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Background Endotoxin tolerance (ET) is a protective mechanism in the process of sepsis, septic shock, and their sequelae including uncontrolled inflammation. Accumulating evidence has shown that peripheral T cells contribute to the induction of ET. However, what and how T-cell development contributes to ET inductions remain unclear. Methods Mice were intraperitoneally injected with LPS at a concentration of 5 mg/kg to establish an LPS tolerance model and were divided into two groups: a group examined 72 h after LPS injection (72-h group) and a group examined 8 days after LPS injection (8-day group). Injection of PBS was used as a control. We performed high-throughput sequencing to analyze the characteristics and changes of CD4+SP TCRβ CDR3 repertoires with respect to V direct to J rearrangement during the ET induction. Moreover, the proportion and proliferation, as well as surface molecules such as CD80 and CD86, of F4/80+ macrophages were analyzed using FCM. Furthermore, ACT assay was designed and administered by the tail vein into murine LPS-induced mouse model to evaluate the role of F4/80+ macrophages on the development of CD4+SP thymocytes in ET condition. Results We found that the frequency and characteristics of the TCRβ chain CDR3 changed obviously under condition of ET, indicating the occurrence of TCR rearrangement and thymocyte diversification. Moreover, the absolute numbers of F4/80+ macrophages, but not other APCs, were increased in thymic medulla at 72-h group, accompanied by the elevated function-related molecules of F4/80+ macrophages. Furthermore, adoptively transferred OVA332-339 peptide-loaded macrophages into Rag-1−/− mice induced the clone deletion of OVA-specific CD4+SP, thereby ameliorating the pathology in lung tissue in LPS challenge. Conclusions These data reveal that the frequency and characteristics of the TCRβ chain CDR3 undergo dynamic programming under conditions of LPS tolerance. Furthermore, the peripheral macrophages may be a key factor which carry peripheral antigen to thymic medulla and affect the negative selection of T-cell population, thereby contributing to the formation of ET. These results suggest that the clone selection in thymus in ET may confer protection against microbial sepsis.

BACKGROUND AND AIMS Increasing evidence in recent years has suggested that microRNA-7 (miR-7) is an important gene implicated in the development of various diseases including HCC. However, the role of miR-7 in autoimmune hepatitis (AIH) is unknown. APPROACH AND RESULTS Herein, we showed that miR-7 deficiency led to exacerbated pathology in Concanavalin-A-induced murine acute autoimmune liver injury (ALI) model, accompanied by hyperactivation state of CD4+ T cells. Depletion of CD4+ T cells reduced the effect of miR-7 deficiency on the pathology of ALI. Interestingly, miR-7 deficiency elevated CD4+ T-cell activation, proliferation, and cytokine production in vitro. Adoptive cell transfer experiments showed that miR-7def CD4+ T cells could exacerbate the pathology of ALI. Further analysis showed that miR-7 expression was up-regulated in activated CD4+ T cells. Importantly, the transcription of pre-miR-7b, a major resource of mature miR-7 in CD4+ T cells, was dominantly dependent on transcription factor CCAAT enhancer binding protein alpha (C/EBPα), which binds to the core promoter region of the miR-7b gene. Global gene analysis showed that mitogen-activated protein kinase 4 (MAPK4) is a target of miR-7 in CD4+ T cells. Finally, the loss of MAPK4 could ameliorate the activation state of CD4+ T cells with or without miR-7 deficiency. Our studies document the important role of miR-7 in the setting of AIH induced by Concanavalin-A. Specifically, we provide evidence that the C/EBPα/miR-7 axis negatively controls CD4+ T-cell activation and function through MAPK4, thereby orchestrating experimental AIH in mice. CONCLUSIONS This study expands on the important role of miR-7 in liver-related diseases and reveals the value of the C/EBPα/miR-7 axis in CD4+ T-cell biological function for the pathogenesis of immune-mediated liver diseases.

Our objective is to study the efficacy and safety of parenteral nutrition (PN) with iron sucrose to prevent anemia in preterm infants.We performed a randomized, double-blind controlled trial in which preterm infants were divided into five groups randomly: a control group (PN without iron sucrose, namely group Iron-0), and intervention groups (PN with iron sucrose 100 μg/kg/d, 200 μg/kg/d, 300 μg/kg/d and 400 μg/kg/d, namely group Iron-1, 2, 3, and 4, respectively). The indicators were red blood cell (RBC) parameters, iron storage and oxidant stress.One hundred infants completed this study. Excepting the RBC count in Iron-2, the value of erythrocyte parameters in intervention groups decreased less than that in the control group. And the decrease of RBC count in Iron-1 (-0.6×1012/L vs -0.9×1012/L, p=0.033), hemoglobin in Iron-4 (-26.0 g/L vs -41.0 g/L, p=0.03) and hematocrit in Iron-1(-9.5% vs -14.0%, p=0.014) was significantly less than in the control group. The change of ferritin in Iron-4 was significantly higher than in the control group (280 ng/ml vs 118 ng/ml, p=0.04). There was no difference in serum iron in intervention groups when compared to the control group (p0.05). Except for the change of malondialdehyde (MDA) in Iron-1, the increase in other intervention groups was higher than in the control group (p0.05).PN with iron sucrose for prevention of anemia in preterm infants is safe and efficacious to some extent.

