自发性高血压大鼠永久性脑缺血模型建立的研究

目的在比较自发性高血压大鼠(SHR)与同龄无高血压Wistar大鼠永久性大脑中动脉阻塞(pMCAO)后脑缺血损伤情况并初步分析其可能机制。方法雄性SHR和Wistar大鼠各30只分别随机分为:pMCAO模型6 h组、假手术6 h组、pMCAO模型24 h组、假手术24 h组和正常组(均n=6)。采用线栓法制作pMCAO模型,术后6、24 h对大鼠进行神经功能学评分后处死,制作脑冠状切片。术后6 h处死大鼠脑部切片行尼氏染色后在组织学层面上观察神经元损伤情况;术后24 h处死大鼠脑部切片行尼氏染色后计算脑梗死体积和水肿程度百分比。正常组脑部切片经苏木精-伊红染色后计算脑部小血管壁/腔比。结果术后6和24 h,不同品系大鼠神经功能学评分差异无统计学意义(P0.05);术后6 h尼氏染色示SHR神经元损伤重于Wistar大鼠。术后24 h SHR脑梗死体积百分比[(28.05±2.38)%]大于Wistar大鼠[(25.23±1.33)%],差异有统计学意义(P0.05)。两品系大鼠之间脑水肿程度差异无显著性。脑部小血管壁/腔比SHR[(11.46±3.74)%]较Wistar大鼠[(8.73±1.73)%]增大(P0.05)。结论 pMCAO术后SHR的脑缺血损伤程度重于Wistar大鼠,可能与高血压引起的脑侧支循环血管壁增厚、僵硬,自我调节能力降低有关。     

沙利度胺联合TACE治疗原发性肝癌疗效与安全性的系统评价

目的:系统评价沙利度胺(thalidomide,TLD)联合肝动脉化疗栓塞术(transcatheter arterial chemoembolization,TACE)治疗原发性肝癌(primary hepatic carcinomas,PHC)的疗效和安全性.方法:计算机检索Cochrane Library(2014年第3期)、Web of Science(1986/2014-03)、Pub Med(1966/2014-03)、CNKI(1917/2014-03)、维普(1989/2014-03)、万方数据库(1998/2014-03),收集所有TLD联合TACE治疗PHC的随机对照试验.由两名评价员严格按照纳入标准选择文献,提取资料,并参照Cochrane系统评价的要求,对选择纳入的随机对照试验进行方法学质量评估后,采用Cochrane协作网提供的Rev Man 5.2软件对总有效率、疾病控制率、生活质量KPS评分、不同年限生存率、甲胎蛋白的变化、血管内皮生长因子(vascular endothelial growth factor,VEGF)的变化及不良反应发生率进行Meta分析.结果:最终纳入22项随机对照试验,包括1590例PHC患者,Meta分析结果显示,TLD联合TA C E组治疗P H C的总有效率(R R合并=1.29,95%C I:1.15-1.44)、疾病控制率(R R合并=1.27,95%CI:1.16-1.39)、生活质量KPS评分(MD合并=9.23,95%CI:6.90-11.55)、半年生存率(RR合并=1.10,95%C I:1.01-1.20)、1年生存率(RR合并=1.25,95%C I:1.13-1.39)、2年生存率(RR合并=1.45,95%CI:1.18-1.78)、3年生存率(R R合并=1.7 0,9 5%C I:1.1 6-2.5 0)、V E G F水平的变化(M D合并=-123.64,95%C I:-143.72--103.55)优于单纯TACE组,差异有统计学意义(均P0.05);不良反应发生率:在药物性皮疹发生率方面,TLD联合TACE组明显高于单纯TACE组,差异有统计学意义(RR=4.50,95%CI:2.34-8.64,P0.00001);在减少消化系应发生率(RR=1.08,95%CI:0.93-1.25)、降低骨髓抑制发生率(RR=1.12,95%CI:0.82-1.52)、降低肝功能异常发生率方面(R R=1.00,95%C I:0.72-1.39),T L D联合TA C E组与单纯TA C E组相近似,差异无统计学意义(均P0.05).结论:目前研究显示,与单纯TACE疗法相比,TLD联合TACE治疗PHC在总有效率、疾病控制率、生活质量KPS评分、半年生存率、1、2、3年生存率、降低V E G F方面具有明显的优势,但在安全性方面,TLD联合TACE组在药物性皮疹发生率方面明显高于单纯TACE组,而在消化系反应、骨髓抑制率、肝功能异常方面与单纯TACE组相似.     

