摘要
研究背景
脑性瘫痪(cerebral palsy, CP,简称脑瘫)是自受孕开始至婴儿期非进行性脑损伤和发育缺陷所导致的一组综合征,主要表现为运动障碍及姿势异常,可伴有或不伴有精神发育迟缓及癫痫,是儿童时期最常见的神经系统疾病之一,严重影响儿童健康及人口素质。随着围产医学的发展、产妇保健水平的提高,早产儿、低出生体重儿的存活率显著增加,与其相对的是,早产儿脑性瘫痪的发病率却呈上升趋势。2006年Kirby等对美国四个州8岁以内儿童脑性瘫痪进行调查统计,患病率为2.9-3.8%o,平均为3.3%o。1997-1998年,我国六省(区)1岁、2岁、3岁、4岁、5岁、6岁年龄组患病率分别为2.26‰、2.24‰、1.94‰、1.58‰、1.80‰、1.77‰,平均患病率为1.92‰。我国现有脑性瘫痪患儿400～500万,致残率为42%-45%,每年新增脑性瘫痪患儿3～4万,已成为新的临床、公共卫生和社会问题。目前各国对脑性瘫痪一般采取三级防治措施。一级防治是找出致病原因,避免脑性瘫痪的出现；二级防治是对脑性瘫痪患儿早期发现、早期干预,尽量减少或减轻后遗症；三级防治是对已经形成脑瘫的患儿坚持康复训练,尽可能地改善功能,最大限度地提高生存质量。脑性瘫痪防治的重点在于完善的一级防治及有效的二级防治手段。脑性瘫痪研究的重点集中在病因分析、致病机制以及修复机制三个方面。但其核心仍是发病机制的探索。
脑性瘫痪的发病机制尚不完全清楚,是自受孕开始至婴儿期非进行性脑损伤和发育缺陷所导致的一组综合征。所有可能导致胎儿脑损伤的危险因素统称为脑瘫的高危因素。研究小儿脑性瘫痪病因及相关围产期高危因素,对降低该病的患病率、早期监测及干预、减少致残率、提高我国人口素质具有重要意义,这也是脑瘫一级防治的核心和根本。目前的资料显示,早产／低出生体重、新生儿窒息/HIE、新生儿高胆红素血症和宫内感染是最主要的围产高危因素。随着医疗技术的进步,尤其是产科及NICU水平的逐年提高,围产高危因素的构成也在不断发生变化。但目前尚缺乏长时间跨度的围产期高危因素变化的研究。本课题第一部分即对近10年来新入院脑瘫患儿的围产高危因素进行调查,试图找到近年来围产高危因素的构成及其变化,为我国脑瘫的一级防治提供临床证据。
由于脑性瘫痪致病机制的不明确,由此造成脑瘫治疗方法的混乱和不确定,为脑瘫的二级防治带来了困难。目前,国内外尚无根治脑瘫的治疗方法。康复运动训练是得到公认的有效治疗和改善脑瘫症状的治疗方法之一,但多数的研究限于临床观察,对于运动训练起效的机理阐述较少。缺氧缺血性脑损伤(Hypoxic-ischemic brain damage,HIBD)是脑性瘫痪的主要致病机制之一,长期是脑瘫研究的热点。为了进一步深入探讨运动训练治疗脑瘫的机理,本课题第二部分选用新生大鼠HIBD模型,观察早期运动训练对新生大鼠缺氧缺血性脑损伤远期神经功能、病理改变、空间学习记忆能力、感觉运动功能、超微结构的影响。试图探讨早期运动训练对HIBD新生大鼠作用的机理,为早期运动训练治疗脑瘫提供实验依据。
无论是一级还是二级防治,其根本仍在于明确脑瘫确切的致病机制。近年来关于脑瘫致病机制的许多研究证实,脑瘫具有明显的遗传易感性。在对瑞典1959-1970年脑性瘫痪患儿调查中发现足月儿偏瘫占60%、痉挛型双瘫占45%,早产儿痉挛型双瘫占32%,几乎全部单纯型共济失调都与遗传有关。研究发现肿瘤坏死因子α、甘露糖结合凝集素基因的多态性会增加脑性瘫痪的危险性。位于19号染色体19q132上的ApoE基因,此基因与神经细胞表面LDL和VLDL受体结合进入神经元细胞,对维持、修复神经细胞膜结构,维持神经递质和参与脑损伤后修复起到重要作用。携带ApoE E4基因或等位基因E2,发生脑性瘫痪的风险性较未携带者明显增加。ApoE4与认知相关,可造成海马萎缩及其连接性丧失,进而造成记忆障碍,影响逻辑能力导致智力低下；还可以导致胆碱能递质减少,进而出现精神运动视觉障碍。位于染色体2q37上的尿苷二磷酸葡萄糖醛酸转移酶(UGTIA1)基因突变是导致新生儿高胆红素血症和导致不随意运动型脑性瘫痪的重要因素之一。UGTIA1基因通过启动子与TATA结合调节转录起始DNA序列,而它突变可造成DNA转录起始频率和精确性异常。纯合子UGTIA1基因突变可影响葡萄糖醛酸转移酶的结构使酶活性下降,导致新生儿血清总胆红素显著升高。
临床观察也发现,暴露在相同高危因素下的不同胎儿或新生儿,其临床结局差别甚大。这使我们想到,脑瘫的致病机制中,遗传因素及微观的生物学通路皆有可能起到非常重要的作用。脑瘫是一种严重影响人类健康和生命的复杂疾病。某些生物学通路在其疾病的发生、发展和转移的过程中发挥了关键作用。随着生物学实验技术的飞速发展,以基因芯片数据为代表的海量实验数据的产出,通过一系列算法和模型整合和分析实验数据,鉴定和模拟疾病相关的生物学通路,发现了很多重要的生物学结论,解释了遗传因素及微观的生物学通路在脑瘫致病中的作用。因此本课题第三部分选取了临床上最常见的脑瘫类型——早产儿脑室周围白质软化症(Periventricular leukomalacia, PVL)作为研究对象,通过对患儿和健康儿童血浆中microRNA基因芯片的表达差异进行分析,探讨microRNA在PVL发病中的作用,为进一步了解PVL的微观生物学通路发病机理,为将来PVL的宫内超早期诊断以及PVL的基因治疗探索出一条新的思路。
第一部分摘要
目的：比较十年来脑性瘫痪患儿相关高危因素构成,探索伴随医疗水平提高等社会大环境的变化下,脑性瘫痪高危因素的变化趋势,为脑性瘫痪的预防及治疗提供依据。
方法：回顾性统计分析2003年至2012年间入院首次诊断为脑性瘫痪的病例中患儿的病例数、性别、年龄及高危因素等构成,并对各年份脑瘫患儿高危因素进行对比分析。
结果：纳入共1040例病例,其中男性750例,女性290例,男女比例为2.59：1。患儿年龄<1岁147例,占14.1%；1-3岁440例,占42.3%；3～6岁294例,占28.3%；≥6岁159例,占15.3%；在10年脑瘫病例近40种高危因素中,早产仍是最重要的高危因素,其次是产时窒息、黄疸、胎膜早破及不良妊娠。10年间高危因素中产前、产时、产后因素构成有差异(χ2=72.234,P<0.05),宫内窘迫、产时窒息、产后窒息及不明确时间HIE的构成有差异(χ2=93.722,P<0.05)。
结论：①本研究发现脑性瘫痪就诊患儿中存在明显的男女性别差异,男性多于女性；②患儿首次就诊年龄偏大,说明高危儿早期发育监测及早期干预工作依然存在较多困难,加强教育,提高对脑瘫的认识是关键；③产前因素所占比重有上升趋势,早产仍是最首位的高危因素,其次是产时窒息、黄疸、胎膜早破及不良妊娠。不同时间窒息中产前因素所占比例呈上升趋势,加强孕期保健,提高产科技术仍要作为目前脑性瘫痪防治的重点。
第二部分摘要
目的：探讨早期运动训练对新生大鼠缺氧缺血性脑损伤远期神经功能、病理改变、空间学习记忆能力、感觉运动功能、超微结构的影响。
方法：90只7d龄SD大鼠按随机数字表法分为运动组、对照组和假手术组,每组各30只。运动组和对照组制备成新生儿缺氧缺血性脑损伤模型,且运动组于缺氧缺血性脑损伤后1周开始每天给予抓握、旋转、行走、平衡等训练。4周后进行神经功能评分,尼氏染色计数海马CA1区和皮层额部神经元数量,并检测突触素、c-fos表达水平；水迷宫检测各组大鼠空间学习记忆能力和感觉功能；透射电镜观察突触和神经元超微结构。
结果：运动组大鼠神经功能评分、空间学习记忆能力均优于对照组,差异有统计学意义(均P<0.05)。对照组大鼠左侧海马CA1区及皮层额部尼氏染色阳性神经元数目较运动组和假手术组明显减少,差异有统计学意义(F=45.550,P<0.05；F=82.521,P<0.05)。运动组大鼠海马CA1和皮层额部突触素、c-fos表达水平明显高于对照组,差异有统计学意义(突触素：F=81.747, P<0.05; F=26.865, P<0.05。c-fos:F=680.750, P<0.05; F=296.617, P<0.05)。透射电镜下显示对照组大鼠海马和皮层突触损伤严重,神经毡区突触减少,突触前膨大肿胀、轮廓不清晰,突触小泡溶解、空泡形成,突触后致密区变薄、薄厚不均,而运动组未见明显异常。
结论：早期运动训练可减少缺氧缺血性脑损伤后海马和皮层额部神经元损伤,增强突触可塑性,从而改善缺氧缺血性脑损伤后远期神经功能,其中突触素和c-fos在海马和皮层额部表达增强可能是其改善的机制之一。
第三部分摘要
目的：比较脑室周围白质软化(periventricular leukomalacia, PVL)患儿和健康儿童血清中microRNA基因芯片的差异表达,筛选出显著差异表达谱,为PVL早期发现、早期诊断提供生物学标记物。并为下一步探讨microRNA在PVL疾病中的发病机制,提供一条新的思路。
方法：收集7例PVL患儿和5例健康儿童的全血,2000r/min离心10min分离血清,从血清中提取RNA,使用Exiqon公司的microRNA芯片筛选microRNA表达谱。以microRNA芯片表达结果为基础,采用microcosm, miranda和targetscan三个数据库及GO分析,筛选出与神经、血管、遗传发育靶基因相关的10个microRNA:hsa-miR-133b、hsa-miR-323a-3p、hsa-miR-330-3p、 hsa-miR-654-5p、hsa-miR-498、hsa-miR-574-5p、hsa-miR-638、hsa-miR-149-3p、 hsa-miR-1228-5p、hsa-miR-671-3p,对其进行实时荧光定量PCR验证。
结果：PVL患儿中microRNA表达谱与健康患儿相比较有显著差异,在3100个microRNA中,有100个microRNA存在差异表达,34个microRNA表达上调,66个表达下调。用实时荧光定量PCR技术验证10个筛选出的microRNA,其中hsa-miR-323a-3p、hsa-miR-671-3p、hsa-miR-330-3p、hsa-miR-654-5p、 hsa-miR-498、hsa-miR-149-3p、hsa-miR-1228-5p共7个与microRNA芯片结果具有同样趋势。
结论：部分microRNA在PVL疾病中的表达有显著差异,提示microRNA有可能与PVL的发病相关,为今后PVL的早期诊断、生物学机制探讨和基因治疗提供新的思路。
全文结论
1.脑性瘫痪就诊患儿中存在明显的男女性别差异；患儿就诊年龄偏大；10年间产前因素所占比重有上升趋势,不同时间窒息中产前因素所占比例呈上升趋势。提示,加强孕期保健及胎儿发育监测、提高产科技术依然是目前脑性瘫痪早期防治的重点。
2.早期运动训练可减少缺氧缺血性脑损伤后海马和皮层额部神经元损伤,增强突触可塑性,从而改善缺氧缺血性脑损伤后远期神经功能,其中突触素和c-fos在海马和皮层额部表达增强可能是其改善的机制之一。
3.部分microRNA在PVL疾病中的表达有显著差异,提示microRNA有可能与PVL的发病相关,为今后PVL的早期诊断、生物学机制探讨和基因治疗提供新的思路。
展望
1.扩大PVL病例数(100例)进一步验证microRNA芯片结果准确性,从而作为PVL早期诊断的生物学标记物。
2. microRNA在PVL发病中关于神经、血管、遗传发育等生物学通路中的作用,是我们今后探讨的重点,希望能从微观角度挖掘其致病的分子机理。
