243 research outputs found
Nintedanib decreases muscle fibrosis and improves muscle function in a murine model of dystrophinopathy
Duchenne muscle dystrophy (DMD) is a genetic disorder characterized by progressive skeletal muscle weakness. Dystrophin deficiency induces instability of the sarcolemma during muscle contraction that leads to muscle necrosis and replacement of muscle by fibro-adipose tissue. Several therapies have been developed to counteract the fibrotic process. We report the effects of nintedanib, a tyrosine kinase inhibitor, in the mdx murine model of DMD. Nintedanib reduced proliferation and migration of human fibroblasts in vitro and decreased the expression of fibrotic genes such as COL1A1, COL3A1, FN1, TGFB1, and PDGFA. We treated seven mdx mice with 60 mg/kg/day nintedanib for 1 month. Electrophysiological studies showed an increase in the amplitude of the motor action potentials and an improvement of the morphology of motor unit potentials in the animals treated. Histological studies demonstrated a significant reduction of the fibrotic areas present in the skeletal muscles. Analysis of mRNA expression from muscles of treated mice showed a reduction in Col1a1, Col3a1, Tgfb1, and Pdgfa. Western blot showed a reduction in the expression of collagen I in skeletal muscles. In conclusion, nintedanib reduced the fibrotic process in a murine model of dystrophinopathy after 1 month of treatment, suggesting its potential use as a therapeutic drug in DMD patients.España, Ministerio de Economía y Competitividad BFU2016-74975-PEspaña, Instituto Ramón y Cajal PI13/0134
Survey on the management of Pompe disease in routine clinical practice in Spain
Antibodies; Diagnosis; Pompe diseaseAnticuerpos; Diagnóstico; Enfermedad de pompeAnticossos; Diagnòstic; Malaltia de pompeBackground
Despite the availability of several clinical guidelines, not all health professionals use their recommendations to manage patients with Pompe disease, a rare genetic disorder involving high-impact therapy. Through several discussion meetings and a survey, the present study aimed to learn about the management of Pompe disease in routine clinical practice in Spain, to improve clinical care in a real-life situation.
Results
The survey was sent to 42 healthcare professionals who manage patients with Pompe disease in their clinical practice. Although most respondents followed the clinical guidelines, clinical practice differed from the expert recommendations in many cases. Approximately 7% did not request a genetic study to confirm the diagnosis before starting treatment, and 21% considered that only two dried blood spot determinations suffice to establish the diagnosis. About 76% requested anti-GAA antibodies when there is a suspicion of lack of treatment efficacy, though a significant percentage of respondents have never requested such antibodies. According to 31% of the respondents, significant impairment of motor function and/or respiratory insufficiency is a requirement for authorizing medication at their hospital. Up to 26% waited for improvements over the clinical follow-up to maintain treatment and withdrew it in the absence of improvement since they did not consider disease stabilization to be a satisfactory outcome.
Conclusions
The results highlight the lack of experience and/or knowledge of some professionals caring for patients with Pompe disease. It is necessary to develop and disseminate simple guidelines that help to apply the expert recommendations better or centralize patient follow-up in highly specialized centers.Sanofi has sponsored this project without participating in the article’s design, data analysis, or writing
Sedimentary evidence of historical and prehistorical earthquakes along the Venta de Bravo Fault System, Acambay Graben (Central Mexico)
The Venta de Bravo normal fault is one of the longest structures in the intra-arc fault system of the Trans-Mexican Volcanic Belt. It defines, together with the Pastores Fault, the 80 km long southern margin of the Acambay Graben. We focus on the westernmost segment of the Venta de Bravo Fault and provide new paleoseismological information, evaluate its earthquake history, and assess the related seismic hazard. We analyzed five trenches, distributed at three different sites, in which Holocene surface faulting offsets interbedded volcanoclastic, fluvio-lacustrine and colluvial deposits. Despite the lack of known historical destructive earthquakes along this fault, we found evidence of at least eight earthquakes during the late Quaternary. Our results indicate that this is one of the major seismic sources of the Acambay Graben, capable of producing by itself earthquakes with magnitudes (MW) up to 6.9, with a slip rate of 0.22-0.24 mm yr− 1 and a recurrence interval between 1940 and 2390 years. In addition, a possible multi-fault rupture of the Venta de Bravo Fault together with other faults of the Acambay Graben could result in a MW > 7 earthquake. These new slip rates, earthquake recurrence rates, and estimation of slips per event help advance our understanding of the seismic hazard posed by the Venta de Bravo Fault and provide new parameters for further hazard assessment
Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2E
Genetic testing is essential for patients with a suspected hereditary myopathy. More than 50% of patients clinically diagnosed with a myopathy carry a variant of unknown significance in a myopathy gene, often leaving them without a genetic diagnosis. Limb-girdle muscular dystrophy (LGMD) type R4/2E is caused by mutations in β-sarcoglycan (SGCB). Together, β-, α-, γ-, and δ-sarcoglycan form a 4-protein transmembrane complex (SGC) that localizes to the sarcolemma. Biallelic loss-of-function mutations in any subunit can lead to LGMD. To provide functional evidence for the pathogenicity of missense variants, we performed deep mutational scanning of SGCB and assessed SGC cell surface localization for all 6,340 possible amino acid changes. Variant functional scores were bimodally distributed and perfectly predicted pathogenicity of known variants. Variants with less severe functional scores more often appeared in patients with slower disease progression, implying a relationship between variant function and disease severity. Amino acid positions intolerant to variation mapped to points of predicted SGC interactions, validated in silico structural models, and enabled accurate prediction of pathogenic variants in other SGC genes. These results will be useful for clinical interpretation of SGCB variants and improving diagnosis of LGMD; we hope they enable wider use of potentially life-saving gene therapy
Hypoxia triggers IFN-I production in muscle: Implications in dermatomyositis
