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Various Pathologies (various + pathology)
Selected AbstractsProbing the corticospinal link between the motor cortex and motoneurones: some neglected aspects of human motor cortical functionACTA PHYSIOLOGICA, Issue 4 2010N. C. Petersen Abstract This review considers the operation of the corticospinal system in primates. There is a relatively widespread cortical area containing corticospinal outputs to a single muscle and thus a motoneurone pool receives corticospinal input from a wide region of the cortex. In addition, corticospinal cells themselves have divergent intraspinal branches which innervate more than one motoneuronal pool but the synergistic couplings involving the many hand muscles are likely to be more diverse than can be accommodated simply by fixed patterns of corticospinal divergence. Many studies using transcranial magnetic stimulation of the human motor cortex have highlighted the capacity of the cortex to modify its apparent excitability in response to altered afferent inputs, training and various pathologies. Studies using cortical stimulation at ,very low' intensities which elicit only short-latency suppression of the discharge of motor units have revealed that the rapidly conducting corticospinal axons (stimulated at higher intensities) drive motoneurones in normal voluntary contractions. There are also major non-linearities generated at a spinal level in the relation between corticospinal output and the output from the motoneurone pool. For example, recent studies have revealed that the efficacy of the human corticospinal connection with motoneurones undergoes activity-dependent changes which influence the size of voluntary contractions. Hence, corticospinal drives must be sculpted continuously to compensate for the changing functional efficacy of the descending systems which activate the motoneurones. This highlights the need for proprioceptive monitoring of movements to ensure their accurate execution. [source] Ovalbumin-induced sensitization affects non-quantal acetylcholine release from motor nerve terminals and alters contractility of skeletal muscles in miceEXPERIMENTAL PHYSIOLOGY, Issue 2 2009Alexander Y. Teplov Skeletal muscles play key roles in the development of various pathologies, including bronchial asthma and several types of auto-immune disorders, e.g. polymyositis. Since most of these maladies have an immunological/allergic element, this paper is devoted to assessing the impact of immunobiological reorganization on the functional properties of isolated skeletal muscles in mice. A combination of two methods (myography and electrophysiology) was used to evaluate extensor digitorum longus (EDL) and diaphragmatic muscle (DM) in this regard. Conventional myographic technique showed that ovalbumin-induced sensitization (OS) produced different changes in the contractile properties of EDL and DM. The amplitudes of carbachol (CCh)-induced contractions increased in DM but decreased in EDL. Those changes were inversely related to OS-mediated changes of non-quantal acetylcholine (ACh) release intensity within the muscle endplate, as shown by the electrophysiologically measured H-effect. These results clearly show that OS-mediated changes of non-quantal ACh release alter the functional properties of postjunctional ACh receptors and therefore contribute to the disturbance of CCh-induced contractility of skeletal muscles. Other mechanisms of OS-mediated changes of skeletal muscle contractility are also proposed and discussed. [source] Mapping of the active site of glutamate carboxypeptidase II by site-directed mutagenesisFEBS JOURNAL, Issue 18 2007Petra Ml, ochová Human glutamate carboxypeptidase II [GCPII (EC 3.4.17.21)] is recognized as a promising pharmacological target for the treatment and imaging of various pathologies, including neurological disorders and prostate cancer. Recently reported crystal structures of GCPII provide structural insight into the organization of the substrate binding cavity and highlight residues implicated in substrate/inhibitor binding in the S1, site of the enzyme. To complement and extend the structural studies, we constructed a model of GCPII in complex with its substrate, N -acetyl- l -aspartyl- l -glutamate, which enabled us to predict additional amino acid residues interacting with the bound substrate, and used site-directed mutagenesis to assess the contribution of individual residues for substrate/inhibitor binding and enzymatic activity of GCPII. We prepared and characterized 12 GCPII mutants targeting the amino acids in the vicinity of substrate/inhibitor binding pockets. The experimental results, together with the molecular modeling, suggest that the amino acid residues delineating the S1, pocket of the enzyme (namely Arg210) contribute primarily to the high affinity binding of GCPII substrates/inhibitors, whereas the residues forming the S1 pocket might be more important for the ,fine-tuning' of GCPII substrate specificity. [source] Routine clinical brain MRI sequences for use at 3.0 TeslaJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 1 2005Hanzhang Lu PhD Abstract Purpose To establish image parameters for some routine clinical