Exon skipping as a therapeutic strategy applied to an RYR1 mutation with pseudo-exon inclusion causing a severe core myopathy.

International audienceCentral core disease is a myopathy often arising from mutations in the type 1 ryanodine receptor (RYR1) gene, encoding the sarcoplasmic reticulum calcium release channel RyR1. No treatment is currently available for this disease. We studied the pathological situation of a severely affected child with two recessive mutations, which resulted in a massive reduction in the amount of RyR1. The paternal mutation induced the inclusion of a new in-frame pseudo-exon in RyR1 mRNA that resulted in the insertion of additional amino acids leading to the instability of the protein. We hypothesized that skipping this additional exon would be sufficient to restore RyR1 expression and to normalize calcium releases. We therefore developed U7-AON lentiviral vectors to force exon skipping on affected primary muscle cells. The efficiency of the exon skipping was evaluated at the mRNA level, at the protein level, and at the functional level using calcium imaging. In these affected cells, we observed a decreased inclusion of the pseudo-exon, an increased RyR1 protein expression, and a restoration of calcium releases of normal amplitude either upon direct RyR1 stimulation or in response to membrane depolarization. This study is the first demonstration of the potential of exon-skipping strategy for the therapy of central core disease, from the molecular to the functional level

A meta-analysis of previous falls and subsequent fracture risk in cohort studies

NC Harvey acknowledges funding from the UK Medical Research Council (MC_PC_21003; MC_PC_21001). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005. Funding for the MrOS USA study comes from the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. Funding for the SOF study comes from the National Institute on Aging (NIA), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), supported by grants (AG05407, AR35582, AG05394, AR35584, and AR35583). Funding for the Health ABC study was from the Intramural research program at the National Institute on Aging under the following contract numbers: NO1-AG-6–2101, NO1-AG-6–2103, and NO1-AG-6–2106.Peer reviewedPostprin

Previous fracture and subsequent fracture risk : a meta-analysis to update FRAX

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX. The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD). We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted β-coefficients. A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination. A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies

Atteintes cardiaques du syndrome de Churg et Strauss (une gravité à ne pas méconnaître)

Les atteintes cardiaques du syndrome de Churg et Strauss (SCS) sont fréquentes et graves. Il faut évoquer ce syndrome devant la dyade asthme et hyperéosinophilie dans un contexte de vascularite. L objectif de cette étude est de décrire les spécificités des formes cardiaques du SCS. C est une des plus grandes séries monocentriques : 23 patients dont 11 ont une atteinte cardiaque. Le pronostic vital était engagé à court terme par 2 tamponnades et 4 myocardites fulminantes. Un patient est décédé de mort subite et un autre transplanté du cœur avec succès. Les ANCA étaient négatifs dans les formes cardiaques. Lorsqu un SCS est suspecté, nous recommandons en urgence : un ECG, un dosage de la troponine et du BNP. Si ce bilan est anormal, l atteinte myocardique est probable ; elle requiert une surveillance monitorée et un traitement spécifique (cyclophosphamide et corticothérapie) si le diagnostic est confirmé. Au stade d insuffisance cardiaque, les b-bloquants (lorsque l asthme est contrôlé) et la greffe cardiaque ne sont pas contre-indiqués.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Using Cementochronology to Discuss the Organization of Past Neanderthal Societies

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APPROCHE TAPHONOMIQUE EN CÉMENTOCHRONOLOGIE : réexamen du niveau 4 du Pech-de-l'Azé I (Carsac, Dordogne, France)

