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Background Hirschsprung disease (HSCR) is a neurodevelopmental disorder with a strong genetic component. Common variants of NRG1 contributed to HSCR risk in Asians, and rare variants of ERBB2 and ITGB4 were found to be associated with HSCR. ERBB2 and ITGB4 are partners of Nrg1/ErbB pathway, which is important in HSCR pathogenesis. We aimed to investigate whether common variants in NRG1, ERBB2 and ITGB4 were associated with HSCR in Chinese Han population. Methods We genotype 17 single nucleotide polymorphisms (SNPs) of NRG1, ERBB2 and ITGB4 in 420 HSCR patients and 1665 controls, and performed association analysis. Results We validated associations of two NRG1 SNPs rs7835688 (PAllelic = 2.2 × 10− 20, OR = 2.21, 95%CI = 1.86–2.62) and rs16879552 (PAllelic = 5.6 × 10− 9, OR = 1.57, 95%CI = 1.35–1.83) with risk to HSCR. SNP rs3744000 located 5′ upstream of ITGB4 showed association with HSCR (PAllelic = 2.4 × 10− 3, OR = 1.27, 95%CI = 1.09–1.49). Four SNPs of ERBB2 exhibited no association. Conclusions Our results suggested that common variation of ITGB4 and NRG1 conferred risk to HSCR in Chinese Han population, which further highlighted Nrg-1/ErbB pathway involving in the pathogenesis of HSCR. Level of evidence

Objective. A case-control study was conducted to explore the value and clinical significance of troponin level and pediatric sequential organ failure score in the evaluation of sepsis 3.0 definition in critically ill children. Methods. 180 children with sepsis who were admitted to the ICU from March 2019 to June 2021 were enrolled in our hospital as the research objects. In addition, 100 children with general infection did not meet the diagnostic criteria of systemic inflammatory response syndrome (SIRS) as controls. The creatine kinase MB (CK-MB) and cardiac troponin I (cTnI) data at the 1st and 24-72 h after admission to pediatric intensive care unit (PICU) were enrolled as the observation indexes of myocardial enzymology. In the meantime, the relevant literature was reviewed to obtain the indicators related to sepsis death. The data of the first examination in the medical history data were enrolled for analysis. According to the definition of sepsis 3.0 in critically ill children, they were assigned into sepsis and nonsepsis group. According to the survival outcome of discharge and 30 days after discharge, the patients were assigned into the death subgroup and survival subgroup and were assigned into the sequential organ failure assessment SOFA score ≥ 2 subgroup and oxygenation index < 200 , mean arterial pressure, and Glasgow coma scale (GCS), and the difference was statistically significant ( P < 0.05 ). The results of COX regression analysis indicated that the variables that were remarkably associated with death from sepsis in children were CK-MB, elevated cTnI levels, and SOFA score ≥ 2 , and serum cTnI and/or CK-MB levels and SOFA score were remarkably higher correlation ( r = 0.453 , P < 0.05 ). In terms of the myocardial enzyme levels in the sepsis group and the nonsepsis group, the levels of CK-MB and (or) cTnI augmented in 121/180 cases (67.22%) in the sepsis group and in 19/100 cases (19.00%) in the nonsepsis group. The levels of CK-MB and (or) cTnI were augmented, and the difference was statistically significant ( P < 0.05 ). The levels of CK-MB and cTnI in the sepsis group at admission to ICU and 24 to 72 hours after admission were remarkably higher compared to the nonsepsis group. The levels of CK-MB and cTnI at 24-72 h were higher compared to ICU. The myocardial enzyme levels of different SOFA scores and survival outcome subgroups in the sepsis group were compared. The subgroup with SFOA score ≥ 2 points had remarkably higher levels of CK-MB and (or) cTnI than the subgroup with P < 0.05 ). Kaplan-Meier method and log-rank test indicated that the survival rates of groups 1 to 4 at 30 days were 33.23%, 78.71%, 40.03%, and 100.00%, respectively. The average survival time and their 95% CI were 12.82 d (10.52~ 16.26 d), 22.34 d (18.76~ 25.81 d), 14.65 d (11.62~ 16.38 d), and 30 d (30.00~ 30.00 d), respectively. Pairwise comparison indicated that the survival time of children in group 1 was the shortest, and that in group 4 was the longest. The results of ROC curve research showed that the CK-MB, cTnI, and SOFA scores and AUC for the combination test were 0.778 (95% CI 0.642–0.914), 0.736 (95% CI 0.602–0.890), 0.848 (95% CI 0.733–0.963), and 0.934 (95% CI 0.854–0.999), respectively. The AUC of combined diagnosis was remarkably higher compared to single factor prediction, and the difference was statistically significant ( P < 0.05 ). Predictive value showed the joint test > SOFA score > CK − MB > cTnI . Conclusion. Troponin level and pediatric SOFA score can be adopted as effective indicators to assess the severity and prognosis of patients with sepsis and can guide the formulation of a reasonable treatment plan.

