急性白血病患儿MTHFR基因G1793A多态性的相关研究

目的 研究亚甲基四氢叶酸还原酶(MTHFR)基因G1793A多态性在AL患儿中的等位基因频率和基因型分布特征,及其与儿童AL发病风险的相关性.方法 应用反转录-PCR-变性梯度凝胶电泳结合DNA测序技术,对109例AL患儿和120例对照儿童的cDNA MTHFR G1793A基因型进行检测.结果 在AL组、ALL组、急性髓细胞白血病(AML)组和对照组中MTHFR 1793 GG、GA、AA基因型频率分别为83.5％、15.6％、0.9％;82.8％、16.1％、1.1％;86.4％、13.6％、0和89.2％、7.5％、3.3％;而MTHFR 1793A等位基因频率分别为8.7％、9.2％、6.8％和7.1％;分别将各病例组人群A等位基因频率及基因型分布与对照组进行比较,发现差异均无统计学意义(P均＞0.05);MTHFR 1793 GA+ AA增加了AL、ALL和AML发病风险(AL:OR=1.71,95％ CI:0.77～3.80,P=0.19;ALL:OR =2.00,95％ CI:0.85 ～4.49,P=0.12;AML:OR=1.36,95％ CI:0.33～5.62,P=0.67),但差异均无统计学意义(P均＞0.05);全部标本中A等位基因总频率为7.9％,与德国犹太人、巴西人、奥地利人、伊朗人及中国哈尔滨人群的差异均具有统计学意义(P均＜0.05).结论 MTHFRG1793A基因多态性与汉族儿童AL的发病无相关性,但该位点多态性分布具有种族差异性.     

5，10-亚甲基四氢叶酸还原酶基因C677T多态性与先天性心脏病关系的Meta分析

摘要 目的 对5,10 亚甲基四氢叶酸还原酶（MTHFR）基因C677T多态性与先天性心脏病（CHD）的相关性研究进行Meta分析。方法 制定原始文献的纳入标准及检索策略,检索PubMed、EMBASE、Ovid、Springer、中国期刊全文数据库、维普中文科技期刊数据库、万方数据库和中国生物医学文献数据库（1994年1月至2009年1月）中的文献,收集MTHFR基因C677T多态性与CHD相关性的病例 对照研究,剔除不符合要求的文献,应用RevMan 4.2软件进行Meta分析,得出合并后的OR值及其95％CI。结果 共18篇文献符合纳入标准进入Meta分析。数据合并结果显示,子代MTHFR基因 677位点TT/CC和(TT+CT)/CC与CHD易感性有统计学意义,OR值（95％CI）分别为1.55（1.24~1.93）和1.23（1.06~1.42）,P<0.05;子代MTHFR基因677位点CT/CC与CHD易感性无统计学意义,OR值（95％CI）为1.15（0.99~1.34）,P>0.05。父亲MTHFR基因677位点TT/CC和(TT+CT)/CC与子代CHD的易感性有统计学意义,OR值（95％CI）分别为1.84（1.23~2.74）和1.33（1.04~1.71）,P<0.05;父亲MTHFR基因677位点CT/CC与子代CHD易感性无统计学意义,OR值（95％CI）为1.25（0.96~1.62）,P>0.05 。母亲MTHFR基因677位点TT/CC、CT/CC和(TT+CT)/CC与子代CHD易感性均无统计学意义,OR值（95％CI）分别为1.20（0.92~1.56）、1.03（0.86~1.24）和1.07（0.90~1.27）,P均>0.05。传递不平衡分析未发现在CHD核心家系的MTHFR基因677位点存在突变的传递不平衡现象,OR值为0.90（95％CI：0.79~1.12）,P>0.05。结论 子代MTHFR基因677位点TT和TT+CT为CHD的危险因素之一;父亲MTHFR基因677位点TT和TT+CT是子代CHD的危险因素之一;母亲MTHFR基因677位点多态性与子代CHD的发生无关。     

