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Budapest, Hungary

Koncz I.,University of Szeged | Szasz B.K.,Hungarian Academy of Sciences | Szabo S.I.,Hungarian Academy of Sciences | Kiss J.P.,Servier | And 5 more authors.
Brain Research Bulletin | Year: 2014

Kainate (KA), used for modelling neurodegenerative diseases, evokes excitotoxicity. However, the precise mechanism of KA-evoked [Ca2+]i increase is unexplored, especially in acute brain slice preparations. We used [Ca2+]i imaging and patch clamp electrophysiology to decipher the mechanism of KA-evoked [Ca2+]i rise and its inhibition by the tricyclic antidepressant desipramine (DMI) in CA1 pyramidal cells in rat hippocampal slices and in cultured hippocampal cells. The effect of KA was dose-dependent and relied totally on extracellular Ca2+. The lack of effect of dl-2-amino-5-phosphonopentanoic acid (AP-5) and abolishment of the response by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) suggested the involvement of non-N-methyl-d-aspartate receptors (non-NMDARs). The predominant role of the Ca2+-impermeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) in the initiation of the Ca2+ response was supported by the inhibitory effect of the selective AMPAR antagonist GYKI 53655 and the ineffectiveness of 1-naphthyl acetylspermine (NASPM), an inhibitor of the Ca2+-permeable AMPARs. The voltage-gated Ca2+ channels (VGCC), blocked by ω-Conotoxin MVIIC+nifedipine+NiCl2, contributed to the [Ca2+]i rise. VGCCs were also involved, similarly to AMPAR current, in the KA-evoked depolarisation. Inhibition of voltage-gated Na+ channels (VGSCs; tetrodotoxin, TTX) did not affect the depolarisation of pyramidal cells but blocked the depolarisation-evoked action potential bursts and reduced the Ca2+ response. The tricyclic antidepressant DMI inhibited the KA-evoked [Ca2+]i rise in a dose-dependent manner. It directly attenuated the AMPA-/KAR current, but its more potent inhibition on the Ca2+ response supports additional effect on VGCCs, VGSCs and Na+/Ca2+ exchangers. The multitarget action on decisive players of excitotoxicity holds out more promise in clinical therapy of neurodegenerative diseases. © 2014 Elsevier Inc. Source


Allaili N.,Institute Du Cerveau Et Of La Moelle Epiniere Icm | Allaili N.,French Institute of Health and Medical Research | Allaili N.,French National Center for Scientific Research | Allaili N.,Paris-Sorbonne University | And 24 more authors.
NMR in Biomedicine | Year: 2015

The hippocampus is crucial for long-term episodic memory and learning. It undergoes structural change in aging and is sensitive to neurodegenerative and psychiatric diseases. MRS studies have seldom been performed in the hippocampus due to technical challenges. The reproducibility of MRS in the hippocampus has not been evaluated at 3 T. The purpose of the present study was to quantify the concentration of metabolites in a small voxel placed in the hippocampus and evaluate the reproducibility of the quantification. Spectra were measured in a 2.4 mL voxel placed in the left hippocampus covering the body and most of the tail of the structure in 10 healthy subjects across three different sessions and quantified using LCModel. High-quality spectra were obtained, which allowed a reliable quantification of 10 metabolites including glutamate and glutamine. Reproducibility of MRS was evaluated with coefficient of variation, standard errors of measurement, and intraclass correlation coefficients. All of these measures showed improvement with increased number of averages. Changes of less than 5% in concentration of N-acetylaspartate, choline-containing compounds, and total creatine and of less than 10% in concentration of myo-inositol and the sum of glutamate and glutamine can be confidently detected between two measurements in a group of 20 subjects. A reliable and reproducible neurochemical profile of the human hippocampus was obtained using MRS at 3 T in a small hippocampal volume. Copyright © 2015 John Wiley & Sons, Ltd. Source


Bruyere O.,University of Liege | Rizzoli R.,University of Geneva | Coxam V.,University Of Clermont Ferrand | Avouac B.,CHU Henri Mondor | And 6 more authors.
Osteoporosis International | Year: 2012

Summary Health claims for food products in Europe are permitted if the nutrient has been shown to have a beneficial nutritional or physiological effect. This paper defines health claims related to bone health and provides guidelines for the design and the methodology of clinical studies to support claims. Introduction Regulation (EC) no. 1924/2006 on nutrition and health claims targeting food products was introduced in Europe stating that health claims shall only be permitted if the substance in respect of which the claim is made has been shown to have a beneficial nutritional or physiological effect. The objective of this paper is to define health claims related to bone health and to provide guidelines for the design and the methodology of clinical studies which need to be adopted to assert such health claims. Methods Literature review followed by a consensus discussion during two 1-day meetings organized by the Group for the Respect of Ethics and Excellence in Science (GREES). Results The GREES identified six acceptable health claims related to bone health based on the potential of food products to show an effect on either the bioavailability of calcium or osteoclast regulatory proteins or bone turnover markers or bone mineral density or bone structure or fracture incidence. The GREES considers that welldesigned human randomized controlled trial on a relevant outcome is the best design to assess health claims. The substantiation of health claim could also be supported by animal studies showing either an improvement in bone strength with the food product or showing the relationship between changes induced by the food product on a surrogate marker and changes in bone strength. Conclusion The consensus reached is that the level of health claim may differ according to the surrogate endpoint used and on additional animal studies provided to support the claim. © International Osteoporosis Foundation and National Osteoporosis Foundation 2011. Source


Dijksman J.,Solusacta | Timmerman P.,Janssen Research and Development | Abbott R.,Shire Pharmaceuticals | Barroso B.,Astellas | And 9 more authors.
Bioanalysis | Year: 2012

The 4th Open Symposium of the European Bioanalytical Forum entitled 'Less is More' was held on 16-18 November 2011 at the Hesperia Tower Hotel, Barcelona, Spain. More than 50 interesting presentations were delivered covering areas with interest for the small- and large-molecule community - biomarker validation; regulations, including an update on new and emerging guidelines and on Global harmonization; technology updates; incurred sample stability; microdosing; dried blood spots and microsampling; challenges of 'free' and 'total' macromolecule quantification; stability issues in ligand binding assays or anomalous results. In excess of 450 delegates from more than 170 institutes and companies (industry, regulators and academia) from all global regions participated in the open and stimulating discussions. This manuscript provides an overview of the highlights discussed at the meeting. © 2012 Future Science Ltd. Source


Cooper C.,University of Oxford | Dere W.,Amgen | Evans W.,Glaxosmithkline | Kanis J.A.,University of Sheffield | And 11 more authors.
Osteoporosis International | Year: 2012

An operational definition of musculoskeletal decline in older people is needed to allow development of interventions for prevention or treatment, as was developed for the treatment of osteoporosis. Frailty and sarcopenia are linked, but distinct, correlates of musculoskeletal aging that have many causes, including age-related changes in body composition, inflammation, and hormonal imbalance. With the emergence of a number of exciting candidate therapies to retard the loss of muscle mass with aging, the derivation of a consensual definition of sarcopenia and physical frailty becomes an urgent priority. Although several consensual definitions have been proposed, these require clinical validation. An operational definition, which might provide a threshold for treatment/trial inclusion, should incorporate a loss of muscle mass as well as evidence of a decrease in muscle strength and/or physical activity. Evidence is required for a link between improvements in the measures of muscle strength and/or physical activity and clinical outcomes to allow development of interventions to improve clinical outcomes in frail older patients. © 2012 International Osteoporosis Foundation and National Osteoporosis Foundation. Source

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