Prospective study reveals a microbiome signature that predicts the occurrence of post-operative enterocolitis in Hirschsprung disease (HSCR) patients

ABSTRACT

Hirschsprung disease (HSCR) is a birth defect with an approximate incidence of 1/5,000 live births, and up to one-third of HSCR patients develop Hirschsprung-associated enterocolitis (HAEC), the leading cause of HSCR-related death. Very little is known about the pathogenesis, prevention, and early diagnosis of HAEC. Here, we used a prospective study to investigate the enteric microbiome composition at the time of surgery as a predictor for developing postoperative HAEC. We identified a microbiome signature containing 21 operational taxonomic units (OTUs) that can potentially predict postoperative HAEC with ~85% accuracy. Furthermore, we identified exclusive breastfeeding as a novel protective factor for total HAEC (i.e., preoperative and postoperative HAEC combined). In addition, we discovered that breastfeeding was associated with a lowered risk for HAEC potentially mediated by modulating the gut microbiome composition characterized by a lower abundance of Gram-negative bacteria and lower LPS concentrations. In conclusion, modulating the gut microbiome by encouraging breastfeeding might prevent HAEC progression in HSCR patients.     

一例结节性硬化症家系的TSC基因变异分析及产前诊断

目的分析1个结节性硬化症(tuberous sclerosis complex,TSC)家系TSC1和TSC2基因变异位点并进行产前诊断。方法应用Sanger测序法分别对先证者及其家庭成员进行TSC1和TSC2基因变异检测分析。结果家系先证者TSC1基因检测未见异常,TSC2基因内含子24中存在1处剪切供位变异位点(c.2837+1dupG),变异位点位于外显子与内含子连接处,家系其他成员及产前诊断胎儿的TSC1和TSC2基因未检测出变异。结论TSC2基因c.2837+1dupG剪切供位变异可能是该结节性硬化症病例的致病原因,应用基因测序方法有助于丰富该疾病致病基因的变异谱。     

JAK2/STAT3通路参与过氧化氢抑制小鼠原代颗粒细胞增殖的研究

目的通过过氧化氢(H2O2)处理体外培养的小鼠原代颗粒细胞(mGC),探讨JAK2/STAT3信号通路在H2O2抑制mGC增殖中的作用。方法应用H2O2、JAK2抑制剂AG490(不同浓度、不同作用时间)处理mGC;用CCK-8、增殖细胞核抗原蛋白(PCNA)水平检测细胞增殖情况,RT-PCR检测JAK2mRNA水平,Western blot检测JAK2、p-JAK2、STAT3、p-STAT3、Cyclin D1的蛋白表达水平。结果 H2O2与AG490均以剂量和时间依赖方式降低mGC活率。750μmol/L的H2O2处理mGC 24h明显降低细胞活率(P0.01),降低PCNA蛋白水平(P0.01),并下调JAK2mRNA和蛋白表达水平(P0.01);80μmol/L的JAK2抑制剂AG490可降低细胞活率(P0.01),且使细胞中的p-JAK2、JAK2、STAT3、p-STAT3、PCNA、Cyclin D1表达均下降(P0.05)。结论 H2O2抑制mGC增殖可能与JAK2/STAT3信号通路有关。     

Combined estrogen replacement therapy on metabolic control in postmenopausal women with diabetes mellitus

Previous studies have shown that the incidence of diabetes is higher when women come to menopause. This study was carried out to examine the effects of combined estrogen replacement therapy (ERT) on diabetes in postmenopausal women. PubMed/MEDLINE was searched for English-language articles published between January 1997 and June 2011. Studies that examined ERT on the incidence of diabetes and randomized clinical trials that evaluated combined ERT (estrogen plus progesterone) on diabetic indices in postmenopausal women were included. Pooled relative risks were calculated using a random- or a fixed-effects model. Sixteen studies comprising 17,971 cases were included. Based on the pooled data, ERT significantly reduced the incidence of diabetes [odds ratio (OR), 0.61; 95% confidence interval (CI), 0.55–0.68, ERT past/current/continuous use vs. never use; OR, 0.57; 95% CI, 0.51–0.65, ERT current/continuous use vs. past/never use]. Women with combined ERT have significantly lower levels of fasting plasma glucose (mean difference, –1.41 mM/L; 95% CI, –2.49 to ?0.33 mM/L) and HbA1c (mean difference, –0.73%; 95% CI, from ?1.28 to ?0.18%) compared with placebo. Furthermore, combined ERT dramatically reduced plasma total cholesterol (mean difference, –0.34 mM/L; 95% CI, from ?0.53 to ?0.15 mM/L) and low-density lipoprotein (mean difference, –0.43 mM/L; 95% CI, from ?0.71 to ?0.14 mM/L) but slightly increased high-density lipoprotein (mean difference, 0.02 mM/L; 95% CI, from ?0.07 to 0.12 mM/L) levels as compared with placebo control. This systemic review and meta-analysis provides evidence that postmenopausal women taking low-dose combined ERT have a decreased risk of developing diabetes and have better diabetic control.     

