非综合征性聋Myo6基因突变特征及促红细胞生成素对耳聋作用的研究
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摘要
研究背景：人类从外界获取的信息中30%来自听觉,听力丧失无疑严重影响人类的生活质量,并且伴随人的一生。耳聋是人类最常见的感觉神经系统缺陷。学语前耳聋是儿童的常见疾病,可导致患儿语言交流障碍,严重影响患儿的语言、智力、身心健康等的发育,影响着我国人口素质。据估计每1000名新生儿中就有1名先天性耳聋患者,随着年龄的增加,永久性耳聋患儿持续增加,5岁前耳聋患儿的发病率上升到2.7‰其中60%为遗传性聋,而不伴随全身其他症状的非综合征性聋(nonsyndromic hearing impairment NSHI)约占遗传性耳聋的70‰引起耳聋的病因很多,其中遗传因素是不可忽视的病因。目前已发现许多基因突变与耳聋有关,现已知非综合征性致聋基因有62个,其中隐性遗传致病基因37个,显性遗传基因25个。而所有遗传因素和环境因素致聋在同一种族以及不同种族之间会有极大的差异,即遗传异质性。语前聋的发病原因及其发病机制一直是国内外耳鼻咽喉科医师、分子生物学家、遗传优生医师和学者们共同关注的热点问题。
目的：探讨中国儿童非综合征性学语前聋患者肌球蛋白6(myosin6, Myo6)基因的突变频率和特性,探讨Myo6在非综合征性耳聋的作用。
方法：收集非综合征性学语前聋患儿及其母亲各41个及听力正常儿童50例,患儿家庭大部分来自广东地区,共计132例；聚合酶链反应扩增肌球蛋白6基因的外显子,变性梯度凝胶电泳(denaturing Gradient Gel electrophoresis, DGGE)筛查变异,发现异常构象带后再行DNA测序确定是否存在突变和检测突变的位点。
结果：在2个患儿母亲和1例患儿中检测出了Myo6基因突变。10号样本为患儿家长,Myo6基因9号外显子杂合突变738T→T／C,其编码的氨基酸无改变,为无义突变。17号样本为患儿家长,有两个突变位点：Myo6基因9号外显子杂合突变739A→A／G,其编码氨基酸发生了改变Ile→Val[异亮氨酸→颉氨酸],为错义突变；Myo6基因13号外显子杂合突变1292T→T／C,其编码氨基酸发生了改变leu→pro[亮氨酸→脯氨酸],为错义突变。33号样本为患儿,有两突变位点：Myo6基因9号外显子杂合突变711T→T／C,其编码氨基酸没发生改变,为无义突变；32号外显子纯合突变3281A→G,其编码的氨基酸发生了改变Asp→Gly[天冬氨酸→甘氨酸],为错义突变。并且17号和33号是母子关系。
结论：Myo6基因的纯合错义突变(3281A→G)很可能是导致非综合征性学语前聋的一个新突变,属于常染色体隐性遗传。
研究背景：根据听觉系统所受影响的性质、原因和病变位置可将耳聋分为传导性聋、感音神经性聋和二者兼有的混合性聋3大类。由外耳和(或)中耳疾病或结构异常所致的集音或传音障碍引起的听觉功能减退称为传导性耳聋可通过听力重建手术来保存和恢复听力,而感音神经性耳聋是一大类常见的难治性、致残性疾病,由于缺乏有效治疗方法,因聋致残者不在少数。而降低感音神经性耳聋发病率最有效的策略是控制耳聋的增加和提供有效的治疗方法。近年已证实,谷氨酸兴奋毒性是神经系统损伤的主要病理机制之一,各种原因引起的耳蜗缺血或噪声损伤的一个重要致聋机理是谷氨酸(glutamate, Glu)兴奋毒性对耳蜗的损害,即：上述病例状态下耳蜗内毛细胞释放兴奋性传入神经递质GIu过多或／和回收不充分,谷氨酸与突触后膜受体的作用,导致神经元过度兴奋,钙超载、细胞内氧自由基的增多,导致以传入神经元树突水肿为特征的兴奋性损害而导致神经元的大量死亡,出现大幅听力下降,重者因迟发性传入神经元死亡致不可逆神经性聋。因此减少神经元的凋亡是最直接和最有效的治疗措施。
目的：观察谷氨酸致豚鼠耳蜗传入神经元兴奋毒性损伤后,耳蜗局部灌注促红细胞生成素(Erythropoietin, EPO)对耳蜗传入神经元的电生理(复合动作电位CAP)的影响。
方法：26只豚鼠分为4组。第一组(8只)：先用微量输液泵经鼓阶持续性灌注谷氨酸(glutamate, Glu20mmol/1,10ul)。60分钟后用微量渗透泵经鼓阶持续性灌注EPO(0.1U/ml,流速0.5ul／h)14天,作为实验组(EPO组)；第二组(8只)：经鼓阶灌注谷氨酸(20mmol/1,10ul)作为实验对照组(Glu组)；第三组(5只)：用微量渗透泵经鼓阶灌注Hanks液做为正常对照组(HBSS组)；第四组(5只豚鼠)：不作任何灌注作为空白对照组(Blank组)。EPO组、Glu组和HBSS组分别在术后1天、术后4周测CAP反应阈,空白对照组测CAP反应阈后处死。
结果：1、术后1天EPO组、Glu组CAP反应阈增高,与HBSS和Blank组有显著性差异(P<0.01)；2、术后4周EPO组CAP反应闽无降低；3、HBSS组、Blank组CAP反应阈无显著性差异(P>0.05)。
结论：1.局部灌注谷氨酸对螺旋神经节细胞有明显的神经毒性；2.局部灌注EPO没有起到对耳蜗神经节的保护作用。
研究背景：3岁以内的婴幼儿常常容易把能拿到的一些小食物含在口中,而磨牙系统发育不完善、喉的保护功能不健全、缺少咀嚼和活泼好动、哭笑等性格因素,在缺少监护或者监护不力及其他意外等情况时易出现误吸而导致气管／支气管异物的发生。3岁以内的婴幼儿是最易发生气管和支气管异物的人群,其中该年龄段7%婴幼儿的意外死亡与误吸异物有关,但即使都是气管异物患儿,不同年龄段的特点也不尽相同,3岁以内不同年龄段患儿气管异物发病机制和临床表现的差异少有研究和报道。
目的：通过比较3岁以内婴幼儿气管／支气管异物的临床资料,总结3岁以内婴幼儿每一年龄段误吸异物后各自临床表现和差异,总结3岁以内婴幼儿气管／支气管异物的临床特点,以进一步提高诊疗水平。
方法：回顾性分析2004年1月～2008年12月间在深圳市儿童医院确诊和治疗的3岁以内的婴幼儿气管、支气管异物316例的临床资料。通过比较不同组别患儿的性别、年龄、异物分布部位、治疗史、异物吸入史,异物种类和致死原因等,同时还分析合并并发症患儿异物在体内滞留时间及异物取出的后果差异。
结果：1岁以内婴儿有52例(中位数年龄为10个月,A组),1-2岁患儿199例(中位数年龄为17个月,B组),2-3岁患儿65例(中位数年龄30个月,C组)。A组有明确异物误吸史者有38例(73.1%),较B组(55.8%)和C组(53.8%)高(P<0.05)。最常见的异物为花生(171例,54.1%)；其次为瓜子(包括葵瓜子、西瓜子和南瓜子)62例(19.6%)；第三位异物种类为动物性异物有35例(11.1%)(包括16例猪骨,8例鱼骨,7例鸡骨和4例其他动物肉),且A组动物性异物的发生比例明显高于B和C组(P＜0.01)。最少的异物种类为无机异物,共5例(图钉一个,橡皮擦一个,螺丝钉一个,小石子一个,塑料玩具一个)。异物于支气管内的分布没有明显的左、右侧差异,左侧异物发生率为41.8%,右侧异物发生率为40.5%,三组不同年龄段患儿异物左、右侧分布也无显著性差异。数据显示,A组(0-1岁)患儿24小时内被送往医院接受治疗比例(50%)最高(P＜0.01)。本组病例中有5个患儿(死亡率：1.58%)因误吸异物而死。
结论：在中国南方1岁以内婴儿阶段最常见的异物为动物性异物。最易发生气管／支气管异物的人群为1至2岁的幼儿。3岁以内的婴、幼儿误吸异物的发病率和死亡率都很高。1岁以内婴儿误吸异物不久后即易发生窒息或／和心肺骤停。但较大幼儿往往是在误诊或误治一段时间后突然发生意外。
Research background:Hearing loss is a common disease in the human population which can cause obstacles in language communication and severely effect human health and life quality.It is estimated that one in every1000new born babies is congenital deaf and60%of which is suffering from hereditary hearing loss, however70%of those is caused by NSHI (nonsyndromic hearing impairment).Hereditary factor maybe be overlooked among lots of reasons that can cause hearing loss. At present many genetic mutation have found to be relevant to the hearing loss. Among62known nonsyndromic hearing loss genes, there are37recssive genes and25dominant genes. Hearing loss caused by genetic factors and environment factors varies among the same race and different races. The cause of prelinguistic deafness and its pathogenesis has become a hot issue among the Otolaryngology, Childcare experts, Eugenics physicians and other scholars.
