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Inappropriate Activation (inappropriate + activation)
Selected AbstractsRegulation of Wnt/,-catenin signaling by protein kinasesDEVELOPMENTAL DYNAMICS, Issue 1 2010Esther M. Verheyen Abstract The Wnt/,-catenin signaling pathway plays essential roles during development and adult tissue homeostasis. Inappropriate activation of the pathway can result in a variety of malignancies. Protein kinases have emerged as key regulators at multiple steps of the Wnt pathway. In this review, we present a synthesis covering the latest information on how Wnt signaling is regulated by diverse protein kinases. Developmental Dynamics 239:34,44, 2010. © 2009 Wiley-Liss, Inc. [source] Reducing conditions significantly attenuate the neuroprotective efficacy of competitive, but not other NMDA receptor antagonists in vitroEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2000Ashley K. Pringle Abstract Inappropriate activation of NMDA receptors during a period of cerebral ischaemia is a crucial event in the pathway leading to neuronal degeneration. However, significant research has failed to deliver a clinically active NMDA receptor antagonist, and competitive NMDA antagonists are ineffective in many experimental models of ischaemia. The NMDA receptor itself has a number of modulatory sites which may affect receptor function under ischaemic conditions. Using rat organotypic hippocampal slice cultures we have investigated whether the redox modulatory site affects the neuroprotective efficacy of NMDA receptor antagonists against excitotoxicity and experimental ischaemia (OGD). NMDA toxicity was significantly enhanced in cultures pretreated with a reducing agent. The noncompetitive antagonist MK-801 and a glycine-site blocker were equally neuroprotective in both normal and reduced conditions, but there was a significant rightward shift in the dose,response curves of the competitive antagonists APV and CPP and the uncompetitive antagonist memantine. OGD produced neuronal damage predominantly in the CA1 region, which was prevented by MK-801 and memantine, but not by APV or CPP. Inclusion of an oxidizing agent during the period of OGD had no effect alone, but significantly enhanced the neuroprotective potency of the competitive antagonists. These data clearly demonstrate that chemical reduction of the redox modulatory site of the NMDA receptor decreases the ability of competitive antagonists to block NMDA receptor-mediated neuronal damage, and that the reducing conditions which occur during simulated ischaemia are sufficient to produce a similar effect. This may have important implications for the design of future neuroprotective agents. [source] Human disease resulting from gene mutations that interfere with appropriate nuclear factor-,B activationIMMUNOLOGICAL REVIEWS, Issue 1 2005Jordan S. Orange Summary:, The nuclear factor (NF)-,B family of transcription factors serves vital roles in a wide array of cell functions. An increasing number of human genetic lesions that result in defined disease entities are linked to inappropriate activation of NF-,B. The resulting aberrant NF-,B function can lead to cellular defects that ultimately impair normal developmental processes, host immune defenses, or both. Molecular defects that lie upstream in cell-signaling pathways and rely upon NF-,B activation tend to give a more specific phenotype, whereas those closer to the actual NF-,B proteins have broader defects. A detailed study of these diseases can provide insight into the biochemistry of NF-,B activation as well as the role of NF-,B in human health. [source] Adult stem cell maintenance and tissue regeneration in the ageing context: the role for A-type lamins as intrinsic modulators of ageing in adult stem cells and their nichesJOURNAL OF ANATOMY, Issue 1 2008Vanja Pekovic Abstract Adult stem cells have been identified in most mammalian tissues of the adult body and are known to support the continuous repair and regeneration of tissues. A generalized decline in tissue regenerative responses associated with age is believed to result from a depletion and/or a loss of function of adult stem cells, which itself may be a driving cause of many age-related disease pathologies. Here we review the striking similarities between tissue phenotypes seen in many degenerative conditions associated with old age and those reported in age-related nuclear envelope disorders caused by mutations in the LMNA gene. The concept is beginning to emerge that nuclear filament proteins, A-type lamins, may act as signalling receptors in the nucleus required for receiving and/or transducing upstream cytosolic signals in a number of pathways central to adult stem cell maintenance as well as adaptive responses to stress. We