Paulsenkearns9818

ing and downstream effectors, (vi) reactive astrogliosis and cytokine release.Introduction Duchenne (DMD) and Becker (BMD) muscular dystrophy are X-linked muscular disorders produced by mutations in the DMD gene which encodes the protein dystrophin. Both diseases are characterized by progressive involvement of skeletal, cardiac, and respiratory muscles. As new treatment strategies become available, reliable biomarkers and outcome measures that can monitor disease progression are needed for clinical trials. Methods We collected clinical and functional data and blood samples from 19 DMD patients, 13 BMD patients, and 66 healthy controls (8 pediatric and 58 adult controls), and blood samples from 15 patients with dysferlinopathy (DYSF) and studied the serum concentration of 4 growth factors involved in the process of muscle fibrosis. We correlated the serum concentration of these growth factors with several muscle function tests, spirometry results and fat fraction identified by quantitative Dixon muscle MRI. Results We found significant differences in the serum concentration of Platelet Derived Growth Factor-AA (PDGF-AA) between DMD patients and pediatric controls, in Connective Tissue Growth Factor (CTGF) between BMD patients and adult controls, and in and Transforming Growth Factor- β1 (TGF-β1) between BMD and DYSF patients. PDGF-AA showed a good correlation with several muscle function tests for both DMD and BMD patients and with thigh fat fraction in BMD patients. Moreover, PDGF-AA levels were increased in muscle biopsies of patients with DMD and BMD as was demonstrated by immunohistochemistry and Real-Time PCR studies. Conclusion Our study suggests that PDGF-AA should be further investigated in a larger cohort of DMD and BMD patients because it might be a good biomarker candidate to monitor the progression of these diseases.Paroxysmal movement disorders (PxMDs) are a clinical and genetically heterogeneous group of movement disorders characterized by episodic involuntary movements (dystonia, dyskinesia, chorea and/or ataxia). Historically, PxMDs were classified clinically (triggers and characteristics of the movements) and this directed single-gene testing. With the advent of next-generation sequencing (NGS), how we classify and investigate PxMDs has been transformed. Next-generation sequencing has enabled new gene discovery (RHOBTB2, TBC1D24), expansion of phenotypes in known PxMDs genes and a better understanding of disease mechanisms. However, PxMDs exhibit phenotypic pleiotropy and genetic heterogeneity, making it challenging to predict genotype based on the clinical phenotype. For example, paroxysmal kinesigenic dyskinesia is most commonly associated with variants in PRRT2 but also variants identified in PNKD, SCN8A, and SCL2A1. There are no radiological or biochemical biomarkers to differentiate genetic causes. Even with NGS, diagnosis rates are variable, ranging from 11 to 51% depending on the cohort studied and technology employed. Thus, a large proportion of patients remain undiagnosed compared to other neurological disorders such as epilepsy, highlighting the need for further genomic research in PxMDs. Whole-genome sequencing, deep-sequencing, copy number variant analysis, detection of deep-intronic variants, mosaicism and repeat expansions, will improve diagnostic rates. Identifying the underlying genetic cause has a significant impact on patient care, modification of treatment, long-term prognostication and genetic counseling. This paper provides an update on the genetics of PxMDs, description of PxMDs classified according to causative gene rather than clinical phenotype, highlighting key clinical features and providing an algorithm for genetic testing of PxMDs.Acceleration parameters have been utilized for the last six decades to investigate pathology in both human and animal models of traumatic brain injury (TBI), design safety equipment, and develop injury thresholds. Previous large animal models have quantified acceleration from impulsive loading forces (i.e., machine/object kinematics) rather than directly measuring head kinematics. No study has evaluated the reproducibility of head kinematics in large animal models. Nine (five males) sexually mature Yucatan swine were exposed to head rotation at a targeted peak angular velocity of 250 rad/s in the coronal plane. The results indicated that the measured peak angular velocity of the skull was 51% of the impulsive load, was experienced over 91% longer duration, and was multi- rather than uni-planar. BI 2536 ic50 These findings were replicated in a second experiment with a smaller cohort (N = 4). The reproducibility of skull kinematics data was mostly within acceptable ranges based on published industry standards, although the coefficients of variation (8.9% for peak angular velocity or 12.3% for duration) were higher than the impulsive loading parameters produced by the machine (1.1 vs. 2.5%, respectively). Immunohistochemical markers of diffuse axonal injury and blood-brain barrier breach were not associated with variation in either skull or machine kinematics, suggesting that the observed levels of variance in skull kinematics may not be biologically meaningful with the current sample sizes. The findings highlight the reproducibility of a large animal acceleration model of TBI and the importance of direct measurements of skull kinematics to determine the magnitude of angular velocity, refine injury criteria, and determine critical thresholds.Leber's hereditary optic neuropathy (LHON) is due to missense point mutations affecting mitochondrial DNA (mtDNA); 90% of cases harbor the m.3460G>A, m.11778G>A, and m.14484T>C primary mutations. Here, we report and discuss five families with patients affected by symptomatic LHON, in which we found five novel mtDNA variants. Remarkably, these mtDNA variants are located in complex I genes, though without strong deleterious effect on respiration in cellular models this finding is likely linked to the tissue specificity of LHON. This study observes that in the case of a strong clinical suspicion of LHON, it is recommended to analyze the whole mtDNA sequence, since new rare mtDNA pathogenic variants causing LHON are increasingly identified.