Zhimin Geng,* Yijing Tao,* Fenglei Zheng, Linlin Wu, Ying Wang, Yujia Wang, Yameng Sun, Songling Fu, Wei Wang, Chunhong Xie, Yiying Zhang, Fangqi Gong Department of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fangqi GongDepartment of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, People’s Republic of ChinaTel/Fax +86 571 86670008Email gongfangqi@zju.edu.cnBackground: Kawasaki disease (KD) is characterized by a disorder of immune response, and its etiology remains unknown. Monocyte is an important member of the body’s innate immune system; however its role in KD is still elusive due to its ambiguous heterogeneity and complex functions. We aim to comprehensively delineate monocyte heterogeneity in healthy and KD infants and to reveal the underlying mechanism for KD.Methods: Peripheral monocytes were enriched from peripheral blood samples of two healthy infants and two KD infants. scRNA-seq was performed to acquire the transcriptomic atlas of monocytes. Bio-information analysis was utilized to identify monocyte subsets and explore their functions and differentiation states. SELL+CD14+CD16- monocytes were validated using flow cytometry.Results: Three monocyte subsets were identified in healthy infants, including CD14+CD16- monocytes, CD14+CD16+ monocytes, and CD14LowCD16+ monocytes. Cell trajectory analysis revealed that the three monocyte subsets represent a linear differentiation, and possess different biological functions. Furthermore, SELL+CD14+CD16- monocytes, which were poorly differentiated and relating to neutrophil activation, were found to be expanded in KD.Conclusion: Our findings provide a valuable resource for deciphering the monocyte heterogeneity in healthy infants and uncover the altered monocyte subsets in KD patients, suggesting potential biomarkers for KD diagnosis and treatment.Keywords: Kawasaki disease, monocyte subsets, scRNA-seq

The goal of this study was to analyze long-term outcome of various pediatric short bowel syndrome (SBS) at an intestinal rehabilitation center in China. One hundred and fifty-seven children with SBS were enrolled in this study from October 1988 to July 2019. Their long-term follow-up outcome was analyzed according to the age of disease onset, parenteral nutrition (PN) duration, and anatomic types of short bowel, respectively. The clinical characteristics, which included demographics, the length of residual small bowel, PN duration, PN dependence, SBS-related complications such as IF-related liver disease (IFALD), catheter-related bloodstream infection (CRBI), and mortality were compared among the groups. The main etiology for SBS were intestinal atresia, NEC, and volvulus. Five of 157 patients did not wean off PN. The incidence of IFALD and CRBI was 24.2 and 22.3%, respectively. Sixteen cases died because of infection and liver failure and eight patients lost to follow-up. The survival rate of the 157 patients was 84.7%. PN duration was longer in the infants and children group (284 ± 457 d vs. 110 ± 64 d, P = 0.021; R = 0.264, P = 0.001) and more patients did not wean off PN than in the neonates group (11.6% vs. 0, P = 0.001; R = 0.295, P

Background and aim Studies about differences in microbial communities between the small intestine and colon in infants with short bowel syndrome (SBS) are rare. We aimed to characterize the bacterial diversity of small bowel stoma effluents and feces of SBS infants. Methods Seven SBS infants were enrolled in this study and provided two samples (one from the stoma and the other from the anus) each. Eleven age-matched healthy controls were recruited to provide one fecal sample each. 16S rRNA gene MiSeq sequencing was conducted to characterize the microbiota diversity and composition. Results The bacterial diversity of the stoma effluents was significantly higher than that in the feces of SBS infants. Proteobacteria dominated in both the stoma effluents and colonic. Acinetobacter (P = 0.004), Klebsiella (P = 0.015), Citrobacter (P = 0.019), and Lactobacillus (P = 0.030) were more abundant in stoma effluents compared to feces of SBS patients, while Bacteroidetes, Bifidobacterium and Veillonella were less abundant in stoma effluents. Significantly higher levels of Proteobacteria, Enterococcus and lower levels of Blautia, Collinsella, Faecalibacterium, Veillonella were present in the fecal samples of SBS patients than those in the healthy controls. Kyoto Encyclopedia of Genes and Genomes pathways related to metabolism and membrane function were depleted in SBS patients. Conclusions The predominant intestinal bacterial groups were different in SBS children before and after the fistula closure. Fecal samples of SBS patients featured overabundant Proteobacteria and less SCFA producing bacteria. Depleted functional profiles of the microbiome were found in fecal samples of SBS patients. Level of evidence III.

Background The calcineurin and nuclear factor of activated T-cells (CaN-NFAT) signaling pathway had been found to be associated with Kawasaki disease (KD) susceptibility and coronary artery aneurysm formation as a contributor. To evaluate serum calcineurin (CaN) and nuclear factor of activated T-cells 1(NFAT1) levels in patients with Kawasaki disease (KD). Methods Serum levels of CaN and NFAT1 were measured by enzyme-linked immunosorbent assay method in 66 healthy children and 74 KD patients at acute, afebrile and subacute stage. Results The serum levels of CaN and NFAT1 increased significantly in the acute stage, and decreased progressively in the afebrile and subacute stage, along with the reduction of C-reactive protein, white blood cells and neutrophil counts. And in the acute stage, the afebrile stage and the subacute stage, the expression of CaN and NFAT1 was upregulated significantly in KD patients compared to that in the healthy control. After the IVIG treatment, the serum levels of CaN and NFAT1 declined significantly in IVIG responders. However, the CaN and NTAT1 levels in the IVIG non-responders declined slowly. And in the afebrile stage, the NFAT1 levels were lower in KD patients with coronary artery lesions (CALs) (268.82 ± 11.96 ng/ml) than those without CALs (285.84 ± 25.13 ng/ml). However, the serum levels of CaN in KD patients with CALs had no significant difference with those in KD patients without CALs. Conclusions The specific regulation of CaN and NFAT1 serum levels in the course of KD was suggested that both of them were related in the development of KD.

