A mutation in the filamin c gene causes myofibrillar myopathy with lower motor neuron syndrome: a case report.

BACKGROUND: Myofibrillar myopathies (MFMs) are a genetically heterogeneous group of muscle disorders. Mutations in the filamin C gene (FLNC) have previously been identified in patients with MFM. The phenotypes of FLNC-related MFM are heterogeneous. CASE PRESENTATION: The patient was a 37-year-old male who first experienced weakness in the distal muscles of his hand, which eventually spread to the lower limbs and proximal muscles. Serum creatine kinase levels were moderately elevated. Obvious neuropathic changes in the electromyographic exam and edema changes in lower distal limb magnetic resonance imaging were observed. Histopathological examination revealed the presence of abnormal protein aggregates and angular atrophy in some muscle fibers. Ultrastructural analysis showed inordinate myofibrillar structures and dissolved myofilaments. DNA sequencing analysis detected a heterozygous missense mutation (c.7123G > A, p.V2375I) in the immunoglobulin (Ig)-like domain 21 of FLNC. CONCLUSIONS: FLNC mutation c.7123G > A, p.V2375I in the immunoglobulin (Ig)-like domain 21 can be associated with distal myopathy with typical MFM features and lower motor neuron syndrome. Although electromyographic examination of our patient showed obvious neuropathic changes, MFM could not be excluded. Therefore, genetic testing is necessary to make an accurate diagnosis.

MiR-16 attenuates ß-amyloid-induced neurotoxicity through targeting ß-site amyloid precursor protein-cleaving enzyme 1 in an Alzheimer's disease cell model.

The aberrant deposition of ß-amyloid (Aß) is closely linked to the pathogenesis and development of Alzheimer's disease (AD). MiR-16 was abnormally downregulated and may be related to the development of AD. However, the functional role and molecular mechanism of miR-16 in AD pathogenesis are still not well elucidated. The expressions of miR-16 and ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) mRNA and protein levels in AD brain tissues and Aß-treated PC12 cellular AD model were examined by qRT-PCR and western blot analyses. Luciferase reporter assay was used to verify the potential target of miR-16. The cell viability, apoptosis, and caspase-3 activity in PC12 cells were determined by the MTT assay, flow cytometry analysis, and caspase-3 activity assay, respectively. Downregulation of miR-16 and upregulation of BACE1 existed in AD tissues and the cellular AD model of PC12. In addition, miR-16 directly suppressed BACE1 expression. Moreover, miR-16 overexpression and BACE1 knockdown facilitated Aß-induced cell toxicity, apoptosis, and caspase-3 activity in N2a cells, which was partially eliminated by overexpression of BACE1. In contrast, BACE1 knockdown reversed the miR-16 inhibition-mediated inhibitory effect on Aß-induced cell toxicity, apoptosis, and caspase-3 activity in PC12 cells. Collectively, miR-16 attenuated Aß-induced neurotoxicity through targeting BACE1 in an Aß insult cellular AD model, providing a potential therapeutic target for AD treatment.

Evaluation of efficacy and safety of Reteplase and Alteplase in the treatment of hyper-acute cerebral infarction.

Objective: The present study aimed to investigate the efficacy and safety of Reteplase (rPA) and Alteplase (rt-PA) in the treatment of hyper-acute cerebral infarction (CI).Methods: Six hundred and eleven patients with hyper-acute CI selected from September 2014 to September 2016 were assigned into the aspirin, rt-PA, rPA, rt-PA + aspirin, and rPA + aspirin groups based on their willingness. The difference of efficacy in five groups were evaluated with National Institute of Health Stroke Scale (NIHSS), modified rankin scale (mRS), and Barthel Index (BI). Coagulation function, blood lipid, and hemodynamics were analyzed. The safety differences were compared by observing the adverse reactions.Results: Compared with the rt-PA, rPA, and aspirin groups, NIHSS score, mRS score, the incidence of non- and symptomatic cerebral hemorrhage as well as the rate of adverse reactions were decreased, while BI were increased in the rt-PA + aspirin and rPA + aspirin groups after treatment. Compared with the rt-PA and rPA groups, total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were lower, whereas the hematocrit, whole blood high shear viscosity, whole blood low shear viscosity, plasma viscosity, erythrocyte electrophoresis time, fibrinogen, erythrocyte sedimentation rate (ESR), K value in blood sedimentation equation, and the comprehensive abnormality degree of blood rheology were higher in the rt-PA + aspirin and rPA + aspirin groups.Conclusion: The efficacy and safety of rt-PA or rPA combined with aspirin in the treatment of hyper-acute CI were better than those of rPA or rt-PA monotherapy.

