POLG 基因变异致线粒体病一家系分析

目的分析POLG基因变异致线粒体病的临床表型及基因变异。方法回顾分析于2019年5月就诊,并经采集外周血DNA进行医学外显子、外显子-内含子交界区靶向二代测序和一代验证,1个确诊为POLG基因变异致线粒体病家系的临床资料。结果先证者,男,10岁,与其同卵双胎哥哥均有相同的体征,深感觉受损、腱反射消失、肌肉可疑萎缩。先证者3个兄姐先后于1岁多夭折。提取患儿及其父母的外周血,先证者及同卵双胎哥哥POLG基因均存在G.2558A(p.R853Q)、c.2890T(p.R964C)复合杂合变异,分别来源于患儿父母亲。结论 POLG基因复合杂合变异线粒体病家系成员有不同的表型;POLG相关疾病,即使同种基因变异,其临床异质性也较大。     

Connexin 36 Mediates Orofacial Pain Hypersensitivity Through GluK2 and TRPA1

Trigeminal neuralgia is a debilitating condition, and the pain easily spreads to other parts of the face. Here, we established a mouse model of partial transection of the infraorbital nerve (pT-ION) and found that the Connexin 36 (Cx36) inhibitor mefloquine caused greater alleviation of pT-ION-induced cold allodynia compared to the reduction of mechanical allodynia. Mefloquine reversed the pT-ION-induced upregulation of Cx36, glutamate receptor ionotropic kainate 2 (GluK2), transient receptor potential ankyrin 1 (TRPA1), and phosphorylated extracellular signal regulated kinase (p-ERK) in the trigeminal ganglion. Cold allodynia but not mechanical allodynia induced by pT-ION or by virus-mediated overexpression of Cx36 in the trigeminal ganglion was reversed by the GluK2 antagonist NS102, and knocking down Cx36 expression in Nav1.8-expressing nociceptors by injecting virus into the orofacial skin area of Nav1.8-Cre mice attenuated cold allodynia but not mechanical allodynia. In conclusion, we show that Cx36 contributes greatly to the development of orofacial pain hypersensitivity through GluK2, TRPA1, and p-ERK signaling.Electronic supplementary materialThe online version of this article (10.1007/s12264-020-00594-4) contains supplementary material, which is available to authorized users.     

Morphological,Functional, and Tissue Characterization of Silent Myocardial Involvement in Patients With Primary Biliary Cholangitis

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Treatment of thalassaemia: a review of the new approaches on transfusion safety and the novel therapeutics

Lifetime red cell concentrate (RCC) transfusions still account for significant iron overload‐related morbidity and mortality despite chelation therapy in thalassaemia. The cumulative risk of transfusion‐transmitted infections is substantial for thalassaemia patients. Pathogen reduction technologies for RCC may imply a proactive approach against new/re‐emerging pathogens and may be an ultimate safeguard for transfusion safety in the developing countries. Red cell alloimmunization may become a significant clinical challenge in thalassaemia. The availability of high‐throughput molecular blood group antigen typing in the donors may allow perfect match transfusion, beyond ABO‐D and CEK antigen‐matched transfusions. Allogeneic stem cell transplantation (A‐SCT) is the only available curative therapy in thalassaemia, but carries a substantial risk of serious adverse events and mortality. Gene addition therapy for correction of the α‐globin chain imbalance overcomes the problems of donor availability and immunological complications of A‐SCT. Gene editing by either gene disruption or correction emerged as a potential alternative to gene addition therapy in beta‐thalassaemia. A new era of novel therapeutics targeting α/β imbalance, ineffective erythropoiesis or iron dysregulation is unfolding in thalassaemia management, and a number of those now have agents in preclinical and clinical development. Hydroxyurea (HU) may improve globin chain imbalance and be beneficial for reducing or omitting transfusion requirement. Ruxolitinib has allowed steady decrease in spleen volume that may serve for avoiding splenectomy in beta‐thalassaemia. Luspatercept may restore normal erythroid differentiation and improve anaemia. Hepcidin mimetics or TMPRSS6 inhibitors may modulate ineffective erythropoiesis by iron restriction and improve anaemia and organ iron loading.     

Immunogenicity of next-generation HPV vaccines in non-human primates: Measles-vectored HPV vaccine versus Pichia pastoris recombinant protein vaccine

Human papillomavirus (HPV) infection is the most common sexually transmitted disease worldwide. HPVs are oncogenic small double-stranded DNA viruses that are the primary causal agent of cervical cancer and other types of cancers, including in the anus, oropharynx, vagina, vulva, and penis. Prophylactic vaccination against HPV is an attractive strategy for preventing cervical cancer and some other types of cancers. However, there are few safe and effective vaccines against HPV infections. Current first-generation commercial HPV vaccines are expensive to produce and deliver.The goal of this study was to develop an alternate potent HPV recombinant L1-based vaccines by producing HPV virus-like particles into a vaccine that is currently used worldwide. Live attenuated measles virus (MV) vaccines have a well-established safety and efficacy record, and recombinant MV (rMV) produced by reverse genetics may be useful for generating candidate HPV vaccines to meet the needs of the developing world.We studied in non-human primate rMV-vectored HPV vaccine in parallel with a classical alum adjuvant recombinant HPV16L1 and 18L1 protein vaccine produced in Pichia pastoris. A combined prime-boost approach using both vaccines was evaluated, as well as immune interference due to pre-existing immunity against the MV.The humoral immune response induced by the MV, Pichia-expressed vaccine, and their combination as priming and boosting approaches was found to elicit HPV16L1 and 18L1 specific total IgG and neutralizing antibody titres. Pre-existing antibodies against measles did not prevent the immune response against HPV16L1 and 18L1.     

