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Introduction: Kawasaki disease (KD), which is the most common multisystem vasculitis with unknown causes in childhood, causes coronary artery lesions (CALs). Treatment with a high dose of intravenous immunoglobulin (IVIG), plus steroids if needed, is the most effective therapy for the acute phase of KD. However, there are some very severe cases who need several times additional treatments and are at risk for CALs. In Japan, there are some scoring systems that initially predict IVIG-resistant patients. However, the problem is that these scoring systems fail in multiethnic populations. The aim of this study is to find universal biomarkers that predict treatment-resistant cases of KD. Methods: The subject was 276 KD patients, including Group 1 (n=214) who needed only 1 st line treatment, Group 2 (n=48) who needed 2 nd line treatment, Group 3 (n=14) who needed 3 rd line treatment or more. Tenascin C (TN-C), Pentraxin 3 (PTX3) and Procalcitonin (PCT) values, which were selected by systematic review, were measured before initial treatment in each group. Results: TN-C; 99.8±41.05 ng/ml in Group 1, 118.0±71.4 ng/ml in Group 2 and 183.0±25.0 ng/ml in Group 3. The TN-C level of Group 3 was significantly higher than that of all the others (p Conclusions: It may be possible to predict treatment-resistant KD cases with high sensitivity and specificity by combining the measurement from the universal biomarkers, TN-C, PTX3 and PCT, before initial treatment.

Background: Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy. Although it is associated with high morbidity and mortality, the related ion channel gene variants in children have not been fully investigated. This study aimed to elucidate the ion channel genetic landscape of LVNC and identify genotype-phenotype correlations in a large Japanese cohort. Methods: We enrolled 206 children with LVNC from 2002 to 2017 in Japan. LVNC was classified as follows: LVNC with congenital heart defects, arrhythmia, dilated phenotype, or normal function. In the enrolled patients, 182 genes associated with cardiomyopathy were screened using next-generation sequencing. Results: We identified 99 pathogenic variants in 40 genes in 87 patients. Of the pathogenic variants, 8.8% were in genes associated with channelopathies, 27% were in sarcomere genes, and 11.5% were in mitochondrial genes. Ion channel gene variants were mostly associated with the arrhythmia classification, whereas sarcomere and mitochondrial gene variants were associated with the dilated phenotype. Echocardiography revealed that the group with ion channel gene variants had almost normal LV ejection fraction and LV diastolic diameter Z scores. Fragmented QRS, old age, and an arrhythmia phenotype were the most significant risk factors for ventricular tachycardia ( P =0.165, 0.0428, and 0.0074, respectively). Moreover, the group with ion channel variants exhibited a greater risk of a higher prevalence of arrhythmias such as ventricular tachycardia, rather than congestive heart failure. Conclusions: This is the first study that focused on genotype-phenotype correlations in a large pediatric LVNC patient cohort with ion channel gene variants that were determined using next-generation sequencing. Ion channel gene variants were strongly correlated with arrhythmia phenotypes. Genetic testing and phenotype specification allow for appropriate medical management of specific LVNC targets.

Cardiomyocytes derived from induced pluripotent stem cells (iPSC) are used to evaluate the function and risk factors of genetic variations linked to congenital and adult heart diseases in human beings. Our purpose in this study was to establish an in vitro cardiac disease model from an immortalized B-cell line stock using patient-specific iPSC-derived cardiomyocytes. Long QT syndrome (LQTS) 3 is caused by a gain-of-function mutation in the SCN5A gene, resulting in a prolonged QT interval as well as the development of early after-depolarizations (EADs). We generated LQT3-iPSC lines from immortalized B-cell lines transformed from peripheral blood obtained from a 24-day-old male (patient #1) and an 11-year-old female (patient #2), both diagnosed with type-3 LQTS due to SCN5A missense mutation (patient #1: exon 28, G4868A, R1623Q; patient #2: exon 20, G3578A, R1193Q). Several control iPSC lines were also created from samples collected from healthy candidates (26–36-year-old male and female). In both the generated patient iPSC lines, mutated genes were not altered after reprogramming, and normal karyotypes were observed. The pluripotency of all these iPSC lines was proven by in vivo teratoma formation and the expression of pluripotent stem cell marker genes and proteins. To evaluate the electrophysiological properties at the multicellular level, we studied the iPSC-derived cardiac cell layers with a microelectrode array mapping system (MED 64, Alpha MED Scientific Inc.). The recorded extracellular electrograms were analyzed to measure the field-potential duration (FPD), which was normalized to account for variations in beating frequency, using Fridericia’s correction (FPDcF, analogous to the QTc interval in the electrocardiogram). FPDcF was observed to be longer in LQT3 patient-derived specimens when compared to that in healthy control specimens (patient #1: P < 0.05, N = 17 and patient #2: P < 0.0001, N = 19 when compared to healthy control N = 39). Moreover, EADs were observed in both LQT3 patient specimens after 15–30 nM of E-4031 was added exclusively to patient samples. The results indicated that LQT3 patient iPSC-derived cardiac cells expressed prolonged QT duration (a common pathophysiological feature of LQTS) and EAD development with marked arrhythmogenicity in our in vitro disease model system.

