注意缺陷多动障碍儿童外周血...1、NO表达水平及临床意义_王菊红.pdf

海南医学2023年4月第34卷第8期Hainan Med J,Apr.2023,Vol.34,No.8注意缺陷多动障碍儿童外周血NOS1、NO表达水平及临床意义王菊红1，黎鹏21.宝鸡市妇幼保健院儿童免疫内分泌科，陕西宝鸡721000；2.宝鸡市中医医院儿科，陕西宝鸡721000【摘要】目的探究注意缺陷多动障碍(ADHD)患儿外周血一氧化氮合酶1(NOS1)、一氧化氮(NO)的表达水平及临床意义。方法选取2019年4月至2021年4月宝鸡市妇幼保健院和宝鸡市中医医院收治的93例ADHD患儿为研究组，并根据临床反应情况将其分为注意力缺陷为主型(PIT)34例(PIT组)、多动-冲动为主型(HIT)19例(HIT组)和混合型(CT)40例(CT组)，另选取同期健康体检儿童122例作为对照组。收集所有受试儿童的一般资料，酶联免疫吸附法(ELISA)检测外周血NOS1、NO水平；采用Pearson相关性分析ADHD患儿外周血NOS1与NO的相关性；多因素Logistic回归分析ADHD发生的影响因素。结果研究组患儿的胎儿宫内窘迫、产程延长、儿童孤独、父母经常吵架比例明显高于对照组，差异均有统计学意义(P0.05)；研究组患儿的外周血NOS1、NO水平分别为(40.236.54)mol/L、(44.5113.43)U/mL，明显高于对照组的(25.345.82)mol/L、(32.8710.34)U/mL，差异均有统计学意义(P0.05)；CT组患儿的外周血NOS1、NO水平分别为(44.197.03)mol/L、(49.8412.39)U/mL，HIT组患儿分别为(36.426.52)mol/L、(42.3112.04)U/mL，明显高于PIT组的(30.236.12)mol/L、(35.4810.96)U/mL，CT组患儿的外周血NOS1、NO水平又明显高于HIT组，差异均有统计学意义(P0.05)；经Pearson相关性分析结果显示，ADHD患儿外周血NOS1水平与NO水平呈正相关(r=0.399，P0.05)；经多因素Logistic回归分析结果显示，胎儿宫内窘迫、产程延长、儿童孤独、父母经常吵架、NOS1、NO是影响ADHD发生的危险因素(P0.05)。结论ADHD患儿外周血NOS1、NO水平上调，两者均可能在ADHD发生发展过程中发挥作用，检测外周血NOS1、NO水平有利于临床预测发生ADHD的可能性。【关键词】注意缺陷多动障碍；一氧化氮合酶1；一氧化氮；临床意义；影响因素【中图分类号】R729【文献标识码】A【文章编号】10036350（2023）08114405Expression levels of NOS1 and NO in peripheral blood of children with attention deficit hyperactivity disorderand their clinical significance.WANG Ju-hong1,LI Peng2.1.Department of Immunoendocrinology for Children,BaojiMaternal and Child Health Hospital,Baoji 721000,Shaanxi,CHINA;2.Department of Paediatrics,Baoji Hospital ofTraditional Chinese Medicine,Baoji 721000,Shaanxi,CHINA【Abstract】ObjectiveTo explore the expression levels and clinical significance of nitric oxide synthase 1(NOS1)and nitric oxide(NO)in peripheral blood of children with attention deficit hyperactivity disorder(ADHD).MethodsA total of 93 children with ADHD treated in Baoji Maternal and Child Health Hospital and Baoji Hospital ofTraditional Chinese Medicine from April 2019 to April 2021 were selected as the study group.According to the clinicalresponse,they were divided into 34 cases of predominantly inattentive type(PIT group),19 cases of hyperactive-impul-sive type(HIT group),and 40 cases of commixture type(CT group).In addition,122 children undergoing physical exam-ination during the same period were selected as the control group.The general information of all children were collected.Enzyme-linked immunosorbent assay(ELISA)method was used to detect the levels of NOS1 and NO in