Publications of Philippe LEFEBVRE
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See detailDerivation of cochlear cells from pathological or isogenic human iPSCs for modeling hereditary hearing loss
Czajkowski, Amandine ULiege; Grobarczyk, Benjamin; Hanon, Kevin ULiege et al

Poster (2016, May)

Alström Syndrome (AS) is a human autosomal recessive genetic disorder characterized by numerous clinical symptoms including deafness. AS is caused by mutations in the ALMS1 gene encoding for ALMS1 protein ... [more ▼]

Alström Syndrome (AS) is a human autosomal recessive genetic disorder characterized by numerous clinical symptoms including deafness. AS is caused by mutations in the ALMS1 gene encoding for ALMS1 protein expressed at the basal body and implicated in ciliogenesis, cell cycle and proliferation (Jagger et al., 2011; Zulato et al., 2011 & Shenje et al., 2014). We are interesting in understanding the unknown mechanisms involving this protein in the genetic deafness of AS patients. To develop a model as closer as possible to the human pathology, we are using human induced pluripotent stem cells (hiPSCs) generated from fibroblasts of healthy and AS patients. Using a stepwise protocol, we demonstrated that healthy hiPSCs (waiting for isogenic hiPSCs) can generate a population of cells with gene and protein expression patterns consistent with the ones of otic progenitor cells (OSCs). At this differentiation stage, we observed some proliferation and apoptotic defects between healthy and AS cells. When human OSCs are co-cultured with mouse feeder cells, they are able to differentiate into hair cells (HCs). We successfully differentiated AS hiPSCs generated from AS patients into HCs. We are currently confirming gene expression pattern and testing HCs functionality.  To exclude patient linked epigenetics and differentiation defects, we are correcting the genomic mutation in the AS hiPSCs to generate isogenic hiPSCs using the CRIPSR/Cas9 system. Thanks to the isogenic hiPSCs we will be able to confirm that these defects are well due to the ALMS1 mutation. [less ▲]

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See detailSwallowing in disorders of consciousness
Bicego, Aminata Yasmina ULiege; Lejoly, Kelly ULiege; Maudoux, Audrey et al

in Revue Neurologique (2014), 170(10),

Detailed reference viewed: 288 (20 ULiège)
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See detailcomment j'explore une otite séromuqueuse chez l'enfant
Dachy, Angélique ULiege; LEFEBVRE, Philippe ULiege; Battisti, Oreste ULiege

in Revue Médicale de Liège (2013), 68

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See detailNovel cooperation between CX3CL1 and CCL26 inducing NK cell chemotaxis via CX3CR1: a possible mechanism for NK cell infiltration of the allergic nasal tissue
EL SHAZLY, Amr ULiege; Castillo-Doloriert, Hugo; Bisig, Bettina et al

Poster (2013)

Background: Recent data indicated that natural killer (NK) cells and chemokines could play a pivotal role in nasal inflammation. CX3CR1, the only receptor for fractalkine/ CX3CL1, is abundantly expressed ... [more ▼]

Background: Recent data indicated that natural killer (NK) cells and chemokines could play a pivotal role in nasal inflammation. CX3CR1, the only receptor for fractalkine/ CX3CL1, is abundantly expressed by NK cells, and was recently shown to also be a receptor for eotaxin-3/CCL26. However, no reports explored the NK cells-CX3CL1-CCL26 axis via CX3CR1 in allergy.
Objective: Our goals were first to determine specifically NK cell recruitment pattern in nasal tissue of allergic chronic rhinosinusitis (ACRS) and non-allergic chronic rhinosinusitis (NACRS) patients in comparison with healthy controls, and secondly, to investigate the function of CX3CR1 in NK cell migration. Methods: Immunohistochemistry, microchemotaxis chambers, flow cytometry and confocal microscopy were used in this study. Results: Herein, we showed that NK cells infiltrated the epithelial layers of nasal tissue only in ACRS patients and not in NACRS patients or controls. NK cells were also more numerous in the stroma of the nasal tissue from ACRS patients compared with NACRS patients or controls. This migration could be mediated by both CX3CL1 and CCL26, as these two chemokines induced NK cell migration. Moreover, both molecules also stimulated cytoskeleton changes and F-actin reorganisation in NK cells. Chemotaxis and cytoskeleton changes were sensitive to genistein, a tyrosine kinase inhibitor. By flow cytometry, we demonstrated that a single antigen nasal provocation challenge increased the expression of CX3CR1 on NK cells in allergic rhinitis (AR) patients. The function of this receptor was associated with a significant augmentation of NK cell chemotaxis against the optimal doses of CX3CL1 and CCL26. Conclusions and Clinical Relevance: Our results highlight a novel role for CX3CR1 in NK cell migration that may contribute to the NK cell trafficking to the allergic upper airway. This could be mediated largely by CX3CL1 and CCL26 stimulation of the tyrosine kinase pathway. [less ▲]

