A High-Fat Diet Induces Muscle Mitochondrial Dysfunction and Impairs Swimming Capacity in Zebrafish: A New Model of Sarcopenic Obesity

Obesity is a highly prevalent disease that can induce metabolic syndrome and is associated with a greater risk of muscular atrophy. Mitochondria play central roles in regulating the physiological metabolism of skeletal muscle; however, whether a decreased mitochondrial function is associated with impaired muscle function is unclear. In this study, we evaluated the effects of a high-fat diet on muscle mitochondrial function in a zebrafish model of sarcopenic obesity (SOB). In SOB zebrafish, a significant decrease in exercise capacity and skeletal muscle fiber cross-sectional area was detected, accompanied by high expression of the atrophy-related markers Atrogin-1 and muscle RING-finger protein-1. Zebrafish with SOB exhibited inhibition of mitochondrial biogenesis and fatty acid oxidation as well as disruption of mitochondrial fusion and fission in atrophic muscle. Thus, our findings showed that muscle atrophy was associated with SOB-induced mitochondrial dysfunction. Overall, these results showed that the SOB zebrafish model established in this study may provide new insights into the development of therapeutic strategies to manage mitochondria-related muscular atrophy.     

重庆地区Ezscan用于筛查糖代谢异常的研究

目的：探索Ezscan在无症状人群中筛查糖代谢异常的能力。方法选取2013年8月至2014年8月进行健康体检的重庆市常驻居民1732例,进行问卷调查、体格检查、空腹血糖（FPG）、葡萄糖耐量试验（OGTT）2h血糖、糖化血红蛋白（HbA1c）、血脂和Ezscan检测。结果Ezscan高评分人群糖代谢异常患病率高于低评分人群。Ezscan筛查糖代谢异常的受试者工作特征曲线下面积（AUC）为0．616,最佳切点值为24％,灵敏度为67．0％;FPG筛查糖代谢异常最佳切点值为5．5mmol／L,灵敏度和特异度分别为70．5％和61．7％,AUC为0．824;FPG为6．1mmol／L时,筛查糖代谢异常的灵敏度为47．2％。结论重庆地区Ezscan筛查糖代谢异常灵敏度高于经典方法FPG（切点值为6．1mmol／L）检测,在无症状人群中,Ezscan可作为一种有效的糖代谢异常早期筛查技术。     

Effect of high-throughput screening of circRNA01724 on a rat model of myocardial ischemia ventricular arrhythmia

BackgroundIt is considered that circRNA can participate in regulating the occurrence and effects of ventricular arrhythmia (VA) through competing endogenous RNA (ceRNA) mechanism, regulating pre-mRNA and regulating parental gene expression. Therefore, we used animal modeling and high-throughput differential screening to screen out circRNA related to VA and study its possible mechanism of action on VA.MethodsThe rat model of myocardial ischemia VA was established. High-throughput screening of the differentiated circRNA was conducted and verified by real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot. Lv-circRNA01724 lentivirus was constructed using molecular biology. Primary isolation of the rat cardiomyocytes, hypoxia modeling, Lv-circRNA01724 transfection, mode of action verification, and dual luciferase detection of circRNA01724 and miR-323-5p was performed.ResultsThrough qRT-PCR verification of circRNA01724, circRNA02230, circRNA02088, miR-323-5p, miR-330-5p, and miR-324-3p expressions, circRNA01724 was selected as the research object. Detection by Western blot showed significantly lower Cx43, ZO-1, and α-catenin expressions in rat myocardial tissue in the model group compared with the control group at 1, 7, 14, and 28 days old. On identification of the isolated primary rat cardiomyocytes by immunofluorescence, the α-SMA characteristic protein expression indicated that the isolation was successful. Verification of rat cardiomyocytes transfected with Lv-circRNA01724 suggested overexpression in cells. The miR-323-5p was also highly expressed in the rat cardiomyocyte hypoxia model following Lv-circRNA01724 transfection. Detection by flow cytometry showed that modeling of the transfected Lv-circRNA01724 had a significant increased apoptotic rate. Detection by Western blot showed that modeling of the transfected Lv-circRNA01724 cells had significantly decreased Cx43, ZO-1, and α-catenin compared with the model group.ConclusionsHigh-throughput screening of circRNA01724 can promote the apoptosis of hypoxic cardiomyocytes, which is related to the rat model of myocardial ischemia VA and may be a potential target for the treatment of VA.     

