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Accumulating Data (accumulating + data)
Selected AbstractsNeutrophil apoptosis: A target for enhancing the resolution of inflammationJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2009János G. Filep Abstract Neutrophils are essential for host defense and their programmed cell death and removal are critical for the optimal expression as well as for efficient resolution of inflammation. Delayed neutrophil apoptosis or impaired clearance of apoptotic neutrophils by macrophages contributes to the progression of chronic inflammation. Under most conditions, neutrophils are exposed to multiple factors and their fate would ultimately depend on the balance between pro-survival and pro-apoptotic signals. Life or death decisions are tightly controlled by a complex network of intracellular signaling pathways. Accumulating data indicate that receptors, such as the formyl peptide receptor 2/lipoxin receptor or ,2 -integrins can generate contrasting cues in neutrophils in a ligand-specific manner and suggest a hierarchy among these signals. In this article, we review recent advances on how pro-apoptosis and pro-survival signals interact to determine the fate of neutrophils and the inflammatory response, and highlight novel pharmacological strategies that could be used to enhance the resolution of inflammation by redirecting neutrophils to apoptosis. J. Cell. Biochem. 108: 1039,1046, 2009. © 2009 Wiley-Liss, Inc. [source] Autoantigens in systemic autoimmunity: critical partner in pathogenesisJOURNAL OF INTERNAL MEDICINE, Issue 6 2009A. Rosen Abstract. Understanding the mechanisms of human autoimmune rheumatic diseases presents a major challenge, due to marked complexity involving multiple domains, including genetics, environment and kinetics. In spite of this, the immune response in each of these diseases is largely specific, with distinct autoantibodies associated with different disease phenotypes. Defining the basis of such specificity will provide important insights into disease mechanism. Accumulating data suggest an interesting paradigm for antigen selection in autoimmunity, in which target tissue and immune effector pathways form a mutually reinforcing partnership. In this model, distinct autoantibody patterns in autoimmunity may be viewed as the integrated, amplified output of several interacting systems, including: (i) the specific target tissue, (ii) the immune effector pathways that modify antigen structure and cause tissue damage and dysfunction, and (iii) the homeostatic pathways activated in response to damage (e.g. regeneration/differentiation/cytokine effects). As unique antigen expression and structure may occur exclusively under these amplifying circumstances, it is useful to view the molecules targeted as ,neo-antigens', that is, antigens expressed under specific conditions, rather than ubiquitously. This model adds an important new dynamic element to selection of antigen targets in autoimmunity, and suggests that the amplifying loop will only be identified by studying the diseased target tissue in vivo. [source] Anti-inflammatory properties of local anesthetics and their present and potential clinical implicationsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 3 2006J. Cassuto Development of new local anesthetic agents has been focused on the potency of their nerve-blocking effects, duration of action and safety and has resulted in a substantial number of agents in clinical use. It is well established and well documented that the nerve blocking effects of local anesthetics are secondary to their interaction with the Na+ channels thereby blocking nerve membrane excitability and the generation of action potentials. Accumulating data suggest however that local anesthetics also posses a wide range of anti-inflammatory actions through their effects on cells of the immune system, as well as on other cells, e.g. microorganisms, thrombocytes and erythrocytes. The potent anti-inflammatory properties of local anesthetics, superior in several aspects to traditional anti-inflammatory agents of the NSAID and steroid groups and with fewer side-effects, has prompted clinicians to introduce them in the treatment of various inflammation-related conditions and diseases. They have proved successful in the treatment of burn injuries, interstitial cystitis, ulcerative proctitis, arthritis and herpes simplex infections. The detailed mechanisms of action are not fully understood but seem to involve a reversible interaction with membrane proteins and lipids thus regulating cell metabolic activity, migration, exocytosis and phagocytosis. [source] Mammalian prenatal development: the influence of maternally derived moleculesBIOESSAYS, Issue 9 2009Cécile Fligny Abstract Normal fetal development is dependent upon an intricate exchange between mother and embryo. Several maternal and embryonic elements can influence this intimate interaction, including genetic, environmental or epigenetic factors, and have a significant impact on embryo development. The interaction of the genetic program of both mother and embryo, within the uterine environment, can shape the development of an individual. Accumulating data from animal models indicate that prenatal events may well initiate long-term changes in the expression of the embryo genetic program, which persist, or may only become apparent, much later in the individual's life. Also, environmental conditions during prenatal development may prompt the adoption of different developmental pathways, leading to alternative life histories. This review focuses on environmental factors, specifically maternally derived molecules, to illustrate how they can influence in utero embryonic development and, by extension, adult life. [source] CD8 T cell responses to viral infections in sequenceCELLULAR MICROBIOLOGY, Issue 