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Jade Winjei Hwang,1 Shao Ju Chien,2 Chih-Chi Wang,3 Kuang-Che Kuo,4 Kuo-Shu Tang,5 Yu Lee,1 Yi-Chun Chen,6 Mao-Hung Lo,2 Ing-Kit Lee,6 Seng-Kee Chuah,7 Chien-Te Lee,8 Chia-Te Kung,9 Liang-Jen Wang10 1Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 2Division of Pediatric Cardiology, Kaohsiung Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kaohsiung, 83301, Taiwan; 3Division of General Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 4Division of Pediatric Infection, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan; 5Division of Pediatric Emergency, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan; 6Division of Infectious Disease, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 7Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 8Department of Nephrology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 9Department of Emergency, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 10Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, TaiwanCorrespondence: Liang-Jen Wang, Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Ta-Pei Road, Kaohsiung, Taiwan, Tel +886-7-7317123 Ext 8753, Fax +886-7-7326817, Email wangliangjen@gmail.comBackground: Vaccinating adolescents is a vital strategy to enhance population protection without imposing overly restrictive measures on our daily lives during the COVID-19 pandemic. As teenagers gain more independence, their willingness to get vaccinated may depend on their own understanding of the pandemic, vaccines, and mental well-being, as well as that of their caregivers. Our study aimed to examine how Taiwanese adolescents and their caregivers perceive COVID-19 vaccination and assess their mental health status.Methods: We invited a total of 138 vaccinated adolescents and their caregivers to complete several questionnaires, including the Drivers of COVID-19 Vaccination Acceptance Scale (DrVac-COVID19S), Impact of Event Scale (IES), and Chinese Health Questionnaire (CHQ).Results: Among the adolescents, 76.8% considered the BNT162b2 vaccine (Pfizer-BioNTech) as the ideal option for COVID-19 vaccination, while 27.5% of caregivers expressed acceptance of any available vaccine. Adolescents scored higher than caregivers in terms of vaccine value (p< 0.001) and autonomy (p< 0.001), but lower in knowledge (p< 0.001), as assessed by the DrVac-COVID19S subscales. The adolescents’ intention to get vaccinated against COVID-19 (DrVac-COVID19S total score) showed a positive correlation with their perception of the pandemic’s impact (IES scores, r=0.214, p=0.012) and their caregivers’ vaccination intention (r=0.371, p< 0.001). Furthermore, adolescents’ mental health demonstrated a positive association with the mental health of their caregiver (CHQ total scores, r=0.481, p< 0.001).Conclusion: During the COVID-19 outbreak, caregivers have encountered heightened levels of mental stress, and this stress has been found to be positively correlated with the mental stress experienced by adolescents and their intentions regarding vaccination. These findings can serve as crucial references for healthcare providers and governments when formulating vaccination policies for adolescents in the future.Keywords: adolescent, autonomy, caregivers, vaccine, psychosomatic, SARS-Cov-2

Motion mode (M-mode) echocardiography is essential for measuring cardiac dimension and ejection fraction. However, the current diagnosis is time-consuming and suffers from diagnosis accuracy variance. This work resorts to building an automatic scheme through well-designed and well-trained deep learning to conquer the situation. That is, we proposed RAMEM, an automatic scheme of real-time M-mode echocardiography, which contributes three aspects to address the challenges: 1) provide MEIS, the first dataset of M-mode echocardiograms, to enable consistent results and support developing an automatic scheme; For detecting objects accurately in echocardiograms, it requires big receptive field for covering long-range diastole to systole cycle. However, the limited receptive field in the typical backbone of convolutional neural networks (CNN) and the losing information risk in non-local block (NL) equipped CNN risk the accuracy requirement. Therefore, we 2) propose panel attention embedding with updated UPANets V2, a convolutional backbone network, in a real-time instance segmentation (RIS) scheme for boosting big object detection performance; 3) introduce AMEM, an efficient algorithm of automatic M-mode echocardiography measurement, for automatic diagnosis; The experimental results show that RAMEM surpasses existing RIS schemes (CNNs with NL & Transformers as the backbone) in PASCAL 2012 SBD and human performances in MEIS.