3.早期功能训练结合基因工程干预(上调或下调相关的microRNA,改变其生物学特征,为临床治疗服务)是今后治疗脑瘫患儿的一个富有希望的方向。
Research background
Cerebral palsy is a group of syndromes,caused by non-progressive brain injury and developmental defects which occured from the moment of conception to infancy.The main clinical manifestations are movement disorders and posture abnormalities, may be associated or not associated with mental retardation and epilepsy.It is one of the most common neurological diseases of childhood andhas a serious impact on children's health and the quality of the population.With the development of perinatal medicine and the elevation of maternal health level,the survival rate of premature children and low birth weight children got a significant upgrade,relatively,the incidence of preterm children with cerebral palsy showed an upward trend.Kirby conducted population-based surveillance of8-year-old children in2006, in four states of America, found the CP prevalence was3.3per1000, ranging from2.9to3.8per1000.In1997-1998, a surveyof China's six provinces (regions) child1year old,2years old,3years old,4years old,5years old,6-year-old age group prevalence rates were2.26per1000、2.24per1000、1.94per1000、1.58per1000、1.80per1000、1.77per1000, the average prevalence rate1.92per1000。The number of children with cerebral palsy in China is from4to5billion, the morbidity is for42percent to45percent, thus an annual increase of cerebral palsy children is about30million to40million. This has become a new clinical problems, public health problems and social problems. At present we general treat cerebral palsy with three-level prevention and control measures. Primary prevention is to find out the causes, to avoid the occurrence of cerebral palsy; Secondary prevention is early discovery, early intervention, as far as possible to reduce or relieve sequelae; Tertiary prevention is help the children insist to cerebral palsy rehabilitation training, as much as possible to improve function, maximize quality of life. The key of prevention and control of cerebral palsy is to perfect the primary prevention and secondary prevention measures. The researches about cerebral palsy focused on the cause analysis, pathogenic mechanism and repair mechanism. However, the core is still the pathogenesis exploration.
The pathogenesis of cerebral palsy is not entirely clear,since it is a group of syndromes of non-progressive brain injury and developmental defects caused from the moment of conception to infancy. All risk factors that may cause fetal brain damage collectively referred to as risk factors for cerebral palsy. Study of cerebral palsy causes and perinatal risk factors, to reduce the prevalence of the disease, early detection and intervention to reduce morbidity and improve the quality of our population is of great significance, which is the core of cerebral palsy primary prevention and fundamental. The current data show that preterm/low birth weight, neonatal asphyxia/HIE, neonatal hyperbilirubinemia and intrauterine infection is the most important perinatal risk factors. With the advances in medical technology, especially the obstetric and NICU level increase year-on-year, perinatal risk factors constitute also constantly change. However, there is a lack of researches on the change of long time span of perinatal high-risk factors. The first chapter of this subject that survey the newly admitted children with cerebral palsy perinatal risk factors in the past10years, trying to find the formation and change of perinatal risk factors in recent years, provide clinical evidence for cerebral palsy of primary prevention in China.
Due to the pathogenesis of cerebral palsy is not clear, causing confusion and uncertainty to the cerebral palsy treatment, makes it difficult for the secondary prevention and therapy of cerebral palsy. At present, there is no radical treatment of cerebral palsy, including domestic and overseas. Rehabilitation exercise training is recognized one of the effective treatment and improve the symptoms of cerebral palsy, but most of the research is limited to clinical observation, and less elaborated mechanism for sports training onset. Hypoxic-ischemic brain damage (HIBD) is one of the main pathogenic mechanisms of cerebral palsy, and long-term cerebral palsy research hotspot. In order to further investigate the mechanism of exercise training in the treatment of cerebral palsy, the second chapter in this study selected neonatal rat HIBD model to observe long-term neurological function, pathological change, spatial learning and memory, sensory and motor function and ultrastructure after the early exercise training on hypoxic-ischemic brain damage. An attempt was made to explore the mechanism of early exercise training on HIBD in neonatal rats to provide experimental evidence for the early exercise training in the treatment of cerebral palsy.