propose that during ageing and in diseases caused by lamin A mutations, dysfunction of the A-type lamin stress-resistant signalling network in adult stem cells, their progenitors and/or stem cell niches leads to a loss of protection against growth-related stress. This in turn triggers an inappropriate activation or a complete failure of self-renewal pathways with the consequent initiation of stress-induced senescence. As such, A-type lamins should be regarded as intrinsic modulators of ageing within adult stem cells and their niches that are essential for survival to old age. [source] Trade-offs between longevity and pathogen resistance in Drosophila melanogaster are mediated by NF,B signalingAGING CELL, Issue 6 2006Sergiy Libert Summary The innate immune response protects numerous organisms, including humans, from the universe of pathogenic molecules, viruses and micro-organisms. Despite its role in promoting pathogen resistance, inappropriate activation and expression of NF,B and other immunity-related effector molecules can lead to cancer, inflammation, and other diseases of aging. Understanding the mechanisms leading to immune system activation as well as the short- and long-term consequences of such activation on health and lifespan is therefore critical for the development of beneficial immuno-modulating and longevity-promoting interventions. Mechanisms of innate immunity are highly conserved across species, and we take advantage of genetic tools in the model organism, Drosophila melanogaster, to study the effects of acute and chronic activation of immunity pathways on pathogen resistance and general fitness of adult flies. Our findings indicate that fat body specific overexpression of a putative pathogen recognition molecule, peptidoglycan recognition protein (PGRP-LE), is sufficient for constitutive up-regulation of the immune response and for enhanced pathogen resistance. Primary components of fitness are unaffected by acute activation, but chronic activation leads to an inflammatory state and reduced lifespan. These phenotypes are dependent on the NF,B-related transcriptional factor, Relish, and they establish a mechanistic basis for a link between immunity, inflammation, and longevity. [source] Shortening of Median Door-to-Balloon Time in Primary Percutaneous Coronary Intervention in Singapore by Simple and Inexpensive Operational Measures: Clinical Practice Improvement ProgramJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 5 2008CHI-HANG LEE M.B.B.S., F.A.C.C. Background: Primary percutaneous coronary intervention is the standard reperfusion strategy for ST-segment elevation myocardial infarction in our center. We aimed to shorten the median door-to-balloon time from over 100 minutes to 90 minutes or less. Methods: We have been using three strategies since March 2007 to shorten the door-to-balloon time: (1) the intervention team is now activated by emergency department physicians (where previously it had been activated by coronary care unit); (2) all members of the intervention team have converted from using pagers to using cell phones; and (3) as soon as the intervention team is activated, patients are transferred immediately to the cardiac catheterization laboratory (where previously they had waited in the emergency department for the intervention team to arrive). An in-house physician and a nurse would stay with the patients before arrival of the intervention team. Results: During 12 months, 285 nontransfer patients (analyzed, n = 270) underwent primary PCI. The shortest monthly median door-to-balloon time was 59 minutes; the longest monthly median door-to-balloon time was 111 minutes. The overall median door-to-balloon time for the entire 12 months was 72 minutes. On a per-month basis, the median door-to-balloon time was 90 minutes or less in 10 of 12 months. On a per-patient basis, the median door-to-balloon time was 90 minutes or less in 182 patients (67.4%). There was 1 case (0.4%) of inappropriate activation by the emergency department. While waiting for the intervention team to convene, 1 patient (0.4%) deteriorated and had to be resuscitated in the cardiac catheterization laboratory. Conclusions: Improved health care delivery can be achieved by changing simple and inexpensive operational processes. [source] Pre- and postsynaptic modulation of monosynaptic reflex by GABAA receptors on turtle spinal cordTHE JOURNAL OF PHYSIOLOGY, Issue 14 2010Wendy Bautista There is growing evidence that activation of high affinity extrasynaptic GABAA receptors in the brain, cerebellum and spinal cord substantia gelatinosa results in a tonic inhibition controlling postsynaptic excitability. The aim of the present study was to determine if GABAA receptors mediating tonic inhibition participate in the modulation