Association between Single Nucleotide Polymorphisms in the ADD3 Gene and Susceptibility to Biliary Atresia

Background and Objectives

Based on the results of previous studies, the ADD3 gene, located in the 10q24.2 region, may be a susceptibility gene of biliary atresia (BA). In this study, two single nucleotide polymorphisms (SNPs) in the ADD3 gene, rs17095355 C/T and rs10509906 G/C, were selected to investigate whether there is an association between these SNPs and susceptibility to BA in a Chinese population.

Methods

A total of 752 Han Chinese (134 BA cases and 618 ethnically matched healthy controls) were included in the present study. The ADD3 gene polymorphisms were genotyped using a TaqMan genotyping assay.

Results

Positive associations were found for the SNP rs17095355 in the codominant model; specifically, the frequencies of the CT and TT genotypes and the T allele were higher in the cases than the controls, demonstrating a significant risk for BA (odds ratio [OR] = 1.62, 95% confidence interval [CI] = 1.02–2.58; OR = 2.89, 95% CI = 1.72–4.86; and OR = 1.75, 95% CI = 1.34–2.29, respectively). Regarding rs10509906, the per-C-allele conferred an OR of 0.70 (95% CI = 0.49–1.00) under the additive model. A greater risk of BA was associated with the T_a-G_b (a for rs17095355 and b for rs10509906) haplotype (OR = 1.82, 95% CI = 1.27–2.61) compared with the C_a-C_b haplotype.

Conclusion

This study suggests that the ADD3 gene plays an important role in BA pathogenesis and reveals a significant association between two SNPs, rs17095355 and rs10509906, and BA.     

Th17及相关细胞因子与酒精性肝硬化患者肝脏硬度值、肝功能及脂联素水平的相关性分析

摘要 目的：探讨Th17及相关细胞因子与酒精性肝硬化患者肝脏硬度值（LSM）、肝功能及脂联素（APN）水平的相关性分析。方法：以2018年1月~2020年1月本院收治的酒精性肝硬化患者72例作为酒精性肝硬化组,同期在本院进行体检的健康志愿者100例作为健康对照组。对比两组研究对象Th17、白介素-17（IL-17）、LSM、肝功能指标、APN水平的差异,采用Pearson检验评估酒精性肝硬化患者Th17及IL-17与病情相关指标的相关性。结果：酒精性肝硬化组患者的Th17细胞分布比例、IL-17水平、LSM均高于健康对照组（P<0.05）。外周血中谷丙转氨酶（ALT）、谷草转氨酶（AST）、总胆红素（STB）的水平高于健康对照组,白蛋白（ALB）的水平低于健康对照组,血清中APN的水平低于健康对照组（P<0.05）。相关性分析发现,酒精性肝硬化患者Th17细胞分布比例及IL-17水平与LSM、ALT、AST、STB的水平呈正相关,与ALB、APN的水平呈负相关（P<0.05）。结论：酒精性肝硬化患者Th17及其细胞因子IL-17表达水平异常增高,可能在反映病情相关指标异常变化程度方面具有积极作用。     

肝移植术后急性肾功能衰竭的相关因素的临床分析

目的:探讨肝移植术后并发急性肾功能衰竭(ARF)的相关因素,为肝移植术后ARF的预防和治疗提供参考。方法:回顾性分析了2005年1月~2010年10月在我院行肝移植术的98例患者的临床资料,对术后并发ARF的相关因素进行分析。结果:98例行肝移植术后发生ARF 13例,发生率为13.27%。单因素分析显示术前血尿素氮(BUN)、术前血清肌酐(Scr)、术前血清白蛋白(Alb)、手术时间、失血量与ARF的发生有关(P<0.05)。多因素Logistic回归法分析表明,术前Scr和BUN是肝移植术后并发ARF的危险因素。结论:术前血BUN、血清Scr、血清Alb、手术时间和失血量是肝移植术后并发ARF主要因素,而术前Scr和BUN水平升高是肝移植术后并发ARF的危险因素。对上述因素加以重点评估和合理控制,可以控制肝移植术后ARF的发生。     