Either primary or secondary prevention, the fundamental is remain the definite pathogenic mechanism of cerebral palsy. In recent years, many studies on the pathogenesis of cerebral palsy show that cerebral palsy has obvious genetic predisposition. Full-term children with hemiplegia accounted for60%, spastic diplegia (45%), preterm children with spastic diplegia32%[2] found in children with cerebral palsy in Sweden from1959to1970survey, almost all pure Freemasonry disorders related to heredity. Studies found that the gene polymorphisms tumor necrosis factor alpha and mannose-binding lectin will increase the risk of cerebral palsy. ApoE gene, located on chromosome1919q132, incorporated into neuronal cell throught binding the surface receptor LDL and VLDL of nerve cells, play an important role in maintaining and repairing nerve cell membrane structure, as well as maintaining neurotransmitter involved in brain damage and repair. Carry the ApoE E4genes or alleles E2significantly increased the risk of cerebral palsy compared with noncarriers. ApoE4is associated with cognitive, can cause hippocampal atrophy and its loss of connectivity, which causes memory impairment, affect the logical ability leads to mental retardation; also can cause a decrease in cholinergic neurotransmitters, thus lead to psychomotor visually impaired. Located on chromosome2q37uridine diphosphate glucuronyl transferase (UGT1A1) gene mutations is one important factor of resulting in neonatal hyperbilirubinemia and leading to dyskinetic cerebral palsy. UGT1A1gene via promoter binding TATA to regulate transcription initiation DNA sequences, which mutations can cause abnormal frequency and accuracy of DNA transcription initiation. The homozygous UGT1A1gene mutations can affect the structure of the glucuronyl transferase enzyme and decrease the activity, resulting significantly higher in neonatal serum total bilirubin.
Clinical observation also found that different fetal or neonatal exposure to the same risk factors got great different clinical outcome. This give us some suggestions-genetic factors would play an important role in pathogenic mechanism of cerebral palsy. In order to understand the role of genetic factors in pathogenic mechanism of cerebral palsy, we selected the most common clinically type of cerebral palsy-premature with periventricular leukomalacia (PVL) as the study object in the third chapter of this subject. By way of comparative analysis microRNA expressions in plasma of children patients and healthy children, to explore the role of microRNAs in the pathogenesis of PVL, get further understand of the pathogenesis of PVL, then explore a new way for the early diagnosis of intrauterine PVL and gene therapy of PVL.
Abstract of part one
Objective To compare the related risk factors of cerebral palsy children in ten years, explore the trend of cerebral palsy risk factors with the change of social environment such as medical level and provide the basis for the prevention and treatment of cerebral palsy.
Methods The hospitalized cases of cerebral palsy diagnosed for the first time in ZhuJiang Hospital of Southern Medical University from2003to2012were analyzed retrospectively, with the constituent of the number, gender, age and risk factors in each year.
Results There are1040cases in this study. There were750males and290females giving a male female ratio of2.59:1. Children<1year old in147cases, accounting for14.1%;1year old-3years old in440cases, accounting for42.3%;3year old-6years old in294cases, accounting for28.3%,>6years old in159cases, accounting for15.3%. In nearly40kinds of risk factors of cerebral palsy of10years, preterm birth remains the most important risk factors, followed by the intrapartum asphyxia, jaundice, adverse pregnancy, and premature rupture of membranes. The constituent of antenatal, intrapartum and postpartum factors were different (χ2=72.234, P<0.05). The constituent of intrauterine distress, intrapartum asphyxia, postpartum asphyxia and not clear time HIE were difference (χ2=93.722, P<0.05).
Conclusions (1) This study found that there is significant gender difference in cerebral palsy children, male more than female;(2) Age of first diagnosed with cerebral palsy is large, which shows that early development monitoring and early intervention for high-risk children is remain difficult, and it is important to strengthen education and to raise awareness of cerebral palsy;(3) Prenatal factors have a rising trend, preterm birth remains the most important risk factors, followed by the intrapartum asphyxia, jaundice, adverse pregnancy, and premature rupture of membranes. The proportion of prenatal factors in the different time asphyxia is on the rise, to strengthen pregnancy care and to improve obstetric techniques are still as is currently the focus of prevention and cure of cerebral palsy.
Abstract of part two
Objective To investigate the effect of early physical training on long-lasting neurological,pathology,spatial learning ability,sensorimotor functionand ultrastructure in neonatal rats submitted to hypoxic-ischemic brain damage(HIBD).
Methods ninety7-day-old Sprague-Dawley rats were randomly divided into three groups:a group that was subjected to left carotid ligation followed by2hours hypoxic stress(the control group);a group that received physical training(Grab,Rotation,Walk,balance)1weeks after the HIBD event(the trained group);a sham-operation group that was subjected to a sham-operation without ligation and hypoxic stress(the sham-operation group.Following four weeks physical training, neurological score, the expression levels of synaptophysin and c-fos were examined; Morris water maze tests and cortex sensorimotor tests were performed; Left hippocampal CA1and cortex neurons and ultrastructure were performed.
Results Compared with the control group, the Neurological score、Spatial learning and memory ability and sensorimotor tests of the trained group were significantly increased, whereas there was no significant difference between the trained group and the sham-operation group. The neurons in the left hippocampal CA1zone and cortex were decreased of the control group.The significant difference compared with trained group was obvious(F=45.550, P<0.05; F=82.521, P<0.05). The expression of synaptophysin and c-fos in the trained group increased significantly compared with that in the control group(synaptophysin:F=81.747, P<0.05; F=26.865, P<0.05. c-fos:F=680.750, P<0.05; F=296.617,P<0.05).The ultrastructure of the left hippocampus and cortex was remarkably abnormal in the control group by the transmission electron microscopy, while no obvious abnormality was observed in the trained group and the sham-operation group.
Conclusions Early physical training can restrain brain damage and ameliorate spatial learning and memory impairments in rats with HIBD. Early exercise rehabilitation can reduce hippocampal and cortical neuronal damage, enhanced synaptic plasticity,and ameliorate the long-term neurological function after HIBD.The strong expression of synaptophysin and c-fos in the hippocampus and cortex caused by early physical training may be one of the improvement mechanisms.
Abstract of part three
ObjectiveTo study the differential microRNAs experssion between patients with periventricular leukomalacia(PVL) and healthy controls, filter out thesignificant differences inexpression profilesforthePVLearlydetection, early diagnosisbiological markers. And further moretoinvestigatemicroRNAsinthe pathogenesis ofPVLdisease, provideanew way of thinking.
Methods Whole blood from7PVL patients and5controls healthies were separated into plasma at2000rpm for10minutes. RNA were harvested using kit.MicroRNAs profiling were performed using Exiqon microRCURY LNA microRNAs array.In addition, Using microcosm,miranda,targetscanand GO analysis, to screen10microRNAs,including hsa-miR-133b, hsa-miR-323a-3p, hsa-miR-330-3p, hsa-miR-654-5p, hsa-miR-498, hsa-miR-574-5p, hsa-miR-638, hsa-miR-149-3p, hsa-miR-1228-5p, hsa-miR-671-3p, associated with the nerves, blood vessels, genetic development of target genes.Then validating them through Real-time quantitative PCR.
ResultsMicroRNAs expression profile was found to be differentially in the PVL patients compared with the healthy donors. Of3100microRNAs detected on the microarray,100microRNAs were found to be differentially expressed in the PVL patients,34pieces of microRNA were up-regulated more than twice in the PVL patients,66pieces were down-redulated more than twice. Real-time PCR detected10microRNAs:hsa-miR-323a-3p, hsa-miR-671-3p, hsa-miR-330-3p, hsa-miR-654-5p, hsa-miR-498, hsa-miR-149-3p, hsa-miR-1228-5p,7of them have the same trend with microRNA microarray results.
ConclusionsThere are significant differences of microRNAs between PVL patients and healthy donors, it maybe play an important role in pathogenesis of PVL. We hope to provide new ideasforthefutureof PVLearly diagnosis, biological mechanismsandgene therapy.