Background: We evaluated the outcomes of pregnancy in women with congenital heart disease (CHD) and their offspring in Taiwan. We also investigated how different severity levels may influence the outcomes., Methods: We used data (2009-2017) from the Birth Certificate Application database in Taiwan, which is linked to the National Health Insurance Research Database and Taiwan Maternal and Child Health Database. We identified 2990 women with CHD who had 4227 births. Based on the CHD subtypes, patients were further divided into "severe CHD" and "simple CHD" groups., Results: Women with CHD have a significant risk of stillbirth. In maternal cardiac events, they had the highest risk of heart failure, followed by arrhythmia. The severity of CHD had a significant effect on the outcomes as well. The neonatal birth event that mothers with CHD have the highest risk of is preterm birth at < 32 weeks of gestation. The prominent difference in neonatal morbidities between mothers with severe and simple CHD is recurrent CHD in the offspring. The offspring of the severe CHD group had a higher risk of severe CHD, whereas those of the simple CHD group had a higher risk of simple CHD., Conclusion: During pregnancy, the monitoring of heart function and cardiac rhythm could be more intensive in mothers with CHD. In addition to accurately assessing fetal growth and development during antenatal care, mothers with severe CHD should be provided with careful fetal heart structure assessment and genetic testing along with counseling., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background/aims: Childhood-onset hypertension is associated with cardiovascular morbidity and adult mortality. This study aimed to assess guideline-adherent hypertension among Taiwanese youth and the agreement on hypertension between the 2017 American Academy of Pediatrics guidelines and the 2004 Fourth Report., Methods: In this cross-sectional study, we collected outpatient blood pressure (OBP) measurements obtained during routine care visits from a large healthcare delivery system between 2009 and 2018 to evaluate the rate of guideline-adherent hypertension and assess patient-related factors of pediatric hypertension., Results: In total, 12,469 children and adolescents who underwent three separate ≥3 OBP measurements over 33,369 person-years with a total of 95,608 BP measurements in an outpatient setting were analyzed. According to the 2017 American Academy of Pediatrics (AAP) guidelines, the rate of pediatric hypertension in the study setting, which included participants aged 1 to 17 years, ranged from 0.78 to 5.95 per 1000 persons. Although there was perfect agreement between the thresholds of the two guidelines for defining hypertension in the age groups of 1-7, 8-12, and 13-17 years (all κ statistic ≥ 0.85), the use of the AAP threshold classified more adolescents as having hypertension. Children and adolescents with hypertension often had complex chronic diseases and required substantial healthcare services in outpatient, emergency, and inpatient settings., Conclusions: The present study provides evidence of guideline-adherent pediatric hypertension and highlights the importance of regularly monitoring blood pressure to identify and manage hypertension in children and adolescents. Further research is required to determine the impact of new thresholds on the detection of target organ damage at a pediatric age., Competing Interests: The authors declare no conflicts of interest.

Background: Infective endocarditis (IE) is an important cause of morbidity and mortality in pediatric patients with heart disease. Little literature has explored differences in the presentation of endocarditis in children with and without heart disease. This study aimed to compare the clinical outcomes and determine the risk of in-hospital death in the study population., Methods: Data were retrospectively collected from 2001 to 2019 from the Chang Gung Research Database (CGRD), which is the largest collection of multi-institutional electronic medical records in Taiwan. Children aged 0-20 years with IE were enrolled. We extracted and analyzed the demographic and clinical features, complications, microbiological information, and outcomes of each patient., Results: Of the 208 patients with IE, 114 had heart disease and 94 did not. Compared to those without heart disease, more streptococcal infections (19.3% vs. 2.1%, p < 0.001) and cardiac complications (29.8% vs. 6.4%, p < 0.001) were observed in patients with heart disease. Although patients with heart disease underwent valve surgery more frequently (43.9% vs. 8.5%, p < 0.001) and had longer hospital stays (28.5 vs. 12.5, p = 0.021), their mortality was lower than that of those without heart disease (3.5% vs. 10.6%, p = 0.041). Thrombocytopenia was independent risk factor for in-hospital mortality in pediatric patients with IE (OR = 6.56, 95% CI: 1.43-40.37)., Conclusion: Among pediatric patients diagnosed with IE, microbiological and clinical features differed between those with and without heart disease. Platelet counts can be used as a risk factor for in-hospital mortality in pediatric patients with IE.

The vaccination of all children may be one of the most important public health measures for preventing a wider spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the community. Therefore, the purpose of this study was to investigate the attitude, intention, decision making, and psychological well-being among the caregivers of children who received SARS-CoV-2 vaccination in Taiwan. The caregivers of children (98 preschool children, 191 school-age children, and 154 adolescents) who received COVID-19 vaccination were invited to fill in the following questionnaires: Adopting Self-Protective Behavior Scale, Drivers of COVID-19 Vaccination Acceptance Scale, Impact of Event Scale, Chinese Health Questionnaire, and Parental Bonding Instrument. Compared to the caregivers of adolescents, the caregivers of preschool children exhibited more protective behaviors toward the COVID-19 pandemic. The caregivers of preschool children also displayed a higher emotional impact than those of adolescents and took a greater interest in the family's opinion about vaccination. Finally, we found that COVID-19 ideological invasion and protective parenting style were significantly related to the prevalence of mental illness among caregivers. The results of this study can be used as an important reference for vaccination health care and policy formulation for adolescents with regard to COVID-19.

Background/purpose: This study investigated the demographic characteristics and influenza complications of paediatric patients and explored the association of different influenza virus types and viral and bacterial coinfections with disease severity., Methods: This retrospective cohort study used data collected in 2010-2016 from the Chang Gung Research Database (CGRD), the largest collection of multi-institutional electronic medical records in Taiwan. Data were retrieved for children aged 0-18 years with laboratory-confirmed influenza. We extracted and analysed the demographic characteristics and the data on clinical features, complications, microbiological information, and advanced therapies of each case., Results: We identified 6193 children with laboratory-confirmed influenza, of whom 1964 (31.7%) were hospitalised. The age of patients with influenza A infection was lower than that of patients with influenza B (4.48 vs. 6.68, p < 0.001). Patients with influenza B infection had a higher incidence of myositis or rhabdomyolysis (4.4%, p < 0.001) and a higher need for advanced therapies (OR, 1.96; 95% CI, 1.32-2.9, p < 0.001). In addition to bacterial (OR, 9.07; 95% CI, 5.29-15.54, p < 0.001) and viral coinfection (OR, 7.73; 95% CI, 5.4-11.07, p < 0.001), dual influenza A and B infection was also a risk factor for influenza complications (OR, 2.13; 95% CI, 1.47-3.09, p < 0.001)., Conclusion: Dual influenza A and B infection and bacterial coinfection can contribute to influenza complications. Early recognition of any influenza complication is critical for the timely initiation of organ-specific advanced therapies to improve influenza-associated outcomes., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

