Serum NLRP3: A potential marker for identifying high-risk coronary arterial aneurysm in children with Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is a vasculitis of unknown etiology in children aged under 5 years. Coronary arterial aneurysm (CAA) is the major complication of KD. It is no longer though to be a self-limiting disease because its cardiovascular sequelae might persist into adulthood. NLRP3 is a key protein of the NLRP3 inflammasome that participates in sterile inflammatory disease. This study investigated the serum levels of NLRP3 in patients with KD at different stages to explore the relationships between serum NLRP3 and clinical parameters. METHODS: A total of 247 children enrolled in this study. There were 123 patients in the acute stage of KD, and 93 healthy children made up the healthy control (HC) group. Among the acute KD patients, 52 had coronary arterial aneurysm (KD-CAA) and 71 did not (KD-NCAA). 36 patient samples were collected after IVIG and aspirin treatment. Additionally, 29 patients were in the cardiovascular sequelae stage. Enzyme-linked immunosorbent assay was used to measure serum NLRP3 levels in all subjects. RESULTS: Serum NLRP3 was elevated in the KD group and was even higher in the KD-CAA subgroup than in the KD-NCAA subgroup of acute-stage patients. Serum NLRP3 declined when the patients were treated with IVIG and aspirin, but during the convalescent (coronary sequelae) stage, serum NLRP3 re-increased. Serum NLRP3 was higher in the ≥ 6-mm-coronary-arterial-diameter group than that the < 6-mm-diameter group. The ROC curve of serum NLRP3 indicated its utility in the prediction of both KD and KD-CAA. CONCLUSIONS: NLRP3 may be involved in the development of KD and CAA in children with KD. Targeting NLRP3 might mitigate CAA, thereby reducing the risk of cardiovascular events in adulthood.

Long term follow-up of patients with patent ductus arteriosus after transcatheter closure.

BACKGROUND: To investigate the concurrent, long-term, and future adverse events and assess the trend of adverse events in pediatric patients with patent ductus arteriosus (PDA) after transcatheter closure. METHODS: A total of 1590 patients underwent transcatheter PDA closure were enrolled, including 465 patients (median age = 22 months) in the training group and 1125 patients in the validation group. Logistic regression analysis was used to assess independent risk factors associated with concurrent adverse events after closure. The chi-square test was used to evaluate the 5-year follow-up trend. RESULTS: Multivariable logistic regression analysis indicated that low age, female, and high pulmonary end diameter were independent risk factors for concurrent adverse events after closure. For patients without concurrent adverse events and for those who with concurrent adverse events but return to normal, the Chi-square test showed no abnormal results at the 5-year follow-up. Furthermore, the follow-up data of the validation group were not significantly different from those of the training group. CONCLUSION: The value of long-term follow-up of children may be limited for those who did not have a concurrent adverse event after closure nor for those who had a concurrent adverse event after closure but returned to normal during the 5-year follow-up period. IMPACT: Follow-up monitoring of adverse events tended to be recommended in pediatric patients with PDA after transcatheter closure. However, follow-up in these pediatric patients is expensive and there is a risk of sedation for echocardiography examination frequently. ·Patients who had no concurrent adverse events after closure did not show any abnormality at 5-year follow-up. ·Most of the patients who had concurrent adverse events after closure returned to normal at 5-year follow-up. The value of long-term follow-up may be limited for the above patients after transcatheter PDA closure.

Pediatric malignant pheochromocytoma with atypical presentation as vision changes, lung metastasis, and recurrence: a case report.

BACKGROUND: This case report documents a case of malignant pheochromocytoma manifested as vision changes with lung metastasis and recurrence. CASE PRESENTATION: A 10-year-old Han Chinese girl presented with vision changes and was eventually diagnosed with pheochromocytoma by contrast-enhanced computed tomography, urine vanillylmandelic acid. After medication for hypertension and surgery, clinical symptoms disappeared. Malignant pheochromocytoma with lung metastasis was confirmed histologically using the Pheochromocytoma of the Adrenal Gland Scaled Score scoring system and genetically with succinate dehydrogenase complex iron sulfur subunit B mutation, and 3 months later, unplanned surgery was performed because of the high risks and signs of recurrence. She is asymptomatic as of the writing of this case report. Our patient's case highlights the importance of considering a diagnosis of malignant pheochromocytoma, and long-term follow-up for possible recurrence. CONCLUSION: Although there are well-recognized classic clinical manifestations associated with pheochromocytoma, atypical presentation, such as vision changes in children, should be considered. In addition, malignant pheochromocytoma children with a high Pheochromocytoma of the Adrenal Gland Scaled Score and succinate dehydrogenase complex iron sulfur subunit B mutation require a long-term follow-up or even unplanned surgery because of the higher risk of recurrence.

A practical nomogram for predicting coronary thrombosis for Kawasaki disease patients with medium or large coronary artery aneurysm.