Full text Conclusions
1. Obviously, the gender of the children with cerebral palsy is different. The proportion of older children is large. Prenatal factors have a rising trend, and the proportion of prenatal factors in the different time asphyxia is on the rise. These findings suggest that strengthen prenatal care and fetal growth monitoring, improve obstetric technology are still the focus of early prevention and treatment of cerebral palsy.
2. Early physical training can restrain brain damage and ameliorate spatial learning and memory impairments in rats with HIBD. Early exercise rehabilitation can reduce hippocampal and cortical neuronal damage, enhanced synaptic plasticity,and ameliorate the long-term neurological function after HIBD.The strong expression of synaptophysin and c-fos in the hippocampus and cortex caused by early physical training may be one of the improvement mechanisms.
3. There are significant differences of microRNAs between PVL patients and healthy donors, it maybe play an important role in pathogenesis and early diagnosis of PVL.
Prospect
1. Expanding the number of PVL cases (n=100) to further verify the accuracy of the microRNA microarray results, thus as biomarkers of PVL early diagnostic.
2. Our direction is to specific the role of microRNA in the incidence of PVL about nerves,blood vessels, and genetic pathways,and to further discuss from the microscopic view.
3. Early functional training combined with genetic engineering intervention (Upgrade or downgrade the mirna to change its biological characteristics, so that can service for clinical treatment)provide a promising future treatment of children with cerebral palsy.
引文
[1]陈秀洁,李树春.小儿脑性瘫痪的定义、分型和诊断条件[J].中华物理医学与康复杂志,2007(5)：309.
[2]汪志国,邱洪斌,鲁向锋,等.小儿脑性瘫痪病因学的研究进展[J].疾病控制杂志,2004(01)：52-55.
[3]Sundrum R, Logan S, Wallace A, et al. Cerebral palsy and socioeconomic status: a retrospective cohort study[J]. Arch Dis Child,2005,90(1):15-18.
[4]Imms C, Reilly S, Carlin J, et al. Diversity of participation in children with cerebral palsy[J]. Dev Med Child Neurol,2008,50(5):363-369.
[5]林庆,李松,刘建蒙,等.我国六省(区)小儿脑性瘫痪患病率及临床类型的调查分析[J].中华儿科杂志,2001(10)：40-42.
[6]脑性瘫痪的社区--家庭康复模式[C].中国湖南长沙：2010.
[7]林庆.全国小儿脑性瘫痪座谈会纪实[Z].1989162-163.
[8]中华医学会儿科学分会神经学组.2004年全国小儿脑性瘫痪专题研讨会纪 要[J].中华儿科杂志,2005(04)：261-262.
[9]Hintz S R, Kendrick D E, Vohr B R, et al. Gender differences in neurodevelopmental outcomes among extremely preterm, extremely-low-birthweight infants[J]. Acta Paediatr,2006,95(10):1239-1248.
[10]Johnston M V, Hagberg H. Sex and the pathogenesis of cerebral palsy[J]. Dev Med Child Neurol,2007,49(1):74-78.
[11]Chounti A, Hagglund G, Wagner P, et al. Sex differences in cerebral palsy incidence and functional ability-a total population study [J]. Acta Paediatr, 2013.
[12]肖丽萍,史惟,康淑蓉,等.上海市闵行区脑瘫登记管理的初步结果[J].中国康复理论与实践,2010(07)：613-616.
[1]中华医学会儿科学分会新生儿学组..新生儿缺氧缺血性脑病诊断标准[J].中国当代儿科杂志,2005,7(2).
[2]Vaynman S, Gomez-Pinilla F. License to run:exercise impacts functional plasticity in the intact and injured central nervous system by using neurotrophins[J]. Neurorehabil Neural Repair,2005,19(4):283-295.
[3]陈小璐,蒋莉.运动康复对缺氧缺血性脑损伤新生大鼠空间学习记忆的影响[J].中国当代儿科杂志,2010(5)：363-367.
[4]方素珍,石坚,李宏,等.感觉统合训练在缺氧缺血性脑病患儿早期干预中的疗效观察[J].中华神经医学杂志,2006,5(8)：845-847.
[5]Levine S. Anoxic-ischemic encephalopathy in rats[J]. Am J Pathol,1960,36: 1-17.
[6]Towfighi J, Mauger D, Vannucci R C, et al. Influence of age on the cerebral lesions in an immature rat model of cerebral hypoxia-ischemia:a light microscopic study[J]. Brain Res Dev Brain Res,1997,100(2):149-160.
[7]Rice J R, Vannucci R C, Brierley J B. The influence of immaturity on hypoxic-ischemic brain damage in the rat[J]. Ann Neurol,1981,9(2):131-141.
[8]巨容,杜江,刘卫鹏,等.阻断子宫血流复制围生期缺氧缺血性脑损伤动物模型[J].广东医学,2006,27(7)：953-955.
[9]Bona E, Johansson B B, Hagberg H. Sensorimotor function and neuropathology five to six weeks after hypoxia-ischemia in seven-day-old rats[J]. Pediatr Res, 1997,42(5):678-683.
[10]钟乐,王霞,余小河,等.新生大鼠缺氧缺血性脑损伤后的远期行为学测试[J].中国当代儿科杂志,2005,7(3)：245-248.
[11]Moskvin A N, Luchakov Y I. Oxygen Tension in Rat Brain during Hypoxia[J]. Bull Exp Biol Med,2013,154(4):435-437.
[12]Gancia P, Pomero G. Therapeutic hypothermia in the prevention of hypoxic-ischaemic encephalopathy:new categories to be enrolled[J]. J Matern Fetal Neonatal Med,2012,25 Suppl 4:94-96.
[13]Nelson M N, White-Traut R C, Vasan U, et al. One-year outcome of auditory-tactile-visual-vestibular intervention in the neonatal intensive care unit: effects of severe prematurity and central nervous system injury[J]. J Child Neurol,2001,16(7):493-498.
[14]刘传军,郭延奎,李亚鲁.早期干预对缺氧缺血脑损伤新生鼠大脑皮质突触重塑的影响[J].中国妇幼保健,2011,26(11)：1702-1705.
[15]徐莉,李玲.康复训练对大鼠脑梗死神经功能恢复的影响[J].中华物理医学与康复杂志,2000,22(2)：86-88.
[16]Sato Y, Nakanishi K, Tokita Y, et al. A highly sulfated chondroitin sulfate preparation, CS-E, prevents excitatory amino acid-induced neuronal cell death[J]. J Neurochem,2008,104(6):1565-1576.
[17]Kakizawa H, Matsui F, Tokita Y, et al. Neuroprotective effect of nipradilol, an NO donor, on hypoxic-ischemic brain injury of neonatal rats[J]. Early Hum Dev,2007,83(8):535-540.
[18]Kumral A, Uysal N, Tugyan K, et al. Erythropoietin improves long-term spatial memory deficits and brain injury following neonatal hypoxia-ischemia in rats[J]. Behav Brain Res,2004,153(1):77-86.
[19]Kumral A, Tuzun F, Oner M G, et al. Erythropoietin in neonatal brain protection: the past, the present and the future[J]. Brain Dev,2011,33(8):632-643.
[20]杨毅飞,徐波,季浏,等. c-fos基因在运动训练增强学习记忆能力中的作用及其机制[J].体育科学,2005(10)：75-78.
[21]Lee T H, Jang M H, Shin M C, et al. Dependence of rat hippocampal c-Fos expression on intensity and duration of exercise[J]. Life Sci,2003,72(12): 1421-1436.
[22]Tsai Y W, Yang Y R, Wang P S, et al. Intermittent hypoxia after transient focal ischemia induces hippocampal neurogenesis and c-Fos expression and reverses spatial memory deficits in rats[J]. PLoS One,2011,6(8):e24001.
[23]蒲昭霞,赵聪敏,李亚伶,等.脑发育不同阶段丰富环境刺激对大鼠海马突触素表达的影响[J].中国儿童保健杂志,2007(6).
[24]Leypoldt F, Flajolet M, Methner A. Neuronal differentiation of cultured human NTERA-2cl.Dl cells leads to increased expression of synapsins[J]. Neurosci Lett,2002,324(1):37-40.
