Danon disease is an X-linked disorder with the clinical triad of cardiomyopathy, skeletal myopathy, and mental retardation. Early diagnosis of this disease remains a challenge, especially in the ...pediatric population. In this study, we developed a targeted panel-based next generation sequencing pipeline to identify mutations by sequencing of selected candidate genes in 136 pediatric patients with either hypertrophic cardiomyopathy (HC) or idiopathic dilated cardiomyopathy (IDC). This led to the identification of lysosome-associated membrane protein 2 ( LAMP2 ) mutations in 4 of the 64 (6%) probands with HC, including 3 novel nonsense mutations (p.Q240X, p.S250X, and p.G22X). No LAMP2 mutation was detected in the other 72 probands with IDC. All 4 probands and one additional affected family member (2 men and 3 women) had an early-onset age and presented either HC alone or combined with Wolff-Parkinson-White syndrome and skeletal myopathy. Immunofluorescence staining and Western blot analysis revealed absent LAMP2 expression in both cardiac and skeletal muscle samples of the first proband and severely decreased LAMP2 expression in the skeletal muscle samples of the second proband. In conclusion, cardiomyopathy in the patients with Danon disease may occur during early childhood and tend to be HC rather than IDC in both affected men and women. Therefore, Danon disease should be considered as one of the leading causes of unexplained ventricular hypertrophy in pediatric patients. The inclusion of LAMP2 gene in cardiomyopathy genetic screening panels may contribute to early diagnosis of Danon disease.
Abstract Background To predict the recurrence of atrial fibrillation is important for selecting patients who will be undergoing catheter ablation, several studies respectively evaluated the risk ...factor of the recurrence of atrial fibrillation post-ablation. Objective To investigate the factors predicting the recurrence of atrial fibrillation (AF) after catheter ablation. Methods 186 patients (55.12 ± 12.06 years, 123 male) including 161 paroxysmal AF and 25 non-paroxysmal AF who underwent catheter ablation were studied. Clinical datum before and during ablation were recorded, and systematic follow-up was conducted after ablation. Univariate and multivariate analyses were carried out to determine the factors predicting late recurrence of AF (LRAF) which means AF recurrence after 3 months. Results There were 47(25.27%) patients who experienced LRAF. Multivariate Logistic regression analysis was carried out to the parameters that P < 0.10 in the univariate analysis, which includes overweight/obesity, metabolic syndrome (MetS), AF categories, duration of AF history, left atrial diameter (LAD), diabetes mellitus, ablation strategies, procedural failure and early recurrence of AF after ablation (ERAF). Ultimately, the results demonstrated that overweight/obesity (OR = 4.71, 95% CI 1.71–12.98, P = 0.003), MetS (OR = 4.41, 95% CI 1.56–12.46, P = 0.005), procedural failure (OR = 58.34, 95% CI 6.83–498.34, P < 0.001), and ERAF (OR = 3.18, 95% CI 1.07–9.44, P = 0.037) were independent predictors of AF recurrence after ablation. Conclusion Overweight/obesity, metabolic syndrome, procedural failure and ERAF are independent predictors of late recurrence of atrial fibrillation in this group of patients.
The grain refinement mechanism and texture evolution of electromagnetically formed polycrystalline Cu sheets were investigated using the electron back-scattered diffraction (EBSD) technique. It is ...found that the average grain size decreases from 35.88 μm to 8.77 μm. The grain refinement was mainly attributed to dynamic recrystallization (DRX) at the grain boundary regions of bulged Cu samples where the inhomogeneous dislocation density and the large lattice misorientation were observed. The DRX mechanisms at the grain boundaries were discussed with respect to the strain-induced grain boundary migration nucleation. Moreover, the orientation distribution function (ODF) of the sample with the strain of 50% demonstrated a strong {110} texture and a relatively weak {001} texture. The texture evolution was discussed using the plastic work values of the grains with various orientations, which were calculated according to the Taylor model and the virtual work principle. The experimental results show that the expended plastic work of the grains with {110} orientation is 9.69 MPa, which is distinctly higher than those of the grains with the {001} and {111} orientations. This indicates that the formation of the {110} orientated texture would be preferred with increasing strain in good agreement with the experimental result.
