Instability and Spatiotemporal Dynamics of Alternans in Paced Cardiac Tissue

We derive an equation that governs the spatiotemporal dynamics of small amplitude alternans in paced cardiac tissue. We show that a pattern-forming linear instability leads to the spontaneous formation of stationary or traveling waves whose nodes divide the tissue into regions with opposite phase of oscillation of action potential duration. This instability is important because it creates dynamically an heterogeneous electrical substrate for inducing fibrillation if the tissue size exceeds a fraction of the pattern wavelength. We compute this wavelength analytically as a function of three basic length scales characterizing dispersion and inter-cellular electrical coupling.Comment: 4 pages, 3 figures, submitted to PR

Toward a 21st-century health care system: Recommendations for health care reform

The coverage, cost, and quality problems of the U.S. health care system are evident. Sustainable health care reform must go beyond financing expanded access to care to substantially changing the organization and delivery of care. The FRESH-Thinking Project (www.fresh-thinking.org) held a series of workshops during which physicians, health policy experts, health insurance executives, business leaders, hospital administrators, economists, and others who represent diverse perspectives came together. This group agreed that the following 8 recommendations are fundamental to successful reform: 1. Replace the current fee-for-service payment system with a payment system that encourages and rewards innovation in the efficient delivery of quality care. The new payment system should invest in the development of outcome measures to guide payment. 2. Establish a securely funded, independent agency to sponsor and evaluate research on the comparative effectiveness of drugs, devices, and other medical interventions. 3. Simplify and rationalize federal and state laws and regulations to facilitate organizational innovation, support care coordination, and streamline financial and administrative functions. 4. Develop a health information technology infrastructure with national standards of interoperability to promote data exchange. 5. Create a national health database with the participation of all payers, delivery systems, and others who own health care data. Agree on methods to make de-identified information from this database on clinical interventions, patient outcomes, and costs available to researchers. 6. Identify revenue sources, including a cap on the tax exclusion of employer-based health insurance, to subsidize health care coverage with the goal of insuring all Americans. 7. Create state or regional insurance exchanges to pool risk, so that Americans without access to employer-based or other group insurance could obtain a standard benefits package through these exchanges. Employers should also be allowed to participate in these exchanges for their employees' coverage. 8. Create a health coverage board with broad stakeholder representation to determine and periodically update the affordable standard benefit package available through state or regional insurance exchanges

Centrioles: active players or passengers during mitosis?

Centrioles are cylinders made of nine microtubule (MT) triplets present in many eukaryotes. Early studies, where centrosomes were seen at the poles of the mitotic spindle led to their coining as “the organ for cell division”. However, a variety of subsequent observational and functional studies showed that centrosomes might not always be essential for mitosis. Here we review the arguments in this debate. We describe the centriole structure and its distribution in the eukaryotic tree of life and clarify its role in the organization of the centrosome and cilia, with an historical perspective. An important aspect of the debate addressed in this review is how centrioles are inherited and the role of the spindle in this process. In particular, germline inheritance of centrosomes, such as their de novo formation in parthenogenetic species, poses many interesting questions. We finish by discussing the most likely functions of centrioles and laying out new research avenues

Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features

SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and consequently which of the three major SOX5 protein isoforms are affected. One intragenic deletion involving only untranslated exons was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

3D aortic morphology and stiffness in MRI using semi-automated cylindrical active surface provides optimized description of the vascular effects of aging and hypertension

Background: Clinically, aortic geometry assessment is mainly based on the measurement of maximal diameters at different anatomic locations, which are subsequently used to indicate prophylactic aortic surgery. However, 3D evaluation of aortic morphology could provide volumetric quantification, which integrates both aortic dilatation and elongation and might thus be more sensitive to early geometric changes than diameters. Precise aortic morphology is also required for the calculation of pulse wave velocity (PWVMRI), an established marker of aortic stiffness. Accordingly, we proposed a 3D semi-automated analysis of thoracic aorta MRI data optimizing morphological and subsequent stiffness assessment. Methods: We studied 74 individuals (40 males, 50 ± 12years): 21 healthy volunteers and 53 patients with hypertension in whom aortic 3D MRI angiography and 2D + t phase-contrast and cine imaging were performed. A semi-automated method was proposed for volumetric aortic segmentation and was evaluated by studying resulting measurements (length, diameters, volumes and PWVMRI) in terms of: 1) reproducibility, 2) correlations with well-established 2D aortic length and diameters, 3) associations with age, carotid-femoral PWV (cf-PWV) and presence of hypertension. Results: The measurements obtained with the proposed method were reproducible (coefficients of variation ≤ 5.1%) and were highly correlated with 2D measurements (arch length: r = 0.80, Bland-Altman mean bias [limits]: 2.7 mm [-25; 30]; PWVMRI: r = 0.95, 0.22 m/s [-1.9; 2.4]). Higher or similar correlations with age were found for the proposed 3D method compared to the 2D approach (arch length: r = 0.47 (2D), r = 0.60 (3D); PWVMRI: r = 0.63 (2D), r = 0.64 (3D)). Moreover, a significant association was found between PWVMRI and cf-PWV (r = 0.49, p < 0.001). All aortic measurements increased with hypertension (p < 0.05) and with age: arch length (+9mm/decade); diameters: ascending (+1.2mm/decade) and descending aorta (+1.0mm/decade); volumes: ascending (+2.6mL/decade) and descending aorta (+4.0mL/decade); PWVMRI (+1.7 m s−1/decade). Conclusions: A semi-automated method based on cylindrical active surfaces was proposed for the 3D segmentation of the aorta using a single MRI dataset, providing aortic diameters at anatomical landmarks, aortic volumes and the aortic centerline length used for PWV estimation. Such measurements were reproducible and comparable to expert measurements, which required time-consuming centerline delineation. Furthermore, expected relationships with age and hypertension were found indicating the consistency of our measurements.Fil: Dietenbeck, Thomas. Université Pierre et Marie Curie; FranciaFil: Craiem, Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Rosenbaum, David. Université Pierre et Marie Curie; FranciaFil: Giron, Alain. Université Pierre et Marie Curie; FranciaFil: De Cesare, Alain. Université Pierre et Marie Curie; FranciaFil: Bouaou, Kévin. Université Pierre et Marie Curie; FranciaFil: Girerd, Xavier. Université Pierre et Marie Curie; FranciaFil: Cluzel, Philippe. Université Pierre et Marie Curie; FranciaFil: Redheuil, Alban. Université Pierre et Marie Curie; FranciaFil: Kachenoura, Nadjia. Université Pierre et Marie Curie; Franci