MTHFR基因多态性与儿童原发性高血压的相关性研究北大核心CSCD

目的分析原发性高血压儿童亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)基因C677T多态性分布特征,探讨其与儿童H型高血压的相关性。方法回顾性选取2021年1~7月于心血管内科住院、初次诊断未经治疗的121例原发性高血压儿童为研究对象,按基因型分为CC型组(19例)、CT型组(51例)和TT型组(51例);按血清同型半胱氨酸(homocysteine,Hcy)水平分为H型高血压组(47例)和单纯高血压组(74例),比较各组间临床资料差异,分析MTHFR基因C677T多态性与儿童H型高血压的相关性。结果原发性高血压儿童T等位基因突变频率高于北京地区健康成年人群和中国汉族成年人群(P<0.001)。TT型组血清Hcy水平高于CC型组和CT型组(P<0.001)。H型高血压组血清Hcy水平高于单纯高血压组(P<0.001),且MTHFR基因C677T多为TT基因型,TT基因型与H型高血压的发生风险存在关联(OR=12.71,P<0.001)。H型高血压组和单纯高血压组间靶器官损伤发生率差异无统计学意义(P>0.05),但初次诊断时,H型高血压组即可存在多脏器受累情况,占11%(5/47)。结论原发性高血压儿童MTHFR基因C677T的T等位基因突变率高且与血清Hcy水平具有一定关联,TT基因型是儿童H型高血压的独立危险因素,与早期靶器官损伤严重程度可能相关。     

亚甲基四氢叶酸还原酶基因多态性与儿童急性淋巴细胞白血病风险的相关性研究

目的 探讨中国汉族儿童亚甲基四氢叶酸还原酶(MTHFR)基因的单核甘酸多态(MTHFR 677C→T及1298 A→C突变)对儿童急性淋巴细胞白血病(ALL)发病风险的影响.方法 收集176例ALL患儿以及与其匹配的170例对照者外周血,通过多重单碱基延伸反应(SNaPshot SNP分型技术)检测MTHFR C677T和A1298C基因型.结合临床资料,比较不同基因型对儿童ALL发病风险的影响及与临床危险度的相关性.结果 MTHFR C677T位点和MTHFR A1298C位点的各基因型在病例组与对照组间分布差异无统计学意义.兼具二种突变的基因型677CT/1298AC分布频率在病例组与对照组间分布差异无统计学意义.MTHFR C677T基因多态性在临床危险度分型及复发组中分布差异有统计学意义.MTHFR 677基因型TT在标危组中占43.0%,高于中危、高危及复发组的频率(P ＜ 0.01).MTHFR 677基因型CC在标危组中占24.0%,低于中危、高危及复发组的频率(P ＜ 0.05).结论 MTHFR 677基因型与儿童ALL的临床危险度分型和复发相关.MTHFR基因677C→T突变可能对中国儿童ALL有一定保护性作用.     

急性淋巴细胞白血病患儿亚甲基四氢叶酸还原酶基因多态性与大剂量甲氨蝶呤不良反应的相关性

目的探讨急性淋巴细胞白血病(ALL)患儿亚甲基四氢叶酸还原酶(MTHFR)基因677位点多态性与大剂量甲氨蝶呤(HDMTX)体内排泄及不良反应的相关性。方法 2008年3月-2010年2月在本院儿科中心和血液内科住院的完全缓解并接受HDMTX治疗的40例ALL患儿,在接受HDMTX治疗前应用PCR-限制性酶切片段长度多态性(RFLP)技术检测MTHFR基因C677T多态性,在HDMTX静脉输注开始后24 h、48 h应用荧光偏振免疫法(FPIA)测定其血浆MTX水平,密切观察ALL患儿HDMTX化疗后的不良反应,对化疗不良反应进行分级。对MTHFR677的基因多态性与MTX不良反应及HDMTX 48 h的MTX水平(MTX-48 h)的相关性进行分析。结果在有HDMTX相关不良反应的ALL患儿中,肝损害和骨髓抑制发生率最高。MTHFR C677T有肝脏损害的基因型分布频率由低到高为CC型40.0%,TT型60.0%,CT型80.0%,CT基因型者肝脏损害发生的风险是CC基因型者的6倍(OR=6.00,95%CI:1.05～34.32,P=0.044);677CT+TT基因型者肝脏损害发生的风险是CC基因型者的4.13倍(OR=4.13,95%CI:1.02～16.67,P=0.047)。MTHFR C677T基因型与骨髓抑制无明显相关性。携有MTHFR突变基因型(CT+TT)患者的48 hMTX血药质量浓度明显高于携带MTHFR野生型基因CC者(P=0.006)。结论 MTHFR 677位基因型可作为ALL患儿HDMTX化疗不良反应和药物体内排泄的有效预测指标。     

