真武汤合苓桂术甘汤改善心肾综合征大鼠模型水钠潴留的作用机制研究

[目的]研究真武汤合苓桂术甘汤对心肾综合征大鼠模型水钠潴留的作用机制。[方法]将60只雄性SD大鼠随机分为两组,即空白组与手术组,空白组大鼠常规饲养,手术组大鼠经5/6肾切除联合异丙肾上腺素皮下注射制备心肾综合征模型,剔除死亡大鼠后,将手术组剩余成模大鼠按体质量分层随机分为空白组、中药组、常规治疗组。中药组给予真武汤合苓桂术甘汤灌胃,给药量为7.29 g生药/(kg·d);常规治疗组给予贝那普利(0.45 mg/kg)+呋塞米(1.8m g/kg);空白组予以等容积生理盐水灌胃,每日1次,连续6周。观察实验过程中各组大鼠的精神状态、活动情况、灵敏度、毛发情况、食欲、大小便等一般情况及死亡情况,比较各组灌胃前、灌胃6周后的血清脑钠肽(BNP)、血肌酐(Scr)、血尿素氮(BUN)、尿水通道蛋白2(AQP2)的前后差值情况。[结果]灌胃6周后,中药组大鼠一般情况较灌胃前改善、喘息不明显,常规治疗组一般情况同样较灌胃前改善。通过比较治疗前后各组大鼠实验室指标差值发现,中药组与常规治疗组BNP均下降,中药改善大鼠心力衰竭情况接近常规治疗组水平,两组下降水平无统计学差异(P0.05);中药组Scr水平较前下降,常规治疗组Scr水平升高;中药组尿AQP2水平较前略增高,与空白组尿AQP2水平无统计学差异(P0.05),常规治疗组尿AQP2水平较前明显升高。[结论]心肾综合征大鼠尿AQP2的表达主要由肾脏调控,AQP2可作为心肾综合征水钠潴留状态的参考指标,真武汤合苓桂术甘汤改善心肾综合征大鼠水钠潴留状态的作用机制可能是通过抑制大鼠肾脏AQP2过度表达,减少水的重吸收,改善了水钠潴留状态。     

妊娠早期糖化血红蛋白联合PAPP-A对妊娠期糖尿病的预测意义

目的:探讨妊娠早期血清学指标糖化血红蛋白(glycohemoglobin,HbA1c)联合妊娠相关血浆蛋白A(pregnancy-associated plasma protein A,PAPP-A)对妊娠期糖尿病(gestational diabetes mellitus,GDM)的预测意义。方法:随机选取2018年12月1日-2019年7月30日孕11~13+6周于我院门诊产检的妊娠妇女,进行临床资料采集并记录妊娠早期(11~13+6周)空腹血糖(fasting plasma glucose,FPG)、HbA1c、PAPP-A中位数倍数(multiple of the median,MoM)水平,根据孕24~28周进行的75 g口服葡萄糖耐量试验(oral glucose tolerance test,OGTT)结果将研究对象分为研究组和对照组,统计分析妊娠早期血清学指标预测GDM的最佳截断值并得出最适宜的联合预测方案。结果:多因素Logistic回归分析显示,高水平FPG和HbA1c、低水平PAPP-A、受孕方式采用辅助生殖技术、有家族糖尿病史以及妊娠早期体质量指数(BMI)为超重或肥胖均是GDM发生的独立危险因素。有糖尿病家族史和使用辅助生殖技术受孕发生GDM的风险显著增高(OR分别为7.206和47.512,均P<0.001)。分析不同预测指标的受试者工作特征(receiver operating characteristic,ROC)曲线及曲线下面积(area under the curve,AUC)显示,PAPP-A MoM联合HbA1c及FPG诊断时AUC最大(0.728),其后依次为PAPPA MoM联合HbA1c(0.721)、HbA1c联合FPG(0.717),均大于HbA1c(0.707)和FPG(0.647),而PAPP-A MoM的AUC为0.380,对GDM没有诊断意义。结论:具有高风险因素的孕妇,推荐在妊娠早期联合检测HbA1c与PAPPA MoM,以早期预测GDM。     

Peripheral whole blood FOXP3 TSDR methylation: a potential marker in severity assessment of autoimmune diseases and chronic infections

