The use of muscle strength assessed with handheld dynamometers as a non-invasive biological marker in myotonic dystrophy type 1 patients: a multicenter study

<p>Abstract</p> <p>Background</p> <p>Myotonic dystrophy type 1 (DM1) is a multisystem disorder that demonstrates variable symptoms and rates of progression. Muscle weakness is considered one of the main problems with a clinical picture that is characterized by distal weakness of the limbs progressing to proximal weakness. The main objective of this study was to characterize the maximal strength of ankle eversion and dorsiflexion in DM1 patients. Manual and handheld dynamometer (HHD) muscle testing were also compared.</p> <p>Methods</p> <p>The maximal strength of 22 patients from Quebec (mean age = 41,1 ± 13,8) and 24 from Lyon (mean age = 41,6 ± 10,2) were compared to 16 matched controls.</p> <p>Results</p> <p>With the use of HHD, an excellent reproducibility of the torque measurements was obtained for both centers in eversion (R²= 0,94/Quebec; 0,89/Lyon) and dorsiflexion (R²= 0,96/Quebec; 0,90/Lyon). The differences between 3 groups of DM1 (mild, moderate, severe) and between them and controls were all statistically significant (p < 0,001). No statistical differences between sites were observed (p > 0.05). The degree of muscle strength decline in dorsiflexion (eversion) were 60% (47%), 77% (71%), and 87% (83%) for DM1 with mild, moderate, and severe impairments, respectively. The smallest mean difference between all DM1 patients taking together was 2.3 Nm, a difference about twice than the standard error of measurement. There was a strong relationship between eversion and dorsiflexion strength profiles (R²= 0,87;Quebec/0,80;Lyon). Using a 10-point scale, manual muscle testing could not discriminate between the 3 groups of DM1 patients.</p> <p>Conclusions</p> <p>The HHD protocol showed discriminative properties suitable for multicentre therapeutic trial. The present results confirmed the capacity of quantitative muscle testing to discriminate between healthy and DM1 patients with different levels of impairments. This study is a preliminary step for the implementation of a valid, reliable and responsive clinical outcome for the measurement of muscle impairments with this population.</p

The physical and cellular conditions of the human pulmonary circulation enable thrombopoesis

Animal evidence that platelet production occurs in the lungs is growing [1]. We have investigated whether there is evidence to support pulmonary platelet production from studies using human conditions. We documented the presence of MK in the human pulmonary circulation and analysed the role of the vascular microenvironment on MK function. Our results suggest that the endothelial microenvironment favors platelet formation and that von Willebrand factor combined with appropriate physical forces in flowing blood are determinant for platelet release. We also demonstrate that MKs have the potential to change ploidy as they circulate. These findings demonstrate a new pathophysiological environment affecting platelet production. They also provide new targets for therapeutic intervention

Evolution de la prise en charge et du pronostic des syndromes coronariens aigus en France entre 1995 et 2010