MTHFR、TS联合作用与ALL患儿HD-MTX化疗毒副作用的关系

目的：探讨 MTHFR、TS基因多态性联合作用对ALL患儿HD-MTX化疗后不良反应的影响,以及与MTX血药浓度变化之间的关系;分析MTHFR、TS基因多态性联合作用在个体化治疗及疾病防治中的作用。方法 ALL患儿73例,提取其基因组DNA,PCR扩增后测序鉴定MTHFR C677T、MTHFR A1298C、TS 5’-UTR的基因型。观察所有ALL患儿HD-MTX化疗后的毒副作用,并监测MTX血药浓度。以Logistic 回归分析基因多态性与化疗毒副作用的危险度;采用Fisher精确概率法比较 HD-MTX 化疗后 MTHFR C677T、MTHFR A1298C、TS 的不同基因型之间42～48 h MTX血药浓度的差异,以P＜0.05为差异有显著性。结果（1）MTHFR677 CT／TT合并1298 AC／CC基因型者,其血红蛋白降低发生的风险下降了2.9倍,而黏膜损害发生的风险则增加了4.3倍,但差异均无显著性。（2）MTHFR1298 AC／CC合并TS 3R／3R基因型者,其发生黏膜损害的风险增加了5.4倍,差异有显著性（χ2＝4.911,P＝0.027）。（3）MTHFR677 CT／TT合并TS 3 R／3R基因型与HD-MTX化疗毒副作用的发生无关。（4）MTHFR677 CT／TT＋MTHFR1298 AC／CC＋TS 3 R／3 R基因型者,其黏膜损害发生的风险增加了7.5倍,且差异有显著性（χ2＝5.295,P ＝0.021）。结论 TS和MTHFRC677T基因多态性可与ALL患儿HD-MTX化疗后黏膜损害的发生有关。     

急性淋巴细胞白血病患儿MTHFR基因多态性与大剂量甲氨蝶呤毒副反应的关系

目的：探讨亚甲基四氢叶酸还原酶（MTHFR）基因单核苷酸多态性对急性淋巴细胞白血病（ALL）患儿使用大剂量甲氨蝶呤（HD-MTX）化疗后毒副反应的影响。方法：应用RT-PCR-变性梯度凝胶电泳结合DNA测序技术,对52例ALL患儿MTHFR C677T、A1298C和G1793A基因型进行检测。按照国立癌症研究所常规毒性判定标准（NCI-CTC）对患儿HD-MTX化疗后的不良反应统一评价。结果：MTHFR 1298AC基因型患儿发生血小板减少的风险较AA型提高了13.7倍（OR=13.7,95%CI=1.18～159.36,P=0.036）。MTHFR C677T和G1793A各基因型发生各类HD-MTX化疗不良反应的差异无统计学意义（P>0.05）。结论：MTHFR A1298C多态性可能与ALL患儿HD-MTX化疗后的毒副反应相关。     

亚甲基四氢叶酸还原酶基因多态性与脑性瘫痪

亚甲基四氢叶酸还原酶(MTHFR)在调节血浆同型半胱氨酸水平和DNA甲基化中起重要作用,MTHFR基因突变可引起酶活性减低,使血浆同型半胱氨酸水平升高及DNA甲基化异常。研究发现MTHFR基因多态性与遗传性易栓症相关,可能引起包括脑性瘫痪在内的不良妊娠结局。     