GNAQ mutation R183Q as a potential cause of familial Sturge-Weber syndrome: A case report.

Sturge-Weber syndrome (SWS) is a rare neurocutaneous disorder whose etiology remains unclear. To investigate the genetic contribution underlying this disease, the genetic variants of a 4-generation family with a history of SWS was analyzed in the present study. SWS was diagnosed in 3 of the family members (II-1, III-11 and IV-6). Sanger sequencing was performed to identify mutations in G protein subunit αq (GNAQ) and RAS p21 protein activator 1 exons in the 3 patients with SWS and other unaffected family members. Notably, a non-synonymous single-nucleotide variant at codon 183 on exon 4 of the GNAQ gene was identified as the only pathogenic site. This variant generated a substitution of arginine (R) with glutamine and resulted in a change of function of the encoded protein. Evolutionary conservation analysis revealed that the mutated residue 183 (R) of GNAQ is highly conserved across several vertebrate species. Furthermore, an immunofluorescence staining assay demonstrated that the substitution of arginine with glutamine resulted in a change in the sub-cellular localization of the GNAQ recombinant protein in vitro. These findings may aid in the development of novel diagnostic markers and/or therapeutic targets for the treatment of patients with familial SWS.

A fast screening protocol for carotid plaques imaging using 3D multi-contrast MRI without contrast agent.

PURPOSE: To implement a fast (~15min) MRI protocol for carotid plaque screening using 3D multi-contrast MRI sequences without contrast agent on a 3Tesla MRI scanner. MATERIALS AND METHODS: 7 healthy volunteers and 25 patients with clinically confirmed transient ischemic attack or suspected cerebrovascular ischemia were included in this study. The proposed protocol, including 3D T1-weighted and T2-weighted SPACE (variable-flip-angle 3D turbo spin echo), and T1-weighted magnetization prepared rapid acquisition gradient echo (MPRAGE) was performed first and was followed by 2D T1-weighted and T2-weighted turbo spin echo, and post-contrast T1-weighted SPACE sequences. Image quality, number of plaques, and vessel wall thicknesses measured at the intersection of the plaques were evaluated and compared between sequences. RESULTS: Average examination time of the proposed protocol was 14.6min. The average image quality scores of 3D T1-weighted, T2-weighted SPACE, and T1-weighted magnetization prepared rapid acquisition gradient echo were 3.69, 3.75, and 3.48, respectively. There was no significant difference in detecting the number of plaques and vulnerable plaques using pre-contrast 3D images with or without post-contrast T1-weighted SPACE. The 3D SPACE and 2D turbo spin echo sequences had excellent agreement (R=0.96 for T1-weighted and 0.98 for T2-weighted, p<0.001) regarding vessel wall thickness measurements. CONCLUSION: The proposed protocol demonstrated the feasibility of attaining carotid plaque screening within a 15-minute scan, which provided sufficient anatomical coverage and critical diagnostic information. This protocol offers the potential for rapid and reliable screening for carotid plaques without contrast agent.

Mutation in the caveolin-3 gene causes asymmetrical distal myopathy.