Dans les pays développés , les syndromes coronariens aigus (SCA) représentent une pathologie fréquente et grave et les maladies cardiovasculaires restent la première cause de mortalité en Europe. Au cours de la dernière décennie, pourtant, plusieurs travaux épidémiologiques ont suggéré une baisse sensible de l'incidence des infarctus et la mortalité cardiovasculaire est dorénavant en recul dans de très nombreux pays, dont la France. La cardiologie est une des disciplines médicales qui a connu les plus grands bouleversements au cours des 25 dernières années et la prise en charge des SCA ainsi que le profil des patients ont considérablement évolué. Dans ce contexte, il nous a paru intéressant d'étudier la manière dont le devenir des patients présentant un infarctus aigu pouvait participer à cette baisse générale de la mortalité cardio-vasculaire. A partir de quatre enquêtes longitudinales successives répertoriant les SCA (USIK 1995, USIC 2000, FAST-MI 2005, FAST-MI 2010) et de l observatoire national des actes de cardiologie interventionnelle (ONACI), nous avons observé, après standardisation sur les caractéristiques initiales des différentes cohortes, une baisse spectaculaire de la mortalité quel que soit le type de SCA (avec sus-décalage ST [SCA ST+] ou ST-elevation myocardial infarction [STEMI] ; sans sus-décalage ST [SCA ST-] ou non-ST-elevation myocardial infarction [NSTEMI]). Cette évolution peut être expliquée par plusieurs paramètres : amélioration de la prise en charge globale, meilleur suivi des recommandations, changement de profils des patients (pour les STEMI), développement de la stratégie invasive et utilisation de nouvelles thérapeutiques, évolution des techniques de cardiologie interventionnelle Ainsi, il apparaît que l'amélioration du pronostic des patients atteints d'infarctus est bien un des éléments ayant pu contribuer à la baisse de la mortalité cardiovasculaire. L enjeu aujourd hui est de maintenir ces résultats, de renforcer les mesures de prévention et d améliorer le pronostic à long terme en développant notamment les programmes d éducation thérapeutique.In developed countries, acute coronary syndromes (ACS) represent a common and serious disease, and cardiovascular disease remains the leading cause of death in Europe. During the last decade, however, several epidemiological studies have suggested a significant reduction in the incidence of myocardial infarction and cardiovascular mortality in many countries, including France. Over the past 25 years, Cardiology has dramatically evolved and the management of ACS, as well as patient risk profile have substantially changed. In this context, we aimed to evaluate how the outcomes of patients with acute myocardial infarction could participate in the general decline in cardiovascular mortality. From four successive longitudinal surveys including ACS (USIK 1995, USIC 2000, FAST-MI 2005, FAST-MI 2010) and the national observatory of interventional cardiology (ONACI) we observed, after standardization of the cohorts on baseline clinical characteristics, a dramatic decline in mortality regardless of the type of ACS (STEMI, ST-elevation myocardial infarction, NSTEMI, non-ST-elevation myocardial infarction). This evolution can be explained by several factors: overall improvement in organization of care, better implementation of recommendations, substantial change in the patient risk profile (for STEMI), increasing use of invasive strategy and adjunctive therapies, improved technique for Interventional Cardiology ... Therefore, the improved prognosis of patients with myocardial infarction appears to be one of the factors that have contributed to the decline in cardiovascular mortality. For the future, the challenge will be to maintain these results, strengthen preventive measures and improve long-term prognosis in particular by developing the therapeutic education programs.PARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Residual Ischemic Risk and Its Determinants in Patients With Previous Myocardial Infarction and Without Prior Stroke or TIA: Insights From the REACH Registry

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135334/1/clc22583.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135334/2/clc22583-sup-0001-AppendixS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135334/3/clc22583_am.pd

Rationale and design of the long-Term rIsk, clinical manaGement, and healthcare Resource utilization of stable coronary artery dISease in post-myocardial infarction patients (TIGRIS) study.

The long-term progression of coronary artery disease as defined by the natural disease course years after a myocardial infarction (MI) is an important but poorly studied area of clinical research. The long-Term rIsk, clinical manaGement, and healthcare Resource utilization of stable coronary artery dISease in post-myocardial infarction patients (TIGRIS) study was designed to address this knowledge gap by evaluating patient management and clinical outcomes following MI in different regions worldwide. TIGRIS (ClinicalTrials.gov Identifier: NCT01866904) is a multicenter, observational, prospective, longitudinal study enrolling patients with history of MI 1 to 3 years previously and high risk of developing atherothrombotic events in a general-practice setting. The primary objective of TIGRIS is to evaluate clinical events (time to first occurrence of any event from the composite cardiovascular endpoint of MI, unstable angina with urgent revascularization, stroke, or death from any cause), and healthcare resource utilization associated with hospitalization for these events (hospitalization duration and procedures) during follow-up. Overall, 9225 patients were enrolled between June 2013 and November 2014 and are being followed in 369 different centers worldwide. This will allow for the description of regional differences in patient characteristics, risk profiles, medical treatment patterns, clinical outcomes, and healthcare resource utilization. Patients will be followed for up to 3 years. Here we report the rationale, design, patient distribution, and selected baseline characteristics of the TIGRIS study. TIGRIS will describe real-world management, quality of life (self-reported health), and healthcare resource utilization for patients with stable coronary artery disease ≥1 year post-MI

0130: Mortality related to cardiogenic shock in critically ill patients in France, 1997-2012