MTHFR基因多态性与儿童支气管哮喘易感性及糖皮质激素疗效的相关性

目的 探讨亚甲基四氢叶酸还原酶（methylenetetrahydrofolate reductase,MTHFR）基因多态性与儿童支气管哮喘易感性及糖皮质激素（glucocorticoid,GC）疗效的相关性。 方法 选取2018年6月至2020年12月住院治疗的儿童支气管哮喘患儿173例为观察组,均接受GC雾化吸入治疗,连续3个月。选取同期体检的健康儿童178例为对照组。采用PCR检测两组受试儿MTHFR基因C677T位点的基因型,分析两组基因型分布差异性;比较观察组不同基因型患儿治疗前后血清免疫球蛋白E、白细胞介素-8（interleukin-8,IL-8）、白三烯B4（leukotriene B4,LTB4）水平,肺功能指标差异及临床疗效差异。 结果 与对照组相比,观察组TT基因型及T等位基因频率均显著升高（P<0.001）;TT/CT基因型及T等位基因是支气管哮喘易感性的独立危险因素（OR分别为6.615、7.055,P<0.001）。GC治疗后3种基因型患儿免疫球蛋白E、IL-8和LTB4水平较治疗前显著降低,第1秒用力呼气容积（forced expiratory volume in 1 second,FEV1）、用力肺活量（forced vital capacity,FVC）、FEV1/FVC%较治疗前显著升高（P<0.001）;TT基因型患儿IL-8和LTB4水平显著低于CC基因型患儿,LTB4水平明显低于CT基因型患儿,TT基因型患儿FVC明显高于CT基因型患儿,FEV1/FVC%显著高于CC基因型患儿（P<0.05）;治疗后3种基因型患儿临床GC治疗疗效比较差异有统计学意义,其中TT基因型患儿GC疗效良好比例显著高于CC基因型患儿（P<0.05）,且TT基因型是GC疗效良好的独立影响因素（OR=2.111,P=0.018）。 结论 MTHFR基因多态性与儿童哮喘易感性及GC疗效相关,携带TT/CT基因型儿童支气管哮喘发病风险更高,TT基因型对GC治疗具有更高的敏感性。     

中国山西人群中叶酸代谢基因MTRR 和MTHFR 与复杂先天畸形关联研究

目的 探讨叶酸代谢基因蛋氨酸合成酶还原酶（MTRR）和5,10 甲基四氢叶酸还原酶（MTHFR）基因多态性是否与复杂先天畸形相关,进一步研究其是否与三胚层发育来源的复杂先天畸形相关。方法 选取中国山西省250 例出生缺陷病例（包括先心病、神经管畸形和颅面畸形等复杂先天畸形）为研究对象,选择MTRR 单核苷酸多态性位点 rs1801394 和MTHFR 单核苷酸多态性位点rs1801133,利用SNaPshot 方法进行基因分型,并与420 例正常对照人群进行比较。结果 rs1801394 和 rs1801133 分别与多个先天出生缺陷有关。在隐性模型下,rs1801394 GG 基因型和rs1801133 CC 基因型的个体发生先天缺陷的概率低, 为出生缺陷的保护性因素。rs1801133 隐性纯合作为保护性因素与外胚层和内胚层器官来源复杂先天畸形相关,rs1801394 隐性纯合作为保护性因素与外胚层、中胚层和内胚层器官来源的复杂先天畸形相关。结论 中国山西人群中叶酸代谢基因MTRR 和MTHFR 与复杂先天畸形相关,并与胚层发育相关。     

Evaluation of the MTHFR C677T allele and the MTHFR gene locus in a German spina bifida population

A number of recent studies have demonstrated that the occurrence and recurrence risk of neural tube defects (NTD) is reduced by folic acid supplementation before and during pregnancy. Epidemiological studies have shown low plasma folate and raised plasma homocysteine in women with spina bifida aperta (SB) children suggesting an abnormal folate metabolism. The 5,10-methylenetetrahydrofolate reductase (MTHFR) variant C677T, resulting in a decreased activity of the enzyme, has been associated with the development of NTD. Several studies demonstrated that homozygosity for the C677T mutation occurs at a higher frequency in patients with SB phenotype than in control individuals. The SB risk is strongest if both the mother and her child have the mutation in the homozygous state. In the present study we compared the frequency of the C- and T-alleles in healthy German individuals (n=153) with German SB patients (n=137). Our study groups reveal no significant difference in C/T-allele frequencies and genotype distributions. A family based association study, the transmission disequilibrium test, confirms the absence of an association between T-allele and SB. In 9 of 40 families we were able to exclude linkage to the MTHFR locus (1p36.3) employing different inheritance models. Conclusion Our data show no evidence for an association between the C677T mutation and the occurrence of the SB phenotype. Therefore we cannot support the hypothesis that the MTHFR variant does account for a significant genetic predisposition to the SB phenotype in the studied German patients. Received: 11 June 1997 / Accepted in revised form: 3 November 1997     