Objective:To ascertain the frequency and characteristics of myosin6gene mutations in Chinese children with prelingual nonsyndromic hearing impairment.
Methods:Most of the cases were collected within Guandong provenience, including41hereditary prelingual deafness children and their mother, and50normal hearing children were used as control, total132cases. Genomic DNA Was extracted from the patients and subjected to the PCR to amplify selected exons of myosin6gene, and then the amplified products were screened for base variations by denaturing Gradient Gel electrophoresis (DGGE). The bands with abnormal performance were sequenced to confirm the mutation.
Results:One patient and the other two patient's mother were confirmed the mutation of Myo6.10sample:T to C substitution was detected at nucleotide738in exon9as hetrozygous state (738T→T/C).17sample:A to G substitution was detected at nucleotide739in exon9as hetrozygous state (739A→A/G), Its encoded amino acid has been changed from lie to Val which is missense mutation. T to C substitution was detected at nucleotide1292in exon13as hetrozygous state(1292T→T/C), its encoded amino acid has been changed from leu to pro which is missense mutation.33sample:T to C substitution was detected at nucleotide711in exon9as hetrozygous state(711T→T/C), A to G substitution was detected at nucleotide3281in exon32as homozygous state(3281A→G), Its encoded amino acid has been changed from Asp to Gly which is missense mutation. And Sample17and sample33are mother and son.
Conclusions:The Homozygous missense of Myo6gene (3281A→G) is probably a novel mutation to cause prelingual nonsyndromic hearing impairment, which is autosomal recessive inheritance.
Background:Deafness can be divided into conductive deafness、 sensorineural deafness and mixed deafness. Conductive deafness can be implemented hearing reconstruction operation to save and restore hearing. Sensorineural deafness is a common refractory crippling disease, due to the lack of effective therapy, disabled persons is not in the minority.In recent years it has been confirmed, Glutamate excitotoxicity is one of the major pathological mechanisms that cause neuronal injury in nervous diseases, the important mechanism of cochlear ischemia or noise damage is excitotoxicity by glutamate damage. One is the acute swelling of the neuron dendrites mediated by Glu binding to ionotropic receptors in the postsynaptic membrane;the other consists of a cascade of subsequent metabolic events, such as the neuronal apoptosis triggered by excessive Ca2+influx. Excessive accumulation of extracellular glutamate may lead to hyperexcitability of neurons.Therefore, minimizing neuronal apoptosis is the most direct and effective therapeutic approach.
Objective:To observe the Glu—induced excitotoxic damage to the cochlear afferent neurons in guinea pig cochlear. To reveal if erythropoietin(EPO) has the protective effects on the glutamate induced excitotoxic damage of cochlear afferent neurons(type I spiral ganglion cell)after perilymphatic perfusion of glutamate.
Method:26guinea pigs were divided into4groups.The first group (8animals, EPO group):glutamate (20mmol/1,10ul) was injected into the left scala tympani,EPO(0.1U/ml, flow rate0.5ul/h) was then continuously delivered to the same scala tympani60minutes post glutamate injection via mini-osmotic pump for14days;the second group (8animals, Glu group): the scala tympani perfusion of glutamate (20mmol/1,10ul) as experimental control;the third group (5animals, HBSS group):Hank's balanced salt solution(HBSS) was continuously perfused into the left seal tympani via a mini-osmotic pump for the normal control;the fourth group(5animals, blank group):as the blank control group without any perilymphatic reperfusion. The CAP thresholds of the first three groups were recorded at1day and4weeks post-perilymphatic perfusion. Blank group were sacrificed after CAP recording.
Results:1One days after tympani perfusion,the CAP threshold of group EPO and group Glu increased, with a significant difference between the HBSS and Blank groups (P<0.01). The CAP threshold of group EPO response has not declined4weeks later;there is no significant difference in CAP response threshold between HBSS group and Blank group (P>0.05).
Conclusion:1.Glutamate application via scala tympani could result in excitoxic damage of cochlear type I spiral ganglion cells of guinea pigs.2. Local application of EPO did not play a protective effect on cochlear ganglion cell against glutamate neurotoxicity.
Background:The age group most commonly affected by tracheobronchial foreign body (FB) aspirations (FBA) is children under the age of3years, in whom7%of deaths are related to FBA. The enhanced risk of aspiration in the0-to3-year-old age group is attributed to inadequately developed posterior dentition, immature neuromuscular mechanisms of deglutition and airway protection and the ubiquitous tendency of children of this age to put objects into their mouths. Failure to provide adequate supervision of a vulnerable child and allowing children easy access to small objects are also contributory factors. Potential differences in susceptibility within these first3years of life have not been studied extensively. The aim of this prospective study was to characterize the similarities and differences in children who experienced FBA at different times during the first3years of life.
Objective:To investigate the clinical pathological features of aspirated tracheobronchial foreign body (FB) cases in children under the age of3years and to improve the level of diagnosis and treatment.
Methods:A retrospective study was conducted examining316children under the age of3years who had been treated for tracheobronchial FB in Shenzhen children's hospital between January2004and December2008. We analyzed the patients for gender, age, FB localization, treatment history, the history of foreign body aspiration (FBA), the type of foreign body and the cause of death. In addition, each patient was analyzed for FB-related complication, the results of bronchoscopic removal and the presence of foreign bodies in the airways.