The effects of anonymity on utilization review has never been examined in the real world. This study aimed to evaluate the impact of removing anonymity protection for claims reviewers on their review decisions. Using a single-blinded repeated measures design, we randomly selected 1457 claims cases (with 12,237 orders) that had been anonymously reviewed and reimbursed in 2016 and had them re-reviewed in a signed review program in 2017 under the Taiwanese National Health Insurance scheme. The signed review policy significantly decreased the likelihood of a deduction decision at the case and the order level (P < 0.001). Furthermore, signed reviewers tended to make more "too lenient" decisions, and were less likely to make "too harsh" decisions. Removing anonymity protection dramatically reduced the deduction rate and overturned the tendency of decisions from "too harsh" to "too lenient". However, whether to maintain the anonymity of utilization reviews is a challenge for health authorities around the globe., (© 2022. The Author(s).)

Objectives: Objective structured clinical examinations (OSCEs) are common for formative assessment. We developed an Online Smart Communicative Education System and aimed to explore the factors that affect the perceptions of both teachers and students for teaching and learning., Methods and Analysis: A two-year cross-sectional cohort study was undertaken. The program includes three parts. Part I Pre-OSCE: an online flipped class in preparation for task-related knowledge and skills. Part II OSCE-day: 10 tasks in one track formative OSCE. Part III Post-OSCE: extended online feedback for participants with further questions after the exam and raters with more feedback after reviewing their performance online. Principal component analysis with varimax rotation was performed to analyze the perceptions of students and teachers to the Online System by means of questionnaires., Results: Seventy-six pharmacy students (male 32.9%) took the exam and 24 raters (male, 25%) participated in the scoring during the OSCEs. The mean G coefficient was 0.88. Seventy-six questionnaires from the students were obtained for the analysis. Results explained the cumulative variance of 73.9% for component (1) "Effects of extended online feedback" : 40% and ( 2) "Facilitation of learning" : 33.9%. Thirty-nine questionnaires from the raters who experienced the Online System were obtained for the analysis (male 23.1%). Results explained a cumulative variance of 77.3% for component (1) "Effects of extended online feedback" : 36.6%, ( 2) "Facilitation of scoring and feedback" : 24.5%, and ( 3) "Feasibility of online platform" : 16.2%, respectively., Conclusion: We demonstrated good reliability for digitizing the scoring system with educational support to facilitate teaching. "Effects of extended online feedback" was the major aspect in explaining the variance from the perceptions of students and raters by factor analysis. In comparison with traditional formative OSCEs, extended online feedback is a novel approach, which extends the process of learning and teaching among the learners and raters and overcomes the barriers of time limitation and distance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Wang, Hsu, Lee, Kang, Monrouxe, Chien and Chen.)

Recent studies emphasize the importance of 5-HT2C receptor (5-HT 2C R) signaling in the regulation of energy homeostasis. The 5-HT 2C R is the only G-protein-coupled receptor known to undergo post-transcriptional adenosine to inosine (A-to-I) editing by adenosine deaminase acting on RNA (ADAR). 5-HT 2C R has emerged as an important role in the modulation of pancreatic β cell functions. This study investigated mechanisms behind the effects of palmitic acid (PA) on insulin secretion in different overexpressed 5-HT 2C R edited isoforms in pancreatic MIN6 β cells. Results showed that the expressions of 5HT 2C R and ADAR2 were upregulated in the pancreatic islets of mice fed with high-fat diet (HFD) compared to control mice. PA treatment significantly induced the expressions of 5-HT 2C R and ADAR2 in pancreatic MIN6 β cells. PA treatment significantly induced the editing of 5-HT 2C R in pancreatic MIN6 β cells. There was no significant difference in cell viability between naïve cells and three overexpressed 5-HT 2C R edited isoforms in pancreatic MIN6 β cells. Overexpressed 5-HT 2C R edited isoforms showed reduced glucose-stimulated insulin secretion (GSIS) compared with green fluorescent protein (GFP) expressed cells. Moreover, 5-HT 2C R edited isoforms displayed reduced endoplasmic reticulum (ER) calcium release and store-operated calcium entry (SOCE) activation, probably through inhibition of stromal interaction molecule 1 trafficking under PA treatment. Altogether, our results show that PA-mediated editing of 5-HT 2C R modulates GSIS through alteration of ER calcium release and SOCE activation in pancreatic MIN6 β cells., (© 2021 Federation of American Societies for Experimental Biology.)

Background: The objective of this research was to evaluate the fertility of Taiwanese women with diagnoses of congenital heart diseases (CHDs). The study also investigated how different forms of CHDs may have variously influenced fertility. Methods: We directed this nationwide, population-based and retrospective matched-cohort research by using data from the Taiwan National Health Insurance Research Database. The CHD group ( n = 6602) included women with congenital structural heart diseases, aged 16-45 years in 2000. The non-CHD group ( n = 6602) was matched according to urbanization and income. The outcomes, involving live birth, abortion, and fertility rates, were followed until the end of 2013. Poisson regression was used to evaluate the incidence rate ratios (IRRs). Results: The CHDs had an inferior rate of live births (IRR 0.74 [95% CI 0.71-0.78]) than the non-CHD group. There was also a lower fertility rate in the CHD group (IRR 0.81 [95% CI 0.78-0.84]) than the non-CHD group. Abortion rates between the two groups were similar. Conclusion: Congenital structural heart disease compromises female fertility, even among patients with simple forms of CHDs. It is suggested that pregnant patients with CHDs are early appeared to and advised personally with multidisciplinary care to improve their outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chien, Lin, Lo, Huang and Yang.)

