Common Genetic Variation And Age at Onset Of Anorexia Nervosa

Background Genetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at onset of AN and age at menarche. Methods A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed which included 9,335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age at onset, early-onset AN (< 13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (SNP-h2) were 0.01-0.04 for age at onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age at onset and early-onset AN estimated from independent GWASs significantly predicted age at onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions Our results provide evidence consistent with a common variant genetic basis for age at onset and implicate biological pathways regulating menarche and reproduction.Peer reviewe

Comparison of 1D and 3D Models for the Estimation of Fractional Flow Reserve

Abstract In this work we propose to validate the predictive capabilities of one-dimensional (1D) blood flow models with full three-dimensional (3D) models in the context of patient-specific coronary hemodynamics in hyperemic conditions. Such conditions mimic the state of coronary circulation during the acquisition of the Fractional Flow Reserve (FFR) index. Demonstrating that 1D models accurately reproduce FFR estimates obtained with 3D models has implications in the approach to computationally estimate FFR. To this end, a sample of 20 patients was employed from which 29 3D geometries of arterial trees were constructed, 9 obtained from coronary computed tomography angiography (CCTA) and 20 from intra-vascular ultrasound (IVUS). For each 3D arterial model, a 1D counterpart was generated. The same outflow and inlet pressure boundary conditions were applied to both (3D and 1D) models. In the 1D setting, pressure losses at stenoses and bifurcations were accounted for through specific lumped models. Comparisons between 1D models (FFR1D) and 3D models (FFR3D) were performed in terms of predicted FFR value. Compared to FFR3D, FFR1D resulted with a difference of 0.00 ± 0.03 and overall predictive capability AUC, Acc, Spe, Sen, PPV and NPV of 0.97, 0.98, 0.90, 0.99, 0.82, and 0.99, with an FFR threshold of 0.8. We conclude that inexpensive FFR1D simulations can be reliably used as a surrogate of demanding FFR3D computations

Thermodynamic analogies for the characterization of 3D human coronary arteries

The thermodynamics of three-dimensional curves is explored through numerical simulations, providing room for a broader range of applications. Such approach, which makes use of elements of information theory, enables the processing of parametric as well as non-parametric data distributed along the curves. Descriptors inspired in thermodynamic concepts are derived to characterize such three-dimensional curves. The methodology is applied to characterize a sample of 48 human coronary arterial trees and compared with standard geometric descriptors. As an application, the usefulness of the thermodynamic descriptors is tested by assessing statistical associations between arterial shape and diseases. The feature space defined by arterial descriptors is analyzed using multivariate kernel density classification methods. A two-tailed U-test with 95% confidence interval showed that some of the proposed thermodynamic descriptors have different mean values for healthy/diseased left anterior descending (LAD) and left circumflex (LCx) arteries. Specifically: in the LAD, the temperatures based on mean number of intersection points and curvature are larger in healthy arteries (p < 0.05); in the LCx, the intersection counting pressure is larger in healthy arteries (p < 0.05). Moreover, the shape of the right coronary artery is thoroughly characterized by these descriptors. Specifically: intersection count thermodynamics, i.e. entropy, temperature and pressure are larger in Σ-Shape RCAs, in turn curvature based entropy and pressure are larger in C-Shape RCAs (p < 0.05).Fil: Bulant, Carlos Alberto. Laboratorio Nacional de Computacao Cientifica; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina. National Institute Of Science And Technology In Medicine Assisted By Scientific Computing; BrasilFil: Blanco, P. J.. National Institute Of Science And Technology In Medicine Assisted By Scientific Computing; Brasil. Laboratorio Nacional de Computacao Cientifica; BrasilFil: Clausse, Alejandro. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; ArgentinaFil: Bezerra, C.. Universidade de Sao Paulo; BrasilFil: Lima, T. P.. Universidade de Sao Paulo; BrasilFil: Ávila, L. F. R.. Universidade de Sao Paulo; BrasilFil: Lemos, P. A.. Universidade de Sao Paulo; BrasilFil: Feijóo, Raúl Antonino. Laboratorio Nacional de Computacao Cientifica, Petropolis; . National Institute Of Science And Technology In Medicine Assisted By Scientific Computing