原位肝移植术后急性肺损伤的相关因素的临床分析

目的:探讨肝移植后急性肺损伤(ALI)的相关因素,为肝移植术后ALI的预防和治疗提供参考。方法:回顾性分析了2005年1月~2010年10月在我院行肝移植术的98例患者的临床资料,对术后并发ALI的相关因素进行分析。结果:98例行肝移植术后发生ALI12例,发生率为12.24%。单因素分析显示年龄、术前血清TBIL、术中失血量、术中尿量和术后血BUN对ALI的发生有显著影响(P<0.05)。多因素Logistic回归法分析表明,术中失血量、术前TBIL、年龄为术后并发ALI的危险因素。结论:术中失血量、术前TBIL、年龄为术后并发ALI的危险因素,对上述因素加以重点评估和合理控制,可以控制肝移植术后ALI的发生。     

肝移植术后急性肾功能衰竭的相关因素的临床分析

目的：探讨肝移植术后并发急性肾功能衰竭（ARF）的相关因素,为肝移植术后ARF的预防和治疗提供参考。方法：回顾性分析了2005年1月-2010年10月在我院行肝移植术的98例患者的临床资料,对术后并发ARF的相关因素进行分析。结果：98例行肝移植术后发生ARF13例,发生率为13．27％。单因素分析显示术前血尿素氮CBUN）、术前血清肌酐（Scr）、术前血清白蛋白（Alb）、手术时间、失血量与ARF的发生有关（P〈0．05）。多因素Logistic回归法分析表明,术前Ser和BUN是肝移植术后并发ARF的危险因素。结论：术前血BUN、血清Scr、血清Alb、手术时间和失血量是肝移植术后并发ARF主要因素,而术前Scr和BUN水平升高是肝移植术后并发ARF的危险因素。对上述因素加以重点评估和合理控制,可以控制肝移植术后ARF的发生。     

原位肝移植术后急性肺损伤的相关因素的临床分析

目的：探讨肝移植后急性肺损伤（ALI）的相关因素,为肝移植术后ALI的预防和治疗提供参考。方法：回顾性分析了2005年1月-2010年10月在我院行肝移植术的98例患者的临床资料,对术后并发ALI的相关因素进行分析。结果：98例行肝移植术后发生ALI12例,发生率为12．24％。单因素分析显示年龄、术前血清TBIL、术中失血量、术中尿量和术后血BUN对ALI的发生有显著影响（P〈0．05）。多因素Logistic回归法分析表明,术中失血量、术前TBIL、年龄为术后并发ALI的危险因素。结论：术中失血量、术前TBIL、年龄为术后并发ALI的危险因素,对上述因素加以重点评估和合理控制,可以控制肝移植术后ALI的发生。     

Rotavirus Replication in the Cholangiocyte Mediates the Temporal Dependence of Murine Biliary Atresia

Biliary atresia (BA) is a neonatal disease that results in obliteration of the biliary tree. The murine model of BA, which mirrors the human disease, is based upon infection of newborn mice with rhesus rotavirus (RRV), leading to an obstructive cholangiopathy. The purpose of this study was to characterize the temporal relationship between viral infection and the induction of this model. BALB/c mice were infected with RRV on day of life (DOL) 0, 3, 5, and 7. Groups were characterized as early-infection (infection by DOL 3) or late-infection (infection after DOL 5). Early RRV infection induced symptoms in 95% of pups with a mortality rate of 80%. In contrast, late infection caused symptoms in only 50% of mice, and 100% of pups survived. The clinical findings correlated with histological analysis of extrahepatic biliary trees, cytokine expression, and viral titers. Primary murine cholangiocytes isolated, cultured, and infected with RRV yielded higher titers of infectious virus in those harvested from DOL 2 versus DOL 9 mice. Less interferon alpha and beta was produced in DOL 2 versus DOL 9 RRV infected primary cholangiocytes. Injection of BALB/c interferon alpha/beta receptor knockout (IFN-αβR^−/−) pups at DOL 7 showed increased symptoms (79%) and mortality (46%) when compared to late infected wild type mice. In conclusion, the degree of injury sustained by relatively immature cholangiocytes due to more robust RRV replication correlated with more severe clinical manifestations of cholangiopathy and higher mortality. Interferon alpha production by cholangiocytes appears to play a regulatory role. These findings confirm a temporal dependence of RRV infection in murine BA and begin to define a pathophysiologic role of the maturing cholangiocyte.     

