Neurochemistry of hyponatremic encephalopathy evaluated by MR spectroscopy

MR spectroscopy in a patient with hyponatremic encephalopathy due to the syndrome of inappropriate secretion of antidiuretic hormone revealed decreased N-acetyl-aspartate, creatine plus phosphocreatine, choline-containing compounds, and myo-inositol, with normal glutamate and increased glutamine, which normalized after Na normalization. The decreased concentrations of creatine plus phosphocreatine, choline-containing compounds and myo-inositol are explained by their release as osmolytes from brain cells to adapt to hypo-osmolality induced cerebral edema. Increased glutamine, which not only acts as an osmolyte but also protects neurons under excitotoxic conditions, may suggest that a disrupted glutamate-glutamine cycle may play an important role in the pathogenesis of hyponatremic encephalopathy.     

Co-occurring WARS2 and CHRNA6 mutations in a child with a severe form of infantile parkinsonism

ObjectiveTo investigate the molecular cause(s) underlying a severe form of infantile-onset parkinsonism and characterize functionally the identified variants.MethodsA trio-based whole exome sequencing (WES) approach was used to identify the candidate variants underlying the disorder. In silico modeling, and in vitro and in vivo studies were performed to explore the impact of these variants on protein function and relevant cellular processes.ResultsWES analysis identified biallelic variants in WARS2, encoding the mitochondrial tryptophanyl tRNA synthetase (mtTrpRS), a gene whose mutations have recently been associated with multiple neurological phenotypes, including childhood-onset, levodopa-responsive or unresponsive parkinsonism in a few patients. A substantial reduction of mtTrpRS levels in mitochondria and reduced OXPHOS function was demonstrated, supporting their pathogenicity. Based on the infantile-onset and severity of the phenotype, additional variants were considered as possible genetic modifiers. Functional assessment of a selected panel of candidates pointed to a de novo missense mutation in CHRNA6, encoding the α6 subunit of neuronal nicotinic receptors, which are involved in the cholinergic modulation of dopamine release in the striatum, as a second event likely contributing to the phenotype. In silico, in vitro (Xenopus oocytes and GH4C1 cells) and in vivo (C. elegans) analyses demonstrated the disruptive effects of the mutation on acetylcholine receptor structure and function.ConclusionOur findings consolidate the association between biallelic WARS2 mutations and movement disorders, and suggest CHRNA6 as a genetic modifier of the phenotype.     

Ammonia metabolism,the brain and fatigue; revisiting the link

This review addresses the ammonia fatigue theory in light of new evidence from exercise and disease studies and aims to provide a view of the role of ammonia during exercise. Hyperammonemia is a condition common to pathological liver disorders and intense or exhausting exercise. In pathology, hyperammonemia is linked to impairment of normal brain function and the onset of the neurological condition, hepatic encephalopathy. Elevated blood ammonia concentrations arise due to a diminished capacity for removal via the liver and lead to increased exposure of organs, such as the brain, to the toxic effects of ammonia. High levels of brain ammonia can lead to deleterious alterations in astrocyte morphology, cerebral energy metabolism and neurotransmission, which may in turn impact on the functioning of important signalling pathways within the neuron. Such changes are believed to contribute to the disturbances in neuropsychological function, in particular the learning, memory, and motor control deficits observed in animal models of liver disease and also patients with cirrhosis. Hyperammonemia in exercise occurs as a result of an increased production by contracting muscle, through adenosine monophosphate (AMP) deamination (the purine nucleotide cycle) and branched chain amino acid (BCAA) deamination prior to oxidation. Plasma concentrations of ammonia during exercise often achieve or exceed those measured in liver disease patients, resulting in increased cerebral uptake. In this article we propose that exercise-induced hyperammonemia may lead to concomitant disturbances in brain function, potentially through similar mechanisms underpinning pathology, which may impact on performance as fatigue or reduced function, especially during extreme exercise.     