Results:Fifty-two infants under the age of one year (median age=10m, group A),199children between the ages of1and2years (median age=17m, group B) and65children between the ages of2and3years (median age=30m, group C) were included in this study. There were38(73.1%) patients with a confirmed history of FBA in group A, a higher percentage than that observed in group B (55.8%) or group C (53.8%)(P<0.05). Earthnuts were the most common cause of FB (171cases,54.1%).Melon seeds (including sunflower seeds, watermelon seeds and pumpkin seeds) were the second most common cause of FB (62cases,19.6%). Animal sources (including16pig bones,8fish bones,7chicken bones and4other animal-based foods) comprised11.1%(35cases) of FB cases and were the third most common cause of FB. The percentage of animal-based FBs observed in group A was higher than in groups B and C (P<0.01). Five inorganic FBs (a pushpin, a rubber band, a screw, a small stone and a plastic toy) were also observed and were the least common type of FB. There were no significant differences in the distribution of FBs between the left(41.8%) and right (40.5%) bronchia. There is no difference in the distribution of FBs among the three groups either.The data show that the youngest cohort of patients (0-1years) is the most likely to be sent to the hospital to receive treatment within24hours of aspiration(50%)(P<0.01). Five patients(1.58%) died as the result of FBA.
Conclusions:FBAs of animal-derived FBs (especially animal bones) are very common in infants in southern China. Children between the ages of1and2years are most likely to suffer from FBA. FBA in children under the age of3years carries significant hazards, including morbidity and mortality. Asphyxia and/or cardiopulmonary arrest is prone to occur shortly after FBA in infants, but these events can occur days later in older children after FBA because of delays in the diagnosis and/or treatment of this condition.
目的：探讨中国儿童非综合征性学语前聋患者肌球蛋白6(myosin6, Myo6)基因的突变频率和特性,探讨Myo6在非综合征性耳聋的作用。
方法：收集非综合征性学语前聋患儿及其母亲各41个及听力正常儿童50例,患儿家庭大部分来自广东地区,共计132例；聚合酶链反应扩增肌球蛋白6基因的外显子,变性梯度凝胶电泳(denaturing Gradient Gel electrophoresis, DGGE)筛查变异,发现异常构象带后再行DNA测序确定是否存在突变和检测突变的位点。
结果：在2个患儿母亲和1例患儿中检测出了Myo6基因突变。10号样本为患儿家长,Myo6基因9号外显子杂合突变738T→T／C,其编码的氨基酸无改变,为无义突变。17号样本为患儿家长,有两个突变位点：Myo6基因9号外显子杂合突变739A→A／G,其编码氨基酸发生了改变Ile→Val[异亮氨酸→颉氨酸],为错义突变；Myo6基因13号外显子杂合突变1292T→T／C,其编码氨基酸发生了改变leu→pro[亮氨酸→脯氨酸],为错义突变。33号样本为患儿,有两突变位点：Myo6基因9号外显子杂合突变711T→T／C,其编码氨基酸没发生改变,为无义突变；32号外显子纯合突变3281A→G,其编码的氨基酸发生了改变Asp→Gly[天冬氨酸→甘氨酸],为错义突变。并且17号和33号是母子关系。
结论：Myo6基因的纯合错义突变(3281A→G)很可能是导致非综合征性学语前聋的一个新突变,属于常染色体隐性遗传。
研究背景：根据听觉系统所受影响的性质、原因和病变位置可将耳聋分为传导性聋、感音神经性聋和二者兼有的混合性聋3大类。由外耳和(或)中耳疾病或结构异常所致的集音或传音障碍引起的听觉功能减退称为传导性耳聋可通过听力重建手术来保存和恢复听力,而感音神经性耳聋是一大类常见的难治性、致残性疾病,由于缺乏有效治疗方法,因聋致残者不在少数。而降低感音神经性耳聋发病率最有效的策略是控制耳聋的增加和提供有效的治疗方法。近年已证实,谷氨酸兴奋毒性是神经系统损伤的主要病理机制之一,各种原因引起的耳蜗缺血或噪声损伤的一个重要致聋机理是谷氨酸(glutamate, Glu)兴奋毒性对耳蜗的损害,即：上述病例状态下耳蜗内毛细胞释放兴奋性传入神经递质GIu过多或／和回收不充分,谷氨酸与突触后膜受体的作用,导致神经元过度兴奋,钙超载、细胞内氧自由基的增多,导致以传入神经元树突水肿为特征的兴奋性损害而导致神经元的大量死亡,出现大幅听力下降,重者因迟发性传入神经元死亡致不可逆神经性聋。因此减少神经元的凋亡是最直接和最有效的治疗措施。
目的：观察谷氨酸致豚鼠耳蜗传入神经元兴奋毒性损伤后,耳蜗局部灌注促红细胞生成素(Erythropoietin, EPO)对耳蜗传入神经元的电生理(复合动作电位CAP)的影响。
方法：26只豚鼠分为4组。第一组(8只)：先用微量输液泵经鼓阶持续性灌注谷氨酸(glutamate, Glu20mmol/1,10ul)。60分钟后用微量渗透泵经鼓阶持续性灌注EPO(0.1U/ml,流速0.5ul／h)14天,作为实验组(EPO组)；第二组(8只)：经鼓阶灌注谷氨酸(20mmol/1,10ul)作为实验对照组(Glu组)；第三组(5只)：用微量渗透泵经鼓阶灌注Hanks液做为正常对照组(HBSS组)；第四组(5只豚鼠)：不作任何灌注作为空白对照组(Blank组)。EPO组、Glu组和HBSS组分别在术后1天、术后4周测CAP反应阈,空白对照组测CAP反应阈后处死。
结果：1、术后1天EPO组、Glu组CAP反应阈增高,与HBSS和Blank组有显著性差异(P<0.01)；2、术后4周EPO组CAP反应闽无降低；3、HBSS组、Blank组CAP反应阈无显著性差异(P>0.05)。
结论：1.局部灌注谷氨酸对螺旋神经节细胞有明显的神经毒性；2.局部灌注EPO没有起到对耳蜗神经节的保护作用。
研究背景：3岁以内的婴幼儿常常容易把能拿到的一些小食物含在口中,而磨牙系统发育不完善、喉的保护功能不健全、缺少咀嚼和活泼好动、哭笑等性格因素,在缺少监护或者监护不力及其他意外等情况时易出现误吸而导致气管／支气管异物的发生。3岁以内的婴幼儿是最易发生气管和支气管异物的人群,其中该年龄段7%婴幼儿的意外死亡与误吸异物有关,但即使都是气管异物患儿,不同年龄段的特点也不尽相同,3岁以内不同年龄段患儿气管异物发病机制和临床表现的差异少有研究和报道。
目的：通过比较3岁以内婴幼儿气管／支气管异物的临床资料,总结3岁以内婴幼儿每一年龄段误吸异物后各自临床表现和差异,总结3岁以内婴幼儿气管／支气管异物的临床特点,以进一步提高诊疗水平。
方法：回顾性分析2004年1月～2008年12月间在深圳市儿童医院确诊和治疗的3岁以内的婴幼儿气管、支气管异物316例的临床资料。通过比较不同组别患儿的性别、年龄、异物分布部位、治疗史、异物吸入史,异物种类和致死原因等,同时还分析合并并发症患儿异物在体内滞留时间及异物取出的后果差异。
结果：1岁以内婴儿有52例(中位数年龄为10个月,A组),1-2岁患儿199例(中位数年龄为17个月,B组),2-3岁患儿65例(中位数年龄30个月,C组)。A组有明确异物误吸史者有38例(73.1%),较B组(55.8%)和C组(53.8%)高(P<0.05)。最常见的异物为花生(171例,54.1%)；其次为瓜子(包括葵瓜子、西瓜子和南瓜子)62例(19.6%)；第三位异物种类为动物性异物有35例(11.1%)(包括16例猪骨,8例鱼骨,7例鸡骨和4例其他动物肉),且A组动物性异物的发生比例明显高于B和C组(P＜0.01)。最少的异物种类为无机异物,共5例(图钉一个,橡皮擦一个,螺丝钉一个,小石子一个,塑料玩具一个)。异物于支气管内的分布没有明显的左、右侧差异,左侧异物发生率为41.8%,右侧异物发生率为40.5%,三组不同年龄段患儿异物左、右侧分布也无显著性差异。数据显示,A组(0-1岁)患儿24小时内被送往医院接受治疗比例(50%)最高(P＜0.01)。本组病例中有5个患儿(死亡率：1.58%)因误吸异物而死。
结论：在中国南方1岁以内婴儿阶段最常见的异物为动物性异物。最易发生气管／支气管异物的人群为1至2岁的幼儿。3岁以内的婴、幼儿误吸异物的发病率和死亡率都很高。1岁以内婴儿误吸异物不久后即易发生窒息或／和心肺骤停。但较大幼儿往往是在误诊或误治一段时间后突然发生意外。
Research background:Hearing loss is a common disease in the human population which can cause obstacles in language communication and severely effect human health and life quality.It is estimated that one in every1000new born babies is congenital deaf and60%of which is suffering from hereditary hearing loss, however70%of those is caused by NSHI (nonsyndromic hearing impairment).Hereditary factor maybe be overlooked among lots of reasons that can cause hearing loss. At present many genetic mutation have found to be relevant to the hearing loss. Among62known nonsyndromic hearing loss genes, there are37recssive genes and25dominant genes. Hearing loss caused by genetic factors and environment factors varies among the same race and different races. The cause of prelinguistic deafness and its pathogenesis has become a hot issue among the Otolaryngology, Childcare experts, Eugenics physicians and other scholars.
