Toll-like receptor 1 (TLR1), a member of the TLR family, assumes a pivotal role in pathogen recognition and the activation of innate immunity. In this study, we have identified a homozygous truncating TLR1 variant associated with immune dysregulation and colitis. Peripheral blood mononuclear cells derived from the patient manifested robust inflammatory signatures and defective TLR1 signaling responses. TLR1-deficient cells demonstrated impaired production of a wide-spectrum of inflammatory cytokines, antimicrobial peptides, and the anti-inflammatory cytokine IL-10 following stimulation with TLR1 ligand. This defect culminated in impaired bactericidal activity and dysregulated termination of the inflammatory response, especially characterized by a significant enhancement of the CXCR3 signaling pathway. TLR1-KO mice exhibited increased susceptibility to Salmonella Typhimurium infection and dextran sulfate sodium-induced colitis, with augmented infiltration of monocytes and macrophages in the pathological colon. The administration of IL-10 significantly alleviated the colitis phenotype associated with TLR1 deficiency in mice. This investigation underscores the crucial function of TLR1 in orchestrating a context-appropriate immune response to microbial invasion while averting excessive inflammation, thereby highlighting its indispensable role in human physiology and disease.

Gastrointestinal polyposis syndromes are primarily characterized by multiple polyps in the gastrointestinal tract, with their pathogenic mechanisms largely related to genetic factors and involving multiple signaling pathways. Adenomatous polyposis syndromes are mainly associated with APC gene variants, while some cases may arise from MUTYH gene variants. Peutz-Jeghers syndrome is primarily linked to STK11 gene variants. Juvenile polyposis syndrome is mainly associated with variants in the SMAD4 and BMPR1A genes. PTEN hamartoma tumor syndrome is predominantly caused by PTEN gene variants. Hereditary mixed polyposis syndrome is primarily related to variants of the GREM1 and BMPR1A genes. This article systematically summarizes the advances in genetic research on Gastrointestinal polyposis syndromes to enhance clinicians' understanding of these diseases and improve their diagnostic and therapeutic approaches.

The collapse of immune homeostasis induces type 1 diabetes (T1D). In T1D, uncontrolled immune attacks against islet β cells reduce insulin secretion, resulting in hyperglycaemia and various complications. Type 1 regulatory (Tr1) cell therapy is a promising approach for the treatment of T1D. Tr1 cells are a subset of regulatory T (Treg) cells that are characterised by high interleukin-10 secretion and forkhead box protein P3 non-expression. Tr1 cells are reduced and have impaired function in patients with T1D. Immunotherapy is used to treat various diseases, and Treg cells have been applied to treat T1D in animal models and clinical trials. However, the safety and efficacy of Tr1 cells in treating diabetes and other diseases remain unclear. In this review, we aim to investigate the identification and biological function of Tr1 cells and related studies on immune diseases; additionally, we discuss the feasibility, limitations, and possible solutions of Tr1 cell therapy in T1D. This review shows that T1D is caused by an immune imbalance where defective Tr1 cells fail to control effector T cells, leading to the destruction of islet β cells. However, Tr1 cell therapy is safe and effective for other immune diseases, suggesting its potential for treating T1D.

Ulcerative colitis (UC) is a form of chronic inflammatory bowel disease of nonspecific origin. This study used an RNA-Sequencing (RNA-Seq) approach to evaluate the transcriptomic landscape of a well-stratified treatment-naïve pediatric UC patient population by comparing them with healthy control children. The data were analyzed to evaluate the mechanisms driving UC-related intestinal inflammation and fibrosis. Intestinal mucosal samples from five pediatric UC patients and five healthy controls were analyzed by RNA-Seq, and results were verified by qPCR. A CRISPR/Cas9 approach was used to knock out the expression of HLA-DRB5, and molecular biology techniques were used for additional mechanistic studies. In these analyses, 2290 genes were found to be differentially expressed between the UC and control samples, of which 1258 and 1032 were upregulated and downregulated, respectively. Gene Ontology analysis showed that these genes were enriched in extracellular matrix (ECM)-related processes and that 7 of 8 differentially expressed genes of interest (PIK3CD, IL1β, IL1α, TIMP1, MMP1, MMP12, COL6A3, and HLADRB5) were upregulated and involved in ECM-receptor interaction and inflammatory bowel disease-related pathways. Increased HLA-DRB5 expression driven by intestinal bacteria was found to promote IL-1α secretion, leading to intestinal inflammation and fibrosis, suggesting a possible target for the treatment of UC. These data suggest that intestinal inflammation is present in pediatric UC patients for extended periods before the onset of symptoms, and intestinal fibrosis begins even during the early stages of UC. Intestinal bacteria were also found to trigger intestinal inflammation and fibrosis, with HLA-DRB5 playing a central role in this process.

