The impact of glucocorticoids therapy on cutaneous wounds in Kawasaki disease: A meta-analysis of randomized controlled trials.

Kawasaki disease (KD) is one of the most challenging diseases that is defined as an acute vasculitis that affects the coronary arteries primarily in children. It causes complications if left untreated at early stages, ultimately leading to death. Corticosteroids have been recognized to treat and cause great impact on the patients with KD. Glucocorticoid is one of the main corticosteroids that are being used to treat KD and cutaneous wounds. However, ineffectiveness of a few glucocorticoids can limit the efficacy of this treatment. This study particularly aimed to elucidate the impact of glucocorticoids on cutaneous wounds in KD. To perform the meta-analysis, a comprehensive literature survey was conducted to unveil the studies and research conducted on Kawasaki patients that revealed different glucocorticoids in the form of specific interventions influencing KD. The literature was searched using numerous keywords, screened and data was extracted to perform the meta-analysis and then it was conducted using the metabin function of R package meta. A total of 2000 patients from both intervention and control groups were employed to carry out the meta-analysis to analyse and evaluate the impact of glucocorticoids on curing KD and cutaneous wounds in patients. The results disclosed that glucocorticoids along with other steroids, mainly IVIG (intravenous immunoglobulin), was an effective intervention to patients suffering from Kawasaki. The results depicted significant outcomes with the values (risk ratio [RR]: 1.08, 95% confidence interval [CI]: 0.58-2.00, p < 0.01) and enlightened the fact that adopting different glucocorticoids may significantly improve the efficacy of skin lesions along with KD. Hence, interventions of glucocorticoids must be utilized in the clinical practice to reduce the incidence of skin wounds and adverse effects caused due to KD.

The safety and effectiveness of clopidogrel versus aspirin in Kawasaki disease with mild-to-moderate liver injury.

Kawasaki disease can be combined with liver injury. As a mainstay treatment for Kawasaki disease, aspirin may cause liver injury. This study aimed to compare the safety and effectiveness of clopidogrel versus aspirin in Kawasaki disease with mild-to-moderate liver injury. This study retrospectively analysed 166 children with Kawasaki disease combined with mild-to-moderate liver injury. The children treated with clopidogrel were less likely to have aggravated liver injury than those treated with aspirin (n = 2/100 vs. n = 13/66, P < 0.001). The initial alanine aminotransferase value of the clopidogrel group was higher (131.5 [98.5, 167.5] vs. 96 [72, 133], P < 0.001), while the time of alanine aminotransferase recovery to normal was similar (5 [4, 7] vs. 4 [3, 7], P = 0.179). No significant fever differences observed between groups: 7.5 [6, 9] for aspirin vs. 7 [6, 8] for clopidogrel group, P = 0.064. The probability of nonresponse to intravenous immunoglobulin (n = 29/100 vs. n = 30/66, P = 0.030) and the days of hospitalization (n = 6 [4, 9] vs. n = 7 [5, 10], P = 0.007) in the clopidogrel group were less than those in the aspirin group. In conclusion, the application of clopidogrel is potentially superior to aspirin in Kawasaki disease combined with mild-to-moderate liver injury.

Autologous followed by allogeneic versus tandem-autologous transplantation in high-risk, newly diagnosed multiple myeloma: a systematic review and meta-analysis.