peripheralblood.Pearson correlation was used to analyze the correlation between NOS1 and NO in the peripheral blood of childrenwith ADHD.Multivariate Logistic regression was used to analyze the influencing factors of ADHD.ResultsThe pro-portion of fetal distress,prolonged labor,children s loneliness,and frequent parental quarrels in the study group weresignificantly higher than those in the control group(P0.05).The levels of NOS1 and NO in peripheral blood of childrenin the study group were(40.236.54)mol/L and(44.5113.43)U/mL,respectively,which were significantly higher than(25.345.82)mol/L and(32.8710.34)U/mL in the control group(P0.05).The levels of NOS1 and NO in peripheralblood of children were(44.197.03)mol/L and(49.8412.39)U/mL in CT group,respectively,(36.426.52)mol/L and(42.3112.04)U/mL in HIT group,which were significantly higher than(30.236.12)mol/L and(35.4810.96)U/mLin PIT group;the levels of NOS1 and NO in CT group were significantly higher than those in HIT group;the differenceswere statistically significant(P0.05).Pearson correlation analysis showed that the level of NOS1 in peripheral blood ofADHD children was positively correlated with the level of NO(r=0.399,P0.05).Multivariate logistic regression analy-sis showed that the fetal distress,prolonged labor,children s loneliness,frequent parental quarrels,NOS1,and NO were 论著 doi:10.3969/j.issn.1003-6350.2023.08.016第一作者：王菊红(1978)，女，主治医师，主要研究方向为儿科临床内科。通讯作者：黎鹏(1983)，男，主治医师，主要研究方向为儿科临床内科，E-mail：。1144Hainan Med J,Apr.2023,Vol.34,No.8海南医学2023年4月第34卷第8期注意缺陷多动障碍(attention deficit hyperactivitydisorder，ADHD)是学龄期儿童表现为注意力不集中、多动和行为冲动的一种精神和神经发育障碍性疾病1。ADHD的发病原因较为复杂，主要影响因素是环境、遗传等2。据报道，ADHD在美国儿童中的发病率为3%5%，在日本儿童中约占4%3；据李世明等4统计ADHD位居中国儿童精神科和儿童保健科门诊病例前三位，发病率为5.6%。ADHD在学龄期儿童中会造成上课学习不专心、运动不稳定、易怒冲动，青少年期直至成年主要表现为注意力不集中，其他症状随着年龄增长而逐渐减弱5。目前，临床上对ADHD患儿主要使用哌甲酯等药物治疗，但伴随着烦躁、食欲下降等不良反应发生，对患儿生活产生影响6。因此，寻找新的治疗靶点对ADHD具有重要的意义。一氧化氮合酶1(nitric oxide synthase 1，NOS1)又称为神经型一氧化氮合酶，是一氧化氮合酶(nitric oxide synthase，NOS)的一种亚型，其主要分布在神经元和内皮细胞中，并催化产生一氧化氮，具有调控神经递质传递、突触形成等作用7。一氧化氮(nitric oxide，NO)是一种存在于人体细胞的小分子物质，主要产生于脑细胞、肌肉细胞、内皮细胞，具有调节免疫反应、增强血小板聚合、血管扩张等功能8。研究发现，NOS1异常活化会导致NO过量产生，从而造成下游细胞凋亡信号被激活，导致脑部神经元及部分功能受损9。因此，本研究通过检测AD-HD患儿外周血NOS1、NO水平，分析两者与疾病发生发展的相关性，以期为临床防治ADHD提供参考依据。1资料与方法1.1一般资料选取2019年4月至2021年4月宝鸡市妇幼保健院和宝鸡市中医医院确诊为ADHD患儿93例为研究组。纳入标准：(1)均按照 美国精神障碍诊断手册(第5版)中ADHD诊断标准10；(2)初次诊断为ADHD，并未接受治疗；(3)患儿临床资料完整，且家属知情并自愿参加本研究。排除标准：(1)合并智力、精神障碍者；(2)合并营养性或消化道、呼吸道疾病者；(3)年龄小于6岁或大于18岁。