Background Kawasaki disease (KD) is a childhood systemic vasculitis of unknown etiology, with its most severe complication being the formation of coronary artery aneurysms. The pathogenesis of KD remains incompletely understood, and there is an ongoing need to develop new therapeutic agents for its treatment. Purpose This study aims to identify biomarkers and potential drug targets for KD, screen natural products with therapeutic potential based on these findings, and elucidate their mechanisms of action in depth. Methods Key genes associated with KD were identified through comprehensive bioinformatics analysis. Virtual screening was subsequently performed using molecular docking, ADMET property evaluation, metabolomics analysis, molecular electrostatic potential (MEP), and frontier molecular orbital (FMO) calculations. The stability and binding free energy of the complexes were assessed via molecular dynamics simulations. Proton nuclear magnetic resonance spectroscopy was employed to verify compound purity. Surface plasmon resonance and cellular thermal shift assays were used to detect the binding affinity between compounds and proteins. Serum levels of sCD137L and sTNF-α in children with KD and healthy controls were compared using ELISA. Finally, therapeutic efficacy and underlying mechanisms were evaluated in a KD cell model. Results CD137 was identified as a biomarker and potential drug target for KD. Hinokiflavone (HF) was identified as a candidate therapeutic agent, forming a stable complex with CD137 under physiological conditions. Serum levels of sCD137L and sTNF-α were significantly elevated in children with KD compared to healthy controls. In vitro experiments demonstrated that HF, by targeting and binding to CD137, inhibits the activation of the NLRP3 inflammasome signaling pathway induced by KD serum. siRNA-mediated knockdown of CD137 further confirmed that this intervention enhances the inhibitory effect of HF on pyroptosis, and that the pyroptosis process is dependent on CD137. Conclusion Our findings highlight the efficacy of HF in treating KD and demonstrate its broader therapeutic potential through targeted inhibition of CD137.

Kawasaki disease (KD) is an acute febrile systemic vasculitis associated with the development of coronary artery lesion and coronary artery aneurysm. This condition is characterized by sustained vascular inflammation and endothelial dysfunction, in which pyroptosis serves as a pivotal driver of inflammatory response. However, the molecular mechanisms linking pyroptosis to endothelium injury and KD pathogenesis remain poorly understood. Analysis of public datasets revealed a marked decrease in T-cadherin (T-cad, CDH13) expression in cardiac tissues from KD patients and KD model mice compared to controls. In vitro and in vivo experiments revealed the reduced T-cad expression in both the treated human umbilical vein endothelial cells (HUVECs) and the abdominal aorta of Lactobacillus casei cell wall extract-induced KD mice. RNA sequencing analysis of HUVECs with siRNA-mediated T-cad knockdown showed significant enrichment of genes involved in pro-inflammatory cascades and pyroptosis-associated pathways. Western blot analysis further validated the upregulation of pyroptosis-associated proteins, including NLRP3, caspase-1, GSDMD, IL-1β, and IL-18, in the T-cad knockdown group compared to controls. These findings were supported by functional assays demonstrating the increased lactate dehydrogenase release, higher TUNEL-positive cells, and elevated reactive oxygen species (ROS) levels in the T-cad knockdown group. Collectively, our results indicate that inflammatory stimuli downregulate T-cad expression in endothelial cells, subsequently reducing superoxide dismutase 2 (SOD2) expression and its enzymatic activity. This leads to ROS accumulation, which activates the NLRP3 inflammasome and initiates pyroptosis. Thus, T-cad deficiency induces pyroptosis in HUVECs via the activation of the SOD2/ROS/NLRP3 pathway. These findings highlight the pivotal role of T-cad deprivation-mediated endothelial cell pyroptosis in the initiation and progression of KD, providing novel insights into its pathophysiology and potential therapeutic targets.

