- 作者列表："Lee MH","Shin HJ","Yoon H","Han SJ","Koh H","Lee MJ
BACKGROUND:Untreated neonatal cholestasis can progress to liver cirrhosis and end stage liver disease in infancy due to prolonged hepatocyte and biliary tree injury and may require liver transplantation. Therefore, non-invasive evaluation of hepatic fibrosis is important in infants with cholestasis. AIM:To investigate the usefulness of periportal thickening (PT) measured on liver magnetic resonance imaging (MRI) for the assessment of hepatic fibrosis in infants with cholestasis including biliary atresia (BA). METHODS:This retrospective study included infants less than 6 mo who underwent liver MRI and biopsy for the evaluation of infantile cholestasis. PT and spleen size were measured on MRI. Serologic assessment was based on aspartate transaminase to platelet ratio index (APRI). The grade of histopathologic fibrosis was assessed by the METAVIR grading system. Correlation and diagnostic performance of PT, normalized spleen size ratio (SR, using the upper normal size limit), and APRI for diagnosing hepatic fibrosis were obtained by receiver-operating characteristic (ROC) curve analysis. RESULTS:A total of 155 patients were included, 110 of which were diagnosed with BA. Mean age at the time of MRI was 57.6 ± 34.4 d. There were positive correlations between fibrosis grade and PT and SR, even after adjusting age (all, P < 0.001). For the diagnosis of significant fibrosis (METAVIR grade F2-F4), the area under the ROC curve was 0.899 (95%CI: 0.840-0.941) for PT (cutoff, 4.2 mm), which was higher than 0.741 (95%CI: 0.664-0.808) for SR and 0.712 (95%CI: 0.634-0.782) for APRI (both, P < 0.001). For the diagnosis of cirrhosis (F4), the area under the ROC curve was the highest with SR as 0.790 (95%CI: 0.718-0.852). CONCLUSION:Liver MRI findings of PT and SR are useful to assess clinically significant hepatic fibrosis (F2 and higher) in infants with cholestasis including BA.
背景: 未经治疗的新生儿胆汁淤积可在婴儿期因长期肝细胞和胆道树损伤而进展为肝硬化和终末期肝病，可能需要肝移植。因此，无创性评价肝纤维化对婴儿胆汁淤积有重要意义。 目的: 探讨肝脏磁共振成像 (MRI) 测量的门静脉周围增厚 (PT) 在评估胆汁淤积 (包括胆道闭锁) 婴儿肝纤维化中的价值。 方法: 这项回顾性研究包括小于 6 个月的婴儿，他们接受了肝脏 MRI 和活检以评估婴儿胆汁淤积。在 MRI 上测量 PT 和脾脏大小。血清学评估基于天冬氨酸转氨酶/血小板比值指数 (APRI)。通过 METAVIR 分级系统评估组织病理学纤维化的分级。通过受试者工作特征 (ROC) 获得 PT 、标准化脾脏大小比 (SR，使用正常大小上限) 和 APRI 诊断肝纤维化的相关性和诊断性能曲线分析。 结果: 共纳入 155 例患者，其中 110 例诊断为 BA。MRI 检查时的平均年龄为 57.6 ± 34.4 d。纤维化分级与 PT 和 SR 呈正相关，即使调整了年龄后 (均 P <0.001)。对于显著纤维化的诊断 (METAVIR 分级 F2-F4)，PT (cutoff，0.899) 的 ROC 曲线下面积为 0.840 (95% CI: 0.941-4.2毫米),SR 高于 0.741 (95% CI: 0.664-0.808)，APRI 高于 0.712 (95% CI: 0.634-0.782) (均 P <0.001)。对于肝硬化 (F4) 的诊断，ROC 曲线下面积最高，SR 为 0.790 (95% CI: 0.718-0.852)。 结论: PT 和 SR 的肝脏 MRI 表现有助于评估包括 BA 在内的胆汁淤积婴儿的临床显著肝纤维化 (F2 及以上)。
METHODS:Shigella species cause diarrheal disease globally. Shigellosis is typically characterized by bloody stools and colitis with mucosal damage and is the leading bacterial cause of diarrheal death worldwide. After the pathogen is orally ingested, it invades and replicates within the colonic epithelium through mechanisms that rely on its type III secretion system (T3SS). Currently, oral infection-based small animal models to study the pathogenesis of shigellosis are lacking. Here, we found that orogastric inoculation of infant rabbits with Shigella flexneri resulted in diarrhea and colonic pathology resembling that found in human shigellosis. Fasting animals prior to S. flexneri inoculation increased the frequency of disease. The pathogen colonized the colon, where both luminal and intraepithelial foci were observed. The intraepithelial foci likely arise through S. flexneri spreading from cell to cell. Robust S. flexneri intestinal colonization, invasion of the colonic epithelium, and epithelial sloughing all required the T3SS as well as IcsA, a factor required for bacterial spreading and adhesion in vitro Expression of the proinflammatory chemokine interleukin 8 (IL-8), detected with in situ mRNA labeling, was higher in animals infected with wild-type S. flexneri versus mutant strains deficient in icsA or T3SS, suggesting that epithelial invasion promotes expression of this chemokine. Collectively, our findings suggest that oral infection of infant rabbits offers a useful experimental model for studies