OBJECTIVES: High-risk multiple myeloma (HRMM) is associated with poor survival, despite many advances in antimyeloma strategies. Autologous followed by allogeneic stem cell transplantation (auto-allo-SCT) has yielded controversial results compared to tandem autologous stem cell transplantation (auto-SCT) in patients with HRMM. We conducted this meta-analysis to compare the efficacy and safety of auto-allo-SCT and tandem-auto-SCT in patients with HRMM. METHODS: Embase, Cochrane Library, and PubMed databases were searched until March 2023. Prospective or retrospective studies comparing the effects of auto-allo-SCT and tandem-auto-SCT were included. Hazard ratios (HRs) and 95% confidence intervals (CIs) for time-to-event outcomes, and odds ratios (ORs) and 95%CIs for dichotomous outcomes were pooled using random-effects models. RESULTS: Three studies involving 491 patients were included. Despite auto-allo-SCT seemed to be associated with improvements in progression-free survival (PFS) (HR [95%CI], 0.71 [0.51-1.00]) and complete response (CR) (OR [95%CI], 3.16 [1.67-5.99]), and reduced relapse/progression rates (47% vs. 55%) in comparison with tandem-auto-SCT, no marked improvement in overall survival (OS). In comparison to tandem-auto-SCT, patients assigned to auto-allo-SCT exhibited a higher risk of transplant-related mortality (TRM) (11.9% vs. 4.1%) and non-relapse mortality (NRM) (12.3% vs. 3.1%). CONCLUSION: Auto-allo-SCT seemed to be associated with improvements in PFS and CR when compared to tandem-auto-SCT in patients with HRMM, but it did not lead to a significant improvement in OS. Furthermore, patients in the auto-allo-SCT group were at a higher risk of developing TRM and NRM. Auto-allo-SCT transplantation should not be routinely incorporated into HRMM therapy but rather should be considered investigational.

The activation of CaN/NFAT signaling pathway in macrophages aggravated Lactobacillus casei cell wall extract-induced Kawasaki disease vasculitis.

OBJECTIVES: By using GWAS(genome-wide association studies) and linkage disequilibrium analysis to investigate the susceptibility genes of KD(Kawasaki disease), previous studies have identified that the CaN(calcineurin)-NFAT(the nuclear factor of activated T cell) signal pathway were significantly associated with susceptibility to KD. However, little is known about the molecular basis of the CaN/NFAT pathway involved in KD. Therefore, in our study we investigate the role of Ca2+/CaN/NFAT signaling pathway in macrophages in vitro and in vivo on coronary artery lesions induced by LCWE (Lactobacillus casei cell wall extract). METHODS AND RESULTS: We observed that LCWE could increase the expression of NFAT1 and NFAT2 in macrophages in vitro, and also enhance the transcriptional activity of NFAT by promoting the nucleus translocation. Similarly, in LCWE-induced mice model, the expression of NFAT1 and NFAT2 and associated proinflammatory factors were increased significantly. In addition, by knocking down or overexpressing NFAT1 or NFAT2 in macrophages, the results indicated that NFAT signaling pathway mediated LCWE-induced immune responses in macrophages and regulated the synthesis of IL(interleukin)-6, IL-1ß and TNF(tumor necrosis factor)-α in LCWE-induced macrophage activation. As well, we found that this process could be suppressed by CaN inhibitor CsA(cyclosporinA). CONCLUSIONS: Therefore, the CaN/NFAT signaling pathway mediated LCWE-induced immune responses in macrophages, and also participated in the LCWE-induced CALs(coronary artery lesions). And also the inhibitory effect of CsA in LCWE-induced cell model towards a strategy to modulate the CaN/NFAT pathway during the acute course of KD might be helpful in alleviate KD-induced CALs.

Similarities and differences between MIS-C and KD: a systematic review and meta-analysis.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a new syndrome with some clinical manifestations similar to Kawasaki disease (KD), which is difficult to distinguish. OBJECTIVE: The study aimed to characterize the demographic characteristics, clinical characteristics, laboratory features, cardiac complications, and treatment of MIS-C compared with KD. STUDY DESIGN: Studies were selected by searching the PubMed, EMBASE and so on before February 28, 2022. Statistical analyses were performed using Review Manager 5.4 software and STATA 14.0. RESULTS: Fourteen studies with 2928 participants were included. MIS-C patients tended to be older and there was no significant difference in the sex ratio. In terms of clinical characteristics, MIS-C patients were more frequently represented with respiratory, gastrointestinal symptoms and shock. At the same time, they had a lower incidence of conjunctivitis than KD patients. MIS-C patients had lower lymphocyte counts, platelet (PLT) counts, erythrocyte sedimentation rates (ESRs), alanine transaminase (ALT), and albumin levels and had higher levels of aspartate transaminase (AST), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), troponin, C-reactive protein (CRP), D-dimer, fibrinogen, ferritin, and creatinine. MIS-C patients had a higher incidence of left ventricle (LV) dysfunction, valvular regurgitation, pericardial effusion, myocarditis, and pericarditis. The incidence of coronary artery lesion (CAL) was lower in MIS-C patients [OR (95% CI): 0.52 (0.29, 0.93), p =0.03], while it was similar in the acute period. MIS-C patients had higher utilization of glucocorticoids (GCs) and lower utilization of intravenous immune globulin (IVIG). CONCLUSIONS: There were specific differences between MIS-C and KD, which might assist clinicians with the accurate recognition of MIS-C and further mechanistic research.