OBJECTIVES:Kawasaki disease (KD) is a systemic vasculitis that affects children under the age of five. Comprehensive data on KD patients with medium or large CAA are limited. This study aims to investigate the risk factors and long-term follow-up of KD patients with medium or large CAA in a Chinese cohort. METHODS:We performed a cohort study of 220 KD patients including 55 patients associated with medium or large CAA and 165 patients without coronary artery abnormality between January 2015 and April 2020. Univariate and multivariate logistic regression analyses were used to identify risk factors. All enrolled patients were followed up for more than 12 months. RESULTS:Days to initial IVIG treatment, IVIG resistance, albumin level and platelet count were independent risk factors for KD patients with medium or large CAA based on multivariate logistic regression analysis. At a mean follow-up duration of 49 months, CAA subgroup analysis showed that 19 medium CAA cases (54.3%) promisingly regressed to normal coronary artery diameter, with the constituent ratios of small, medium, and large CAA being 31.4%, 8.6%, and 5.7%, respectively. In contrast, none of large CAA subgroup returned to normal coronary arteries. The constituent ratio of small, medium and large CAA was 15.0%, 25.0% and 60.0%. Besides, we found that coronary thrombosis occurred in 11 acute-phase cases (20.0%; 2 in the medium CAA, 9 in the large CAA), which increased to 18 cases (32.7%; 5 in the medium CAA, 13 in the large CAA) at the end of follow-up. CONCLUSIONS:Days to initial IVIG treatment, IVIG resistance, albumin levels and platelet count were risk factors for KD patients with medium or large CAA. The prognosis of medium or large CAA is not ideal during a long-term follow-up, particularly for large CAA.

BackgroundThis study aimed to analyze the risk factors of coronary artery lesions (CAL) in patients with Kawasaki disease (KD) and establish predictive models for CAL in patients with KD.MethodsThis retrospective cohort study included KD patients admitted to Shengjing Hospital of China Medical University, collecting data on 41 demographic, clinical, and laboratory parameters. LASSO regression identified key predictive variables. The dataset was split into 70% training and 30% validation. Ten models were trained using 10-fold cross-validation, with the training set balanced through ROSE oversampling. Model performance was assessed using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy.ResultsThe CatBoost algorithm achieved the best results: AUC, 0.953; sensitivity, 0.908; specificity, 0.860; and accuracy, 0.883. Internal validation results were as follows: AUC, 0.874; sensitivity, 0.721; specificity, 0.848; accuracy, 0.837. External validation results were as follows: AUC, 0.876.sensitivity, 0.894; specificity, 0.954.ConclusionsWe present a machine-learning model that predicts the risk of CAL in patients with KD in China, aiding doctors in creating personalized treatment strategies to improve outcomes.

BACKGROUND:Kawasaki disease (KD) is an acute febrile systemic vasculitis characterized by vascular inflammation. Its pathogenesis has been linked to the infiltration of IgA+ plasma cells within the respiratory tract, suggesting the upper airway may act as a potential portal of entry. However, evidence connecting respiratory infections to KD remains limited. This study aimed to explore the relationship between oral microbiota and KD development. METHODS:Oral swab samples were collected from 25 KD patients before and after intravenous immunoglobulin (IVIG) treatment, as well as from 25 healthy controls. Metagenomic sequencing was performed to characterize overall microbial composition and identify potential microbial markers associated with KD. RESULTS:Significant alterations in oral microbiota composition were observed between KD patients and healthy controls. The diversity of oral microbiota in KD patients was markedly lower than that in healthy controls, and exhibited an upward trend following IVIG treatment. Elevated levels of Streptococcus, Prevotella, and Veillonella, along with reduced levels of Haemophilus, Neisseria, and Rothia, were closely associated with KD development. Putative novel pathogen Abiotrophia defectiva was significantly enriched in patients with KD. Correlation analysis revealed that the relative abundances of several Haemophilus species were positively correlated with albumin levels in KD patients before IVIG treatment. Additionally, the anti-inflammatory bacterium Rothia mucilaginosa may play a protective role against the development of coronary artery lesions in KD. CONCLUSION:These findings provide new evidence that distinct alterations in the oral microbiome are associated with KD development. Oral microbiota-based biomarkers may represent a potential strategy for KD therapy.