[25]Abe T, Kunz A, Shimamura M, et al. The neuroprotective effect of prostaglandin E2 EP1 receptor inhibition has a wide therapeutic window, is sustained in time and is not sexually dimorphic[J]. J Cereb Blood Flow Metab,2009,29(1): 66-72.
[26]张媛媛,李斐,金星明,等.生命早期前爪感觉和精细动作剥夺对大鼠海马Schaffer-CA1通路突触可塑性的影响[J].中国儿童保健杂志,2010(1).
[1]Yehezkely-Schildkraut V, Kutai M, Hugeirat Y, et al. Thrombophilia:a risk factor for cerebral palsy?[J]. Isr Med Assoc J,2005,7(12):808-811.
[2]Gibson C S, Maclennan A H, Hague W M, et al. Associations between inherited thrombophilias, gestational age, and cerebral palsy [J]. Am J Obstet Gynecol, 2005,193(4):1437.
[3]Stark A, Brennecke J, Bushati N, et al. Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3'UTR evolution[J]. Cell,2005, 123(6):1133-1146.
[4]Alvarez-Garcia I, Miska E A. MicroRNA functions in animal development and human disease[J]. Development,2005,132(21):4653-4662.
[5]Zhao Y, Samal E, Srivastava D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis[J]. Nature, 2005,436(7048):214-220.
[6]Chin L J, Slack F J. A truth serum for cancer--microRNAs have major potential as cancer biomarkers[J]. Cell Res,2008,18(10):983-984.
[7]Mitchell P S, Parkin R K, Kroh E M, et al. Circulating microRNAs as stable blood-based markers for cancer detection[J]. Proc Natl Acad Sci U S A,2008, 105(30):10513-10518.
[8]Wang K, Zhang S, Marzolf B, et al. Circulating microRNAs, potential biomarkers for drug-induced liver injury[J]. Proc Natl Acad Sci U S A,2009, 106(11):4402-4407.
[9]Lewis B P, Burge C B, Bartel D P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets[J]. Cell,2005,120(1):15-20.
[10]Tang G, Reinhart B J, Bartel D P, et al. A biochemical framework for RNA silencing in plants[J]. Genes Dev,2003,17(1):49-63.
[11]Zeng Y, Wagner E J, Cullen B R. Both natural and designed micro RNAs can inhibit the expression of cognate mRNAs when expressed in human cells[J]. Mol Cell,2002,9(6):1327-1333.
[12]Bartel D P. MicroRNAs:genomics, biogenesis, mechanism, and function[J]. Cell, 2004,116(2):281-297.
[13]Chen C Z, Li L, Lodish H F, et al. MicroRNAs modulate hematopoietic lineage differentiation[J]. Science,2004,303(5654):83-86.
[14]Lee Y, Ahn C, Han J, et al. The nuclear RNase Ⅲ Drosha initiates microRNA processing[J]. Nature,2003,425(6956):415-419.
[15]Denli A M, Tops B B, Plasterk R H, et al. Processing of primary microRNAs by the Microprocessor complex[J]. Nature,2004,432(7014):231-235.
[16]Schroda M. RNA silencing in Chlamydomonas:mechanisms and tools[J]. Curr Genet,2006,49(2):69-84.
[17]Lee Y, Hur I, Park S Y, et al. The role of PACT in the RNA silencing pathway[J]. EMBO J,2006,25(3):522-532.
[18]Chendrimada T P, Finn K J, Ji X, et al. MicroRNA silencing through RISC recruitment of eIF6[J]. Nature,2007,447(7146):823-828.
[19]Macrae I J, Ma E, Zhou M, et al. In vitro reconstitution of the human RISC-loading complex[J]. Proc Natl Acad Sci U S A,2008,105(2):512-517.
[20]Han J, Lee Y, Yeom K H, et al. Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex[J]. Cell,2006,125(5):887-901.
[21]Murphy D, Dancis B, Brown J R. The evolution of core proteins involved in microRNA biogenesis[J]. BMC Evol Biol,2008,8:92.
[22]Palatnik J F, Allen E, Wu X, et al. Control of leaf morphogenesis by microRNAs[J]. Nature,2003,425(6955):257-263.
[23]Zhang W, Duan S, Kistner E O, et al. Evaluation of genetic variation contributing to differences in gene expression between populations [J]. Am J Hum Genet,2008,82(3):631-640.
[24]Chen J F, Mandel E M, Thomson J M, et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation[J]. Nat Genet, 2006,38(2):228-233.
[25]Zhao Y, Samal E, Srivastava D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis[J]. Nature, 2005,436(7048):214-220.
[26]Iorio M V, Ferracin M, Liu C G, et al. MicroRNA gene expression deregulation in human breast cancer[J]. Cancer Res,2005,65(16):7065-7070.
[27]Xu P, Vernooy S Y, Guo M, et al. The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism[J]. Curr Biol,2003,13(9): 790-795.
[28]Back S A. Perinatal white matter injury:the changing spectrum of pathology and emerging insights into pathogenetic mechanisms[J]. Ment Retard Dev Disabil Res Rev,2006,12(2):129-140.
[29]Zou J, Li W Q, Li Q, et al. Two functional microRNA-126s repress a novel target gene p21-activated kinase 1 to regulate vascular integrity in zebrafish[J]. Circ Res,2011,108(2):201-209.
[30]刘大全,李东华,刘洪斌.MiR-141增强人血管内皮细胞增殖及迁移能力[J].基础医学与临床,2010(08).
[31]翁春华.血管生成素特异]microRNAs的鉴定与功能分析[D].浙江大学,2010.
[32]Warrington A E, Barbarese E, Pfeiffer S E. Differential myelinogenic capacity of specific developmental stages of the oligodendrocyte lineage upon transplantation into hypomyelinating hosts[J]. J Neurosci Res,1993,34(1):1-13.
[33]Back S A, Han B H, Luo N L, et al. Selective vulnerability of late oligodendrocyte progenitors to hypoxia-ischemia[J]. J Neurosci,2002,22(2): 455-463.
[34]Houbaviy H B, Murray M F, Sharp P A. Embryonic stem cell-specific MicroRNAs[J]. Dev Cell,2003,5(2):351-358.
[35]Conaco C, Otto S, Han J J, et al. Reciprocal actions of REST and a microRNA promote neuronal identity[J]. Proc Natl Acad Sci U S A,2006,103(7): 2422-2427.
[36]Emery B. Transcriptional and post-transcriptional control of CNS myelination[J]. Curr Opin Neurobiol,2010,20(5):601-607.
[37]Dugas J C, Cuellar T L, Scholze A, et al. Dicerl and miR-219 Are required for normal oligodendrocyte differentiation and myelination[J]. Neuron,2010,65(5): 597-611.
[38]Zhao X, He X, Han X, et al. MicroRNA-mediated control of oligodendrocyte differentiation[J]. Neuron,2010,65(5):612-626.
[39]Budde H, Schmitt S, Fitzner D, et al. Control of oligodendroglial cell number by the miR-17-92 cluster[J]. Development,2010,137(13):2127-2132.
[40]贺雪莲,于洋,周永杰,等.少突胶质细胞相关microRNA差异性调控大脑和小脑神经前体细胞的增殖[J].第三军医大学学报,2011(16).
[41]Liu D Z, Tian Y, Ander B P, et al. Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures[J]. J Cereb Blood Flow Metab,2010,30(1):92-101.
[1]陈秀洁,李树春.小儿脑性瘫痪的定义、分型和诊断条件[J].中华物理医学与康复杂志,2007(5)：309.
[2]Rosenbaum P, Paneth N, Leviton A, et al. A report:the definition and classification of cerebral palsy April 2006[J]. Dev Med Child Neurol Suppl, 2007,109:8-14.
[3]Vincer M J, Allen A C, Joseph K S, et al. Increasing prevalence of cerebral palsy among very preterm infants:a population-based study[J]. Pediatrics,2006, 118(6):e1621-e1626.
[4]Kirby R S, Wingate M S, Van Naarden B K, et al. Prevalence and functioning of children with cerebral palsy in four areas of the United States in 2006:a report from the Autism and Developmental Disabilities Monitoring Network [J]. Res Dev Disabil,2011,32(2):462-469.
[5]林庆,李松,刘建蒙,等.我国六省(区)小儿脑性瘫痪患病率及临床类型的调查分析[J].中华儿科杂志,2001(10)：40-42.