Efficacy and toxicity of carfilzomib- or bortezomib-based regimens for treatment of transplant-ineligible patients with newly diagnosed multiple myeloma: A meta-analysis.

BACKGROUND: Multiple myeloma is a clonal disorder of malignant plasma cells that comprises approximately 10% of hematologic malignancies. The aim of this study was to investigate the efficacy and toxicity of carfilzomib- or bortezomib-based regimens for treatment of transplant-ineligible patients with newly diagnosed multiple myeloma by performing a meta-analysis of randomized controlled trials (RCTs). METHODS: Data mining was conducted in March 2022 across PubMed, EMBASE and ClinicalTrials.gov. All published RCTs which assessed efficacy and toxicity of carfilzomib-based regimens treatment for transplant-ineligible patients with newly diagnosed multiple myeloma when compared with a bortezomib-based regimens were included. RESULTS: Our meta-analysis showed that the overall response rate (ORR) (Odds ratio = 1.33, 95% CI 1.05-1.69, P = .02) was significantly higher in the carfilzomib-based regimens group than in the bortezomib-based regimens group. However, the difference in ORR did not translate into improvements in progression-free survival (PFS), overall survival (OS) and complete response rate (CRR). Adverse events of grade 3 or worse that occurred with a higher incidence in the carfilzomib-based regimens group compared with the bortezomib-based regimens group were dyspnea, hypertension, acute kidney injury, and heart failure. CONCLUSIONS: The carfilzomib-based regimens did not improve PFS, OS and CRR compared with the bortezomib-based regimens in transplant-ineligible patients with newly diagnosed multiple myeloma, and they showed higher toxicity.

Risk factors of postoperative low cardiac output syndrome in children with congenital heart disease: A systematic review and meta-analysis.

Background: Low cardiac output syndrome (LCOS) is the most common complication after cardiac surgery, which is associated with the extension of postoperative hospital stay and postoperative death in children with congenital heart disease (CHD). Although there are some studies on the risk factors of LCOS in children with CHD, an unified conclusion is lack at present. Purposes: To synthesize the risk factors of LCOS after CHD in children, and to provide evidence-based insights into the early identification and early intervention of LCOS. Methods: The databases of the China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database (VIP), PubMed, Cochrane Library, Embase and Web of Science were searched for relevant articles that were published between the establishing time of each database and January 2022. Based on retrospective records or cohort studies, the influencing factors of postoperative low cardiac output in children with congenital heart disease were included in Meta analysis.This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The risk of bias was evaluated according to the Newcastle-Ottawa Scale (NOS). RevMan 5.4 software was used to conduct the meta-analysis. Results: A total of 1,886 records were screened, of which 18 were included in the final review. In total, 37 risk factors were identified in the systematic review. Meta- analysis showed that age, type of CHD, cardiac reoperation, biventricular shunt before operation, CPB duration, ACC duration, postoperative residual shunt, cTn-1 level 2 h after CPB > 14 ng/ml and postoperative 24 h MR-ProADM level > 1.5 nmol/l were independent risk factors of LCOS. Additionally, the level of blood oxygen saturation before the operation was found to have no statistically significant relationship with LOCS. Conclusion: The risk factors of postoperative LCOS in children with CHD are related to disease condition, intraoperative time and postoperative related indexes, so early prevention should be aimed at high-risk children. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022323043.