To investigate the impact of intravenous immunoglobulin (IVIG) timing on coronary artery outcomes and treatment response in children with Kawasaki disease (KD). This retrospective study analyzed 2,988 pediatric patients with Kawasaki disease (KD) who received initial IVIG treatment within 3–7 days of fever onset. Patients were categorized by IVIG initiation time: Group A (day 3 of fever, n = 134), Group B (day 4 of fever, n = 465), Group C (day 5 of fever, n = 1101), Group D (day 6 of fever, n = 833), and Group E (day 7 of fever, n = 455). We compared baseline characteristics, IVIG resistance, and convalescent-phase coronary artery lesions (CALs). Multivariate logistic regression analyzed the association between early initiation (days 3–4 of fever) of initial IVIG therapy and IVIG resistance or convalescent-phase CALs. Propensity score matching (PSM) was used to match the early (days 3–4 of fever, n = 590) and conventional (days 5–7 of fever, n = 590) treatment groups. Baseline data during the acute phase revealed that with delayed initiation of initial IVIG treatment, serum albumin (ALB), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels in children with KD showed a significant overall decreasing trend (P < 0.001), while platelet (PLT) counts and the incidence of acute-phase CALs showed a significant overall increase (P < 0.001). However, no significant difference was found in convalescent-phase CALs incidence among groups. IVIG resistance was more common among children who required early treatment (P < 0.001). PSM analysis showed no significant difference in acute or convalescent-phase CALs between the early and conventional groups. In the multivariate logistic regression analysis after adjusting for confounders, early IVIG initiation was not significantly associated with convalescent-phase CALs but was associated with a significantly increased risk of IVIG resistance (OR: 1.74; 95

Objective:To develop and validate a nomogram for the individualized prediction of persistent coronary artery aneurysms (CAAs) in children with Kawasaki disease (KD) who have developed CAAs in the acute phase. Methods:This retrospective cohort study enrolled children diagnosed with KD and complicated by CAA between September 2015 and December 2023. The primary outcome was defined as the persistence of CAA 90 days after disease onset. Predictor selection was performed using 1,000 bootstrap resamples combined with LASSO regression for stability. A predictive model was constructed using multivariate logistic regression. The model's discrimination, calibration, and clinical utility were assessed by the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis (DCA). Results:A total of 135 children were included, of whom 80 (59.3%) had persistent CAAs. Stability selection identified the maximum coronary artery Z-score (ZM), age < 12 months (Age1), and total bile acid (TBA) as key predictors. The parsimonious model (Model B) built on these predictors demonstrated excellent performance, with an optimism-corrected AUC of 0.933 (95% CI: 0.905-0.960). It was well-calibrated, and DCA showed a positive net benefit across a wide threshold probability range of 5%-100%. Conclusion:This study successfully developed a nomogram based on ZM, Age1, and TBA. This tool can effectively identify KD children at risk of persistent CAAs, providing an intuitive and quantitative decision-making aid for precise risk stratification and optimized long-term management in this high-risk population.

Kawasaki disease (KD) is the leading cause of acquired cardiovascular disease in children and is characterized by intense immune activation and platelet dysfunction. High platelet reactivity (HPR) is increasingly recognized as a biological basis of aspirin resistance (AR), which may increase the risk of adverse coronary outcomes, including coronary artery aneurysms (CAA). However, the hematologic dynamics and genetic determinants underlying AR in KD remain unclear. In this study, the association between AR and CAA was assessed using chi-square analysis. We compared platelet parameters between KD aspirin-resistant (KD-AR) and KD non-aspirin-resistant (KD-NAR) patients across different disease phases using linear mixed-effects models (LMM). Baseline complete blood count (CBC) derived inflammatory indices, including the systemic immune-inflammation index (SII), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR), were evaluated using restricted cubic spline (RCS) and receiver operating characteristic (ROC) analyses. Integrated transcriptomic and expression quantitative trait loci (eQTL) analyses were performed to identify candidate genetic factors associated with the KD-AR phenotype. The results showed that AR was significantly associated with CAA formation. LMM showed significant phase-dependent changes in platelet parameters, with distinct longitudinal trajectories between KD-AR and KD-NAR patients. Between-group differences were mainly observed during the subacute phase (D7-14), when KD-AR patients showed lower platelet count (PLT) and plateletcrit (PCT), but higher platelet distribution width (PDW) and platelet large cell ratio (PLCR). Baseline SII, PLR, and NLR were significantly elevated in KD-AR patients (all P < 0.001). RCS analyses demonstrated significant overall associations between these indices and AR risk (all P overall < 0.001). ROC analyses showed moderate discrimination for SII (AUC = 0.702) and NLR (AUC = 0.722), whereas PLR showed lower performance (AUC = 0.626). MBP was consistently upregulated in HPR-associated samples, and eQTL integration identified MBP/rs8090438 as a candidate variant linked to KD-AR. These findings suggest that AR in KD represents a multifactorial phenotype involving immune-driven platelet dysregulation and genetic susceptibility. Baseline inflammatory indices, particularly NLR and SII, may assist in early identification of KD patients at increased likelihood of AR.

