4,235 research outputs found
Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration
No full textMicroglia, the resident immune cells of the central nervous system (CNS), play an important role in CNS homeostasis during development, adulthood and ageing. Their phenotype and function have been widely studied, but most studies have focused on their local interactions in the CNS. Microglia are derived from a particular developmental niche, are long-lived, locally replaced and form a significant part of the communication route between the peripheral immune system and the CNS; all these components of microglia biology contribute to maintaining homeostasis. Microglia function is tightly regulated by the CNS microenvironment, and increasing evidence suggests that disturbances, such as neurodegeneration and ageing, can have profound consequences for microglial phenotype and function. We describe the possible biological mechanisms underlying the altered threshold for microglial activation, also known as 'microglial priming', seen in CNS disease and ageing and consider how priming may contribute to turning immune-to-brain communication from a homeostatic pathway into a maladaptive response that contributes to symptoms and progression of diseases of the CNS
Long term impact of systemic bacterial infection on the cerebral vasculature and microglia
No full textBackground: Systemic infection leads to generation of inflammatory mediators that result in metabolic and behavioural changes. Repeated or chronic systemic inflammation leads to a state of innate immune tolerance: a protective mechanism against over-activity of the immune system. In this study we investigated the immune adaptation of microglia and brain vascular endothelial cells in response to systemic inflammation or bacterial infection. Methods: Mice were given repeated doses of lipopolysaccharide (LPS) or a single injection of live Salmonella typhimurium. Inflammatory cytokines were measured in serum, spleen and brain, and microglial phenotype studied by immunohistochemistry.mice were infected with Salmonella typhimurium and subsequently challenged with a focal unilateral, intracerebral injection of LPS. Results: Repeated systemic LPS challenges resulted in increased brain IL-1?, TNF? and IL-12 levels, despite attenuated systemic cytokine production. Each LPS challenge induced significant changes in burrowing behaviour. In contrast, brain IL-1? and IL-12 levels in Salmonella typhimurium infected mice increased over three weeks, with high interferon-? levels in the circulation. Behavioural changes were only observed during the acute phase of the infection. Microglia and cerebral vasculature display an activated phenotype, and focal intracerebral injection of LPS 4 weeks after infection results in an exaggerated local inflammatory response when compared to non-infected mice. Conclusions: These studies reveal that the innate immune cells in the brain do not become tolerant to systemic infection, but are primed instead. This may lead to prolonged and damaging cytokine production that may have aprofound effect on the onset and/ or progression of pre-existing neurodegenerative disease.Humans and animals are regularly exposed to bacterial and viral pathogens that can have a considerable impact on our day-to-day living [1]. Upon infection, a set of immune, physiological, metabolic, and behavioural responses is initiated, representing a highly organized strategy of the organism to fight infection. Pro-inflammatory mediators generated in peripheral tissue communicate with the brain to modify behaviour [2], which aids our ability to fight and eliminate the pathogen. The communication pathways from the site of inflammation to the brain have been investigated in animal models and systemic challenge with lipopolysaccharide (LPS) or double stranded RNA (poly I:C) have been widely used to mimic aspects of bacterial and viral infection respectively [3, 4]. These studies have provided evidence that systemically generated inflammatory mediators signal to the brain via both neural and humoral routes, the latter signalling via the circumventricular organs or across the blood-brain barrier (BBB). Signalling into the brain via these routes evokes a response in the perivascular macrophages (PVMs) and microglia, which in turn synthesise diverse inflammatory mediators including cytokines, prostaglandins and nitric oxide [2, 5, 6]. Immune-to-brain communication also occurs in humans who show changes in mood and cognition following systemic inflammation or infection, which are associated with changes in activity in particular regions of the CNS [7-9]. While these changes are part of our normal homeostasis, it is increasingly evident that systemic inflammation has a detrimental effect in animals and also humans, that suffer from chronic neurodegeneration [10, 11]. We, and others, have shown that microglia become primed by on-going neuropathology in the brain, which increases their response towards subsequent inflammatory stimuli, including systemic inflammation [12, 13] Similar findings have been made in aged rodents [14, 15], where it has been shown that there is an exaggerated behavioural and innate immune response in the brainto systemic bacterial and viral infections, but the molecular mechanisms underlying the microglial priming under these conditions is far from understood.Humans and animals are rarely exposed to a single acute systemic inflammatory event: they rather encounter infectious pathogens that replicate in vivo or are exposed to low concentrations of LPS over a prolonged period of time. There is limited information on the impact of non-neurotrophic bacterial infections on the CNS and whether prolonged systemic inflammation will give rise to either a hyper-(priming) or hypo-(tolerance) innate immune response in the brain in response to a subsequent inflammatory stimulus.In this study we measured the levels of cytokines in the serum, spleen and brain as well as assessing sickness behaviour following a systemic bacterial infection using attenuated Salmonella typhimurium SL3261: we compared the effect to that of repeated LPS injections. We show that Salmonella typhimurium caused acute, transient behavioural changes and a robust peripheral immune response that peaks at day 7. Systemic inflammation resulted in a delayed increase in cytokine production in the brain and priming of microglia, which persisted up to four weeks post infection. These effects were not mimicked by repeated LPS challenges. It is well recognised that systemic bacterial and viral infections are significant contributors to morbidity in the elderly [16], and it has been suggested that primed microglia play a role in the increased clinical symptoms seen in patients with Alzheimer’s disease who have systemic inflammation or infections [11, 17]. We show here that systemic infection leads to prolonged cytokine synthesis in the brain and also priming of brain innate immune cells to a subsequent focal inflammatory challenge in the brain parenchyma