Objective:To ascertain the frequency and characteristics of myosin6gene mutations in Chinese children with prelingual nonsyndromic hearing impairment.
Methods:Most of the cases were collected within Guandong provenience, including41hereditary prelingual deafness children and their mother, and50normal hearing children were used as control, total132cases. Genomic DNA Was extracted from the patients and subjected to the PCR to amplify selected exons of myosin6gene, and then the amplified products were screened for base variations by denaturing Gradient Gel electrophoresis (DGGE). The bands with abnormal performance were sequenced to confirm the mutation.
Results:One patient and the other two patient's mother were confirmed the mutation of Myo6.10sample:T to C substitution was detected at nucleotide738in exon9as hetrozygous state (738T→T/C).17sample:A to G substitution was detected at nucleotide739in exon9as hetrozygous state (739A→A/G), Its encoded amino acid has been changed from lie to Val which is missense mutation. T to C substitution was detected at nucleotide1292in exon13as hetrozygous state(1292T→T/C), its encoded amino acid has been changed from leu to pro which is missense mutation.33sample:T to C substitution was detected at nucleotide711in exon9as hetrozygous state(711T→T/C), A to G substitution was detected at nucleotide3281in exon32as homozygous state(3281A→G), Its encoded amino acid has been changed from Asp to Gly which is missense mutation. And Sample17and sample33are mother and son.
Conclusions:The Homozygous missense of Myo6gene (3281A→G) is probably a novel mutation to cause prelingual nonsyndromic hearing impairment, which is autosomal recessive inheritance.
Background:Deafness can be divided into conductive deafness、 sensorineural deafness and mixed deafness. Conductive deafness can be implemented hearing reconstruction operation to save and restore hearing. Sensorineural deafness is a common refractory crippling disease, due to the lack of effective therapy, disabled persons is not in the minority.In recent years it has been confirmed, Glutamate excitotoxicity is one of the major pathological mechanisms that cause neuronal injury in nervous diseases, the important mechanism of cochlear ischemia or noise damage is excitotoxicity by glutamate damage. One is the acute swelling of the neuron dendrites mediated by Glu binding to ionotropic receptors in the postsynaptic membrane;the other consists of a cascade of subsequent metabolic events, such as the neuronal apoptosis triggered by excessive Ca2+influx. Excessive accumulation of extracellular glutamate may lead to hyperexcitability of neurons.Therefore, minimizing neuronal apoptosis is the most direct and effective therapeutic approach.
Objective:To observe the Glu—induced excitotoxic damage to the cochlear afferent neurons in guinea pig cochlear. To reveal if erythropoietin(EPO) has the protective effects on the glutamate induced excitotoxic damage of cochlear afferent neurons(type I spiral ganglion cell)after perilymphatic perfusion of glutamate.
Method:26guinea pigs were divided into4groups.The first group (8animals, EPO group):glutamate (20mmol/1,10ul) was injected into the left scala tympani,EPO(0.1U/ml, flow rate0.5ul/h) was then continuously delivered to the same scala tympani60minutes post glutamate injection via mini-osmotic pump for14days;the second group (8animals, Glu group): the scala tympani perfusion of glutamate (20mmol/1,10ul) as experimental control;the third group (5animals, HBSS group):Hank's balanced salt solution(HBSS) was continuously perfused into the left seal tympani via a mini-osmotic pump for the normal control;the fourth group(5animals, blank group):as the blank control group without any perilymphatic reperfusion. The CAP thresholds of the first three groups were recorded at1day and4weeks post-perilymphatic perfusion. Blank group were sacrificed after CAP recording.
Results:1One days after tympani perfusion,the CAP threshold of group EPO and group Glu increased, with a significant difference between the HBSS and Blank groups (P<0.01). The CAP threshold of group EPO response has not declined4weeks later;there is no significant difference in CAP response threshold between HBSS group and Blank group (P>0.05).
Conclusion:1.Glutamate application via scala tympani could result in excitoxic damage of cochlear type I spiral ganglion cells of guinea pigs.2. Local application of EPO did not play a protective effect on cochlear ganglion cell against glutamate neurotoxicity.
Background:The age group most commonly affected by tracheobronchial foreign body (FB) aspirations (FBA) is children under the age of3years, in whom7%of deaths are related to FBA. The enhanced risk of aspiration in the0-to3-year-old age group is attributed to inadequately developed posterior dentition, immature neuromuscular mechanisms of deglutition and airway protection and the ubiquitous tendency of children of this age to put objects into their mouths. Failure to provide adequate supervision of a vulnerable child and allowing children easy access to small objects are also contributory factors. Potential differences in susceptibility within these first3years of life have not been studied extensively. The aim of this prospective study was to characterize the similarities and differences in children who experienced FBA at different times during the first3years of life.
Objective:To investigate the clinical pathological features of aspirated tracheobronchial foreign body (FB) cases in children under the age of3years and to improve the level of diagnosis and treatment.
Methods:A retrospective study was conducted examining316children under the age of3years who had been treated for tracheobronchial FB in Shenzhen children's hospital between January2004and December2008. We analyzed the patients for gender, age, FB localization, treatment history, the history of foreign body aspiration (FBA), the type of foreign body and the cause of death. In addition, each patient was analyzed for FB-related complication, the results of bronchoscopic removal and the presence of foreign bodies in the airways.