With improved survival rates among congenital heart disease (CHD) patients, pulmonary arterial hypertension (PAH) linked to CHD becomes more prevalent in both children and adults. PAH remains a significant contributor to morbidity and mortality in this population. Although genome-wide association studies (GWAS) have identified potential genetic variants with PAH risk and prognosis, the identification of circulating biomarkers with causal roles in CHD-PAH remains unclear. We employed the summary data-based Mendelian randomization (SMR) method, integrating expression profile data from the Gene Expression Omnibus (GEO) database related to CHD-PAH. This approach aimed to pinpoint genes causally associated with risk of CHD-PAH. We used a two-sample Mendelian randomization (MR) approach to efficiently screen for circulating proteins affecting CHD-PAH, leveraging publicly available genetic data from the UK biobank Pharma Proteomics Project (UKB-PPP) (54,219 UKB participants). Genetic determinants (cis-SNPs) of circulating proteins were used as instruments, and MR analyses assessed the influence of these proteins on CHD-PAH susceptibility in the largest PAH GWAS (2085 cases and 9659 controls). We conducted colocalization analyses to ensure shared genetic signals between circulating proteins and PAH and performed immune cell infiltration analysis to understand immune regulatory mechanisms in CHD-PAH. We found that a 1 SD increase in circulating S100 calcium binding protein A3 (S100A3) levels correlated with a reduced PAH risk (OR: 0.073, 95% CI: 0.020-0.267; p = 0.00799). Sensitivity analyses including various cis-SNPs, provided consistent estimates for S100A3 (inverse variance weighted (IVW) OR: 0.085, 95% CI: 0.032-0.225; p = 7.5 × 10-7 and MR-Egger OR: 0.212, 95% CI: 0.013-3.376; p = 0.387). Colocalization analyses confirmed a shared genetic signal for S100A3 and PAH, with a posterior probability of 99.9%. Transcriptomic investigations further highlighted S100A3's protective role in CHD-PAH. Our study using SMR and GEO data identified S100A3 as a gene associated with a reduced risk of PAH in CHD patients. Elevated circulating levels of S100A3 were linked to a reduced PAH risk, and transcriptomic evidence further supported its protective function in CHD-PAH.

PURPOSE:Kawasaki disease (KD) is an acute systemic vasculitis and a leading cause of acquired heart disease in children in developed countries. This study endeavors to explore the role and underlying mechanisms of EIF2AK3 in KD-related vasculitis, thereby offering novel therapeutic perspectives. METHODS:DNA from 910 KD patients and 848 controls were genotyped for rs13045 using TaqMan® to analyze the association with KD susceptibility. Concurrently, EIF2AK3 expression under KD inflammatory conditions was assessed using qRT-PCR, Western blot, and immunofluorescence. Pro-inflammatory cytokine levels were measured following EIF2AK3 knockdown or overexpression, and RNA sequencing was explored the downstream signaling pathways. For in vivo experiment, a Lactobacillus casei cell wall extract (LCWE)-induced KD mouse model with Eif2ak3 knockdown was established. ELISA and HE staining were used to investigate the degree of vasculitis between Eif2ak3 knockdown and control groups. RESULTS:The EIF2AK3/rs13045 polymorphism was associated with KD susceptibility, with the rs13045 C allele downregulating EIF2AK3. EIF2AK3 expression was increased significantly during KD inflammatory conditions. EIF2AK3 knockdown or pharmacological inhibition (GSK2606414) reduced pro-inflammatory cytokines (IL-1β/IL-6/IL-8/TNF-α) expression, while overexpression of EIF2AK3 elevated them. Mechanistically, EIF2AK3 promoted pro-inflammatory cytokines expression through activation of the MAPK-ERK1/2 pathway. Furthermore, EIF2AK3 downregulation inhibited the endothelial-to-mesenchymal transition (EndoMT), thereby impairing HUVECs migration. These findings were also recapitulated in the KD mouse model. CONCLUSION:EIF2AK3/rs13045 is a novel susceptibility locus for KD in the southern Chinese population. Our findings reveal that EIF2AK3 upregulates pro-inflammatory cytokines, thereby promoting KD-associated vasculitis via the MAPK-ERK1/2 pathway. This discovery suggests EIF2AK3 as a potential therapeutic target for the management of KD.