AIM We aimed to explore risk factors associated with parenteral nutrition-associated cholestasis (PNAC) in very-low-birthweight (VLBW) infants. METHODS VLBW infants receiving parenteral nutrition (PN) for at least 14 days were enrolled in a retrospective dual-centre study and divided into two groups chronologically: group A (2000-2007) and group B (2008-2015). The incidence of PNAC and related factors were investigated. We compared the differences between PNAC and non-PNAC groups. A multivariate binary logistic regression analysis was carried out to identify the potential risk factors of PNAC. RESULTS A total of 387 VLBW infants (53 in group A and 334 in group B) were enrolled in the study. The total incidence of PNAC was 6.7%, 9.4% in group A and 6.3% in group B. The dosage of amino acid (P = 0.009), glucose (P = 0.006), PN calories (P = 0.021) and the ratio of glucose/fat (P = 0.014) were significantly higher in group B than in group A. Non-protein energy to nitrogen ratio (P = 0.017) was lower in group B. Birthweight was significantly lower in the PNAC group than in the non-PNAC group (P = 0.021). Subgroup analysis showed that gestational age and duration of PN were significantly different between the PNAC and non-PNAC groups (P

Yanqi Qi,* Jiawen Xu,* Zhe Lin,* Yijing Tao, Fenglei Zheng, Yujia Wang, Yameng Sun, Songling Fu, Wei Wang, Chunhong Xie, Yiying Zhang, Fangqi Gong Department of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fangqi GongDepartment of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, People’s Republic of ChinaTel/Fax +86-571-88873008Email gongfangqi@zju.edu.cnIntroduction: Kawasaki disease (KD) is an acute febrile systemic vasculitis, but the etiology remains unknown. We studied serum levels of CD147, DcR3, and IL33 in different stages of KD to explore the value of CD147, DcR3, and IL33 in the pathophysiology of KD.Methods: We measured serum levels of CD147, DcR3, and IL33 by enzyme-linked immunosorbent assay (ELISA) at different stages with 71 KD patients and 66 healthy control children. We apply for network tools GeneMANIA and Cytoscape APP to analyze the functions of these pro-inflammatory factors at the gene and protein level.Results: Serum levels of CD147, DcR3, and IL33 were significantly increased in KD patients before IVIG treatment. Serum levels of CD147, DcR3, and IL33 gradually decreased over time after the treatment of IVIG. Eight cases were IVIG non-responders, while nine KD patients got CALs, but they did not overlap. And there were no statistical differences between group IVIG responders and IVIG non-responders or between groups without CALs and with CALs. We explored the functions of CD147, DcR3, and IL33 from GeneMANIA and Cytoscape APP and found these third pro-inflammatory factors were coexpressed, physical interactions, genetic interactions with other KD-related factors.Conclusion: CD147, DcR3, and IL33 are involved in the pathophysiology of KD, which provides novel evidence for diagnosing and treating KD with their inhibitors.Keywords: Kawasaki disease, coronary artery lesions, CD147, DcR3, IL33, PI3K/AKT pathway

Background Infants with neonatal-onset diarrhea present with intractable diarrhea in the first few weeks of life. A monogenic mutation is one of the disease etiologies and the use of next-generation sequencing (NGS) has made it possible to screen patients for their mutations. Main body We retrospectively reviewed the clinical data of four children from unrelated families, who presented with neonatal-onset, chronic, watery, non-bloody diarrhea. After genetic whole-exome sequencing, novel mutations were identified in the EPCAM gene of two children. Congenital chloride diarrhea was diagnosed in one case, which was associated with an SLC26A3 mutation, in which the patient presented with watery diarrhea, malnutrition, and hypochloremic alkalosis. Patient 4 was diagnosed with microvillus inclusion disease and possessed novel compound heterozygous mutations in the MYO5B gene. A review of the genetic variants of SLC26A3 reported in East Asia revealed that c.269_270 dupAA (p.G91Kfs*3) is the most frequent SLC26A3 mutation in China, compared with c.2063-1 G > T in Japan and Korea. EPCAM and MYO5B genetic variants were only sporadically reported in East Asia. Conclusion This study expands our knowledge of the clinical manifestations and molecular genetics of neonatal-onset watery diarrhea. Early diagnosis could be achieved by genomic analysis in those infants whose histology features are not typical. The discovery of four novel mutations in the EPCAM gene and two novel mutations in the MYO5B gene provides further etiological evidence for the association of genetic mutations with neonatal-onset diarrhea. To date, c.269_270 dupAA is the most frequent SLC26A3 mutation in China.