National audienceIntroduction This paper propose the application of A. J. Stutz method of diagenetic cementum modification identification to the skeletochronological analysis of Level 4 of the Pech-de-l'Azé I study previously published by some of us (Armand et al., 2001). Skeletochronology is based on the observation of seasonal cementum deposits and has long been used in zooarchaeology to access the season of death of human preys (Saxon and Higham, 1968; Spiess, 1979 ; Burke, 1995; Martin, 1994; Pike-Tay et al., 1999). Cementum is a bonelike tissue that allows the connection between tooth roots and the gingival, through the periodontal ligament, (Lieberman and Meadow, 1992 ; Klevezal', 1996; Dieckwisch, 2001). It apposes itself along mammal tooth roots from their formation, until the death of the animal. In most mammal populations, this growth follows predictable seasonal cycles which exhibit the succession of a fast growth deposit (also called "Zone") from mid-spring to autumn and a slow growth one (Annulus and/or LAG) in winter (Klevezal' and Kleinenberg, 1969 ; Martin, 1994; Burke and Castanet, 1995; Klevezal', 1996 ; Moffit, 1998 ; Peck, 2004). Seasonal patterns of cementum depositions produce microscopically distinct incremental levels, which may exhibit one or more of a variety of ultrastructural, microstructural, and histological patterns (Figure 1). Taphonomy and cementum Although lots of researchers have underlined the existence of post-mortem modification of the tooth tissues (Figure 2), few of them specifically focalised on the taphonomic modifications that can alter the seasonal record such as weathering (Figure 2). One of the most important of these taphonomic processes is the apatite crystal re-crystallisation that can mimic biogenic deposit that cannot be identified with the classical methods used (Stutz, 2002a, 2002b). However, in polarizing microscopy (Gilbert, 1989), the use of the Lambda plate can help to resolve this issue by colouring the taphonomic and the biogenic deposit in two different ways (figure 3). Figure 4 proposes an example of the lambda plate application for the identification of diagenesis modifications. We present the application of this method to the skeletochronological study of Pech-de-l'Azé I level 4 originally conducted by some of us (Armand et al, 2001). Our objectives was firstly to propose a revaluation of the previous seasonal results and, secondly, to present an example of the impact of that kind of modifications on archaeological series. Revision of the Pech-de-l'Azé I The previous skeletochronological study of Pech-de-l'Azé I was conducted on the two main taxa identified in the level 4: the red deer and the bison. It highlighted the well preservation of the cementum increment (Armand et al., 2001) and proposed a deer slaughter during the good season and a bison hunt during the bad season (fig. 5). The revaluation has concerned the same material and the observations were made with the lambda plate inserted. Twelve teeth were analysed and taphonomic modification were identified on several of them (tab. 1). It appears that five of the twelve teeth exhibited some apatite recrystallisations and/or a lost of their collagen structure that conducted to the lost of a part of the seasonal records. For these teeth, the post-mortem modifications were too important to propose a precise age at death. In addition, in three cases, we weren't able to establish the season of death (fig. 6). Moreover a black deposit on the outer-edge of the cementum was identified. It appears that it was previously interpreted as a slow growth deposit. The use of the lambda plate has helped us to recognize it as a non biogenic material and, consequently, to correct the previous identification. Discussion By tacking into account the post-mortem modification, we were able to propose a modified seasonal spectrum of the Pech-de-l'Azé I fauna, in which four seasonal result were different from the prior study (fig. 7). The red deer hunting season wasn't really modified contrary to the bison one. At the end of this study, it appears that the bisons were killed at the end of the good season contrary to what was previously proposed. These new data modify the perception we had of the subsistence strategies by rejecting the hypothesis of a bison hunt during the winter. A second sampling in the same level (not presented here) has confirmed the results of this study (Rendu, 2007). The conclusions of this paper underline, that although most of the skeletochronological samples are not affected by these kinds of alterations, they appears to be quite common. They may have important consequences on the skeletochronological results, especially for the small samples. However, while taphonomic modifications of the cementum records might interfere with the seasonal interpretations, it is now possible to resolve these problems. Consequently, the technique developed by A. J. Stutz (2002a, 2002b) helps to magnify the reliability of one of the most accurate method to discuss the season of death of ungulate preys.Alors que la cémentochronologie est une méthode de plus en plus utilisée pour reconstituer la saisonnalité de prédation des animaux présents en contexte archéologique, peu d'études incluent la recherche systématique des modifications taphonomiques qui peuvent affecter le cément. Ce travail propose une présentation des phénomènes de remobilisations diagénétiques de l'enregistrement saisonnier. À travers la reprise de l'analyse du niveau 4 du gisement du Pech-de-l'Azé I, nous proposons une illustration de leurs conséquences sur les études cémentochronologiques