Co-occurrence of Klebsiella variicola and Klebsiella pneumoniae Both Carrying bla KPC from a Respiratory Intensive Care Unit Patient.

OBJECTIVE: The aim of this study was to use whole-genome sequencing to characterize Klebsiella pneumoniae SKp2F and Klebsiella variicola SKv2E, both carrying bla KPC, co-isolated from the same sputum specimen. METHODS: Antimicrobial susceptibility testing was performed using microbroth dilution. Biofilm formation was determined by crystal violet staining and virulence was measured by a serum killing assay. Whole-genome sequencing of SKp2F and SKv2E was performed using an Illumina sequencer and the genetic characteristics were analyzed by computer. RESULTS: SKp2F and SKv2E were sensitive only to tigecycline and polymyxin among the tested antibiotics. The biofilm-forming ability of SKv2E is stronger than that of SKp2F. The grades of serum resistance of SKp2F and SKv2E are 4 and 3. MLST analysis of the 6,115,610 bp and 5,403,687 bp of SKv2E and SKp2F showed associations with ST1615 and ST631, respectively. SKv2E carried 13 resistance genes (bla KPC-2, bla TEM-1A, bla LEN17, aadA16, arr-3, qnrB4, oqxA/B, dfrA27, sul1, tetD, fosA, qacEΔ1) and SKp2F carried 23 (bla KPC-2, bla CTX-M-3, bla TEM-1B, bla CTX-M-65, bla SHV-27, aac(6')-IIa, rmtB, arr-3, aph(3')-Ia, aadA16, qnrS1, aac(6')-Ib-cr, qnrB91, oqxA/B, mph(A), tet(A), fosA, dfrA27, and two copies of qacEΔ1-sul1). Most of them were carried by various mobile genetic elements, such as IncFIB(K)/IncFII(K)/IncFII(Yp), IncFII(K) plasmid, Tn6338, and In469. Both SKv2E and SKp2F carried a large number of virulence factors, including type 1 and 3 fimbriae, capsule, aerobactin (iutA), ent siderophore (entABCDEFS, fepABCDGfes), and salmochelin (iroE/iroEN). SKv2E also carried type IV pili (pilW), fimbrial adherence (steB, stfD), and capsule biosynthesis gene (glf). CONCLUSION: bla KPC-2-carrying K. variicola and K. pneumoniae, which carried multiple resistance genes, virulence factors, and highly similar mobile genetic elements, were identified from the same specimen, indicating that clinical samples may carry multiple bacteria. We should avoid misidentification, and bear in mind that resistance genes carrying mobile genetic elements can be transmitted or integrated between bacteria in the same host.

The Network of Pro-Inflammatory Factors CD147, DcR3, and IL33 in the Development of Kawasaki Disease.

INTRODUCTION: 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.

Altered Monocyte Subsets in Kawasaki Disease Revealed by Single-cell RNA-Sequencing.

BACKGROUND: 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.

KCa3.1 Inhibition of Macrophages Suppresses Inflammatory Response Leading to Endothelial Damage in a Cell Model of Kawasaki Disease.

PURPOSE: 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.

Crucial transcripts predict response to initial immunoglobulin treatment in acute Kawasaki disease.

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.

The elevated serum levels of calcineurin and nuclear factor of activated T-cells 1 in children with Kawasaki disease.

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.

The role of Ca2+/NFAT in Dysfunction and Inflammation of Human Coronary Endothelial Cells induced by Sera from patients with Kawasaki disease.

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.

MiR-32-5p influences high glucose-induced cardiac fibroblast proliferation and phenotypic alteration by inhibiting DUSP1.