Fear of Movement Is Related to Trunk Stiffness in Low Back Pain

Background

Psychological features have been related to trunk muscle activation patterns in low back pain (LBP). We hypothesised higher pain-related fear would relate to changes in trunk mechanical properties, such as higher trunk stiffness.

Objectives

To evaluate the relationship between trunk mechanical properties and psychological features in people with recurrent LBP.

Methods

The relationship between pain-related fear (Tampa Scale for Kinesiophobia, TSK; Photograph Series of Daily Activities, PHODA-SeV; Fear Avoidance Beliefs Questionnaire, FABQ; Pain Catastrophizing Scale, PCS) and trunk mechanical properties (estimated from the response of the trunk to a sudden sagittal plane forwards or backwards perturbation by unpredictable release of a load) was explored in a case-controlled study of 14 LBP participants. Regression analysis (r ²) tested the linear relationships between pain-related fear and trunk mechanical properties (trunk stiffness and damping). Mechanical properties were also compared with t-tests between groups based on stratification according to high/low scores based on median values for each psychological measure.

Results

Fear of movement (TSK) was positively associated with trunk stiffness (but not damping) in response to a forward perturbation (r² = 0.33, P = 0.03), but not backward perturbation (r² = 0.22, P = 0.09). Other pain-related fear constructs (PHODA-SeV, FABQ, PCS) were not associated with trunk stiffness or damping. Trunk stiffness was greater for individuals with high kinesiophobia (TSK) for forward (P = 0.03) perturbations, and greater with forward perturbation for those with high fear avoidance scores (FABQ-W, P = 0.01).

Conclusions

Fear of movement is positively (but weakly) associated with trunk stiffness. This provides preliminary support an interaction between biological and psychological features of LBP, suggesting this condition may be best understood if these domains are not considered in isolation.     

Prediction of Glycated Hemoglobin Levels at 3 Months after Metabolic Surgery Based on the 7-Day Plasma Metabolic Profile

Metabolic surgery has been shown to provide better glycemic control for type 2 diabetes than conventional therapies. Still, the outcomes of the surgery are variable, and prognostic markers reflecting the metabolic changes by the surgery are yet to be established. NMR-based plasma metabolomics followed by multivariate regression was used to test the correlation between the metabolomic profile at 7-days after surgery and glycated hemoglobin (HbA1c) levels at 3-months (and up to 12 months with less patients), and to identify the relevant markers. Metabolomic profiles at 7-days could differentiate the patients according to the HbA1c improvement status at 3-months. The HbA1c values were predicted based on the metabolomics profile with partial least square regression, and found to be correlated with the observed values. Metabolite analysis suggested that 3-Hydroxybutyrate (3-HB) and glucose contributes to this prediction, and the [3-HB]/[glucose] exhibited a modest to good correlation with the HbA1c level at 3-months. The prediction of 3-month HbA1c using 7-day metabolomic profile and the suggested new criterion [3-HB]/[glucose] could augment current prognostic modalities and help clinicians decide if drug therapy is necessary.     

Netrin-1 and Semaphorin 3A Predict the Development of Acute Kidney Injury in Liver Transplant Patients

Acute kidney injury (AKI) is a serious complication after liver transplantation. Currently there are no validated biomarkers available for early diagnosis of AKI. The current study was carried out to determine the usefulness of the recently identified biomarkers netrin-1 and semaphorin 3A in predicting AKI in liver transplant patients. A total of 63 patients’ samples were collected and analyzed. AKI was detected at 48 hours after liver transplantation using serum creatinine as a marker. In contrast, urine netrin-1 (897.8±112.4 pg/mg creatinine), semaphorin 3A (847.9±93.3 pg/mg creatinine) and NGAL (2172.2±378.1 ng/mg creatinine) levels were increased significantly and peaked at 2 hours after liver transplantation but were no longer significantly elevated at 6 hours after transplantation. The predictive power of netrin-1, as demonstrated by the area under the receiver-operating characteristic curve for diagnosis of AKI at 2, 6, and 24 hours after liver transplantation was 0.66, 0.57 and 0.59, respectively. The area under the curve for diagnosis of AKI was 0.63 and 0.65 for semaphorin 3A and NGAL at 2 hr respectively. Combined analysis of two or more biomarkers for simultaneous occurrence in urine did not improve the AUC for the prediction of AKI whereas the AUC was improved significantly (0.732) only when at least 1 of the 3 biomarkers in urine was positive for predicting AKI. Adjusting for BMI, all three biomarkers at 2 hours remained independent predictors of AKI with an odds ratio of 1.003 (95% confidence interval: 1.000 to 1.006; P = 0.0364). These studies demonstrate that semaphorin 3A and netrin-1 can be useful early diagnostic biomarkers of AKI after liver transplantation.     