Innate lymphoid cells (ILCs) are the counterpart of T helper cells in the innate immune system and share multiple phenotypes with T helper cells. Inducible T-cell costimulator (ICOS) is recognized on T cells and participates in T-cell activation and T and B-cell engagement in lymphoid tissues. However, the role of ICOS in ILC3s and ILC3-involved interactions with the immune microenvironment remains unclear. Here, we found that ICOS expression on human ILC3s was correlated with the activated state of ILC3s. ICOS costimulation enhanced the survival, proliferation, and capacity of ILC3s to produce cytokines (IL-22, IL-17A, IFN-γ, TNF, and GM-CSF). Via synergistic effects of ICOS and CD40 signaling, B cells promoted ILC3 functions, and ILC3-induced T-cell-independent B-cell IgA and IgM secretion primarily required CD40 signaling. Hence, ICOS is essential for the nonredundant role of ILC3s and their interaction with adjacent B cells.

Mesenchymal stem cells (MSCs) have been used to achieve exciting therapeutic outcomes in many animal studies and clinical trials for various autoimmune diseases, including inflammatory bowel disease (IBD). Type 1 regulatory T (Tr1) cells are the main source of interleukin (IL) 10 in the intestine. Whether Tr1 cells are involved during MSC-mediated IBD treatment is unclear. We treated a murine model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis with human umbilical cord-derived MSCs (hUCMSCs) and found that the disease severity was alleviated significantly in a dose-dependent manner. hUCMSCs increased the proportion of Tr1 cells and decreased that of T helper (Th)-1 and Th17 cells in the spleen and mesenteric lymph nodes in different stages of colitis. We found that the upregulation of Tr1 cells by hUCMSCs was abrogated after blocking indoleamine-2,3-dioxygenase (IDO), and IDO knockdown in hUCMSCs reversed the increase in Tr1 cell proportions caused by hUCMSCs in colitis. Moreover, hUCMSCs inhibited apoptosis and promoted the proliferation of Tr1 cells. Our results suggest that Tr1 cells play an important role in the amelioration of IBD by MSCs, and they are the target population for the alleviation of IBD by MSCs, providing meaningful references for the study of therapeutic mechanisms of MSCs in other inflammatory diseases.

Background Innate lymphoid cells (ILCs), so far studied mostly in mouse models, are important tissue-resident innate immune cells that play important roles in the colorectal cancer microenvironment and maintain mucosal tissue homeostasis. Plasmacytoid dendritic cells (pDCs) present complexity in various tumor types and are correlated with poor prognosis. pDCs can promote HIV-1–induced group 3 ILC (ILC3) depletion through the CD95 pathway. However, the role of ILC3s in human colon cancer and their correlation with other immune cells, especially pDCs, remain unclear. Methods We characterized ILCs and pDCs in the tumor microenvironment of 58 colon cancer patients by flow cytometry and selected three patients for RNA sequencing. Results ILC3s were negatively correlated, and pDCs were positively correlated, with cancer pathological stage. There was a negative correlation between the numbers of ILC3s and pDCs in tumor tissues. RNA sequencing confirmed the correlations between ILC3s and pDCs and highlighted the potential function of many ILC- and pDC-associated differentially expressed genes in the regulation of tumor immunity. pDCs can induce apoptosis of ILC3s through the CD95 pathway in the tumor-like microenvironment. Conclusions One of the interactions between ILC3s and pDCs is via the CD95 pathway, which may help explain the role of ILC3s in colon cancer.

