Songling Fu

Evaluation of intravenous immunoglobulin resistance and coronary artery lesions in relation to Th1/Th2 cytokine profiles in patients with Kawasaki disease

OBJECTIVE To investigate the roles of serum Th1 and Th2 cytokines in Kawasaki disease (KD) and determine whether the Th1/Th2 cytokine profiles in children with KD may be involved in intravenous immunoglobulin (IVIG) resistance and development of coronary artery lesions (CALs). METHODS Serum Th1 and Th2 cytokines, including interferon-γ (IFNγ), tumor necrosis factor α (TNFα), interleukin-10 (IL-10), IL-6, IL-4, and IL-2, were measured using a cytometric bead array in the serum of 143 patients with KD before and after treatment with IVIG (pre-IVIG, at 3 days after temperature normalization following IVIG treatment [post-IVIG], and 1 month posttreatment). RESULTS Levels of IL-6, IL-10, TNFα, and IFNγ were significantly increased in KD patients pre-IVIG. Post-IVIG, the levels of IL-6, IL-10, and IFNγ quickly decreased. The levels of TNFα decreased significantly after IVIG treatment in KD patients without CALs post-IVIG and in KD patients who were IVIG responders, but increased slightly in KD patients with CALs post-IVIG and in KD patients who were IVIG nonresponders. Before IVIG treatment, the levels of IL-4, IL-6, IL-10, and IFNγ were significantly higher in KD patients with CALs than in those without CALs. The post-IVIG levels of IL-6 and IL-10 were significantly higher in IVIG nonresponders than in IVIG responders. Pre-IVIG, an IL-10 level >8 pg/ml had a sensitivity of 75.0% and a specificity of 64.4% for predicting CALs, while a TNFα level <2 pg/ml had a sensitivity of 66.7% and a specificity of 74.2% for predicting IVIG resistance. Post-IVIG, an IL-6 level >10 pg/ml had a sensitivity of 67.9% and a specificity of 81.7% for predicting CALs, while an IL-10 level >6 pg/ml had a sensitivity of 53.6% and a specificity of 86% for predicting CALs. CONCLUSION Determination of the serum Th1/Th2 cytokine profile may be helpful for predicting the disease prognosis and targeting treatment strategies in patients with KD.

MTHFR C677T Polymorphism and Risk of Congenital Heart Defects: Evidence from 29 Case-Control and TDT Studies

Background Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme for folate metabolism in humans; it is encoded by the MTHFR gene. Several studies have assessed the association between MTHFR C677T polymorphism and the risk of congenital heart defects (CHDs), while the results were inconsistent. Methods and Findings Multiple electronic databases were searched to identify relevant studies published up to July 22, 2012. Data from case-control and TDT studies were integrated in an allelic model using the Catmap and Metafor software. Twenty-nine publications were included in this meta-analysis. The overall meta-analysis showed significant association between MTHFR C677T polymorphism and CHDs risk in children with heterogeneity (P heterogeneity = 0.000) and publication bias (P egger = 0.039), but it turned into null after the trim-and-fill method was implemented (OR = 1.12, 95% CI = 0.95–1.31). Nevertheless, positive results were obtained after stratified by ethnicity and sample size in all subgroups except the mixed population. For mothers, there was significant association between the variant and CHDs without heterogeneity (P heterogeneity = 0.150, OR = 1.16, 95% CI = 1.05–1.29) and publication bias (P egger = 0.981). However, the results varied across each subgroup in the stratified analysis of ethnicity and sample size. Conclusions Both infant and maternal MTHFR C677T polymorphisms may contribute to the risk of CHDs.

Macrophage activation syndrome in Kawasaki Disease: More common than we thought?

OBJECTIVES To analyze the clinical characteristics, treatment, and outcomes of Kawasaki Disease (KD) patients associated with macrophage activation syndrome (MAS) and to compare two diagnostic standards (the HLH 2009 and Ravelli׳s criteria). METHODS All of the studied patients with Kawasaki Disease (KD) were treated at The Children׳s Hospital, Zhejiang University School of Medicine, during 2007-2010. Clinical and laboratory findings were analyzed. RESULTS In 719 KD patients, eight patients (1.11%, 81.3 ± 49.4 months, all male) were diagnosed by Ravelli׳s criteria, but only three (0.42%) patients were diagnosed by the HLH 2009 criteria. Aspartate aminotransferase increased significantly in all cases. Alanine aminotransferase, lactate dehydrogenase, and serum ferritin increased significantly in seven cases. Cytopenia and hypertriglyceridemia (>1.5mmol/L) were found in six and five cases, respectively. Hypofibrinogenemia (<1.5g/L) was found in two cases. Three cases showed evidence of hemophagocytosis, but only one case met the HLH 2009 criteria. Ectasia of the coronary arteries occurred in two cases. Seven patients were non-responsive to IVIG. One case died after the combined application of DXM, VP16, and CSA. CONCLUSIONS MAS may be a frequently under-recognized complication of KD, because the understanding of complications and diagnostic criteria are still in progress. The HLH 2009 criteria have low sensitivity and specificity for the diagnosis of MAS complicating KD. When hepatosplenomegaly is present in KD patients with abnormal laboratory findings, such as cytopenia, liver dysfunction, hyperferritinemia, elevated serum LDH, hypofibrinogenemia, and hypertriglyceridemia, the presence of MAS should be considered.

