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Cellular and molecular mechanisms underlying the regulation of IL-10 expression in human CD4+ T cellsRoberts, Ceri Anne January 2017 (has links)
No description available.
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A micro-macro sense-making model for knowledge creation and utilization in healthcare organizationsLam, Louisa Mei Chun January 2014 (has links)
The purpose of this research is to study how new knowledge is created, used, and shared at both micro- and macro- levels in healthcare organizations so as understand how this can improve evidence-based practice and provide new roles for information professionals to better EBM and clinical decision-making. Using Dervin's SMM as the primary research framework, supplemented with Snowden's Cynefin Framework for data analysis, the results demonstrated that individual knowledge was created in the gap-bridging process as the sense-making moment. Situation movement state and gap-bridging strategies were two predictors for knowledge creation. The knowledge gaps were identified and a wide range of gap-bridging strategies were employed to cross the gaps and create new knowledge. This micro process of knowledge creation is linked to the organizational level thorough knowledge sharing. This whole process of knowledge creation, utilization and sharing were mapped into a new micro-macro sense-making model, showing all the barriers and enablers identified in this research. These findings have filled the missing gaps in the literature and answered the long-standing question of how new knowledge is created in organizations. These findings would be able to shed new light to the practice of EBM. Some possible ways are to shift the attention to the use of medical knowledge, place more emphasis to the use of case-based reasoning approach, develop personalized medicine, and raise the importance of narratives in clinical practice. The new roles for information professionals in support for KM include: 1) the provision of different case-based reasoning systems; 2) use of IT tools in KM to assist clinicians to make sense of the situation; 3) taking user-centered verbing approach to organize knowledge sources; 4) building up expertise network; 5) use of narratives and storytelling for knowledge sharing; 6) engaging in virtual communities of practice; and 7) equipping library space to facilitate learning.
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Recognition of facial expressions of pain using spatial frequency informationWang, Shan January 2017 (has links)
Individuals’ pain experiences can be communicated both verbally and non-verbally. Facial expressions are a primary non-verbal channel of pain communication, and so need to be clearly and unambiguously recognised and differentiated from other non-noxious emotional expressions. It is known that we are able to identify others’ pain from their facial expressions in an accurate and efficient manner, even under challenging visual conditions. However, little is known about how facial expressions are processed by observers, and what information is actually used, to make the identification of pain possible. To account for this, the current thesis considered facial expressions as a type of visual stimulus and investigated possible mechanisms that underpin the recognition of pain expressions from the perspective of perceptual information analysis. Spatial frequency (SF) information is a type of fundamental perceptual information that encodes different characteristics of a visual display. For a facial expression, low-SF information conveys the large-scale facial configuration and structural changes, whereas high-SF information depicts the fine details of facial features. In order to understand how we recognise pain expressions in terms of SF analysis, a series of experiments were conducted within this thesis to primarily investigate the role of low-SF and high-SF information in the recognition of pain expressions (Experiment 1–4), and the temporal feature of low-SF and high-SF information processing in pain recognition (Experiment 5–7). Data of this thesis revealed that although pain expressions could be recognised with either low-SF or high-SF information available, low-SF information plays a prominent role that leads to more accurate judgements (Experiment 1) and is preferentially perceived by observers (Experiment 2–4). Moreover, the processing of low-SF information shows a temporal advantage over high-SF information (Experiment 5). Pain expressions presented with low-SF information only was decoded more rapidly than those presented with high-SF (Experiment 6), and the asynchrony between low-SF and high-SF processing originated from a very early stage of information extraction (Experiment 7). Therefore, the decoding of low-SF pain expressions is not only faster in duration but also precedes the decoding of high-SF pain. Altogether, these findings suggest that when we differentiate facial expressions of pain from non-noxious emotions, the coarse low-SF information plays a key role by providing a preliminary understanding of the overall quality of pain expressions rapidly, and the fine-detailed high-SF information is integrated at a later stage and plays a trivial role. More interestingly, this pattern was found not only for the recognition of pain expressions, but also the core emotions investigated, which suggests that expressions of pain and core emotions share similar visual perceptual properties. This thesis provides a visuoperceptual account of how we recognise facial expressions of pain and suggests that in addition to analysing a series of facial action units the recognition of pain expressions is also a visual perceptual process that relies heavily on the perceptual information analysis. Limitations that were associated with the research contained within this thesis were acknowledged, suggesting directions for future research.