Raman spectroscopy has been efficiently used to recognize breast cancer tissue by detecting the characteristic changes in tissue composition in cancerization. In addition to chemical composition, the ...change in bio-structure may be easily obtained via polarized micro-Raman spectroscopy, aiding in identifying the cancerization process and diagnosis. In this study, a polarized Raman spectral technique is employed to obtain rich structural features and, combined with deep learning technology, to achieve discrimination of breast cancer tissue. The results reconfirm that the orientation of collagen fibers changes from parallel to vertical during breast cancerization, and there are significant structural differences between cancerous and normal tissues, which is consistent with previous reports. Optical anisotropy of collagen fibers weakens in cancer tissue, which is closely related with the tumor's progression. To distinguish breast cancer tissue, a discrimination model is established based on a two-dimensional convolutional neural network (2D-CNN), where the input is a matrix containing the Raman spectra acquired at a set of linear polarization angles varying from 0° to 360°. As a result, an average discrimination accuracy of 96.01% for test samples is achieved, better than that of the KNN classifier and 1D-CNN that are based on non-polarized Raman spectra. This study implies that polarized Raman spectroscopy combined with 2D-CNN can effectively detect changes in the structure and components of tissues, innovatively improving the identification and automatic diagnosis of breast cancer with label-free probing and analysis.
The economic development of China’s mountainous areas has been rapid, but the impact of flash floods is often ignored during regional development planning. Therefore, a method needed to be developed ...to simulate flash flood disasters and analyze the trends in flash flood disasters with regional development. Taking Guanshan River Basin as the research area, we combined the digital elevation model (DEM) with the inflow hydrograph, using the topography-based hydrological model (TOPMODEL). Verified by historical flash flood disasters, the watershed model was built based on the finite volume conservation flood routing model (FLO-2D). Then, we simulated the hazard distribution of flash flood disasters, developed a risk status assessment factor (RSAF) for flash flood disasters and calculated the increased ratio from 2003 to 2018. The results show that in 2003, the total hazard area of flash flood disasters affecting human settlements was 61,121 m2, which increased to 118,404 m2 in 2018. Since 2003, with the development of the regional economy, more residents moved to risk and extreme risk zones; thus, the risk of flash flood disasters also increased. Due to the significant damage caused by the flash flood on 5 August 2012, some of the local residents moved away from the high risk and extreme risk zones, indicating that the risk trend of flash flood hazard was consistent with the regional development of Guanshan River. We provide suggestions for regional economic development planning; the risk assessment for flash flood disasters must be considered to ensure the stable development of the regional economy, and using the RSAF would be efficient.
When 3D laser scanning (LIDAR) is used for navigation of autonomous vehicles operated on unstructured terrain, it is necessary to register the acquired point cloud and accurately perform point cloud ...reconstruction of the terrain in time. This paper proposes a novel registration method to deal with uneven-density and high-noise of unstructured terrain point clouds. It has two steps of operation, namely initial registration and accurate registration. Multisensor data is firstly used for initial registration. An improved Iterative Closest Point (ICP) algorithm is then deployed for accurate registration. This algorithm extracts key points and builds feature descriptors based on the neighborhood normal vector, point cloud density and curvature. An adaptive threshold is introduced to accelerate iterative convergence. Experimental results are given to show that our two-step registration method can effectively solve the uneven-density and high-noise problem in registration of unstructured terrain point clouds, thereby improving the accuracy of terrain point cloud reconstruction.