全静脉营养加谷氨酰胺对危重症患者血浆内毒素、肿瘤坏死因子-a水平及预后的影响

目的观察全静脉营养加谷氨酰胺（Gln）对危重症患者血浆内毒素（LPS）、肿瘤坏死因子-a（TNF-a）水平及预后的影响。方法将120例危重症患者随机分为观察组和对照组,每组60例。对照组给予常规全静脉营养支持,观察组在对照组全静脉营养支持基础上给予Gln。比较两组患者血浆Gln、LPS和TNF-a水平的变化,以及肠外营养支持治疗时间、住院天数和预后情况。结果观察组血浆Gln水平逐渐升高,与治疗前比较,差异有统计学意义（P〈0．01）。观察组血浆LPS和TNF-a水平逐渐降低,对照组逐渐升高,与治疗前比较,差异均有统计学意义（P〈0．05或P〈0．01）;治疗第3天及第7天两组之间Gln、LPS及TNF—a水平比较,差异均有统计学意义（P〈0．01）。观察组患者肠外营养支持治疗时间和住院天数均显著短于对照组（P〈0．01）,感染发生率亦显著低于对照组（P〈0．05）。结论全静脉营养加Gln在危重症患者治疗中可有效改善胃肠道功能,降低血浆LPS和TNF—d水平,改善预后。     

免疫强化肠内营养在老年全胃切除术后患者中的临床应用

目的探讨谷氨酰胺强化肠内营养支持对老年患者全胃切除术后营养及免疫功能的影响。方法选择我院普外科2008年2月至2010年8月期间接受全胃切除术的84例进展期胃癌老年患者作为研究对象,平均分为谷氨酰胺强化肠内营养(Gln)组、肠内营养(EN)组和肠外营养(PN)组。观察肛门排气恢复时间、术后并发症发生率、住院时间等,分别于术前、术后第2和第10天检测血清总蛋白、白蛋白、前白蛋白和转铁蛋白水平,并于术前和术后第10天检测外周血CD4和CD8 T细胞百分数、CD4/CD8以及免疫球蛋白IgM和IgG水平。结果 3组患者均按计划完成治疗。Gln组和EN组患者术后肛门排气时间和住院时间均显著短于PN组(P<0.05)。3组患者术后并发症和消化道症状发生率差异均无统计学意义(P>0.05),仅PN组1例患者在术后6d发生吻合口漏,经引流、抗感染、抑制消化液分泌等治疗后于术后54d痊愈出院。3组患者术前总蛋白、白蛋白、前白蛋白及转铁蛋白水平的差异均无统计学意义(P>0.05),术后第2天各组患者上述各指标均较术前明显下降(P<0.05),但各组之间比较差异无统计学意义(P>0.05);术后第10天时各项指标不同程度恢复,且Gln组和EN组患者术后10d各指标均显著高于术后2d(P<0.05);除转铁蛋白之外,Gln组与EN组患者术后第10天总蛋白、白蛋白、前白蛋白水平明显高于PN组(P<0.05),Gln组与EN组之间比较差异无统计学意义(P>0.05)。术前3组患者各项免疫学指标之间的差异无统计学意义(P>0.05);术后第10天Gln组患者CD4和CD8T细胞百分数、CD4/CD8比值以及血清IgM和IgG水平均已基本恢复甚至略超过术前水平,且除IgM以外均明显高于EN组和PN组相应结果(P<0.05);术后第10天EN组和PN组各项指标除EN组IgG以外仍明显低于术前水平(P<0.05)。结论老年胃癌患者行全胃切除术后早期应用谷氨酰胺强化肠内营养是安全可行的。在恢复和改善营养及免疫功能同时,可更好地促进患者术后恢复、缩短住院时间,是此类患者术后营养支持治疗的最佳选择之一。     

谷氨酰胺对内毒素激活大鼠枯否细胞的免疫调理作用

目的　探讨谷氨酰胺调节大鼠枯否细胞（KC）免疫功能的可能机制。方法　体外培养条件下,内毒素(LPS)激活KC,采用聚苯乙稀颗粒检测KC的非特异吞噬作用,3-氢尿嘧啶(3H-Uridine)掺入法反映KC合成RNA的能力,生物素链亲和素酶联免疫吸附法（ELISA）法检测KC肿瘤坏死因子(TNF)-α和白细胞介素(IL)-6的分泌量。结果　培养液中谷氨酰胺的浓度从0.000mmol/L上升到0.500mmol/L时,KC吞噬聚苯乙稀颗粒数量、3H-Uridine掺入量、TNF-α和IL-6分泌量分别从(8.80±0.74)/细胞、(20425±2768)DPM/1×106细胞、(105±80)μg/L、(12±2)μg/L上升到(18.53±2.15)/细胞、(39328±2169)DPM/1×106细胞、(300±30)μg/L、(37±4)μg/L。结论　KC的非特异性吞噬作用、3H-Uridine掺入量、TNF-α和IL-6分泌量依赖于培养液中谷氨酰胺的含量,谷氨酰胺缺乏或不足导致KC的特异性和非特异性的免疫功能低下。     