Reflections of a Jewish, Lesbian Author
No full textIn this essay, Jewish lesbian author Leslea Newman speaks of the importance of finding one's own identity reflected in works of literature, citing examples of her own work, and recommending the writings of other Jewish lesbian authors of merit
Evidence for an early inflammatory response in the central nervous system of mice with scrapie
No full textIn Alzheimer's disease, the most prevalent of the neurodegenerative diseases, inflammation of the CNS contributes to the pathology and is a target for therapy. In contrast, the group of neurodegenerative conditions known as the Prion Diseases have been widely reported as lacking any inflammatory elements despite the many similarities between the pathologies of Alzheimer's Disease and Prion Diseases? We have found evidence for an inflammatory component in mouse scrapie, characterized by microglial activation and T-lymphocyte recruitment, which appears long before any clinical signs of the disease and spreads along well-defined anatomical pathways. These observations emphasize the potential value of murine scrapie as a model for studying the inflammatory pathology of other neurodegenerative diseases.</p
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Rewarding successful performance
No full textIs it particularly difficult to reward employees' performance in public organizations? Here it will forcefully be suggested that this assumption is false, that managers in or out of government have powerful informal rewards at their command. Certainly, there are important differences in the formal personnel and pay policies between government and smaller businesses. Clearly, most employees in businesses are not subject to the variety of goals and constituents that often occur in public organizations; yet it will be suggested here that dwelling on the limitations of normal procedures and external links is the leading contributor to the neglect of rewarding good performance in government. In public organizations, the expectation that performance in itself cannot be rewarded leads to few rewards for good performance, a classic self-fulfilling hypothesis.
The chapter begins with an analysis of the limitations of formal policies for effectively rewarding performance. This is followed by an argument for the use of informal systems to reward performance, with special attention to the strengths and limitations of this approach. Finally, the chapter concludes with specific steps that individual managers and policymakers alike can take to implement effective informal procedures to reward good performance
Mentally tough athletes are more aware of unsupportive coaching behaviours: Perceptions of coach behaviour, motivational climate, and mental toughness in sport
No full textIn this study, we tested an a priori model that included coach behaviour, motivational climate, and mental toughness among 290 athletes. Structural equation modelling demonstrated that supportive coach behaviours were related to a task-involving climate, and that task-involving climates positively associated with mental toughness. The path between supportive coach behaviours and mental toughness was insignificant. When task-involving climate was taken into account, however, supportive coach behaviours were positively associated with task-involving climates, which in turn was positively associated with mental toughness. This study illustrates the importance of coach behaviour in relation to shaping the motivational climate, which in turn may impact on the development of mental toughness among athletes
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A method of modelling the performance of rainwater collection systems in the UK
No full textAssessing Model Fit: Caveats and Recommendations for Confirmatory Factor Analysis and Exploratory Structural Equation Modeling
No full textDespite the limitations of overgeneralizing cutoff values for confirmatory factor analysis (CFA; e.g., Marsh, Hau, & Wen, 2004), they are still often employed as golden rules for assessing factorial validity in sport and exercise psychology. The purpose of this study was to investigate the appropriateness of using the CFA approach with these cutoff values for typical multidimensional measures. Furthermore, we ought to examine how a model could be respecified to achieve acceptable fit and explored whether exploratory structural equation modeling (ESEM) provides a more appropriate assessment of model fit. Six multidimensional measures commonly used in sport and exercise psychology research were examined using CFA and ESEM. Despite demonstrating good validity in previous research, all eight failed to meet the cutoff values proposed by Hu and Bentler. ESEM improved model fit in all measures. In conclusion, we suggest that model misfit in this study demonstrates the problem with interpreting cutoff values rigidly. Furthermore, we recommend ESEM as a preferred approach to examining model fit in multidimensional measures
Changes in prevalence and intensity of infection of Profilicollis altmani (Perry, 1942) cystacanth (Acanthocephala) parasitizing the mole crab Emerita analoga (Stimpson, 1857): an El Niño cascade effect?