HIFα Regulates Developmental Myelination Independent of Autocrine Wnt Signaling

The developing CNS is exposed to physiological hypoxia, under which hypoxia-inducible factor α (HIFα) is stabilized and plays a crucial role in regulating neural development. The cellular and molecular mechanisms of HIFα in developmental myelination remain incompletely understood. A previous concept proposes that HIFα regulates CNS developmental myelination by activating the autocrine Wnt/β-catenin signaling in oligodendrocyte progenitor cells (OPCs). Here, by analyzing a battery of genetic mice of both sexes, we presented in vivo evidence supporting an alternative understanding of oligodendroglial HIFα-regulated developmental myelination. At the cellular level, we found that HIFα was required for developmental myelination by transiently controlling upstream OPC differentiation but not downstream oligodendrocyte maturation and that HIFα dysregulation in OPCs but not oligodendrocytes disturbed normal developmental myelination. We demonstrated that HIFα played a minor, if any, role in regulating canonical Wnt signaling in the oligodendroglial lineage or in the CNS. At the molecular level, blocking autocrine Wnt signaling did not affect HIFα-regulated OPC differentiation and myelination. We further identified HIFα–Sox9 regulatory axis as an underlying molecular mechanism in HIFα-regulated OPC differentiation. Our findings support a concept shift in our mechanistic understanding of HIFα-regulated CNS myelination from the previous Wnt-dependent view to a Wnt-independent one and unveil a previously unappreciated HIFα–Sox9 pathway in regulating OPC differentiation.SIGNIFICANCE STATEMENT Promoting disturbed developmental myelination is a promising option in treating diffuse white matter injury, previously called periventricular leukomalacia, a major form of brain injury affecting premature infants. In the developing CNS, hypoxia-inducible factor α (HIFα) is a key regulator that adapts neural cells to physiological and pathologic hypoxic cues. The role and mechanism of HIFα in oligodendroglial myelination, which is severely disturbed in preterm infants affected with diffuse white matter injury, is incompletely understood. Our findings presented here represent a concept shift in our mechanistic understanding of HIFα-regulated developmental myelination and suggest the potential of intervening with an oligodendroglial HIFα-mediated signaling pathway to mitigate disturbed myelination in premature white matter injury.     

Characterization of membrane occupation and recognition nexus repeat containing 3, meiosis expressed gene 1 binding partner,in mouse male germ cells

Mammalian spermatogenesis is a well-organized process of cell development and differentiation. Meiosis expressed gene 1 (MEIG1) plays an essential role in the regulation of spermiogenesis. To explore potential mechanisms of MEIG1''s action, a yeast two-hybrid screen was conducted, and several potential binding partners were identified; one of them was membrane occupation and recognition nexus repeat containing 3 (MORN3). MORN3 mRNA is only abundant in mouse testis. In the testis, Morn3 mRNA is highly expressed in the spermiogenesis stage. Specific anti-MORN3 polyclonal antibody was generated against N-terminus of the full-length MORN3 protein, and MORN3 expression and localization was examined in vitro and in vivo. In transfected Chinese hamster ovary cells, the antibody specifically crossed-reacted the full-length MORN3 protein, and immunofluorescence staining revealed that MORN3 was localized throughout the cytoplasm. Among multiple mouse tissues, about 25 kDa protein, was identified only in the testis. The protein was highly expressed after day 20 of birth. Immunofluorescence staining on mixed testicular cells isolated from adult wild-type mice demonstrated that MORN3 was expressed in the acrosome in germ cells throughout spermiogenesis. The protein was also present in the manchette of elongating spermatids. The total MORN3 expression and acrosome localization were not changed in the Meig 1-deficient mice. However, its expression in manchette was dramatically reduced in the mutant mice. Our studies suggest that MORN3 is another regulator for spermatogenesis, probably together with MEIG1.     

非高密度脂蛋白胆固醇水平与冠心病患者冠状动脉病变Gensini评分的相关性研究

目的 探讨非高密度脂蛋白胆固醇水平(non-HDL-C)与冠心病(CHD)患者冠状动脉病变Gensini评分的关系及临床意义。方法 对225例疑诊或既往临床诊断CHD患者予以冠状动脉造影(CAG),将造影阴性的39例作为对照组(HC组),造影阳性的186例患者诊断为CHD,结合临床特点分为心绞痛组(AP组)122例和心肌梗死组(AMI组)64例。采用Gensini评分对冠状动脉病变程度评分,测定患者全套血脂水平,探讨non-HDL-C及相关脂质成分与冠状动脉病变程度Gensini评分的相关性;同时对他汀类药物强化降脂达标,低密度脂蛋白胆固醇(LDL-C)<1.80 mmol/L的AP组患者进行non-HDL-C与冠状动脉病变程度Gensini评分的亚组分析。结果 AMI组non-HDL-C水平高于AP组及HC组,AP组non-HDL-C水平高于HC组,差异均有统计学意义(P<0.05);CHD患者non-HDL-C水平与Gensini评分呈正相关(r=0.562,P<0.05);LDL-C控制达标的AP组患者,高non-HDL-C组(≥2.60 mmol/L)比低non-HDL-C组(<2.60 mmol/L)Gensini评分明显升高,差异均有统计学意义(P<0.05)。结论 non-HDL-C与冠状动脉病变程度密切相关,non-HDL-C在评估LDL-C控制达标患者的冠状动脉病变程度及再发心血管事件风险上有一定价值,可作为LDL-C达标后心血管残余风险新的观察指标。     

