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ITFG2, as an immune-modulatory intracellular protein that modulate the fate of B cells and negatively regulates mTORC1 signaling. ITFG2 is highly expressed in the heart, but its pathophysiological function in heart disease is unclear. In this study, we found that in MI mice, overexpression of ITFG2 via an AAV9 vector significantly reduced the infarct size and ameliorated cardiac function. Knockdown of endogenous ITFG2 by shRNA partially aggravated ischemia-induced cardiac dysfunction. In cardiac-specific ITFG2 transgenic (TG) mice, myocardial infarction size was smaller, eject fraction (EF) and fractional shortening (FS) was higher compared to those in wild-type (WT) mice, suggesting ITFG2 reversed cardiac dysfunction induced by MI. In hypoxic neonatal cardiomyocytes (NMCMs), overexpression of ITFG2 maintained mitochondrial function by increasing intracellular ATP production, reducing ROS levels, and preserving the mitochondrial membrane potential (MMP). Overexpression of ITFG2 reversed the mitochondrial respiratory dysfunction in NMCMs induced by hypoxia. Knockdown of endogenous ITFG2 by siRNA did the opposite. Mechanism, ITFG2 formed a complex with NEDD4-2 and ATP 5b and inhibited the binding of NEDD4-2 with ATP 5b leading to the reduction ubiquitination of ATP 5b. Our findings reveal a previously unknown ability of ITFG2 to protect the heart against ischemic injury by interacting with ATP 5b and thereby regulating mitochondrial function. ITFG2 has promise as a novel strategy for the clinical management of MI.
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Mitochondries du myocarde , Infarctus du myocarde , Myocytes cardiaques , Animaux , Mâle , Souris , Cellules cultivées , Souris de lignée C57BL , Souris transgéniques , Mitochondries du myocarde/métabolisme , Infarctus du myocarde/métabolisme , Infarctus du myocarde/anatomopathologie , Infarctus du myocarde/immunologie , Myocytes cardiaques/métabolisme , Myocytes cardiaques/anatomopathologieRÉSUMÉ
Background: An increasing number of observational studies have suggested an association between dental caries and Alzheimer's disease (AD). The association between dental caries and Alzheimer's disease may be mediated by confounders or reverse causality. In this study, we conducted bidirectional two-sample Mendelian randomization (MR) to estimate the bidirectional causality between dental caries and AD. Materials and Methods: Genome-wide association study (GWAS) summary statistics of dental caries were extracted from a published meta-analysis which included a total of 487,823 participants. GWAS datasets of AD and AD onset age were obtained from the FinnGen bank. A bidirectional two-sample analysis was performed to explore the causality between dental caries and AD. Results: For the dental caries-AD causality estimation, there was no significant association between dental caries and AD, neither with the AD GWASs from the FinnGen database (OR: 1.041, p = 0.874) nor with those from the International Genomics of Alzheimer's Project (OR: 1.162, p = 0.409). In addition, the genetic susceptibility to dental caries was not related to the onset age of AD. No causality existed between dental caries and early-onset AD (OR: 0.515, p = 0.302) or late-onset AD (OR: 1.329, p = 0.347). For the AD-dental caries relationship, no causality was detected by the IVW method (OR: 1.000, p = 0.717). Findings from other MR methods were consistent. The pleiotropy test and sensitivity analysis confirmed the validity of these MR results. Conclusions: In this bidirectional MR study, robust evidence to support a bidirectional causal effect between dental caries and AD from the GWAS results within large-scale European-descent populations was absent. Having dental caries would not alter the onset age of AD.