This study aims to validate the reliability of cardiac magnetic resonance (CMR) parameters for estimating left ventricular end diastolic pressure (LVEDP) in heart failure patients with preserved ejection fraction (HFpEF) and compare their accuracy to conventional echocardiographic ones, with reference to left heart catheterisation. Sixty patients with exertional dyspnoea (New York Heart Association function class II to III) were consecutively enrolled. CMR-derived time-volume curve and deformation parameters, conventional echocardiographic diastolic indices as well as LVEDP evaluated by left heart catheterisation were collected and analysed. Fifty-one patients, who accomplished all three examinations, were divided into HFpEF group and non-HFpEF group based on LVEDP measurements. Compared to the non-HFpEF group, CMR-derived time-volume curve showed lower peak filling rate adjusted for end diastolic volume (PFR/EDV, p = 0.027), longer time to peak filling rate (T-PFR, p

Endotoxin tolerance is an important state for the prevention of lethal infection and inflammatory response, which is closely associated with the participation of innate immune cells. Moreover, mesenteric lymph nodes (MLNs)-resident immune cells, such as CD4+Foxp3+ regulatory T (Treg) cells and dendritic cells, play important roles in the maintenance of peripheral immune tolerance. However, the potential roles of these cells in MLNs in the development of endotoxin tolerance remain largely unknown. Recent research work showed that CD4+Foxp3+ Treg cells contributed to the development of endotoxin tolerance. Here, we further analyzed the possible change on CD4+Foxp3+Tregs population in MLNs in murine LPS-induced endotoxin tolerance model. Our data showed that the proportion and absolute number of CD4+Foxp3+Tregs, expressing altered levels of CTLA4 and GITR, significantly increased in MLNs of murine LPS-induced tolerance model. Moreover, the expression level of TGF-β in MLNs also increased obviously. Furthermore, TGF-β blockade could obviously reduce the proportion and absolute number of CD4+Foxp3+Tregs in MLNs and subsequently impair the protection effect against LPS rechallenge. Of note, we found that tolerogenic dendritic cell (Tol-DC), expressing lower levels of MHC-II and CD86 molecules, dominantly secreted TGF-β in MLNs in murine LPS-induced tolerance model. In all, our data provided an unknown phenomenon that the total cell number of CD4+Foxp3+Tregs significantly increased in MLNs in endotoxin tolerance, which was related to MLN-resident TGF-β secreting CD11c+DCs, providing a new fundamental basis for the understanding on the potential roles of MLN-resident immune cells in the development of endotoxin tolerance.

Changes of global and segmental ventricular strain at different deterioration levels of cardiac function in patients with dilated cardiomyopathy (DCM) using cardiac magnetic resonance (CMR) have not yet been explored. In total, 101 patients diagnosed with DCM consecutively underwent CMR. They were categorized according to the reduction in left ventricular ejection fraction (LVEF) into the following groups: moderately reduced (n = 43) and severely reduced group (n = 58). LV global longitudinal strain (GLS), global radial strain (GRS), global circumferential strain (GCS), and segmental strain values were assessed using tissue tracking technique. LV segmental circumferential strain (CS) and radial strain (RS) in healthy volunteers increased from base to apex stepwisely. The LV base-to-apex increasing pattern disappeared in the moderate DCM group (RS: 26.61% ± 20.63% versus 21.97% ± 4.85% versus 29.05% ± 9.90%, P > 0.05; CS: -13.16% ± 6.40% versus -12.96%± 2.45% versus -15.32% ± 3.89%, P > 0.05). While in the severe group, CS and RS of base segment had the highest values, there was no significant difference between mid and apex segments. GLSLV, GRSLV, and GCSLV were significantly reduced in moderate and severe groups in steps, similar to the three parameters of RV. During a 17-month median follow-up, 25 patients had an index composite outcome event. GLSLV > -11.62%, GCSLV > -9.35%, and GRSLV≤ 12.42% were significantly associated with the occurrence of cardiac events in DCM patients. LV segmental values reduce non-homogeneously in DCM patients with moderately and severely deteriorated heart function.