IntroductionMost of data reporting epidemiology of cardiogenic shock (CS) concern patients with acute myocardial infarction admitted in intensive care unit of cardiology. However, CS patients managed in critical care unit (CCU) have often multiorgan failure and seem to have different characteristics and outcome. To our best knowledge no study reported characteristics and clinical outcomes of CS patients admitted in CCU.AimTo report key features, Mortality and Trends in mortality in a large cohort of patients with CS admitting in 33 French CCUs from 1997 to 2012.Methods and resultsWe queried the 1997–2012 database of Parisian area ICUs-the CubRea (Intensive Care Database User Group) database to identify all hospital stays with a principal or an associated diagnosis of CS (National classification of disease R 570). Among 303 314 hospital stays, 17 494 (5.8%) were CS. The patients were managed in 60% of cases in universitary centers. Mean age was 64.3±17.0. Men accounted for 11047 (63.1%). Mean SAPS II was 62.0±24.3. Among CS, only 535 (3.06%) were AMI whereas 2685 (15.3%) were cardiac arrest and 858 (4.9%) were drug intoxications. Mechanical ventilation was required in 12967 (74.1%) of cases, inotropes in 14640 (83.7%) of cases and renal support in 3886 (22.2%) of cases. Mean duration of hospital was 19.1 days±24.7. Intrahospital Mortality was high (46.2%). Predictors of intrahospital death are reported in Table. Over the 15-year period, mortality decreased (49.8% in 1997-2000 and 42.7% in 2009-2012, p<0.001) whereas the patients were more critically ill (SAPS II 58.8±25.4 in 1997-2000 vs 64.2 8±23.6 in 2009-2012, p<0.001).Conclusionit is the first study reporting the prevalence, determinants and prognostic factors of CS patients managed in reanimation. The mortality of these very critically ill patients remains high. However over the 15-year period, even if these patients are more and more critically ill, early mortality decreased.Abstratct 0130 – TableVariablesOR95% CIDrug intoxication.307.236.401Age (<60 yo).436.383.496Mechanical circulatory support.681.3781.228Sepsis.715.637.8022009-2012.998.8851.125SAPS II1.0361.0331.038Acidosis1.4531.2641.670Mechanical ventilation1.7181.4831.990Acute respiratory distress syndrome1.7941.5582.0661997-20001.8141.4522.267Hemodialysis1.8201.6092.060Inotropic use1.9821.1133.530Disseminated intravascular coagulation2.1191.5912.822Cardiac arrest4.3333.8404.88

Generation of a human induced pluripotent stem cell line (UQACi001-A) from a severe epidermolysis bullosa simplex patient with the heterozygous mutation p.R125S in the KRT14 gene

We have generated UQACi001-A, a new induced pluripotent stem cell (iPSC) line derived from skin fibroblasts of a male patient with the generalized severe epidermolysis bullosa simplex phenotype (EBS-gen sev) and carrying the keratin 14 (K14) R125S mutation. Fibroblasts were reprogrammed using non-integrating Sendai virus vectors. The iPSC line displayed normal molecular karyotype, expressed pluripotency markers, is capable of differentiating into three embryonic germ layers and is genetically identical to the originating parental fibroblasts. The established iPSC model provides a valuable resource for studying the rare disease of epidermolysis bullosa simplex and developing new therapies as DNA editing by CRISPR/Cas9 technology

Towards development of a statistical framework to evaluate myotonic dystrophy type 1 mRNA biomarkers in the context of a clinical trial

Myotonic dystrophy type 1 (DM1) is a rare genetic disorder, characterised by muscular dystrophy, myotonia, and other symptoms. DM1 is caused by the expansion of a CTG repeat in the 3'-untranslated region of DMPK. Longer CTG expansions are associated with greater symptom severity and earlier age at onset. The primary mechanism of pathogenesis is thought to be mediated by a gain of function of the CUG-containing RNA, that leads to transdysregulation of RNA metabolism of many other genes. Specifically, the alternative splicing (AS) and alternative polyadenylation (APA) of many genes is known to be disrupted. In the context of clinical trials of emerging DM1 treatments, it is important to be able to objectively quantify treatment efficacy at the level of molecular biomarkers. We show how previously described candidate mRNA biomarkers can be used to model an effective reduction in CTG length, using modern high-dimensional statistics (machine learning), and a blood and muscle mRNA microarray dataset. We show how this model could be used to detect treatment effects in the context of a clinical trial

Recycling existing data: a greener future for clinical registries

This article concerns the potential benefits of clinical disease registers, but points to the problems inherent in maintaining high quality reliable datasets. It comments on a recent (accompanying) paper from the West of Scotland that extracted data from existing administrative and clinical datasets to produce a meaningful registry