Saisonnalité des activités de prédation des chasseurs aurignaciens d’Isturitz

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Cost-effectiveness of treatment of women aged 70 years and older with both osteopenia and microstructural deterioration

Objective Treatment is usually withheld from women with osteopenia even though they are the source of over 70% of all women having fragility fractures. As microstructural deterioration increases fracture risk and zoledronate reduces it, we aimed to determine whether identifying and treating women with osteopenia and severe microstructural deterioration is cost-effective. We also compared the health economic outcomes of ‘global’ versus ‘targeted’ treatment using SFS of women aged ≥70 years with osteopenia. Design We assessed the cost-effectiveness from using a Markov model that simulated 10-year follow up of women with osteopenia. Decision analysis compared measurement of distal radial microstructure using high resolution peripheral computed tomography (at a cost of USD $210) to target women with severe microstructural deterioration for zoledronate treatment, compared to standard care defined as measurement of bone mineral density (BMD) with treatment recommended when femoral neck BMD T score is ≤−2.5 SD with or without a prevalent fracture. In the ‘global’ treatment approach, high resolution peripheral quantitative tomography (HRpQCT) was not undertaken. Setting US healthcare system. Participants A hypothetical cohort of 1000 women aged ≥70 years with osteopenia and no previous fractures was studied. Measures Fractures, deaths, years of life lived, quality-adjusted life years (QALYs) lived and costs. Data inputs were obtained from published sources. A 3 Results Women in the standard care group incurred 327 fractures during 7341.0 years and 4914.2 QALYs lived. Women in the intervention group incurred 300 fractures (number needed to treat 37) during 7359.2 years and 4928.8 QALYs lived. Net costs were USD$4,862,669 and $4,952,004, respectively, equating to 18.1 years of life saved and 14.6 QALYs saved, and incremental cost-effectiveness ratios of$4992 per year of life saved and $6135 per QALY saved. These ratios are well within the threshold considered to be cost-effective. Sensitivity analyses indicated the results were robust. Relative to standard of care, ‘global’ and ‘targeted’ treatment respectively resulted in 0.0364 vs. 0.0181 years of life (YoLS) saved per person, and 0.0292 and 0.0146 QALYs saved per person. The net costs per person for the respective approaches were$US 359 and $US 89. The incremental cost-effectiveness ratios were$9864 per YoLS and $12,290 per QALY saved for the ‘global’ approach and$4992 per YoLS and $6135 per QALY saved for the ‘targeted’ approach. Conclusion Identifying and treating women ≥70 years of age with osteopenia and microstructural deterioration with zoledronate cost-effectively reduces the morbidity and mortality imposed by fragility fractures. This ‘targeted’ approach is more cost-effective than a ‘global’ approach and incurs only 25 Implication Women with osteopenia with bone fragility due to microstructural deterioration should be identified and targeted for treatment. Summary Women with osteopenia have 70$4992/year of life saved and $6135 per QALY saved

Deterioration of cortical and trabecular microstructure identifies women with osteopenia or normal bone mineral density at imminent and long-term risk for fragility fracture : A prospective study

More than 70% of women sustaining fractures have osteopenia or “normal” bone mineral density (BMD). These women remain undetected using the BMD threshold of −2.5 SD for osteoporosis. As microstructural deterioration increases bone fragility disproportionate to the bone loss producing osteopenia/normal BMD, we hypothesized that the structural fragility score (SFS) of ≥70 units, a measure capturing severe cortical and trabecular deterioration, will identify these women. Distal radial images were acquired using high‐resolution peripheral quantitative tomography in postmenopausal French women, mean age 67 years (range 42–96 years); 1539 women were followed for 4 years (QUALYOR) and 561 women followed for 8 years (OFELY). Women with osteopenia or normal BMD accounted for ~80% of fractures. Women ≥70 years, 29.2% of the cohort, accounted for 39.2% to 61.5% of fractures depending on follow‐up duration. Women having fractures had a higher SFS, lower BMD, and a higher fracture risk assessment score (FRAX) than women remaining fracture‐free. In each BMD category (osteoporosis, osteopenia, normal BMD), fracture incidence was two to three times higher in women with SFS ≥70 than <70. In multivariable analyses, associations with fractures remained for BMD and SFS, not FRAX. BMD was no longer, or weakly, associated with fractures after accounting for SFS, whereas SFS remained associated with fracture after accounting for BMD. SFS detected two‐to threefold more women having fractures than BMD or FRAX. SFS in women with osteopenia/normal BMD conferred an odds ratio for fracture of 2.69 to 5.19 for women of any age and 4.98 to 12.2 for women ≥70 years. Receiver‐operator curve (ROC) analyses showed a significant area under the curve (AUC) for SFS, but not BMD or FRAX for the women ≥70 years of age. Targeting women aged ≥70 years with osteopenia indicated that treating 25% using SFS to allocate treatment conferred a cost‐effectiveness ratio < USD $21,000/QALY saved. Quantifying microstructural deterioration complements BMD by identifying women without osteoporosis at imminent and longer‐term fracture risk. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research

