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目的探讨大剂量甲氨蝶呤静滴+鞘内注射治疗急性淋巴细胞白血病(ALL)患儿时中枢神经系统损伤的监测指标。方法2003年1～12月在青岛大学医学院附属医院收治的42例标危ALL患儿中。在行大剂量甲氨蝶呤静滴+鞘内注射化疗前及化疗后15、30、45d腰穿留取脑脊液(CSF)各1mL,用双抗体夹心酶联免疫法测定CSF中神经元特异性烯醇化酶(NSE)的质量浓度。结果化疗后,CSF中NSE质量浓度升高,于第15天达峰值,化疗30dNSE质量浓度下降,与化疗前比较差异有统计学意义;化疗45d后NSE质量浓度与化疗前比较差异无统计学意义。结论CSF中NSE是ALL患儿行大剂量甲氨蝶呤静滴+鞘内注射化疗时,神经细胞急性损伤的一个有价值的预报因子。     

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目的观察单纯性肥胖儿童和健康正常体重儿童血清脑源性神经营养因子(BDNF)质量浓度的差异,探讨BDNF与儿童肥胖及瘦素抵抗、胰岛素抵抗的关系。方法南京军区福州总医院儿科等于2004年5月至2005年5月应用酶联免疫法检测单纯性肥胖儿童(37例)和健康儿童(31例)血清BDNF质量浓度与胰岛素(INS)浓度,应用放射免疫法检测血清瘦素(LEP)质量浓度。比较两组儿童血清BDNF、INS、LEP的差异,分析血清BDNF质量浓度与血清LEP质量浓度和INS浓度的关系。结果(1)两组儿童的体重指数(BMI)、BDNF、INS及LEP均差异显著(BMI:F=175·05,P<0·01;BDNF:F=12·35,P<0·01;INS:F=21·71,P<0·01;LEP:F=48·89,P<0·01),肥胖组BMI、INS及LEP均明显高于健康组,而肥胖组BDNF明显低于健康组。(2)影响LEP的因素依次为BMI、丙氨酸转氨酶(ALT)、BDNF(R2=0·5946,F=0·31,P<0·01);影响INS的因素依次为BMI、BDNF(R2=0·2647,F=11·34,P<0·01)。去除BMI、ALT影响后,BDNF与LEP、INS负相关(BDNF与LEP:r=-0·2455,P<0·05;BDNF与INS:r=-0·2878,P<0·05)。结论(1)肥胖儿童血清BDNF缺乏,未发现“BDNF抵抗”的特点。(2)学龄前儿童血清LEP、INS受BMI影响最大,还受血清BDNF影响。BDNF是二者独立的负相关因素。     

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目的观察病毒性脑炎(病脑)患儿血浆溶血磷脂酸(LPA)浓度动态变化,并探讨其临床意义。方法2004年9月至2005年9月,对保定市儿童医院收治的102例病脑住院患儿,按入院日期随机分为观察I组(52例)和观察II组(50例),两组均给常规治疗,观察I组加用复方丹参注射液。两组均在入院治疗前采静脉血5mL,治疗后5,7,10,14d分别于清晨采空腹静脉血5mL,采用比色测定法测定血浆LPA浓度,同时测定凝血指标。设健康儿童20例为对照组,并进行比较。结果病脑病情轻度者,LPA浓度于治疗后不同时间的差异不显著,P>0·05;重度病脑患儿发病后LPA即明显升高,以后渐降低,治疗14d时基本正常。观察I组LPA恢复正常时间较观察II组短,病情好转亦快。10d时观察I组比观察II组临床治愈好转的例数多,P<0·05。凝血指标的变化与LPA呈正相关。结论病脑患儿急性期LPA浓度升高,证明病脑存在血栓前状态,LPA升高与病情严重程度呈正相关,随病情好转而恢复正常。提示病脑患儿尤其是重度者应予以抗凝治疗。LPA浓度可作为病脑病情严重程度及估计预后指标之一,可用于指导治疗。     