Fenglei Zheng,* Yijing Tao,* Jingjing Liu, Zhimin Geng, Ying Wang, Yujia Wang, Songling Fu, Wei Wang, Chunhong Xie, Yiying Zhang, Fangqi Gong Department of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fangqi GongDepartment of Cardiology, Children’s Hospital, Zhejiang University School of Medicine; National Clinical Research Center for Child Health, No. 3333, Binsheng Road, Hangzhou, 310052, People’s Republic of ChinaTel/Fax +86-571-86670008Email gongfangqi@zju.edu.cnPurpose: Macrophages-mediated inflammation is linked with endothelial damage of Kawasaki disease (KD). KCa3.1, a calcium-activated potassium channel, modulates inflammation of macrophages. However, little is known about the role of KCa3.1 in inflammation by macrophages involved in KD. Hence, this study is aimed to explore the potential role of KCa3.1 in regulating inflammatory response by macrophages and subsequent vascular injury in an in vitro model of KD.Methods: RAW264.7 cells were stimulated with Lactobacillus casei cell wall extract (LCWE) with or without TRAM-34 or PDTC or AG490. Subsequently, mouse coronary artery endothelial cells (MCAECs) were incubated with RAW264.7 cells-conditioned medium to mimic local inflammatory lesions in KD. CCKi8 assay was used to evaluate cell viability. The mRNA levels of inflammatory mediators were detected by qRT-PCR. Expressions of KCa3.1, MCAECs injury-associated molecules, proteins involved in signal pathways of nuclear factor-κB (NF-κB), signal transducers and activators of transcription (STAT) 3 and p38 were evaluated by Western blot.Results: Our study showed that LCWE increased KCa3.1 protein level in RAW264.7 macrophages and KCa3.1 inhibition by TRAM-34 notably suppressed the expression of pro-inflammatory molecules in LCWE-treated macrophages via blocking the activation of NF-κB and STAT3 pathways. Besides, the inflammation and damage of MCAECs were attenuated in the TRAM-34-treated group compared with the KD model group. This vascular protective role was dependent on the down-regulation of NF-κB and STAT3 signal pathways, which was confirmed by using inhibitors of NF-κB and STAT3.Conclusion: This study demonstrates that KCa3.1 blockade of macrophages suppresses inflammatory reaction leading to mouse coronary artery endothelial cell injury in a cell model of KD by hampering the activation of NF-κB and STAT3 signaling pathway. These findings imply that KCa3.1 may be a potential therapeutic target for KD.Keywords: Kawasaki disease, macrophages, inflammation, KCa3.1, vascular damage

BackgroundA considerable number of non-ischemic dilated cardiomyopathy (NDCM) patients had been found to have normalized left ventricular (LV) size and systolic function with tailored medical treatments. Accordingly, we aimed to evaluate if strain parameters assessed by cardiovascular magnetic resonance (CMR) feature tracking (FT) analysis could predict the NDCM recovery.Methods79 newly diagnosed NDCM patients who underwent baseline and follow-up CMR scans were enrolled. Recovery was defined as a current normalized LV size and systolic function evaluated by CMR.ResultsAmong 79 patients, 21 (27%) were confirmed recovered at a median follow-up of 36 months. Recovered patients presented with faster heart rates (HR) and larger body surface area (BSA) at baseline (P api/bas) and a lower standard deviation of time to peak radial strain in 16 segments of the LV (SD16-TTPRS). According to a multivariate logistic regression model, RSapi/bas(P = 0.035) and SD16-TTPRS (P = 0.012) resulted as significant predictors for differentiation of recovered from unrecovered patients. The sensitivity and specificity of RSapi/basand SD16-TTPRS for predicting recovered conditions were 76%, 67%, and 91%, 59%, with the area under the curve of 0.75 and 0.76, respectively. Further, Kaplan Meier survival analysis showed that patients with RSapi/bas ≥ 0.95% and SD16-FTPRS ≤ 111 ms had the highest recovery rate (65%, P = 0.027).ConclusionsRSapi/basand CMR SD16-TTPRS may be used as non-invasive parameters for predicting LV recovery in NDCM. This finding may be beneficial for subsequent treatments and prognosis of NDCM patients. Registration number: ChiCTR-POC-17012586.

Background: Kawasaki disease (KD) is an acute vasculitis of childhood, which has a typical coronary artery aneurysm complication. Cerebral arteries are usually spared from the disease process. Intracranial aneurysms and hemorrhage strokes are rarely reported.Case presentation: A 12-year-old boy presented with a sudden disturbance of consciousness caused by an intracranial aneurysm’s rupture. Through later clinical manifestations and echocardiography, we found that he had been in Kawasaki disease 20 days before the hospitalization.Conclusions: This case shows a close link between Kawasaki disease and cerebral aneurysm complication. It arouses more attention to applying aspirin appropriately in the perioperative intracranial surgery period of KD patients. For febrile patients with high-risk factors for KD, echocardiograms may be performed before day 5 of fever.

Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2‐like sequences in rDNA promoter upon T‐cell activation in vitro. The elevated pre‐rRNA level of T cells is also observed in both mouse heart or skin transplantation models and in kidney transplanted patients. Importantly, T‐cell activation can be significantly suppressed by inhibiting NF45/NF90‐dependent rDNA transcription. Amazingly, CX5461, a rDNA transcription‐specific inhibitor, outperformed FK506, the most commonly used immunosuppressant, both in terms of potency and off‐target activity (i.e., toxicity), as demonstrated by a series of skin and heart allograft models. Collectively, this reveals NF45/NF90‐mediated rDNA transcription as a novel signaling pathway essential for T‐cell activation and as a new target for the development of safe and effective immunosuppressants., This study reveals NFAT‐NF45/NF90‐mediated rDNA transcription as a key regulating axis in modulating T cell activation. Targeting ribosome biogenesis could be a novel immunosuppressive therapy for organ transplantation.

Additional file 1. Calculation of torsional shear angle from basal and apical slices.