Lymphatic endothelial cell homeostasis plays important roles in normal physiological cardiac functions, and its dysfunction significantly influences pathological cardiac remodeling after myocardial ...infarction (MI). Our results revealed that sphingosine 1-phosphate receptor 1 (S1pr1) expression in cardiac lymphatic endothelial cells (LECs) was sharply changed after MI. It has been shown that S1pr1 tightly controlled LEC functions and homeostasis. We thus hypothesized that lymphatic endothelial S1pr1 might be involved in post-MI cardiac remodeling. We generated LEC-conditional S1pr1 transgenic mice, in which S1pr1 expression was reduced in cardiac LECs. We performed the left anterior descending coronary artery (LAD) ligation operation to induce MI in these mice. Cardiac functions and remodeling were examined by echocardiography analysis and serial histological analysis. Meanwhile, we performed adoptive cell transfer experiments to monitor macrophage trafficking in post-MI myocardium and their draining lymphatic system. Furthermore,
in vitro
cell culture experiments and mechanism studies were undertaken to uncover the molecular mechanism by which LEC-S1pr1 regulated cardiac inflammation and remodeling after MI. Our results showed that S1pr1 expression significantly decreased in cardiac LECs after MI. Our
in vivo
experiments showed that the reduced expression of LEC-S1pr1 deteriorated cardiac function and worsened pathological cardiac remodeling after MI. Our further results demonstrated that the reduced expression of LEC-S1pr1 did not influence macrophage infiltration in an early inflammatory phase of MI, but significantly affected macrophages clearance in the later phase of MI via afferent cardiac lymphatics, and thus influenced inflammatory responses and cardiac outcome after MI. Further study showed that S1P/S1pr1 activated ERK signaling pathway and enhanced CCL2 expression, which promoted macrophage trafficking in a paracrine manner. This study reveals that cardiac lymphatic endothelial cells tightly control macrophage trafficking via lymphatic vessels in injured hearts via S1P/S1pr1/ERK/CCL2 pathway and thus regulate post-MI immune modulation and heart repair. This study highlights the importance of cardiac lymphatic vessel system in orchestrating post-MI immune responses and cardiac remodeling by regulating macrophage transit in injured hearts. Our finding implies that a feasible modulation of S1pr1 signaling in LECs might provide a promising target to resolve excessive inflammation and to ameliorate adverse cardiac remodeling after MI.
Complex fractionated atrial electrographic (CFAE) catheter ablation is a new approach for the treatment of atrial fibrillation (AF). It is unclear if acute results of this approach correspond to ...long-term outcome. The purpose of this study was to prospectively assess acute and long-term successes of an ablation approach combining pulmonary vein isolation (PVI) and ablation of CFAE areas for treatment of persistent AF. PVI and ablation of CFAE areas were performed in 35 patients with persistent AF (30 men, 57 ± 9 years of age). At the end of the ablation procedure AF had terminated in 23 of 35 patients (66%) by conversion to sinus rhythm (8 of 23 patients, 35%) or organization to atrial tachycardia (15 of 23 patients, 65%). AF persisted in 12 of 35 patients (34%). At the end of the follow-up period (19 ± 12 months), sinus rhythm was present in 26 of 35 patients (74%), including 9 patients with a repeat procedure. This group of 26 patients consisted of 7 of 8 patients (88%) with acute sinus rhythm after the first ablation, 11 of 15 patients (73%) with organization, and 8 of 12 patients (66%) with ongoing AF (p = 0.32). In conclusion, a combined approach of PVI and CFAE ablation in persistent AF leads to acute AF termination in 66% and long-term maintenance of sinus rhythm in 74% of cases. However, long-term outcome was not predictable by acute results of the ablation procedure.
The purpose of this paper is to investigate the possible mechanisms of resistance to chemotherapy in melanoma from the perspective of molecular biology and to discuss the strategies to overcome them. ...Cisplatin, a DNA-damaging compound that triggers apoptotic cell death, is commonly used in the treatment of malignant melanoma. However, most patients develop mechanisms of acquired resistance and about 25% of them do not achieve tumor regression at all, due to intrinsic resistance to therapy. In the current study, we reported the tumor xenografts of the human A375 melanoma, after 40-weeks’ consecutive therapy with cisplatin that developed resistance as a result of EphB4 overexpression. Moreover, the expression of phospho-AKT and phospho-ERK were significantly increased in cisplatin-resistant tumors. In addition, combined of cisplatin with EphB4 selective inhibitor could abrogate this acquired mechanism of drug resistance due to an enhanced apoptotic effect in cisplatin-resistant xenografts. In summary, these results help to understand the mechanisms of acquired resistance to chemotherapy and provide important information for clinical treatment strategies.
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