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目的通过分析不同刺激速率下的脑干听觉诱发电位变化,观察有缺氧病史的早产儿在纠正胎龄足月时的脑功能状态。方法2002年7月至2004年7月复旦大学儿科医院新生儿科收治的早产儿,缺氧组:39例,有缺氧病史,除外其它听力及脑损伤高危因素;对照组:30例,无缺氧病史,无其他听力损伤高危因素。两组于纠正胎龄37～42周时进行脑干听觉诱发电位检查,声刺激速率为21.1/s、51.1/s和91.1/s,分析Ⅰ、Ⅲ、Ⅴ波的潜伏期、振幅、峰间期等参数,进行t检验。结果在60dBnHL刺激强度下,随刺激速率增加,各组Ⅰ、Ⅲ、Ⅴ波的潜伏期、峰间期均逐渐延长,振幅下降。在常规21.1/s时,缺氧组仅表现为Ⅴ波潜伏期和Ⅲ～Ⅴ峰间期延长;随刺激速率增加,不仅上述差异更加显著,而且Ⅲ波潜伏期、Ⅴ波振幅及Ⅰ～Ⅲ、Ⅰ～Ⅴ峰间期也表现出差异。结论有缺氧病史的早产儿在纠正胎龄足月时脑干功能仍存在异常,提高刺激速率有助于异常的检出,为更好地研究新生儿脑干功能状态及发育规律提供了新的方法。     

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目的探讨托吡酯对癫疒间患儿部分内分泌功能的影响。方法于2003年6月~2004年6月对山东省立医院儿科符合癫疒间诊断的36例患儿分别于治疗前、治疗3个月、治疗6个月测量血中部分内分泌激素,并对其进行比较。结果血三碘甲状腺氨酸(T3)在治疗3个月时较治疗前明显增高(P<0.05),6个月时增高不明显;而胰岛素、皮质醇、C-肽在治疗3个月、6个月时则明显降低(P<0.05),但在治疗3、6个月之间T3、胰岛素、皮质醇、C-肽并无明显变化;T4、TSH、生长激素在治疗过程中无明显变化;体重指数在治疗3个月时明显下降,6个月时又有所回升。结论托吡酯对生长激素无明显影响,不影响儿童的生长发育。     

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??Abstract?? Attention deficit hyperactivity disorder??ADHD??is the most popular mental disorder. It influenced 5%??10% of children and about 4% of adults. There are a huge number of researches about ADHD every year. ADHD is a long-term??chronic condition if it is not treated correctly. ADHD may lead to bed prognosis??even some troubles with the law. So it is very important to make early diagnosis and intervention for ADHD. The new Diagnostic and Statistical Manual of Mental Disorders??5th Edition ??DSM-???? has a number of changes to ADHD. To master the changes in DSM-??is the best way to get quickly and thoroughly updated on diagnostic criteria and classifications of ADHD.     

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目的探讨中枢神经系统感染患儿脑脊液中胰岛素样生长因子(IGFs)的变化及意义。方法选择2001年2月至2003年6月在新乡医学院一附院治疗的化脓性脑膜炎患儿30例、病毒性脑炎30例,以非中枢神经系统疾病、非感染性疾病的患儿30例作对照组。脑脊液中胰岛素样生长因子Ⅰ(IGFⅠ)用放射免疫分析法检测,脑脊液中胰岛素样生长因子Ⅱ(IGFⅡ)用免疫放射分析法检测。结果(1)化脓性脑膜炎患儿脑脊液中IGFⅠ、IGFⅡ质量浓度均显著高于病毒性脑炎组及对照组(P<0.01);(2)化脓性脑膜炎患儿脑脊液中IGFⅡ的质量浓度与蛋白质浓度呈正相关(r=0.821,P<0.05),与葡萄糖浓度呈负相关(r=-0.742,P<0.01);(3)化脓性脑膜炎患儿脑脊液中IGFⅠ的质量浓度与蛋白质浓度呈正相关(r=0.862,P<0.01)。结论IGFs参与了化脓性脑膜炎的病理生理过程,并参与了脑脊液中葡萄糖和蛋白质的代谢。脑脊液中IGFⅠ、IGFⅡ的浓度可作为鉴别化脓性脑膜炎和病毒性脑炎的一项辅助指标。     