Background: Attention-deficit/hyperactivity disorder (ADHD) has been linked to pediatric asthma patients treated with montelukast. This study is the first to use a nationwide health insurance research database (NHIRD) to study whether asthmatic children using montelukast are at an increased risk of ADHD., Methods: We used data from the Taiwan NHIRD, which is a longitudinal database of one million randomly selected subjects. The enrolled patients were followed up until 2013. Patients younger than and equal to 12 years old with new-onset asthma (ICD-9 CM code 493.X) diagnosed between 1997 and 2013 were enrolled. A multivariate Cox regression analysis was conducted to evaluate the association between montelukast treatment and the risk of ADHD (ICD-9-CM code 314.X)., Results: We enrolled a total of 54,487 asthmatic children younger than and equal to 12 years old who had at least one claim of inpatient admission or at least three claims of an ambulatory visit. Montelukast users and match controls were identified by matching age, gender, residence, the comorbidities including allergic rhinitis and atopic dermatitis, admission or emergency department visits due to asthma attack, and index date of starting montelukast in a 1:1 ratio, with 12,806 in the montelukast group and 12,806 in the non-montelukast group. The montelukast group had a similar risk of ADHD (n = 632, 4.94%) as the non-montelukast group (n = 610, 4.76%) [adjusted hazard ratio 1.04; 95% confidence interval, 0.93 to 1.17]. In children treated with montelukast, high cumulative days of montelukast use did not increase the risk of ADHD., Conclusion: This nationwide population-based cohort study reveals that asthma children treated with montelukast were not at an increased risk of developing ADHD. Nevertheless, validation of our retrospective survey requires further prospective study., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article, (Copyright © 2020 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Dome formation can occur in cultured tubular epithelial cells originating from various tissues, including the mammary gland and the kidney. The isolation and characterization of normal kidney epithelial stem cells that give rise to dome-forming tubular cells have never been reported. We attempted to isolate and characterize canine kidney epithelial stem cells using a simple cell culture method that we have previously used to isolate other adult human stem cells. Dome-forming kidney epithelial cells were derived from dissociated adult canine kidney tissues that were cultured in a modified keratinocyte serum-free medium supplemented with N -acetyl-l-cysteine, l-ascorbic acid 2-phosphate, nicotinamide, and fetal bovine serum. These cells exhibited high self-renewal capacity in long-term culture (growth for >13 months and 30 cumulative population doublings) and exhibited characteristics of stem cells, including (1) deficiency in gap junctional intercellular communication, (2) anchorage-independent growth, (3) expression of stem cell markers octamer-binding transcription factor 4 and SRY (sex determining region Y)-box 2, (4) expression of cell surface markers CD24 and CD133, and (5) multipotent differentiation into osteoblasts, adipocytes, chondrocytes, and dome-forming tubular cells. Most of these characteristics are shared by the well-known canine renal tubule-derived immortalized Madin-Darby Canine Kidney cell line. Furthermore, the putative canine kidney stem cells developed in this study formed budding tubule-like organoids on Matrigel and required high cell density (>4,000 cells/cm 2 ) for sustained growth and confluency for dome formation. The signal transducer and activator of transcription-3 (STAT3) phosphorylation inhibitor, AG490, inhibited colony-forming efficiency and dome formation, whereas lipopolysaccharide, an activator of STAT3, increased colony-forming efficiency in a dose-dependent manner. These results are consistent with the hypothesis that high cell density induces STAT3 expression, which promotes both stem cell self-renewal and differentiation into tubular cells. Our novel cell culture method should be useful for the future development of normal human kidney stem cells for clinical applications and for studying mechanisms of nephrotoxicity.

Background: Extracorporeal membrane oxygenation (ECMO) is widely used in patients with potentially reversible acute cardiac and/or pulmonary failure who are unresponsive to conventional treatment. Patients with profound left ventricular (LV) dysfunction under venous-arterial (V-A) ECMO may experience LV distention, pulmonary edema, and thrombus formation. It is critical to unload the left ventricle to prevent such complications. The aim of this study was to identify the risks, timing and methods of LV decompression in pediatric peripheral ECMO., Methods: Between August 2006 and November 2017, 51 patients received peripheral ECMO support in our pediatric intensive care unit. All of them were less than 18 years of age and non-cardiotomy surgery-related. We retrospectively reviewed the patients' clinical presentations, decompression methods and outcomes., Results: The overall success rate of ECMO removal was 76.5% (39/51), and the survival rate after discharge was 62.7% (32/51). The myocarditis group had the most favorable outcomes among the ECMO patients (100% survival). LV decompression was needed in 12 patients who had profound LV dysfunction under V-A ECMO. Five patients received medical treatment successfully, and the other 7 patients underwent intra-aortic balloon pump (IABP) procedures. In the IABP group, 1 patient still needed further pigtail-decompression. All of our decompression patients survived with good neurological outcomes (Glasgow Outcome Scale 5)., Conclusions: The patients with profound LV dysfunction under peripheral VA ECMO were at risk of thromboembolic events and LV decompress was needed. If medical decompression fails, IABP is a feasible approach for LV decompression in pediatric peripheral ECMO.

