1,721,023 research outputs found
The biological consequences and clinical implications of extracellular histone binding to coagulation Factors I and II
No full textThe Pathological Roles of Neutrophil Extracellular Traps (NETs) in Sepsis
Full text linkNeutrophils are amongst the first immune cells to defend against microbial infection and neutrophil extracellular traps (NETs) formation is an efficient microbicidal mechanism to prevent pathogen dissemination. However, NETs can also cause harm by promoting intravascular thrombosis and organ injury in animal models. Although NETs are recognised as targets for developing new therapeutic strategies, there is currently lack of robust and specific methods to quantify NETs, particularly in clinical settings.
To progress the translational relevance of NETs formation, this thesis establishes a novel assay for quantifying NETs formation and assesses its clinical relevance. To evaluate the pathogenic roles of NETs, complementary in vivo studies were carried out in two septic mouse models, without or with anti-NETs therapy.
The NETs formation assay was initially developed using plasma and sera from septic patients (n=54) admitted to the intensive care units (ICU) of Aintree and Royal Liverpool University Hospitals, or healthy volunteers (n=20). Differentiated neutrophil-like cell line (PLB-985) and isolated healthy (n=10) or patient (n=10) neutrophils were used to investigate the convenient source of neutrophils. Fluorescent staining of extracellular DNA demonstrated that ex vivo NETs formation was induced by directly incubating heterologous neutrophils with plasma or sera from ICU patients, but not normal plasma, unless supplemented with phorbol 12-myristate 13-acetate (PMA). Using this ex vivo NETs assay, critically ill patients can be stratified into 4 groups, absent, mild, moderate and strong NETs formation.
To determine the clinical potential of this assay, the NETs-forming capacity was measured in plasma from a consecutive cohort of prospectively recruited adult ICU patients (n= 341) admitted to the Royal Liverpool University hospital. Strong NETs- forming capacity was predominantly associated with critically ill patients diagnosed with sepsis. In addition, moderate to strong NETs formation was associated with higher sequential organ failure assessment (SOFA) scores on ICU admission and throughout the study duration (three days following admission). Multivariate regression analysis showed after adjusting for Acute Physiology and Chronic Health Evaluation (APACHE) II that measuring the degree of NETs formation in ICU admission could independently predict disseminated intravascular coagulation (DIC) and mortality whereas known NETs degradation markers, could not. High interleukin (IL)-8 levels were strongly associated with NETs-forming capacity of plasma and blocking IL-8 using either an anti-IL-8 monoclonal antibody or inhibitors of CXCR1/2 signaling (using reparixin) significantly attenuated NETs formation.
The pathogenic implications of NETs was determined in two mouse models of sepsis including cecal ligation and puncture (CLP) and intraperitoneal injection of Escherichia coli; sham operated animals or intraperitoneal injection of saline were used as controls. The roles of NETs in both models of sepsis were investigated by depleting neutrophils and treating with DNase I or reparixin.
Both the ex vivo assay and in vivo quantification of NETs showed dramatic increases, particularly in the lungs of septic mice. The agreement of both assays demonstrated that the ex vivo assay reflects in vivo NETs formation. The extent of NETs formation was strongly associated with fibrin deposition and lung injury, both of which were dramatically reduced by neutrophil depletion and DNase I treatment. Macrophage inflammatory protein-2 (MIP-2), the CXCR1/2 ligand in mice, was significantly elevated and correlated to levels of NETs release. Inhibition of CXCR1/2 using reparixin decreased NETs formation, fibrin deposition and multiple organ injury without impairing bacterial clearance, and improved survival in septic mice. This study demonstrates that measuring ex vivo NETs formation induced by plasma, reflects in vivo NETs. Targeting NETs formation using inhibitors of IL-8 signaling may have therapeutic benefit in patients with sepsis
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
The convergent model of coagulation.
No full textIt is increasingly apparent that the pathologic interplay between coagulation and innate immunity, ie, immunothrombosis, forms the common basis of many challenges across the boundaries of specialized medicine and cannot be fully explained by the conventional concepts of cascade and cell-based coagulation. To improve our understanding of coagulation, we propose a model of coagulation that converges with inflammation and innate immune activation as a unified response toward vascular injury. Evolutionarily integral to the convergent response are damage-associated molecular patterns, which are released as a consequence of injury. Damage-associated molecular patterns facilitate diverse interactions within and between systems, not only to complement and reinforce cell-based clot formation but also to steer the response toward clot resolution and wound healing. By extending coagulation beyond its current boundaries, the convergent model aims to deliver novel diagnostics and therapeutics for contemporary and unexpected challenges across medicine, as exposed by COVID-19 and vaccine-induced immune thrombotic thrombocytopenia
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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