BackgroundKawasaki disease (KD) is the primary cause of acquired heart disease in children. Intravenous immunoglobulin (IVIG) is the first-line therapy for KD; however, IVIG resistance can occur. Reliable treatment efficacy prediction tools for Chinese patients are lacking, which this study aimed to address.MethodsThis retrospective cohort study enrolled patients diagnosed with KD admitted to Shengjing Hospital of China Medical University and collected data on 36 demographic, clinical, and laboratory parameters. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to identify key predictive variables. The dataset was divided into training (70%) and validation (30%) sets. Ten models were trained through 10-fold cross-validation, and the training set data were balanced using the ROSE method for oversampling. The performance of each model was evaluated using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy. Patients with KD admitted to Guangzhou Women and Children’s Medical Centre, Guangzhou Medical University, between January 2023 and December 2024 were enrolled as an external validation cohort.ResultsThe CatBoost machine learning algorithm achieved the best comprehensive results (AUC: 0·960; sensitivity: 0·883; specificity: 0·889, and accuracy: 0·887). The internal validation results with CatBoost were AUC: 0·862; 95% confidence interval [CI]: 0·6453–0·7651; sensitivity: 0·716; specificity: 0·877; and accuracy: 0·861. The external validation results were AUC: 0·834; 95% CI: 0·783–0·884; sensitivity: 0·817; specificity: 0·838, and accuracy: 0·835.ConclusionsWe present a machine learning model that can predict the risk of IVIG non-responsiveness in patients with KD in China. This model may help doctors develop personalized treatment strategies, thus improving the prognosis of KD.

ObjectiveWhile systemic factors influence Kawasaki disease outcomes, this study specifically determines the independent and incremental prognostic value of the coronary aneurysm's own characteristics—maximum Z-score (ZM), morphology, and Location—for predicting persistence one year after onset.MethodsThis retrospective cohort study enrolled 135 children with KD and coronary artery aneurysms (CAA). We analyzed the maximum Z-score (ZM), morphology (fusiform/saccular), and coronary artery Location (Left/Right/Bilateral) of the index aneurysm (the largest by Z-score). Univariable and multivariable logistic regression were used to identify independent predictors. The predictive performance of a model containing only ZM was compared to that of the Comprehensive Aneurysm Characteristic (CAC) model, which incorporates ZM, morphology, and Location, by assessing the area under the receiver operating characteristic curve (AUC). A descriptive analysis was additionally performed on a high-risk subgroup defined by a ZM ≥ 5.0.ResultsThe early ZM was a strong predictor of persistent coronary aneurysms at one year (OR = 4.925, P < 0.001), with an AUC of 0.909. In the multivariable analysis, larger ZM (aOR = 6.775, 95% CI: 3.133–14.648, P < 0.001), saccular morphology (aOR = 7.648, 95% CI: 1.428–40.967, P < 0.05), and LAD involvement (aOR = 4.304, 95% CI: 1.163–15.928, P < 0.05) emerged as independent predictors. The CAC model demonstrated a statistically significant improvement in predictive ability over the ZM-only model (AUC: 0.941 vs. 0.909, P = 0.025). Exploratory analysis of the high-risk subgroup (ZM ≥ 5.0) revealed a markedly higher prevalence of saccular morphology in patients with persistent aneurysms, suggesting it may serve as a crucial risk signal independent of absolute size in this population. The CAC model also showed excellent calibration and superior clinical utility across a wide range of decision thresholds.ConclusionThe intrinsic characteristics of a coronary aneurysm—its size, shape, and distribution—collectively provide powerful, independent prediction of its persistence at one year. The strong association of specific morphological features with persistence in the high-risk subgroup underscores the value of anatomy-based assessment for refining risk stratification, complementing evaluations based on systemic host factors.

Kawasaki disease (KD) is a condition characterized by acute multi-system vasculitis and high fever in infants and children. Intravenous immunoglobulin (IVIG) is the established therapeutic approach of KD,foralleviating inflammation and mitigate the risk of arterial wall dilation and the development of coronary artery aneurysms (CAA). But almost 20% of the patients developed resistance to IVIG and displayed persistent fever after standard primary treatment. TSPAN5, belonging to the Tetraspanin family, has been demonstrated to modulate innate immunity in a range of human diseases. It accomplishes this by engaging with integrins and actively participating in the process of infection recognition. However, its relevance to susceptibility and IVIG therapy response of KD was unexposed. In the present study, our Integrative analysis of KD transcriptomic data and GTEx data revealed that the eQTL rs12504972 might modify the downregulation of TSPAN5 in KD patients. Moreover, our findings suggest a potential association between TSPAN5/rs12504972 and an elevated susceptibility as well as IVIG resistance among patients with Kawasaki disease in southern China. The results provided a new insight that TSPAN5 triggered KD susceptibility and resistance of IVIG therapy on the genomic level.