brain MRI pulse sequences at 3.0 T with the goal of maintaining, as much as possible, the well-characterized 1.5-T image contrast characteristics for daily clinical diagnosis, while benefiting from the increased signal to noise at higher field. Materials and Methods A total of 10 healthy subjects were scanned on 1.5-T and 3.0-T systems for T1 and T2 relaxation time measurements of major gray and white matter structures. The relaxation times were subsequently used to determine 3.0-T acquisition parameters for spin-echo (SE), T1 -weighted, fast spin echo (FSE) or turbo spin echo (TSE), T2 -weighted, and fluid-attenuated inversion recovery (FLAIR) pulse sequences that give image characteristics comparable to 1.5 T, to facilitate routine clinical diagnostics. Application of the routine clinical sequences was performed in 10 subjects, five normal subjects and five patients with various pathologies. Results T1 and T2 relaxation times were, respectively, 14% to 30% longer and 12% to 19% shorter at 3.0 T when compared to the values at 1.5 T, depending on the region evaluated. When using appropriate parameters, routine clinical images acquired at 3.0 T showed similar image characteristics to those obtained at 1.5 T, but with higher signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), which can be used to reduce the number of averages and scan times. Recommended imaging parameters for these sequences are provided. Conclusion When parameters are adjusted for changes in relaxation rates, routine clinical scans at 3.0 T can provide similar image appearance as 1.5 T, but with superior image quality and/or increased speed. J. Magn. Reson. Imaging 2005;22:13,22. © 2005 Wiley-Liss, Inc. [source] Increased metastatic potential of tumor cells in von Willebrand factor-deficient miceJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2006V. TERRAUBE Summary.,Background:,The key role played by von Willebrand factor (VWF) in platelet adhesion suggests a potential implication in various pathologies, where this process is involved. In cancer metastasis development, tumor cells interact with platelets and the vessel wall to extravasate from the circulation. As a potential mediator of platelet,tumor cell interactions, VWF could influence this early step of tumor spread and therefore play a role in cancer metastasis.Objectives:,To investigate whether VWF is involved in metastasis development.Methods:,In a first step, we characterized the interaction between murine melanoma cells B16-BL6 and VWF in vitro. In a second step, an experimental metastasis model was used to compare the formation of pulmonary metastatic foci in C57BL/6 wild-type and VWF-null mice following the injection of B16-BL6 cells or Lewis lung carcinoma cells.Results:,In vitro adhesion assays revealed that VWF is able to promote a dose-dependent adhesion of B16-BL6 cells via its Arg-Gly-Asp (RGD) sequence. In the experimental metastasis model, we found a significant increase in the number of pulmonary metastatic foci in VWF-null mice compared with the wild-type mice, a phenotype that could be corrected by restoring VWF plasma levels. We also showed that increased survival of the tumor cells in the lungs during the first 24 h in the absence of VWF was the cause of this increased metastasis.Conclusion:,These findings suggest that VWF plays a protective role against tumor cell dissemination in vivo. Underlying mechanisms remain to be investigated. [source] Post-pathological keel-loss compensation in ammonoid growthLETHAIA, Issue 1 2002ALAIN MORARD Among the various pathologies documented in ammonoids, impairs affecting the apertural margin may have long-lasting sequelae on subsequent shell geometry. An interesting healing pattern, known as sculptural compensation, led to the permanent replacement of an ornament by adjacent sculptural elements. Moreover, in several ventrally impaired individuals the symmetry was preserved. Those developed annular ribs in place of any previous ventral ornamentation (keel, sulcus or smooth area). This phenomenon is known from diverse ammonite families. Monestieria resouchei (Monestier 1931), type species of ,Monestieriinae' Sapunov 1965, displays exactly that type of annularly-ribbed morphology and has been shown to be otherwise similar to species of Grammoceratinae Buckman 1904 occurring in the same beds, thus corroborating its pathological nature and leading to the rejection of that taxon. Now, keel absence in Praehaploceras Monestier 1931 and Buckmanites Guex 1973 cannot be explained by the same process as they do not have annular ribs. Moreover, the absence of any clue of malformation, their relative frequency and specific characteristics exclude the previously suggested synonymies with Pseudolioceras Buckman 1889 as equivalent pathological forms. In consequence, their rehabilitation is herein proposed. They should be included within Harpoceratinae Neumayr 1875. [source] Modifications and oxidation of lipids and proteins in human serum detected by thermochemiluminescenceLUMINESCENCE: THE JOURNAL OF BIOLOGICAL AND CHEMICAL LUMINESCENCE, Issue 2 2003Sergei Shnizer Abstract Detection of electronically excited species (EES) in body fluids may constitute an important diagnostic