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Maladie d'Alzheimer , Humains , Maladie d'Alzheimer/épidémiologie , Causalité , Étude d'association pangénomique , Analyse de randomisation mendélienneRÉSUMÉ
OBJECTIVE: Status epilepticus (SE) is a common neurological emergency with unsatisfying prognoses, and accurate prediction of functional outcome is beneficial in clinical decision-making. The relationship between serum albumin concentration and outcome of SE patients has yet to be unveiled. METHODS: Clinical profiles of SE patients admitted to Xiangya Hospital, Central South University, from April 2017 to November 2020, were analyzed retrospectively. Outcomes of SE patients at discharge were divided into two groups based on the modified Rankin Scale (mRS): favorable outcome (mRS: 0-3) and unfavorable outcome (mRS: 4-6). RESULTS: Fifty-one patients were enrolled. Unfavorable functional outcome at discharge was reported in 60.8% (31/51). Serum albumin concentration at admission and the Encephalitis-NCSE-Diazepam resistance-Image abnormalities-Tracheal intubation (END-IT) score remained independent predictors for functional outcome of SE patients. A lower albumin concentration at admission and higher END-IT score indicated a higher chance of unfavorable outcome for SE patients. The cut-off value of serum albumin to predict unfavorable outcome was 35.2 g/L, with a sensitivity of 67.7% and specificity of 85.0%, and an area under the receiver operating characteristic curve (ROC) of .738 (95% CI: .600-.876, p = .004). The preferable END-IT score with optimal sensitivity (74.2%) and specificity (60%) was 2 and the area under the ROC was .742, with 95% CI of .608-.876 (p = .004). SIGNIFICANCE: Serum albumin concentration at admission and the END-IT score are two independent predictive factors for short-term outcome of SE patients, moreover, the serum albumin concentration is not inferior to the END-IT score in indicating functional outcome at discharge.
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Sérumalbumine , État de mal épileptique , État de mal épileptique/sang , État de mal épileptique/thérapie , Humains , Mâle , Femelle , Adulte , Adulte d'âge moyen , Hospitalisation , Sérumalbumine/analyse , Pronostic , Anticonvulsivants/usage thérapeutiqueRÉSUMÉ
BACKGROUND: Congenital myasthenic syndromes (CMS) refer to a series of inherited disorders caused by defects in various proteins. Mutation in the collagen-like tail subunit of asymmetric acetylcholinesterase (COLQ) is the second-most common cause of CMS. However, data on pharmacological treatments are limited. OBJECTIVE: In this study, we reviewed related reports to determine the most appropriate pharmacological strategy for CMS caused by COLQ mutations. A literature review and meta-analysis were also performed. PubMed, MEDLINE, Web of Science, and Cochrane Library databases were searched to identify studies published in English before July 22, 2022. RESULTS: A total of 42 studies including 164 patients with CMS due to 72 different COLQ mutations were selected for evaluation. Most studies were case reports, and none were randomized clinical trials. Our meta-analysis revealed evidence that ß-adrenergic agonists, including salbutamol and ephedrine, can be used as first-line pharmacological treatments for CMS patients with COLQ mutations, as 98.7% of patients (74/75) treated with ß-adrenergic agonists showed positive effects. In addition, AChEIs should be avoided in CMS patients with COLQ mutations, as 90.5% (105/116) of patients treated with AChEIs showed either no or negative effects. CONCLUSION: (1) ß-adrenergic agonist therapy is the first pharmacological strategy for treating CMS with COLQ mutations. (2) AChEIs should be avoided in patients with CMS with COLQ mutations.
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Syndromes myasthéniques congénitaux , Humains , Syndromes myasthéniques congénitaux/traitement médicamenteux , Syndromes myasthéniques congénitaux/génétique , Acetylcholinesterase/génétique , Acetylcholinesterase/métabolisme , Protéines du muscle/génétique , Protéines du muscle/métabolisme , Protéines du muscle/usage thérapeutique , Mutation , Agonistes bêta-adrénergiques/usage thérapeutique , Collagène/génétique , Collagène/usage thérapeutiqueRÉSUMÉ
BACKGROUND: Myotonic dystrophy type 1 (DM1), one of the most common forms of adult-onset muscular dystrophy, is caused by abnormally expanded CTG repeats in the 3' untranslated region of the DMPK gene. The CUG repeats transcribed from the expanded CTG repeats sequestrate a splicing factor, MBNL1, causing the clinical symptoms in DM1. Nowadays, only symptomatic treatments are available for DM1, and no rational therapy is available. Recently, upregulation of MBNL1 expression has been found to be one of the promising therapies for DM1. METHODS: All experiments were conducted in the C2C12 myoblasts and HSALR mice, a DM1 mouse model. Real-time PCR and western blot were used to detect the mRNA and protein level, respectively. The rotarod exercise, grip strength and hanging time were used to evaluate the muscle strength of mice. RESULTS: In this study, we demonstrated that calcitriol, an active form of vitamin D3, increased MBNL1 in C2C12 mouse myoblasts as well as in HSALR mice model for DM1. In HSALR mice model, calcitriol improved muscle strength, and corrected aberrant splicing in skeletal muscle. Besides, calcitriol reduced the number of central nuclei, and improved muscle histopathology in HSALR mice. In addition, we identified that calcitriol upregulated MBNL1 expression via activating the promoter of Mbnl1 in C2C12 myogenic cells. CONCLUSION: Our study suggests that calcitriol is a potential pharmacological strategy for DM1 that enhances MBNL1 expression.