Background Kawasaki disease is a pediatric acute systemic vasculitis that specifically involves the coronary arteries. Timely initiation of immunoglobulin plus aspirin is necessary for diminishing the incidence of coronary artery abnormalities (CAAs). The optimal dose of aspirin, however, remains controversial. The trial aims to evaluate if low -dose aspirin is noninferior to moderate -dose in reducing the risk of CAAs during the initial treatment of Kawasaki disease. Methods This is a multi -center, prospective, randomized, open -label, blinded endpoint, noninferiority trial to be conducted in China. The planned study duration is from 2023 to 2026. Data will be analyzed according to intention -to -treat principles. Participants are children and adolescents under the age of 18 with Kawasaki disease, recruited from the inpatient units. A sample size of 1,346 participants will provide 80% power with a one-sided significance level of 0.025. Qualifying children will be randomized (1:1) to receive either intravenous immunoglobulin (2 g/kg) plus oral moderate -dose aspirin (30-50 mg kg -1 d -1 ) until the patient is afebrile for at least 48 hours, or immunoglobulin plus low -dose aspirin (3-5 mg kg -1 d -1 ) as initial treatment. The primary outcome will be the occurrence of CAAs at 8 weeks after immunoglobulin infusion. Independent blinded pediatric cardiologists will assess the primary endpoint using echocardiography. Conclusions There is a shortage of consensus on the dose of aspirin therapy for Kawasaki disease due to the lack of evidence. The results of our randomized trial will provide more concrete evidence for the efficacy and adverse events of lowor moderate -dose aspirin in the acute phase of Kawasaki disease.

BACKGROUND:Abdominal aortic aneurysm (AAA) is a catastrophic disease with little effective therapy, likely due to the limited understanding of the mechanisms underlying AAA development and progression. ATF3 (activating transcription factor 3) has been increasingly recognized as a key regulator of cardiovascular diseases. However, the role of ATF3 in AAA development and progression remains elusive.METHODS:Genome-wide RNA sequencing analysis was performed on the aorta isolated from saline or Ang II (angiotensin II)-induced AAA mice, and ATF3 was identified as the potential key gene for AAA development. To examine the role of ATF3 in AAA development, vascular smooth muscle cell-specific ATF3 knockdown or overexpressed mice by recombinant adeno-associated virus serotype 9 vectors carrying ATF3, or shRNA-ATF3 with SM22 alpha (smooth muscle protein 22-alpha) promoter were used in Ang II-induced AAA mice. In human and murine vascular smooth muscle cells, gain or loss of function experiments were performed to investigate the role of ATF3 in vascular smooth muscle cell proliferation and apoptosis.RESULTS:In both Ang II-induced AAA mice and patients with AAA, the expression of ATF3 was reduced in aneurysm tissues but increased in aortic lesion tissues. The deficiency of ATF3 in vascular smooth muscle cell promoted AAA formation in Ang II-induced AAA mice. PDGFRB (platelet-derived growth factor receptor beta) was identified as the target of ATF3, which mediated vascular smooth muscle cell proliferation in response to TNF-alpha (tumor necrosis factor-alpha) at the early stage of AAA. ATF3 suppressed the mitochondria-dependent apoptosis at the advanced stage by upregulating its direct target BCL2. Our chromatin immunoprecipitation results also demonstrated that the recruitment of NF kappa B1 and P300/BAF/H3K27ac complex to the ATF3 promoter induces ATF3 transcription via enhancer activation. NFKB1 inhibitor (andrographolide) inhibits the expression of ATF3 by blocking the recruiters NFKB1 and ATF3-enhancer to the ATF3-promoter region, ultimately leading to AAA development.CONCLUSIONS:Our results demonstrate a previously unrecognized role of ATF3 in AAA development and progression, and ATF3 may serve as a novel therapeutic and prognostic marker for AAA.

