Pediatric reference intervals for muscle coenzyme Q10

Coenzyme Q₁₀ (CoQ₁₀) is present in humans in both the reduced (ubiquinol, CoQ₁₀H₂) and oxidized (ubiquinone, CoQ₁₀) forms. CoQ₁₀ is an essential cofactor in mitochondrial oxidative phosphorylation, and is necessary for ATP production. Total, reduced and oxidized CoQ₁₀ levels in skeletal muscle of 148 children were determined by HPLC coupled with electrochemical detection, and we established three level thresholds for total CoQ₁₀ in muscle. We defined as “severe deficiency”, CoQ₁₀ levels falling in the range between 0.82 and 4.88 μmol/g tissue; as “intermediate deficiency”, those ranging between 5.40 and 9.80 μmol/g tissue, and as “mild deficiency”, the amount of CoQ₁₀ included between 10.21 and 19.10 μmol/g tissue. Early identification of CoQ₁₀ deficiency has important implications in children, not only for those with primary CoQ₁₀ defect, but also for patients with neurodegenerative disorders, in order to encourage earlier supplementation with this agent also in mild and intermediate deficiency.     

Neuronal phospholipid deacylation is essential for axonal and synaptic integrity

Recessively-inherited deficiency in the catalytic activity of calcium-independent phospholipase A2-beta (iPLA2β) and neuropathy target esterase (NTE) causes infantile neuroaxonal dystrophy and hereditary spastic paraplegia, respectively. Thus, these two related phospholipases have non-redundant functions that are essential for structural integrity of synapses and axons. Both enzymes are expressed in essentially all neurons and also have independent roles in glia. iPLA2β liberates sn-2 fatty acid and lysophospholipids from diacyl-phospholipids. Ca^2 +-calmodulin tonically-inhibits iPLA2β, but this can be alleviated by oleoyl-CoA. Together with fatty acyl-CoA-mediated conversion of lysophospholipid to diacyl-phospholipid this may regulate sn-2 fatty acyl composition of phospholipids. In the nervous system, iPLA2β is especially important for the turnover of polyunsaturated fatty acid-associated phospholipid at synapses. More information is required on the interplay between iPLA2β and iPLA2‐gamma in deacylation of neuronal mitochondrial phospholipids. NTE reduces levels of phosphatidylcholine (PtdCho) by degrading it to glycerophosphocholine and two free fatty acids. The substrate for NTE may be nascent PtdCho complexed with a phospholipid-binding protein. Protein kinase A-mediated phosphorylation enhances PtdCho synthesis and may allow PtdCho accumulation by coordinate inhibition of NTE activity. NTE operates primarily at the endoplasmic reticulum in neuronal soma but is also present in axons. NTE-mediated PtdCho homeostasis facilitates membrane trafficking and this appears most critical for the integrity of axon terminals in the spinal cord and hippocampus. For maintenance of peripheral nerve axons, iPLA2β activity may be able to compensate for NTE-deficiency but not vice-versa. Whether agonists acting at neuronal receptors modulate the activity of either enzyme remains to be determined. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.     

不同时机行血管介入栓塞术治疗颅内动脉瘤的疗效及对患者预后、神经功能和血清炎性因子的影响

摘要 目的：探讨不同时机行血管介入栓塞术治疗颅内动脉瘤的疗效及对患者预后、神经功能和血清炎性因子的影响。方法：选择2019年3月到2020年12月期间我院收治的80例颅内动脉瘤患者,按手术时间的不同将其分为早期组、延期组,其中早期组36例,发病至手术时间≤72 h;延期组44例,发病至手术时间＞72 h,对比两组疗效、预后、神经功能、血清炎性因子及并发症发生率。结果：早期组的完全栓塞率高于延期组,基本栓塞率低于延期组（P<0.05）。两组术后3个月美国国立卫生研究院卒中量表（NIHSS）、改良Rankin量表评分均较术前下降,且早期组低于延期组（P<0.05）。早期组的预后良好率高于延期组（P<0.05）。两组术后3 d血清白介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）水平下降,且早期组低于延期组（P<0.05）,白介素-10（IL-10）水平升高,且早期组高于延期组（P<0.05）。早期组的并发症发生率低于延期组（P<0.05）。结论：早期行血管介入栓塞术治疗颅内动脉瘤患者,可提高完全栓塞率,减轻神经功能损伤及炎性应激,降低并发症的发生风险,促进预后和生活质量改善。     