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Young people with and without chronic pain : the role of anxietyFisher, Emma January 2015 (has links)
Everyday pain is common during childhood and adolescence. However, pain that persists is associated with poorer functioning including missed developmental milestones, disrupted emotional functioning, and social isolation. Children and adolescents with chronic pain often report high levels of anxiety. Anxiety, the cognitive, physiological, and behavioural reaction to a threatening stimulus, is associated with disability and poor functioning within this population. Anxiety is common during childhood and adolescence beyond a context of pain. Adolescence is a time of change and autonomy and experiencing long-term pain can inhibit those goals. Youth with higher levels of anxiety also experience higher levels of social isolation and poorer coping skills. Yet psychological interventions do not typically target anxiety to improve the functioning of children and adolescents. My primary research aim is to investigate the role of anxiety within the context of pain for adolescents. Specifically, I investigate the effect of anxiety on functioning and behaviour, and determine the characteristics of anxiety between adolescents with and without chronic pain. Finally, it is important to assess whether anxiety can be reduced in children and adolescents with chronic pain through psychological interventions and I investigate the efficacy of psychological treatments for children and adolescents with chronic pain for the outcomes anxiety, pain, disability, depression, and sleep. First, in Chapter One I review the current literature with a specific focus on anxiety within a paediatric population with chronic pain, identifying the gaps in the current research. In Chapters 2-4, I present one secondary data analysis study and two empirical studies that investigate the role of anxiety. In Chapter Two, I investigate the effect of anxiety experienced during early adolescence on the development of chronic pain, pain- related anxiety, and pain- related disability in later adolescence. This study showed that higher general anxiety at 13 years of age, and higher pain-related anxiety at 17 years of age in adolescence were associated with pain-related disability. Having established the importance of anxiety in Chapter Two, I next investigate the characteristics of anxiety in adolescents, and further identify differences of anxiety characteristics between adolescents with and without chronic pain in Chapter Three. I found that adolescent’s worry was predominantly 8 about personal competence: being criticised, being perceived negatively, and selfcriticism. There were no differences between adolescent with and without chronic pain. In Chapter Four, I adopt a more motivational stance, to investigate how the role of goals and anxiety promote approach and avoidance of activities when in pain. Goals promoted the approach of activities when in pain but only when high pain intensity vignettes were presented. Anxiety about pain, but not general anxiety predicted avoidance of activities due to pain. The findings from these three studies demonstrate the detrimental impact of elevated anxiety and therefore, it was next important to investigate whether anxiety can be reduced by psychological interventions in children and adolescents with chronic pain. I conduct two systematic reviews in Chapter Five that investigate how efficacious psychological therapies are at reducing anxiety within a paediatric population. Analyses revealed that psychological therapies were not beneficial at reducing anxiety in this population, but were beneficial at reducing pain and disability, particularly posttreatment. Finally, in Chapter Six, I present my discussion and conclusions. Collectively, my findings from this thesis show that anxiety is an important variable to consider when investigating and treating pain in children and adolescents. Higher levels of anxiety experienced early in life are important to identify and treat. Nevertheless, adolescents with and without chronic pain have similar worries and characteristics of worry in later adolescence, and anxiety about pain is most detrimental to functioning when in pain. Finally, psychological interventions for children and adolescents with chronic pain do not frequently target anxiety and systematic reviews do not show a reduction in anxiety after receiving psychological therapies in this population. I conclude with a new model of how anxiety contributes to disability in this population and provide implications for research and practice.