Mutations in the gene encoding caveolin-3 (CAV3) can cause a broad spectrum of clinical phenotypes, including limb girdle muscular dystrophy, rippling muscle disease, distal myopathy (MD), idiopathic persistent elevation of serum creatine kinase and cardiomyopathy. MD is a relatively rare subtype of caveolinopathy. Here, we report a sporadic case of a middle-aged female Chinese patient with MD in which a CAV3 mutation was identical to that previously reported in cases of rippling muscle disease. T1-weighted enhanced skeletal muscle MRI of the lower limbs showed an abnormal signal in the distal and proximal muscles. A muscle biopsy revealed moderate dystrophic changes, and immunohistochemical staining showed reduced CAV-3 expression in the plasmalemma. Genetic analysis revealed a heterozygous c.136G > A (p.Ala46Thr) CAV3 mutation that appeared to be de novo because it was absent from the patient's parents. This study suggested that the CAV3 c.136G > A (p.Ala46Thr) mutation can cause MD as well as different phenotypes in different individuals, suggesting that additional unknown loci must affect the disease phenotypes.

Sequence variants on chromosome 9p21 are associated with ischemic stroke and the lipids level in Chinese Han population.

BACKGROUND: Several studies have demonstrated that variants on chromosome 9p21 confer susceptibility to ischemic stroke (IS) disease. But, the results of variants' roles in Chinese IS population are blank or inconsistent. METHODS: We performed a case-control analysis in 116 patients with IS and 118 non-IS controls of Han background to determine whether 4 single nucleotide polymorphisms were associated with IS. DNA was extracted from saliva using a magnetic nanoparticles-based method. RESULTS: After we adjusted for clinical parameters, we found that the rs10757278-GG genotype conveyed 1.88-fold (95% confidence interval [CI], 1.1-3.1; P = .015), the rs1537378-C allele conveyed 2.0-fold (95% CI, 1.2-3.5; P = .008), and the rs1333047-TT genotype conveyed 1.64-fold (95% CI, 1.02-2.6; P = .041) increased risk of IS, respectively. In addition, there is a significant difference of the lipids level between GG genotype compared with that of AA genotype in rs10757278 (P < .05). CONCLUSIONS: This study is the first one to demonstrate that the rs10757278-GG genotype, the rs1537378-C allele, and rs1333047-TT genotype are associated with IS in Chinese Han populations. More importantly, the variant of rs10757278 may have different degrees of influence on lipids level.

[Astrocytic gap junction in the hippocampus of rats with lithium pilocarpine-induced epilepsy].

OBJECTIVE: To investigate the changes in the gap junction of the hippocampal astrocytes of a rat model of lithium pilocarpine-induced epilepsies. METHODS: Lithium chloride and pilocarpine were injected intraperitoneally in SD rats to induce status epilepticus (SE). At 2, 12, 24 h and 3, 7, 15, 30 and 60 days after SE, the rats were sacrificed to observe the pathological changes in the hippocampus using Nissl staining. Immunohistochemistry for GFAP and connexin43 (CX43) were used to evaluate reactive astrogliosis and the changes in the astrocytic gap junctions. RESULTS: SE induced by lithium and pilocarpine lasted for 6-30 h, and after a seizure-free period of about 30-45 days, the rats developed spontaneous recurrent seizures. Nissl staining showed that the most obvious neuronal damage occurred 12-24 h after seizure onset. Reactive gliosis began to be progressively prominent after 7 days till the end of the observation. GFAP expression increased 7 days after SE induction, intensified at 30 days, and became the most prominent at 60 days. In control rats, CX43 immunostaining was diffuse in the hippocampus; in the epileptic rats, diffuse CX43-positive varicosities appeared in the molecular layer and stratum oriens of the CA1 and CA3 areas 2 after seizure onset, and the number, length and immunostaining intensity of the varicosities increased at 12 h. These changes became the most prominent at 24 h after seizure onset, followed by gradual decrease of the immunoactivity, which was virtually absent till 30 and 60 days. CONCLUSION: The hippocampal astrocytic gap junction coupling increases in acute SE to maintain the stability of the extracellular microenvironment. The defects in gap junction coupling of the astrocytes in chronic temporal lobe epilepsy may contribute to the development of spontaneous seizures.