New Hyperekplexia Mutations Provide Insight into Glycine Receptor Assembly,Trafficking, and Activation Mechanisms

Hyperekplexia is a syndrome of readily provoked startle responses, alongside episodic and generalized hypertonia, that presents within the first month of life. Inhibitory glycine receptors are pentameric ligand-gated ion channels with a definitive and clinically well stratified linkage to hyperekplexia. Most hyperekplexia cases are caused by mutations in the α1 subunit of the human glycine receptor (hGlyR) gene (GLRA1). Here we analyzed 68 new unrelated hyperekplexia probands for GLRA1 mutations and identified 19 mutations, of which 9 were novel. Electrophysiological analysis demonstrated that the dominant mutations p.Q226E, p.V280M, and p.R414H induced spontaneous channel activity, indicating that this is a recurring mechanism in hGlyR pathophysiology. p.Q226E, at the top of TM1, most likely induced tonic activation via an enhanced electrostatic attraction to p.R271 at the top of TM2, suggesting a structural mechanism for channel activation. Receptors incorporating p.P230S (which is heterozygous with p.R65W) desensitized much faster than wild type receptors and represent a new TM1 site capable of modulating desensitization. The recessive mutations p.R72C, p.R218W, p.L291P, p.D388A, and p.E375X precluded cell surface expression unless co-expressed with α1 wild type subunits. The recessive p.E375X mutation resulted in subunit truncation upstream of the TM4 domain. Surprisingly, on the basis of three independent assays, we were able to infer that p.E375X truncated subunits are incorporated into functional hGlyRs together with unmutated α1 or α1 plus β subunits. These aberrant receptors exhibit significantly reduced glycine sensitivity. To our knowledge, this is the first suggestion that subunits lacking TM4 domains might be incorporated into functional pentameric ligand-gated ion channel receptors.     

Vascular endothelial growth factor polymorphisms and risk of Alzheimer's disease: A meta-analysis

There were conflicting results about whether promoter polymorphisms (− 2578C/A, − 1154G/A) of vascular endothelial growth factor (VEGF) gene is a risk factor of Alzheimer's disease (AD). To determine the relationship between them, a meta-analysis is needed urgently. We searched all the reports about VEGF promoter polymorphisms (− 2578C/A, − 1154G/A) and AD risk from PubMed, Web of Science, Cochrane Collaboration and Google Scholar database for the period up to 1 August, 2012. A total of 7 studies were included in this meta-analysis. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated applying fixed or random effects models. There was no significant association between VEGF − 2578C/A polymorphisms and AD risk in all gene models (OR = 1.08, 95% CI = 0.94–1.23 for A vs. C; OR = 1.19, 95% CI = 0.89–1.59 for AA vs. CC; OR = 1.15, 95% CI = 0.91–1.45 for AA vs. CC + CA; OR = 1.11, 95% CI = 0.98–1.25 for AA + CA vs. CC). Similar results were provided in subgroup analysis by ethnicity. For the VEGF − 1154G/A polymorphisms, lack of an association was also found (A vs. G: OR = 0.89, 95% CI = 0.79–1.01; AA vs. GG: OR = 0.82, 95% CI = 0.62–1.08; AA vs. GA + GG: OR = 0.89, 95% CI = 0.68–1.16; AA + AG vs. GG: OR = 0.85, 95% CI = 0.72–1.00). Conclusively, the result of this meta-analysis suggested that VEGF promoter polymorphisms (− 2578C/A, − 1154G/A) might not contribute to the susceptibility of AD.     

Mechanisms of transformation of nicotinamide mononucleotides to cerebral infarction hemorrhage based on MCAO model