Introduction: Onsite scoring is common in traditional OSCEs although there is the potential for an audience effect facilitating or inhibiting performance. We aim to (1) analyze the reliability between onsite scoring (OS) and remote scoring (RS); and (2) explore the factors that affect the scoring in different locations. Methods: A total of 154 students and 84 raters were enrolled in a single-site during 2013-2015. We selected six stations randomly from a 12-station national high-stakes OSCE. We applied generalisability theory for the analysis and investigated the perceptions that affected RS scoring. Results: The internal consistency reliability Cronbach's α of the checklists was 0.92. The kappa agreement was 0.623 and the G value was 0.93. The major source of variance comes from the students themselves, but some from locations and raters. The three-component analysis including Technical Feasibility , Facilitates Wellbeing , and Observational and Attention Deficits explained 73.886% of the total variance in RS scoring. Conclusions: Our study has demonstrated moderate agreement and good reliability between OS and RS ratings. We validated the factors of facility operation and quality for RS raters. Remote scoring can provide an alternative forum for the raters to overcome the barriers of distance, space, and avoid the audience effect.

Background/purpose: To investigate the correlations among endothelial function assessment parameters, asymmetric dimethylarginine (ADMA)-related biomarkers, and traditional risk factors in adipose children., Methods: We enrolled adipose children aged 7-18 years between July 2014 and August 2016 as well as normal-weight controls from the outpatient clinic. Vascular measurements including echocardiography, carotid intima media thickness, pulse wave velocity (PWV), and flow-mediated dilation (FMD) were measured. Venous blood samples including traditional metabolic and endothelial dysfunction parameters were analyzed. Participants were grouped as adipose vs. normal-weight and as adipose with hypertension vs. adipose without hypertension. Clinical presentations, laboratory data, and cardiovascular measurement were compared., Results: Of the 105 enrolled children, 85 were adipose. Adipose children had higher systolic blood pressure, larger left ventricular (LV) mass, and adverse traditional metabolic biomarkers. FMD was significantly reduced (8.25 (5.32-12.06) % vs. 12.49 (7.18-16.58) %, p = 0.018) in the adipose group. PWV was markedly increased (4.65 (4.2-5.5) m/sec vs. 3.95 (3.38-4.35) m/sec, p < 0.001) in the hypertensive adipose children. Endothelial dysfunction parameters were not significantly changed in this study., Conclusion: Adipose children were at higher risk of hypertension and LV hypertrophy. FMD, PWV and traditional cardiovascular biomarkers can detect subtle vascular changes. Hypertension is an important sign of arterial involvement in adipose children. Although ADMA-related biomarkers were not statistically significant, future studies are needed to confirm its correlation with adiposity and hypertension in children. The early detection and prevention of endothelial dysfunction may decrease the rate of progression to cardiovascular consequences in later life., (Copyright © 2018. Published by Elsevier B.V.)

Porphyromonas (P.) gingivalis infection leading to the periodontitis has been associated with the development of systemic diseases, including cardiovascular diseases and diabetes. However, the effect of a high concentration of glucose (HG) on the invasion efficiency of P. gingivalis and the consequent modulation of pathogenesis in vascular cells, especially in the vascular smooth muscle cells (VSMCs), remains unclear. Hence, the aim of this study was to investigate whether treating P. gingivalis with HG could change its invasion capability and result in VSMC calcification and the underlying mechanism. Human aortic SMCs (HASMCs) and P. gingivalis strain CCUG25226 were used in this study. We found that HGPg infection of HASMCs could initiate the HASMC calcification by stimulating the autocrine regulation of bone morphogenetic protein (BMP) 4 in HASMCs. The upregulation of BMP4 expression in HASMCs was mediated by toll-like receptor 4 and ERK1/2-p38 signaling after P. gingivalis infection. Moreover, the autocrine action of BMP4 in HGPg infection-initiated HASMC calcification upregulated BMP4-specific downstream smad1/5/8-runx2 signaling to increase the expressions of bone-related matrix proteins, that is, osteopontin, osteocalcin, and alkaline phosphatase. This study elucidates the detailed mechanism of HGPg infection-initiated calcification of HASMCs and indicates a possible therapeutic role of BMP4 in P. gingivalis infection-associated vascular calcification., (© 2017 Wiley Periodicals, Inc.)

Although Numb is well-recognized as a cell-fate determinant in stem/progenitor cells, accumulating evidence supports that Numb also has a critical role in adult tissues and cancers, in particular, in the context of regulation of tumor suppressor p53. Herein, we identified Numb as a novel substrate of Polo-like kinase 1 (Plk1). Of significance, we showed that Plk1-mediated phosphorylation of Numb leads to its enhanced proteasomal degradation and impaired Numb/p53 pathway, thus providing another mechanism how Plk1 antagonizes p53 during DNA damage response. In addition, the novel phosphorylation event identified by us further supports the notion that post-translational modifications of Numb uncouple Numb from p53 and lead to p53 destabilization. Finally, our data generated from both human cancer cell lines and mouse xenograft model showed that cancer cells carrying the unphosphorylated form of Numb by Plk1 are more sensitive to doxorubicin, a classical chemotherapeutic drug. Therefore, our work may provide future strategies for improving the efficacy of chemotherapy by targeting Numb phosphorylation by Plk1.