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See detailNovel cooperation between CX3CL1 and CCL26 inducing NK cell chemotaxis via CX3CR1: a possible mechanism for NK cell infiltration of the allergic nasal tissue.
EL SHAZLY, Amr ULiege; Castillo- Doloriert, Hugo; Bisig, Bettina et al

in Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology (2013), 43(3), 322-31

BACKGROUND: Recent data indicated that natural killer (NK) cells and chemokines could play a pivotal role in nasal inflammation. CX3CR1, the only receptor for fractalkine/CX3CL1, is abundantly expressed ... [more ▼]

BACKGROUND: Recent data indicated that natural killer (NK) cells and chemokines could play a pivotal role in nasal inflammation. CX3CR1, the only receptor for fractalkine/CX3CL1, is abundantly expressed by NK cells, and was recently shown to also be a receptor for eotaxin-3/CCL26. However, no reports explored the NK cells-CX3CL1-CCL26 axis via CX3CR1 in allergy. OBJECTIVE: Our goals were first to determine specifically NK cell recruitment pattern in nasal tissue of allergic chronic rhinosinusitis (ACRS) and non-allergic chronic rhinosinusitis (NACRS) patients in comparison with healthy controls, and secondly, to investigate the function of CX3CR1 in NK cell migration. METHODS: Immunohistochemistry, microchemotaxis chambers, flow cytometry and confocal microscopy were used in this study. RESULTS: Herein, we showed that NK cells infiltrated the epithelial layers of nasal tissue only in ACRS patients and not in NACRS patients or controls. NK cells were also more numerous in the stroma of the nasal tissue from ACRS patients compared with NACRS patients or controls. This migration could be mediated by both CX3CL1 and CCL26, as these two chemokines induced NK cell migration. Moreover, both molecules also stimulated cytoskeleton changes and F-actin reorganisation in NK cells. Chemotaxis and cytoskeleton changes were sensitive to genistein, a tyrosine kinase inhibitor. By flow cytometry, we demonstrated that a single antigen nasal provocation challenge increased the expression of CX3CR1 on NK cells in allergic rhinitis (AR) patients. The function of this receptor was associated with a significant augmentation of NK cell chemotaxis against the optimal doses of CX3CL1 and CCL26. CONCLUSIONS AND CLINICAL RELEVANCE: Our results highlight a novel role for CX3CR1 in NK cell migration that may contribute to the NK cell trafficking to the allergic upper airway. This could be mediated largely by CX3CL1 and CCL26 stimulation of the tyrosine kinase pathway. [less ▲]

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See detailThe neuroscience of tinnitus: Perspectives from human neuroimaging studies
Maudoux, Audrey ULiege; Vanneste, Sven; De Ridder, Dirk et al

Conference (2012, November)

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See detailAuditory Resting-State Network Connectivity in Tinnitus: a Functionnal MRI Study.
MAUDOUX, Audrey ULiege; LEFEBVRE, Philippe ULiege; CABAY, Jean-Evrard ULiege et al

in PLoS ONE (2012)

The underlying functional neuroanatomy of tinnitus remains poorly understood. Few studies have focused on functional cerebral connectivity changes in tinnitus patients. The aim of this study was to test ... [more ▼]