Increasing evidence in recent years has suggested that microRNA-7 (miR-7) is an important gene implicated in the development of various diseases including HCC. However, the role of miR-7 in autoimmune hepatitis (AIH) is unknown.Herein, we showed that miR-7 deficiency led to exacerbated pathology in Concanavalin-A-induced murine acute autoimmune liver injury (ALI) model, accompanied by hyperactivation state of CD4This study expands on the important role of miR-7 in liver-related diseases and reveals the value of the C/EBPα/miR-7 axis in CD4

Parenteral nutrition-associated liver disease (PNALD) is a major complication of long-term parenteral nutrition (PN). The pathogenesis of PNALD remains unclear. We investigated the changes in taxonomic and functional composition of gut microbiota and serum bile acid levels in a rat model of PNALD.Male 4-week-old Sprague Dawley rats received either total parenteral nutrition or standard chow with 0.9% saline for 7 days. The taxonomic composition of cecal microbiota and its functional composition associated with bile acid metabolism were measured.There were differences in taxonomic composition between the two groups. The abundance of the secondary bile acid biosynthesis pathway was higher in the TPN group (p 0.05) with an increase in the percentage of bacteria expressing 7-alpha-hydroxysteroid dehydrogenase (p 0.05). The abundance of enzymes associated with bile salt hydrolase was also higher (p 0.05) in the TPN group. The TPN group showed a distinct bile acid profile characterized by a higher ratio of secondary bile acids to primary bile acids.The alteration of bile acid-associated microbiota may lead to increased secondary bile acid production in a rat model of PNALD.

Although intravenous immunoglobulin (IVIG) can effectively treat Kawasaki disease (KD), 10–20% of KD patients show no beneficial clinical response. Developing reliable criteria to discriminate non-responders is important for early planning of appropriate regimens. To predict the non-responders before IVIG treatment, gene expression dataset of 110 responders and 61 non-responders was obtained from Gene Expression Omnibus. After weighted gene co-expression network analysis, we found that modules positively correlated with the non-responders were mainly associated with myeloid cell activation. Transcripts up-regulated in the non-responders, IL1R2, GK, HK3, C5orf32, CXCL16, NAMPT and EMILIN2, were proven to play key roles via interaction with other transcripts in co-expression network. The crucial transcripts may affect the clinical response to IVIG treatment in acute KD. And these transcripts may serve as biomarkers and therapeutic targets for precise diagnosis and treatment of the non-responders.

Ca2+/nuclear factor of activated T-cells (Ca2+/NFAT) signaling pathway may play a crucial role in the pathogenesis of Kawasaki disease (KD). We investigated the poorly understood Ca2+/NFAT regulation of coronary artery endothelial cells and consequent dysfunction in KD pathogenesis. Human coronary artery endothelial cells (HCAECs) stimulated with sera from patients with KD, compared with sera from healthy children, exhibited significant increases in proliferation and angiogenesis, higher levels of NFATc1 and NFATc3 and some inflammatory molecules, and increased nuclear translocation of NFATc1 and NFATc3. HCAECs stimulated with sera from patients with KD treated with cyclosporine A (CsA) showed decreased proliferation, angiogenesis, NFATc1 and inflammatory molecules levels as compared with results for untreated HCAECs. In conclusion, our data reveal that KD sera activate the Ca2+/NFAT in HCAECs, leading to dysfunction and inflammation of endothelial cells. CsA has cytoprotective effects by ameliorating endothelial cell homeostasis via Ca2+/NFAT.

The aim of this study was to assess the effects of a fish oil-based lipid emulsion on intestinal failure-associated liver disease (IFALD) in children. From January 2014 through June 2017, we enrolled 32 children with IF on long-term parenteral nutrition (PN). When the levels of any three of seven liver indicators (TBA, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, gamma glutamyl transferase (γ-GT), total bilirubin (TB), or direct bilirubin (DB)) were two times higher than normal levels, we switched a 50:50 mix of soybean oil and medium-chain triglycerides (MCT) lipid emulsion (with an average dose of 1.30 g/kg/day) to a fish oil-based lipid emulsion (1 g/kg/day) and measured liver function in the children. Meanwhile, inflammation and oxidative stress-related markers were also measured. The average fish oil therapy duration was 26 ± 21 days, and the median duration of PN support was 84 days. With fish oil therapy, levels of TBA, ALT, AST, γ-GT, TB, and DB all significantly decreased. Enteral nutrition was introduced following fish oil resulting in higher energy intake (99.88 ± 31.06 kcal/kg/day) compared with before fish oil (67.90 ± 27.31 kcal/kg/day, P = 0.001). No significant difference was found in average PN energy (P = 0.147). In addition, levels of inflammatory indicators like tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and white blood cell (WBC) significantly decreased. Fish oil therapy alleviates IFALD in children.

Background The gut microbiota plays a vital role in modulating the metabolic and immune functions of the intestines. We aimed to analyze the dysbiosis of microbiota in infants with short bowel syndrome (SBS) with different complications. Procedure We included 26 fecal samples from 18 infants with SBS during parenteral nutrition. The samples were categorized into three groups: asymptomatic, parenteral nutrition-associated liver disease (PNALD), and central line-associated bloodstream infection (CLABSI). Seven healthy infants were enrolled as controls. Fecal microbiota, secretory IgA, calprotectin, bile acids, and short chain fatty acids were detected. Results The bacterial diversity of the Asymptomatic and Control Groups was significantly higher than that in the PNALD and CLABSI Groups. Proteobacteria was the most pronounced phylum in the PNALD and CLABSI Groups. Decreased acetate was observed in all SBS samples; however, fecal secretory IgA and calprotectin and the proportion of primary and secondary bile acids did not differ from those in healthy controls. Conclusions Marked alterations of the intestinal microbiota with decreased level of acetate were shown in SBS patients compared with healthy controls. Over-abundance of Proteobacteria (especially Enterobacteriaceae ) was found in the samples from the PNALD and CLABSI Groups. Level of evidence Prognosis Study, Level I.