The incidence of endometrial serous carcinoma (ESC) has been increasing, and ESC is resistant to treatment. We report a patient with ESC who responded to radiotherapy for multiple recurrences. The first recurrence was detected in the vaginal wall and left internal iliac lymph node 5 months after the initial treatment. Concurrent chemoradiotherapy (CCRT) was administered. Radiation was delivered using the intensity modulated radiation therapy technique. The second recurrent tumor was detected in the right internal iliac lymph node after 4 months, and CCRT was conducted. After 4 months, the third recurrence was detected in the right common iliac node, and CCRT was performed. After 8 months, the fourth recurrence was detected in the horizontal portion of the duodenum, and radiotherapy was administered. After 9 months, the fifth recurrence was detected in the vaginal wall. Interstitial brachytherapy was conducted. Grade 2 gastrointestinal injury, nausea and radiodermatitis were observed. During the subsequent 13-month follow-up, there has been no recurrence. Although ESC is resistant to treatment, radiotherapy could be effective in some cases. Even when multiple recurrences occur, radiotherapy may be considered a treatment option if the irradiation level is permissible.

Background Kawasaki disease (KD), a systemic vasculitis, is suspected to be related to abnormalities in innate immunity. Based on the important role of IL-1 signaling in innate immunity, we investigated the effects of an anti-IL-1β antibody using a Candida albicans water-soluble fraction (CAWS)-induced mouse model of KD. Methods CAWS (0.5 mg/mouse) was injected intraperitoneally into 5-week-old DBA/2 mice on five consecutive days. An anti-Murine IL-1β antibody (01BSUR) was administered at various doses (2.5, 5.0, and 10.0 mg/kg) and time points (2 days before, same day, and 2, 5, 7, and 14 days after CAWS administration). After 4 weeks, vasculitis in the aortic root was investigated histologically. Cytokines including IL-1β, -6, -10, and TNF-α were also measured. Results Groups administered 01BSUR at all doses showed a significant reduction in the area of vasculitis. In addition, 01BSUR inhibited vasculitis until 7 days after CAWS administration. In the analysis of various time points, the level of IL-6 was lower in all groups compared to the CAWS only group, but the levels of IL-1β, TNFα, and IL-10 were lower when 01BSUR was administered before CAWS. On the other hand, TNFα and IL-10 levels were restored when 01BSUR was administered after CAWS, suggesting that 01BSUR may have additional effects beyond blocking IL-1β signaling. Conclusions The anti-IL-1β antibody significantly attenuated CAWS-induced vasculitis. The mechanism of inhibiting vasculitis is thought to include inhibition of the IL-1β pathway and additional effects beyond blocking IL-1β signaling.

BACKGROUND Tenascin-C (TN-C) is an extracellular matrix glycoprotein that is heavily upregulated at sites of inflammation. We conducted a retrospective study to assess the utility of TN-C as a novel biomarker to predict the risk of developing coronary artery lesions (CAL) and resistance to intravenous immunoglobulin (IVIG) in patients with Kawasaki disease (KD).Methods and Results:We collected blood samples of 111 KD patients (IVIG-responder: 89, IVIG-resistant: 22; CAL: 8) and 23 healthy controls, and measured the serum levels of TN-C. TN-C levels on admission were significantly higher in patients than in healthy controls and in patients during convalescence after IVIG administration (69.6 vs. 20.4 vs. 39.7 ng/ml, respectively; P

Background: Kawasaki disease (KD) is a systemic vasculitis and the leading cause of acquired heart disease. There are some cases that show unresponsiveness to initial intravenous immunoglobulin (IVIG) and require addition treatment. High incidence of coronary artery lesions (CAL) is seen in unresponsive cases. Pentraxin 3 (PTX3) is produced at the site of vascular inflammation, and used as a new biomarker for vasculitis. The aim of this study is to explore the application of PTX3 to KD. Methods: 128 patients with KD are enrolled. Blood samples are collected at before IVIG and 1, 3, 6 month later from the onset of KD. PTX3 values are compared with IVIG unresponsive scoring system by Kobayashi et al. (Circulation, 2006). Results: Mean values of PTX3 before IVIG and 1, 3, 6 month were respectively 25.1*, 7.1*, 3.8, 3.6 ng/ml (asterisk shows statistical significance with age-matched control: 3.6). Mean values of PTX3 in unresponsiveness (n=20) and responsiveness (n=108) at before IVIG and 1, 3, 6 month were 46.8* vs. 20.9, 9.1* vs. 6.7, 4.2 vs. 3.7, 3.9 vs. 3.5 ng/ml (asterisk shows statistical significance between two groups). There is statistical positive correlation between PTX3 and score points by Kobayashi et al. (r=0.602, p=0.000). According to the statistical analysis, the area under the ROC curve (AUC) was 0.87 and sensitivity and specificity of PTX3 as IVIG unresponsiveness prediction were 90 and 81 %, if cut off value was set as 28 ng/ml. Conclusions: 1. vasculitis continues at least 1 month after onset of disease. 2. PTX3 can be a candidate biomarker for prediction of unresponsiveness in patients with KD.