Results:Fifty-two infants under the age of one year (median age=10m, group A),199children between the ages of1and2years (median age=17m, group B) and65children between the ages of2and3years (median age=30m, group C) were included in this study. There were38(73.1%) patients with a confirmed history of FBA in group A, a higher percentage than that observed in group B (55.8%) or group C (53.8%)(P<0.05). Earthnuts were the most common cause of FB (171cases,54.1%).Melon seeds (including sunflower seeds, watermelon seeds and pumpkin seeds) were the second most common cause of FB (62cases,19.6%). Animal sources (including16pig bones,8fish bones,7chicken bones and4other animal-based foods) comprised11.1%(35cases) of FB cases and were the third most common cause of FB. The percentage of animal-based FBs observed in group A was higher than in groups B and C (P<0.01). Five inorganic FBs (a pushpin, a rubber band, a screw, a small stone and a plastic toy) were also observed and were the least common type of FB. There were no significant differences in the distribution of FBs between the left(41.8%) and right (40.5%) bronchia. There is no difference in the distribution of FBs among the three groups either.The data show that the youngest cohort of patients (0-1years) is the most likely to be sent to the hospital to receive treatment within24hours of aspiration(50%)(P<0.01). Five patients(1.58%) died as the result of FBA.
Conclusions:FBAs of animal-derived FBs (especially animal bones) are very common in infants in southern China. Children between the ages of1and2years are most likely to suffer from FBA. FBA in children under the age of3years carries significant hazards, including morbidity and mortality. Asphyxia and/or cardiopulmonary arrest is prone to occur shortly after FBA in infants, but these events can occur days later in older children after FBA because of delays in the diagnosis and/or treatment of this condition.
引文
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1.第二次全国残疾人抽样调查领导小组,中华人民共和国国家统计局。2006年第二次全国残疾人抽样调查主要数据公报。中国康复理论与实践,2006,12(12)：1013。
2. Marazita ML, Ploushmall JM, Rawlings B, et al. Genetic epidemiological studies of early—onset deafness in the US school—age population.Am J Med Genet,1993,46:486-491.
3.李晨璞,支雄莉,韩英荣。肌球蛋白VⅥ定向运动的蒙特卡罗模拟。生物学杂志,27：8-12。
4.Lalwani AK, Goldstein J A, Kelley M J, et al. Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myo— sin MYH9. Am J Hum Genet,2000,67:1121—1128.
5.Adato A, Veli D, Kalinski H, et al. Mutation profile of all 49 exons of the human myosin VIIA gene, an d haplotype analysis, in Usher 1 B families from diverse origins. Am J Hum Genet,1997,61:813-821.
6.Ahmed ZM, Morell IL1, Riazuddin S, et al. Mutations of MY06 arc associated with recessive deafness, DFNB37. Am J Hurn Genet, 2003,72:1315-1322.
5. Lister L, Roberts R, Schmitz S, et al. Myosin VI:a multifunctional motor. Biochem. Soc. Trans.2004,32:685-688.
6.Hasson T, Gillespie P G, Garcia J A et al. Unconventional Myosins in Inner-Ear Sensory Epithelia. J Cell Biol,1997,137:1287-1307.
7. Self T, Sobe T, Copeland NG, et al. Role of myosin VI inthe diferentiation of cochlear hair cells. De V Biol,1999,214:331-341.
8.Ahman D, Sweeney H L, Spudieh J A, et al.The mechanism of myosin VI translocation and its load—induced anchoring. Cell,2004,116:737—749.
9.Ahituv N, Sobe T, Robertson N G, et al.Genomic structure of the human unconventional myosin 6 gene. Gene,2000,261:269-275.
10. Rouxl I., Hosie S., Johnson S. L. et al. Myosin VI is required for the proper maturation and function of inner hair cell ribbon synapses. Human Molecular Genetics,2009,18:4615-4628.
ll.Redowicz MJ. Myosins and deafness. J Muscle Res Cell Motil,1999,20: 241-248.
12.Avraham KB, Hasson T, Sobe T, et al. Characterization of unconventional MY06, the human homologue of the gene responsible for deafness in Snell's waltzer mice. Hum Mol Genet,1997,6:1225-1231.
13. Kappler J A, Starr C J, Chan D Ket, et al.A nonsense mutation in the gene encoding a zebrafish myosin VI isoform causes defects in hair-cell mechanotransduction; Proc Natl Acad Sci USA.2004,101:13056-13061.
14. Self T, Sobe T, Copeland N G, et al. Role of myosin VI in the differentiation of cochlear hair cells. Development Biology,1999,214:331-341.
15. Melchionda S, Ahituv N,2, Bisceglia L et al. MY06, the Human Homologue of the Gene Responsible for Deafness in Snell's Waltzer Mice, Is Mutated in Autosomal Dominant Nonsyndromic Hearing Loss. Am J Hum Genet.,2003,72: 1315-1322.
16. Sato 0, White H D, Inoue A et al. Human Deafness Mutation of Myosin VI (C442Y) Accelerates the ADP Dissociation Rate. J. Biol. Chem., 2004,279:28844-28854.
17. Mohiddin S A, Ahmed Z M, Griffith A J, et al.Novel association of hypertrophic cardiomyopathy,sensorineural deafness, and a mutation in unconventional myosin VI (MY06). J. Med. Genet.,2004;41;309-314.
18. Seiler C, Ben—David, Sidi S, et al. MyosinⅥ is required for structural integrity ofthe apical surface of sensory hair cells in zebrafish. Dev Biol,2004,272:328-338.
19. Liburd N, Ghosh M, Riazuddin S, et al.Novel mutations of MY015A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith-Magenis syndrome.Hum Genet.2001,109:535-41.
20. Wang A, Liang Y, Fridell RA, et al. Association of unconventional myosin MY015 mutations with human non-syndromic deafness DFNB3. Science 1998:280:1447-51.
1.屈涓,邱建华,王锦玲。谷氨酸的神经毒性对内耳的影响。听力学及言语疾病杂志,2004,12：201-203。
2.Ci J, Kato K, Ikeda J, et al. A narrow window for rescuing cells by the inhibition of calcium influx and the importance of influx route in rat cortical neuronal cell death by glutamate. Neurosci Lett,2001,304:29-32.
3. Pujol R, Puel JL, Gervais d'A. et al. Pathophysiology of the glutamatergic synapses in the cochlea. Acta Otolaryngol (Stockh),1993,113:330-334.
4. Jager W, Goiny M, Herrera-Marschitz M, et al. Noise-induced aspartate and glutamate efflux in the guinea pig cochlea and hearing loss. Exp Brain Res,2000,134:426-434.
5. Noguchi CT, Asavaritikrai P, Teng R, et al. Role of erythropoietin in the brain. Crit Rev Oncol Hematol 2007,64:157-159.
6. Montero M., Rom Poulsen F.,Noraberg J.,et al. Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen-glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures. Experimental Neurology,2007,204:106-117.
7.Picciotti. P, Torsello. A, Cantore. I, et al. Expression of vascular endothelial growth factor and its receptors in the cochlea of various experimental animals. Acta Oto-Laryngologica,2005,125:1152-1157.
8.张永全,蒋明,孙虹。神经营养素-3对豚鼠耳蜗传入神经元兴奋毒性损伤的保护作用。听力学及言语疾病杂志,2005,13：329-332。
9.卢圣栋主编,现代分子生物学实验技术,中国协和医科大学出版社.第2版.北京.1999.437。
10. Nordang L, Cestreicher E, Arnold W, et al. Glutamate is the afferent neurotransmitter in the human cochlea.Acta Otolaryngol.,2000,120:359-362.
