , Nave Klaus-Armin , Saher Gesine
Published: December 2016

Background: Studying astrocytes in higher brain functions has been hampered by the lack of genetic tools for the efficient expression of inducible Cre recombinase throughout the CNS, including the neocortex. Methods: Therefore, we generated BAC transgenic mice, in which CreERT2 is expressed under control of the Aldh1l1 regulatory region. Results: When crossbred to Cre reporter mice, adult Aldh1l1-CreERT2 mice show efficient gene targeting in astrocytes. No such Cre-mediated recombination was detectable in CNS neurons, oligodendrocytes, and microglia. As expected, Aldh1l1-CreERT2 expression was evident in several peripheral organs, including liver and kidney. Conclusions: Taken together, Aldh1l1-CreERT2 mice are a useful tool for studying astrocytes in neurovascular coupling, brain metabolism, synaptic plasticity and other aspects of neuron-glia interactions.
Diurnal cycle of ozone throughout the troposphere over Frankfurt as measured by MOZAIC-IAGOS commercial aircraft
Authors: Petetin H. , Thouret V. , Athier G. , Blot R. , Boulanger D. , Cousin J.-M. , Gaudel A. , Nédélec P. , Cooper O.
Published: December 2016

Ozone is generally assumed to have weak diurnal variations in the free troposphere due to lower production rates than in the boundary layer, in addition to a much lower NO titration and the absence of dry deposition at the surface. However, this hypothesis has not been proven due to a lack of high frequency observations at multiple times per day. For the first time, we take benefit from the frequent O3 vertical profiles measured above Frankfurt in the framework of the MOZAIC-IAGOS program to investigate the diurnal variations of O3 mixing ratios at multiple pressure levels throughout the troposphere. With about 21,000 aircraft profiles between 1994 and 2012 (98 per month on average), distributed throughout the day, this is the only dataset that can allow such a study. As expected, strong diurnal variations are observed close to the surface, in particular during spring and summer (enhanced photochemistry and surface deposition). Higher in altitude, our observations show a decrease of the diurnal cycle, with no diurnal cycle discernible above 750 hPa, whatever the season. Similar results are observed for the different percentiles of the O3 distribution (5th, 25th, 50th, 75th, 95th). An insight of the changes of the diurnal cycles between 1994–2003 and 2004–2012 is also given. We found higher O3 mixing ratios during the latter period, particularly on the lowest pressure levels, despite lower mixing ratios during summer.
Reflections of Research
Authors: Wilkinson Robert
Published: December 2016

The British Heart Foundation (BHF) annual image competition, Reflections of Research, provides a glimpse into the cutting-edge research that the BHF funds
Mental health in carers with cardiovascular disease
Authors: Shiue Ivy
Published: December 2016

Background:

Little is known about the mental health of carers who have physical health conditions. This study aimed to investigate the prevalence and characteristics of adult carers with and without cardiovascular disease and their mental health status in Scotland's population using an independent dataset.

Methods:

Data from the Scottish Health Surveys for 2012 and 2013 were analysed. Information on demographics, lifestyle, regular care provided and mental health was obtained. Chi-square tests, t-tests and survey-weighted logistic and multinomial regression modelling were performed to test the associations among the study variables, between the exposure and the outcome accordingly.

Results:

The percentage of people providing care in the entire study sample (n=1721; 17.7%) is similar to those with cardiovascular disease (n=662; 18.0%) and those without (n=1059; 17.5%). The Scottish regions with the highest proportion of adult carers are Borders, Orkney and Lanarkshire. Carers with cardiovascular disease were more likely to lose sleep over anxiety and feel constantly under strain than patients who do not provide care. Mental health appeared to be worse in Scottish carers without cardiovascular disease than in those with such conditions.