Prevention of neural tube defects with folic acid: The Chinese experience

Neural tube defects(NTDs) are a group of congenital malformations of the central nervous system that are caused by the closure failure of the embryonic neural tube by the 28 th day of conception. Anencephaly and spina bifida are the two major subtypes. Fetuses with anencephaly are often stillborn or electively aborted due to prenatal diagnosis, or they die shortly after birth. Most infants with spina bifida are live-born and, with proper surgical treatment, can survive into adulthood. However, these children often have life-long physical disabilities. China has one of the highest prevalence of NTDs in the world. Inadequate dietary folate intake is believed to be the main cause of the cluster. Unlike many other countries that use staple fortification with folic acid as the public health strategy to prevent NTDs, the Chinese government provides all women who have a rural household registration and who plan to become pregnant with folic acid supplements, free of charge, through a nation-wide program started in 2009. Two to three years after the initiation of the program, the folic acid supplementation rate increased to 85% in the areas of the highest NTD prevalence. The mean plasma folate level of women during early and mid-pregnancy doubled the level before the program was introduced. However, most women began taking folic acid supplements when they knew that they were pregnant. This is too late for the protection of the embryonic neural tube. In a postprogram survey of the women who reported folic acid supplementation, less than a quarter of the women began taking supplements prior to pregnancy, indicating that the remaining three quarters of the fetuses remained unprotected during the time of neural tube formation. Therefore, staple food fortification with folic acid should be considered as a priority in the prevention of NTDs.     

叶酸代谢障碍神经管畸形动物模型的基因组拷贝数变异研究

目的 检测甲氨蝶呤(MTX)诱导叶酸代谢障碍神经管畸形(NTDs)小鼠胚胎神经组织的基因组拷贝数变异(CNVs),探讨叶酸代谢障碍与NTDs发生的分子遗传学机制.方法 采用本实验室已建立的MTX诱导的叶酸代谢障碍NTDs C57BL/6J小鼠模型,于孕第7.5天采用MTX干预,收集孕鼠血清及NTDs小鼠胚胎神经组织;用NimbleGen高分辨率微阵列比较基因组杂交(array-CGH)芯片对NTDs小鼠胚胎神经组织进行全基因组CNVs分析,反转录(RT)-PCR验证新发现的CNVs;用液相色谱串联质谱法(LC-MS/MS)与酶学方法检测孕鼠血清中叶酸与其相关代谢产物水平及二氢叶酸还原酶(DHFR)活性.结果 array-CGH分析发现,NTD小鼠胚胎神经组织全基因组存在3个高可信度CNVs,分别位于XqE3、XqA1.1-qA2和XqA1.1染色体,RT-PCR验证了这3个CNVs的存在.与对照组相比,MTX干预后,NTDs孕鼠血清中5-甲基四氢叶酸、5-甲酰四氢叶酸、S-腺苷甲硫氨酸水平及DHFR活性明显降低,差异均有统计学意义(P均＜0.05).结论 MTX诱导的NTDs小鼠胚胎神经组织中存在明显的CNVs,叶酸代谢紊乱可通过CNVs导致小鼠胚胎神经管发育障碍.     

Cultural considerations in the care of children with spina bifida

Spina bifida occurs when the neural tube fails to close during early fetal development, resulting in a range of neural tube defects (NTDs). The cause of spina bifida is not fully understood, but scientists believe that NTDs are the result of genetic and environmental factors acting simultaneously. The Centers for Disease Control reports that spina bifida and other NTDs occur more frequently in some ethnic groups, such as Hispanic people, than in others. The United States is increasingly multicultural and diverse, and it is becoming more difficult to categorize individuals into a single racial/ethnic group. This article uses the term ethnicity as defined by the Institute of Medicine and avoids using race unless part of a particular study.     