Background The pathogenesis of parenteral nutrition-associated cholestasis (PNAC) has not been clarified. The objective of this study was to explore the incidence of PNAC in premature infants without surgery and to identify associated risk factors. Materials and methods Premature neonates who received parenteral nutrition (PN) at least 14 days were included in a retrospective, dual-center study. Cholestasis was diagnosed as conjugated bilirubin ≥2 mg/dL. Infants with metabolic liver disease, cyanotic congenital heart disease, congenital syphilis, hepadnaviridae infection, and those who underwent surgery were excluded. Infants were divided into 3 groups chronologically: group A (2000-2004, n = 50), group B (2005-2009, n = 283), and group C (2010-2014, n = 741). A case-controlled study was conducted by comparing infants with PNAC to those without PNAC. Results Of 1074 premature neonates, PNAC was confirmed in 53 infants (4.93%). There were 6.8% very low birth weight (BW) infants and 20.0% extremely low BW infants who developed PNAC. The incidence of PNAC decreased slightly during 2000-2014 (8.0%, 6.4%, and 4.2% in groups A, B, and C, respectively). Compared with those without PNAC, infants with PNAC (n = 53) had significantly younger gestational age, lower BW, longer PN duration, and higher rate of sepsis. Logistic regression showed male sex, PN duration ≥43 days, and sepsis were statistically correlated with PNAC. Conclusions Prolonged duration (≥43 days), male sex, and sepsis are probably independent risk factors for developing PNAC in premature neonates.

For delivery of parenteral nutrition (PN), long-term central access is often required in infants with intestinal failure (IF). Compared to central venous catheters (CVCs), peripherally inserted central catheters (PICCs) are less invasive, as they are smaller, and they can even be placed without general anesthesia. In this study, we report the complications of long-term use of PICCs, and compare our results with previously published research.We reviewed the infants in the Xin Hua Hospital to determine the incidence of catheter-related bloodstream infections (CRBSIs) as well as other complication rates.A total of 43 infants diagnosed with intestinal failure and receiving PN through a PICC met the inclusion criteria. There were 66 PICCs accounting for 2563 catheter days, and a total of 29 complications were been recorded. The overall incidence of complications was 11.31 per 1000 catheter days, and the incidence of CRBSI was 5.85 per 1000 catheter days. Gram-positive bacterial species were the most common organisms growing in blood cultures. As for the risk factors, we find that low weight when PICC was inserted was associated with an increased risk of complications as well as low mean weight during the PICC dwelling time.We did not find an increased incidence rate of CRBSI in using PICC as an alternative to CVC. Also, as PICCs offer an advantage over CVCs in placing and nursing, we recommended PICCs as the first choice in patients with IF.

Objective To assess the incidence of extrauterine growth restriction (EUGR) in very low‐birth‐weight infants (VLBWIs) and evaluate the nutrition factors in VLBWIs associated with inadequate nutrient intakes during hospitalization. Methods A total of 128 VLBWIs were divided into an EUGR group (n = 87) and a non‐EUGR group (n = 41). Growth and parenteral nutrition (PN) and enteral nutrition (EN) practices were analyzed. Actual energy and protein intakes were subtracted from recommended energy (120 kcal/kg/d) and protein (3.75 g/kg/d) intakes, and nutrition deficits were calculated. Results Growth restriction was 21.9% at birth and 68.0% at discharge. Compared with established guidelines, PN was started late, and the maximum amino acid intake was low in both groups. EN interruption rate was higher in the EUGR group. The average energy intake in the first day after PN termination was lower in the EUGR group. There were significant differences in actual energy and protein intakes in the 2 groups for several weeks during hospitalization. The cumulative energy and protein deficits were significantly higher in the first 8 weeks and during the third to seventh weeks in the EUGR group, respectively. Step regression analysis showed that there was a significant negative correlation between the cumulative deficit of energy and changes of weight z‐scores (r = −0.001, P < .05): as the energy deficit loss increased by 100 kcal, the weight z‐scores dropped by 0.1 SD. Conclusion Inadequate nutrition intake aggravated the occurrence of EUGR in VLBWIs, especially the energy intake.

Endotoxin tolerance is an important state for the prevention of lethal infection and inflammatory response, which is closely associated with the participation of innate immune cells. Moreover, mesenteric lymph nodes (MLNs)-resident immune cells, such as CD4

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer worldwide. The high mortality rate of NSCLC is due to a limited number of diagnosis being made at an early stage of disease. Therefore, the development of a novel biological marker for the diagnosis and prognosis prediction of NSCLC remains urgent. Current literature shows that microRNA-21 (miRNA-21/miR-21), as an oncogenic miRNA, is involved in the growth, metastasis and apoptosis of NSCLC cells through its control of various target molecules and signaling pathways. Notably, a growing body of evidence further shows that miR-21 is closely associated with the prognosis prediction, recurrence and diagnosis of cancer patients, indicating that miR-21 may be a novel promising biomarker for the diagnosis and prognosis prediction of NSCLC. The present review aimed to provide a summary of recent findings on the associated progression toward finding a novel biomarker for NSCLC.