目的:建立姜黄素预处理的大鼠急性肝脏缺血再灌注模型,初步探讨姜黄素对急性缺血再灌注后大鼠肝脏的保护作用.方法:10只SD大鼠随机分为假手术组(n=3)、溶剂对照组(n=3)和实验组(n=4).实验组和溶剂对照组大鼠在进行急性肝脏缺血再灌注前分别腹腔注射姜黄素和1％羧甲基纤维素钠(CMC)进行预处理.假手术组大鼠不进行急性肝脏缺血再灌注.采用超高效液相色谱-质谱(UPLC-MS)联用法分析各组大鼠血清中姜黄素水平,胆管导管术和荧光分析法检测各组大鼠胆汁流量,丙二醛(MDA)试剂盒检测各组大鼠肝脏组织中MDA水平.结果:腹腔注射200 mg·kg-1姜黄素1h后大鼠血清中姜黄素水平达到(0.17±0.05) mg·L-1,并在注射3 h后降到检测线以下.实验组大鼠肝脏组织中MDA水平为(9.18±1.78) mmol·g-1,低于溶剂对照组(527.54 mmol·g-1±237.38 mmol·g-1)和假手术组(162.73 mmol·g-1±90.50 mmol·g-1).实验组大鼠在缺血再灌注后胆汁流量恢复到基线的40％左右,与溶剂对照组比较差异无统计学意义(P＞0.05),假手术组大鼠胆汁流量则保持在基线水平.结论:姜黄素腹腔注射给药后能迅速进入大鼠血液循环,并在体内较快代谢,其水平在给药3h后降到检测线以下.姜黄素预处理能有效降低缺血再灌注后肝脏组织中MDA水平,对肝脏起到保护作用,但对恢复胆汁流量的效果不明显.