Differential Gene Expression in the Liver of the African Lungfish,Protopterus annectens,after 6 Months of Aestivation in Air or 1 Day of Arousal from 6 Months of Aestivation

The African lungfish, Protopterus annectens, can undergo aestivation during drought. Aestivation has three phases: induction, maintenance and arousal. The objective of this study was to examine the differential gene expression in the liver of P. annectens after 6 months (the maintenance phase) of aestivation as compared with the freshwater control, or after 1 day of arousal from 6 months aestivation as compared with 6 months of aestivation using suppression subtractive hybridization. During the maintenance phase of aestivation, the mRNA expression of argininosuccinate synthetase 1 and carbamoyl phosphate synthetase III were up-regulated, indicating an increase in the ornithine-urea cycle capacity to detoxify ammonia to urea. There was also an increase in the expression of betaine homocysteine-S-transferase 1 which could reduce and prevent the accumulation of hepatic homocysteine. On the other hand, the down-regulation of superoxide dismutase 1 expression could signify a decrease in ROS production during the maintenance phase of aestivation. In addition, the maintenance phase was marked by decreases in expressions of genes related to blood coagulation, complement fixation and iron and copper metabolism, which could be strategies used to prevent thrombosis and to conserve energy. Unlike the maintenance phase of aestivation, there were increases in expressions of genes related to nitrogen, carbohydrate and lipid metabolism and fatty acid transport after 1 day of arousal from 6 months aestivation. There were also up-regulation in expressions of genes that were involved in the electron transport system and ATP synthesis, indicating a greater demand for metabolic energy during arousal. Overall, our results signify the importance of sustaining a low rate of waste production and conservation of energy store during the maintenance phase, and the dependence on internal energy store for repair and structural modification during the arousal phase, of aestivation in the liver of P. annectens.     

大鼠2/3肝切除72 h后再生肝脏质膜比较蛋白质组学研究

大鼠2/3肝切除模型为研究肝细胞增殖和生理性血管生成提供了一个很好的活体内模型.为了揭示肝再生过程中与肝细胞增殖终止相关及与血管生成启动相关的质膜蛋白质,本研究对大鼠肝2/3部分切除72 h后的肝脏质膜进行了研究：利用两步蔗糖密度梯度离心法对切除组和假手术组的肝脏质膜进行纯化;然后通过双向电泳和质谱技术对肝切除样品进行了比较分析并对几个关键蛋白程序性凋亡相关蛋白-6和丝蛋白-A进行了免疫印迹验证.相对于假手术对照组(Sham组),21种蛋白质在切除后72 h的肝脏中上调,15种蛋白质下调.所鉴定的差异表达蛋白参与了血管生成、细胞分裂增殖和凋亡、细胞分化调控、肝脏组织重新构建、代谢及应急反应.本研究为肝脏再生及其血管生成的研究提供了理论依据.     

Prognostic Impact of 9-Month High-Sensitivity C-Reactive Protein Levels on Long-Term Clinical Outcomes and In-Stent Restenosis in Patients at 9 Months after Drug-Eluting Stent Implantation

Introduction

The level of 9-month high-sensitivity C-reactive protein (hsCRP) in predicting cardiovascular outcomes is scanty in patients at 9 months after receiving drug-eluting stent (DES) implantations. This study aims to evaluate the relationship between 9-month follow-up hsCRP levels and long-term clinical outcomes in patients at 9 months after receiving DES.

Methods

A total of 1,763 patients who received 9-month follow-up angiography were enrolled and grouped according to hsCRP level 9 months after the DES implantation: group I (718 patients, hsCRP<1.0 mg/L), group II (639 patients, 1.0≦hsCRP≦3.0 mg/L), and group III (406 patients, hsCRP>3.0 mg/L).