Congenital chylous ascites in the neonatal period is a rare entity. Total parenteral nutrition (TPN), medium chain triglyceride (MCT)-based diet, octreotide and repeated paracentesis are regarded as appropriate medical treatment for congenital chylous ascites, and surgery is recommended when conservative therapy has failed. We present two cases in which ascites were confirmed via an abdominal sonogram and diagnostic paracentesis. In our clinical experience, rice soup combined with PN can be a safe and effective intervention.先天性乳糜腹在新生儿时期较为罕见，目前其主要治疗手段包括全肠外营养、 中链脂肪酸为基础的饮食、奥曲肽以及反复腹腔穿刺引流术，当保守治疗失败 时则建议手术。本文提供了两例通过腹部超声和诊断性腹腔穿刺确诊的先天性 乳糜腹病例。根据我们的临床治疗经验，口服米汤结合肠外营养是先天性乳糜 腹的一种安全有效的治疗方法。.

Recent evidence showed that microRNA-7 (miR-7) played an important role in the pathologies of lung-related diseases. However, the potential role of miR-7 in acute lung injury (ALI) still remains poorly understood. Here, we assessed the effect of miR-7 deficiency on the pathology of ALI. We, first, found that the expression of miR-7 was upregulated in lung tissue in murine LPS-induced ALI model. Notably, we generated miR-7 knock down mice by using miRNA-Sponge technique and found that miR-7 deficiency could ameliorate the pathologies of lung as evidenced by accelerated body weight recovery, reduced level of bronchoalveolar lavage (BAL) proinflammatory cytokines and decreased number of BAL cells in ALI mice. Moreover, the proportion and number of various immune cells in BAL, including innate immune cell F4/80+ macrophages, γδT cells, NK1.1+ T cells, and CD11c+DCs, as well as adaptive immune cell CD4+ T cells and CD8+ T cells, also significantly changed, respectively. Mechanistic evidence showed that KLF4, a target molecule of miR-7, was upregulated in lung tissues in ALI model, accompanied by altered transduction of NF-κB, AKT, and ERK pathway. These data provided a previously unknown role of miR-7 in pathology of ALI, which could ultimately aid the understanding of development of ALI and the development of new therapeutic strategies against clinical inflammatory lung diseases.

The aim of this study was to identify the underlying molecular mechanism for the development of megacystis microcolon intestinal hypoperistalsis syndrome in 4 Chinese patients. We found a c.770G>A (p.R257H) mutation in 3 patients, and a c.769C>T (p.R257C) mutation in the fourth patient by using whole-exome sequencing and targeted Sanger sequencing. The immunohistochemical investigation and transmission electron microscopy revealed an apparent defect of the intestinal smooth muscle, and hypoganglionosis. Our report suggested that R257 variant in the ACTG2 appear to be more frequent in populations of Asian ancestry; mutation of this locus could cause alterations of the intestinal and bladder smooth muscle filaments.

To investigate the change of CD4(+) T cell activity in microRNA-126 (miR-126) knockdown (KD) mice and explore its significance.The expression level of mature miR-126 in CD4(+) CD62L(+) T cells purified by magnetic-activated cell sorting (MACS) was analyzed by real-time PCR using specific probe. Furthermore, the expression levels of CD69, CD62L and CD44 molecules, as well as intracellular proliferating nuclear antigen Ki-67, in CD4(+) T cells in miR-126 KD mice were detected by fluorescence-activated cell sorting (FACS). Moreover, the apoptosis of CD4(+) T cells was analyzed by annexin V/PI staining assay combined with flow cytometry. Finally, the relative expressions of function-related cytokines including interleukine 4 (IL-4), IL-10, IL-12, transforming growth factor (TGF-β), interferon (IFN-γ) and tumor necrosis factor (TNF-α) in CD4(+) T cells were determined by real-time PCR.Compared with wild-type (WT) mice, the expression level of mature miR-126 in CD4(+) T cells in miR-126 KD mice was dramatically reduced. Furthermore, the proportion of CD62L(+) in CD4(+) T cells also decreased significantly, while the proportions of CD69(+), CD44(+) and Ki-67(+) cells were remarkably elevated. Meanwhile, the apoptosis proportion of CD4(+) T cells in vivo dropped dramatically in miR-126 KD mice. Finally, the mRNA expressions of IL-4 and IL-10 in CD4(+)T cells were significantly downregulated, but IL-12, TGF-β, TNF-α and IFN-γ mRNAs were obviously up-regulated.miR-126 knockdown could significantly enhance the functional activity of CD4(+) T cells in vivo and promote cell differentiation into Th1 cells.

The incidence of tumors with life-threatening effects has increased gradually over time; however, the mechanisms involved in tumor development have not been fully elucidated. Recent studies have shown that microRNA-7 (miR-7), which is endogenous non-coding RNA molecules of approximately 23 nucleotides, plays an important role in the occurrence and development of tumors as a key tumor suppressor. Mechanistic evidence showed that miR-7 is closely related to the growth, metastasis, and prognosis of various malignant tumors through regulating different target molecules, which suggest that miR-7 may be a new target for the clinical diagnosis and treatment of various tumors. In this review, we summarize current knowledge of the relationship between miR-7 and tumor development, diagnosis, and treatment.