The underlying functional neuroanatomy of tinnitus remains poorly understood. Few studies have focused on functional cerebral connectivity changes in tinnitus patients. The aim of this study was to test if functional MRI ‘‘resting-state’’ connectivity patterns in auditory network differ between tinnitus patients and normal controls. Thirteen chronic tinnitus subjects and fifteen age-matched healthy controls were studied on a 3 tesla MRI. Connectivity was investigated using independent component analysis and an automated component selection approach taking into account the spatial and temporal properties of each component. Connectivity in extra-auditory regions such as brainstem, basal ganglia/NAc, cerebellum, parahippocampal, right prefrontal, parietal, and sensorimotor areas was found to be increased in tinnitus subjects. The right primary auditory cortex, left prefrontal, left fusiform gyrus, and bilateral occipital regions showed a decreased connectivity in tinnitus. These results show that there is a modification of cortical and subcortical functional connectivity in tinnitus encompassing attentional, mnemonic, and emotional networks. Our data corroborate the hypothesized implication of non-auditory regions in tinnitus physiopathology and suggest that various regions of the brain seem involved in the persistent awareness of the phenomenon as well as in the development of the associated distress. leading to disabling chronic tinnitus. [less ▲]

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See detailAuditory resting-state network connectivity in tinnitus: a functional MRI study.
MAUDOUX, Audrey ULiege; Lefèbvre, Philippe ULiege; CABAY, Jean-Evrard ULiege et al

in PLoS ONE (2012), 7(5), 36222

The underlying functional neuroanatomy of tinnitus remains poorly understood. Few studies have focused on functional cerebral connectivity changes in tinnitus patients. The aim of this study was to test ... [more ▼]

The underlying functional neuroanatomy of tinnitus remains poorly understood. Few studies have focused on functional cerebral connectivity changes in tinnitus patients. The aim of this study was to test if functional MRI "resting-state" connectivity patterns in auditory network differ between tinnitus patients and normal controls. Thirteen chronic tinnitus subjects and fifteen age-matched healthy controls were studied on a 3 tesla MRI. Connectivity was investigated using independent component analysis and an automated component selection approach taking into account the spatial and temporal properties of each component. Connectivity in extra-auditory regions such as brainstem, basal ganglia/NAc, cerebellum, parahippocampal, right prefrontal, parietal, and sensorimotor areas was found to be increased in tinnitus subjects. The right primary auditory cortex, left prefrontal, left fusiform gyrus, and bilateral occipital regions showed a decreased connectivity in tinnitus. These results show that there is a modification of cortical and subcortical functional connectivity in tinnitus encompassing attentional, mnemonic, and emotional networks. Our data corroborate the hypothesized implication of non-auditory regions in tinnitus physiopathology and suggest that various regions of the brain seem involved in the persistent awareness of the phenomenon as well as in the development of the associated distress leading to disabling chronic tinnitus. [less ▲]

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See detailConnectivity graph analysis of the auditory resting state network in tinnitus.
MAUDOUX, Audrey ULiege; Lefèbvre, Philippe ULiege; Cabay, J.-E. et al

in Brain Research (2012), 1485

Thirteen chronic tinnitus patients and fifteen age-matched healthy controls were studied on a 3T magnetic resonance imaging (MRI) scanner during resting condition (i.e. eyes closed, no task performance ... [more ▼]