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Dystrophie myotonique , Souris , Animaux , Dystrophie myotonique/traitement médicamenteux , Dystrophie myotonique/génétique , Dystrophie myotonique/métabolisme , Calcitriol/pharmacologie , Protéines de liaison à l'ARN/génétique , Protéines de liaison à l'ARN/métabolisme , Myoblastes/métabolisme , Modèles animaux de maladie humaine , Muscles squelettiques/anatomopathologie , Épissage alternatif , Protéines de liaison à l'ADN/métabolismeRÉSUMÉ
Objectives: Multiple sclerosis (MS) is a chronic inflammatory autoimmune and degenerative disorder of the central nervous system. Telomeres are protective structures located at the ends of linear chromosomes, and leukocyte telomere length (LTL) is closely connected with cell aging and senescence. However, the relationship between LTL and the risk of MS remains unknown. Methods: We performed a two-sample Mendelian randomization (MR) to evaluate whether LTL was causally associated with MS risk. Results: In our MR analysis, 12 LTL-related variants were selected as valid instrumental variables, and a causal relationship between LTL and MS was suggested. The risk of MS nearly doubled as the genetically predicted LTL shortened by one standard deviation (SD) under the inverse variance weighted (IVW) fixed effect model (odds ratio (OR) = 2.00, 95% confidence interval (CI): 1.52-2.62, p = 6.01e-07). Similar estimated causal effects were also observed under different MR models. The MR-Egger regression test did not reveal any evidence of directional pleiotropy (intercept = -0.005, stand error (SE) = 0.03, p = 0.87). The Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analysis also indicated no directional pleiotropy or outliers for any LTL-related IVs (p-global test = 0.13). In addition, a leave-one-out sensitivity analysis showed similar findings, which further emphasized the validity and stability of the causal relationship. Conclusions: Our results suggest a potential causal effect of LTL on the risk of MS. Genetically predicted shorter LTL could increase the risk of MS in the European population. LTL should be noted and emphasized in the pathogenesis and treatment of MS.
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Analyse de randomisation mendélienne , Sclérose en plaques , Étude d'association pangénomique , Humains , Leucocytes , Sclérose en plaques/génétique , Polymorphisme de nucléotide simple , Télomère/génétiqueRÉSUMÉ
Background: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease affecting the motor neurons. Although much research has been conducted in this field, few bibliometric studies have been conducted. This study aimed to provide an overview of publishing characteristics and trends in ALS research since 2000 using a bibliometric analysis. Methods: We conducted a comprehensive literature search in the Web of Science (WOS) Core Collection database for scientific output related to ALS from 2000 to 2022. The retrieved dataset was refined using Google OpenRefine and analyzed using bibliometrix. Results: A total of 29,391 articles published since 2000 were retrieved, with an average annual growth rate of 6.35%. Ninety-six countries and regions contributed to ALS research, among which the United States had the dominant position with the highest number of publications (n = 8,202) and citations (n = 558,561). An association analysis was performed to form networks of country collaboration and keyword co-occurrence. The evolution of topic trends was demonstrated in terms of both frequency and proportion. Conclusion: The output of ALS research has increased steadily over the years, and the United States and Western Europe are leaders in this field. There is an upgradation in the pathomechanism and clinical research on ALS.