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目的探讨儿童幽门螺杆菌(H.pylori)感染及抗H.pylori治疗对儿童肠道菌群状态的影响。方法将浙江大学医学院附属儿童医院2004年410月门诊收治的68例慢性胃炎、十二指肠球炎患儿分为H.pylori阳性组36例、H.pylori阴性组32例二组。称取68例患儿新鲜粪便1.0g,分别进行需氧和厌氧培养,分离肠道菌群中最有代表性的三种需氧菌(肠杆菌、肠球菌、酵母菌)和四种厌氧菌(双歧杆菌、乳杆菌、类杆菌、产气荚膜梭菌),菌落记数,同时计算B/E比值来代表定植抗力。对36例H.pylori阳性组中的26例患儿进行“三联”抗H.pylori治疗1周后留取新鲜粪便进行肠道菌群分析,5例患儿在停药1个月后再次进行肠道菌群分析。结果H.pylori阳性组和H.pylori阴性组上述三种需氧菌和四种厌氧菌的菌落检出率比较,差异无统计学意义(P>0.05)。抗H.pylori治疗1周后双歧杆菌、乳杆菌、类杆菌菌落数量较治疗前明显降低(P<0.05),B/E值明显下降(P<0.01),酵母菌的检出率明显增加(P<0.05),产气荚膜梭菌检出率下降(P<0.05)。5例患儿在停药1个月后,乳酸杆菌数量仍继续下降,肠杆菌数量继续增加,双歧杆菌、类杆菌数量有所恢复,但仍低于治疗前。结论儿童H.pylori感染后对肠道菌群影响不大;三联疗法抗H.pylori治疗对儿童肠道菌群产生明显的影响,因此在治疗H.pylori感染时须考虑到大量抗生素治疗后可能对患儿的副作用及潜在的危险。     

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目的观察单纯性肥胖儿童血浆瘦素及可溶性瘦素受体质量浓度的变化,探讨其相互之间及与体重指数(BMI)之间的关系。方法于2005-06北京儿童医院采用酶联免疫吸附试验(ELISA)对40例3~6岁的单纯性肥胖儿童及按性别、年龄1∶1配对的40例正常儿童进行了血浆瘦素及可溶性瘦素受体质量浓度的检测。结果肥胖儿童血浆瘦素质量浓度(22.26±2.30)μg/L较正常儿童(3.36±0.23)μg/L明显升高,可溶性瘦素受体质量浓度(100.10±24.60)μg/L较正常儿童(132.31±30.17)μg/L则明显降低(P<0.001)。相关性分析显示,瘦素与可溶性瘦素受体水平之间呈负相关;BMI与瘦素呈正相关,而与可溶性瘦素受体呈负相关(P<0.05)。结论学龄前肥胖儿童已存在明显的瘦素抵抗现象,而可溶性瘦素受体表达减少,可能参与了瘦素抵抗的发生。     