No full textPrevalence and intensity changes in cystacanths of the acanthocephalan Profilicollis altmani parasitizing the mole crab Emerita analoga under El Niño (EN) and non-El Niño (non-EN) conditions are analyzed. Both, mean
intensity and prevalence of infection by P. altmani differ significantly for the whole size range and for each size class of 10 mm intervals (except prevalence for size classes exceeding 18 mm carapace length) between EN (1998) and non-EN (2002) years, without observed size distribution
differences in the intermediate host E. analoga under either condition. Significant difference in infestation rates of the intermediate host E. analoga is discussed as being an EN cascade effect on predators such as sea birds (i.e., Larus spp. and Calidris sp.), acting as definitive hosts of P. altmani, and which are known to decrease significantly in abundance during EN
Distributed cognition and computer supported collaborative design: The organisation of work in construction engineering
No full textThis thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.The intellectual contribution of this thesis lies within the area of computer supported co-operative work (CSCW), and more specifically, computer supported co-operative design (CSCD). CSCW is concerned with the development of information systems and technological support for multi-participant work activities. Research into CSCW seeks to understand how people and organisations interact with one another, and to integrate this understanding with the development of computer based tools to support real world settings.
Much of the technology developed to support the work of designers has been developed to aid individuals working alone, with tools like computer aided drafting (CAD), scheduling, and database software. The growth of interest in ‘groupware’ has led many technology developers to adapt these design tools for use in group situations. However, joint activities are different from those performed alone, and organisational structures can both interfere with, and supplement co-operative work practices in a way that the current technologies cannot provide support for. To develop effective group design tools, we need to understand more about collaborative processes in design.
This thesis draws from the theoretical underpinning of cognitive science and the methods of anthropology and sociology, in an interdisciplinary study of design performance in the construction industry. Fieldwork is used as a method of qualitative data collection and this is examined within the analytic framework of distributed cognition. The results of this analysis provide a useful and usable description of the work of design that technology developers can use to support collaborative design work. In line with the methods of distributed cognition, the activities observed in the workplace studies are examined in terms of their processes and representations. The resources that were available to the design participants are made explicit, as are their situation-specific work patterns.
Two case studies of design are examined. The first of these describes design work in a civil engineering project, which involves a number of different design activities. The second describes the work of consulting engineers in building design, focusing on a more limited design role, which is used to back up and supplement areas of the first study that were understood to be particularly relevant.
The findings of the study demonstrate how design processes operate simultaneously at personal, organisational and inter-organisational levels. The distinction between the formal, organisational procedures, and the informal, social processes that compliment them is examined to show how these are interrelated in the performance of the design task and their importance to the mechanisms used to co-ordinate actions. The findings of the study have implications for the development of novel technologies to augment the engineering design process, and have already been used in the development of assistive design technologies.
The thesis demonstrates that the framework of distributed cognition can be used in the analysis of cognition within a setting, involving multiple individuals, in concert with 'natural' and 'artificial' artefacts. The thesis makes clear a number of processes in design that can only be examined from a perspective which includes the social dimensions of work. The methods of study focus on the resources in collaborative activities, whilst the analysis, structured in terms of the representations and processes of collaborative activity, shows that the method can be used effectively in the development of CSCW and CSCD technologies
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