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Background: Glycogen storage disease (GSDs) is characterized by abnormally inherited glycogen metabolism. GSD IXd, which is caused by mutations in the PHKA1 gene, is an X-linked rare disease with mild myopathic symptoms. To date, only 13 patients with GSD IXd have been reported. In this study, we aimed to expand the clinicopathological-genetic spectrum of GSD IXd at a neuromuscular center in China. Methods: Data on patients diagnosed with GSD IXd at our neuromuscular center were collected retrospectively. Clinical features, electrophysiology, muscle pathology, and genetic information were analyzed. Results: Between 2015 and 2021, three patients were diagnosed with GSD IXd based on clinical manifestations, pathological findings, and genetic testing. One patient presented with mitochondrial myopathy. All patients exhibited muscle weakness and elevated levels of creatine kinase. Electromyography-detected myopathic changes were found in two patients, whereas one patient refused to undergo this examination. Pathological examinations in all patients revealed subsarcolemmal accumulation of glycogen under PAS staining. All patients had mutations in the PHKA1 gene and the patient with mitochondrial myopathy also had a mutation in the MT-TL1 gene. Conclusion: Our study expands the clinicogenotype and phenotype of GSD IXd in a Chinese population. Our study also expands the known mutation spectrum for GSD IXd, contributing to a better characterization and understanding of this ultrarare neuromuscular disorder.
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Congenital myasthenic syndrome (CMS) encompasses a heterogeneous group of inherited disorders affecting nerve transmission across the neuromuscular junction. The aim of this study was to characterize the clinical, physiological, pathohistological and genetic features of nine unrelated Chinese patients with CMS from a single neuromuscular centre. A total of nine patients aged from neonates to 34 years were enrolled who exhibited initial symptoms. Physical examinations revealed that all patients exhibited muscle weakness. Muscle biopsies demonstrated multiple myopathological changes, including increased fibre size variation, myofibrillar network disarray, necrosis, myofiber grouping, regeneration, fibre atrophy and angular fibres. Genetic testing revealed six different mutated genes, including AGRN (2/9), CHRNE (1/9), GFPT1 (1/9), GMPPB (1/9), PLEC (3/9) and SCN4A (1/9). In addition, patients exhibited differential responses to pharmacological treatment. Prompt utilization of genetic testing will identify novel variants and expand our understanding of the phenotype of this rare syndrome. Our findings contribute to the clinical, pathohistological and genetic spectrum of congenital myasthenic syndrome in China.
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Syndromes myasthéniques congénitaux , Atrophie , Biopsie , Humains , Mutation/génétique , Syndromes myasthéniques congénitaux/diagnostic , Syndromes myasthéniques congénitaux/génétique , Syndromes myasthéniques congénitaux/anatomopathologie , Canal sodique voltage-dépendant NAV1.4/génétique , Phénotype , Transmission synaptiqueRÉSUMÉ
Montelukast, cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, is used clinically for patients with asthma, chronic obstructive pulmonary diseases (COPD), and allergic rhinitis. It has been reported that CysLT1R antagonists could reduce the risks of cardiovascular diseases in animal studies. Cardiac fibrosis is one of the major causes of heart failure. But little is known about the role of Montelukast in cardiac fibrosis and its underlying mechanism. In transverse aortic constriction (TAC) mice, Montelukast improved cardiac pumping function and inhibited cardiac fibrosis by down-regulation of the proteins related to the fibrosis, such as connective tissue growth factor (CTGF), Transforming Growth Factor ß (TGF-ß), and Alpha-smooth muscle actin (α-SMA). Montelukast reduced cell proliferation and collagen production in neonatal cardiac fibroblasts (CFs) with the pretreatment of 20% serum, while down-regulating the expression of TGF-ß, CTGF and α-SMA. Molecules docking methods estimated a high affinity of Montelukast to Apelin receptor (APJ) and an effective chemical structure for Montelukast binding APJ. In Chinese hamster ovary (CHO) cells with stable overexpressing APJ, Montelukast inhibited forskolin (1 µM)-mediated cyclic adenosine monophosphate (cAMP) production and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation, while these effects were reversed by pertussis toxin (PTX) pretreatment. APJ silence disrupted the effects of Montelukast in CFs pretreatment by serum 20%. So we concluded that Montelukast inhibited cardiac fibrosis due presumably to the coupling to the APJ-mediated Gi signaling pathway, which may be a promising therapeutic target for cardiac fibrosis.
