Reconstruire l’histoire de la santé en Région Centre au Moyen Age et à la Renaissance : le projet SaRC

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Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease characterized by the loss of lower motor neurons. SBMA is caused by expansions of a polyglutamine tract in the gene coding for androgen receptor (AR). Expression of polyglutamine-expanded AR causes damage to motor neurons and skeletal muscle cells. Here we investigated the effect of β-agonist stimulation in SBMA myotube cells derived from mice and patients, and in knock-in mice. We show that treatment of myotubes expressing polyglutamine-expanded AR with the β-agonist clenbuterol increases their size. Clenbuterol activated the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway and decreased the accumulation of polyglutamine-expanded AR. Treatment of SBMA knock-in mice with clenbuterol, which was started at disease onset, ameliorated motor function and extended survival. Clenbuterol improved muscle pathology, attenuated the glycolytic-to-oxidative metabolic alterations occurring in SBMA muscles and induced hypertrophy of both glycolytic and oxidative fibers. These results indicate that β-agonist stimulation is a novel therapeutic strategy for SBMA

Non-neural phenotype of spinal and bulbar muscular atrophy: Results from a large cohort of Italian patients

Objective: To carry out a deep characterisation of the main androgen-responsive tissues involved in spinal and bulbar muscular atrophy (SBMA). Methods: 73 consecutive Italian patients underwent a full clinical protocol including biochemical and hormonal analyses, genitourinary examination, bone metabolism and densitometry, cardiological evaluation and muscle pathology. Results: Creatine kinase levels were slightly to markedly elevated in almost all cases (68 of the 73; 94%). 30 (41%) patients had fasting glucose above the reference limit, and many patients had total cholesterol (40; 54.7%), low-density lipoproteins cholesterol (29; 39.7%) and triglyceride (35; 48%) levels above the recommended values. Although testosterone, luteinising hormone and follicle-stimulating hormone values were generally normal, in one-third of cases we calculated an increased Androgen Sensitivity Index reflecting the presence of androgen resistance in these patients. According to the International Prostate Symptom Score (IPSS), 7/70 (10%) patients reported severe lower urinal tract symptoms (IPSS score >19), and 21/73 (30%) patients were moderately symptomatic (IPSS score from 8 to 19). In addition, 3 patients were carriers of an indwelling bladder catheter. Videourodynamic evaluation indicated that 4 of the 7 patients reporting severe urinary symptoms had an overt prostate-unrelated bladder outlet obstruction. Dual-energy X-ray absorptiometry scan data were consistent with low bone mass in 25/61 (41%) patients. Low bone mass was more frequent at the femoral than at the lumbar level. Skeletal muscle biopsy was carried out in 20 patients and myogenic changes in addition to the neurogenic atrophy were mostly observed. Conclusions: Our study provides evidence of a wide non-neural clinical phenotype in SBMA, suggesting the need for comprehensive multidisciplinary protocols for these patients. \ua9 2016 Published by the BMJ Publishing Group Limited

Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy

Spinal and bulbar muscular atrophy (SBMA) is characterized by loss of motoneurons and sensory neurons, accompanied by atrophy of muscle cells. SBMA is due to an androgen receptor containing a polyglutamine tract (ARpolyQ) that misfolds and aggregates, thereby perturbing the protein quality control (PQC) system. Using SBMA AR113Q mice we analyzed proteotoxic stress-induced alterations of HSPB8-mediated PQC machinery promoting clearance of misfolded proteins by autophagy. In muscle of symptomatic AR113Q male mice, we found expression upregulation of Pax-7, myogenin, E2-ubiquitin ligase UBE2Q1 and acetylcholine receptor (AchR), but not of MyoD, and of two E3-ligases (MuRF-1 and Cullin3). TGF beta 1 and PGC-1 alpha were also robustly upregulated. We also found a dramatic perturbation of the autophagic response, with upregulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3) and of the HSPB8-mediated PQC response. Both HSPB8 and its co-chaperone BAG3 were robustly upregulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Notably, the BAG3: BAG1 ratio increased in muscle suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Thus, mutant ARpolyQ induces a potent autophagic response in muscle cells. Alteration in HSPB8-based PQC machinery may represent muscle-specific biomarkers useful to assess SBMA progression in mice and patients in response to pharmacological treatments

Murder and the MMPI-2: The Necessity of Knowledgeable Legal Professionals

Part I of this Comment discusses the basic structure and purpose of the MMPI-2, the development and evolution of the MMPI into the MMPI-2, and reliability and validity issues. Part II provides a basic understanding of the correct administration, scoring, and interpretation of the MMPI-2 and describes standards for expert testimony. Part III presents a historical overview of the use of the MMPI-2 in court. The different types of cases in which the MMPI-2 is used are discussed along with the many applications of its use. Part IV describes the legal standards of admissibility of scientific evidence in court and how the MMPI-2 fares under each standard. Part V analyzes the use of the MMPI-2 in murder trials, including the prevalence and application of the MMPI-2 in murder cases. Part VI provides a thorough discussion of some of the misapplications of the MMPI-2 in murder cases. Part VII recommends possible solutions to the issues raised by the use of the MMPI-2 in murder trials. Part VIII of this Comment concludes that the widespread use of the MMPI-2 in the legal arena necessitates that legal professionals be knowledgeable about the basic structure and process of the MMPI-2. Despite the sometimes negative reviews of the MMPI-2, it remains a valuable assessment tool for use in murder trials, when used correctly by both psychologists and legal professionals