The causes of gastrointestinal (GI) bleeding in pediatrics are diverse. Unlike Meckel's diverticulum, anal fissure, polyps, inflammatory bowel disease, and infectious colitis, vascular malformation is not typically considered an etiology of GI bleeding in pediatrics, which can easily cause a delay in diagnosis or be misdiagnosed as reported (Abdoon, 2010; Al-Mehaidib, Alnassar, & Alshamrani, 2009). Vascular malformation, as an important cause of lower GI bleeding, is usually diagnosed in the elderly (Sami, Al-Araji, & Ragunath, 2014). It can affect any segment of the tract, usually the cecum and right colon in adults (Nishimura et al., 2015). Previous studies on children have shown that segmental lesions in the GI tract were found (Abdoon, 2010; Al-Mehaidib et al., 2009; Chuang et al., 2011; de la Torre Mondragón, Gómez, Mora Tiscarreño, & Ramírez Mayans, 1995; Uhlig, Stephan, Deutscher, Kiess, & Richter, 2004), but involvement of the entire colon is rare. In this case, we report an Asian boy presenting with GI bleeding diagnosed as diffused vascular malformation of the entire colon. Case A 13-year-old Asian boy was admitted into the hospital due to discontinuous hematochezia for 2 years and abdominal pain for over 1 month. The boy had no history of disease, surgery, medication, or family history. There was not much blood in his stool and bleeding would stop spontaneously. Either bright red or dark red bloody stools were seen in the course of his disease. At physical examination, he was generally in good condition, but had had a mild anemic appearance and complained of mild tenderness across the entire abdomen. The palpation of his abdomen was soft with no venous exposure. No hemorrhoids were found and no other abnormalities were observed. Blood routine examination showed the hemoglobin level decreased slightly as 92 g/L, and other parameters, such as white blood cell count, neutrophils, red blood cell count, and platelet count, were all within the normal range. Different tests were performed to determine the presence of the following pathogens: test for urine routine, coagulation routine, liver function, kidney function, and stool parasite were normal. Antibodies to hepatitis B/C viruses, Treponema pallidum, and HIV were all negative. The levels of ceruloplasmin and alpha fetoprotein were both normal. The ultrasonography of the intestines, liver, spleen, kidneys, and heart were without any abnormalities. Furthermore, under gastroscopy, no thickened vessels were seen in the esophagus and gastric fundus. Colonoscopy showed normal mucosal but with blood vessels dilated, tortuous, and thickened throughout the entire colon (Figure 1). The terminal ileum and ileocecal valve were normal. Capsule endoscopy was also performed showing no abnormalities of the small intestine.FIGURE 1.: Colonoscopy of vascular malformation in different sites of colon. (A) The ascending colon. (B) The transverse colon. (C) The descending colon. (D) The sigmoid colon. (E) The rectum. (F) The anal tube.The pathological results suggested that there was a little infiltration of lymphocytes and plasma cells in the intestinal tract with eosinophils 2–3/hpf. Therefore, vascular malformation was considered an etiology of the GI bleeding. To further clarify the bleeding site, digital subtraction angiography was recommended but the boy did not obtain his parents' permission. The boy was totally freed from hematochezia and abdominal pain after using octreotide for 5 days and was discharged. Discussion The frequency of vascular malformation of the colon as a cause of lower GI bleeding is 0.6% among adults in a recent study (Tsai et al., 2018) and is unknown for children. In adults, advanced age, especially over 60 years old, heart disease, use of anticoagulant drugs, etc. have been considered risk factors of vascular malformation (Nishimura et al., 2016), whereas scarce data have been identified in children. The mean age of clinical onset was 2.3 years and average delayed diagnosis was 2.9 years (de la Torre Mondragón et al., 1995). Vascular malformation can be incidentally found with various clinical manifestations, of which GI bleeding is the most common problem. Patients may present with chronic and recurrent bleeding, as was in our case. In previous studies, lesions were segmental, and any segment of the GI tract can be affected (Chuang et al., 2011; de la Torre Mondragón et al., 1995; Uhlig et al., 2004). However, the boy in our study presented with diffused lesions of the entire colon, which is rarely reported. Endoscopy and angiography are widely used in diagnosis of vascular malformation, of which endoscopy is the main tool (Sami et al., 2014). At the time of endoscopy, prominent lesions might be visualized and treated with endoscopic therapy. However, there are limitations; for example, lesions or bleeding sites can be missed during endoscopy due to a variety of reasons, such as poor visibility, size, and location of lesions (Sidhu, Sanders, Morris, & McAlindon, 2007). Angiography, as a supplemental tool, could be used to locate lesions or bleeding sites. In our case, the boy underwent endoscopy but did not undergo angiography without his parents' permission. We were unable to identify the bleeding sites, but the boy recovered well after taking octreotide. Due to the lack of evidence on outcome and treatment of vascular malformation, it is suggested that the disease management should be individualized depending on the lesion site, severity of bleeding, and general impairment. Conclusion This case highlights that vascular malformation should be kept in mind when dealing with GI bleeding, even in children; especially when patients have recurrent bleeding. Endoscopy is an essential tool for making this diagnosis.

Wilms tumor (WT) is the most common malignant renal neoplasm in children; however, the underlying molecular mechanisms are not well understood. According to the competing endogenous RNA (ceRNA) theory, long non-coding RNAs (lncRNAs) can regulate the expression of target genes by adsorbing microRNAs (miRNAs/miRs). However, the role of lncRNAs in WT has not been fully elucidated. The aim of the present study was to construct a ceRNA network to identify the potential lncRNAs involved in WT. The expression profiles of lncRNAs, miRNAs and mRNAs in 120 WT and six normal tissues were obtained from the Therapeutically Applicable Research to Generate Effective Treatments database. A total of 442 lncRNAs, 214 miRNAs and 4,912 mRNAs were identified as differentially expressed in WT and were enriched in 472 Gene Ontology terms (355 biological processes, 89 cellular components and 29 molecular functions) and 18 Kyoto Encyclopedia of Genes and Genomes pathways. A lncRNA-miRNA-mRNA ceRNA network of WT consisting of with 32 lncRNAs, 14 miRNAs and 158 mRNAs was constructed, based on the bioinformatics analysis of the miR target prediction database and the miRNAcode, miRTarBase and TargetScan databases. Subsequently, three lncRNAs, three miRNAs and 17 mRNAs, which had a significant effect on the overall survival rate of patients with WT, were identified based on the survival analysis. The three lncRNAs were also differentially expressed in the late and early stages of WT and were validated using the GSE66405 dataset obtained from the Gene Expression Omnibus database. In conclusion, the present study generated a specific lncRNA-related ceRNA network of WT, which may provide a novel perspective on the molecular mechanisms underlying the progression and prognosis of the disease.