强化谷氨酰胺的肠外营养支持在肝癌肝切除术后的临床研究

目的探讨肝癌肝切除术后患者给予含谷氨酰胺（Gln）的肠外营养（PN）支持的应用效果。方法将42例肝癌肝切除术后患者随机分为两组：对照组接受不含Gln的PN,研究组接受含Gln的PN。术后第1d开始进行等氮等热量营养支持,共7d。测定治疗前后的血清免疫球蛋白指标变化,进行APACHEⅡ评分,观察感染并发症的发生率。结果研究组术后第8d IgG指标明显高于对照组,APACHEⅡ评分明显低于对照组,组间差异有统计学意义（P〈0．05）;研究组感染并发症发生率较对照组低,但组间差异无统计学意义（P〉0．05）。结论强化谷氨酰胺的肠外营养支持可以改善肝癌肝切除术后患者的免疫状况,减轻术后炎性反应。     

表皮生长因子对放射性肠炎全肠外营养大鼠谷氨酰胺代谢酶的影响

目的：探讨表皮生长因子（ＥＧＦ）对接受长期全肠外营养（ＴＰＮ）的放射性肠炎大鼠组织谷氨酰胺代谢酶的影响,方法大鼠皮下注射ＥＧＦ,观察其对大鼠肝,骨骼肌及小肠粘膜组织内谷酰胺酶和谷氨酰胺合成酶的变化。结果应用ＥＧＦ后大鼠肝、,骨骼肌肉的谷氨酰胺合成酶及肝、小肠粘膜的谷氨酰胺酶活性,动脉血、小肠和肝谷氨酰胺浓度增加,小肠谷氨酰胺摄取率增加。结论ＥＧＦ显著增加谷氨酰胺代谢酶的活性,增加肠粘膜代谢的主要能     

接触丙烯腈工人血中一氧化氮与一氧化氮合酶的变化

目的 探讨职业性接触丙烯腈对人体血管内皮功能的影响。方法 以某石化厂从事腈纶纤维生产的 111名工人为接触组,条件相近的不接触任何毒物及不进行有害作业的健康体检者89人为对照组。进行血清 一氧化氮代谢产物水平、血清总一氧化氮合酶(tNOS)活力、血清诱导型一氧化氮合酶(iNOS)活力测定,作为评 估血管内皮功能的指标。结果与对照组比较,接触组NO水平显著降低(P<0.01)。以NO水平为应变量,以 接触丙烯腈、性别、年龄、家族史、吸烟量、饮酒量、血清三酰甘油等指标自变量,进行逐步多元线性回归分析。接 触丙烯腈与血清NO水平呈显著负相关(P<0.01),且相关性随工龄的延长而增加。结论 职业性接触丙烯腈 可损害血管内皮功能,且这种损害可能具有累积效应。     

谷胱甘肽合成酶系基因协调表达体系的构建

通过 PCR获得 E.coli B谷胱甘肽合成酶系基因 ( gsh I,gsh II)片段 ,结合定点突变稀有起始密码子 ,设定 gsh I与 gsh II位置与距离 ,构建双顺反子重组表达载体 p Trc99A/gsh I- gsh II,建立GSHI、GSH- II蛋白表达体系。结果表明 :以 0 .0 8mmol/L IPTG于 2 8℃诱导工程菌 E.coli BL2 1( DE3) ( p Trc99A/gsh I- gsh II) ,GSH- I、GSH- II蛋白比为 4.5∶ 1 ( m∶ m)时谷胱甘肽合成能力最高 ,达到每克湿菌体 8.5 mg。通过构建单顺反子重组表达载体 p Trc99A/gsh I、p Trc99A/gsh II测定GSH- I与 GSH- II蛋白的最适配比 ,结果表明 :在 GSH- I、GSH- II蛋白总量恒定的情况下 ,要提高谷胱甘肽产率 ,两者比例以 3∶ 1～ 6∶ 1为宜