Du Bronze moyen au début du Bronze final dans le Sud-Est de la France (Provence-Alpes-Côte d’Azur, Languedoc-Roussillon, Sud de Rhône-Alpes et de l’Auvergne)

International audienceThis work constitutes an overview of data from the Middle and the beginning of the Late Bronze Age in south-eastern France, area that encompasses the administrative regions of Languedoc-Roussillon and Provence-Alpes-Côte d’Azur,as well as the south of Rhône-Alpes and Auvergne. At the beginning of the Middle Bronze Age, the pottery styles show clear analogies to the Italian peninsula, the precise origin of which can differ from one area to another. There seems however to be consistency in funerary practices and the deposition metal objects. At the end of this period, italic influenced pottery styles become standardised in a large area covering the Mediterranean coast. In Auvergne these Mediterranean influences disappear in favour of the Duffaits style from the Centre-West of France. At the beginning of the Late Bronze Age, cultural areas are redefined even though their boundaries remain permeable. The stylistic links with the north of Italy and the presence of cremation burials are mainly limited to the footholds of the Southern Alps. In contrast, pottery groups of the Rhône Valley incorporate characteristics from the North that are reminiscent of the «southern cannelated» group of the “Tumulus Culture”. The composition of the hoards and their objects can also be compared to the Saone area and the Paris Basin. These observations lead towards an increasing cultural distinction between the area around the Rhône and the Alps during the first phase of the Late Bronze Age. They prefigure the ascension of the North-Alpine material culture that penetrates the middle and lower Rhône Valley during the middle phase of the Late Bronze Age.Ce travail constitue une synthèse des données concernant le Bronze moyen et le début du Bronze final dans le quart Sud-Est de la France, restreint aux entités administratives du Languedoc-Roussillon et de Provence-Alpes-Côte d’Azur ainsi qu’au sud de la région Rhône-Alpes et de l’Auvergne. Au début du Bronze moyen, les styles céramiques montrent des affinités avec la péninsule italienne, dont l’origine précise semble néanmoins varier en fonction des secteurs. Une grande cohérence peut également être décelée dans les pratiques funéraires et de dépôts d’objets métalliques. A la fin de cette période, une homogénéisation des styles céramiques, d’affinité toujours italique, concerne une grande partie du littoral méditerranéen. En parallèle, en Auvergne, les caractères méditerranéens disparaissent au profit du style des Duffaitsdu Centre ouest. Au début du Bronze final, une recomposition des espaces culturels est manifeste bien que leurs limites soient largement perméables. Les connexions stylistiques avec le nord de l’Italie restent principalement limitées aux contreforts des Alpes méridionales, de même que l’apparition de sépultures à incinérations. En revanche, la vallée du Rhône voit l’apparition de faciès céramiques intégrant des caractères septentrionaux, évoquant le groupe cannelé méridional de la “culture des Tumulus”, ainsi que de dépôts d’objets métalliques dont la composition et la typologie des objets trouvent également des comparaisons dans la région de la Saône et le Bassin parisien. Ces observations vont donc dans le sens d’une distinction culturelle croissante entre les régions rhodaniennes et alpines lors de l’étape initiale du Bronze final. Elles préfigurent l’ascendance des cultures matérielles nord-alpines qui intéresseront la moyenne et basse vallée du Rhône lors de l’étape moyenne de cette période