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Acétates , Animaux , Cellules CHO , Cricetinae , Cricetulus , Cyclopropanes , Fibrose , Humains , Souris , Quinoléines , Récepteurs aux leucotriènes , Sulfures , Facteur de croissance transformant bêtaRÉSUMÉ
[This corrects the article DOI: 10.3389/fneur.2021.761636.].
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Limb-girdle muscular dystrophy (LGMD) is a group of clinically and genetically heterogeneous neuromuscular disorders. LGMD-R7, which is caused by telethonin gene (TCAP) mutations, is one of the rarest forms of LGMD, and only a small number of LGMD-R7 cases have been described and mostly include patients from Brazil. A total of two LGMD-R7 patients were enrolled at a Chinese neuromuscular center. Demographic and clinical data were collected. Laboratory investigations and electromyography were performed. Routine and immunohistochemistry staining of muscle specimens was performed, and a next-generation sequencing panel array for genes associated with hereditary neuromuscular disorders was used for analysis. The patients exhibited predominant muscle weakness. Electromyography revealed myopathic changes. The muscle biopsy showed myopathic features, such as increased fiber size variation, muscle fiber atrophy and regeneration, slight hyperplasia of the connective tissue, and disarray of the myofibrillar network. Two patients were confirmed to have mutations in the open reading frame of TCAP by next-generation sequencing. One patient had compound heterozygous mutations, and the other patient harbored a novel homozygous mutation. Western blotting analysis of the skeletal muscle lysate confirmed the absence of telethonin in the patients. We described two LGMD-R7 patients presenting a classical LGMD phenotype and a novel homozygous TCAP mutation. Our research expands the spectrum of LGMD-R7 due to TCAP mutations based on patients from a Chinese neuromuscular center.
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Dystrophies musculaires des ceintures , Chine , Séquençage nucléotidique à haut débit , Humains , Dystrophies musculaires des ceintures/génétique , Dystrophies musculaires des ceintures/anatomopathologie , Mutation , PhénotypeRÉSUMÉ
OBJECTIVE: To introduce an effective approach for accurate identification and treatment of type IIb uterine malformation using synchronized hysteroscopy and laparoscopy. DESIGN: Step-by-step video explanation of the surgical procedure with still pictures and surgical video clips to demonstrate the detailed technique. The patient provided written informed consent for video and data collection for research purposes. The study was approved by the local ethics committee of Shengjing Hospital of China Medical University. SETTING: Academic medical center. PATIENT(S): A 32-year-old young woman diagnosed with a right unicornuate uterus with a left rudimentary horn, with a 2-year history of dysmenorrhea. INTERVENTION(S): First, the patient was diagnosed with a unicornuate uterus with a rudimentary horn using ultrasonography and magnetic resonance imaging before the surgery. During surgery, synchronized hysteroscopy and laparoscopy coupled with a light test was performed to make a definite identification of the type IIb uterine malformation. During treatment of the type IIb uterine malformation, there were two key steps: resected the rudimentary horn and reserved more myometrial tissue to reduce the risk of uterine rupture in a subsequent pregnancy; and corrected the uterus to prevent future uterine prolapse. For the suture technique, suturing during resection was performed instead of suturing after complete resection to reduce the intraoperative bleeding as much as possible. Furthermore, tubal catheterization and hydrotubation under hysteroscopy monitoring were performed. MAIN OUTCOME MEASURE(S): Value and feasibility of synchronized hysteroscopic and laparoscopic identification and treatment of the type IIb uterine malformation. RESULT(S): The total operation time was 89 minutes. The postoperative pathological findings revealed that the endometrium was found in the rudimentary horn. No dysmenorrhea was found during follow-up. At 26 months after the operation, the patient became pregnant naturally. Cesarean section was performed at 36 weeks + 2 days owing to premature rupture of the membranes. CONCLUSION(S): For the accurate identification and management of a type IIb uterine malformation, synchronized hysteroscopy and laparoscopy is an effective and feasible method.