同期选取在本院体检的健康儿童122例为对照组。本研究获得两家医院的伦理委员会批准。1.2研究方法1.2.1一般资料收集收集两组受检儿童的年龄、性别、体质量指数(BMI)、胎儿宫内窘迫、产程延长、儿童孤独及父母经常吵架等情况。1.2.2样本采集及保存采集ADHD患儿入院后24 h内清晨空腹肘静脉血5 mL，对照组于体检当天清晨采集空腹肘静脉血 5 mL，收集于 EDTA 抗凝管内，分离血浆，保存备用。1.2.3外周血NOS1、NO水平检测采用酶标分析仪(HBS-1096C，南京德铁实验设备有限公司)检测NOS1、NO水平，实验操作均按说明书由专业技术人员严格进行。人NOS1酶联免疫吸附法(enzyme-linkedimmunosorbent assay，ELISA)试剂盒购于上海泽叶生物科技有限公司，货号：H-EL-NOS1/nNOS；人 NOELISA 试剂盒购于上海广锐生物科技有限公司，货号：20191215。1.3分组标准93例ADHD患儿根据临床反应情况分为注意力缺陷为主型(predominantly inattentivetype，PIT)组 34 例，多动-冲动为主型(predominantlyhyperactivity-impulse type，HIT)组19例，混合型(com-bined type，CT)组40例。1.4观察指标比较对照组和研究组受检者的一般资料及外周血 NOS1、NO 水平；比较三种分型ADHD患儿外周血NOS1、NO水平；分析外周血NOS1与NO水平的相关性。1.5统计学方法应用SPSS25.0统计学软件分析全文数据。计量资料均呈正态分布且方差齐，以均数标准差(x-s)表示，两组间比较采用独立样本t检验；三组数据比较采用单因素方差分析，进一步两两比较采用LSD-t检验；计数资料两组间比较采用2检验；采用Pearson相关性分析ADHD患儿外周血NOS1水平与NO水平的相关性；采用多因素Logistic回归分析ADHD发生的影响因素。以P0.05为差异有统计学意义。2结果2.1研究组和对照组受检者的一般资料比较研究组患儿的胎儿宫内窘迫、产程延长、儿童孤独、父母经常吵架比例明显高于对照组，差异均有统计学意义(P0.05)，见表1。2.2研究组和对照组受检者的外周血NOS1、NO水平比较研究组患儿的外周血NOS1、NO水平明显高于对照组，差异均有统计学意义(P0.05)，见表2。2.3三种分型ADHD患儿外周血 NOS1、NO水平比较CT组和HIT组ADHD患儿的外周血NOS1、NO水平明显高于PIT组，CT组ADHD患儿的外周血NOS1、NO水平明显高于HIT组，差异均有统计学意义(P0.05)，见表3。2.4ADHD患儿外周血NOS1与NO水平的相关性经Pearson相关性分析结果显示，ADHD患儿外周血NOS1水平与NO水平呈正相关(r=0.399，P=0.000)，见图1。the risk factors of ADHD(P0.05).ConclusionThe levels of NOS1 and NO in the peripheral blood of children withADHD are up-regulated.Both of them may play a role in the occurrence and development of ADHD.The detection ofthe levels of NOS1 and NO in the peripheral blood is helpful for clinical prediction of the possibility of ADHD.【Key words】Attention deficit hyperactivity disorder;Nitric oxide synthase 1;Nitric oxide;Clinical significance;Influence factor1145海南医学2023年4月第34卷第8期Hainan Med J,Apr.2023,Vol.34,No.82.5影响ADHD发生的危险因素以是否发生ADHD为因变量(未发生=0、发生=1)，将赋值后的自变量胎儿宫内窘迫、产程延长、儿童孤独、父母经常吵架、NOS1、NO纳入多因素Logistic回归分析模型，结果显示胎儿宫内窘迫、产程延长、儿童孤独、父母经常吵架、NOS1、NO 是影响 ADHD 发生的危险因素(P0.05)，见表4。3讨论ADHD又称脑功能轻微失调综合征或儿童多动症，主要特征表现为多动、注意缺陷、冲动等11。近年来，ADHD的患病率逐年增加。目前对于ADHD的具体发病机制尚不太明确，一般研究认为其与心理、社会、生物等多种因素密切相关12。据影像学技术显示，ADHD患儿的小脑体积和前额皮层呈现缩小状态，且活动能力明显减弱。研究发现，ADHD患儿去甲肾上腺素和多巴胺等一些神经递质表达异常，基因也会影响ADHD的发生率13。据报道，全球ADHD的儿童患病率为8%12%，半数以上的ADHD患儿疾病症状会持续到成年14。该病不仅影响学龄期儿童的智力发展，而且对成年甚至终身的社会生活活动产生严重的影响。因此，对ADHD进行早期诊断和及时治疗对儿童有关键性的影响。ADHD的致病病理主要是脑功能障碍或神经发育异常，NOS1和NO分布于神经元及脑细胞中，因此对中枢神经系统发育过程具有重要调控作用。NOS在体内主要分为三种亚型，NOS1、诱导型一氧化氮合酶和内皮型一氧化氮合酶，其中NOS1广泛存在于大脑的海马、前额叶、皮质、下丘脑等部位15。王淑静等16在动物试验中发现，NOS1在患有局灶性脑缺血的大鼠体内含量升高，原因在于局灶性脑缺血造成大鼠前额叶皮质区神经元损伤，导致机体应激水平提高。