Results

Group III patients had a lower cardiovascular event-free survival rate than group I or II patients during a follow-up of 64±45 months (64.5% vs. 71.6% vs. 72.8%, respectively, p = 0.012). Multivariate analysis showed that a follow-up hsCRP level <3.0 mg/L was an independent predictor of a major adverse cardiovascular event (cardiac death, reinfarction, target lesion revascularization, stenting in a new lesion, or coronary bypass surgery). Group III patients had a higher restenosis rate (11.3% vs. 5.8% vs. 6.6%, respectively, p = 0.002) and loss index (0.21±0.32 vs. 0.16±0.24 vs. 0.18±0.28, respectively, p = 0.001) than group I or II patients in 9-month follow-up angiography.

Conclusions

A high 9-month follow-up hsCRP level is an independent predictor of long-term clinical cardiovascular outcomes in patients at 9 months after DES implantation. It is also associated with a higher restenosis rate, larger late loss and loss index at 9 months after DES implantation.     

肝移植术后替米夫定联合乙肝免疫球蛋白预防乙肝复发的研究

目的:评价在肝移植后替米夫定联合乙肝免疫球蛋白(HBIG)预防乙肝复发的临床疗效和安全性.方法:68例肝移植患者分为2组:32例患者应用拉米夫定联合HBIG预防预防乙肝的复发;36例患者应用替米夫定联合HBIG预防.观察两组患者用药干预后体内乙肝病毒DNA拷贝数(HBV DNA)、乙肝表面抗原(HB sAg)、乙肝E抗原(HBeAg)的变化以及用药过程中的不良反应.结果:拉米夫定联合HBIG组有4例患者在随访期间复发乙肝,复发率为12.5％,而替米夫定联合HBIG组未见患者复发乙肝.两组患者在治疗过程中均未见到明显的药物引起的不良反应.结论:替米夫定联合HBIG在肝移植术后预防乙肝复发中的临床疗效显著、安全性好,具有推广价值.     

Plasma Pentraxin 3 Levels Do Not Predict Coronary Events but Reflect Metabolic Disorders in Patients with Coronary Artery Disease in the CARE Trial

Chronic inflammation closely associates with obesity, metabolic syndrome, diabetes mellitus, and atherosclerosis. Evidence indicates that the immunomodulator pentraxin 3 (PTX3) may serve as a biomarker of these cardiometabolic disorders, but whether PTX3 predicts cardiovascular complications is unknown. We examined the association of plasma PTX3 levels with recurrent coronary events via a prospective, nested, case-control design in the CARE trial. Among 4159 patients who had a prior myocardial infarction 3 to 20 months before enrollment and also had total cholesterol levels <240 mg/dL and LDL cholesterol levels between 115 and 175 mg/dL, we measured plasma PTX3 levels at baseline by high-sensitivity ELISA in 413 cases with recurrent myocardial infarction or coronary death during a 5-year follow-up period, and in 366 sex- and age-matched controls. Cases with recurrent coronary events and controls had similar PTX3 levels, and PTX3 did not predict recurrent coronary events — a finding that contrasts with that of C-reactive protein (CRP) and serum amyloid A (SAA) in this cohort. We then associated PTX3 levels with metabolic disorders. Low plasma PTX3 levels correlated with high body-mass index, waist circumference, and triglycerides; and with low HDL cholesterol. Overall, PTX3 levels correlated inversely with the number of metabolic syndrome components. PTX3 levels also correlated inversely with apoCIII and tissue plasminogen activator, but did not associate with CRP. Although the study further links low PTX3 levels with various features associated with metabolic syndrome, the results do not indicate that PTX3 can predict recurrent coronary events among MI survivors.     

Sex Differences in the Neural Processing of Aversive Interoceptive Events: The Benefit of Relief

Do men and women process and experience unpleasant bodily states differently? We used fMRI to determine brain processing before, during and after an aversive respiratory stimulation. No sex difference emerged during anticipation or stimulation. However, after the offset of the stimulation, men but not women showed enhanced activation of brain regions that are important for interoception and reward processing. Moreover, this activation was highest in those males who rated the preceding stimulation as most unpleasant. These results indicate that men are particularly sensitive to reward associated with the termination of an aversive event, which may signal relief.