BACKGROUND: The current study aimed to investigate the effects of miR-32-5p on cardiac fibroblasts (CFs) that were induced with high levels of glucose; we also aimed to identify the potential mechanisms involved in the regulation of DUSP1 expression. METHODS: Human CFs were transfected with a miR-32-5p inhibitor or mimic and were treated with a normal concentration or a high concentration of glucose. Flow cytometry analysis was performed to identify cardiac fibroblasts by examining vimentin, fibronectin (FN) and α-actin expression in human CFs. qRT-PCR and western blot assays were performed to confirm the expression of miR-32-5p, DUSP1 and cardiac fibrosis relevant proteins. The proliferation of CFs was assessed by using MTT assay. An immunocytofluorescent staining assay was performed to determine the protein level of α-SMA and to investigate the degree of phenotypic changes in human CFs. The specific relationship between miR-32-5p and DUSP1 was investigated by a dual luciferase reporter assay. Cell apoptosis rates were measured with flow cytometry and the annexin V-FITC and propidine iodide (PI) staining method. RESULTS: A luciferase reporter assay indicated that miR-32-5p could directly target DUSP1. High glucose levels resulted in the overexpression of miR-32-5p, which downregulated DUSP1 expression. Both the upregulation of miR-32-5p and the downregulation of DUSP1 promoted cell apoptosis, proliferation and phenotypic changes in human CFs. CONCLUSIONS: All findings in this study provide further evidence for the positive effects of miR-32-5p on cell proliferation and the phenotypic changes in CFs by inhibiting DUSP1 expression, and reveal that miR-32-5p could serve as prognostic diagnostic target for cardiac fibrosis.

MiR-150-5p retards the progression of myocardial fibrosis by targeting EGR1.

To investigate the differential expression of microRNA-150-5p (miR-150-5p) and early growth response 1 (EGR1) in myocardial fibrosis (MF) cells, and determine the effect between miR-150-5p and EGR1 on MF. Human MF cells were generated via Trypanosoma cruzi (T. cruzi) infection, a mouse model of MF was generated via angiotensin II. The expression levels of miR-150-5p and EGR1 were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assay. The correlation between miR-150-5p and EGR1 was confirmed by a luciferase reporter assay. The viability, proliferation, and apoptotic rate were detected by cell counting kit-8 (CCK-8), colony-formation and flow cytometry assays. Hematoxylin-eosin (HE) staining and Masson staining visualized the degree of MF. Echocardiography was performed to obtain the levels of left ventricle fractional shortening (LVFS) and left ventricle ejection fraction (LVEF), computer algorithms and a videographics program were used to obtain the levels of left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP) and ±left ventricular dp/dt maximum (LV dp/dtmax). We found that the expression of miR-150-5p in MF cells was lower than normal cardiomyocytes, while the expression level of EGR1 in MF cells were higher than normal cardiomyocytes. Cell experiments demonstrated that EGR1 and miR-150-5p could influence the development of MF, and the expression of EGR1 in cardiomyocytes was regulated by miR-150-5p directly. Lastly, we confirmed that sh-Egr1 would decrease the severity of MF, while miR-150-5p antagomir could aggravate MF. Our results illustrate the mechanism of MF development, and provide a potential target for MF treatment.

Biomarkers of intravenous immunoglobulin resistance and coronary artery lesions in Kawasaki disease.

BACKGROUND: Currently, there are no reliable indicators for predicting intravenous immunoglobulin resistance and coronary artery lesions in the early stage of Kawasaki disease. METHODS: A total of 300 patients with Kawasaki disease were studied retrospectively. Laboratory data were compared between the intravenous immunoglobulin resistant (29 patients) and responsive groups, and between the groups with coronary artery lesions (48 patients) and without coronary artery lesions. RESULTS: The intravenous immunoglobulin resistant group had significantly higher D-dimer, globulin, interleukin-6 and serum ferritin levels in comparison to the intravenous immunoglobulin responder group. D-dimer level had a sensitivity of 87.0% and a specificity of 56.3% for predicting intravenous immunoglobulin resistance at a cutoff point of 1.09 mg/L. Globulin had a sensitivity of 62.1% and a specificity of 82.3% for predicting intravenous immunoglobulin resistance at a cutoff point of 34.7 g/L. Serum ferritin level had a sensitivity of 42.9% and a specificity of 88.8% for predicting intravenous immunoglobulin resistance at a cutoff point of 269.7 ng/mL. The patients with coronary artery lesions had higher D-dimer and tumor necrosis factor-α level. D-dimer level had a sensitivity of 50% and a specificity of 78.6% for predicting coronary artery lesions at a cutoff point of 1.84 mg/L. Based on analysis by multivariate logistic regression, serum ferritin and globulin were independent risks for intravenous immunoglobulin resistance, D-dimer was independent risk for coronary artery lesions. CONCLUSIONS: Elevated serum ferritin, globulin and D-dimer levels are significantly associated with intravenous immunoglobulin resistance in Kawasaki disease. Moreover, serum D-dimer is significantly increased in Kawasaki disease with coronary artery lesions.