of the pathogenesis of shigellosis and for testing of new therapeutics.IMPORTANCEShigella species are the leading bacterial cause of diarrheal death globally. The pathogen causes bacillary dysentery, a bloody diarrheal disease characterized by damage to the colonic mucosa and is usually spread through the fecal-oral route. Small animal models of shigellosis that rely on the oral route of infection are lacking. Here, we found that orogastric inoculation of infant rabbits with S. flexneri led to a diarrheal disease and colonic pathology reminiscent of human shigellosis. Diarrhea, intestinal colonization, and pathology in this model were dependent on the S. flexneri type III secretion system and IcsA, canonical Shigella virulence factors. Thus, oral infection of infant rabbits offers a feasible model to study the pathogenesis of shigellosis and to develop and test new therapeutics.
METHODS:PURPOSE:To quantify the effects of absorbed radiation dose on healthy liver parenchyma following radioembolisation (RE) using [99mTc]TcMebrofenin to analyse both global and regional liver function. METHODS:Patients having RE to treat hepatic disease underwent a [99mTc]TcMebrofenin hepatobilliary scintigraphy (HBS) study at both baseline and 8 weeks following treatment. Changes in global liver uptake rate were compared with healthy liver absorbed dose measures derived from the post-treatment 90Y PET/CT, including average dose, minimum dose to 70% of the volume (D70) and volume receiving at least 50 Gy (V50). Changes in functional burden associated with treatment and spared liver volumes in patients receiving lobar RE were also assessed, as were changes experienced by regional volumes corresponding to various dose ranges. Standard liver function pathology tests (LFTs) (bilirubin, albumin, ALP, AST, ALT and GGT) were examined for changes between baseline and post-treatment. RESULTS:Thirty-five patients were included in the study, of which, 9 had lobar treatment. A significant linear correlation was found between both baseline global liver uptake rate (negative) and D70 with change in global liver uptake rate. Patients undergoing lobar treatments demonstrated a shift in functional burden, and a significant difference was seen between the mean dose corresponding to liver volumes that increased their functional burden (9 Gy) and those that decreased their functional burden (35 Gy). No baseline LFTs predicted a decrease in global liver function; however, D70 demonstrated a linear correlation with changes in bilirubin and GGT. CONCLUSIONS:Given the significant negative relationship between baseline and change in global liver uptake rate, baseline HBS studies should not be used alone to disqualify patients considered for RE. In terms of treatment planning and evaluation, D70 may be the most appropriate metric of dose, with values greater than 15 Gy indicative of a likely drop in global liver function. The evidence of increasing functional burden in spared liver volumes suggests that patients at risk of complications could benefit from a lobar approach to treatment.
METHODS:NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for inflammatory bowel diseases. In this study, we found that Libertellenone M (Lib M), a secondary metabolite from the endophytic fungus Phomopsis sp. S12, has anti-inflammatory potential both in vitro and in vivo. Lib M selectively inhibited the expression of proinflammatory cytokine IL-1β and IL-18 in LPS-activated macrophages. The cleavage of pro-caspase 1 was remarkably reduced by Lib M in macrophages stimulated with three NLRP3 inflammasome activators. Administering Lib M attenuated dextran sulfate sodium-induced experimental acute colitis in mice and significantly reduced the production of these cytokines and cleaved caspase 1 in colon tissues. Apart from inhibition of NLRP3 inflammasome assembly, Lib M also suppressed NF-κB nuclear translocation in macrophages. Taken together, these findings suggest that Lib M-mediated inhibition of NLRP3 inflammasome activation could protect against colitis-like inflammatory diseases, and that this compound derived from a plant-associated fungus might inspire the exploration of novel immunosuppressive agents.