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Hystéroscopie/méthodes , Laparoscopie/méthodes , Malformations urogénitales/diagnostic , Malformations urogénitales/chirurgie , Utérus/malformations , Adulte , Chine , Femelle , Humains , /méthodes , Sensibilité et spécificité , Échographie , Malformations urogénitales/anatomopathologie , Utérus/imagerie diagnostique , Utérus/anatomopathologie , Utérus/chirurgieRÉSUMÉ
Objective: p75 neurotrophin receptor (p75NTR) is associated with the pathogenesis of amyotrophic lateral sclerosis (ALS). However, its role is not fully understood. The aim of this study was to evaluate the association between ALS and the extracellular domain of p75NTR(p75ECD) in urine. Methods: We conducted a comprehensive literature search using keywords in the PubMed, Embase, Science, and the Cochrane Library, and identified five case control studies, with the latest date of search being 18 April 2021. Results: The results showed that urinary p75ECD levels were significantly higher in patients with ALS compared to non-neurological control (weighted mean difference (WMD) = 4.18, 95% CI [2.525, 6.990], p < 0.001), and other neurological diseases (WMD = 6.005, 95% CI [1.596, 10.414], p = 0.008). Increased urinary p75ECD levels were inversely associated with ALSFRS-R in ALS patients (r = -0.32, 95% CI [-0.43, -0.21], p < 0.001). Conclusions: Given the associations between p75ECD and ALS found in this meta-analysis, urinary p75ECD levels have potential to be used as a diagnostic biomarker and a progression indicator in the future.
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Sclérose latérale amyotrophique , Sclérose latérale amyotrophique/diagnostic , Études cas-témoins , HumainsRÉSUMÉ
Background: Congenital myopathy constitutes a heterogeneous group of orphan diseases that are mainly classified on the basis of muscle biopsy findings. This study aims to estimate the prevalence of congenital myopathy through a systematic review and meta-analysis of the literature. Methods: The PubMed, MEDLINE, Web of Science, and Cochrane Library databases were searched for original research articles published in English prior to July 30, 2021. The quality of the included studies was assessed by a checklist adapted from STrengthening the Reporting of OBservational studies in Epidemiology (STROBE). To derive the pooled epidemiological prevalence estimates, a meta-analysis was performed using the random effects model. Heterogeneity was assessed using the Cochrane Q statistic as well as the I 2 statistic. Results: A total of 11 studies were included in the systematic review and meta-analysis. Of the 11 studies included, 10 (90.9%) were considered medium-quality, one (9.1%) was considered low-quality, and no study was assessed as having a high overall quality. The pooled prevalence of congenital myopathy in the all-age population was 1.50 (95% CI, 0.93-2.06) per 100,000, while the prevalence in the child population was 2.73 (95% CI, 1.34-4.12) per 100,000. In the pediatric population, the prevalence among males was 2.92 (95% CI, -1.70 to 7.55) per 100,000, while the prevalence among females was 2.47 (95% CI, -1.67 to 6.61) per 100,000. The prevalence estimates of the all-age population per 100,000 were 0.20 (95% CI 0.10-0.35) for nemaline myopathy, 0.37 (95% CI 0.21-0.53) for core myopathy, 0.08 (95% CI -0.01 to 0.18) for centronuclear myopathy, 0.23 (95% CI 0.04-0.42) for congenital fiber-type disproportion myopathy, and 0.34 (95% CI, 0.24-0.44) for unspecified congenital myopathies. In addition, the prevalence estimates of the pediatric population per 100,000 were 0.22 (95% CI 0.03-0.40) for nemaline myopathy, 0.46 (95% CI 0.03-0.90) for core myopathy, 0.44 (95% CI 0.03-0.84) for centronuclear myopathy, 0.25 (95% CI -0.05 to 0.54) for congenital fiber-type disproportion myopathy, and 2.63 (95% CI 1.64-3.62) for unspecified congenital myopathies. Conclusions: Accurate estimates of the prevalence of congenital myopathy are fundamental to supporting public health decision-making. The high heterogeneity and the lack of high-quality studies highlight the need to conduct higher-quality studies on orphan diseases.