[6]张传东,张新民.小儿脑瘫的病因研究进展[J].中国民康医学,2008(12)：1356-1357.
[7]唐久来,李海华,史惟,等.小儿脑性瘫痪诊疗指南探讨[J].实用儿科临床杂志,2009(24)：1914-1917.
[8]杨李,唐久来,吴德.小儿脑瘫的遗传学研究进展[J].中国优生与遗传杂志,2008(6)：4-6.
[9]Hemminki K, Sundquist K, Li X. Familial risks for main neurological diseases in siblings based on hospitalizations in Sweden [J]. Twin Res Hum Genet,2006, 9(4):580-586.
[10]Lerer I, Sagi M, Meiner V, et al. Deletion of the ANKRD15 gene at 9p24.3 causes parent-of-ori gin-dependent inheritance of familial cerebral palsy [J]. Hum Mol Genet,2005,14(24):3911-3920.
[11]Mchale D P, Jackson A P, Campbell, et al. A gene for ataxic cerebral palsy maps to chromosome 9p12-q12[J]. Eur J Hum Genet,2000,8(4):267-272.
[12]Moreno-De-Luca A, Ledbetter D H, Martin C L. Genetic [corrected] insights into the causes and classification of [corrected] cerebral palsiespJ]. Lancet Neurol,2012,11(3):283-292.
[13]杨李,吴德,唐久来.小儿脑瘫病因学的研究进展[J].中国实用儿科杂志, 2008(9)：710-712.
[14]石岩,漆洪波.宫内感染与脑瘫[J].实用妇产科杂志,2009(8)：458-459.
[15]Sameshima H, Ikenoue T. Developmental effects on neonatal mortality and subsequent cerebral palsy in infants exposed to intrauterine infection[J]. Early Hum Dev,2007,83(8):517-519.
[16]Bersani I, Thomas W, Speer C P. Chorioamnionitis-the good or the evil for neonatal outcome?[J]. J Matern Fetal Neonatal Med,2012,25 Suppl 1:12-16.
[17]Wu Y W. Systematic review of chorioamnionitis and cerebral palsy [J]. Ment Retard Dev Disabil Res Rev,2002,8(1):25-29.
[18]Shatrov J G, Birch S C, Lam L T, et al. Chorioamnionitis and cerebral palsy:a meta-analysis[J]. Obstet Gynecol,2010,116(2 Pt 1):387-392.
[19]Mcmichael G, Maclennan A, Gibson C, et al. Cytomegalovirus and Epstein-Barr virus may be associated with some cases of cerebral palsy [J]. J Matern Fetal Neonatal Med,2012,25(10):2078-2081.
[20]Pharoah P O. Risk of cerebral palsy in multiple pregnancies[J]. Clin Perinatol, 2006,33(2):301-313.
[21]Petterson B, Nelson K B, Watson L, et al. Twins, triplets, and cerebral palsy in births in Western Australia in the 1980s[J]. BMJ,1993,307(6914):1239-1243.
[22]Hack K E, Koopman-Esseboom C, Derks J B, et al. Long-term neurodevelopmental outcome of monochorionic and matched dichorionic twins[J]. PLoS One,2009,4(8):e6815.
[23]王红,周丛乐,姜毅,等.妊娠高血压综合征对新生儿脑损伤和远期神经发育影响的研究[Z].中国浙江宁波：200548-50.
[24]Mann J R, Mcdermott S, Griffith M I, et al. Uncovering the complex relationship between pre-eclampsia, preterm birth and cerebral palsy [J]. Paediatr Perinat Epidemiol,2011,25(2):100-110.
[25]张硕,宋薇薇.早产与脑瘫[J].中国实用妇科与产科杂志,2012(11)：815-818.
[26]Gibbs R S. The relationship between infections and adverse pregnancy outcomes: an overview[J]. Ann Periodontol,2001,6(1):153-163.
[27]汪志国,邱洪斌,鲁向锋,等.125例脑瘫患儿病因调查分析[J].黑龙江医药科学,2004(2)：24-25.
[28]吴小颖,庄德义,廖亚琼.极低和超低出生体重儿严重脑损伤的高危因素及预后分析[J].吉林医学,2013(1).
[29]范琦慧.不同分娩方式对胎婴儿的健康影响[Z].中国浙江嘉兴：200938-41.
[30]Moster D, Wilcox A J, Vollset S E, et al. Cerebral palsy among term and postterm births[J]. JAMA,2010,304(9):976-982.
[31]苑运阁.分娩方式与产程对新生儿窒息的影响[J].中国妇幼健康研究,2007(2).
[32]陈自励,刘敬,封志纯.新生儿窒息诊断和分度标准建议[J].中国当代儿科杂志,2013(1)：1.
[33]叶鸿瑁.继续深入开展我国的新生儿窒息复苏工作,降低新生儿窒息的病死率和伤残率[J].中华围产医学杂志,2011,14(3)：129-131.
[34]Pschirrer E R, Yeomans E R. Does asphyxia cause cerebral palsy?[J]. Semin Perinatal,2000,24(3):215-220.
[35]Perlman J M. Intrapartum hypoxic-ischemic cerebral injury and subsequent cerebral palsy:medicolegal issues[J]. Pediatrics,1997,99(6):851-859.
[36]Blair E, Stanley F J. Intrapartum asphyxia:a rare cause of cerebral palsy[J]. J Pediatr,1988,112(4):515-519.
[37]余海燕,刘兴会.胎儿窘迫诊断标准的国外指南解读[J].现代妇产科进展,2011(10)：764-767.
[38]中华医学会儿科学分会新生儿学组.新生儿缺氧缺血性脑病诊断标准[J].中华儿科杂志,2005(8)：584.
[39]Malin G L, Morris R K, Khan K S. Strength of association between umbilical cord pH and perinatal and long term outcomes:systematic review and meta-analysis[J]. BMJ,2010,340:c1471.
[40]Fukuda S, Mizuno K, Kawai S, et al. Reduction in cerebral blood flow volume in infants complicated with hypoxic ischemic encephalopathy resulting in cerebral palsy[J]. Brain Dev,2008,30(4):246-253.
[41]Martinez-Biarge M, Diez-Sebastian J, Wusthoff C J, et al. Feeding and communication impairments in infants with central grey matter lesions following perinatal hypoxic-ischaemic injury[J]. Eur J Paediatr Neurol,2012,16(6): 688-696.
[42]Perez A, Ritter S, Brotschi B, et al. Long-Term Neurodevelopmental Outcome with Hypoxic-Ischemic Encephalopathy [J]. J Pediatr,2013.
[43]侯梅,王松青.不随意运动型脑性瘫痪的临床研究进展[J].中华儿科杂志,2005(04)：269-271.
[44]侯梅,王海桥,孙殿荣,等.胆红素脑病引起的脑性瘫痪及其促发因素分析[J].中国实用儿科杂志,2009(11)：855-858.
[45]Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation[J]. Pediatrics,2004,114(1):297-316.
[46]王瑾.新生儿高胆红素血症的病因调查及相关基因研究[D].复旦大学,2011.
[47]李小燕,唐久来,梁兵,等.易感基因-尿苷二磷酸葡萄糖醛酸基转移酶TATA盒突变与高胆红素血症及不随意运动型脑性瘫痪的相关性[J].实用儿科临床杂志,2010(02)：137-139.
[48]吴升华.尿苷二磷酸葡萄糖醛酸基转移酶与黄疸[J].国外医学.遗传学分册,2002(01)：48-51.
[49]张红军.胆红素葡萄糖醛酸基转移酶基因的研究进展[J].国外医学(临床生 物化学与检验学分册),1998(02)：52-55.
[50]Drougia A, Giapros V, Krallis N, et al. Incidence and risk factors for cerebral palsy in infants with perinatal problems:a 15-year review[J]. Early Hum Dev, 2007,83(8):541-547.
[51]Mcintyre S, Taitz D, Keogh J, et al. A systematic review of risk factors for cerebral palsy in children born at term in developed countries[J]. Dev Med Child Neurol,2012.
[52]Adams-Chapman I, Stoll B J. Neonatal infection and long-term neurodevelopmental outcome in the preterm infant[J]. Curr Opin Infect Dis, 2006,19(3):290-297.