of monosynaptic reflex (MSR) in the vertebrate spinal cord. Using an in vitro turtle lumbar spinal cord preparation, we show that conditioning stimulation of a dorsal root depressed the test monosynaptic reflex (MSR) at long condition,test intervals. This long duration inhibition is similar to the one seen in mammalian spinal cord and it is dependent on GABAA as it was completely blocked by 20 ,m picrotoxin (PTX) or bicuculline (BIC) or 1 ,m gabazine, simultaneously depressing the dorsal root potential (DRP) without MSR facilitation. Interestingly 100 ,m picrotoxin or BIC potentiated the MSR, depressed the DRP, and produced a long lasting motoneurone after-discharge. Furosemide, a selective antagonist of extrasynaptic GABAA receptors, affects receptor subtypes with ,4/6 subunits, and in a similar way to higher concentrations of PTX or BIC, also potentiated the MSR but did not affect the DRP, suggesting the presence of ,4/6 GABAA receptors at motoneurones. Our results suggest that (1) the turtle spinal cord has a GABAA mediated long duration inhibition similar to presynaptic inhibition observed in mammals, (2) GABAA receptors located at the motoneurones and primary afferents might produce tonic inhibition of monosynaptic reflex, and (3) GABAA receptors modulate motoneurone excitability reducing the probability of spurious and inappropriate activation. [source] Post-stroke tactile allodynia and its modulation by vestibular stimulation: a MEG case studyACTA NEUROLOGICA SCANDINAVICA, Issue 6 2009P. D. McGeoch Background,,, There is behavioural evidence that caloric vestibular stimulation (CVS) can alleviate central pain. Several such patients have also noted that it reduces tactile allodynia, an especially ill-understood phenomenon in these patients. Aims of the study,,, The first aim is to use magnetoencephalography (MEG) to study neural activity associated with tactile allodynia in central post-stroke pain (CPSP). The second is to assess how this would be affected, if at all, by CVS. The third is to assess the ability of the VESTAL solution for MEG to detect anterior cingulate activation. Methods,,, A 58-year-old woman with CPSP, and marked unilateral tactile allodynia, participated in a MEG study with imaging pre- and post-CVS. Results,,, Tactile simulation within the patient's allodynic area resulted in contralateral activation of the primary motor and anterior cingulate cortices, which had normalized 24 h post-CVS. Conclusions,,, We suggest that the unexpected primary motor cortex activation in response to light touch in the allodynic area arises from inappropriate activation of a normal mechanism, which may occur when a threat to homeostasis is present, to lower motor thresholds and allow for more rapid performance of corrective actions. We propose this may be mediated by the interoceptive cortex in the dorsal posterior insula. [source] Activation of extracellular signal-regulated kinase (ERK) in G2 phase delays mitotic entry through p21CIP1CELL PROLIFERATION, Issue 4 2006S. Dangi In contrast, the role of extracellular signal-regulated kinase during G2 phase and mitosis (M phase) is largely undefined. Previous studies have suggested that inhibition of basal extracellular signal-regulated kinase activity delays G2 - and M-phase progression. In the current investigation, we have examined the consequence of activating the extracellular signal-regulated kinase pathway during G2 phase on subsequent progression through mitosis. Using synchronized HeLa cells, we show that activation of the extracellular signal-regulated kinase pathway with phorbol 12-myristate 13-acetate or epidermal growth factor during G2 phase causes a rapid cell cycle arrest in G2 as measured by flow cytometry, mitotic indices and cyclin B1 expression. This G2 -phase arrest was reversed by pre-treatment with bisindolylmaleimide or U0126, which are selective inhibitors of protein kinase C proteins or the extracellular signal-regulated kinase activators, MEK1/2, respectively. The extracellular signal-regulated kinase-mediated delay in M-phase entry appeared to involve de novo synthesis of the cyclin-dependent kinase inhibitor, p21CIP1, during G2 through a p53-independent mechanism. To establish a function for the increased expression of p21CIP1 and delayed cell cycle progression, we show that extracellular signal-regulated kinase activation in G2 -phase cells results in an increased number of cells containing chromosome aberrations characteristic of genomic instability. The presence of chromosome aberrations following extracellular signal-regulated kinase activation during G2 -phase was further augmented in cells lacking p21CIP1. These findings suggest that p21CIP1 mediated inhibition of cell cycle progression during G2/M phase protects against