阻塞性睡眠呼吸暂停低通气综合征患者CYP3A4基因多态性的检测

目的探讨阻塞性睡眠呼吸暂停低通气综合征(OSAHS)CYP3A4基因的多态性,了解其对芬太尼类药物的敏感性及不同基因型的人群分布特征,指导临床个体化用药。方法对50例OSAHS患者进行CYP3A4基因的多态性检测,采静脉血,通过DNA抽提-PCR扩增-焦磷酸测序方法检测CYP3A4基因。结果野生纯合型型34例(68%),突变杂合型15例(30%),突变纯合型型1例(2%)。结论OSAHS患者中约2%为AA型,该型对芬太尼类药物极其敏感,术后有易发生窒息的风险,应高度警惕芬太尼类药物呼吸抑制的潜在风险。     

石斛合剂对高脂高糖糖尿病大鼠心肌细胞Ca^2+代谢的影响

目的以糖尿病心肌病大鼠为研究对象,探讨石斛合剂对糖尿病心肌病心肌细胞Ca^2+代谢的影响。方法 Wistar大鼠24只,取5只作为正常组,余19只采用高脂高糖饮食联合链脲佐菌素腹腔注射进行糖尿病心肌病造模。成模后,随机分为模型组、二甲双胍组、石斛合剂组。二甲双胍组、石斛合剂组分别予二甲双胍、石斛合剂灌胃,正常组、模型组予生理盐水灌胃。4周后,测空腹血糖,取左心室心肌组织进行组织病理学观察和心肌细胞内游离钙(MyoCa^2+)浓度测定,Western blot法检测肌浆网Ca^2+-ATP酶(SERCA2a)、L型钙通道α1C亚单位蛋白(CACNA1C)蛋白表达,RT-PCR法测定SERCA2a mRNA表达。结果石斛合剂组心肌纤维较模型组、二甲双胍组排列整齐,断裂较少。与正常组比较,模型组血糖、心肌细胞MyoCa^2+含量和CACNA1C蛋白表达明显升高(P<0.01,P<0.05),SERCA2a mRNA和蛋白表达明显降低(P<0.01)。与模型组比较,石斛合剂组血糖、心肌细胞MyoCa^2+含量和CACNA1C蛋白表达明显降低(P<0.01,P<0.05),SERCA2a mRNA和蛋白表达明显升高(P<0.01,P<0.05);二甲双胍组血糖明显降低(P<0.01)。与二甲双胍组比较,石斛合剂组心肌细胞MyoCa^2+含量明显降低(P<0.01,P<0.05),血糖、SERCA2a mRNA和蛋白表达明显升高(P<0.05)。结论石斛合剂通过提高SERCA2a mRNA和蛋白表达,加快摄取Ca^2+的速率,降低细胞质Ca^2+负荷,缓解钙超载,最终达到维持糖尿病心肌病钙稳态的作用,有效维持心肌细胞的正常收缩舒张功能;其降糖作用不是预防糖尿病心肌病的主要机理,而在于抑制CACNA1C蛋白表达,抑制钙诱导钙释放过程。     

Insulin-like growth factor-1 as predictive factor of difficult laryngoscopy in patients with GH-producing pituitary adenoma: A pilot study

BackgroundGrowth hormone (GH)-producing pituitary tumors account for 10 to 15% of pituitary tumors. The hypersecretion of GH may induce changes in the airway anatomy through the activation of Insulin-like Growth factor 1(IGF-1) pathway. We sought investigate the role IGF-1 as a potential predictive factor of difficult laryngoscopy in patients with GH-producing pituitary adenoma.MethodsThis study was a single center retrospective study. We included 33 patients undergoing transsphenoidal resection of GH-producing pituitary. We recorded demographic data, el-Ganzouri risk index (EGRI) and modified Look-Evaluate-Mallampati-Obstruction-Neck mobility (mLEMON) score, and pituitary hormone plasma levels. We performed ordinal logistic regression to analyze the relationship between IGF-1 and EGRI, mLEMON, and Cormack-Lehane Grade score and a multiple logistic regression to test the capability of EGRI, mLEMON and IGF-1 levels to predict Cormack-Lehane score. Receiver operating curve (ROC), area under the curve (AUC), and cut-off value of IGF-1 were calculated.ResultsOnly 14 (42.8%) and 12 (36.36%) patients showed predictive factors of difficult intubation according to EGRI and mLEMON score, respectively. IGF-1 significantly correlated with Cormack-Lehane (p = 0.005879) but not with mLEMON and EGRI (p = 0.3080 and 0.4146, respectively). In multiple regression model IGF-1 correlated only with Cormack-Lehane grade (p = 0.0089). Area under ROC was 0.8571 and cut-off value of IGF-1 was 186.15 ng/ml.ConclusionHigher IGF-1 levels correlate with the probability of having a higher Cormack-Lehane score; classical bedside scores, such as mLEMON and EGRI, were not able to predict difficult laryngoscopy in our population.