本研究中，研究组患儿外周血NOS1水平明显高于对照组，其中CT组和HIT组患儿外周血NOS1水平明显高于PIT组，CT组患儿外周血NOS1水平明显高于HIT组，提示NOS1可能与ADHD疾病的发生发展有相关性，推测，高水平NOS1可能通过触发有关信号通路，进而继发机体应表1研究组和对照组受检者的一般资料比较x-s，例(%)Table 1Comparison on the general data of subjects between the study group and the control group x-s,n(%)临床指标年龄(岁)男/女BMI(kg/m2)胎儿宫内窘迫(是/否)产程延长(是/否)儿童孤独(是/否)父母经常吵架(是/否)对照组(n=122)8.952.7267(54.92)/55(45.08)19.123.6710(8.20)/112(91.80)8(6.56)/114(93.44)5(4.10)/117(95.90)12(9.84)/110(90.16)研究组(n=93)9.042.9450(53.76)/43(46.24)18.933.8144(47.31)/49(52.69)30(32.26)/63(67.74)24(25.81)/69(74.19)20(21.51)/73(78.49)t/2值0.2320.0280.37042.92923.95621.3115.672P值0.8170.8660.7120.0000.0000.0000.017表2研究组和对照组受检者的外周血NOS1、NO水平比较(x-s)Table 2Comparison on the peripheral blood NOS1 and NO levels ofsubjects between the control group and the study group(x-s)组别研究组对照组t值P值例数93122NOS1(mol/L)40.236.5425.345.8217.6130.001NO(U/mL)44.5113.4332.8710.347.1810.001表3三种分型ADHD患儿外周血NOS1、NO水平比较(x-s)Table 3Comparison on NOS1 and NO levels in peripheral bloodamong children with ADHD of three types(x-s)组别PIT组HIT组CT组F值P值例数341940NOS1(mol/L)30.236.1236.426.52a44.197.03ab41.3440.001NO(U/mL)35.4810.9642.3112.04a49.8412.39ab13.6250.001注：与PIT组比较，aP0.05；与HIT组比较，bP0.05。Note:Compared with PIT group,aP0.05;Compared with HIT group,bP0.05.表4影响ADHD发生的多因素Logistic回归分析Table 4Multivariate Logistic regression analysis of the factorsaffecting the occurrence of ADHD自变量胎儿宫内窘迫产程延长儿童孤独父母经常吵架NOS1NOB值1.3831.4731.3991.0630.7550.690SE0.3520.4270.3260.3670.2140.203wald15.43811.89918.4158.38412.43811.558P值0.0000.0010.0000.0030.0000.000OR3.9874.3624.0512.8942.1271.99495%CI2.0007.9481.88910.0732.1387.6751.4105.9411.3983.2351.3402.968图1ADHD患儿外周血NOS1与NO水平相关性分析的散点图Figure 1Scatter chart of correlation analysis of NOS1 and NO levelsin peripheral blood of children with ADHD1146Hainan Med J,Apr.2023,Vol.34,No.8海南医学2023年4月第34卷第8期激水平，从而在ADHD发病过程中发挥促进作用，但其具体机制有待进一步研究证实。NO在神经元中担任信使和递质样的角色，具有调节脑血流量、保护神经元、扩张血管、抑制血小板聚集的功能17。研究发现，可通过NOS间接反映NO在组织细胞中的分布。然而，当NO表达过量时，会导致大量羟基及二氧化氮自由基被激活，进而引发蛋白质、核酸等受损，同时对神经元产生毒性18。李浩源等19研究得出，血清NO水平表达异常可对动脉血压产生影响，继而增加脑出血的风险。张彦博等20在轻度胃肠炎伴婴幼儿良性惊厥患儿中发现，导致患儿发生惊厥的原因可能在于血清NO水平及NOS活力的升高。何桂媛等21论述miR-146在支气管哮喘过程中的作用得出，miR-146基因可调控诱导型NOS1，导致其表达下调，NO产量随之下降。本研究显示，研究组患儿外周血NO水平明显高于对照组，CT组和HIT组患儿外周血NO水平明显高于PIT组，CT组患儿外周血NO水平明显高于HIT组，提示外周血NO可能与ADHD的发生发展有关，究其原因，NO水平升高可能通过影响神经系统进而参与ADHD病情发展过程，但有待进一步证实NO以何种形式发挥作用。本研究中ADHD患儿外周血NOS1与NO水平呈正相关，提示NOS1可能与NO相互作用，进而共同影响ADHD病理过程，但相互作用机制有待深入探讨。