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??Objective To compare the etiologic factors??clinical features and prognosis in newborns with gastrointestinal perforation. Methods A retrospective study of the clinical data from 80 cases with diagnosis of gastrointestinal perforation collected from January 2004 to December 2015 was performed. Based on whether they were full-term??the cases were divided into two groups??then the clinical features??etiologic factors and prognosis were compared. Results Among the 80 neonates with gastrointestinal perforation??there were 62 preterm infants and 18 full-term infants. The main causes of gastrointestinal perforation for the two groups was necrotizing enterocolitis??with the most frequent clinical symptom of abdominal distension.cases. Compared with full-term infants??the incidence of preterm shock??dyspnea??DIC??and poor reaction was significantly higher in preterm infants??P??0.05??.The mean time period of perforation in preterm infants group was 9??1.75??20?? d??while it was 4.5??1??7.75?? d in full-term infants group.There were 62 cases that received surgical treatment??8 cases of which were gastric perforation and 54 cases were intestinal perforation. The exact site of perforation of the 18 cases who refused surgical treatment was not clear. Of all the cases??32 infants died with the overall mortality rate of 40%. For the preterm infants??the mortality was 41.9% ??26 cases????while it was 33.3% ??6 cases?? in the full-term infants group. Conclusion Neonatal gastrointestinal perforation is one of the serious diseases in neonatal period??which has a very high mortality rate. Early diagnosis??active treatment and timely surgical intervention can significantly improve survival rates and improve the prognosis.     

甲基丙二酸血症诊治研究进展

甲基丙二酸血症是一种常见的有机酸血症,属于常染色体隐性遗传病,临床表现无特异性,以反复呕吐及嗜睡、惊厥等神经系统症状为主.诊断依靠串联质谱检测血中的酰基肉碱和气相色谱-质谱检测尿甲基丙二酸.对伴有同型半胱氨酸血症患儿,治疗以维生素B12、甜菜碱和左旋肉碱为主;对不伴有同型半胱氨酸血症患儿以限制天然蛋白质摄入,给予去除异亮氨酸、缬氨酸、甲硫氨酸和苏氨酸的特殊奶粉及左旋肉碱治疗为主.维生素B12治疗有效型预后较好,治疗无效型预后较差.     

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??Abstract??Objective??To summarize the clinical features and prognosis of epilepsy in children with MMA. Methods??From Jan. 1997 to Dec. 2009 in Department of Pediatrics??Peking University First Hospital??the medical records of hospitalized MMA patients complicated with epilepsy were retrospectively reviewed. The clinical manifestations??laboratory examination results??and treatment modalities were analyzed. Results??From 63 pediatric inpatients diagnosed with MMA??27 children ??42.9%?? complicated with epilepsy were enrolled in this study. These 27 patients were also accompanied with other neurological manifestations?? including mental retardation or regression ??n = 22????lethargy ??n = 10????increased muscle tone ??n = 8????muscle hypotonia ??n = 8????recurrent vomiting ??n = 4????tremor ??n = 2????ataxia ??n = 2????and abnormal posture ??n = 1??.The onset age of seizure ranged from 8 days to 11 years. The seizure types included partial seizure??n = 21????generalized tonic-clonic seizure ??n = 5????tonic seizure ??n = 3????myoclonic seizure ??n = 3????and epileptic spasm ??n = 2??. Five patients had 2 or 3 seizure types. Nine patients ??33.3%?? had a history of status epilepticus. EEG showed slow background activity in 17 patients??focal or multifocal discharges in 16 patients??generalized discharges in 4 patients??hypsarrathmia in 2 patients??and suppression-burst pattern in 1 patient. Cranial MRI showed cerebral atrophy ??n = 14????white matter changes ??n = 12????agenesis of corpus callosum ??n = 2????abnormal signal in basal ganglia ??n = 2????and cerebellar atrophy ??n = 1??. Twenty-one patients were MMA combined with homocysteinemia.Seventeen patients were confirmed with cobalamin C disease and one with partial mutase deficiency ??mut-??. Vitamin B12-responsive patients had a better outcome compared with vitamin B12-unresponsive patients. Conclusion??Epilepsy is a common manifestation of patients with MMA.Partial seizures is more common than other seizure types.Urine organic acid analysis should be performed for children with unknown cause of epilepsy combined with other neurological manifestations?? so as to promptly identify the etiology and improve the prognosis.     