ObjectiveThe study aims at discussing the effect of nicotinamide mononucleotides on protecting hemorrhagic transformation of cerebral infarction in the middle cerebral artery occlusion (MCAO) model.MethodMale mice aged 4–5 weeks and weighing about 22–35 g in Shanghai Ninth People’s Hospital are divided into three groups: sham group, collagenase intracerebral hemorrhage model (cICH + Vehicle) group and collagenase nicotinamide mononucleotide (cICH + NMN) group. Then, the intervention therapy research is carried out. After 24 h, the neurological function, brain edema, hematoma volume, body weight, hemorrhage volume, RNA expression level, apoptosis, inflammatory factors and reactive oxygen species (ROS) content in surrounding tissues of mice are analyzed comprehensively.ResultsCompared with the other two groups, nicotinamide mononucleotides in MCAO model have significant effects on improving neurological function, brain edema, inflammatory factors, body weight and cell apoptosis in mice, but have no significant effect on hemorrhage volume and hematoma volume in mice.ConclusionNicotinamide mononucleotides can significantly improve the collagenase-induced intracerebral hemorrhage (ICH) model in mice under MCAO model, and they can protect the brain tissue of mice from RNA level to tissue cell level or mouse body weight and volume level.     

尤瑞克林联合血管内介入对急性脑梗死患者神经功能、炎性因子和血液流变学的影响

目的:探讨血管内介入联合尤瑞克林对急性脑梗死(ACI)患者炎性因子、血液流变学以及神经功能的影响。方法:选取我院于2017年4月～2019年12月间收治的80例ACI患者,采用随机数字表法分为对照组(n=40)和研究组(n=40),对照组给予血管内介入溶栓治疗,研究组在对照组基础上联合尤瑞克林治疗,比较两组患者疗效、神经功能、炎性因子、血液流变学和不良反应。结果:研究组治疗14 d后的临床总有效率为90.00%(36/40),高于对照组的72.50%(29/40)(P0.05)。两组治疗14 d后血清白介素-6(IL-6)、白介素-1β(IL-1β)、单核细胞趋化蛋白-1(MCP-1)水平、美国国立卫生研究院卒中量表(NIHSS)评分以及血浆黏度、全血黏度高切、全血黏度低切、红细胞聚集指数均较治疗前下降,且研究组低于对照组(P0.05)。两组不良反应发生率比较差异无统计学意义(P0.05)。结论:尤瑞克林联合血管内介入治疗ACI患者,疗效显著,可有效改善机体神经功能、炎性因子和血液流变学,且安全性较好。     

血管内支架介入成形术对老年缺血性脑血管病患者的神经功能、动脉血流速度及预后的影响

摘要 目的：探讨血管内支架介入成形术对老年缺血性脑血管病（ICVD）患者的神经功能、动脉血流速度及预后的影响。方法：选取2018年3月~2019年4月期间我院收治的117例老年ICVD患者作为研究对象,根据随机数字表法分为对照组（n=58）和研究组（n=59）,其中对照组患者予以保守药物治疗,研究组患者予以血管内支架介入成形术治疗,比较两组患者疗效、神经功能、动脉血流速度、预后及并发症情况。结果：研究组治疗6个月后的临床总有效率为91.53%（54/59）,高于对照组的72.41%（42/58）（P<0.05）。两组患者治疗后1个月、治疗后3个月、治疗后6个月美国国立卫生研究院卒中量表（NIHSS）评分均下降（P<0.05）,且研究组低于对照组（P<0.05）。两组患者治疗后6个月大脑中动脉、基底动脉、颈内动脉血流速度均升高（P<0.05）,且研究组高于对照组（P<0.05）。两组患者治疗后1个月、治疗后3个月、治疗后6个月改良Rankin量表（mRS）评分呈下降趋势（P<0.05）,且研究组低于对照组（P<0.05）。两组患者并发症发生率对比未见统计学差异（χ²=2.261,P=0.133）。结论：老年ICVD患者经血管内支架介入成形术治疗后的疗效显著,可有效改善患者神经功能、动脉血流速度及预后,且不增加并发症发生率,具有较高的临床应用价值。     

Structural basis of defects in the sacsin HEPN domain responsible for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)

Sacsin is a 520-kDa protein mutated in the early-onset neurodevelopmental and neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The C terminus of the protein contains an HEPN (higher eukaryotes and prokaryotes nucleotide-binding) domain of unknown function. Here, we determined the high-resolution 1.9-Å crystal structure of the HEPN domain from human sacsin. The structure is composed of five parallel α-helices with a large loop of several short helical segments. Two HEPN protomers assemble as a dimer to form a large positively charged cavity at the dimer interface that binds GTP and other nucleotides. The crystal structure reveals that the ARSACS N4549D mutation disrupts dimerization and protein folding. This study provides novel insights into the oligomerization state of sacsin and functions that are lost in mutations that cause ARSACS.