Neural tube defects : Prevention by folic acid and other vitamins

Folic acid has been demonstrated in clinical trials to reduce significantly the recurrence (and probably occurrence) of neural tube defects (NTD). In the U.K., there has been no decline in prevalence of NTD since the publication of the findings with folic acid. This article examines a series of questions relating to the action of folic acid, with emphasis on the use of mouse models as a source of experimental information which cannot easily be obtained by direct study of humans. Several mouse genetic NTD models exhibit sensitivity to prevention by folic acid, whereas other mice which develop morphologically similar NTD are resistant. Folic acid normalises neurulation in the sensitive mouse strains, providing evidence for a direct effect on the developing embryo, not on the pregnant female. Mouse studies do not support the proposed action of folic acid in encouraging thein utero demise of affected fetuses (i.e. terathanasia). Polymorphic variants of several folate-related enzymes have been shown to influence risk of NTD in humans and an inherited abnormality of folate metabolism has been demonstrated in one mouse NTD model. However, the biochemical basis of the action of folic acid in preventing NTD remains to be determined in detail. NTD in one folate-resistant mouse strain can be prevented by myoinositol, bothin utero andin vitro, raising the possibility of a therapeutic role also in humans. Gene-gene interactions seem likely to underlie the majority of NTD, suggesting that poly-therapy involving folic acid and other agents, such as myo-inositol, may prove more effective in preventing NTD than folic acid treatment alone.     

Burden of genetic disorders in india

India, like other developing countries, is facing an accelerating demographic switch to non-communicable diseases. In the cities congenital malformations and genetic disorders are important causes of morbidity and mortality. Due to the high birth rate in India a very large number of infants with genetic disorders are bom every year almost half a million with malformations and 21000 with Down syndrome. In a multi-centric study on the causes of referral for genetic counselling the top four disorders were repeated abortions (12.4 %), identifiable syndromes (12.1 %), chromosomal disorders (11.3%) and mental retardation (11%). In a more recent study in a private hospital the top reasons for referral were reproductive genetics (38.9%) -comprising prenatal diagnosis, recurrent abortions, infertility and Torch infections mental retardation +- multiple congenital anomalies (16.1%), Down syndrome (9.1%), thalassemiaJ haemophilia ( 8.8 %), and muscle dystrophyJ spinal muscular atrophy (8.4 %). The disorders for which prenatal has been done over an 18-month-period are given. A recent study carried out in three centers (Mumbai, Delhi and Baroda) on 94,610 newborns by using a uniform proforma showed a malformation frequency of 2.03 %, the commonest malformations are neural tube defects and musculo-skeletal disorders. The frequency of Down syndrome among 94610 births was 0.87 per 1000, or 1 per 1150. Screening of 112,269 newborns for aminoacid disorders showed four disorders to be the commonest-tyrosinemia, maple syrup urine disease and phenylketonuria. Screening of cases of mental retardation for aminoacid disorders revealed four to be the commonest-hyperglycinemia, homocystinuria, alkaptonuria, and maple syrup urine disease. Metabolic studies of cases of mental retardation in AIIMS, Delhi and KEM Hospital, Mumbai, demonstrated that common disorders were those of mucopolysaccharides, lysosomes, Wilson disease, glycogen storage disease and galactosemia. It is estimated that betathalassemia has a frequency at birth of 1: 2700, which means that about 9,000 cases of thalassemia major are born every year. Almost 5200 infants with sickle cell disease are born every year. Disorders, which deserve to be screened in the newborn period, are hypothyroidism and G-6-PD deficiency, while screening for aminoacid and other metabofic disorders could presently be restricted to symptomatic infants. An erratum to this article is available at .     

Maternal Folate and Vitamin B12 Status and Neural Tube Defects in Northern Iran: A Case Control Study

Objective

This study was conducted to determine the serum level of folic acid and vitamin B12 in neural tube defects pregnancies (NTD) and healthy controls in Northern Iran.