Association between three-dimensional vessel geometry and the presence of atherosclerotic plaques in the left anterior descending coronary artery of high-risk patients

Geometrical risk factors for coronary atherosclerosis were proposed in the eighties as a complement to fluid dynamic and biomechanical mechanisms for atherosclerotic genesis and progression. Up to date there are no conclusive results in the subject, although several studies suggest that there is an underlying relation between geometry and disease. Coronary computed tomography angiographies of 48 patients were processed, and the left anterior descending artery (LAD) of each patient was geometrically characterized by computing point-wise curvature. Distal averaging of this feature was used as discriminating variable to identify healthy and diseased arteries. Standard statistical analysis was performed and a binary classifier was used to assess the discriminating capability of the so called average distal curvature (κ¯d). A significant difference between the distribution of κ¯d in healthy and diseased LADs was found (p < 0.01). Performance of the classifier for a cut-off value of κ¯d=0.0537 mm−1 in terms of accuracy, sensitivity and specificity is 75%, 70% and 80% respectively. The area under the receiver-operator curve is 0.75. The results presented here support the hypothesis of a significant correlation between low values of average distal curvature and stenotic lesions in LAD arteries.Fil: Bulant, C. A.. National Institute Of Science And Technology In Medicine Assisted By Scientific Computing; Brasil. Laboratorio Nacional de Computacao Cientifica; BrasilFil: Blanco, P. J.. National Institute Of Science And Technology In Medicine Assisted By Scientific Computing; Brasil. Laboratorio Nacional de Computacao Cientifica; BrasilFil: Clausse, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Assunção, A. N.. Universidade de Sao Paulo; BrasilFil: Lima, T. P.. Universidade de Sao Paulo; BrasilFil: Ávila, L. F. R.. Universidade de Sao Paulo; BrasilFil: Feijóo, Raúl Antonino. Laboratorio Nacional de Computacao Cientifica; Brasil. National Institute Of Science And Technology In Medicine Assisted By Scientific Computing; BrasilFil: Lemos, P. A.. Universidade de Sao Paulo; Brasi

Sheltered in Stromal Tissue Cells, <i>Trypanosoma cruzi</i> Orchestrates Inflammatory Neovascularization via Activation of the Mast Cell Chymase Pathway

Microangiopathy may worsen the clinical outcome of Chagas disease. Given the obstacles to investigating the dynamics of inflammation and angiogenesis in heart tissues parasitized by Trypanosoma cruzi, here we used intravital microscopy (IVM) to investigate microcirculatory alterations in the hamster cheek pouch (HCP) infected by green fluorescent protein-expressing T. cruzi (GFP-T. cruzi). IVM performed 3 days post-infection (3 dpi) consistently showed increased baseline levels of plasma extravasation. Illustrating the reciprocal benefits that microvascular leakage brings to the host-parasite relationship, these findings suggest that intracellular amastigotes, acting from inside out, stimulate angiogenesis while enhancing the delivery of plasma-borne nutrients and prosurvival factors to the infection foci. Using a computer-based analysis of images (3 dpi), we found that proangiogenic indexes were positively correlated with transcriptional levels of proinflammatory cytokines (pro-IL1β and IFN-γ). Intracellular GFP-parasites were targeted by delaying for 24 h the oral administration of the trypanocidal drug benznidazole. A classification algorithm showed that benznidazole (>24 h) blunted angiogenesis (7 dpi) in the HCP. Unbiased proteomics (3 dpi) combined to pharmacological targeting of chymase with two inhibitors (chymostatin and TY-51469) linked T. cruzi-induced neovascularization (7 dpi) to the proangiogenic activity of chymase, a serine protease stored in secretory granules from mast cells