Immune dysregulation is a cardinal feature of autoimmune diseases and chronic microbial infections. In particular, regulatory T cells are downregulated in autoimmune diseases while upregulated in chronic microbial infections. FOXP3 is the master regulator of Treg development. Treg-specific demethylated region (TSDR) is a highly conserved locus on the FOXP3 gene that is fully demethylated in natural Tregs but methylated in effector T cells. In our study, we used high resolution melt-polymerase chain reaction (HRM-PCR) to determine the FOXP3 TSDR methylation status in autoimmune diseases and chronic microbial infections. We found that FOXP3 TSDR to have the highest mean melting temperature (highly methylated) in active SLE patients compared to all the other groups (p?<?0.001). The psoriasis group also had a significantly high mean melting temperature (78.62?±?0.20) when compared with the inactive SLE group (78.49?±?0.29, p?<?0.05) and control group (78.44?±?0.25, p?<?0.01). There was no significant difference in melting temperature between inactive SLE and healthy controls. Disease activity in SLE was directly associated with methylation of the FOXP3 TSDR. On the other hand, patients with chronic microbial infections had significantly lower FOXP3 TSDR mean melting temperature (demethylated) when compared with healthy controls (78.28?±?0.21 vs 78.44?±?0.25, p?<?0.05). Our results suggest that the use of HRM-PCR to detect FOXP3 TSDR methylation status is a reliable and easy method to predict natural regulatory T cell levels in peripheral blood in different disease conditions. Determining FOXP3 TSDR methylation status can be a useful tool in diagnosis, and monitoring the severity of autoimmune diseases and chronic microbial infections.     

Mortality,length of stay and costs associated with acute graft-versus-host disease during hospitalization for allogeneic hematopoietic stem cell transplantation

Objective: Acute graft-versus-host disease (aGVHD) is a common and life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The extent to which aGVHD increases inpatient costs associated with allo-HSCT has not been thoroughly evaluated. In this analysis, mortality, hospital length of stay (LOS) and costs associated with aGVHD during allo-HSCT admissions are evaluated.

Methods: This is a retrospective analysis of discharge records from the National Inpatient Sample database for patients receiving allo-HSCT between 1 January 2009 and 31 December 2013. Allo-HSCT discharges with an aGVHD diagnosis were included in the aGVHD group and those without any graft-versus-host disease (GVHD) diagnosis comprised the non-GVHD group. Mortality, LOS and costs were compared between the two groups, as well as within subgroups, including age (<18 vs. ≥18 years) and survival status (alive vs. deceased) at discharge.

Results: Overall, mortality (16.2% vs. 5.3%; p?<?.01), median hospital LOS (42.0 vs. 26.0 days; p?<?.01) and median total costs ($173,144 vs. $98,982; p?<?.01) were significantly increased in patients with aGVHD versus those without GVHD during hospitalizations for allo-HSCT, irrespective of age group. Patients with aGVHD who were <18 years of age had a lower mortality rate but greater hospital LOS and total costs versus patients aged ≥18 years. Patients who died during allo-HSCT hospitalization had longer LOS and incurred greater costs than those who survived in both the aGVHD and non-GVHD groups.

Conclusion: Occurrence of aGVHD during allo-HSCT admissions resulted in a tripling of the mortality rate and a near doubling of hospital LOS and total costs. In addition, death during allo-HSCT hospitalizations was associated with greater healthcare utilization and costs. Effectively mitigating aGVHD may improve survival and substantially reduce hospital LOS and costs for allo-HSCT.     

Genetic toxicity assessment using liver cell models: past,present, and future

ABSTRACT

Genotoxic compounds may be detoxified to non-genotoxic metabolites while many pro-carcinogens require metabolic activation to exert their genotoxicity in vivo. Standard genotoxicity assays were developed and utilized for risk assessment for over 40 years. Most of these assays are conducted in metabolically incompetent rodent or human cell lines. Deficient in normal metabolism and relying on exogenous metabolic activation systems, the current in vitro genotoxicity assays often have yielded high false positive rates, which trigger unnecessary and costly in vivo studies. Metabolically active cells such as hepatocytes have been recognized as a promising cell model in predicting genotoxicity of carcinogens in vivo. In recent years, significant advances in tissue culture and biological technologies provided new opportunities for using hepatocytes in genetic toxicology. This review encompasses published studies (both in vitro and in vivo) using hepatocytes for genotoxicity assessment. Findings from both standard and newly developed genotoxicity assays are summarized. Various liver cell models used for genotoxicity assessment are described, including the potential application of advanced liver cell models such as 3D spheroids, organoids, and engineered hepatocytes. An integrated strategy, that includes the use of human-based cells with enhanced biological relevance and throughput, and applying the quantitative analysis of data, may provide an approach for future genotoxicity risk assessment.