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Intracellular mechanisms in chronic pain statesDelaney, Ada January 2007 (has links)
Neuropathic pain is a pervasive chronic condition that lacks adequate therapeutic treatment, making the identification of new candidate targets for drug development a priority. Underlying the development of this pathological pain state is a process of neuronal plasticity, termed central sensitisation that results in hyperexcitability of sensory neurons in the spinal cord. Stimulation of peripheral nociceptive inputs can cause downstream activation of kinases in the spinal dorsal horn that may contribute to the generation of this hyperexcitable state in the spinal cord. Here, using the chronic constriction injury (CCI) model of neuropathic pain, the role played by p42/44 and p38 mitogen-activated protein (MAP) kinases was addressed. Inhibition of both the p42/44 and p38 MAP kinase pathways attenuated the behavioural reflex sensitisation seen following nerve injury. The study explored the part played by spinal VPAC2 and NK2 receptors, (which respond to the afferent excitatory neuropeptides VIP and NKA respectively), in addition to glially mediated events in the activation of these kinases. Following nerve injury, both spinal activation of p42/44 and p38 MAP kinases and behavioural sensitisation (which was sensitive to p42/44 and p38 pathway inhibitors) was prevented by VPAC2, NK2 and NMDA receptor antagonists and glial or TNF-a inhibitors. The NMDA receptor, which is thought to be crucially involved in central sensitisation in the spinal cord, binds to the multivalent adapter protein PSD-95; an interaction which is necessary for the development of neuropathic behavioural reflex sensitisation. Here we show that mutant mice expressing a single point mutation in the Src homology 3 (SH3) domain of PSD-95 (PSD-95SH3W470L mutants), have intact neuropathic behavioural reflexes but blunted inflammatory responses. These findings indicate that different domains of the same protein may contribute selectively to different pain states. Examining further the role played by PSD-95, we found that the expression of both PSD- 95 and one of its signalling partner kinases, Pyk 2, was increased in the same superficial dorsal horn neurons following nerve injury. These studies suggest the importance of specific receptors and signalling pathways, non-neuronal cells and of protein:protein complexes associated with the NMDA receptor in chronic pain states and point to their future potential in the design of novel therapeutic targets.
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Initiation, propagation and resolution of inflammationRossi, Adriano Giorgio January 2010 (has links)
In order to gain a better understanding of the mechanisms controlling inflammatory processes with a view to developing novel therapies for inflammatory disease, the research presented in this thesis has been focused on unravelling the molecular complexities associated with the initiation, propagation and resolution of inflammation. Although neutrophilic and eosinophilic granulocytes are key effector cells in orchestrating host defence against invading bacteria and parasites, their over-recruitment, uncontrolled activation and defective removal by macrophages play a prominent role in generating tissue damage associated with chronic inflammatory conditions such as asthma and rheumatoid arthritis. Much of the work presented in this thesis investigates these processes and the findings are divided into three overlapping sections; initiation, propagation and resolution of the inflammatory process. Section 1 describes studies principally investigating the mechanisms governing the initiation and regulation of the inflammatory process. The main focus of this section involves work investigating the activation and responsiveness of neutrophils, eosinophils, macrophages and platelets to agents such as various lipids, small peptides and nitric oxide. Section 2 presents publications describing the propagation of the inflammatory process in various in vivo models of skin and lung inflammation including studies investigating relevant in vitro inflammatory processes. Section 3 describes research focusing on the processes governing the resolution of inflammation especially the phenomena of apoptosis and macrophage clearance of apoptotic cells. This includes in vitro studies investigating the mechanisms regulating human granulocyte apoptosis and in vivo work investigating the effects of apoptosis modulation in different models of inflammation.