inappropriate activation of signalling pathways, which may cause excessive chromosome damage and be detrimental to cell survival. [source] Neutrophils and monocytes as potentially important sources of proinflammatory cytokines in diabetesCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2006E. Hatanaka Summary Neutrophils and monocytes play a central role in host defence. The invading leucocytes are capable of synthesizing and releasing a variety of proinflammatory mediators including cytokines. Given the importance of cytokines in the progression of chronic and acute inflammatory processes, we aimed to ascertain whether the release of interleukin (IL)-8, IL-1,, tumour necrosis factor (TNF)-, and IL-1ra of neutrophils and monocytes was modified in diabetes. To this end, we measured the release of cytokines in suspensions of cell culture in basal and lipopolysaccharide (LPS)-stimulated conditions. In basal conditions, neutrophils of diabetics release 1·6, 3·2, 1·9 and 1·9-fold higher amounts of IL-8, IL-1,, TNF-, and IL-1ra, respectively, than do healthy controls. Under our experimental conditions, this effect was more evident for neutrophils than for monocytes. Incremental cytokine production was also found to occur when neutrophils were stimulated with LPS. IL-8, IL-1, and TNF-, increased, respectively, by 4·0, 1·7 and 2·8-fold. Although the effect was more marked for neutrophils, monocytes showed a tendency for increased cytokine production. The discovery of this increase in cytokines released by the neutrophils of diabetics contributes towards a clearer understanding of other deficiencies described for neutrophils in diabetes, such as the migration of neutrophils to inflammatory sites, phagocytes, release of lytic proteases, production of reactive oxygen species and apoptosis. The excessive production of cytokines may lead to inappropriate activation and tissue injury and even to increased susceptibility to invasive microorganisms. Thus, the increased responsiveness of neutrophils of diabetics demonstrated in this study may be considered part of the scenario of diabetes physiopathology. [source] Trauma Team Activation Criteria as Predictors of Patient Disposition from the Emergency DepartmentACADEMIC EMERGENCY MEDICINE, Issue 1 2004Michael A. Kohn MD Many trauma centers use mainly physiologic, first-tier criteria and mechanism-related, second-tier criteria to determine whether and at what level to activate a multidisciplinary trauma team in response to an out-of-hospital call. Some of these criteria result in a large number of unnecessary team activations while identifying only a few additional patients who require immediate operative intervention. Objectives: To separately evaluate the incremental predictive value of individual first-tier and second-tier trauma team activation criteria for severe injury as reflected by patient disposition from the emergency department (ED). Methods: This was a prospective cohort study in which activation criteria were collected prospectively on all adult patients for whom the trauma team was activated during a five-month period at an urban, Level 1 trauma center. Severe injury disposition ("appropriate" team activation) was defined as immediate operative intervention, admission to the intensive care unit (ICU), or death in the ED. Data analysis consisted of recursive partitioning and multiple logistic regression. Results: Of the 305 activations for the mainly physiologic first-tier criteria, 157 (51.5%) resulted in severe injury disposition. The first-tier criterion that caused the greatest increase in "inappropriate" activations for the lowest increase in "appropriate" activations was "age > 65." Of the 34 additional activations due to this criterion, seven (20.6%) resulted in severe injury disposition. Of the 700 activations for second-tier, mechanism-related criteria, 54 (7.7%) resulted in ICU or operating room admissions, and none resulted in ED death. The four least predictive second-tier criteria were "motorcycle crash with separation of rider,""pedestrian hit by motor vehicle,""motor vehicle crash with rollover," and "motor vehicle crash with death of occupant." Of the 452 activations for these four criteria, only 18 (4.0%) resulted in ICU or operating room admission. Conclusions: The four least predictive second-tier, mechanism-related criteria added little sensitivity to the trauma team activation rule at the cost of substantially decreased specificity, and they should be modified or eliminated. The first-tier, mainly physiologic criteria were all useful in predicting the need for an immediate multidisciplinary response. If increased specificity of the first-tier criteria is desired, the first criterion to eliminate is "age > 65." [source] | ||||||||||||||||||||||