Methods

This case-control study was performed on women with neural tube defects pregnancies and controls with unaffected pregnancies in Northern Iran during 2006. Twenty three pregnant women whose pregnancies were diagnosed as NTD by a second-trimester ultrasonographic examination were recruited as cases. The control group (n=23) consisted of women who were selected among socio-economic status (SES) matched women who had a normal targeted ultrasound during the second trimester with documented normal fet al outcome. Fetal NTD was suspected with targeted second-trimester ultrasound during the 16^th week of gestation and confirmed with high maternal serum α-fetoprotein levels. Folate, vitamin B₁₂, homocysteine and alpha fetoprotein were evaluated after target ultrasonography.

Findings

Serum alpha fetoprotein level (mean±SD) in cases and controls was 120.2±64.1 and 50±33.5 iu/ml, respectively (P<0.05). The mean±SD folate in cases and controls was 8.4±4.2 versus 9.3±4.2 ng/ml, respectively. This difference was not significant. Folate deficiency was found in 30.4% of the cases and 13% of the controls (OR=2.9, 95%: 0.54–19.8). Vitamin B12 deficiency was found in 13% of cases and 17.7% of the controls (OR=0.7, 95%: 0.1-4.9).

Conclusion

This study showed that the probability of having a newborn with NTDs in maternal folate deficiency is three times higher than with normal folate in Northern Iran.     

维甲酸致大鼠胚胎神经管畸形的组织形态学观察

目的 利用维甲酸制作先天性神经管畸形的动物模型已获得公认，但对于其导致神经组织错构瘤的发生却未见报道。本实验利用维甲酸口服制作大鼠神经管畸形动物模型，观察其出现神经组织畸胎瘤、脊髓裂开、脊柱裂等畸形形态学特点，探讨其发生机制。方法 利用成熟未孕的Wistar大鼠，在妊娠10dN经胃管注入维甲酸，诱导产生神经管畸形动物模型，分别在妊娠15d、17d、19d时剖宫取出胎鼠，进行实体观察、畸形统计，同时对神经管畸形进行病理形态学研究。对照组仅给予橄榄油，剖宫时间及观察项目同致畸组。结果 维甲酸致畸组共获得胎鼠99只，48．3％(48／99)孕鼠胚胎肉眼观察出现腰骶部显性脊柱裂。在48只显性脊柱裂胎鼠中，分别取不同胎龄(15d、17d、19d)各3只脊髓裂开的畸形胎鼠共9只，做石蜡切片，全部同时见到表现为多个神经管紊乱排列、骶尾部增生肿物，提示神经组织错构瘤的发生。结论 维甲酸可以干扰神经发育，导致脊柱裂、脊髓裂开和神经错构瘤的发生。     

神经管缺损大鼠转化生长因子-β2及其受体的表达

目的建立大鼠脊柱裂动物模型，探讨神经管缺损的产生和转化生长因子-β2（TGF-β2）及其受体（TGFβRI、TGFβRⅡ）的关系。方法维甲酸灌胃建立Wistar大鼠脊柱裂动物模型，用RT-PCR方法检测各组胎鼠脊髓和脑中TGF-β2、TGFβRI及TGFβRⅡ的mRNA表达水平，用免疫组织化学方法检测各组胎鼠脊髓和脑中TGF-β2、TGFβRI以及TGFβRⅡ的蛋白表达水平。结果维甲酸组胎鼠体重明显低于对照组，脊柱裂的发生率为73．1％。脊柱裂胎鼠脊髓组织中TGF-β2的mRNA及蛋白表达水平与对照组相比显著降低，TGFβRI和TGFβRⅡ的mRNA及蛋白水平与对照组相比显著升高。脊柱裂胎鼠脑组织中TGF-β2、TGFβRI和TGFβRII的mRAN及蛋白表达水平与对照组相比无显著差异。结论TGF-β2在神经管的发育中起重要作用，TGF-β2表达的降低与神经管缺损的发生有关。受体TGFβRI及TGFβRⅡ的表达水平可能是反应性的增加，TGF-β2通过它们对神经管的发育起作用。