Biliary atresia (BA) is an idiopathic neonatal cholestatic disease. Recent genome-wide association study (GWAS) revealed that common variation of ADD3, GPC1, ARF6, and EFEMP1 gene was associated with BA susceptibility. We aimed to evaluate the association of these genes with BA in Chinese population. Twenty single nucleotide polymorphisms (SNPs) in these four genes were genotyped in 340 BA patients and 1,665 controls. Three SNPs in ADD3 were significantly associated with BA, and rs17095355 was the top SNP (PAllele = 3.23×10-6). Meta-analysis of published data and current data indicated that rs17095355 was associated with BA susceptibility in Asians and Caucasians. Three associated SNPs were expression quantitative trait loci (eQTL) for ADD3. Two GPC1 SNPs in high linkage disequilibrium (LD) showed nominal association with BA susceptibility (PAllele = 0.03 for rs6707262 and PAllele = 0.04 for rs6750380), and were eQTL of GPC1. Haplotype harboring these two SNPs almost reached the study-wide significance (P = 0.0035). No association for ARF6 and EFEMP1 was found with BA risk in the current population. Our study validated associations of ADD3 and GPC1 SNPs with BA risk in Chinese population and provided evidence of epistatic contributions of genetic factors to BA susceptibility.

Hirschsprung’s disease (HSCR) is the most common congenital cause of intestinal obstruction in children. Sotos syndrome (SoS) is an overgrowth disorder with constipation and sometimes accompanied by HSCR. NSD1 gene mutation is the main cause of SoS. We aimed to investigate association of NSD1 common single nucleotide polymorphisms (SNPs) with HSCR susceptibility in Chinese Han population. We genotyped 15 SNPs encompassing NSD1 gene region in 420 HSCR patients and 1665 controls on Fludigm EP1 platform. Association analysis was performed between cases and controls. Rs244709 was the most associated SNP with HSCR susceptibility of the sample set (PAllelic = 9.69 × 10−5, OR = 1.37, 95% CI: 1.17–1.61). Gender stratification analysis revealed that NSD1 SNPs were associated with HSCR in males, but not in females. The nonsynonymous coding SNP rs28932178 in NSD1 exon 5 represented the most significant signal in males (PAllelic = 6.43 × 10−5, OR = 1.42, 95% CI: 1.20–1.69). The associated SNPs were expression quantitative trait loci (eQTLs) of nearby genes in multiple tissues. NSD1 expression levels were higher in aganglionic colon tissues than ganglionic tissues (P = 3.00 × 10−6). NSD1 variation conferred risk to HSCR in males, indicating SoS and HSCR may share common genetic factors.

To promote efficient screening of active angiogenic drugs from traditional medicines, we constructed a human embryonic kidney-293 cell model using vascular endothelial growth factor (VEGF) gene promoter as the drug target. In this model, VEGF gene promoter may regulate the expression of the luciferase reporter gene by responding to the stimulation of drug molecules. This cell model allows rapid and efficient screening of vascular-inducing active components from several drug monomer molecules. Furthermore, we used rat bone marrow mesenchymal stem cells (rMSCs) to conduct a preliminary study on the activity of alantolactone. Using simvastatin as a positive control, we investigated the effects of alantolactone on the expression of vascular-related cell marker molecules such as VEGF and α-smooth muscle actin (α-SMA) in rMSCs. According to our results, 0.1, 1, 3 and 5 μM of alantolactone upregulated the transcriptional luciferase gene activity of VEGF promoter, and a significant difference from that in the control group was observed. Among them, 3μM of alantolactone showed the better effect than that of 3 μM of simvastatin (P = 0.036) and other concentrations of alantolactone and simvastatin showed similar effects. Compared with that in the control group, rMSCs induced with 1μM alantolactone for 3 days showed a significant increase in the relative mRNA expressions of VEGF and α-SMA genes. However, these effect of 5 μM alantolactone were weaker than those of 5 μM simvastatin (P < 0.05); rMSCs treated with 1 μM alantolactone for 3 days showed brighter green fluorescence (FITC marker) of α-SMA and VEGF in situ expression than that observed in the control group and similar fluorescence intensity than that of simvastatin group in an immunoradiometric assay. The above results demonstrate the reliability of the highly efficient system for screening of active drug molecules and confirmed the vascular induction function of alantolactone at the gene and protein levels.

Biliary atresia (BA) is an idiopathic neonatal cholestatic disease. Recent genome-wide association study (GWAS) revealed that common variation of ADD3, GPC1, ARF6, and EFEMP1 gene was associated with BA susceptibility. We aimed to evaluate the association of these genes with BA in Chinese population. Twenty single nucleotide polymorphisms (SNPs) in these four genes were genotyped in 340 BA patients and 1,665 controls. Three SNPs in ADD3 were significantly associated with BA, and rs17095355 was the top SNP (PAllele = 3.23×10-6). Meta-analysis of published data and current data indicated that rs17095355 was associated with BA susceptibility in Asians and Caucasians. Three associated SNPs were expression quantitative trait loci (eQTL) for ADD3. Two GPC1 SNPs in high linkage disequilibrium (LD) showed nominal association with BA susceptibility (PAllele = 0.03 for rs6707262 and PAllele = 0.04 for rs6750380), and were eQTL of GPC1. Haplotype harboring these two SNPs almost reached the study-wide significance (P = 0.0035). No association for ARF6 and EFEMP1 was found with BA risk in the current population. Our study validated associations of ADD3 and GPC1 SNPs with BA risk in Chinese population and provided evidence of epistatic contributions of genetic factors to BA susceptibility.