Background/purpose: To investigate mid- to long-term outcomes in children with coronary artery fistula (CAF)., Methods: We retrospectively reviewed the medical records of patients seen between September 1996 and August 2011. We enrolled those diagnosed with CAF via echocardiography (Philips SONOS 7500 system and Philips IE33) or angiography. The mean follow time was 42.58 ± 3.4 months (range, 1-166 months). For comparative purposes, participants were grouped as acquired versus congenital, and symptomatic versus asymptomatic. We also measured the size of the coronary artery (CA) in patients with CA dilatation (CAD)., Results: Out of 122 CAF patients, spontaneous closure was detected in 37 patients at 21.59 ± 3.45 months after diagnosis. This timeframe did not differ between the acquired and congenital groups (21.64 ± 6.26 months vs. 21.57 ± 4.15 months; p = 0.991). Ninety patients were asymptomatic and remained so; their spontaneous closure rate was 28.89%. Moreover, 24 patients had CAD, including 17 with Kawasaki disease and seven with congenital CAF. The CAs of all congenital-CAF-plus-CAD patients were initially > 5 mm; these patients underwent percutaneous transcatheter intervention, and their CA sizes decreased significantly (6.11 ± 0.79 mm vs. 3.76 ± 0.36 mm; p = 0.002)., Conclusion: With the advanced sensitivity of echocardiography, CAF can be detected more easily than ever before. Most patients with small CAFs are asymptomatic and may experience spontaneous closure. Therefore, management of CAF depends on symptoms; if patients are asymptomatic and have small CAFs, intervention may not be necessary, especially in acquired cases. However, if patients present with symptoms or persistent dilatation of the proximal CA, surgical or percutaneous closure should be performed., (Copyright © 2015. Published by Elsevier B.V.)

Arginine (ARG) and citrulline (CIT) are essential for nitric oxide (NO) synthesis. Their metabolites are interrelated, and involved in blood pressure (BP) control, chronic kidney disease (CKD), and cardiovascular disease (CVD). Although CVD is the leading cause of mortality in CKD, little is known about subclinical CVD in early-stage childhood CKD. Twenty-four-hour ambulatory BP monitoring and arterial stiffness assessment allows the earlier possible detection of subclinical CVD. We investigated whether urinary CIT and ARG metabolites and their ratios are correlated with BP load and vascular abnormalities in children and adolescents with early-stage CKD. We enrolled 55 pediatric patients with mild-to-moderate CKD. Seventy percent (30/43) had at least one out of BP load abnormality on ambulatory BP monitoring, mainly increased asleep systolic BP (SBP) load (40%), asleep SBP or diastolic BP load > 95th percentile (40%), and nocturnal SBP nondipping (35%). Low urinary CIT level and CIT/ARG ratio were associated with BP load abnormalities in children with early CKD. Urinary CIT/ARG ratio was correlated with arterial stiffness, represented as pulse-wave velocity and augmentation index. SBP and diastolic BP loads were negatively correlated with urinary CIT, ARG, asymmetric dimethylarginine (an endogenous NO synthase inhibitor), and CIT/ARG ratio, while positively associated with dimethylamine/asymmetric dimethylarginine ratio and pulse-wave velocity. Early assessments of BP load abnormalities, urinary biomarkers in the CIT-ARG-NO pathway, and arterial stiffness parameters should increase early preventive care toward decreasing hypertension and CV remodeling in pediatric CKD., (Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Increased numbers of eosinophils in the esophagus are common in several esophageal and systemic diseases, and a prominent feature of eosinophilic esophagitis. Mouse models can provide insight into the mechanisms of eosinophil infiltration and their pathogenic role. SHARPIN-deficient cpdm mice develop a chronic proliferative dermatitis and an esophagitis characterized by epithelial hyperplasia and the accumulation of eosinophils in the serosa, submucosa, lamina propria and epithelium of the esophagus. We conducted a detailed investigation of the pathogenesis of the esophagitis by light microscopy, immunohistochemistry, and gene expression as the mice aged from 4 to 10 weeks. The thickness of the esophageal epithelium and the number of eosinophils in the esophagus both increased with age. There were scattered apoptotic epithelial cells in mice at 6-10 weeks of age that reacted with antibodies to activated caspase 3 and caspase 9. The expression of CCL11 (eotaxin-1), IL4, IL13 and TSLP was increased in cpdm mice compared with wild type (WT) mice, and there was no change in the expression of CCL24 (eotaxin-2), IL5 and IL33. The expression of chitinase-like 3 and 4 (YM1 and YM2) proteins, markers of type 2 inflammation, was greatly increased in cpdm mice, and this was replicated in vitro by incubation of WT esophagus in the presence of IL4 and IL13. Immunohistochemistry showed that these proteins were localized in esophageal epithelial cells. The severity of the esophagitis was not affected by crossing SHARPIN-deficient mice with lymphocyte-deficient Rag1 null mice indicating that the inflammation is independent of B and T lymphocytes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Kawasaki disease shock syndrome (KDSS) and toxic shock syndrome (TSS) can present as shock and fever with skin rash, but the management of these 2 groups of patients is different. This report proposes to help clinicians earlier distinguish these 2 diseases and expedite institution of appropriate therapy., Methods: We retrospectively reviewed the medical records of patients admitted to the pediatric intensive care unit with the diagnosis of KDSS or TSS from January 2000 through December 2010. Clinical, laboratory and echocardiographic data were collected for analysis of differences between them., Results: Seventeen patients met the inclusion criteria of KDSS and 16 had a confirmed diagnosis of TSS. The mean age of the KDSS group was significantly younger than that of the TSS group (36.8 ± 41.1 vs. 113.3 ± 55.6 months, P < 0.001). Significantly lower hemoglobulin and age-adjusted hemoglobulin concentrations were noted in the KDSS group [Hb, age-adjusted Z score, -1.88 (range, -3.9 to 3.9) vs. 0.89 (range, -6.4 to 10.8), P = 0.006]. The median platelet count of the KDSS group was nearly twice that of the TSS group [312 × 10³ per μL (range, 116-518) vs. 184.5 × 10³ per μL (range: 31-629), P = 0.021]. Echocardiographic abnormalities, such as valvulitis (mitral or tricuspid regurgitation) and coronary artery lesions, were significantly more common in the KDSS group (P = 0.022)., Conclusions: Echocardiography, anemia and thrombocytosis are useful early differentiating features between KDSS and TSS patients.