5 2004Michael A. Brehm Summary Our current understanding of virus-specific T cell responses has been shaped by model systems with mice, where naive animals are infected with a single viral pathogen. Paradigms derived from such models, however, may not always be applicable to a natural setting, where a host is exposed to numerous pathogens over its lifetime. Accumulating data in animal models and with some human diseases indicate that a host's prior history of infections can impact the specificity of future CD8 T cell responses, even to unrelated viruses. This can have both beneficial and detrimental consequences for the host, including altered clearance of virus, distinct forms of immunopathology, and substantial changes in the pool of memory T cells. Here we will describe the characteristics of CD8 T cells and the dynamics of their response to heterologous viral infections in sequence. [source] Immune function in hypopituitarism: time to reconsider?CLINICAL ENDOCRINOLOGY, Issue 4 2010Annice Mukherjee Summary Hypopituitarism is not currently considered as a potential cause of immune disruption in humans. Accumulating data from in vitro and animal models support a role for the pituitary gland in immune regulation. Furthermore, the increased mortality risk noted in patients with adult hypopituitarism remains poorly explained and immune dysfunction could conceivably contribute to this observation. In a recent issue of Clinical & Experimental Immunology, we presented new data relating to immune status in adults with treated, severe hypopituitarism. We observed humoral immune deficiency in a significant proportion, despite stable pituitary replacement, including growth hormone (GH). This was especially evident in those with low pretreatment IGF-I levels and appeared independent of anticonvulsant use or corticosteroid replacement. These observations require substantiation with future studies. In this short review, we summarize existing data relating to the effects of pituitary hormones on immune function and discuss potential clinical implications surrounding the hypothesis of immune dysregulation in severe hypopituitarism. [source] Sequential methods and group sequential designs for comparative clinical trialsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2003Véronique Sébille Abstract Comparative clinical trials are performed to assess whether a new treatment has superior efficacy than a placebo or a standard treatment (one-sided formulation) or whether two active treatments have different efficacies (two-sided formulation) in a given population. The reference approach is the single-stage design and the statistical test is performed after inclusion and evaluation of a predetermined sample size. In practice, the single-stage design is sometimes difficult to implement because of ethical concerns and/or economic reasons. Thus, specific early termination procedures have been developed to allow repeated statistical analyses to be performed on accumulating data and stop the trial as soon as the information is sufficient to conclude. Two main different approaches can be used. The first one is derived from strictly sequential methods and includes the sequential probability ratio test and the triangular test. The second one is derived from group sequential designs and includes Peto, Pocock, and O'Brien and Fleming methods, , and , spending functions, and one-parameter boundaries. We review all these methods and describe the bases on which they rely as well as their statistical properties. We also compare these methods and comment on their advantages and drawbacks. We present software packages which are available for the planning, monitoring and analysis of comparative clinical trials with these methods and discuss the practical problems encountered when using them. The latest versions of all these methods can offer substantial sample size reductions when compared with the single-stage design not only in the case of clear efficacy but also in the case of complete lack of efficacy of the new treatment. The software packages make their use quite simple. However, it has to be stressed that using these methods requires efficient logistics with real-time data monitoring and, apart from survival studies or long-term clinical trials with censored endpoints, is most appropriate when the endpoint is obtained quickly when compared with the recruitment rate. [source] Electrophysiological characterization of neural stem/progenitor cells during in vitro differentiation: Study with an immortalized neuroectodermal cell lineJOURNAL OF NEUROSCIENCE RESEARCH, Issue 8 2007M. Jelitai Abstract Despite the accumulating data on the molecular and cell biological characteristics of neural stem/progenitor cells, their electrophysiological properties are not well understood. In the present work, changes in the membrane properties and current profiles were investigated in the course of in vitro-induced neuron formation in NE-4C cells. Induction by retinoic acid resulted in neuronal differentiation of about 50% of cells. Voltage-dependent Na+ currents appeared early in neuronal commitment, often preceding any morphological changes. A-type K+ currents were detected only at the stage of network formation by neuronal processes. Flat, epithelial- like, nestin-expressing progenitors persisted beside differentiated neurons and astrocytes. Stem/progenitor cells were gap junction coupled and displayed large, symmetrical, voltage-independent currents. By the blocking of gap junction communication, voltage-independent conductance was significantly reduced, and delayed-rectifying K+ currents became detectable. Our data indicate that voltage-independent symmetrical currents and gap junction coupling are characteristic physiological features of neural stem and progenitor cells regardless of the developmental state of their