儿童左束支区域起搏六例临床观察

目的探讨儿童左束支区域起搏(LBBAP)的安全性及有效性.方法回顾性分析2019年1月至6月于北京安贞医院小儿心脏科住院采用LBBAP方式行永久心脏起搏器植入术的6例患儿(男1例、女5例)的临床资料、起搏心电图及参数并进行随访.组间比较采用t检验.结果6例患儿年龄9~14岁,体重26~48 kg;三度房室传导阻滞5例,右室心尖起搏术后伴心功能下降1例;1例患儿心功能降低,余5例心功能均正常;QRS波时限(95±13)ms;左心室舒张末径(LVEDD)Z值为1.85±0.65.起搏心电图V1呈右束支传导阻滞样,QRS波时限(111±20)ms,与术前相比,差异无统计学意义(t=-1.610,P>0.05).起搏阈值为(0.85±0.26)V,感知(15.0±4.3)mV,阻抗(717±72)Ω.3例可记录到P电位.起搏钉至左心室激动时间为(56±5)ms,不同输出电压下数值恒定.术后超声提示电极均位于室间隔左心室心内膜下.随访无心肌穿孔、电极脱位等并发症发生,患儿术后3个月阈值、感知及阻抗分别为(0.60±0.09)V、(16.1±3.9)mV、(662±78)Ω.左心室射血分数(LVEF)降低者LBBAP术后3d恢复正常(45%比57%).术后3个月LVEDD Z值降至(1.1±0.3),较术前明显减小(t=2.383,P<0.05).结论LBBAP可实现窄QRS波起搏,接近生理性起搏,起搏参数稳定,可快速、有效地纠正长期心动过缓所致的左心扩大及长期右室心尖起搏所致的心功能低下及心脏扩大.较大年龄儿童行LBBAP近期安全性、有效性好,远期潜在风险有待进一步观察研究.     

SGCE基因变异致儿童肌阵挛肌张力障碍综合征临床特点及基因分析

目的探讨SGCE基因变异导致儿童期起病的肌阵挛肌张力障碍综合征患儿的临床特点及基因分型.方法收集2018年5月至2019年10月首都医科大学附属北京儿童医院神经内科和北京大学第一医院儿科共同收集的9例经全外显子组测序方法以及多重链接依赖的探针扩增技术确诊的SGCE基因变异导致的肌阵挛肌张力障碍综合征患儿的临床资料,并对患儿进行随访,对临床特点及基因变异结果进行回顾性总结分析.结果9例患儿中男4例、女5例,起病年龄1岁~3岁2月龄.首发症状为肌阵挛者4例,肌张力障碍者5例.病程中,9例均有肌阵挛症状,8例有肌张力障碍症状.8例肌阵挛表现为双上肢不自主抖动.6例病程中曾有下肢突然抖动一下,导致步态不稳甚至跌倒.肌张力障碍症状表现为行走姿势异常,其中5例右下肢受累,3例左下肢受累.3例有阳性家族史.9例患儿智力发育均正常.发作期及发作间期视频脑电图未见明显异常,肌电图及头颅磁共振成像正常.基因结果示9例携带SGCE基因变异,其中3例为移码变异,2例为无义变异,2例为错义变异,1例为大片段缺失变异,1例为剪切位点变异;7例为遗传性变异,均为父源,2例为新生变异.治疗上,8例加用美多芭口服,6例肌阵挛较前有所减少,走路姿势不同程度改善.4例加用硝西泮,2例有效.结论SGCE基因变异可导致肌阵挛肌张力障碍综合征,多在幼儿期或学龄前期起病,肌阵挛和肌张力障碍均可为首发症状.非癫痫性肌阵挛是其突出症状,且有上肢优势特点.绝大多数病程中伴肌张力障碍,部分肌张力障碍可自行缓解.SGCE基因为母源印记基因,遗传性变异多为父源.     