Kawasaki disease (KD) is the main cause of acquired heart disease in children. Coronary thrombosis is a serious cardiovascular complication of KD, which affects the long-term treatment effect. The purpose was to develop and validate a model for predicting coronary thrombosis in KD with medium or large coronary artery aneurysm (CAA). A total of 358 consecutive KD patients with medium or large CAA from Chongqing Children's Hospital were enrolled retrospectively. The demographic data, clinical characteristics, laboratory features before intravenous immunoglobulin (IVIG) treatment, and all radiological features during hospitalization and follow-up were collected. Eligible patients follow-up for > 2 years. Follow-up was weekly for the first 1 month, monthly for the next 11 months, and every 3-6 months after 1 year. The main examinations included echocardiogram and electrocardiogram. The primary endpoint was defined as coronary thrombosis during the follow-up. Coronary thrombosis was assessed by echocardiographic assessment of the presence of echoes in the lumen of the right coronary artery, left main coronary artery, left anterior descending artery, or left circumflex artery by echocardiologists. The independent risk factors were identified using univariate analyses and multivariate logistic regression analyses, and the nomogram was constructed for predicting coronary thrombosis. Tenfold cross-validation was used to perform internal validation. The area under the ROC curve (AUC), calibration curve, and decision curve analysis were used to evaluate the discrimination, calibration, and clinical utility of the nomogram, respectively. Multivariate logistic regression analysis revealed that male (odds ratio [OR] 3.491; 95% confidence interval [CI] 1.570-7.765), large CAA (OR 3.725; 95% CI 1.388-9.999), no use high-dose aspirin prior to IVIG (OR 3.114; 95% CI 1.291-7.510), two-vessel coronary artery involvement (OR 4.433; 95% CI 1.732-11.344), three-vessel coronary artery involvement (OR 5.417; 95% CI 2.048-14.328), four-vessel coronary artery involvement (OR 13.183; 95% CI 3.408-50.997), serum fibrinogen level > 5.325 g/L (OR 14.233; 95% CI 5.479-36.921), serum thrombin time level ≤ 15.15 s (OR 3.576; 95% CI 1.756-7.284) were significantly associated with coronary thrombosis. The nomogram was established based on these variables. The AUC of the nomogram were 0.920, and tenfold cross-validation (repeated 100 times) showed that the average AUC was 0.902. Moreover, the nomogram had a well-fitted calibration curve and also exhibited good clinical usage. The nomogram is based on six ready-made clinical variables, is easy to use, has excellent diagnostic performance, and can help clinicians make better clinical decisions on the management and treatment of KD patients with medium or large CAA.

The Relationship Between Lipoprotein-Associated Phospholipase-A2 and Coronary Artery Aneurysm in Children With Kawasaki Disease.

Background: Coronary artery lesions including aneurysm, as the most severe complications of Kawasaki disease (KD), remain of great concern. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is implicated in the regulation of inflammatory response and lipid metabolism. Since excessive inflammatory response and aberrant lipid metabolism have involved in the development of KD, we in this study sought to investigate the relationship between coronary artery aneurysm (CAA) and Lp-PLA2 and other blood parameters in children with KD. Methods: The participants included 71 KD patients, 63 healthy controls (HCs) and 51 febrile controls (FCs). KD patients were divided into KD-CAA (KD with CAA) group and KD-NCAA (KD without CAA) group. Serum Lp-PLA2 levels were measured using enzyme-linked immunosorbent assays. Other routine clinical parameters were also detected. Results: Serum Lp-PLA2 levels in KD group [4.83 µg/mL (3.95-6.77)] were significantly higher than those in HC [1.29 µg/mL (0.95-2.05)] and FC [1.74 µg/mL (1.18-2.74)] groups. KD-CAA group [5.56 µg/mL (4.55-22.01)] presented substantially higher serum Lp-PLA2 levels as compared with KD-NCAA group [4.64 µg/mL (2.60-5.55)]. In KD group, serum Lp-PLA2 level was positively related with erythrocyte sedimentation rate, the levels of leukocytes, platelets, albumin, creatine kinase-MB, and D-dimer, and the Z-scores of left main CA, right CA, left anterior descending CA, and left circumflex CA; and negatively related with mean corpuscular hemoglobin concentration and mean platelet volume. Moreover, receiver operating characteristic curves showed that Lp-PLA2 exhibited superior and moderate diagnostic performance for distinguishing KD patients from HC and FC ones, respectively, and possessed the potential ability to predict the occurrence of CAAs in KD. Conclusion: Lp-PLA2 may be related to KD and the formation of CAAs, and thus may serve as a potential diagnostic biomarker for KD.

PINK1/TAX1BP1-directed mitophagy attenuates vascular endothelial injury induced by copper oxide nanoparticles.