Rationale: Oseltamivir-induced alimentary tract hemorrhage and liver injury are rarely reported in children and adult individuals. In this study, we described the clinical features and outcomes of oseltamivir-induced alimentary tract hemorrhage and liver injury in a child. Patient concerns: Here, we present a case of a 6-year-old Asian boy with hematemesis and elevated alanine aminotransferase (ALT) (80 U/L) and aspartate aminotransferase (AST) (69 U/L) levels on day 2 of oseltamivir administration. The presence of alimentary tract hemorrhage and liver injury was diagnosed. The ALT level reached 1931.3U/L, accompanied by an increase in total bilirubin (TBIL) to 53.3 mu mol/L on day 15 after oseltamivir administration. Additional tests were performed to determine the presence of viruses that can cause hepatitis and autoantibodies, and the results from these tests were all negative. Diagnosis: Drug-induced liver injury was considered. Interventions: This patient was treated with compound glycyrrhizin and reduced glutathione and glucocorticoid. Outcomes: The liver enzymes recovered within 6 weeks without any symptoms of liver-related diseases after treatment with glucocorticoid. This treatment therefore helps reduce ALT and TBIL levels and protects the liver from further injury. Lessons: Oral oseltamivir is widely used to treat influenza and the adverse effects of this drug were mostly mild. However, clinicians should always be alert for oseltamivir-induced alimentary tract hemorrhage and liver injury when prescribing oseltamivir for children.

例1 男,6岁,因"肛门塞入异物18 h"于2017年11月收入吉林大学第一医院,入院前18 h患儿因惧怕排便自行将铅笔塞入肛门中,具体长度描述不清,无便血,无发热,12 h前出现下腹隐痛,呕吐3次,呕吐物为未消化食物,无胆汁及血丝,予甘油缓泻剂40 ml通便,未将异物排出,至当地医院行腹部X线片未见异常,建议至我院行结肠镜下异物取出.体格检查:体温36.8℃,脉搏98次/min,呼吸20次/min,血压96/68 mmHg(1 mmHg=0.133 kPa),一般状态良好,平卧位、坐位时腹痛明显,腹软,下腹轻压痛,无肌紧张及反跳痛,肠鸣音3次/min,肛门指诊未触及异物,指套无血迹.心肺及神经系统查体无异常.辅助检查:腹部彩超示右下腹乙状结肠内可见一长条状强回声,长约62 mm,考虑异物(图1).入院诊断为"结肠异物",行急诊结肠镜下异物取出术.常规清洁灌肠后于静脉麻醉下行结肠镜检查,进镜20 cm乙状结肠内可见1支铅笔(长8.6 cm)嵌顿于直肠乙状结肠交界处,附近肠腔黏膜散在条形充血、糜烂、浅溃疡,圈套器套取异物末端,拉动异物时阻力较大,拉直肠腔后,顺利取出,镜下未见穿孔及出血(图2、3).术后行腹部立位X线片未见穿孔征象,腹痛及呕吐症状消失,腹部查体无压痛,术后无不适,第2天出院.