Background: Homocysteine and pro-inflammatory mediators such as cyclooxygenase-2 (COX-2) have been linked to vascular dysfunction and risks of cardiovascular diseases. Fulvic acid (FA), a class of compounds of humic substances, possesses various pharmacological properties. However, the effect of FA on inflammatory responses of the monocytes remains unclear. We investigated the regulatory effect of FA on homocysteine-induced COX-2 expression in human monocytes., Methods: Peripheral blood monocytes and U937 cells were used for all experiments. Real-time PCR and ELISA assay were used to analyze the COX-2 mRNA expression and PGE2 secretion, respectively. Specific inhibitors were used to investigate the mechanism of homocysteine-mediating COX-2 mRNA expression and PGE2 secretion. Luciferase assay, transcription factor ELISA, and chromatin immunoprecipitation were used to determine the role of nuclear factor-κB in FA-mediated inhibition of homocysteine effect on monocytes., Results: The results show that pretreating monocytes with FA inhibited the homocysteine-induced COX-2 expression in a dose-dependent manner. Stimulation of U937 monocytes with homocysteine induced rapid increases in the phosphorylation of ERK and JNK; the inhibitor for ERK and JNK attenuated the homocysteine-induced nuclear factor-κB activation and COX-2 expression. Transcription factor ELISA and chromatin immunoprecipitation assays showed that FA blocked the homocysteine-induced increases in the binding activity and in vivo promoter binding of nuclear factor-κB in monocytes., Conclusions: Our findings provide a molecular mechanism by which FA inhibits homocysteine-induced COX-2 expression in monocytes, and a basis for using FA in pharmaceutical therapy against inflammation.

Background: Less attention has been paid to evaluating subclinical cardiovascular disease (CVD) in the early stage of pediatric chronic kidney disease (CKD). Ambulatory blood pressure monitoring (ABPM) and arterial stiffness are the earliest detectable assessments of subclinical CVD. Asymmetric dimethylarginine (ADMA) is an analog of L-arginine (ARG) that inhibits nitric oxide (NO) production; thus the ARG-to-ADMA ratio (AAR) is an index of NO. Homocysteine (HCY) is a risk factor for CVD and it can be metabolized to L-cysteine (CYS). Given that HCY and ADMA/NO are closely linked and related to hypertension, we therefore investigated whether ARG and HCY metabolites, arterial stiffness parameters, ABPM profile, and left ventricular hypertrophy (LVH) are interrelated in children and adolescents with early CKD., Methods and results: This cross-sectional study included 57 pediatric patients with CKD stages 1-3. Two-thirds of the children with CKD stages 1-3 exhibited BP abnormalities accessed by ABPM. Children with CKD stages 2-3 had higher HCY, but lower CYS levels. The plasma HCY level was increased in children with LVH and abnormal ABPM. Systolic BP positively correlated with biomarkers AAR, HCY, and CYS. LV mass positively correlated with AAR, HCY, and CYS., Conclusions: BP abnormalities were prevalent and associated with AAR, HCY, and CYS in children with early CKD. Our data highlighted the effect of NO and the HCY pathway on CKD-related hypertension.

Macrophage accumulation in the arterial wall and smooth muscle cell (SMC) proliferation are features of type 2 diabetes mellitus (DM) and its vascular complications. However, the effects of diabetic monocyte-derived macrophages on vascular SMC proliferation are not clearly understood. In the present study, we investigated the pro-proliferative effect of macrophages isolated from DM patients on vascular SMCs. Macrophage-conditioned media (MCM) were prepared from macrophages isolated from DM patients. DM-MCM treatment induced HASMC proliferation, decreased p21(Cip1) and p27(Kip1) expressions, and increased microRNA (miR)-17-5p and miR-221 expressions. Inhibition of either miR-17-5p or miR-221 inhibited DM-MCM-induced cell proliferation. Inhibition of miR-17-5p abolished DM-MCM-induced p21(Cip1) down-regulation; and inhibition of miR-221 attenuated the DM-MCM-induced p27(Kip1) down-regulation. Furthermore, blocking assays demonstrated that PDGF-CC in DM-MCM is the major mediators of cell proliferation in SMCs. In conclusion, our present data support the hypothesis that SMC proliferation stimulated by macrophages may play critical roles in vascular complications in DM patients and suggest a new mechanism by which arterial disease is accelerated in diabetes.