Dermatomyositis is an inflammatory myopathy characterized by symmetrical proximal muscle weakness and skin changes. Muscle biopsy hallmarks include perifascicular atrophy, loss of intramuscular capillaries, perivascular and perimysial inflammation and the overexpression of IFN-inducible genes. Among them, the retinoic-acid inducible gene 1 (RIG-I) is specifically overexpressed in perifascicular areas of dermatomyositis muscle. The aim of this work was to study if RIG-I expression may be modulated by hypoxia using an in vitro approach. We identified putative hypoxia response elements (HRE) in RIG-I regulatory regions and luciferase assays confirmed that RIG-I is a new HIF-inducible gene. We observed an increase expression of RIG-I both by Real time PCR and Western blot in hypoxic conditions in human muscle cells. Cell transfection with a constitutive RIG-I expression vector increased levels of phospho-IRF-3, indicating that RIG-I promotes binding of transcription factors to the enhancer sequence of IFN. Moreover, release of IFN-beta was observed in hypoxic conditions. Finally, HIF-1 alpha overexpression was confirmed in the muscle biopsies and in some RIG-I positive perifascicular muscle fibres but not in controls. Our results indicate that hypoxia triggers the production of IFN-I in vitro, and may contribute to the pathogenesis of DM together with other inflammatory factors
Evidence of recent ruptures in the central faults of the Acambay Graben (central Mexico)
The Acambay Graben, within the central part of the Trans-Mexican Volcanic Belt, is one of the major sources of continental earthquakes in Mexico. To date, the activity and paleoseismological history of the axial faults of the graben are not well constrained. We provide morphological, structural and sedimentological evidence of the seismogenic nature of two of the axial structures, the Temascalcingo and the Tepuxtepec fault systems. Faults consist of multiple parallel scarps with en echelon and horse-splay patterns. Fault systems extend for 60 km and displace Quaternary to Upper Miocene volcanic edifices and volcano-sedimentary materials. Surface lengths of individual fault traces range between 3 and 25 km, and observed throws reach a minimum of 150-200 m. The long-term and short-term slip rate of the Temascalcingo fault system in the studied section presents similar values, ranging from 0.06 ± 0.02 (minimum long term) to 0.12 ± 0.02 mm y−1 (maximum value of average short-term). Only the long-term slip rate of the Tepuxtepec system could be constrained in 0.01-0.02 mm/y, being a minimum estimate. The Holocene fault rupture history at two sites provided evidence of six ruptures since 12,500-11,195 BCE, among which three ruptures should have occurred between 11,847 ± 652 BCE and 11,425 ± 465 BCE Variable single event displacements (SEDs, between 6 and 77) are interpreted as the result of fault interdependences and/or the interaction with the latest volcanic activity. Also, small displacements triggered by activity on other faults probably contributed to slip variability, i.e., faults display primary and secondary behavior
Applying the win ratio method in clinical trials of orphan drugs: an analysis of data from the COMET trial of avalglucosidase alfa in patients with late-onset Pompe disease
Background: Clinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context. Methods: All possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant’s response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses (“win ratio”), with ties excluded. Results: In the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30–4.29, p = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13–3.62, p = 0.018). Conclusion: The win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains
Different Approaches to Analyze Muscle Fat Replacement With Dixon MRI in Pompe Disease
Altres ajuts: Asociación Española de Enfermos de Glucogenosis (AEEG)Quantitative MRI is an increasingly used method to monitor disease progression in muscular disorders due to its ability to measure changes in muscle fat content (reported as fat fraction) over a short period. Being able to objectively measure such changes is crucial for the development of new treatments in clinical trials. However, the analysis of the images involved continues to be a daunting task because of the time needed. Whether a more specific analysis selecting individual muscles or a global one analyzing the whole thigh or compartments could be a suitable alternative has only been marginally studied. In our study we compare three methods of analysis of 2-point-dixon images in a cohort of 34 patients with late onset Pompe disease followed over a period of one year. We measured fat fraction on MRIs obtained at baseline and at year 1, and we calculated the increment of fat fraction. We correlated the results obtained with the results of muscle function tests to investigate whether the three methods of analysis were equivalent or not. We observed significant differences between the three methods in the estimation of the fat fraction at both baseline and year 1, but no difference was found in the increment in fat fraction between baseline and year 1. When we correlated the fat fraction obtained with each method and the muscle function tests, we found a significant correlation with most tests in all three methods, although in most comparisons the highest correlation coefficient was found with the analysis of individual muscles. We conclude that the fastest strategy of analysis assessing compartments or the whole thigh could be reliable for certain cohorts of patients where the variable to study is the fat increment. In other sorts of studies, an individual muscle approach seems the most reliable technique
Neurofilament Light and Its Association With CNS Involvement in Patients With Classic Infantile Pompe Disease
Search for the doubly charmed baryon Xi(+)(cc)
A search for the doubly charmed baryon Ξ+cc is performed through its decay to the Λ+cK−π+ final state, using proton-proton collision data collected with the LHCb detector at centre-of-mass energies of 7, 8 and 13 TeV. The data correspond to a total integrated luminosity of 9 fb−1. No significant signal is observed in the mass range from 3.4 to 3.8 GeV/c2. Upper limits are set at 95% credibility level on the ratio of the Ξ+cc production cross-section times the branching fraction to that of Λ+c and Ξ++cc baryons. The limits are determined as functions of the Ξ+cc mass for different lifetime hypotheses, in the rapidity range from 2.0 to 4.5 and the transverse momentum range from 4 to 15 GeV/c
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