[53]郭春燕.新生儿败血症病原菌构成及耐药状况的变迁[J].中国新生儿科杂志,2006(02)：94-96.
[54]Wu J H, Chen C Y, Tsao P N, et al. Neonatal sepsis:a 6-year analysis in a neonatal care unit in Taiwan[J]. Pediatr Neonatol,2009,50(3):88-95.
[55]Schlapbach L J, Aebischer M, Adams M, et al. Impact of sepsis on neurodevelopmental outcome in a Swiss National Cohort of extremely premature infants[J]. Pediatrics,2011,128(2):e348-e357.
[56]Soraisham A S, Amin H J, Al-Hindi M Y, et al. Does necrotising enterocolitis impact the neurodevelopmental and growth outcomes in preterm infants with birthweight< or=1250 g?[J]. J Paediatr Child Health,2006,42(9):499-504.
[57]Stoll B J, Hansen N I, Adams-Chapman I, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection [J]. JAMA,2004,292(19):2357-2365.
[58]吴仕孝.新生儿颅内感染[J].实用儿科临床杂志,2005(02)：97-99.
[59]Fuller D G, Duke T, Shann F, et al. Antibiotic treatment for bacterial meningitis in children in developing countries[J]. Ann Trop Paediatr,2003,23(4):233-253.
[1]唐强,李雪静.综合康复疗法治疗小儿脑瘫的现状研究[J].中国康复,2009(4)：269-271.
[2]Daadi M M, Davis A S, Arac A, et al. Human neural stem cell grafts modify microglial response and enhance axonal sprouting in neonatal hypoxic-ischemic brain injury[J]. Stroke,2010,41(3):516-523.
[3]Tongiorgi E. Activity-dependent expression of brain-derived neurotrophic factor in dendrites:facts and open questions[J]. Neurosci Res,2008,61(4):335-346.
[4]Li Y, Chopp M. Marrow stromal cell transplantation in stroke and traumatic brain injury[J]. Neurosci Lett,2009,456(3):120-123.
[5]Cambier S, Gline S, Mu D, et al. Integrin alpha(v)beta8-mediated activation of transforming growth factor-beta by perivascular astrocytes:an angiogenic control switch[J]. Am J Pathol,2005,166(6):1883-1894.
[6]Chen J, Zhang Z G, Li Y, et al. Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats[J]. Circ Res,2003,92(6):692-699.
[7]Lee H J, Kim K S, Park I H, et al. Human neural stem cells over-expressing VEGF provide neuroprotection, angiogenesis and functional recovery in mouse stroke model[J]. PLoS One,2007,2(1):e156.
[8]Xu N, Papagiannakopoulos T, Pan G, et al. MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells[J]. Cell,2009,137(4):647-658.
[9]Yue F, Chen B, Wu D, et al. Biological properties of neural progenitor cells isolated from the hippocampus of adult cynomolgus monkeys[J]. Chin Med J (Engl),2006,119(2):110-116.
[10]Madhavan L, Ourednik V, Ourednik J. Neural stem/progenitor cells initiate the formation of cellular networks that provide neuroprotection by growth factor-modulated antioxidant expression[J]. Stem Cells,2008,26(1):254-265.
[11]Lee J S, Hong J M, Moon G J, et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke[J]. Stem Cells,2010,28(6):1099-1106.
[12]Fansa H, Keilhoff G. Comparison of different biogenic matrices seeded with cultured Schwann cells for bridging peripheral nerve defects[J]. Neurol Res, 2004,26(2):167-173.
[13]毛英丽,贾飞勇,胡晓兰,等.脑性瘫痪的早期诊断及治疗[J].中国妇幼保健,2009(9)：1235-1236.
[14]麦坚凝.国内脑性瘫痪康复治疗的现状和展望[J].中华儿科杂志,2005(4)：241-243.
[15]Gluckman P D, Wyatt J S, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy:multicentre randomised trial[J]. Lancet,2005,365(9460):663-670.
[16]Liu Z, Xiong T, Meads C. Clinical effectiveness of treatment with hyperbaric oxygen for neonatal hypoxic-ischaemic encephalopathy:systematic review of Chinese literature[J]. BMJ,2006,333(7564):374.
[17]Li L, Qu Y, Li J, et al. Relationship between HIF-1alpha expression and neuronal apoptosis in neonatal rats with hypoxia-ischemia brain injury[J]. Brain Res, 2007,1180:133-139.
[18]Mu D, Chang Y S, Vexler Z S, et al. Hypoxia-inducible factor 1 alpha and erythropoietin upregulation with deferoxamine salvage after neonatal stroke [J]. Exp Neurol,2005,195(2):407-415.
[19]Lundberg C, Englund U, Trono D, et al. Differentiation of the RN33B cell line into forebrain projection neurons after transplantation into the neonatal rat brain[J]. Exp Neurol,2002,175(2):370-387.
[20]栾佐,尹国才,胡晓红,等.人神经干细胞移植治疗重度新生儿缺氧缺血性脑病一例[J].中华儿科杂志,2005(8)：580-583.
[21]Pena-Segura J L, Marco-Olloqui M, Cabrerizo D D R, et al. [Early care and botulinum toxin. Our experience in the 21st century][J]. Rev Neurol,2008,47 Suppl 1:S25-S33.
[22]Jankovic J. Botulinum toxin in clinical practice[J]. J Neurol Neurosurg Psychiatry,2004,75(7):951-957.
[23]张峰,陈福建,刘辉,等.黄豆床垫联合舒乐安定对缓解脑瘫患儿肌紧张疗效观察[J].广州医药,2011(6).
[24]陈静,陈志芬,沙丽娜.康复指导对脑瘫患儿康复效果的影响[J].中国实用神经疾病杂志,2006(5)：105.
[25]史惟,施炳培,廖元贵,等.运动发育推拿法治疗小儿脑瘫[J].中国康复,2004(6).
[26]左月仙,李爱霞,马贵林.婴幼儿偏瘫型脑瘫患儿上肢作业治疗临床疗效分析[J].中国康复理论与实践,2010(11).
[27]余志华,董小丽,何雁梅,等.脑瘫患儿构音障碍语言治疗疗效观察[J].中国康复理论与实践,2008(2).
[28]刘冬芝.脑瘫儿童的早期智力干预[J].中国实用神经疾病杂志,2010(7).
[29]汪美君,兰金山,李胜.播放音乐对局部麻醉鼻内镜手术患者焦虑及疼痛的影响[J].护理与康复,2011(10)：844-845.
[30]Unsal-Delialioglu S, Kaya K, Ozel S, et al. Depression in mothers of children with cerebral palsy and related factors in Turkey:a controlled study[J]. Int J Rehabil Res,2009,32(3):199-204.
[31]夏慧芸,刘振寰.脑瘫患儿心理行为异常及其治疗进展[J].中国儿童保健杂志,2011(10)：921-923.
[32]任世光,王淑哲.高危新生儿早期干预程序和方法[J].中国儿童保健杂志,2007(1)：4-6.
[33]王琴玉,孙砚辉,许能,等.不同时窗针刺对脑瘫幼鼠海马CA1区神经元及脑组织神经生长因子表达的影响[J].针刺研究,2004(3)：174-178.
[34]丁春华,刘焕荣,张少丹,等.针灸治疗幼鼠缺血缺氧性脑病的实验研究[J].中国应用生理学杂志,2005(4).
[35]Zheng X R, Zhang S S, Yin F, et al. Neuroprotection of VEGF-expression neural stem cells in neonatal cerebral palsy rats[J]. Behav Brain Res,2012,230(1): 108-115.
[36]Luan Z, Liu W, Qu S, et al. Effects of neural progenitor cell transplantation in children with severe cerebral palsy[J]. Cell Transplant,2012,21 Suppl 1: S91-S98.
[37]Purandare C, Shitole D G, Belle V, et al. Therapeutic potential of autologous stem cell transplantation for cerebral palsy[J]. Case Rep Transplant,2012,2012: 825289.
[38]杜侃,栾佐,屈素清,等.骨髓间充质干细胞移植治疗小儿重度脑性瘫痪的疗效观察[J].临床儿科杂志,2011(1)：55-58.