tool in various pathologies. Examples of such products are triplet excited carbonyls (TEC), which can be a source for photon emission in the 400,550,nm range. The aim of the present study was to determine the actual contribution of lipid and protein components (protein carbonyls) to photon emission generated by thermochemiluminescence (TCL) during the heating of biological fluids. In this study, a new TCL Photometer device, designed by Lumitest Ltd, Israel, was used. Samples were heated to a constant temperature of 80,±,0.5°C for 280,s and photon emission was measured at several time points. In order to compare the results of TCL measurements to conventional methods of detecting lipid and protein oxidation, each examined sample was also heated in a waterbath at 80°C for 10,280,s. Lipid and protein oxidation were subsequently measured using conventional methods. The TCL of four polyunsaturated fatty acids (PUFA) with three to six double bonds was measured. The elevation of the PUFA TCL amplitude correlated with the increase in the number of double bonds of PUFA. A correlation between the increase in TCL intensity and protein carbonyl generation in bovine serum albumin (BSA) was also observed. In the venous blood serum, our study showed that an increase of TCL intensity during heating reflected the cleavage of TEC of lipid origin. Our study suggests that biological molecules such as proteins, lipids and other molecules, which may become unstable during heating, are capable of generating EES. We demonstrated that a TCL curve can be used as a kinetic model for measuring oxidative processes, which reflects modifications of different molecules involved in the oxidative stress phenomena. Copyright © 2003 John Wiley & Sons, Ltd. [source] On the Role of Iron and one of its Chelating Agents in the Production of Protoporphyrin IX Generated by 5-Aminolevulinic Acid and its Hexyl Ester Derivative Tested on an Epidermal Equivalent of Human SkinPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 4 2006Pascal Uehlinger ABSTRACT Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) or its derivatives as precursors of protoporphyrin IX (PPIX) is routinely used in dermatology for the treatment of various pathologies. However, this methodology suffers to some extent from a limited efficacy. Therefore, the main goal of this study was to investigate the modulation and pharma-cokinetics of PPIX buildup after a 5 h incubation with ALA (1.5 mM) and one of its derivatives, the hexyl ester of ALA (h-ALA) (1.5 mM), on the human epidermal equivalent EpidexÔ. PPIX production was modulated with (L+) ascorbic acid iron (II) salt (LAI) or the iron (II)-specific chelating agent deferoxamine (DFO). PPIX fluorescence from the EpidexÔ layers was measured up to 150 h after the precursor administration using a microspectrofluorometer (,ex: 400 ± 20 nm; ,det: 635 nm). The maximum PPIX fluorescence intensity induced by h-ALA was about 1.7x larger than that induced by ALA. The addition of DFO resulted in a more than 50% increase in PPIX fluorescence for both precursors. The decay half life measured for PPIX fluorescence is 30 and 42.5 h, respectively, for ALA and h-ALA. These half lives are doubled when the samples contain DFO. In the samples with the highest fluorescence intensity, a modified fluorescence spectrum was observed after 10 h, with the emergence of a peak at 590 nm, which is attributed to zinc protoporphyrin IX (Zn PPIX). [source] Chemokine receptor CCR2 undergoes transportin1-dependent nuclear translocationPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 21 2008Nicolas Favre Abstract Chemokines (CCs) are small chemoattractant cytokines involved in a wide variety of biological and pathological processes. Released by cells in the milieu, and extracellular matrix and activating signalling cascades upon binding to specific G protein-coupled receptors (GPCRs), they trigger many cellular events. In various pathologies, CCs are directly responsible for excessive recruitment of leukocytes to inflammatory sites and recent studies using chemokine receptor (CCR) antagonists permitted these molecules to reach the market for medical use. While interaction of CCs with their receptors has been extensively documented, downstream GPCR signalling cascades triggered by CC are less well understood. Given the pivotal role of chemokine receptor 2 (CCR2) in monocyte recruitment, activation and differentiation and its implication in several autoimmune-inflammatory pathologies, we searched for potential new CCR2-interacting proteins by engineering a modified CCR2 that we used as bait. Herein, we show the direct interaction of CCR2 with transportin1 (TRN1), which we demonstrate is followed by CCR2 receptor internalization. Further characterization of this novel interaction revealed that TRN1-binding to CCR2 increased upon time in agonist treated cells and promotes its nuclear translocation in a TRN1-dependent manner. Finally, we provide evidence that following translocation, the receptor localizes at the outer edge of the nuclear envelope where it is finally released from TRN1. [source] Plasmid DNA electrotransfer for intracellular and secreted proteins expression: new methodological developments