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GNE myopathy is a heterogeneous group of ultrarare neuromuscular disorders caused by mutations in the GNE gene. An estimated prevalence of 1~21/1,000,000 leads to a deficiency of data and a lack of availability of samples to conduct clinical research on this neuromuscular disorder. Although GNE, which is the mutated gene responsible for the disease, is well known as the key enzyme in the biosynthesis pathway of sialic acid, the clinicopathological-genetic spectrum of GNE mutant patients is still unclear and expanding. This study presents ten unrelated patients with GNE myopathy, discovering five novel missense mutations. Clinical, electrophysiological, imaging, pathological and genetic data are presented in a retrospective manner. Interestingly, several patients in the cohort were found to have peripheral neuropathy and inflammatory cell infiltration in muscle biopsies, which have seldom been reported. This study, conducted by a neuromuscular centre in China, is the first attempt to highlight these abnormal clinicopathological features and associate them with genetic mutations in GNE myopathy.
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Myopathies distales/diagnostic , Myopathies distales/génétique , Prédisposition génétique à une maladie , Complexes multienzymatiques/génétique , Mutation , Phénotype , Adulte , Âge de début , Marqueurs biologiques , Biopsie , Femelle , Études d'associations génétiques , Séquençage nucléotidique à haut débit , Humains , Mâle , Jeune adulteRÉSUMÉ
Titin, one of the largest proteins in humans, is a major component of muscle sarcomeres. Pathogenic variants in the titin gene (TTN) have been reported to cause a range of skeletal muscle diseases, collectively known as titinopathy. Titinopathy is a heterogeneous group of disabling diseases characterized by muscle weakness. In our study, we aimed to establish the clinicopathological-genetic spectrum of titinopathy from a single neuromuscular center. Three patients were diagnosed as having definite titinopathy, and additional three patients were diagnosed as having possible titinopathy according to the diagnostic criteria. All the patients showed initial symptoms from age one to 40 years. Physical examination revealed that five patients had muscle weakness, and that one patient experienced behavioral changes. Muscle biopsy specimens obtained from all six patients demonstrated multiple myopathological changes, including increased fiber size variation, muscle fiber hypertrophy or atrophy, formation of centralized cell nuclei, necklace cytoplasmic bodies, and formation of rimmed vacuoles and cores. Genetic testing revealed 11 different TTN alterations, including missense (6/11), nonsense (2/11), frameshift (2/11), and splicing (1/11) mutations. Our study provides further evidence that TTN mutations are more likely to be responsible for an increasing proportion of various myopathies, such as hereditary myopathy with early respiratory failure (HMERF), core myopathy, and distal myopathy with rimmed vacuoles, than currently recognized mutations. Our findings expand the clinical, pathohistological and genetic spectrum of titinopathy.
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Myopathies distales , Maladies musculaires , Adolescent , Adulte , Enfant , Enfant d'âge préscolaire , Chine , Humains , Nourrisson , Muscles squelettiques , Mutation , Jeune adulteRÉSUMÉ
Objectives: The epidemiological and clinical characteristics of patients with coronavirus disease 2019 (COVID-19) have been researched. However, the prevalence of repositivity by real-time PCR for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. Methods: A retrospective study was conducted involving 599 discharged patients with COVID-19 in a single medical centre. The clinical features of patients during their hospitalization and 14-day post-discharge quarantine were collected. Results: A total of 122 patients (20.4%) out of 599 patients retested positive after discharge. Specifically, 94 (15.7%) retested positive within 24 h of discharge, and another 28 patients (4.7%) were repositive on day 7 after discharge, although none showed any clinical symptomatic recurrence. Both repositives and nonrepositives have similar patterns of IgG and IgM. Notably, the length of hospitalization of non-repositive patients was longer than that of 24-h repositive patients and 7-day repositive patients. In addition, the length of hospitalization of 24-h repositive patients was shorter than that of 7-day repositive patients, indicating that the length of hospitalization was also a determinant of viral shedding. Conclusion: Our study provides further information for improving the management of recovered and discharged patients, and further studies should be performed to elucidate the infectiveness of individuals with prolonged or RNA repositivity.