Molecular biology of testicular germ cell tumors: Unique features awaiting clinical application

Testicular germ cell tumors (TGCTs) are the most common solid tumors in young adult men characterized by distinct biologic features and clinical behavior. Both genetic predispositions and environmental factors probably play a substantial role in their etiology. TGTCs arise from a malignant transformation of primordial germ cells in a process that starts prenatally, is often associated with a certain degree of gonadal dysgenesis, and involves the acquirement of several specific aberrations, including activation of SCF–CKIT, amplification of 12p with up-regulation of stem cell genes, and subsequent genetic and epigenetic alterations. Their embryonic and germ origin determines the unique sensitivity of TGCTs to platinum-based chemotherapy. Contrary to the vast majority of other malignancies, no molecular prognostic/predictive factors nor targeted therapy is available for patients with these tumors. This review summarizes the principal molecular characteristics of TGCTs that could represent a potential basis for development of novel diagnostic and treatment approaches.     

Hypoxia-induced factor-1 alpha upregulates vascular endothelial growth factor C to promote lymphangiogenesis and angiogenesis in breast cancer patients

Hypoxia-induced factor-1 alpha （HIF-1α） affects many effector molecules and regulates tumor lymphangio- genesis and angiogenesis during hypoxia. The aim of this study was to investigate the role of HIF-1α in the regu- lation of vascular endothelial growth factor C （VEGF-C） expression and its effect on lymphangiogenesis and an- giogenesis in breast cancer. Lymphatic vessel density （LVD）, microvessel density （MVD） and the expressions of HIF-1α and VEGF-C proteins were evaluated by immunohistochemistry in 75 breast cancer samples. There was a significant correlation between HIF-1α and VEGF-C （P = 0.014, r = 0.273, Spearman＇s coefficient of correlation）. HIF-1α and VEGF-C overexpression was significantly correlated with higher LVD （P = 0.003 and P = 0.017, re- spectively）, regional lymph nodal involvement （P = 0.002 and P = 0.004, respectively） and advanced tumor, node, metastasis （TNM） classification （P = 0.001 and P = 0.01, respectively）. Higher MVD was observed in the group expressing higher levels of HIF-1α and VEGF-C （P = 0.033 and P = 0.037, respectively）. Univariate analysis showed shorter survival time in patients expressing higher levels of HIF-1α and VEGF-C. HIF-1α was also found to be an independent prognostic factor of overall survival in multivariate analysis. The results suggest that HIF-1α may affect VEGF-C expression, thus acting as a crucial regulator of lymphangiogenesis and angiogenesis in breast cancer. This study highlights promising potential of HIF- 1α as a therapeutic target against tumor lymph node me- tastasis.     

Remifentanil for labour analgesia: a double‐blinded,randomised controlled trial of maternal and neonatal effects of patient‐controlled analgesia versus continuous infusion

This trial aimed to compare the maternal and neonatal effects of remifentanil given by patient‐controlled analgesia (PCA) or continuous infusion for labour analgesia. Patient controlled analgesia was administered using increasing stepwise boluses from 0.1 to 0.4 μg.kg^?1 (0.1 μg.kg^?1 increment, 2 min lockout, n = 30). Continuous infusion used rates from 0.05 to 0.2 μg.kg^?1.min^?1 (0.05 μg.kg^?1.min^?1 increment, n = 30). Dose increments were given on request. Women reported lowest pain scores (median (IQR [range]) of 3 (2–4 [2–5]) for PCA and 4 (3–5.25 [3–7]) for continuous infusion (p = 0.004) at 60 min after the beginning of analgesia. The mean (SD) remifentanil umbilical vein/maternal artery ratio in the PCA and infusion groups were 0.74 (0.45) vs 0.70 (0.52), respectively (p = 0.776). The mean (SD) umbilical artery/umbilical vein ratios were 0.31 (0.12) vs 0.26 (0.07), respectively (p = 0.088). Maternal and neonatal adverse reactions of remifentanil were similar between the two groups. The total remifentanil consumption (median (IQR [range]) during PCA administration was lower than continuous infusion, 1.34 (1.22–1.48 [0.89–1.69]) mg vs 1.49 (1.35–1.61 [1.12–1.70] mg; p = 0.011). The results suggest that remifentanil PCA provides better pain relief and similar placental transfer compared with continuous infusion.     

Down-regulation of MeCP2 in Hirschsprung's disease

Background/Purpose

Hirschsprung's disease (HSCR) is a congenital disorder characterized by the absence of intramural ganglion cells which are highly associated with impaired proliferation and migration of neural crest cells. Whether methyl CpG binding protein 2 (MeCP2) is related with HSCR still remains unknown. This study investigates the involvement of MeCP2 in HSCR.

Methods

Quantitative real time PCR and western blot were used to detect the expression level of MeCP2 both in the aganglionic/diseased segment and the ganglionic/normal segment. In vitro assays we used siRNAs to knock-down the expression of MeCP2 in SH-SY5Y cell lines, and furthermore, MTT and transwell assays were used to detect the proliferation and migration ability, respectively. In addition, bisulfite sequencing (BSP) and miRNA analysis were used to examine why MeCP2 is decreased in HSCR samples.

Results

MeCP2 exhibited a lower expression level in tissues of HSCR patients compared with the controls. The down-regulation may also suppress the proliferative ability of the cells. However, there was no significant difference in the MeCP2 methylation level between cases and controls. Similarly, there was no difference between cases and controls in miRNA-34b (miR-34b) which is predicted to regulate MeCP2 through complementary binding to the 3′-untranslated region of MeCP2.

Conclusion

Our results indicated that an aberrant decreased level of MeCP2 may play an important role in the pathogenesis of HSCR.