Melatonin induces apoptosis of colorectal cancer cells through HDAC4 nuclear import mediated by CaMKII inactivation

Melatonin induces apoptosis in many different cancer cell lines, including colorectal cancer. However, the precise mechanisms involved remain largely unresolved. In this study, we provide evidence to reveal a new mechanism by which melatonin induces apoptosis of colorectal cancer LoVo cells. Melatonin at pharmacological concentrations significantly suppressed cell proliferation and induced apoptosis in a dose‐dependent manner. The observed apoptosis was accompanied by the melatonin‐induced dephosphorylation and nuclear import of histone deacetylase 4 (HDAC4). Pretreatment with a HDAC4‐specific siRNA effectively attenuated the melatonin‐induced apoptosis, indicating that nuclear localization of HDAC4 is required for melatonin‐induced apoptosis. Moreover, constitutively active Ca²⁺/calmodulin‐dependent protein kinase II alpha (CaMKIIα) abrogated the melatonin‐induced HDAC4 nuclear import and apoptosis of LoVo cells. Furthermore, melatonin decreased H3 acetylation on bcl‐2 promoter, leading to a reduction of bcl‐2 expression, whereas constitutively active CaMKIIα(T286D) or HDAC4‐specific siRNA abrogated the effect of melatonin. In conclusion, the present study provides evidence that melatonin‐induced apoptosis in colorectal cancer LoVo cells largely depends on the nuclear import of HDAC4 and subsequent H3 deacetylation via the inactivation of CaMKIIα.     

抗信号识别颗粒抗体阳性肌病伴心脏损害1例

1临床资料患者,男,43岁,因"四肢近端肌肉无力9个月,加剧1周"于2013年9月22日入院。患者于9个月前无明显诱因下出现四肢肌肉无力,以近端肌力减退为主,主要表现为上楼梯费力,提重物困难,易疲劳,尚可参加工作,无发热、皮疹、肌痛、感觉异常等,无明显晨轻暮重的波动现象,上述症状逐渐加重,劳动耐量和日常生活能力进行性下     

局部晚期食管鳞癌新辅助放疗剂量与病理完全缓解关系分析

目的 探讨接受新辅助放化疗的局部晚期食管鳞癌患者新辅助放疗剂量与病理完全缓解(pCR)的关系。方法 收集2017-2019年间在四川大学华西医院肿瘤中心经病理确诊为食管鳞癌并接受新辅助放化疗和手术的 116例局部晚期患者临床资料。116例患者中 40~45Gy组 80例,≥45Gy组 36例,分析两组术后pCR率。结果 全组患者的pCR率为38.8%(45/116),40~45Gy组与≥45Gy组的pCR率分别为44%(35/80)和28%(10/36)(P=0.105)。结论 术前新辅助采用较高的放疗剂量不增加局部晚期食管鳞癌的pCR率,有必要进行前瞻性的临床研究确定合适的新辅助放疗剂量。     

Next-generation sequencing through multigene panel testing for the diagnosis of hereditary epidermolysis bullosa in Chinese population

Epidermolysis bullosa (EB) is a heritable blistering disorder. We performed a next-generation sequencing-based multigene panel test and successfully predicted 100% of the EB types, including, 36 EB simplex (EBS), 13 junctional EB (JEB), 86 dystrophic EB (DEB), and 3 Kindler EB. Chinese JEB and recessive DEB (RDEB) patients have relatively mild phenotypes; for severe type separately accounts for 45.5% and 23.8%, respectively. We identified 96 novel and 49 recurrent pathogenic variants in 11 genes, although we failed to detect the second mutation in one JEB and five RDEB patients. We identified one novel p.E475K mosaic mutation in the clinically normal mother of one out of 13 EBS patients with KRT5 mutations, one recurrent p.G2034R mosaic mutation, and one novel p.G2043R mosaic mutation in the clinically normal relatives of two out of 19 dominant DEB patients. This study shows that next-generation technology could be an effective tool in diagnosing EB.