11.Janssen R,Schweitzer L, Jensen KF. Glutamate neurotoxicity in the developing rat cochlea; physiological and morphological approaches[J]. Brain Res.,1991,28:255-264.
12. Carricondo F, Bartolome MV, Vicente-Torres MA, et al. Sensitivity to glutamate neurotoxicity in different developmental periods of the rat cochlea. Adv Otorhinolaryngol.,2002,59:91-95.
13. Sunami K, Yamane H, Nakagawa T, et al. Glutamate toxicity induced degeneration of outer hair cells with a temporal increase of nitric oxide production in the guinea pig cochlea.Eur Arch Otorhinolaryngol,1999,256:323-9.
14. Schindler RA, JadstoneHB, Scott N, et al. Enhanced preservation of the auditory nerve following cochlear perfusion with nerve growth factor. Am. J. Otol.1995,18:304-310.
15. Caye'-Thomasen P, Wagner N,Lidegaard F.B,et al.Erythropoietin and erythropoietin receptor expression in the guinea pig inner ear. Hear Res.,2005,203:21-7.
16.Andreeva N, Nyamaa A, Haupt H, et al. Recombinant human erythropoietin prevents ischemia-induced apoptosis and necrosis in explant cultures of the rat organ of Corti.Neurosci Lett.,2006,396:86-90.
17. Nurdanat B, Athanasia W, Priya G, et al. Neurite outgrowth on cultured spiral ganglion neurons induced by erythropoietin. Hearing Research,2008,243:121-126.
18. Shaheen FA, Mansuri NA, Sheikh IA, et al. Reversible uremic deafness:is it correlated with the degree of anemia? Ann Otol Rhinol Laryngol, 1997,106:391-393.
19. Sasaki, R., Pleiotropic functions of erythropoietin. Internal Med. 2003,42:142-149.
20. Marti, H. H., Bernaudin, M., Petit, E., et al., Neuroprotection and angiogenesis:dual role of erythropoietin in brain ischemia. News Physiol. Sci.2000,15:225-229.
21.Monge A, Nagy I, Bonabi S, et al. The effect of erythropoietin on gentamicin-induced auditory hair cell loss. Laryngoscope,2006,116:312-316
22. Frederiksen BL, Caye'-Thomasen P, Lund SP, et al. Does erythropoietin augment noise induced hearing loss? Hear Res.2007,223:129-137.
23. Monge Naldi A, Gassmann M., Bodmer D. Erythropoietin but not VEGF has a protective effect on auditory hair cells in the inner ear. Cell. Mol. Life Sci.2009,66:3595-9.
1.Cataneo AJ, Reibscheid SM, Ruiz Junior RL, et al, Foreign body in the tracheobronchial tree. Clin Pediatr.1997;36:701-706.
2. Oguz F, Citak A, Unuvar E, et al, Airway foreign bodies in childhood. Int. J. Pediat. Otorhinolaryngol.2000:52:11-16.
3. Tan HK, Brown K, McGill T, et al, Airway foreign bodies (FB):a 10-year review. Int. J. Pediat. Otorhinolaryngol 2000;56:91-99.
4. Daniilidis J., Symeonidis B.,Triaridis K.et al, Foreign body in the airways:a review of 90 cases. Arch.Otolaryngol.1997;103:570-573.
5. Wiseman N.E.,The diagnosis of foreign body aspiration in childhood, J. Pediat. Surg.1984;19:531-535.
6. Shubha A.M., Das K., Tracheobronchial foreign bodies in infants. Int. J. Pediat. Otorhinolaryngol.2009;73:1385-1389.
7. Puhakka H., Svedstrom E., Kero, P. et al, Tracheabronchial foreign bodies; a persistent problem in pediatric patients, AJDC.1989;143:543-545.
8. Weissberg D., Schwartz I.,Foreign bodies in the tracheabronchial tree, Chest.1987:91:730-733.
9. Zhijun C, Fugao Z, Niankai Z, et al, Therapeutic experience from 1,428 patients with pediatric tracheobronchial foreign body. J. Pediat.Surg.2008;43:718-721.
10. Tahir N, Ramsden WH, Stringer MD, Tracheobronchial anatomy and the distribution of inhaled foreign bodies in children.Eur. J. Pediat.2009;168:289-295.
11. Vanlooi j A. J., Roodp, P.M. Hoevel J. et al, Aspirated forieign bodies in children:Why are they more commonly found on the left? Clin. Otolaryngol.2003;28:364-367.
12. Kosloske A. M., Bronchoscopic extraction of aspirated foreign bodies in children, AJDC.1982;136:924-927.
13. Altmann A. E., Ozanne-Smith J., Non-fatal asphyxiation and foreign body ingestion in children 0-14 years, Inj. Prev.1997; 3:176-182.
14. Byard R. W., Mechanism of unexpected death in infants and young children following foreign body ingestion, J. Forensic Sci.1996; 41:438-441.
15. Altmann A. E., Ozanne-Smith J., Non-fatal asphyxiation and foreign body ingestion in children 0-14 years, Inj. Prev.1997;3:176-182.
16.Senkaya I., agdie K.,Gebitekin C.,Management of foreign body aspiration in infancy and childhood.A life～threatening problem. Turk. J. Pediat.1997,39:353—362.
2. Marazita ML, Ploushmall JM, RawlingsB, et al. Genetic epideMiological studies of early—onset deafness in the US school—age population. Am J Med Genet,1993,46:486-491.
3.李晨璞,支雄莉,韩英荣。肌球蛋白VⅥ定向运动的蒙特卡罗模拟。生物学杂志,27：8-12。
4. Lalwani AK, Goldstein J A, Kelley M J, et al. Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9. Am J Hum Genet,2000,67:1121—1128.
5. Adato A, Veli D, Kalinski H, et al. Mutation profile of all 49 exons of the human myosin VIIA gene, an d haplotype analysis, in Usher 1 B families from diverse origins. Am J Hum Genet,1997,61:813-821.
6. Ahmed ZM,Morell IL1, Riazuddin S, et al. Mutations of MYO6 are associated with recessive deafness, DFNB37. Am J Hurn Genet,2003,72:1315-1322.
5. Lister L, Roberts R, Schmitz S, et al. Myosin VI:a multifunctional motor. Biochem. Soc. Trans.2004,32:685-688.
6. Hasson T, Gillespie P G, Garcia J A et al.Unconventional Myosins in Inner-Ear Sensory Epithelia. J Cell Biol,1997,137:1287-1307.
7.Self T, Sobe T, Copeland NG, et al. Role of myosin VI inthe diferentiation of cochlear hair cells. De V Biol,1999,214:331-341.
8. Ahman D, Sweeney H L, Spudieh J A, et al.The mechanism of myosin VI translocation and its load—induced anchoring. Cell,2004,116:737—749.
9.Ahituv N, Sobe T, Robertson N G, et al.Genomic structure of the human unconventional myosin 6 gene. Gene,2000,261:269-275.
10. Rouxl I., Hosie S., Johnson S. L. et al. Myosin VI is required for the proper maturation and function of inner hair cell ribbon synapses. Human Molecular Genetics,2009,18:4615-4628.
11.Redowicz MJ. Myosins and deafness.J Muscle Res Cell Motil,1999,20: 241-248.