本研究发现，胎儿宫内窘迫、产程延长、儿童孤独、父母经常吵架、NOS1、NO是影响ADHD发生的危险因素，提示胎儿宫内窘迫、产程延长、儿童孤独、父母经常吵架的发生，外周血NOS1、NO水平升高均可能会增加ADHD的发生风险。张平等22在对ADHD相关危险因素探讨中发现，胎儿宫内窘迫、产程延长、父母管教环境及家庭关系是否和睦是影响ADHD发生的危险因素。本研究中ADHD发生的影响因素与张平等22研究结果部分一致。因此，及时关注产妇状况、注重儿童生长环境，并监控外周血NOS1、NO水平有利于判定是否发生ADHD。综上所述，ADHD患儿外周血NOS1、NO水平表达上调，两者可能相互影响，从而协同影响ADHD发生及病情发展过程，检测外周血NOS1、NO水平有助于临床及时预测发生ADHD的儿童，以便采取措施干预。但NOS1、NO影响ADHD患儿的具体机制尚未探究清楚，后期将增加样本量进行多方面探讨。参考文献1 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Chacko A,Bedard AV,Marks D,et al.Sequenced neurocognitive andbehavioral parent training for the treatment of ADHD in school-agechildren J.Child Neuropsychol,2018,24(4):427-450.15 Zhou QG,Zhu XH,Nemes AD,et al.Neuronal nitric oxide synthaseand affective disorders J.IBRO Rep,2018,5(1):116-132.16 Wang SJ,Hu ZJ,Yang JJ,et al.Effects of focal cerebral ischemia onneuronal nitric oxide synthase in prefrontal cortex of rats J.Chinese1147海南医学2023年4月第34卷第8期Hainan Med J,Apr.2023,Vol.34,No.8拷贝数变异测序在稽留流产遗传学检测中的应用覃颖1，毛锦江1，钟文富2贵港市人民医院产科1、检验科2，广西贵港537100【摘要】目的探讨拷贝数变异测序(CNV-seq)技术在研究早期稽留流产原因中的应用价值。方法选取2020年1月至2021年12月在贵港市人民医院就诊的220例稽留流产患者，对其绒毛/胎儿组织进行拷贝数变异测序(CNV-Seq)，分析稽留流产与染色体异常的相关性。结果220例稽留流产标本中，成功检测215例，成功率为97.73%。结果检出染色体异常140例(65.28%)，染色体正常75 例(34.72%)。染色体异常中，数目异常型113例(80.71%)，最为常见，其中三体型 82 例(58.57%)，X 单体型 13 例(9.29%)，三倍体 18 例(12.86%)。嵌合体 13 例(6.05%)，染色体片段缺失/重复14例(6.51%)。孕妇年龄35岁组发生染色体异常率为72.58%，略高于孕妇年龄0.05)。结论CNV-seq对流产物的遗传学诊断具有明确的应用价值，染色体数目异常是导致早期流产最常见的原因之一，对再生育指导具有重要意义。【关键词】稽留流产；绒毛；核型；拷贝数变异测序；下一代测序【中图分类号】R714.21【文献标识码】A【文章编号】10036350（2023）08114804Application of copy number variation sequencing in genetic detection of missed abortion.QIN Ying1,MAOJing-jiang1,ZHONG Wen-fu2.Department of Obstetrics1,Department of Clinical Laboratory2,Guigang Peoples Hospital,Guigang 537100,Guangxi,CHINA【Abstract】ObjectiveTo explore the application value of copy number variation sequencing(CNV-seq)technology in studying the causes of early missed abortion.MethodsA total of 220 patients of missed abortion ad-mitted to Guigang Peoples Hospital from January 2020 to December 2021 were selected.CNV-Seq was performed onthe villus/fetal tissue of the patients to analyze the correlation between missed abortion and chromosomal abnormali-ties.ResultsAmong the 220 patients,215 were detected successfully,with a success detection rate of 97.73%,including140 cases(65.28%)of chromosomal abnormalities and 75 cases(34.72%)of normal chromosomes.Among the 140 casesof chromosomal abno