Conclusion:

A longitudinal study could monitor the changes in both mental health and cardiovascular disease status and how they are associated. Continuous support in the community for all Scottish carers with and without any long-term conditions should be considered.
Examining platelets to establish new heart disease therapies
Authors: Palmer Sarah Jane
Published: December 2016

This section presents a variety of conditions, treatments, clinical procedures and developments in the field of cardiovascular care. It aims to update and refresh nurses' knowledge on correct theory and practice, as well as introduce students and junior nurses to aspects of practice
Part 2: Oral health care for the housebound patient
Authors: Critchlow Diana
Published: December 2016

Oral disease can have a significant impact on the health and wellbeing of the housebound patient. The aetiology of oral conditions such as dental caries and periodontal disease have been well investigated and there is a solid evidence base in how to best prevent their progress. The Department of Health document Delivering better oral health: an evidence-based toolkit for prevention is a valuable resource that outlines the current best preventative evidence in the form of practical advice for clinicians and patients. This article aims to distil and present this advice for the benefit of community nurses. It will identify areas of particular importance for people with additional needs, particularly the elderly and infirm. Outlining how to best tailor preventative advice and treatment for this patient group.
STORAGE MANAGEMENT OF CLINICAL RESEARCH SUPPLIES OF A PHASE IIB/III, NATIONAL, MULTI-CENTRE, DOUBLE-BLIND AND RANDOMIZED STUDY
Authors: Kawamoto Junior Luiz Teruo , Da Silva Adriano Maniçoba , Ferreira William De Paula , Rodrigues Enio Fernandes , Harada Lila M.
Published: December 2016

Abstract:  New drugs suffer a long and slow proceeding to reach the market. On the one hand there are difficulties from the regulatory agency that delays the onset of clinical trial studies, on the other hand there is a slow patient recruitment during the course of the trial that prevents its completion. An efficient management of clinical trial supplies throughout the supply chain is essential. Thus, the objective of this study was to characterize the clinical supplies storage management in a national, multi-centre, double-blind and randomized study to evaluate the efficiency and safety of a combination of drugs to treat acute pain. The study was primarily focused on storage conditions of clinical supplies, detailing their distribution to the research sites. According to the data observed in this study, the clinical supplies storage management was not determinant for the slow patient recruitment process that reflected the delay to the end of the study. And although the centers were located in different states, there were no delays, loss or damage during storage and distribution that could compromise the proper stock and storage management of clinical trial supplies.
The effect of computer-assisted foreign language teaching on the student’s attitude and success
Authors: Kocaman Orhan , İskender Murat
Published: December 2016

This research was carried out to determine the impact of computer-assisted teaching on teaching English. The first phase of the research was designed as an experiment and computer-assisted teaching and traditional teaching methods were conducted synchronically in two different groups. In the second phase, effects of variables such as gender, age, receiving private lesson and types of high schools of the students who attended the implementation were analysed.The sample of the research consisted of 40 first year undergraduate students from the first bachelor’s level program and another 40 from the second bachelor’s level program   in the Department of Computer Education and Instructional Technology in the Faculty of Education at Sakarya University in 2003-2004 academic year fall semester.  The students of the first bachelor’s level program were assigned to be the control group and the students of the second bachelor’s level program were assigned to be the experimental group. The experimental group was given the computer-assisted lessons for twelve weeks but traditional teaching methods were meanwhile used in the classes of the control group. The experimental group used a compact disc in the laboratory as an educational material, which was prepared by the researcher.Data for attitude evaluation were gathered by questionnaires and success was evaluated through students’ examination grades. In determining the success rate, pre-test and post-test grades were used as the data.At the end of the research, the results revealed that traditional teaching methods caused the students grouped according to the variables such as gender, age, private lessons and types of high schools to develop a negative attitude towards English lessons whereas computer-assisted teaching method led the students to develop a positive attitude. Although it was observed that traditional teaching methods made a positive impact on the success of the students in English classes, this impact was weaker than computer-assisted teaching did in the other group. The students who studied English in computer-assisted teaching classes showed a more positive attitude towards English classes than the ones who studied English using traditional teaching methods.
The teaching of pragmatics by native and nonnative language teachers: What they know and what they report doing
Authors: Cohen Andrew D.
Published: December 2016