cellular environment. © 2007 Wiley-Liss, Inc. [source] EARLY INITIATION OF PHOSPHATE LOWERING DIETARY THERAPY IN NON-DIALYSIS CHRONIC KIDNEY DISEASE: A CRITICAL REVIEWJOURNAL OF RENAL CARE, Issue 2009M.K. Sigrist SUMMARY Dietary management of hyperphosphatemia and hyperparathyroidism have long been important elements in the clinical management of CKD stage 4 and 5 for the prevention of mineral bone disease. The rationale for phosphate lowering has been further justified, given the accumulating data to support the association of phosphate with vascular damage, in this population who are at high risk of cardiovascular (CV) death. Phosphate is a novel CV risk factor in both CKD and in the general population, and a growing body of literature suggests that high normal serum phosphate may be a risk factor for progression of CKD. Few studies have examined hard outcomes after phosphate lowering. Nonetheless, given the balance of data both in cell, animal and human studies, the use of phosphate lowering strategies at earlier stages of CKD, perhaps even prior to serum phosphate level rising, may well be justified. This review will discuss the complications associated with higher serum phosphate, the potential benefits of early phosphate intervention, practical considerations of low phosphate diets and novel strategies for evaluating these strategies in clinical practice. [source] A COMPARISON OF THE IMPRECISE BETA CLASS, THE RANDOMIZED PLAY-THE-WINNER RULE AND THE TRIANGULAR TEST FOR CLINICAL TRIALS WITH BINARY RESPONSESAUSTRALIAN & NEW ZEALAND JOURNAL OF STATISTICS, Issue 1 2007Lyle C. Gurrin Summary This paper develops clinical trial designs that compare two treatments with a binary outcome. The imprecise beta class (IBC), a class of beta probability distributions, is used in a robust Bayesian framework to calculate posterior upper and lower expectations for treatment success rates using accumulating data. The posterior expectation for the difference in success rates can be used to decide when there is sufficient evidence for randomized treatment allocation to cease. This design is formally related to the randomized play-the-winner (RPW) design, an adaptive allocation scheme where randomization probabilities are updated sequentially to favour the treatment with the higher observed success rate. A connection is also made between the IBC and the sequential clinical trial design based on the triangular test. Theoretical and simulation results are presented to show that the expected sample sizes on the truly inferior arm are lower using the IBC compared with either the triangular test or the RPW design, and that the IBC performs well against established criteria involving error rates and the expected number of treatment failures. [source] The Role of Cystatin C in Cerebral Amyloid Angiopathy and Stroke: Cell Biology and Animal ModelsBRAIN PATHOLOGY, Issue 1 2006Efrat Levy A variant of the cysteine protease inhibitor, cystatin c, forms amyloid deposited in the cerebral vasculature of patients with hereditary cerebral hemorrhage with amyloidosis, icelandic type (hchwa-i), leading to cerebral hemorrhages early in life. however, cystatin c is also implicated in neuronal degenerative diseases in which it does not form the amyloid protein, such as alzheimer disease (ad). accumulating data suggest involvement of cystatin c in the pathogenic processes leading to amyloid deposition in cerebral vasculature and most significantly to cerebral hemorrhage in patients with cerebral amyloid angiopathy (caa). This review focuses on cell culture and animal models used to study the role of cystatin c in these processes. [source] Neuronal migration disorders: clinical, neuroradiologic and genetics aspectsACTA PAEDIATRICA, Issue 3 2009Alberto Spalice Disorders of neuronal migration are a heterogeneous group of disorders of nervous system development. One of the most frequent disorders is lissencephaly, characterized by a paucity of normal gyri and sulci resulting in a ,smooth brain'. There are two pathologic subtypes: classical and cobblestone. Six different genes could be responsible for this entity (LIS1, DCX, TUBA1A, VLDLR, ARX, RELN), although co-delection of YWHAE gene with LIS1 could result in Miller,Dieker Syndrome. Heterotopia is defined as a cluster of normal neurons in abnormal locations, and divided into three main groups: periventricular nodular heterotopia, subcortical heterotopia and marginal glioneural heterotopia. Genetically, heterotopia is related to Filamin A (FLNA) or ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2) genes mutations. Polymicrogyria is described as an augmentation of small circonvolutions separated by shallow enlarged sulci; bilateral frontoparietal form is characterized by bilateral, symmetric polymicrogyria in the frontoparietal regions. Bilateral perisylvian polymicrogyria results in a clinical syndrome manifested by mild mental retardation, epilepsy and pseudobulbar palsy. Gene mutations linked to this disorder are SRPX2, PAX6, TBR2, KIAA1279, RAB3GAP1 and COL18A1. Schizencephaly, consisting in a cleft of cerebral hemisphere connecting extra-axial subaracnoid spaces and ventricles, is another important disorder of neuronal migration whose clinical characteristics are extremely variable. EMX2 gene could be implicated in its genesis. Focal cortical dysplasia is characterized by three different types of altered cortical laminations, and represents one of most severe cause of epilepsy in children. TSC1 gene could play a role in its etiology. Conclusion: This review reports the main clinical, genetical and neuroradiological aspects of these disorders. It is hoped that accumulating data of the development mechanisms underlying the expanded network formation in the brain will lead to the development of therapeutic options for neuronal migration disorders. [source] | |||||||||||||