- 作者列表："Krishna M","Salako A","Fofanova T","Kellermayer R
BACKGROUND:The incidence of pediatric inflammatory bowel diseases (PIBDs: Crohn's disease [CD], ulcerative colitis [UC]) is on the rise around the world. Yet, the critical risk factors for this rising incidence are not well understood. Demographic characteristics of PIBD may improve our understanding of their developmental origins and aid in prevention. METHODS:Four hundred eighty-eight consecutive PIBD patients diagnosed at Texas Children's Hospital from 13 counties around Houston were studied. An annual incidence map was created by ZIP code of residence at diagnosis by using ArcGIS and the American Community Survey from the US Census Bureau. Correlation between demographic variables and PIBD incidence was examined. A model to explain incidence from different health factors was created in R. RESULTS:Hispanic children were more likely to be diagnosed with UC (P < 0.01) and unclassified IBD (IBD-U) (P < 0.03) compared with other races/ethnicities. A significant positive correlation (r = 0.35, P < 0.0001) between median household income and PIBD incidence was observed (UC: r = 0.23, P < 0.0001; CD: r = 0.22, P = 0.0004). ZIP codes with majority college-educated adults had a higher incidence of PIBD than ZIP codes with majority high school-educated adults (P < 0.0001). Pediatric cases with CD were more common in ZIP codes where the majority of adults were college educated (P < 0.0001). Pediatric cases with UC, however, were more common in ZIP codes where the majority of adults were high school educated (P = 0.0036). CONCLUSIONS:Hispanic children more commonly present with UC and IBD-U in southern USA. Household income and/or adult education-related environmental/dietary differences may be important in the developmental origins of PIBD in large metro areas, such as Houston.
背景: 儿童炎症性肠病 (PIBDs: 克罗恩病 [CD]，溃疡性结肠炎 [UC]) 的发病率在全球范围内呈上升趋势。然而，这种发病率上升的关键风险因素尚不清楚。PIBD 的人口学特征可能会提高我们对其发育起源的理解，并有助于预防。 方法: 对来自休斯顿周围 13 个县的在德克萨斯儿童医院诊断的 488 例连续 PIBD 患者进行研究。使用 ArcGIS 和美国人口普查局的美国社区调查，通过诊断时居住的邮政编码创建了年度发病率图。检查人口统计学变量与 PIBD 发病率之间的相关性。在 R 中创建了一个模型来解释来自不同健康因素的发病率。 结果: 与其他种族/种族相比，西班牙裔儿童更容易被诊断为 UC (P < 0.01) 和未分类 IBD (IBD-U) (P <0.03)。家庭收入中位数与 PIBD 发病率呈显著正相关 (r = 0.35，P <0.0001) (UC: r = 0.23，P <0.0001; CD: r = 0.22, P = 0.0004)。大多数受过大学教育的成年人的邮政编码比大多数受过高中教育的成年人的邮政编码有更高的 PIBD 发生率 (P <0.0001)。儿童 CD 病例在大多数成人受过大学教育的邮政编码中更常见 (P <0.0001)。然而，UC 的儿科病例在大多数成人受过高中教育的邮政编码中更常见 (P = 0.0036)。 结论: 在美国南部，西班牙裔儿童更常出现 UC 和 IBD-U。家庭收入和/或成人教育相关的环境/饮食差异可能在大型地铁地区 (如休斯顿) PIBD 的发展起源中很重要。
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.