The paper focuses on how nonnative teachers of a target language (NNTs) deal with pragmatics in their classes. It starts with a discussion of what pragmatics entails. Next, issues relating to the teaching of pragmatics are identified, such as the language background of the teacher, comparisons between second- (L2) and foreign-language (FL) instruction, and the potential role of digital media and other means in providing models for pragmatic behavior. Then, an international survey is presented which probed into the experiences of NNTs of various languages while teaching the pragmatics of their language of instruction. A total of 113 teachers were asked to indicate what they taught with regard to pragmatics, 30 native-language teachers (NTs) and 83 NNTs. They were also asked to report on their experience as teachers of L2 and FL pragmatics (e.g., if they encountered classroom moments when they did not feel like an authority on some aspect of pragmatics, what they did about it). Since pragmatics is a meeting of language and culture, the teacher respondents were asked to assess their knowledge regarding pragmalinguistics (i.e., the language forms) and sociopragmatics (sociocultural knowledge). In addition, they were asked to give their opinion regarding similarities and differences between the teaching of FL as opposed to L2 pragmatics, as this traditional dichotomy gives way to a more hybrid reality in an increasingly globalized world. Similarly, they were asked about their methods for teaching pragmatics (e.g., their use of digital media and their handling of dialect differences). Finally, they were asked to suggest areas in which they would like to see research conducted that would inform the teaching of pragmatics. The paper reports the findings from the study, including statistical differences in reported teaching of criticism, sarcasm, and cursing, as well as in the use of digital media and in having students gather data on pragmatics.
Dynamics of classroom WTC: Results of a semester study
Authors: Mystkowska-Wiertelak Anna
Published: December 2016

The fact that L2 willingness to communicate (WTC) can fluctuate over different time scales is no longer disputed as numerous studies have proved a dynamic rather than trait-like character of the concept (cf. MacIntyre & Legatto, 2011; MacIntyre, Burns, & Jessome, 2011; Mystkowska-Wiertelak & Pawlak, 2014). The changes in the intensity of L2 learners’ readiness to engage in communication in the classroom context have been investigated in a number of studies attempting also to establish factors capable of stimulating or hindering WTC (e.g., Cao & Philip, 2006; Pawlak & Mystkowska-Wiertelak, 2015; Peng, 2014). Many of empirical explorations of L2 learners’ WTC, although representing the ecological perspective, provide solely a snapshot of classroom reality, thus generating a question if such one-at-a-time picture frame can sufficiently accommodate diverse factors that impinge on learners’ readiness to engage in communication. The application of a longitudinal design was thus dictated by the author’s intention to gather information on WTC ebbs and flows not only during single lessons but also continuing over a number of lessons conducted throughout a semester of study, which allowed for exploring a wider spectrum of conditions that affect WTC of advanced learners of English attending speaking classes. Detailed lesson plans, interview and questionnaire data were used to interpret WTC fluctuations reported by the participants at 5-min intervals in the course of 7 lessons. Qualitative and quantitative analysis of the data revealed that the intensity of communicative behaviour depends on an intricate interplay of personal and group-related factors, with a special role ascribed to the instructor whose knowledge of the group characteristics and needs coupled with didactic skills can greatly contribute to increasing WTC in the classroom.
Critical thinking in the intercultural context: Investigating EFL textbooks
Authors: Sobkowiak Paweł
Published: December 2016