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Persisting inflammation after critical illness : prevalence, risk factors and association with physical recoveryGriffith, David Morgan January 2014 (has links)
Introduction: Survivors of critical illness suffer physical, psychological, and social problems. The factors hindering recovery and the best rehabilitation interventions remain illusive. Critical illness is associated with inflammation that persists in some individuals and this might affect recovery. The hypotheses for the thesis are 1. Persistent inflammation is common after critical illness. 2. Persistent inflammation is associated with functional recovery. 3. Persistent inflammation is associated with critical illness-induced viral reactivation. 4. Biomarkers may help predict functional disability. The main part of the project was based on 197 of the 240 patients enrolled in the RECOVER trial who also consented to take part in an inflammation sub study. Systematic Review. Aims: Prevalence of systemic inflammation in ICU survivors; association of inflammation with physical recovery. 7433 references identified. 208 full text articles were reviewed. 57 were eligible. 22 studies included the relevant data. CRP at ICU discharge was elevated ( > 10mg/L) in most cases (70% of mixed medical/surgical patients and 100% of severe sepsis survivors). Lower CRP observed in trauma patients (23mg/L), VAP (46mg/L), > 6 days in ICU (45mg/L), and medical ICU patients (36mg/L). CRP was higher in sepsis (107mg/L) and surgical ICU patients (99mg/L). IL-6, TNF-a, and PCT were elevated in most patients at ICU discharge. Ninety percent of acute COPD exacerbations admitted to ICU had elevated CRP at hospital discharge and 43% general adult ICU patients fulfilled SIRS criteria 3 days after ICU discharge. Anaemic ICU survivors had elevated CRP and IL-6 at 6 months. There were no studies that measured both inflammation and physical function after ICU discharge. Association of inflammation with functional outcome after critical illness. Aims: Prevalence of inflammation in heterogeneous ICU cohort, association of CRP with Rivermead Mobility Index (RMI) and other outcome measures at 3 months. At ICU discharge, 173 patients (94%) had elevated serum CRP with a median concentration of 27 (11-60) mg/L. At hospital discharge 169 patients (90%) had elevated CRP with a median concentration of 21 (8-42) mg/L, At 3 months 72 patients (59%) had elevated CRP with a median concentration of 4 (1-12) mg/L. CRP was associated with RMI (p < 0.01), and percentage of predicted handgrip strength (HGS) (p=0.03) at 3 months. CMV infection, systemic inflammation and the post ICU syndrome. Aims: Prevalence of active and latent CMV at ICU discharge; association between CMV, inflammation, and recovery. 115 patients (62.8%) had latent CMV. 13 (11.4%) had active CMV (11.4% of those with prior CMV and 7.2% of ICU survivors). Active CMV associated with longer hospital length of stay (57 days v 28 days p=0.016), poorer baseline physical function (HGS 12 v 16 p=0.032; RMI 1 v 2 p=0.018). At 3 months, patients with latent CMV infection had higher CRP (5.4 v 2.8mg/L p=0.06), higher HNE (118 v 91.3 pg/mL p < 0.00), lower TGF β (9.2 v 11.4 ng/mL p=0.01), and were slower on 2 min timed up and go test (p=0.03). Active CMV infection at ICU discharge was not associated with inflammation or physical function at 3 months. Prediction of physical disability after ICU discharge. Aims: To identify risk factors for poor physical function; to derive a prognostic index to identify for poor functional outcome. Age, Functional Comorbidity Index, Scottish Index of Multiple Deprivation quintile, CMV IgG status, ventilator days, baseline RMI, physical component of SGA, CRP, and SLPI met statistical criteria for consideration in the multivariable models. 2 linear multivariable models with reasonable fit (R2=0.175; 0.193) were constructed. AUCs were 0.759 for the clinical model and 0.725 for the model incorporating biochemical markers. The models did not perform any better than a baseline assessment of mobility (RMI).
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The development of a grounded-theory of (dis)belief in chronic painNewton, B. J. January 2015 (has links)
BACKGROUND & AIMS Chronic pain has profound psycho-social consequences for the individual and those around them. Individuals encounter loss of function, poor emotional health and stigma. Associated with stigma is the experience of disbelief: when others do not accept the individual’s account of their pain as true. Whilst research alludes to the disbelief experience, there is a distinct lack of a coherent model that explains what happens. In this thesis I aimed to develop a tentative grounded-theory of disbelief. METHOD I utilised Strauss and Corbin’s (1998) approach to grounded-theory. Through a collaborating Pain Management department in the West Midlands, I recruited thirteen individuals experiencing chronic pain; nine were female and all were white British. Pain duration ranged from 3 to 73 years and participants had a variety of diagnoses. I recorded semi-structured interviews with participants. Data collection and analysis were iterative and followed theoretical sampling principles. FINDINGS In the (Dis)belief Model, I propose inaccessibility as the core concept. This refers to the private nature of pain that is inaccessible to others. I conceive of need drivers: motivating forces that seek to attain or protect something of value and avoid something not of value. The need drivers and the inaccessible character of pain drive the four process components in the model: pain expression, pain appraisal, belief expression and belief appraisal. Pain can be expressed or concealed. Individuals and others make sense of the pain and appraise its credibility. Those in pain encounter doubt, challenges, support, pain acknowledgement and professional (in)action. The appraisal of this behaviour as (dis)belief is affected by the individual’s underlying needs and is idiosyncratic. Finally, time and experience influence the (dis)belief phenomenon. CLINICAL IMPLICATIONS Based on the model, I propose six interactional approaches that might help clinicians communicate their belief in the patient’s pain. These are listening; being curious, unassuming and sensitive; mobilising resources; and managing expectations.