S100A12 on circulating endothelial cells surface in children with Kawasaki disease.

The purpose of this study was to investigate the expression of S100A12 on the surface of circulating endothelial cells (CECs) in children with Kawasaki disease (KD) and the correlations between S100A12 and coronary artery lesions (CALs). The ratio of CECs to mononuclear cells (CECs/MNC), the positive rate of S100A12 on CECs surface (CECs-S100A12/CECs), and the fluorescence intensity of S100A12 on CECs surface (FI-S100A12-CECs) were evaluated respectively in 42 patients with acute stage (A-KD), subacute stage (SA-KD) and convalescent stage KD (C-KD). The CECs/MNC ratio increased significantly in patients with A-KD and SA-KD with CALs. The CECs-S100A12/CECs rate and FI-S100A12-CECs level were significantly higher in patients with KD than in the controls. The FI-S100A12-CECs level decreased to near half levels in patients with SA-KD and C-KD without CALs, but increased continuously in patients with SA-KD with CALs. The CECs/MNC ratio and FI-S100A12-CECs level in patients with SA-KD with CALs were significantly higher than in patients with SA-KD without CALs. The FI-S100A12-CECs level was significantly higher in patients with C-KD with CALs than in C-KD without CALs. The S100A12 expression on the CECs surface increased significantly in patients with KD and persisted for a longer time in patients with CALs, suggesting that the S100A12 expression on CECs may be involved in the development of CALs.

Reverse regulation of soluble receptor for advanced glycation end products and proinflammatory factor resistin and S100A12 in Kawasaki disease

IntroductionKawasaki disease (KD), an acute febrile disease, characterized by systemic vasculitis, predominantly affects infants and children under 5 years of age. Coronary artery lesions (CALs) are its most critical complication, and the etiology remains unknown yet. In order to explore the value of resistin, S100A12 and soluble receptor for advanced glycation end products (sRAGE) in the pathophysiology of KD, we studied the serum levels of resistin, S100A12 and sRAGE in different stages of KD.MethodsSerum levels of resistin, S100A12 and sRAGE were measured by enzyme-linked immunosorbent assay (ELISA) method in 15 healthy children and 40 KD patients at acute, afebrile and subacute stage.ResultsThe resistin and S100A12 levels, including the ratio of resistin to sRAGE and S100A12 to sRAGE increased significantly in the acute stage, and decreased progressively in the afebrile and subacute stage. However, the sRAGE levels decreased significantly in the acute stage, and increased progressively in the afebrile and subacute stage. In the acute, afebrile and subacute stage, the resistin levels were higher in intravenous immunoglobulin (IVIG) non-responders (0.64 ± 0.30, 0.48 ± 0.35, 0.28 ± 0.19, × 102 ng/ml) than in IVIG responders (0.35 ± 0.24, 0.21 ± 0.19, 0.12 ± 0.05, × 102 ng/ml). In the acute and subacute stage, the S100A12 levels were higher in IVIG non-responders (7.92 ± 2.61, 4.98 ± 4.75, × 102 ng/ml) than in IVIG responders (5.05 ± 3.22, 2.35 ± 2.26, × 102 ng/ml). In the afebrile and subacute stage, the sRAGE levels were lower in IVIG non-responders (3.51 ± 2.64, 3.65 ± 3.27, × 102 pg/ml) than in IVIG responders (6.00 ± 2.78, 7.19 ± 2.88, × 102 pg/ml). The resistin levels were positively correlated with S100A12 levels. The sRAGE levels were negatively related with S100A12 and resistin levels.ConclusionsResistin, S100A12 and sRAGE are involved in the pathophysiology of KD.

Expression of receptor for advanced glycation end products (RAGE) on the surface of circulating endothelial cells is upregulated in Kawasaki disease

Introduction:The aim of this study was to investigate the expression of receptor for advanced glycation end products (RAGE) on the surface of circulating endothelial cells (CECs) in patients with Kawasaki disease (KD).Methods:The positive rate of RAGE on the surface of CECs (CECs-RAGE/CECs) and the fluorescence intensity of RAGE on the surface of CECs (FI-RAGE-CECs) were evaluated in 89 patients with KD in the acute stage (A-KD), subacute stage (SA-KD), or convalescent stage (C-KD).Results:CECs-RAGE/CECs and the FI-RAGE-CECs increased significantly in patients with KD. The CECs-RAGE/CECs was significantly higher in C-KD patients with coronary artery lesions (CALs) than in those without CALs. The FI-RAGE-CECs level was significantly higher in SA-KD and C-KD patients with CALs than in A-KD patients. In SA-KD and C-KD patients, the CECs-RAGE/CECs and FI-RAGE-CECs levels decreased in intravenous immunoglobulin (IVIG)-respondent patients but increased progressively in IVIG-resistant patients and were significantly higher in IVIG-resistant patients than in IVIG-respondent patients.Discussion:The results suggest that the expression levels of RAGE on the surface of CECs are upregulated in KD patients, and that the upregulated expression levels of RAGE on the surface of CECs can be aggravated in SA-KD and C-KD patients with CALs, and also in IVIG-resistant SA-KD and C-KD patients. The RAGE expression on CECs is involved in the pathophysiology of KD.