Thirteen chronic tinnitus patients and fifteen age-matched healthy controls were studied on a 3T magnetic resonance imaging (MRI) scanner during resting condition (i.e. eyes closed, no task performance). The auditory resting-state component was selected using an automatic component selection approach. Functional connectivity (correlations/anti-correlations) in the extracted network was portrayed by integrating the independent component analysis (ICA) approach with a graph theory method. Tinnitus and control groups showed different graph connectivity patterns. In the control group, the connectivity graph was divided into two distinct anti-correlated networks. The first one encompassed the auditory cortices and the insula. The second one encompassed frontoparietal and anterior cingulate cortices, brainstem, amygdala, basal ganglia/nucleus accumbens and parahippocampal regions. In the tinnitus group, only one of the two previously described networks was observed, encompassing the auditory cortices and the insula. Direct group comparison showed, in the tinnitus group, an increased functional connectivity between auditory cortices and the left parahippocampal region surviving multiple comparisons. We investigated a possible correlation between four tinnitus relevant measures (tinnitus handicap inventory (THI) and tinnitus questionnaire (TQ) scores, tinnitus duration and tinnitus intensity during the scanning session) and the connectivity pattern in the tinnitus population. We observed a significant positive correlation between the beta values of the posterior cingulate/precuneus region and the THI score. Our results show a modified functional connectivity pattern in tinnitus sufferers and highlight the role of the parahippocampal region in tinnitus physiopathology. They also point out the importance of the activity and connectivity pattern of the posterior cingulate cortex/precuneus region to the development of the tinnitus associated distress. This article is part of a Special Issue entitled: Tinnitus Neuroscience. [less ▲]

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See detailImplantation of esterified hyaluronic acid in microdissected Reinke's space after vocal fold microsurgery
FINCK, Camille ULiege; Harmegnies, Bernard; Remacle, Angélique ULiege et al

in Journal of Voice (2010), 24(5), 626-635

laryngeal and vocal results obtained after microflap excision of benign vocal fold lesions and immediate implantation of esterified hyaluronic acid(EHA) in the surgical wound are described in this study ... [more ▼]

laryngeal and vocal results obtained after microflap excision of benign vocal fold lesions and immediate implantation of esterified hyaluronic acid(EHA) in the surgical wound are described in this study. Prospective and comparative study on 83 patients ( 33 implanted with EHA and 50 not implanted). Longest follow up is 4 years. The objectives are to confirm the innocuity of the technique, to demonstrate the laryngeal and vocal evolution at short and long term, and to evaluate the eventual positive impact of EHA implantation on the pliability of the superficial layer of the lamina propria (SLLP) and on voice. The use of EHA implant in microdissected SLLP is safe and leads to good laryngeal and vocal outcomes in the treated patients. [less ▲]

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See detailSox10 is not necessary for auditory neurons survival
Breuskin, I; Bodson, M; Thelen, Nicolas ULiege et al

Poster (2008)

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See detailCaspases, the enemy within, and their role in oxidative stress-induced apoptosis of inner ear sensory cells
Van De Water, T. R.; Lallemend, François; Eshraghi, A. A. et al

in Otology and Neurotology (2004), 25(4), 627-632

This review covers the general roles of members of the cysteine protease family of caspases in the process of apoptosis (programmed cell death) looking at their participation in both the "extrinsic" cell ... [more ▼]

This review covers the general roles of members of the cysteine protease family of caspases in the process of apoptosis (programmed cell death) looking at their participation in both the "extrinsic" cell death receptor and the "intrinsic" mitochondrial cell death pathways. It defines the difference between initiator and effector caspases and shows the progression of caspase activations that ends up in the apoptotic cell death and elimination of a damaged cell. The review then presents what is currently know about the participation of caspases in the programmed cell death of inner ear sensory cells during the process of normal development and maturation of the inner ear and their importance in this process as illustrated by the results of caspase-3 gene knockout experiments. The participation of specific caspases and the sequence of their activation in the elimination (apoptosis) of damaged sensory cells from adult inner ears after an injury that generates oxidative stress are reviewed. Both the possibility and the potential efficacy of caspase inhibition with a broad-spectrum pancaspase inhibitor as an interventional therapy to treat and rescue oxidative stress-damaged inner ear sensory cells from apoptosis are presented and discussed. [less ▲]

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See detailIn vitro ototoxicity of aminoglycosides and platin derivatives. A semi-automatic assay for sensory hair cell damage in explanted rat organ of corti.
Malgrange, B.; LEFEBVRE, Philippe ULiege; van de Water, T.R. et al

in Toxicology in Vitro (1998), 12 (6)

The ototoxic damage that drugs such as neomycin, kanamycin, colistin, cisplatin, transplatin and carboplatin cause on outer and inner hair cells in postnatal day 3 rat cochlear explants was investigated ... [more ▼]