反射性共聚焦显微镜对早期蕈样肉芽肿定位诊断与疗效监测的研究

【摘要】 目的 分析早期蕈样肉芽肿（MF）皮损的反射性共聚焦显微镜（RCM）与组织病理学特征的一致性,探讨RCM作为病理学诊断早期MF的辅助价值及动态监测治疗反应的可行性。方法 2014年1月至2018年1月在杭州市第三人民医院皮肤科门诊收集临床疑诊MF病例40例,男26例,女14例,年龄（47.0 ± 17.6）岁。根据总结的早期MF的RCM特征,对活检部位进行初步定位后行组织病理学检查,对比MF的RCM与病理特征。对MF确诊病例进行窄谱中波紫外线联合干扰素治疗,运用RCM对靶向皮损跟踪随访,9个月后评价疗效。结果 在40例临床疑诊MF病例中,根据RCM特征初步诊断典型MF 8例,疑似MF18例,排除14例;根据MF病理学特征诊断典型MF12例,疑似14例,排除14例。一致性分析显示,RCM特征分类与病理诊断结果的Kappa系数为0.848,P < 0.01。RCM与组织病理学特征之间表皮低折光细胞浸润的相关性最高（Kappa系数 = 1,P = 0.005）,其次是红斑期的真皮纤维化（Kappa系数 = 0.714,P = 0.035）。MF的RCM特征随着治疗的进行逐步恢复正常,但直至临床皮损完全缓解,非典型淋巴细胞依然存在。结论 RCM技术可用于早期疑诊MF皮损的病理取材定位,同时可尝试作为一种动态监测MF疗效的方法。     

Stage-specific regulation of oligodendrocyte development by Hedgehog signaling in the spinal cord

Elucidation of signaling pathways that control oligodendrocyte (OL) development is a prerequisite for developing novel strategies for myelin repair in neurological diseases. Despite the extensive work outlining the importance of Hedgehog (Hh) signaling in the commitment and generation of OL progenitor cells (OPCs), there are conflicting reports on the role of Hh signaling in regulating OL differentiation and maturation. In the present study, we systematically investigated OPC specification and differentiation in genetically modified mouse models of Smoothened (Smo), an essential component of the Hh signaling pathway in vertebrates. Through conditional gain-of-function strategy, we demonstrated that hyperactivation of Smo in neural progenitors induced transient ectopic OPC generation and precocious OL differentiation accompanied by the co-induction of Olig2 and Nkx2.2. After the commitment of OL lineage, Smo activity is not required for OL differentiation, and sustained expression of Smo in OPCs stimulated cell proliferation but inhibited terminal differentiation. These findings have uncovered the stage-specific regulation of OL development by Smo-mediated Hh signaling, providing novel insights into the molecular regulation of OL differentiation and myelin repair.     

二甲双胍增强放射对CT26WT细胞及小鼠移植瘤效应机制研究

目的 探讨二甲双胍(Met)联合放射对结肠癌CT26WT细胞及移植瘤的抑制作用及其机制研究。方法 利用CellTiter-Glo化学发光细胞活性试验检测0.5、1.0、5.0、10.0μmol/L的Met对CT26WT细胞活力影响,克隆形成试验检测对照组、10.0μmol/L的Met、15Gy照射、15Gy+10.0μmol/L的Met组对CT26WT细胞的增殖抑制作用。构建Bablc小鼠皮下移植瘤模型,肿瘤体积>150mm³随机分对照组、单纯15Gy照射、Met组、15Gy+Met组,照射前24h给予小鼠750 mg/kg的Met,定期测量肿瘤体积及小鼠体重绘制肿瘤生长曲线及生存时间曲线。蛋白质印迹法检测上述处理条件下CT26WT细胞及移植瘤组织中P-H2AX、Sting蛋白表达;并利用免疫组化方法检测移植瘤组织中CD8a (+) T细胞的浸润情况。结果 0、0.5、1.0、5.0、10.0μmol/L的Met的相对细胞存活率分别为100%、87.9%、87.8%、87.3%、76.5%(P<0.05),其中10.0μmol/L较5.0μmol/L抑制作用更强(P<0.001)。克隆形成实验结果显示对照组、Met组、15Gy组、15Gy+Met组细胞克隆形成率分别为34.0%、24.0%、22.3%、14.0%(P<0.001)。与对照组比较,Met组、15Gy组、15Gy+Met组细胞内Sting蛋白表达分别增加2.99、1.37、4.41倍(P<0.001、<0.01、<0.001)。15Gy+Met组P-H2AX蛋白表达较15Gy组增加1.43倍(P<0.001)。移植瘤体积15Gy+Met组较对照组生长缓慢,最终结果为(1007.0±388.5)、(2639.0±242.9) mm³,(P<0.05),15Gy+Met组小鼠总生存期较对照组增加(48d︰32d,P<0.001)。移植瘤组织中P-H2AX、Sting蛋白表达量在15Gy+Met组较对照组分别增加8.8、1.6倍(P均<0.001)。15Gy+Met组CD8a (+) T细胞浸润在较对照组明显增高(P<0.01)。结论 Met与放射联合能协同抑制结肠癌细胞增殖、克隆形成,可能作用机制是通过加重DNA损伤、激活Sting信号通路导致肿瘤组织中CD8a (+) T细胞增加加强对肿瘤细胞的杀伤作用。     