Anomalous Origin of the Right Pulmonary Artery from the Abdominal Aorta With Aberrant Right Subclavian Artery and Left Patent Ductus Arteriosus

Anomalous origin of the pulmonary artery (AOPA) from the aorta is a rare congenital heart malformation. This report describes a case of AOPA from the abdominal aorta in association with an aberrant right subclavian artery and a patent ductus arteriosus, which never has been reported previously in the literature.

A new model to predict intravenous immunoglobin-resistant Kawasaki disease

Objectives To clarify the independent risk factors and construct predictive model for intravenous immunoglobin (IVIG)-resistant KD (IVIGRKD). Results The ratio of male to female in the overall samples was 1.62:1 and the incidence of IVIGR was 17.9%. Multivariate regression analysis showed that the OR (95% CI) values of fever duration ≥ 7 days, delayed diagnosis, gamma-glutamyl transferase ≥ 25 U/L, serum sodium ≤ 135 mmol/L, neutrophil-to-lymphocyte ratio ≥ 2.8 and platelets ≤ 350 × 109/L were 2.94 (2.17–4.00), 1.64 (1.07–2.53), 1.38 (1.07–1.79), 1.68 (1.30–2.19), 1.58 (1.22–2.06) and 1.39 (1.08–1.80), respectively. Based on these OR values, a new predictive model was established with an AUC of 0.685, a sensitivity of 60.7% and a specificity of 66.5%, and showed superiority to formerly reported models. Further analysis of patients ≤ 6 months old gave rise to improved predictions for IVIGRKD with an AUC of 0.746 relative the new model for the total samples. Materials and Methods A total of 2,126 KD cases were enrolled in this study. Clinical indicators showing significant differences were screened using univariate analysis, and the independent risk factors were further elucidated using multivariate regression analysis. A new model was constructed, and the predictive ability was evaluated with the area under the curve (AUC) value and the sensitivity and specificity by using the receiver operating characteristic (ROC) curve. Conclusions The new model for predicting IVIGRKD in this study is superior to those reported previously, and further analysis of patients with IVIGRKD younger than 6 months old allowed optimization of the predictive model.

Notch4 signaling pathway in a Kawasaki disease mouse model induced by Lactobacillus casei cell wall extract

The present study aimed to explore the role of the Notch4 signaling pathway in a mouse model of Kawasaki disease (KD) induced by Lactobacillus casei cell wall extract (LCWE). BALB/c male mice (4–6 weeks old) were intraperitoneally injected with 500 µg LCWE in phosphate-buffered saline (PBS) or PBS alone (control group). At days 3, 7, 14 and 28, the numbers of circulating endothelial progenitor cells (EPCs) in the peripheral blood and the expression of Notch4 on the surface of EPCs were detected. In addition, the levels of vascular cell adhesion molecule 1 (VCAM-1) and P-selectin in the roots of coronary arteries were evaluated. The results demonstrated that the level of circulating EPCs increased significantly at day 3, decreased progressively from day 3 onwards, and recovered to the normal level at day 28. Furthermore, the expression of Notch4 on the surface of EPCs was evidently higher in the KD model compared with that in the control group at day 7. In the endothelial cells of the coronary artery root, the protein levels of VCAM-1 and P-selectin protein increased in the KD model. In conclusion, the Notch4 signaling pathway participated in the coronary artery lesions in the KD animal model induced by LCWE.

Notch4 Signaling Pathway of Endothelial Progenitor Cells in a Kawasaki Disease Model Induced by Lactobacillus casei Cell Wall Extract

The Notch4 signaling pathway of endothelial progenitor cells (EPCs) may play a crucial role in Kawasaki disease (KD). We investigated the proliferation, adhesion, migration, angiogenesis, and expression levels of Notch4, recombination signal-binding protein-Jκ (RBP-Jκ), P-selectin, and vascular cell adhesion molecule-1 (VCAM-1) of bone marrow (BM) EPCs in a KD model induced by Lactobacillus casei cell wall extract. The numbers of BM EPCs decreased significantly in the KD models. The Notch4 expression level on the EPC surface was higher in the KD models than in the controls. The proliferative, adhesive, migratory, and angiogenic properties, and double immunofluorescence-binding rate of BM EPCs were significantly impaired in the KD models. The levels of Notch4 and P-selectin mRNA were lower in the KD models than in the controls on day 3. The RBP-Jκ mRNA levels were lower in the KD models than in the controls on days 3 and 7. The levels of RBP-Jκ and vascular endothelial growth factor receptor-2 proteins decreased in the early stage. In conclusion, the BM EPC functions and bioactivities in the KD models were impaired, and the Notch4 signaling pathway is associated with KD.