健康人微伏级T波电交替渐量修正平均法检测分析

目的探讨渐量修正平均法检测健康人微伏级T波电交替(microvolt T wave alternans,MTWA)的正常范围。方法平板运动提升心率,渐量修正平均法检测120例健康志愿者各胸前导联T波交替电压(alternans voltage,Valt),分析其大小分布范围及与性别、年龄的关系。结果(1)各胸前导联T波交替电压数据均呈偏态分布;胸前导联Valt大小与年龄无关;V4、V5导联Valt男女性别间差异有统计学意义,女性高于男性。(2)各胸前导联T波交替电压有较大差别,第75百分位数分别为V1导联8.0μV;V2导联5.0μV;V3导联2.0μV;V4导联男性2.0μV,女性6.0μV;V5导联男性4.5μV,女性6.5μV;V6导联7.0μV;胸前导联T波交替电压最大值(Vmax)第75百分位数11.0μV。结论:渐量修正平均法检测健康人微伏级T波电交替不同胸前导联之间有较大差别;确定正常标准需要因导联而异。     

Phase I and scintigraphy studies to evaluate safety,tolerability, pharmacokinetics,and lung deposition of inhaled GDC‐0214 in healthy volunteers

Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m (^99mTc)‐radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose‐proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding‐corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways. ^99mTc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma C_max similar to that observed in phase I at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Many factors drive asthma pathogenesis, including several cytokines that signal through the Janus kinase 1 (JAK1) pathway. Inhibition of JAK1 is a possible target for asthma treatments, but previous studies show oral JAK1 inhibitors lead to increased risk of severe infections, malignancy and cardiovascular events.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated the safety, pharmacokinetics, and lung deposition of GDC‐0214, an inhaled JAK1 inhibitor designed to target the lungs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Inhaled delivery of a JAK inhibitor for 14 days exhibited low systemic exposure, leading to few adverse events and limited systemic toxicity, while demonstrating high deposition in the lungs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Local pulmonary application of JAK inhibitors may be an effective treatment for asthma with limited systemic risks.     

Pol ι表达水平对行食管癌术后辅助放疗患者的生存影响

目的：探讨DNA 聚合酶 ι（DNA polymerase ι,Pol ι）表达水平对行食管癌术后辅助放疗患者的生存影响。方法：采用免疫组化方法检测97例行术后辅助放疗的食管癌患者组织中Pol ι的表达情况,分析Pol ι表达水平对这些患者生存的影响。结果：20例食管癌患者组织中Pol ι呈低表达,77例食管癌患者组织中Pol ι呈高表达;生存曲线显示Pol ι表达水平与行术后辅助放疗的食管癌患者生存呈负相关;COX回归分析显示Pol ι表达水平是影响食管癌根治术后辅助放疗患者生存的独立预后因素。结论：Pol ι可能是判断行食管癌术后辅助放疗患者预后的潜在分子标志物。     

维拉帕米脉冲控释片的设计和制备

目的：针对高血压、心绞痛常在凌晨发作的特点,研制夜间服药、凌晨释放的维拉帕米(VR)脉冲控释片。方法：全面考察影响药物释放滞后时间的因素。选用3种强崩解剂的不同用量,考察片芯崩解剂对时滞的影响。通过均匀设计实验考察外层包衣的组成和片剂的硬度,多元回归筛选最优处方,并考察不同溶出条件对控释效果的影响。结果：片芯所用的3种崩解剂以羧甲基淀粉钠的崩解性能较好,用量设计在25％左右。外层包衣处方中PEG 6000增加,氢化蓖麻油(HCO)、乙烯-醋酸乙烯共聚物(EVA)用量减少,硬度减小,释放滞后时间减少。由此确定释放滞后时间为3和5h的两个基本处方。结论：VR压制包衣片在体外溶出实验中能实现脉冲释药,并能通过调节辅料用量实现不同控释效果。     

急性心肌梗死冠脉介入治疗前后中医辨证治疗思路与方法——附70例患者治疗分析

在对急性心肌梗死(AMI)的救治中,冠脉介入治疗有着不可替代的作用,在应用冠脉介入治疗手段干预的情况下,如何进行中医的辨证治疗是一个值得探讨的论题。作为率先在全国开展冠脉介入治疗的中医院,我们将近3年来在我院成功接受冠脉介入治疗和中医治疗的AMI患者的思路与方法总结于下。     

各向同性的3D T2 SPAIR SPACE序列在正常人肘部神经显像的应用

目的:观察磁共振3D T2 SPAIR (spectral adiabatic inversion recovery) SPACE序列在正常人肘部神经的显示情况,并观察其在不同人群中的显示差异?方法:在3.0 T MR下对64例正常人的2D FS-T2WI序列及3D T2 SPAIR SPACE序列平扫?对每个志愿者的3D T2 SPAIR SPACE序列的原始数据进行尺神经?正中神经及桡神经的曲面重建及最大密度投影重建,分别重建出矢状位及冠状位图像?分别统计3根神经的两种重建方法在上臂?肘关节及前臂的显示率?统计3根神经在2D FS-T2WI序列及3D T2 SPAIR SPACE序列上相对周围肌肉信号增高的比率? 结果:64例志愿者的尺神经?正中神经及桡神经在曲面重建上可以全部清晰显示?尺神经在上臂?肘关节及前臂的最大密度投影图像上的显示率分别为92%?83%?98%,正中神经在上臂?肘关节及前臂的最大密度投影图像上的显示率分别为81%?89%?80%,桡神经在上臂?肘关节的最大密度投影图像上的显示率分别为94%?95%?尺神经信号增高在2D FS-T2WI序列上为55%,而在3D T2 SPAIR SPACE序列上仅仅为30%?结论:3D T2 SPAIR SPACE序列对正常人的肘部神经显示效果好,对正常人尺神经信号增高显示更可靠?