Juvenile gout in methylmalonic acidemia

Methylmalonic acidemia (MMA) is an inborn error of metabolism caused by either deficiency of the enzyme methylmalonyl‐CoA mutase or a defect in adenosyl‐cobalamin synthesis. Chronic kidney disease is its common complication and, in combination with persistent acidosis, leads to hyperuricemia. Symptomatic hyperuricemia or gout, however, has not been reported in MMA. We herein report two pediatric cases of MMA caused by MMAB mutations (cblB defect) with renal tubular acidosis, chronic kidney disease, hyperuricemia, and gout. The clinical findings of gout in these cases included recurrent first metatarsophalangeal arthritis and/or tophi. The patients responded to treatment with colchicine and allopurinol.     

Stabilization of blood methylmalonic acid level in methylmalonic acidemia after liver transplantation

Chen PW, Hwu WL, Ho MC, Lee NC, Chien YH, Ni YH, Lee PH. Stabilization of blood methylmalonic acid level in methylmalonic acidemia after liver transplantation.
Pediatr Transplantation 2010: 14: 337–341. © 2009 John Wiley & Sons A/S. Abstract: Methylmalonic acidemia with complete mutase deficiency (mut⁰ type) is an inborn error of metabolism with high mortality and morbidity. LT has been suggested to be a solution to this disease, but elevation of urinary and blood MMA was still observed after LT. In this study, we measured dry blood spot MMA and its precursor propionyl‐carnitine (C3‐carnitine) for mut⁰ patients. The results revealed that when C3‐carnitine rose during metabolic stress, MMA rose exponentially (up to 1000 μmol/L) in patients who did not undergo LT. In patients who underwent LT, MMA rose to 100–200 μmol/L when C3‐carnitine reached 10–20 μmol/L. However, when C3‐carnitine rose further to 40–50 μmol/L, MMA levels just stayed put. Therefore, LT stabilized blood MMA level, though there might be a threshold for blood MMA clearance by the donor liver. This finding should be critical to understand the long‐term outcome for LT in methylmalonic acidemia.     

甲基丙二酸血症儿童尿液硫化氢的变化及意义

目的　探讨尿硫化氢（H2S）在甲基丙二酸血症（methylmalonic acidemia,MMA）患儿尿液中的变化及临床价值。方法　将2016年9月至2017年11月在北京大学第一医院就诊的20例MMA 患儿作为病例组（男13例,女7例）,同时将20例健康儿童作为对照组（男11例,女9例）,留取所有儿童新鲜尿液。采用自由基检测仪检测正常儿童与MMA 患儿尿液中的H2S浓度,对照病例组与对照组尿H2S浓度的差异,并对结果进行分析。结果　20例MMA患儿尿H2S浓度（64.9±52.0） μmmol/L高于对照组尿H2S 浓度（43.9±40.0） μmmol/L,差异具有统计学意义（Z＝-3.435,P＝0.001）;尿H2S浓度辅助判断MMA的ROC 曲线分析中曲线下面积（AUC）为0.818,以尿H2S浓度47.72 μmmol/L为界值,辅助判断MMA 的敏感度为95%,特异度为60%。结论　MMA 患儿尿液H2S含量高,尿H2S浓度检测有助于MMA的尽早诊断,或可作为新生儿筛查、MMA 患儿动态观察和疗效评估的参考指标。     

儿童危重型甲基丙二酸血症临床特点及基因分析

目的分析危重型甲基丙二酸血症的临床及基因学特点。方法回顾分析2015年9月至2018年12月34例危重型甲基丙二酸血症患儿的临床资料,其中11例行基因检测。结果 34例患儿中男18例、女16例,中位发病年龄为11.5个月。所有患儿均存在2个及以上脏器功能障碍或衰竭,除常见血液系统、肝、肾、心、肺血管及神经系统损害外,11例合并纤维蛋白原水平降低,3例合并第四脑室中、侧孔先天性闭锁脑发育畸形(Dandy-Walker畸形)。11例行基因检测的患儿中,9例为MMACHC基因突变,c.609GA位点突变为合并型甲基丙二酸血症热点突变,其中2例行基因检测的脑发育畸形患儿均存在c.609GA位点突变;另2例为单纯型甲基丙二酸血症,均为甲基丙二酰辅酶A变位酶(MUT)基因突变所致。结论危重型甲基丙二酸血症患儿神经损害最常见,部分可合并脑发育畸形,且可能与c.609GA基因位点突变有关;可合并纤维蛋白原水平降低。     