Inhibition of endogenous hydrogen sulfide production improves viral elimination in CVB3-infected myocardium in mice.

BACKGROUND: To find whether administration of hydrogen sulfide has interaction with coxsackie virus B3 (CVB3) replication and spread. METHODS: Six-week-old inbred male Balb/c mice were injected intraperitoneally with CVB3. Mice were randomized to four groups (n = 10 for each group): group N (sham infection + vehicle), group C (virus + vehicle), group P (virus + DL-proparglygylcine (PAG)), and group S (virus + sodium hydrogen sulfide (NaHS)). PAG and NaHS were administered intraperitoneally daily and mice were killed on day 4 after viral inoculation. Serum specimens were obtained to assay tumor necrosis factor-α (TNFα) level, and heart specimens were harvested for histological examination, 50% tissue culture infection dose (TCID50) assay, reverse transcription-polymerase chain reaction and Western blot analysis. RESULTS: The ratio of heart-weight to body-weight and inflammatory scores showed no significant difference between infected groups. The circulatory and local concentrations of TNFα, nitric oxide synthase 2 messenger RNA, and protein were higher in group P, and were lower in group S compared to those in group C. Mice treated with PAG and NaHS had significantly lower and higher viral stocks than those inoculated with CVB3 only, respectively. CONCLUSION: Inhibition of endogenous hydrogen sulfide production contributed to viral clearance in acute viremia of CVB3-induced myocarditis.

A new scoring system to predict Kawasaki disease with coronary artery lesions.

OBJECTIVES: To clarify the independent risk factors and construct a scoring system for Kawasaki disease (KD) with coronary artery lesions (CAL) at acute and subacute stages. METHOD: Data of KD inpatients at acute and subacute stages were reviewed in a tertiary care center from January 2009 to December 2014. RESULTS: A total of 2305 acute and subacute KD cases were enrolled in this study with a CAL rate of 24.1%. The OR (95%CI) values of male, total fever duration ≥ 8 days, IVIG resistance (IVIGR), albumin (ALB) ≤ 35.9 g/L, eosionphils (EO) ≥ 2.2%, and monocytes (MO) ≥ 5.9% were 1.45 (1.15-1.82), 1.78 (1.43-2.22), 1.42 (1.09-1.85), 1.53 (1.23-1.91), 1.17 (0.94-1.45), and 1.37 (1.09-1.69), respectively. In patients ≤ 6 months old, the OR (95%CI) values for total fever duration ≥8 days, delayed diagnosis, and ALB ≤ 35.9 g/L were 3.61 (2.02-6.45), 3.49 (1.49-8.16), and 2.07 (1.14-3.74), respectively. ROC curve showed that the AUC value and sensitivity and specificity of predicting KD with CAL in patients ≤ 6 months old were 0.731, 64.7%, and 80.9%, respectively. CONCLUSIONS: The independent risk factors for acute and subacute KD combined with CAL, including being a boy, long fever duration, IVIGR, low ALB, elevated EO, and MO. Joint of parameters (total fever duration ≥ 8 days, delayed diagnosis, and ALB ≤ 35.9 g/L) can be used to predict the occurrence of CAL in KD patients ≤ 6 months old.