Copper oxide nanoparticles (CuONPs) are widely used metal oxide NPs owing to their excellent physical-chemical properties. Circulation translocation of CuONPs after inhalation leads to vascular endothelial injury. Mitochondria, an important regulatory hub for maintaining cell functions, are signaling organelles in responses to NPs-induced injury. However, how mitochondrial dynamics (fission and fusion) and mitophagy (an autophagy process to degrade damaged mitochondria) are elaborately orchestrated to maintain mitochondrial homeostasis in CuONPs-induced vascular endothelial injury is still unclear. In this study, we demonstrated that CuONPs exposure disturbed mitochondrial dynamics through oxidative stress-dependent manner in vascular endothelial cells, as evidenced by the increase of mitochondrial fission and the accumulation of fragmented mitochondria. Inhibition of mitochondrial fission with Mdivi-1 aggravated CuONPs-induced mtROS production and cell death. Furthermore, we found that mitochondrial fission led to the activation of PINK1-mediated mitophagy, and pharmacological inhibition with wortmannin, chloroquine or genetical inhibition with siRNA-mediated knockdown of PINK1 profoundly repressed mitophagy, suggesting that the protective role of mitochondrial fission and PINK1-mediated mitophagy in CuONPs-induced toxicity. Intriguingly, we identified that TAX1BP1 was the primary receptor to link the ubiquitinated mitochondria with autophagosomes, since TAX1BP1 knockdown elevated mtROS production, decreased mitochondrial clearance and aggravated CuONPs-induced cells death. More importantly, we verified that urolithin A, a mitophagy activator, promoted mtROS clearance and the removal of damaged mitochondria induced by CuONPs exposure both in vitro and in vivo. Overall, our findings indicated that modulating mitophagy may be a therapeutic strategy for pathological vascular endothelial injury caused by NPs exposure.

Hypomethylation of C1q/tumor necrosis factor-related protein-1 promoter region in whole blood and risks for coronary artery aneurysms in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is characterized as a self-limited systemic vasculitis. C1q/tumor necrosis factor-related protein-1 (CTRP1) had been associated with the occurrence of vasculitis in KD. Methylation at the promoter region of certain genes was reported to be involved in the development process of KD. This study aims to investigate the methylation levels of CTRP1 in KD, as well as, its potential to predict coronary artery aneurysms (CAAs). METHODS: 31 patients with KD and 14 healthy controls (HCs) were recruited into this study. The KD group was further divided into KD with CAA (KD-CAAs) group and KD without NCAAs (KD-NCAAs) group. Methylation levels of CpG sites were determined by MethylTarget sequencing, a method that uses multiple targeted CpG methylation analysis. RESULTS: The methylation levels of CTRP1 promoter region in the KD group were lower than that in the HC group at all predicted CpG sites, especially at sites 34, 51, 69, 79, 176 and 206. Compared with KD-CAAs group, the methylation levels of almost every CpG sites of CTRP1 were increased in the KD-NCAAs group, with site 69 and 154 found to be strongly related to the occurrence of CAAs. CONCLUSIONS: The difference in methylation levels of CTRP1 promoter may be involved in the development process of KD, and may be a potential predictive marker for the occurrence of CAAs.

Safety of longer linezolid regimen in children with drug-resistant tuberculosis and extensive tuberculosis in Southwest China.

OBJECTIVES: Linezolid (LNZ) has recently been listed by the World Health Organization (WHO) as a Group A agent for the treatment of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) in longer regimens (18-20 months). However, little is known about the safety of LNZ in longer TB treatment regimens in children. METHODS: Here we report 31 children who received LNZ treatment for drug-resistant tuberculosis (DR-TB) and extensive tuberculosis in the Children's Hospital of Chongqing Medical University, China, during September 2016 to March 2019. The mean duration of LNZ treatment was 8.56 months (range, 1-24 months). RESULTS: Of the 31 patients, 13 (42%) had suspected or confirmed adverse events (AEs) related to LNZ treatment, including digestive symptoms, haematological toxicity, neuropathy and lactic acidosis. Haematological toxicity was the most frequent AE, presenting as leukopenia (9/13) and anaemia (5/13). No hepatotoxicity or nephrotoxicity was observed. Two patients suffered from life-threatening lactic acidosis when the LNZ dose was increased to 1.2 g daily, however they recovered following LNZ withdrawal. CONCLUSION: A high rate of AEs of LNZ treatment was observed in children receiving a longer regimen, which might relate to the treatment course and dose. Haematological toxicity was the most frequent AE in children. It is necessary to regularly monitor the blood chemistry and lactic acid concentration during LNZ treatment.

Classification of difference between inhibition constants of an inhibitor to facilitate identifying the inhibition type.

To identify the common inhibition types, the putative decision system is unsatisfactory. In a new decision system, Michaelis-Menten constants and maximal reaction rates were plotted versus inhibitor concentrations for deriving K(ik) and K(iv) as the inhibition constants, respectively; their difference was quantified as the ratio of the larger one to the smaller one. Such ratios below 2.0 suggested uncompetitive inhibitors, over 5.0 suggested noncompetitive or competitive inhibitors, and from 2.0 to 5.0 suggested mixed inhibitors. By the new decision system, (i) the simulation recovery of uncompetitive inhibitors under CVs of 2% or 5% was improved by four times, but that of competitive or noncompetitive inhibitors was improved slightly; (ii) the recovery of L-phenylalanine as an uncompetitive inhibitor of intestinal alkaline phosphatase reached 38%, while the putative decision system lost all; the recovery of xanthine as a competitive inhibitor of uricase was improved slightly. Therefore, the new decision system was better.