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Post-cure/statistiques et données numériques , Détection de l'acide nucléique du virus de la COVID-19/statistiques et données numériques , COVID-19/diagnostic , SARS-CoV-2/isolement et purification , Adolescent , Adulte , Anticorps antiviraux/sang , Anticorps antiviraux/immunologie , COVID-19/sang , COVID-19/épidémiologie , COVID-19/thérapie , Femelle , Humains , Immunoglobuline G/sang , Immunoglobuline G/immunologie , Immunoglobuline M/sang , Immunoglobuline M/immunologie , Durée du séjour/statistiques et données numériques , Mâle , Adulte d'âge moyen , Sortie du patient , ARN viral/isolement et purification , Études rétrospectives , RT-PCR/statistiques et données numériques , SARS-CoV-2/génétique , SARS-CoV-2/immunologie , Indice de gravité de la maladie , Excrétion virale/immunologie , Jeune adulteRÉSUMÉ
BACKGROUND: The long interspersed element-1 (L1) participates in memory formation, and DNA methylation patterns of L1 may suggest resilience or vulnerability factors for Post-Traumatic Stress Disorder (PTSD), of which the principal manifestation is a pathological exacerbation of fear memory. However, the unique roles of L1 in the reconsolidation of fear memory remain poorly understood. OBJECTIVE: The study aimed to investigate the role of L1 in the reconsolidation of context-dependent fear memory. METHODS: Mice underwent fear conditioning and fear recall in the observation chambers. Fear memory was assessed by calculating the percentage of time spent freezing in 5 min. The medial prefrontal cortex (mPFC) and hippocampus were removed for further analysis. Open Reading Frame 1 (ORF1) mRNA and ORF2 mRNA of L1 were analyzed by real-time quantitative polymerase chain reaction. After reactivation of fear memory, lamivudine was administered and its effects on fear memory reconsolidation were observed. RESULTS: ORF1 and ORF2 mRNA expressions in the mPFC and hippocampus after recent (24 h) and remote (14 days) fear memory recall exhibited augmentation via different temporal and spatial patterns. Reconsolidation of fear memory was markedly inhibited in mice treated with lamivudine, which could block L1. DNA methyltransferase mRNA expression declined following lamivudine treatment in remote fear memory recall. CONCLUSION: The retrotransposition of L1 participated in the reconsolidation of fear memory after reactivation of fear memory, and with lamivudine treatment, spontaneous recovery decreased with time after recent and remote fear memory recall, providing clues for understanding the roles of L1 in fear memory.
Sujet(s)
Peur/effets des médicaments et des substances chimiques , Éléments LINE/effets des médicaments et des substances chimiques , Mémoire/effets des médicaments et des substances chimiques , Animaux , Hippocampe/effets des médicaments et des substances chimiques , Lamivudine/usage thérapeutique , Mâle , Mémoire à long terme/effets des médicaments et des substances chimiques , Souris , Cadres ouverts de lecture/effets des médicaments et des substances chimiques , Cortex préfrontal/effets des médicaments et des substances chimiques , Inhibiteurs de la transcriptase inverse/usage thérapeutique , Troubles de stress post-traumatique/traitement médicamenteuxRÉSUMÉ
BACKGROUND: Congenital myasthenic syndromes (CMSs) are a heterogeneous group of neuromuscular disorders. Mutations of the nicotinic acetylcholine receptor epsilon subunit gene (CHRNE) are the most common causes of these disorders. CMSs are gaining increasing recognition by clinicians. However, pharmacological treatment of CMS with CHRNE mutations has only been discussed in a small number of case reports. OBJECTIVE: This study aims to determine how to choose an appropriate pharmacological strategy for CMS with CHRNE mutations. METHODS: A meta-analysis was performed. PubMed, MEDLINE, Web of Science, and Cochrane Library databases were searched for studies published in English prior to June 1, 2020. The extracted data included clinical information, gene mutations, pharmacological treatment, and treatment effects. RESULTS: A total of 48 studies and 208 CMS patients with CHRNE mutations were included in our meta-analysis. Ten different pharmacological strategies were used in these patients. Our research found that ß2-adrenergic receptor agonists had the best treatment effect for CMS patients with CHRNE mutations, especially in patients with primary AChR deficiency. In addition, our analysis found no evidence that age at disease onset influences the treatment results. CONCLUSION: This meta-analysis provides evidence that (1) ß2-adrenergic receptor agonist therapy could be the first choice of pharmacological strategy for treating CMS with CHRNE mutations; (2) a single-drug-regime, rather than a combination therapy, should be the first choice of treatment; and (3) it is never too late to initiate pharmacological treatment.