Prion Protein Is a Key Determinant of Alcohol Sensitivity through the Modulation of N-Methyl-D-Aspartate Receptor (NMDAR) Activity

The prion protein (PrP) is absolutely required for the development of prion diseases; nevertheless, its physiological functions in the central nervous system remain elusive. Using a combination of behavioral, electrophysiological and biochemical approaches in transgenic mouse models, we provide strong evidence for a crucial role of PrP in alcohol sensitivity. Indeed, PrP knock out (PrP−/−) mice presented a greater sensitivity to the sedative effects of EtOH compared to wild-type (wt) control mice. Conversely, compared to wt mice, those over-expressing mouse, human or hamster PrP genes presented a relative insensitivity to ethanol-induced sedation. An acute tolerance (i.e. reversion) to ethanol inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potentials in hippocampal slices developed slower in PrP−/− mice than in wt mice. We show that PrP is required to induce acute tolerance to ethanol by activating a Src-protein tyrosine kinase-dependent intracellular signaling pathway. In an attempt to decipher the molecular mechanisms underlying PrP-dependent ethanol effect, we looked for changes in lipid raft features in hippocampus of ethanol-treated wt mice compared to PrP−/− mice. Ethanol induced rapid and transient changes of buoyancy of lipid raft-associated proteins in hippocampus of wt but not PrP−/− mice suggesting a possible mechanistic link for PrP-dependent signal transduction. Together, our results reveal a hitherto unknown physiological role of PrP on the regulation of NMDAR activity and highlight its crucial role in synaptic functions

Endovascular treatment for carotid artery stenosis after neck irradiation.

International audienceBACKGROUND: To lower the risk of complications, carotid angioplasty and stenting (CAS) has been proposed as an alternative to open surgery for carotid artery stenosis after neck irradiation. However, there are little postoperative data to support the benefits of this strategy. This study evaluated the outcome of CAS in patients who had undergone neck irradiation. METHODS: This retrospective study was conducted at 15 vascular surgery or interventional radiology centers in France between January 1998 and July 2006. A total of 135 patients (115 men) with a mean age of 67 +/- 8 years (range, 43-88) underwent CAS for 149 irradiation-induced lesions. The interval between irradiation and discovery of the lesions was 12 +/- 8 years. Mean diameter reduction was 81% (range, 50%-95%), and stenosis was symptomatic in 34%. Contralateral carotid lesions were observed in 48% of patients, including thrombosis in 18 and stenosis >50% in 53. RESULTS: Technical failure occurred during CAS in three cases. The overall technical success rate was 98%. A cerebral protection device was used in 59%. No death, one transient ischemic attack, and two strokes occurred during the first postoperative month. Mean follow-up was 30 months. Six patients were lost to follow-up. Survival rates were 93.9% at 1 year and 75.3% at 3 years. Complications after the first postoperative month included neurologic events in six, carotid thrombosis in nine, and restenosis in 18. The rates of freedom from neurologic and anatomic events were, respectively, 96.2% and 93.2% at 1 year and 93.1% and 85.9% at 3 years. CONCLUSION: The immediate outcome of CAS for irradiation-induced carotid artery stenosis was satisfactory. Medium-term neurologic outcome was acceptable, but the incidence of anatomic events such as thrombosis and restenosis was high. A randomized study is needed to confirm that the outcome of the endovascular and surgical therapy is comparable in this indication

Contribution of a preliminary socio-anthropological survey to the development of a therapeutic patient education programme for patients receiving oral chemotherapy

Introduction: For a long time patients with cancer receiving chemotherapy were ’captive’, and were considered as passive during the administration of their treatment. The development of oral treatments over the last decade has considerably changed this situation. However, very little is known about the behaviour of the patients and the physicians in this new setting. Our team carried out a social anthropological survey on patients who were autonomous in the management of their oral chemotherapy, before developing a therapeutic patient educational programme. Objectives: The objective of the survey was to identify the mental representations and behaviour of patients and prescribing oncologists. Methods: The survey included 42 patients receiving oral chemotherapy and 10 oncologists from two cancer centres in the Rhône-Alpes region in France between January and March 2007. Different qualitative study methods were used: repeated focus groups and individual face-to-face or telephone interviews. Results and discussion: The results of this survey were used to develop the objectives for a therapeutic educational programme. The way patients managed their oral chemotherapy was found to be linked to their beliefs about the treatment efficacy and toxicity. The structure and contents of the educational sessions were adapted to take into consideration the identified representation

The role of the non‐neuronal cholinergic system in inflammation and degradation processes in osteoarthritis

International audienceObjectivesThe non‐neuronal cholinergic system represents non‐neuronal cells that have the biochemical machinery to synthetize de novo and/or respond to acetylcholine (ACh). We investigated this biochemical machinery in chondrocytes and its involvement in osteoarthritis (OA).MethodsExpression of the biochemical machinery for ACh metabolism and nicotinic ACh receptors (nAChR), particularly α7nAChR, in human OA and murine chondrocytes was determined by PCR and ligand‐binding. We investigated the mRNA expression of the human duplicate α7nACh subunit, called CHRFAM7A, which is responsible for a truncated α7nAChR. We assessed the effect of nAChR on chondrocytes activated by IL1β and the involvement of α7nAChR using chondrocytes from wild‐type (WT) and α7‐deficient Chrna7‐/‐mice. The role of α7nAChR in OA was explored after medial meniscectomy (MNX) in WT and Chrna7‐/‐mice.ResultsHuman and murine chondrocytes express the biochemical partners of the non‐neuronal cholinergic system (n=5) and a functional α7nAChR at their cell surface. The expression of CHRFAM7A in human OA chondrocytes correlated positively with MMP3 (r=0.38, p<0.05) and MMP13 (r=0.48, p<0.05) expression (n=23). Nicotine decreased the IL1β‐induced IL6 and MMPs expression in a dose‐dependent manner in WT but not in Chrna7‐/‐chondrocytes. MNX Chrna7‐/‐mice displayed more severe OA cartilage damage (OARSI score of 4.46±1.09, n=7) than MNX WT mice (3.05±0.9, n=9, p<0.05).ConclusionThe non‐neuronal cholinergic system is functionally expressed in chondrocytes. Stimulation of nAChR induces anti‐inflammatory and anti‐catabolic activity through α7nAChR, but the anti‐catabolic activity may be mitigated by truncated α7nAChR in human chondrocytes. In vivo experiments strongly suggest that α7nAChR has a protective role in OA