12. Avraham KB, Hasson T, Sobe T, et al. Characterization of unconventional MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice. Hum Mol Genet,1997,6:1225-1231.
13. Kappler J A, Starr C J, Chan D Ket, et al. A nonsense mutation in the gene encoding a zebrafish myosin VI isoform causes defects in hair-cell mechanotransduction; Proc Natl Acad Sci U S A.2004,101:13056-13061.
14. Self T, Sobe T, Copeland N G, et al. Role of myosin VI in the differentiation of cochlear hair cells.Development Biology,1999,214:331-341.
15. Melchionda S, Ahituv N,2, Bisceglia L et al. MY06, the Human Homologue of the Gene Responsible for Deafness in Snell's Waltzer Mice, Is Mutated in Autosomal Dominant Nonsyndromic Hearing Loss. Am J Hum Genet.,2003,72: 1315-1322.
16. Sato O, White H D, Inoue A et al. Human Deafness Mutation of Myosin VI (C442Y) Accelerates the ADP Dissociation Rate.J. Biol. Chem. 2004,279:28844-28854.
17. Mohiddin S A, Ahmed Z M, Griffith A J, et al. Novel association of hypertrophic cardiomyopathy, sensorineural deafness, and a mutation in unconventional myosin Ⅵ (MY06). J. Med. Genet.,2004;41;309-314.
18. Seiler C, Ben—David, Sidi S, et al. MyosinⅥ is required for structural integrity ofthe apical surface of sensory hair cells in zebrafish. Dev Biol,2004,272:328-338.
19.Liburd N, Ghosh M, Riazuddin S, et al. Novel mutations of MY015A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith-Magenis syndrome. Hum Genet.2001,109:535-41.
20. Wang A, Liang Y, Fridell RA, et al. Association of unconventional myosin MY015 mutations with human non-syndromic deafness DFNB3. Science 1998:280:1447-51.
1.屈涓,邱建华,王锦玲。谷氨酸的神经毒性对内耳的影响。听力学及言语疾病杂志,2004,12：201-203。
2. Ci J, Kato K, Ikeda J, et al. A narrow window for rescuing cells by the inhibition of calcium influx and the importance of influx route in rat cortical neuronal cell death by glutamate. Neurosci Lett,2001,304:29-32.
3. Pujol R, Puel JL, Gervais d'A. et al. Pathophysiology of the glutamatergic synapses in the cochlea. Acta Otolaryngol (Stockh),1993,113:330-334.
4. Jager W, Goiny M, Herrera-Marschitz M, et al. Noise-induced aspartate and glutamate efflux in the guinea pig cochlea and hearing loss. Exp Brain Res,2000,134:426-434.
5. Noguchi CT, Asavaritikrai P, Teng R, et al. Role of erythropoietin in the brain. Crit Rev Oncol Hematol 2007,64:157-159.
6. Montero M., Rom Poulsen F., Noraberg J., et al. Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen-glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures. Experimental Neurology,2007,204:106-117.
7. Picciotti.P, Torsello. A, Cantore. I, et al. Expression of vascular endothelial growth factor and its receptors in the cochlea of various experimental animals. Acta Oto-Laryngologica,2005,125:1152-1157.
8.张永全,蒋明,孙虹。神经营养素-3对豚鼠耳蜗传入神经元兴奋毒性损伤的保护作用。听力学及言语疾病杂志,2005,13：329-332。
9.卢圣栋主编,现代分子生物学实验技术,中国协和医科大学出版社.第2版.北京.1999.437。
10. Nordang L, Cestreicher E, Arnold W, et al. Glutamate is the afferent neurotransmitter in the human cochlea. Acta Otolaryngol.,2000, 120:359-362.
ll.Janssen R, Schweitzer L, Jensen KF. Glutamate neurotoxicity in the developing rat cochlea; physiological and morphological approaches[J]. Brain Res.,1991,28:255-264.
12. Carricondo F, Bartolome MV,Vicente-Torres MA, et al.Sensitivity to glutamate neurotoxicity in different developmental periods of the rat cochlea. Adv Otorhinolaryngol.,2002,59:91-95.
13. Sunami K, Yamane H, Nakagawa T, et al. Glutamate toxicity induced degeneration of outer hair cells with a temporal increase of nitric oxide production in the guinea pig cochlea. Eur Arch Otorhinolaryngol,1999,256:323-9.
14. Schindler RA, Jadstone HB, Scott N, et al. Enhanced preservation of the auditory nerve following cochlear perfusion with nerve growth factor. Am. J. Otol.1995,18:304-310.
15. Caye'-Thomasen P, Wagner N,Lidegaard F.B,et al. Erythropoietin and erythropoietin receptor expression in the guinea pig inner ear. Hear Res.,2005,203:21-7.
16. Andreeva N, Nyamaa A, Haupt H, et al. Recombinant human erythropoietin prevents ischemia-induced apoptosis and necrosis in explant cultures of the rat organ of Corti. Neurosci Lett.,2006,396:86-90.
17. Nurdanat B, Athanasia W, Priya G, et al. Neurite outgrowth on cultured spiral ganglion neurons induced by erythropoietin. Hearing Research,2008,243:121-126.
18. Shaheen FA, Mansuri NA, Sheikh IA, et al. Reversible uremic deafness:is it correlated with the degree of anemia? Ann Otol Rhinol Laryngol, 1997,106:391-393.
19. Sasaki, R., Pleiotropic functions of erythropoietin. Internal Med. 2003,42:142-149.
20. Marti, H. H., Bernaudin, M., Petit, E., et al., Neuroprotection and angiogenesis:dual role of erythropoietin in brain ischemia. News Physiol. Sci.2000,15:225-229.
21.Monge A, Nagy I, Bonabi S, et al.The effect of erythropoietin on gentamicin-induced auditory hair cell loss. Laryngoscope,2006, 116:312-316
22. Frederiksen BL, Caye'-Thomasen P, Lund SP,et al. Does erythropoietin augment noise induced hearing loss? Hear Res.2007,223:129-137.
23. Monge Naldi A, Gassmann M., Bodmer D. Erythropoietin but not VEGF has a protective effect on auditory hair cells in the inner ear.Cell. Mol. Life Sci.2009,66:3595-9.
1. Cataneo AJ, Reibscheid SM, Ruiz Junior RL, et al, Foreign body in the tracheobronchial tree. Clin Pediatr.1997;36:701-706.
2. Oguz F, Citak A, Unuvar E, et al,Airway foreign bodies in childhood. Int. J. Pediat. Otorhinolaryngol.2000;52:11-16.
3. Tan HK, Brown K, McGill T, et al, Airway foreign bodies (FB):a 10-year review. Int.J.Pediat. Otorhinolaryngol 2000;56:91-99.
4. Daniilidis J., Symeonidis B., Triaridis K. et al, Foreign body in the airways:a review of 90 cases. Arch. Otolaryngol.1997;103:570-573.
5. Wiseman N.E.,The diagnosis of foreign body aspiration in childhood, J. Pediat. Surg.1984:19:531-535.
6. Shubha A.M., Das K., Tracheobronchial foreign bodies in infants. Int. J. Pediat. Otorhinolaryngol.2009;73:1385-1389.
7. Puhakka H., Svedstrom E., Kero, P. et al, Tracheabronchial foreign bodies; a persistent problem in pediatric patients, AJDC.1989;143:543-545.
8.Weissberg D., Schwartz I., Foreign bodies in the tracheabronchial tree, Chest.1987:91:730-733.