Mutations in TGM6 induce the unfolded protein response in SCA35

Spinocerebellar ataxia type 35 (SCA35) is a rare autosomal-dominant neurodegenerative disease caused by mutations in the TGM6 gene, which codes for transglutaminase 6 (TG6). Mutations in TG6 induce cerebellar degeneration by an unknown mechanism. We identified seven patients bearing new mutations in TGM6. To gain insights into the molecular basis of mutant TG6-induced neurotoxicity, we analyzed all of the seven new TG6 mutants and the five TG6 mutants previously linked to SCA35. We found that wild-type (TG6-WT) mainly localized to the nucleus and perinuclear area, whereas five TG6 mutations showed nuclear depletion, increased accumulation in the perinuclear area, insolubility and loss of enzymatic function. Aberrant accumulation of these TG6 mutants in the perinuclear area led to activation of the unfolded protein response (UPR), suggesting that specific TG6 mutants elicit an endoplasmic reticulum (ER) stress response. Mutations associated with activation of the UPR caused death of primary neurons and reduced the survival of novel D. melanogaster models of SCA35. These results indicate that mutations differently impacting on TG6 function cause neuronal dysfunction and death through diverse mechanisms and highlight the UPR as a potential therapeutic target for patient treatment

Combining historic records and multi-criteria habitat suitability analysis for the potential reintroduction of Lake Sturgeon (Acipenser fulvescens Rafinesque) into tributaries of Lake Erie

Predicting the location and quality of habitat for imperiled species is an increasingly important application of modeling technology. The Lake Sturgeon (Acipenser fulvescens) is a widely-extirpated fish of the Laurentian Great Lakes whose recovery is dependent on the availability and connectivity of suitable stream habitat today. This is especially true in Lake Erie, where the largest Lake Sturgeon fishery was once found. I predicted that modern habitat suitability would be dependent on land use legacies from the past 200 years, with western Lake Erie tributaries having less suitable habitat compared to the eastern Lake Erie tributaries. I developed a multi-criteria habitat suitability analysis framework that was applied to two different spatial scales (watershed and stream segment) to predict the location and quality of habitat for spawning adults and juveniles in historically-used U.S. tributaries of Lake Erie. I also tested the transferability of the model framework by applying it to a stream where extant Lake Sturgeon spawn currently: the Black River in northern Michigan. My results suggest that a broad range of habitat qualities exist across the study region, with predictions aligning with several smaller-scale habitat suitability projects in the past in several of the watersheds analyzed here. Most low-scoring watersheds were located to the west, while the highest-scoring watersheds were located to the east, as predicted. The model found a high degree of agreement between the watershed scale and reach scale, suggesting that the framework could be applied at either scale accurately depending on input data availability. The model predicted that the Black River watershed is fairly suitable (40-50% suitable) for Lake Sturgeon, which warrants further investigation and ground-truthing of the model’s real-world accuracy given that the Black River is known to be highly suitable for the species. Additional spatially-explicit analysis of these results in the future will aim to reveal patterns in habitat connectivity from river mouth upstream for each watershed. My results can be used on the fine scale by managers seeking to develop local Lake Sturgeon reintroduction and restoration projects but also at the large scale for the purpose of communication and habitat connectivity for the benefit of multiple populations of Lake Sturgeon

Les enjeux d’un diagnostic sans cautelae medicorum : analyser les urines dans l’Hortus sanitatis

Le traité De urinis, qui clôt le recueil connu sous le nom d’Hortus sanitatis (texte latin daté de 1491), s’avère être une rédaction remaniée du De urinarum iudiciis de Bartolomeo da Montagnana (publié en 1487). Dans cette contribution, l’auteure propose une lecture des contenus du De urinis afin d’en saisir la place dans l’économie générale de l’Hortus et la relation complexe qu’ils entretiennent avec leur source. En effet, le De urinis, normalement assez fidèle au De urinarum iudiciis de Montagnana, omet le chapitre où ce dernier traite des précautions des médecins (De cautelis medicorum). Cette absence mérite une réflexion sur les stratégies du discours et le destinataire du De urinis.The treatise De urinis closes the collection of texts known as Hortus sanitatis (Latin text dated from 1491) and is a rewriting of Bartolomeo da Montagnana’s De urinarum iudiciis, published in 1487. In this article, the author recommends reading the contents of De urinis in order to grasp the status of the treatise in the general economy of the Hortus and its complex relationship with its source. In fact, De urinis is quite faithful to Montagnana’s De urinarum iudiciis. Yet, it overlooks the last chapter on physicians’ prudence (De cautelis medicorum) of Montagnana’s treatise. This lack deserves a careful consideration on the strategies of the proposal and the beneficiary of De urinis

Insulin-like growth factor 1 signaling in motor neuron and polyglutamine diseases: From molecular pathogenesis to therapeutic perspectives

The pleiotropic peptide insulin-like growth factor 1 (IGF-I) regulates human body homeostasis and cell growth. IGF-I activates two major signaling pathways, namely phosphoinositide-3-kinase (PI3K)/protein kinase B (PKB/Akt) and Ras/extracellular signal-regulated kinase (ERK), which contribute to brain development, metabolism and function as well as to neuronal maintenance and survival. In this review, we discuss the general and tissue-specific effects of the IGF-I pathways. In addition, we present a comprehensive overview examining the role of IGF-I in neurodegenerative diseases, such as spinal and muscular atrophy, amyotrophic lateral sclerosis, and polyglutamine diseases. In each disease, we analyze the disturbances of the IGF-I pathway, the modification of the disease protein by IGF-I signaling, and the therapeutic strategies based on the use of IGF-I developed to date. Lastly, we highlight present and future considerations in the use of IGF-I for the treatment of these disorders