[39]Liptak G S. Complementary and alternative therapies for cerebral palsy [J]. Ment Retard Dev Disabil Res Rev,2005,11(2):156-163.
[40]于炎冰,张黎,伍成奇,等.显微神经外科手术治疗痉挛型脑瘫738例临床观察[J].中华神经外科杂志,2004(1)：62-65.
[1]Bonellie S R, Currie D, Chalmers J. Comparison of risk factors for cerebral palsy in twins and singletons[J]. Dev Med Child Neurol,2005,47(9):587-591.
[2]Costeff H. Estimated frequency of genetic and nongenetic causes of congenital idiopathic cerebral palsy in west Sweden[J]. Ann Hum Genet,2004,68(Pt 5): 515-520.
[3]Kuroda M M, Weck M E, Sarwark J F, et al. Association of apolipoprotein E genotype and cerebral palsy in children[J]. Pediatrics,2007,119(2):306-313.
[4]李晓捷,王立苹,孙奇峰.载脂蛋白E基因多态性与脑性瘫痪相关性的初步研究[J].中华物理医学与康复杂志,2011,33(1).
[5]Small B J, Rosnick C B, Fratiglioni L, et al. Apolipoprotein E and cognitive performance:a meta-analysis[J]. Psychol Aging,2004,19(4):592-600.
[6]Luciano M, Gow A J, Harris S E, et al. Cognitive ability at age 11 and 70 years, information processing speed, and APOE variation:the Lothian Birth Cohort 1936 study[J]. Psychol Aging,2009,24(1):129-138.
[7]Parasuraman R, Greenwood P M, Sunderland T. The apolipoprotein E gene, attention, and brain function[J]. Neuropsychology,2002,16(2):254-274.
[8]Reid S, Halliday J, Ditchfield M, et al. Factor V Leiden mutation:a contributory factor for cerebral palsy?[J]. Dev Med Child Neurol,2006,48(1):14-19.
[9]Gibson C S, Maclennan A H, Hague W M, et al. Associations between inherited thrombophilias, gestational age, and cerebral palsy[J]. Am J Obstet Gynecol, 2005,193(4):1437.
[10]Gibson C S, Maclennan A H, Goldwater P N, et al. The association between inherited cytokine polymorphisms and cerebral palsy[J]. Am J Obstet Gynecol, 2006,194(3):671-674.
[11]Akaba K, Kimura T, Sasaki A, et al. Neonatal hyperbilirubinemia and mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene:a common missense mutation among Japanese, Koreans and Chinese[J]. Biochem Mol Biol Int,1998,46(1):21-26.
[12]Kilic I, Cakaloz I, Atalay E. Frequency of UDP-glucuronosyltransferase 1 (UGT1A1) gene promoter polymorphisms in neonates with prolonged and pathological jaundice in the Denizli region of Turkey[J]. Int J Clin Pharmacol Ther,2007,45(8):475-476.
[13]Sugatani J, Mizushima K, Osabe M, et al. Transcriptional regulation of human UGTIA1 gene expression through distal and proximal promoter motifs: implication of defects in the UGT1A1 gene promoter[J]. Naunyn Schmiedebergs Arch Pharmacol,2008,377(4-6):597-605.
[14]Seppen J, van Til N P, van der Rijt R, et al. Immune response to lentiviral bilirubin UDP-glucuronosyltransferase gene transfer in fetal and neonatal rats[J]. Gene Ther,2006,13(8):672-677.
[15]Agrawal S K, Kumar P, Rathi R, et al. UGTIA1 gene polymorphisms in North Indian neonates presenting with unconjugated hyperbilirubinemia[J]. Pediatr Res,2009,65(6):675-680.
[16]Roy-Chowdhury N, Deocharan B, Bejjanki H R, et al. Presence of the genetic marker for Gilbert syndrome is associated with increased level and duration of neonatal jaundice[J]. Acta Paediatr,2002,91(1):100-101.
[17]Erichsen H C, Engel S A, Eck P K, et al. Genetic variation in the sodium-dependent vitamin C transporters, SLC23A1, and SLC23A2 and risk for preterm delivery[J]. Am J Epidemiol,2006,163(3):245-254.
[18]Johnson W G, Scholl T O, Spychala J R, et al. Common dihydrofolate reductase 19-base pair deletion allele:a novel risk factor for preterm delivery [J]. Am J Clin Nutr,2005,81(3):664-668.
[19]Lee S H, Girard S, Macina D, et al. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily[J]. Nat Genet,2001,28(1):42-45.
[20]Gibson C S, Maclennan A H, Dekker G A, et al. Genetic polymorphisms and spontaneous preterm birth[J]. Obstet Gynecol,2007,109(2 Pt 1):384-391.
[21]Ratts V S, Tao X J, Webster C B, et al. Expression of BCL-2, BAX and BAK in the trophoblast layer of the term human placenta:a unique model of apoptosis within a syncytium[J]. Placenta,2000,21(4):361-366.
[22]Chen W, Jadhav V, Tang J, et al. HIF-1alpha inhibition ameliorates neonatal brain injury in a rat pup hypoxic-ischemic model[J]. Neurobiol Dis,2008,31(3): 433-441.
[23]Shrivastava K, Shukla D, Bansal A, et al. Neuroprotective effect of cobalt chloride on hypobaric hypoxia-induced oxidative stress[J]. Neurochem Int, 2008,52(3):368-375.
[24]Halterman M W, Gill M, Dejesus C, et al. The endoplasmic reticulum stress response factor CHOP-10 protects against hypoxia-induced neuronal death [J]. J Biol Chem,2010,285(28):21329-21340.
[25]Drougia A, Giapros V, Krallis N, et al. Incidence and risk factors for cerebral palsy in infants with perinatal problems:a 15-year review[J]. Early Hum Dev, 2007,83(8):541-547.
[26]Pang Y, Zheng B, Fan L W, et al. IGF-1 protects oligodendrocyte progenitors against TNFalpha-induced damage by activation of PI3K/Akt and interruption of the mitochondrial apoptotic pathway[J]. Glia,2007,55(11):1099-1107.
[27]Back S A. Perinatal white matter injury:the changing spectrum of pathology and emerging insights into pathogenetic mechanisms [J]. Ment Retard Dev Disabil Res Rev,2006,12(2):129-140.
[28]French H M, Reid M, Mamontov P, et al. Oxidative stress disrupts oligodendrocyte maturation [J]. J Neurosci Res,2009,87(14):3076-3087.
[29]Inage Y W. Itoh M, Takashima S. Correlation between cerebrovascular maturity and periventricular leukomalacia[J]. Pediatr Neurol,2000,22(3):204-208.
[30]王海兰.早产儿脑室周围白质软化与胎龄的相关性分析[J].河北医学,2007(10).
[31]Bracci R, Buonocore G. Chorioamnionitis:a risk factor for fetal and neonatal morbidity[J]. Biol Neonate,2003,83(2):85-96.
[32]Yanowitz T D, Jordan J A, Gilmour C H, et al. Hemodynamic disturbances in premature infants born after chorioamnionitis:association with cord blood cytokine concentrations[J]. Pediatr Res,2002,51(3):310-316.
[33]何柳芳,陈惠金.感染/炎性反应对早产儿脑室周围白质软化发生的影响[J].实用儿科临床杂志,2008(6)：472-474.
[34]Dommergues M A, Patkai J, Renauld J C, et al. Proinflammatory cytokines and interleukin-9 exacerbate excitotoxic lesions of the newborn murine neopallium[J]. Ann Neurol,2000,47(1):54-63.
[35]Haynes R L, Folkerth R D, Keefe R J, et al. Nitrosative and oxidative injury to premyelinating oligodendrocytes in periventricular leukomalacia[J]. J Neuropathol Exp Neurol,2003,62(5):441-450.
[36]Folkerth R D, Haynes R L, Borenstein N S, et al. Developmental lag in superoxide dismutases relative to other antioxidant enzymes in premyelinated human telencephalic white matter[J]. J Neuropathol Exp Neurol,2004,63(9): 990-999.
[37]Savman K, Nilsson U A, Blennow M, et al. Non-protein-bound iron is elevated in cerebrospinal fluid from preterm infants with posthemorrhagic ventricular dilatation[J]. Pediatr Res,2001,49(2):208-212.