1,720,960 research outputs found
Reducing conditions produce a loss of neuroprotective efficacy of competitive but not non-competitive antagonists in a model of NMDA-mediated excitotoxicity in organotypic hippocampal slice cultures
No full textExperimental data indicate that NMDA receptor activation is strongly implicated in the pathogenesis of cerebral ischaemia. However, the results from in vivo studies are equivocal, with NMDA antagonists being active in only some models. It has recently been demonstrated that competitive and non-competitive NMDA antagonists behave differently under normal and ischaemic conditions. These studies have used organotypic hippocampal slice cultures to investigate whether this disparity is due to redox-modulation of the NMDA receptor which occurs in ischaemia. NMDA-mediated toxicity was concentration dependent with little damage occurring with less than 10 µM NMDA and maximal damage produced by 30 µM. NMDA toxicity was significantly enhanced by pre-treatment with 1 mM dithiothreitol, a reducing agent, such that damage occurred at 1 nM NMDA, and maximal damage was produced by 10 µM. The efficacy of MK-801 was not altered by reducing conditions, but the EC50 of the competitive antagonist APV was increased by 20-fold. These data strongly suggest that the neuroprotective efficacy of NMDA antagonists is significantly altered under ischaemic conditions, and that more beneficial effects will be obtained with antagonists having a higher affinity for the receptor in the reduced configuration
Reducing conditions significantly attenuate the neuroprotective efficacy of competitive, but not other NMDA receptor antagonists in vitro
No full textInappropriate 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
A microdialysis method for the recovery of IL-1beta, IL-6 and nerve growth factor from human brain in vivo
No full textIntracerebral microdialysis is used extensively as a research tool in the investigation of the neurochemical and metabolic changes that occur following acute brain injury. Microdialysis has enabled elucidation of intra-cerebral levels of substances such as lactate, pyruvate and glycerol but, as yet, has not been used effectively to recover macromolecules from the human brain. Traumatic brain injury is known to result in the generation of cytokines and neurotrophins into extracellular fluid compartment of the brain, with effects on neuronal damage and repair. We have developed a technique of in vivo sampling of the interstitial fluid of the brain of patients with severe head injuries which has allowed the measurement of IL-1?, IL-6 and nerve growth factor. This report confirms the safety and effectiveness of this modified microdialysis method in the clinical setting of a neurological intensive care unit. The technique provides a timely addition to the armamentarium of the clinical scientist and will potentially lead to a greater understanding of neuroinflammation following acute traumatic brain injury
Polymorphisms in matrix metalloproteinase-1, -3, -9, and -12 genes in relation to subarachnoid hemorrhage
No full textBackground and Purpose:
Intracranial aneurysm, which underlies the vast majority of subarachnoid hemorrhage incidences, has a multifactorial etiology, and the importance of genetic factors is increasingly recognized. Development and rupture of intracranial aneurysms involve degradation and remodeling of the vascular wall matrix in which the matrix metalloproteinases (MMPs) play an important role. The possible impact of MMP gene polymorphisms on susceptibility to intracranial aneurysms is still controversial, with conflicting data from different reported studies. Methods:
In this study we analyzed 5 different functional promoter polymorphisms in the MMP-1, MMP-3, MMP-9, and MMP-12 genes in a sample of 92 patients with aneurysmal subarachnoid hemorrhage and 158 healthy control subjects, all from southern England. Results:
No significant difference was detected between the patient and control groups in genotype distribution of any of the polymorphisms studied. Conclusions:
The data do not support the hypothesis that MMP gene variations influence the development of intracranial aneurysms in the population studied
Characterisation of a novel class of polyamine-based neuroprotective compounds
No full textProlonged cerebral ischaemia initiates complex intra- and inter-cellular signalling cascades ultimately resulting in neuronal death. Well-characterised mediators of ischaemic cell death are glutamate, free radicals and nitric oxide. Many drugs that block these mechanisms are neuroprotective in vitro, but have unfavourable side-effect profiles in man. We have recently demonstrated that the compound L-arginyl-3,4-spermidine (L-Arg3,4) is neuroprotective in vitro through an interaction with several of these mechanisms, and prevents ischaemic neurodegeneration in vivo with no gross side effects. In this study, we have used solid-phase combinatorial chemistry, to synthesise a number of analogues of L-Arg3,4, and investigate the structure-activity relationship using an in vitro, organotypic hippocampal slice culture model of cerebral ischaemia. A number of molecular features were identified which were essential for the neuroprotective activity including the requirement for a positive charge and an amino acid in the L-configuration. Relatively minor alterations to both the terminal arginine and polyamine moieties significantly attenuated neuroprotective efficacy. Our data implies that these compounds are neuroprotective through a currently undefined mechanism rather than non-specific ionic interactions described previously for other polyamine-containing compounds
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
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
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