Three novel and six common mutations in 11 patients with methylmalonic acidemia

BACKGROUND: Patients with a defect in methylmalonyl-coenzyme A mutase (MCM) are classified as having methylmalonic acidemia, which is divided into two subclasses: mut(0) and mut(-). Fifty-five disease-causing mutations have been identified. Although most are private mutations, only three (E117X, G717V, and N219Y) are reportedly common in Japanese, Black, and Caucasian populations, respectively. Here we identified mutations in 11 Japanese patients with MCM deficiency. METHODS: Mutational analysis was performed in 11 unrelated Japanese patients with MCM deficiency using polymerase chain reaction and direct sequencing. RESULTS: Three novel (L494X, R727X, and 449_461del) and six previously reported (R93H, E117X, N219Y, R369H, G648D and IVS2 + 5G>A) mutations were identified. The L494X mutation was found in three unrelated patients, and the R93H, E117X, R369H, G648D, and IVS2 + 5G>A mutations occurred more than once. Two of the patients were classified as mut(-) phenotype because of residual [(14)C]-propionate incorporation in the presence of a high concentration of hydroxocobalamin. The two mut(-) patients were heterozygous for the G648D mutation and presented with lethargy and metabolic acidosis after 2 years of life. Their psychomotor development has been documented as normal. The patients with the R727X or c.374_385del [corrected] mutations clinically exhibited mut(0) phenotype. Two patients with mut(0) phenotype died in infancy. One presented early in the neonatal period; the other was symptomatic in the late infantile period. CONCLUSIONS: The L494X, R93H, E117X, R369H, G648D, and IVS2 + 5G>A mutations are found in more than two unrelated families in the Japanese population. The short-term outcome was generally poor in patients with mut(0), and therefore alternative treatments should be considered.     

Renal cell carcinoma harboring somatic TSC2 mutations in a child with methylmalonic acidemia

Pediatric renal cell carcinoma (RCC) is a rare cancer that can be associated with inherited diseases including tuberous sclerosis complex (TSC) caused by germline mutations in TSC1 or TSC2. Somatic mutations in TSC1 and TSC2 have also been reported in adult RCC, which predict response to mTOR inhibitors. Here, we present the first case of RCC in a child with methylmalonic acidemia (MMA). Clinical whole exome sequencing of blood and tumor samples confirmed the diagnosis of MMA and revealed two somatic inactivating mutations in TSC2, suggesting the potential consideration of an mTOR inhibitor in the event of tumor recurrence.     

Dietary therapy in two patients with vitamin B12-unresponsive methylmalonic acidemia

The biochemical and therapeutic responses to dietary therapy were studied in a 25-month-old girl and a 1-month-old girl with methylmalonic acidemia (MMA-emia), which was unresponsive to vitamin B₁₂.The minimum daily intake of protein which patients could tolerate and display a good development was between 1.0 and 1.2 g per kg body weight. Supplementation with amino acid mixture devoid of toxic amino acids was required to prevent protein malnutrition when daily protein intake was restricted to 0.6 g per kg body weight. Caloric intake should be sufficient, not only to promote growth but also to prevent a rise in MMA level, especially when a patient has ketoacidosis.It was found that MMA excretion per mg creatinine in random urine specimens correlated significantly with serum MMA and twenty four-hour output of MMA per kg body weight. Therefore measurement of MMA in a single urine specimen is useful for evaluating the in vivo accumulation of MMA.