1病例资料 患儿男,3个月18天,体重7.7 kg,因腹泻半个月、间断发热7d于2017年8月28日入院.入院时患儿生命体征:T38℃,P 126次/min,R 30次/min,血压未测.既往无食物、药物过敏史.一般状态及精神状态可,枕部可见明显枕秃,口腔黏膜可见白色膜状物附着,肠鸣音活跃,余无特殊.血常规:白细胞(WBC) 6.63×109·L-1,中性核细胞百分比(NE)0.35,淋巴细胞百分比(LY) 0.47,C-反应蛋白(CRP) 39.2 mg.L-1.入院诊断:“迁延性腹泻、鹅口疮”.患儿CRP明显升高,考虑存在细菌感染.在头孢曲松皮试阴性后于8月29日给予注射用头孢曲松钠(上海罗氏制药有限公司,批号:SH6284)0.6 g +5％葡萄糖注射液50 ml,ivd,qd.使用3d患儿无异常.第4天(9月1日),患儿在静脉滴注头孢曲松(滴速1 ml-min-1)约2 min后,突然出现剧烈哭闹,颈部频繁后仰,既而出现颜面部及口周青紫,双眼向上凝视,随后意识丧失,阵发性咳嗽,喉中痰鸣,四肢末梢发凉,拟诊断:过敏性休克.立即停用头孢曲松,给予地塞米松注射液3 mg iv、盐酸肾上腺素注射液0.3 mg im,同时给予吸氧及心电监护,患儿心率波动于180 ～210次/min,呼吸维持在30～ 50次/min,经皮血氧饱和度波动于95％以上,1min后患儿症状缓解,立即进入睡眠状态,后生命体征逐渐平稳,血压70/55 mmHg,心率120次/min.患儿复查血常规基本正常,CRP 4.19 mg·L-1,血培养回报为阴性.因患儿病情基本好转,给予出院继续口服罗红霉素25 mg,bid.

1 病例资料 患儿, 女, 11 岁, 因 "腹泻2 年, 腹痛、 腹胀10 d, 呕吐3 d" 入院. 患儿2 年前无明显诱因出现腹泻, 为不成形便, 每日2 ～3 次, 便中无黏液及脓血, 无腹痛, 无发热, 未予特殊处置; 10 d前患儿出现腹痛, 以右下腹为主, 为持续性钝痛, 夜间较重,排便后可自行缓解, 伴腹胀, 未系统诊治; 3d前患儿出现呕吐, 每日3 ～5 次, 非喷射性, 呕吐物为未消化食物, 就诊于当地诊所, 静脉用药 (具体不详) 1d症状无缓解, 后就诊于我院门诊, 行腹部彩超提示腹腔积液 (较深处60 mm ) , 门诊以 "腹腔积液"入院. 病程中患儿无低热, 无咳嗽, 无乏力、 盗汗,饮食、 睡眠、 尿量正常, 体重增长缓慢.

Nonalcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases in children. Since the clinical manifestations of NAFLD lack specificity, the diagnosis of this disease is mainly based on clinical symptoms and auxiliary examinations. Serum liver enzymes, blood lipid levels and homeostasis model assessment of insulin resistance are commonly used in clinical practice, and cytokeratin-18, triglyceride glucose index may become new markers for the diagnosis of NAFLD in children. Imaging examinations such as ultrasound, magnetic resonance imaging and computed tomography have their own limitations in the diagnosis of NAFLD in children, while controlled attenuation parameter and acoustic radiation force impulse may have a high value in future. The scoring systems for NAFLD need to be validated by clinical research. At present, liver biopsy remains the “gold standard” for the diagnosis of NAFLD in children. This article summarizes the latest research advances in NAFLD in children and discusses the diagnostic values of laboratory markers and imaging examinations.

如何提高七年制医学生的临床实践能力以适应中国目前的医疗环境，是医学高等教育的棘手问题。传统医学模式弊病较多，需要探索新型的医学教育模式以改变现状。笔者初步尝试PBL教学与标准化病人教学方法相结合，将临床技能、临床思维培养与临床实践相结合的教学模式，取得了一定的效果，可为未来医学教育提供一条新思路。