Spotlight on childhood blindness

Leber congenital amaurosis (LCA) is a rare disease that severely affects vision in early life. It is characterized by genetic and clinical heterogeneity due to complex and not fully understood pathogenetic mechanisms. It is also now widely known as a disease model for gene therapy. In this issue of the JCI, two independent research groups report valuable new data on LCA. Specifically, they provide important insights into the pathophysiological mechanisms of LCA and offer strong hope that the outcome of gene therapy for retinal degenerative diseases will be successful

Early Coronary Calcifications are Related to Cholesterol Burden in Heterozygous Familial Hypercholesterolemia

International audienceBackgroundThe identification of high-risk patients with Heterozygous Familial Hypercholesterolemia (HeFH) that may benefit from early treatment is challenging. Coronary Artery Calcification (CAC) score accounts for coronary atherosclerotic burden. It has proven its accuracy in cardiovascular risk (CVR) assessment in the general population but data in HeFH are lacking.ObjectiveThe aim of our study was to assess CAC prevalence and its relationship with lifelong cholesterol exposure, calculated by Total Cholesterol Burden (TCB) in patients with HeFH.Methods112 HeFH patients (50% males, median age 45) regularly followed-up since diagnosis were prospectively recruited at Pitié-Salpêtrière Hospital, Paris, France. CAC score was assessed using non contrast multi-detector computed tomography. TCB was calculated as total cholesterol (TC) x age at diagnosis plus annually assessed TC.ResultsThe prevalence of CAC was 58%. Patients without CAC showed lower TCB than patients with CAC (298±110 vs 417.9±89 mmol-years/l, p<0.001). Among patients <45 (n=56), 39% exhibited CAC and a higher TCB compared to patients without CAC (352±71 vs 255±88 mmol-years/l, p<0.001) due to higher TC levels at diagnosis (10.2±2 vs 8.7±2 mmol/l, p=0.01). Multivariate analysis indicated that TCB was independently associated toCAC.ConclusionsAsymptomatic HeFH subjects exhibit early coronary atherosclerosis directly associated with TCB. Cholesterol burden and CAC score may be useful to identify higher risk HeFH patients who can benefitfrom earlier and more aggressive treatment

Myocardial fibrosis assessed by magnetic resonance imaging in asymptomatic heterozygous familial hypercholesterolemia: the cholcoeur study

International audienceBackgroundFamilial Hypercholesterolemia (FH) is an underdiagnosed condition with an increased cardiovascular risk. It is unknown whether lipid accumulation plays a role in structural myocardial changes. Cardiovascular Magnetic Resonance (CMR) is the reference technique for the morpho-functional evaluation of heart chambers through cine sequences and for myocardial tissue characterization through late gadolinium enhancement (LGE) and T1 mapping images. We aimed to assess the prevalence of myocardial fibrosis in FH patients.MethodsSeventy-two asymptomatic subjects with genetically confirmed FH (mean age 49·24, range 40 to 60 years) were prospectively recruited along with 31 controls without dyslipidaemia matched for age, sex, BMI, and other cardiovascular risk factors. All underwent CMR including cine, LGE, pre- and post-contrast T1 mapping. Extracellular volume (ECV) and enhancement rate of the myocardium (ERM = difference between pre- and post-contrast myocardial T1, normalized by pre-contrast myocardial T1) were calculated.FindingsFive FH patients and none of the controls had intramyocardial LGE (p= 0·188). While no changes in Native T1 and ECV were found, post-contrast T1 was significantly lower (430·6 ± 55ms vs. 476·1 ± 43ms, p<0·001) and ERM was higher (57·44± 5·99 % vs 53·04±4·88, p=0·005) in HeFH patients compared to controls. Moreover, low post-contrast T1 was independently associated with the presence of xanthoma (HR 5·221 [1·04-26·28], p= 0·045). A composite score combining the presence of LGE, high native T1 and high ERM (defined as ≥ mean ± 1·5 SD) was found in 20·8% of the HeFH patients vs. 0% in controls (p<0·000, after adjustment for main confounders).InterpretationCMR revealed early changes in myocardial tissue characteristics in HeFH patients, that should foster further work to better understand and prevent the underlying pathophysiological processes