The multicultural world has made intercultural teaching necessary. It should focus on students’ ability to comprehend quickly and accurately, and then act appropriately and effectively in a culturally complex environment in order to achieve the desired goal. Intercultural competence is important for successful communication across cultures, and so is critical thinking since the two, if they are not “parallel” (Bennett, 2013), at least overlap (Deardorff, 2009). This article tries to shed light on the linkage between intercultural and critical thinking skills and reports on the findings of research done on whether and to what extent EFL textbooks used in Polish schools contribute to fostering critical thinking skills in students. The study analyzed the cultural content of 20 coursebooks to check whether they go beyond merely depicting the target culture, or various foreign cultures, and involve students in practicing critical thinking, that is, prompt them to explore intercultural encounters and processes, and scrutinize how diverse cultures influence their own understanding of reality. The research revealed an insignificant and limited capacity of the textbooks to develop students’ critical thinking.
Review of Written corrective feedback for L2 development; Authors: John Bitchener, Neomy Storch; Publisher: Multilingual Matters, 2016; ISBN: 9781783095032; Pages: 156
Authors: Pawlak Mirosław
Published: December 2016

Book review
Value-Focused Thinking Model to Evaluate SHM System Alternatives From Military end User Requirements Point of View
Authors: Klimaszewski Sławomir
Published: December 2016

The article describes Value-Focused Thinking (VFT) model developed in order to evaluate various alternatives for implementation of Structural Health Monitoring (SHM) system on a military aircraft. Four SHM system alternatives are considered based on: visual inspection (current approach), piezoelectric (PZT) sensors, Fiber Bragg Grating (FBG) sensors and Comparative Vacuum Monitoring (CVM) sensors. A numerical example is shown to illustrate the model capability. Sensitivity analyses are performed on values such as Cost, Performance, Aircraft Availability and Technology Readiness Level in order to examine influence of these values on overall value of structural state of awareness provided by particular SHM system alternative.
Exemplification of Tomographic Method to Evaluate the Quality of Welded Joints Made from EN 5754-H22 Alloy
Authors: Błachnio Józef , Kułaszka Artur , Chalimoniuk Marek , Woźny Piotr
Published: December 2016

The quality of welded joints depends on many factors. The relevant standards stipulate technical conditions of welds quality assessment, which provides the basis for stating whether the given joint is compatible with the requirements or whether it is defective. In practice, making welded joints that are totally devoid of defects is extremely difficult. To conduct the control of inner structure of the given joint a non-destructive method with the application of industrial CT scanner might be applied. This modern diagnosing method combines the x-ray examination with advanced computer technology. The basic advantage of computer-assisted tomography consists in examining objects in three dimensions and the possibility to carry out three-dimensional reconstructions. The aim of this article is to discuss the use of this method to evaluate the quality of welded joints made of aluminium alloys. Capabilities of computer-assisted tomography were depicted by the case of weld probes constructed with TIG (ang. Tungsten Inert Gas) welding by different process variables. One has made the analysis of the quality of probes showing the smallest and the biggest internal and external welding defects.
The Selected Problems of Studies of Aircraft Landing Gear
Authors: Rośkowicz Marek , Leszczyński Piotr
Published: December 2016

The article portrays the results of experimental studies conducted in the field of static strength test of main landing gear of lightweight aircraft as well as in the area of establishing the pneumatic tyre characteristics of main landing gear. The studies were carried out in compliance with methodologies of performing studies for the purposes of solutions implemented in aviation structures. It was stated that static strength tests of landing gear should not be done with the use of shock absorbers, due to the fact that this element, distinguished by high viscoelastic properties, by being statically loaded, is subject to displacements that do not occur during normal operation of the aircraft. Excessive displacements of shock absorber result in the load distribution in other landing gear elements being incompatible with project assumptions, which in turn leads to this strength test being interrupted, bearing in mind significantly lower loads than anticipated. It was also concluded that in order to determine pneumatic tyre characteristics it is not necessary to carry out tests on the whole landing gear strut, because the results obtained in the compression test of the wheel itself with pneumatic tyre are identical as the results acquired during tests conducted in accordance with methodology. Test preparation process with the use of the wheel itself and its realization is less time-consuming, less expensive and does not entail the necessity to build complex test stands.