Hepatitis B virus infection and the risk of cancer among the Chinese population

The relationship between hepatitis B virus (HBV) and nonhepatocellular cancers remains inconclusive. This large case-control study aimed to assess the associations between HBV infection status and multiple cancers. Cases (n = 50 392) and controls (n = 11 361) were consecutively recruited from 2008 to 2016 at the First Affiliated Hospital of Nanjing Medical University. Multivariable adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression by adjusting age and gender. A meta-analysis based on published studies was also performed to verify the associations. Of these, 12.1% of cases and 5.5% of controls were hepatitis B surface antigen (HBsAg) seropositive. We observed significant associations between HBsAg seropositivity and esophagus cancer (aOR [95% CI] = 1.32 [1.13-1.54]), stomach cancer (1.46 [1.30-1.65]), hepatocellular carcinoma (HCC; 39.11 [35.08-43.59]), intrahepatic and extrahepatic bile duct carcinoma (ICC and ECC; 3.83 [2.58-5.67] and 1.72 [1.28-2.31]), pancreatic cancer (PaC; 1.37 [1.13-1.65]), non-Hodgkin lymphoma (NHL; 1.88 [1.61-2.20]) and leukemia (11.48 [4.05-32.56]). Additionally, compared to participants with HBsAg−/anti-HBs−/anti-HBc−, participants with HBsAg−/anti-HBs−/anti-HBc+, indicating past HBV-infected, had an increased risk of esophagus cancer (aOR [95% CI] = 1.46 [1.24-1.73]), stomach cancer (1.20 [1.04-1.39]), HCC (4.80 [3.95-5.84]) and leukemia (15.62 [2.05-119.17]). Then the overall meta-analysis also verified that HBsAg seropositivity was significantly associated with stomach cancer (OR [95% CI] = 1.23 [1.14-1.33]), ICC (4.05 [2.78-5.90]), ECC (1.73 [1.30-2.30]), PaC (1.26 [1.09-1.46]), NHL (1.95 [1.55-2.44]) and leukemia (1.54 [1.26-1.88]). In conclusion, both our case-control study and meta-analysis confirmed the significant association of HBsAg seropositivity with stomach cancer, ICC, ECC, PaC, NHL and leukemia. Of note, our findings also suggested that the risk of stomach cancer elevated for people whoever exposed to HBV.     

Recurrent BRCA1 Mutation,but no BRCA2 Mutation,in Vietnamese Patients with Ovarian Carcinoma Detected with Next Generation Sequencing

Background: Identification of germline and somatic BRCA1/2 mutations in ovarian cancer is important for genetic counseling and treatment decision making with poly ADP ribose polymerase inhibitors. Unfortunately, data on the frequency of BRCA1/2 mutations in Vietnamese patients are scare. Methods: We aim to explore the occurrence of BRCA1/2 mutations in 101 Vietnamese patients with ovarian cancer including serous (n = 58), endometrioid (n = 14), mucinous (n = 24), and clear cell (n = 5) carcinomas. BRCA1/2 mutations were detected from formalin-fixed parafin-embedded tumor samples using the OncomineTM BRCA Research Assay on Personal Genome Machine Platform with Ion Reporter Software for sequencing data analysis. The presence of pathogenic mutations was confirmed by Sanger sequencing. Results: We found no BRCA2 mutation in the entire cohort. Four types of pathogenic mutations in BRCA1 (Ser454Ter, Gln541Ter, Arg1751Ter, and Gln1779AsnfsTer14) were detected in 8 unrelated patients (7.9%) belonging to serous and endometrioid carcinoma groups. Except for the c.1360_1361delAG (Ser454Ter) mutation in BRCA1 exon 11 that was somatic, the other mutations in exons 11, 20, and 22 were germline.  Interestingly, the recurrent Arg1751Ter mutation in BRCA1 exon 20 appeared in 4 patients, suggesting that this is a founder mutation in Vietnamese patients. Conclusion: Mutational analysis of tumor tissue using next generation sequencing allowed the detection of both germline and somatic BRCA1/2 mutations.