The ototoxic damage that drugs such as neomycin, kanamycin, colistin, cisplatin, transplatin and carboplatin cause on outer and inner hair cells in postnatal day 3 rat cochlear explants was investigated. Phalloidin-fluorescein conjugate-stained stereocilia bundles of sensory hair cells were quantified by video image analysis as a measurement of ototoxic effect. The video image quantification system established dose-response curves for ototoxic drugs (e.g. calculation of an IC50) and allowed comparisons between several ototoxins from the same family. This methodology provided the means to assess the efficacy of otoprotectant agents in preventing ototoxicity. Poly-l-aspartate (10-5M) and poly-l-glutamate (10-5M) protected auditory hair cells from neomycin (10-3M) toxicity while reduced glutathione (10-3M) provided protection against cisplatin (10-4M)-induced hair cell damage. [less ▲]

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See detailKainate and Nmda Toxicity for Cultured Developing and Adult Rat Spiral Ganglion Neurons: Further Evidence for a Glutamatergic Excitatory Neurotransmission at the Inner Hair Cell Synapse
Lefèbvre, Philippe ULiege; Weber, T.; Leprince, Pierre ULiege et al

in Brain Research (1991), 555(1), 75-83

In the inner ear, the excitatory amino acid glutamate is a proposed neurotransmitter acting at the synapse between hair cells and afferent auditory neurons. Using cultures of 5-day-old rat auditory ... [more ▼]

In the inner ear, the excitatory amino acid glutamate is a proposed neurotransmitter acting at the synapse between hair cells and afferent auditory neurons. Using cultures of 5-day-old rat auditory neurons, we show that the afferent auditory neuronal population can be divided, on the basis of its sensitivity to the neuronotoxic effect of glutamate and its analogs, in at least 3 subpopulations, one responding to N-methyl-D-aspartate (NMDA), one responding to kainate and a third minor one unresponsive to NMDA, kainic acid and glutamate. No toxic effect of quisqualate is observed. The use of specific antagonists (kynurenate and 2-amino-5-phosphonovalerate (DAP-5) demonstrates the specificity of the receptors to the excitatory amino acids on the afferent auditory neurons. Afferent auditory neurons from adult rats can also be cultured and in these preparations only the large neurons are sensitive to glutamate, kainate and NMDA while the small neurons are not responsive, suggesting that a glutamatergic neurotransmission occurs only at this synapse between the inner hair cells and the large radial afferent auditory neurons. We also show that, in vitro, the organ of Corti releases, in response to an increased potassium concentration and in the presence of calcium, a toxic activity for the afferent auditory neurons that is antagonized by kynurenate and DAP-5. Pathophysiological implications are discussed. [less ▲]

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See detailIn Vitro Kinetics of a Newborn Rat Astroglia-Derived Neuronotoxic Activity
Leprince, Pierre ULiege; rigo, Jean-Michel; Lefebvre, Philippe ULiege et al

in Neuroscience Letters (1989), 102(2-3), 268-72

A low-molecular weight astrocyte-derived neuronotoxic activity (ANTA) was detected, using a colorimetric bioassay of cell survival, by its effect on cultured granule cells. This neuronotoxic activity was ... [more ▼]

A low-molecular weight astrocyte-derived neuronotoxic activity (ANTA) was detected, using a colorimetric bioassay of cell survival, by its effect on cultured granule cells. This neuronotoxic activity was found to be released rapidly from newborn rat astrocytes in culture upon incubation in 50 mM K+-containing growth medium. The release by astrocytes could be induced repetitively by successive incubations in high-K+ medium alternating with incubations in normal medium. Astrocytes were also found to inactivate rapidly isobutanol-extracted ANTA in normal K+-containing growth medium. Kinetic studies showed that ANTA induces a slow (greater than 12 h) degeneration of cultured granule cells. ANTA is shown here to be an intermediate of normal astrocyte metabolism and to display appropriate kinetic characteristics compatible with its proposed role in inducing part of the delayed neuronal loss that occurs after a brain injury (secondary neuronal death). [less ▲]

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