1,721,024 research outputs found
Immunomodulatory effect of specialised pro-resolving mediators in humans
Full text linkInflammation is a protective response but if dysregulated it can lead to chronic inflammatory conditions. Currently, these diseases are treated by inhibiting the factors that drive inflammation but such treatments can interfere with the tissue healing processes, e.g. NSAIDs or impair antimicrobial immunity, e.g. corticosteroids and biologics. Resolution is the other end of inflammatory spectrum and has been demonstrated to be an active process mediated by specific cellular events, soluble mediators and their receptors, that provide counter-regulatory signals to switch inflammation off. In this regard, specialised pro-resolving lipid mediators (SPMs), as effector molecules of resolution have shown promise as a novel therapeutic option to treat dysregulated inflammation. However, research supporting beneficial effect of SPMs has been largely conducted in murine models and there is a need to translate it for patient benefit. A human model of resolution of inflammation can facilitate investigation of the pharmacological action of SPM based therapies and their comparison with known anti-inflammatory agents. To attain this objective, I first performed a detailed characterisation of cantharidin skin blister model and learnt that neutrophil clearance, an important sign of resolution, can be affected by stromal scaffold around inflammatory contents. Therefore, I developed a novel model of self-resolving acute inflammation triggered by intradermal injection of UV killed E. coli bacteria (UVkEc), where local inflammatory exudate was acquired into a suction blister raised during onset and resolution phases of inflammatory response. UVkEc triggered self-resolving dermal inflammation model allowed appreciation of quantifiable indices of resolution such as clearance of neutrophils, reduction of inflammatory stimulus, pro-inflammatory cytokines and lipid mediators as well as vascular hyperaemia. In addition, I identified the presence of different classes of SPMs and their receptors at the junction between onset and resolution. Using this model, I showed that local therapeutic supplementation of SPMs, in physiological dose range, reduced neutrophil numbers during resolution but had modest effect on clearance of the inflammatory stimulus, reduction of pro-inflammatory cytokines or switch of macrophages to a pro-resolving phenotype. In another approach, I demonstrated that an oral, SPM inducing small molecule, JBT-101, a CB2 receptor agonist (chemical name: ajulemic acid) inhibited neutrophil numbers at onset coincident with enhanced clearance of inflammatory stimulus and reduction in levels of leukotriene B4, prostanoids and IL-8. It also increased the levels of the SPMs including lipoxin A4, resolvin D1 and resolvin D3 during resolution. However, there was lack of correlation between the rise in SPMs and the effect of JBT-101 on resolution indices and there was no inverse correlation between levels of SPMs and neutrophil numbers during onset or resolution. Using UVkEc triggered self-resolving dermal inflammation model as a tool, this thesis demonstrates that in humans, effect of SPMs, at physiological doses, may be limited only to enhancing neutrophil clearance. It also shows that orally active SPM inducing molecule, JBT-101, at doses currently being employed in phase II clinical trials, has a potent anti-inflammatory effect and uncovers that its main mechanism is possibly via inhibiting the pro-inflammatory mediators than by inducing SPMs. Investigation of effect of pro-resolving therapies on resolution indices in humans can inform their future clinical development
The Role of Prostaglandin E2 in Critical Illness-Induced Immune Dysfunction
Full text linkDysregulation of the inflammatory profile in magnitude or duration following severe infectious or sterile insults including sepsis, burn and trauma is associated with a period of immunoparalysis, the acquisition of hospital acquired-infections and an associated increase in mortality. Prostaglandin E2 (PGE2), a cyclooxygenase (COX)-derived eicosanoid classically regarded as pro-inflammatory, regulates multiple aspects of the immune response and has been ascribed a causal role in immunoparalysis during alternate disease states. Systematic review of the clinical literature relating COX-inhibiting non-steroidal anti-inflammatory drugs (NSAIDs) use with either susceptibility to or outcome from acute infection revealed epidemiological evidence of benefit from NSAID administration during severe inflammatory states (sepsis), but not minor infection, providing a rationale for investigation of a mechanistic contribution to critical illness-induced immune dysfunction (CIIID). PGE2, at pathophysiologically relevant concentrations (IC50 317pg/mL, 95% CI 105 – 959pg/mL), suppressed ex vivo whole blood (WB) cytokine secretion: a validated measure of clinically relevant immune dysfunction. EP4 receptor-mediated increase in intracellular cyclic adenosine monophosphate (cAMP) was determined as the principal pathway, antagonism of which afforded an alternate immunorestorative strategy to established immunoadjuvant agents (interferon-γ and granulocyte-macrophage colony stimulating factor). A complementary in vitro bioassay of PGE2-mediated monocyte deactivation employing 1α, 25 dihydroxycholecalciferol differentiated (vitamin D3, 10ng/ml) Mono Mac 6 (MM6), a human cell line, mirrored this response. Pre-clinical evaluation of an association between PGE2 release during the systemic inflammatory response syndrome (SIRS) and subsequent immunoparalysis using the human intravenous endotoxin model (2ng/kg), however neither confirmed this link, nor refuted it, failing to replicate key immunological features of CIIID (sustained reduction in monocyte HLA-DR expression, WB cytokine secretion and absolute lymphocyte count). Mass spectroscopic analysis of plasma revealed significant elevation of COX-derived PGF2α, thromboxane A2 and PGE2, the latter peaking at 3hours, 7.8x higher than baseline values (10pg/mL compared to 1.3pg/mL). These did not suppress MM6 cytokine release. Compelling arguments suggest PGE2 contributes to CIIID. Alternative or adapted techniques will be required to determine the validity of this premise, potentially identifying a novel therapeutic immunorestorative strategy in the critically ill
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
Rheumatoid arthritis and SLE
No full textA 60-year-old man presented with a 4-week history of a gradually worsening ankle pain and swelling. He gave no history of morning stiffness, or symptoms in any other joints. There was no preceding history of infection (including of the gastrointestinal or genitourinary tract) and no history of previous inflammatory disease (including the skin and eye). There was a family history of rheumatoid arthritis with his daughter having been diagnosed with this condition at the age of 30. He smoked 10 cigarettes per day and drank 6 units of alcohol per week. He had been treated with diclofenac by his primary care physician but had derived little benefit from this. On examination, he had tenderness with clinically apparent synovial swelling at the left ankle (Figure 22.1A). The remainder of the physical examination was normal. The differential diagnosis of an inflammatory monoarthritis includes septic arthritis and crystal arthritis and to exclude these diagnoses the patient underwent an ultrasound guided joint aspiration (Figure 22.2). No organisms were identified on synovial fluid microscopy or culture and no crystals were seen on polarized light microscopy. Further investigations revealed the following: ESR 16 mm/h, CRP 17 mg/L (normal < 5 mg/L), rheumatoid factor 72 IU/mL (positive > 20 IU/ mL), anti-CCP antibody 81 U/mL (positive > 10 U/mL), chest radiograph normal
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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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