目的:探讨华南地区汉族儿童CYP2C19基因多态性的分布,为个体化抗血小板治疗提供依据.方法:选择2015年5月至2016年5月在广州市妇女儿童医疗中心就诊的华南地区汉族儿童1311例,收集外周静脉血行CYP2C19基因rs4244285、rs4986893位点多态性检测,比较不同性别、不同地区CYP2C19代谢表型的分布特征.结果:在1311例儿童中,CYP2C19 rs4244285基因型分布为GG型46.61%、GA型43.25%、AA型10.14%,CYP2C19 rs4986893的基因型分布为GG型89.86%、GA型9.61%、AA型0.50%.CYP2C19基因型*1*1、*1*2、*1*3、*2*2、*2*3、*3*3的分布频率分别为39.36%、40.35%、6.86%、10.30%、2.59%、0.54%;CYP2C19等位基因*1、*2、*3的分布频率分别为62.97%、31.77%、5.26%.CYP2C19代谢表型分布频率为快代谢型39.30%、中间代谢型47.37%、慢代谢型13.33%,不同性别CYP2C19代谢表型分布一致(P>0.05).CYP2C19的等位基因和代谢表型分布与广州、北京、福建、湖北、重庆、云南地区比较,差异无统计学意义(均P＞0.05).结论:华南地区汉族儿童CYP2C19基因具有多态性,基因型以CYP2C19*1*2为主,等位基因以CYP2C19*1为主,代谢表型以中间代谢型为主.

Objective Balloon angioplasty (BA) has been the treatment of choice for pulmonary artery stenosis (PAS) in children. There remains, however, a significant proportion of resistant lesions. The ultra-high pressure (UHP) balloons might be effective in a subset of these lesions. In this study, we analyzed the safety and efficacy with short- to mid-term follow-up results of UHP BA for PAS in children with congenital heart defects (CHD) in our center. Methods This is a retrospective cohort study in a single tertiary heart center. Children diagnosed with PAS associated with CHD were referred for UHP BA. All data with these children were collected for analysis with updated follow-up. Results A total of 37 UHP BAs were performed consecutively in 28 children. The success rate was 78.4%. A significantly (P = 0.005) larger ratio of the balloon to the minimal luminal diameter at the stenotic waist (balloon/waist ratio) was present in the success group (median 3.00, 1.64–8.33) compared to that in the failure group (median 1.94, 1.41 ± 4.00). Stepwise logistic regression analysis further identified that the balloon/waist ratio and the presence of therapeutic tears were two independent predictors of procedural success. The receiver operating characteristic curve revealed a cut-off value of 2.57 for the balloon/waist ratio to best differentiate success from failure cases. Signs of therapeutic tears were present in eight cases, all of whom were in the success group. Perioperative acute adverse events were recorded in 16 patients, including 11 pulmonary artery injuries, three pulmonary hemorrhages, and two pulmonary artery aneurysms. During a median follow-up period of 10.4 (0.1–21.0) months, nine cases experienced restenosis at a median time of 40 (4–325) days after angioplasty. Conclusions The UHP BA is safe and effective for the primary treatment of PAS in infants and children with CHD. The success rate is high with a low incidence of severe complications. The predictors of success are a larger balloon/waist ratio and the presence of therapeutic tears. The occurrence of restenosis during follow-up, however, remains a problem. A larger number of cases and longer periods of follow-up are needed for further study.

Kawasaki disease (KD) is an acute systemic vasculitis primarily affecting infants and children. Activated platelets predispose patients to coronary artery structural lesions that may lead to thrombotic cardiovascular events. To discover potential proteins underlying platelet activation in KD, we conducted a protein chip assay of 34 cytokines and discovered thymic stromal lymphopoietin (TSLP) was aberrantly expressed, which remained elevated after intravenous immunoglobulin G (IVIG) treatment and during convalescence in KD patients in comparison to healthy controls. Enzyme-linked immunosorbent assay (ELISA) corroborated the upregulation of TSLP in KD patients, which was exacerbated in convalescent patients complicated with thrombosis. TSLP receptors on platelets were also significantly upregulated in KD patients complicated with thrombosis. Platelet activation, apoptosis, and mitochondrial autophagy (mitophagy) were increased in convalescence KD patients complicated with thrombosis. In vitro, TSLP induced platelet activation and platelet mitophagy in healthy blood donors, as observed in KD patients. TSLP, similar to mitophagy agonist carbonyl cyanide 3-chlorophenyl hydrazone (CCCP), promoted thrombosis, which was attenuated by the mitophagy inhibitor Mdivi-1. Co-immunoprecipitation in TSLP-treated platelets revealed TSLP receptor (TSLPR) bound to mitophagy regulators, Parkin and Voltage Dependent Anion Channel Protein 1 (VDAC1).Thus, our results demonstrated that TSLP induced platelet mitophagy via a novel TSLPR/Parkin/VDAC1 pathway that promoted thrombosis in KD. These results suggest TSLP as a novel therapeutic target against KD-associated thrombosis.