9. Zhijun C, Fugao Z, Niankai Z, et al, Therapeutic experience from 1,428 patients with pediatric tracheobronchial foreign body. J.Pediat. Surg.2008;43:718-721.
10. Tahir N, Ramsden WH, Stringer MD, Tracheobronchial anatomy and the distribution of inhaled foreign bodies in children. Eur. J. Pediat.2009:168:289-295.
11.Vanlooij A. J., Roodp, P.M. Hoevel J. et al, Aspirated forieign bodies in children:Why are they more commonly found on the left? Clin. Otolaryngol.2003;28:364-367.
12. Kosloske A. M., Bronchoscopic extraction of aspirated foreign bodies in children, AJDC.1982;136:924-927.
13. Altmann A. E., Ozanne-Smith J., Non-fatal asphyxiation and foreign body ingestion in children 0-14 years, Inj. Prev.1997;3:176-182.
14. Byard R. W., Mechanism of unexpected death in infants and young children following foreign body ingestion, J. Forensic Sci.1996; 41:438-441.
15. Altmann A. E., Ozanne-Smith J., Non-fatal asphyxiation and foreign body ingestion in children 0-14 years, Inj. Prev.1997; 3:176-182.
16. Senkaya I.,agdie K.,Gebitekin C.,Management of foreign body aspiration in infancy and childhood. A life～threatening problem. Turk. J. Pediat.1997,39:353—362.
[1]. Pucci S, Mazzarelli P, Missiroli F, et al. Neuroprotection:VEGF, IL-6, and clusterin:the dark side of the moon. Prog Brain Res, 2008,173:555-73.
[2]. Breen EC. VEGF in biological control. J Cell Biochem, 2007,102:1358-67.
[3]. Germani A, Di Campli C, Pompilio G, et al. Regenerative therapy in peripheral artery disease. Cardiovasc Ther,2009,27:289-304.
[4]. Sodha NR, Chu LM, Boodhwani M, et al. Pharmacotherapy for end-stage coronary artery disease. Expert Opin Pharmacother,2010,11:207-13.
[5]. Sun FY, Guo X. Molecular and cellular mechanisms of neuroprotection by vascular endothelial growth factor. J Neurosci Res,2005,79:180-4.
[6]. Nicoletti JN, Shah SK, McCloskey DP, et al. Vascular endothelial growth factor is up-regulated after status epilepticus and protects against seizure-induced neuronal loss in hippocampus. Neuroscience,2008, 151:232-41.
[7]. Lee C, Agoston DV. Inhibition of VEGF receptor 2 increased cell death of dentate hilar neurons after traumatic brain injury. Exp Neurol,2009, 220:400-3.
[8]. Hermann DM, Zechariah A. Implications of vascular endothelial growth factor for postischemic neurovascular remodeling. J Cereb Blood Flow Metab,2009,29:1620-43.
[9]. Del Bo R, Ghezzi S, Scarpini E, et al. VEGF genetic variability is associated with increased risk of developing Alzheimer's disease. J Neurol Sci,2009,283:66-8.
[10]. Burger S, Noack M, Kirazov LP, et al. Vascular endothelial growth factor (VEGF) affects processing of amyloid precursor protein and beta-amyloidogenesis in brain slice cultures derived from transgenic Tg2576 mouse brain. Int J Dev Neurosci,2009,27:517-23.
[11]. Patel NS, Mathura VS, Bachmeier C, et al. Alzheimer's beta-amyloid peptide blocks vascular endothelial growth factor mediated signaling via direct interaction with VEGFR-2. J Neurochem,2010,112:66-76.
[12]. Le Prell CG, Yamashita D, Minami SB, et al. Mechanisms of noise-induced hearing loss indicate multiple methods of prevention. Hear Res,2007,226:22-43.
[13]. Cheng AG, Cunningham LL, Rubel EW. Mechanisms of hair cell death and protection. Curr Opin Otolaryngol Head Neck Surg,2005,13:343-8.
[14]. Rybak LP, Ramkumar V. Ototoxicity. Kidney Int,2007,72:931-5.
[15]. Picciotti PM, Torsello A, Cantore I, et al. Expression of vascular endothelial growth factor and its receptors in the cochlea of various experimental animals. Acta Otolaryngol,2005,125:1152-7.
[16]. Picciotti P, Torsello A, Wolf FI, et al. Age-dependent modifications of expression level of VEGF and its receptors in the inner ear. Exp Gerontol,2004,39:1253-8.
[17]. Picciotti PM, Fetoni AR, Paludetti G, et al. Vascular endothelial growth factor (VEGF) expression in noise-induced hearing loss. Hear Res, 2006,214:76-83.
[18]. Selivanova 0, Heinrich UR, Brieger J, et al. Fast alterations of vascular endothelial growth factor (VEGF) expression and that of its receptors (Flt-1, Flk-1 and Neuropilin) in the cochlea of guinea pigs after moderate noise exposure. Eur Arch Otorhinolaryngol,2007,264:121-8.
[19]. Zou J, Pyykko I, Sutinen P, et al. Vibration induced hearing loss in guinea pig cochlea:expression of TNF-alpha and VEGF. Hear Res,2005, 202:13-20.
1.第二次全国残疾人抽样调查领导小组,中华人民共和国国家统计局。2006年第二次全国残疾人抽样调查主要数据公报。中国康复理论与实践,2006,12(12)：1013。
2. Marazita ML, Ploushmall JM, Rawlings B, et al. Genetic epidemiological studies of early—onset deafness in the US school—age population.Am J Med Genet,1993,46:486-491.
3.李晨璞,支雄莉,韩英荣。肌球蛋白VⅥ定向运动的蒙特卡罗模拟。生物学杂志,27：8-12。
4.Lalwani AK, Goldstein J A, Kelley M J, et al. Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myo— sin MYH9. Am J Hum Genet,2000,67:1121—1128.
5.Adato A, Veli D, Kalinski H, et al. Mutation profile of all 49 exons of the human myosin VIIA gene, an d haplotype analysis, in Usher 1 B families from diverse origins. Am J Hum Genet,1997,61:813-821.
6.Ahmed ZM, Morell IL1, Riazuddin S, et al. Mutations of MY06 arc associated with recessive deafness, DFNB37. Am J Hurn Genet, 2003,72:1315-1322.
5. Lister L, Roberts R, Schmitz S, et al. Myosin VI:a multifunctional motor. Biochem. Soc. Trans.2004,32:685-688.
6.Hasson T, Gillespie P G, Garcia J A et al. Unconventional Myosins in Inner-Ear Sensory Epithelia. J Cell Biol,1997,137:1287-1307.
7. Self T, Sobe T, Copeland NG, et al. Role of myosin VI inthe diferentiation of cochlear hair cells. De V Biol,1999,214:331-341.
8.Ahman D, Sweeney H L, Spudieh J A, et al.The mechanism of myosin VI translocation and its load—induced anchoring. Cell,2004,116:737—749.
9.Ahituv N, Sobe T, Robertson N G, et al.Genomic structure of the human unconventional myosin 6 gene. Gene,2000,261:269-275.
10. Rouxl I., Hosie S., Johnson S. L. et al. Myosin VI is required for the proper maturation and function of inner hair cell ribbon synapses. Human Molecular Genetics,2009,18:4615-4628.
ll.Redowicz MJ. Myosins and deafness. J Muscle Res Cell Motil,1999,20: 241-248.
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