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NKG2D-dependent cross talk between NK cells and CD4 T cells in chronic hepatitis BHuang, W. C. January 2016 (has links)
NK cells are emerging as potent regulators of adaptive immunity in virus infection. Our group recently documented the partially TRAIL-dependent deletion of HBV-specific T cells by NK cells. For this study, we investigated the underlying interactions between NK cells and T cells through the NKG2D pathway in chronic HBV infection. In this study, we observed that activated and HBV-specific T cells, especially the CD4 fraction, expressed NKG2D ligands (NKG2D-L) not normally seen on T cells. NKG2D-L upregulation was further enriched on CD4 T cells in HBV-infected livers compared to the circulation and control livers. Oxidative stress, one noteworthy pathogenic feature of HBV infection, was demonstrated to recapitulate the T cell NKG2D-L upregulation pattern seen in patients with chronic hepatitis B (CHB). NK cells from patients with CHB maintained NKG2D expression and their increased activation and cytotoxicity could be driven by NKG2D-L expressing cells. In line with the distinctive features of T cells and NK cells in CHB, we discovered a positive correlation between activation of NKG2D+NK cells and the NKG2D-L (MICA/B) levels on CD4 T cells. Additionally, the pro-inflammatory cytokine IFN-α, used in HBV treatment, was shown to favour for NKG2D-mediated regulation. To conclude, we provide the first ex vivo evidence that human T cells, particularly those sequestered within tissues, can become visible to the stress surveillance system by the induction of NKG2D-L. We show that in active CHB, T cells upregulate NKG2D-L which can drive NK cell activation and cytotoxicity via the NKG2D pathway. These interactions may be triggered by aberrant oxidative stress and result in a homeostatic response of "damage removal", thereby limiting T cell antiviral immunity. Therefore, efforts to manipulate the HBV-infected liver milieu in order to decrease T cell oxidative stress and diminish constraints from NK cells and the NKG2D pathway should be considered to reduce HBV pathogenesis and promote immunity.
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Human guanylate binding proteins : generation of tools, and their role during Toxoplasma gondii infectionJohnston, A. C. January 2017 (has links)
Guanylate binding proteins (GBPs) are large GTPases that are substantially upregulated by interferons during infection. The human genome consists of seven GBP family members with high sequence identity. GBPs have been implicated to confer host resistance to a number of pathogens across several species. In mice, specific GBP family members are responsible for host defence mechanisms, including the induction of inflammasome responses during bacterial infections, and the disruption of pathogen vacuoles leading to effective protection against the parasite Toxoplasma gondii, and the bacteria Salmonella enterica typhimurium and Chlamydia trachomatis. Toxoplasma is an apicomplexan intracellular parasite that resides within a parasitophorous vacuole (PV), and can cause severe complications and even death in humans and other animals. The aim of this project was to analyse the characteristics and roles of individual human GBP family members in cells at steady state and in Toxoplasma infected cells. The first step was to develop tools to study the proteins, including producing and characterising specific antibodies, establishing cell overexpression systems and characterising cells deficient in certain GBPs. Using these tools, the subcellular localisations of GBP1 and GBP4 were determined to the cytoplasm and nucleus respectively. It was concluded that during type I and II Toxoplasma infection GBP1 and 4 are not recruited to the PV like in the mouse. Despite this, in human epithelial cells, GBP1 plays an important and specific role in the restriction of Toxoplasma replication. It was deduced that GBP4 protein levels are dramatically reduced during infection with the type I, but not the type II strain of Toxoplasma. GBP4 protein levels could be stabilised during type I Toxoplasma infection with an inhibitor of cysteine, serine and threonine proteases. Using an antibody specific for GBP1 and 2, a large dataset of potential interaction partners in a Toxoplasma strain-specific fashion was generated. The tools produced, specifically the GBP-specific antibodies, provide a valuable resource that can be used by other lab members and collaborators to more fully understand the functions of these interesting and important large GTPases.
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