Abstract Objective To investigate the clinical manifestations, laboratory data and coronary artery lesions of refractory Kawasaki disease, and to follow up the patients in the near to medium term. Methods Patients with refractory KD admitted to Guangzhou Women and Children's Medical Center between January 1, 2016 and December 31, 2020 were collected and their clinical data were retrospectively analyzed. Results A total of 42 patients were diagnosed with refractory KD, including 31 (73.81%) and 11 (26.19%) were male and female, respectively, with a median age of 26.7±19.3 (2-99) months. The average time, from onset to diagnosis and IVIG use, was 5.8±0.9 (4-12 ) days, while the fever lasted for 14.8±4.0 (8-34) days. A total of 29 patients exhibited coronary artery disease complications. All patients exhibited persistent or recurrent fever after two doses of IVIG therapy. A total of 41 patients were given a methylprednisolone regimen for up to three consecutive days as follows, while one patient continued to receive IVIG. The diameter of coronary arteries returned to normal 10 patients during the follow-up period, patients with medium and huge tumors exhibited shrunken diameter of coronary arteries, although they were not completely normal. Follow-up observations are still ongoing. Conclusion There is no unified diagnostic criteria and treatment plan for children with refractory KD. For patients that still experience fever after two IVIG treatments, clinicians need to consider the possibility of this type of KD. Development of an effective treatment plan is imperative to shortening fever time and prevention of progressive aggravation of coronary artery disease. Longer follow-up observation is also needed for this group of patients with coronary artery outcomes.

Objective:To investigate the clinical manifestations, diagnosis, treatment and prognosis of Kawasaki disease (KD) complicated with acute abdomen in children.Methods:Clinical manifestations, laboratory examinations, abdominal B-ultrasound scans, abdominal plain films, abdominal CT findings, coronary artery lesions and prognosis of 16 children with KD and acute abdomen admitted to Guangzhou Women and Children′s Medical Center, Guangzhou Medical University from August 1, 2015 to July 31, 2019 were retrospectively analyzed.The measurement data of age, leukocyte, hemoglobin, platelet and biochemical indexes are expressed by M (range). Results:A total of 16 cases were included, involving 7 males and 9 females aged 4 years and 8 months (7 months to 8 years). Among them, 9 cases of KD complicated with cholecystitis, 5 cases with intestinal obstruction, 2 cases with acute appendicitis, 2 cases with necrotizing enterocolitis, 2 cases with acute peritonitis and 1 case with acute pancreatitis.There were 3 cases complica-ted with 2 or more kinds of acute abdomen diseases.All 16 patients had symptoms of abdominal pain, 7 cases had vomiting, 4 cases had obvious abdominal distension and 1 case had bloody stool.Abdominal B-ultrasound was performed in all cases, and 8 cases showed enlargement of gallbladder and edema and thickening of gallbladder wall, 2 cases of appendicitis, 2 cases of intestinal obstruction and 1 case of pancreatic enlargement.Abdominal plain film examination was performed in 8 cases, suggesting necrotizing enterocolitis in 2 cases and intestinal obstruction in 2 cases.Abdominal CT examination was performed in 3 cases, including edema of gallbladder wall in 1 case, peritonitis in 1 case, intestinal obstruction in 2 cases and enlargement of pancreas in 1 case.All the 16 cases were treated with pulsed intravenous immunoglobulin (IVIG) at 2 g/kg and antiplatelet agents.Eight IVIG-resistant cases were treated with the second dose of IVIG at 2 g/kg, among whom, 4 children still had fever and intravenous Methylprednisone was given.Two cases underwent enterostomy and abdominal puncture drainage.All the 16 children were followed up until 6 months after discharge, and 4 cases (25%) were complicated with coronary artery aneurysm (CAA) during the acute stage or follow-up period.Conclusions:KD complicated with acute abdomen is more commonly manifested as cholecystitis and intestinal obstruction.Besides the classic symptoms of KD, abdominal pain and vomiting are the most common in KD with acute abdomen.Abdominal ultrasound, plain film and CT examinations are conductive to the early diagnosis of KD complicated with acute abdomen.In addition, the incidence of IVIG-resistance and CAA is relatively high in children with KD complicated with acute abdomen.