and applicationsTHE JOURNAL OF GENE MEDICINE, Issue S1 2004Carole Bloquel Abstract In vivo electrotransfer is a physical method of gene delivery in various tissues and organs, relying on the injection of a plasmid DNA followed by electric pulse delivery. The importance of the association between cell permeabilization and DNA electrophoresis for electrotransfer efficiency has been highlighted. In vivo electrotransfer is of special interest since it is the most efficient non-viral strategy of gene delivery and also because of its low cost, easiness of realization and safety. The potentiality of this technique can be further improved by optimizing plasmid biodistribution in the targeted organ, plasmid structure, and the design of the encoded protein. In particular, we found that plasmids of smaller size were electrotransferred more efficiently than large plasmids. It is also of importance to study and understand kinetic expression of the transgene, which can be very variable, depending on many factors including cellular localization of the protein, physiological activity and regulation. The most widely targeted tissue is skeletal muscle, because this strategy is not only promising for the treatment of muscle disorders, but also for the systemic secretion of therapeutic proteins. Vaccination and oncology gene therapy are also major fields of application of electrotransfer, whereas application to other organs such as liver, brain and cornea are expanding. Many published studies have shown that plasmid electrotransfer can lead to long-lasting therapeutic effects in various pathologies such as cancer, blood disorders, rheumatoid arthritis or muscle ischemia. DNA electrotransfer is also a powerful laboratory tool to study gene function in a given tissue. Copyright © 2004 John Wiley & Sons, Ltd. [source] Therapeutic Targets in Liver Transplantation: Angiotensin II in Nonsteatotic Grafts and Angiotensin-(1,7) in Steatotic GraftsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2009I. Alfany-Fernandez Numerous steatotic livers are discarded as unsuitable for transplantation because of their poor tolerance of ischemia-reperfusion(I/R). The injurious effects of angiotensin (Ang)-II and the benefits of Ang-(1,7) in various pathologies are well documented. We examined the generation of Ang II and Ang-(1,7) in steatotic and nonsteatotic liver grafts from Zucker rats following transplantation. We also studied in both liver grafts the effects of Ang-II receptors antagonists and Ang-(1,7) receptor antagonists on hepatic I/R damage associated with transplantation. Nonsteatotic grafts showed higher Ang II levels than steatotic grafts, whereas steatotic grafts showed higher Ang-(1,7) levels than nonsteatotic grafts. Ang II receptor antagonists protected only nonsteatotic grafts against damage, whereas Ang-(1,7) receptor antagonists were effective only in steatotic grafts. The protection conferred by Ang II receptor antagonists in nonsteatotic grafts was associated with ERK 1/2 overexpression, whereas the beneficial effects of Ang-(1,7) receptor antagonists in steatotic grafts may be mediated by NO inhibition. Our results show that Ang II receptor antagonists are effective only in nonsteatotic liver transplantation and point to a novel therapeutic target in liver transplantation based on Ang-(1,7), which is specific for steatotic liver grafts. [source] Structure of aminopeptidase N from Escherichia coli complexed with the transition-state analogue aminophosphinic inhibitor PL250ACTA CRYSTALLOGRAPHICA SECTION D, Issue 8 2009Marie-Claude Fournié-Zaluski Aminopeptidase N (APN; EC 3.4.11.2) purified from Escherichia coli has been crystallized with the optically pure aminophosphinic inhibitor PL250, H3N+ -CH(CH3)-P(O)(OH)-CH2 -CH(CH2Ph)-CONH-CH(CH2Ph)CO2,, which mimics the transition state of the hydrolysis reaction. PL250 inhibits APN with a Ki of 1.5,2.2,nM and its three-dimensional structure in complex with E. coli APN showed its interaction with the S1, S,1 and S,2 subsites of the catalytic site. In this structure, the Zn ion was shown to be pentacoordinated by His297, His301 and Glu320 of APN and the two O atoms of the phosphinic moiety of PL250. One of these O atoms is also involved in a hydrogen bond to Tyr381, supporting the proposed role of this amino acid in the stabilization of the transition state of the enzymatic process. The strength of the phosphinic zinc binding and the occupancy of the S,2 subsite account for the 100-fold increase in affinity of PL250 compared with the dipeptide-derived inhibitor bestatin (Ki = 4.1 × 10,6,M). Accordingly, the removal of the C-terminal phenylalanine of PL250 resulted in a large decrease in affinity (Ki = 2.17 × 10,7,M). Furthermore, it was observed that the C-terminal carboxyl group of the inhibitor makes no direct interactions with the amino acids of the APN active site. Interestingly, PL250 exhibits the same inhibitory potency for E. coli APN and for mammalian enzymes, suggesting that the structure of the complex could be used as a template for the rational design of various human APN inhibitors needed to study the role of this aminopeptidase in various pathologies. 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