Adulthood hypertension can be programmed by corticosteroid exposure in early life. Oxidative stress, epigenetic regulation by histone deacetylases (HDACs), and alterations of renin-angiotensin system (RAS) are involved in the developmental programming of hypertension. We examined whether melatonin prevented neonatal dexamethasone (DEX)-induced programmed hypertension and how melatonin prevented these processes. We also examined whether HDAC inhibition by trichostatin A (TSA, a HDAC inhibitor) had similar effects. Male offspring were assigned to 5 groups (n=6/group): control, DEX, melatonin, DEX+melatonin, and DEX+TSA. Male rat pups were injected i.p. with DEX on day 1 (0.5mg/kg BW), day 2 (0.3mg/kg BW), and day 3 (0.1mg/kg BW) after birth. Melatonin was administered in drinking water at the dose of 0.01% during the lactation period. The DEX+TSA group received DEX and 0.5mg/kg TSA subcutaneous injection once daily for 1 week. All rats were killed at 16 weeks of age. Neonatal DEX exposure induced hypertension in male offspring at 16 weeks of age, which melatonin prevented. Neonatal DEX exposure decreased gene expression related to apoptosis, nephrogenesis, RAS, and sodium transporters. Yet DEX treatment increased protein levels of HDAC-1, -2, and -3 in the kidney. Melatonin therapy preserved the decreases of gene expression and decreased HDACs. Similarly, HDAC inhibition prevented DEX-induced programmed hypertension. In conclusion, melatonin therapy exerts a long-term protection against neonatal DEX-induced programmed hypertension. Its beneficial effects include alterations of RAS components and inhibition of class I HDACs. Given that the similar protective effects of melatonin and TSA, melatonin might inhibit HDACs to epigenetic regulation of hypertension-related genes to prevent programmed hypertension., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: This study aimed to investigate intima-media thickness (IMT) of the common carotid arteries in children with acute Kawasaki disease (KD)., Methods: Between 2009 and 2011, patients fulfilling the criteria for KD, including a fever lasting >5 days, were prospectively enrolled in this study. Laboratory data, echocardiography, and IMT were measured and compared with matched controls., Results: A total of 70 common carotid IMTs were measured in 35 children. We studied 21 patients aged 3-60 months old with acute KD and 14 febrile patients aged 3-194 months old with acute infection and similar characteristics to those of KD patients. Children with KD had a significantly higher IMT compared with the controls (0.550 ± 0.081 mm vs. 0.483 ± 0.046 mm, P = 0.01)., Conclusions: IMT during the acute stage of KD is increased, suggesting that IMT could be a useful diagnostic tool in the early diagnosis of KD.

Nitric oxide (NO) deficiency mediates oxidative stress in the kidney and is involved in the development of hypertension. NO synthesis occurs via 2 pathways: nitric oxide synthase (NOS) dependent and NOS-independent. We tested whether the development of hypertension is prevented by restoration of NO by dietary l-citrulline or nitrate supplementation in young spontaneously hypertensive rats (SHRs). Male SHRs and normotensive Wistar Kyoto control rats (WKYs)s age 4 weeks were assigned to 4 groups: untreated SHRs and WKYs, and SHRs and WKYs that received 0.25% l-citrulline for 8 weeks. In our second series of studies, we replaced l-citrulline with 1 mmol/kg/d sodium nitrate. All rats were sacrificed at age 12 weeks. We found an increase in the blood pressure of SHRs was prevented by dietary supplementation of l-citrulline or nitrate. Both treatments restored NO bioavailability and reduced oxidative stress in SHR kidneys. l-Citrulline therapy reduced levels of l-arginine and asymmetric dimethylarginine (ADMA)-an endogenous inhibitor of NOS-and increased the l-arginine-to-ADMA ratio in SHR kidneys. Nitrate treatment reduced plasma levels of l-arginine and ADMA concurrently in SHRs. Our findings suggest that both NOS-dependent and -independent approaches in the prehypertensive stage toward augmentation of NO can prevent the development of hypertension in young SHRs., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Nitric oxide (NO) deficiency contributes to hypertension. We previously showed that neuronal nitric oxide synthase (nNOS) was involved in hypertension and kidney damage in spontaneously hypertensive rats (SHRs). The protein inhibitor of nNOS (PIN) has been reported to inhibit activity of nNOS.Thus, we tested whether increased PIN in the kidney results in hypertension and whether small interfering RNA (siRNA) targeting PIN attenuates hypertension in SHRs. Four-week-old male SHRs were assigned into three groups (n = 6-7/group): SHR; SHR + PIN, SHR that received siRNA targeting PIN; and SHR + NC, SHR treated with random negative control siRNA. Rats were sacrificed at 12 weeks of age. PIN protein expression was inhibited considerably when PIN siRNA was transfected into NRK52E cells (90% siRNA at 1 nM). The increases of BP were attenuated by siRNA targeting PIN in 12-week-old SHRs. Immunostaining of nNOS-α and total nNOS was greater in SHR + PIN group than SHR. Moreover, renal superoxide production and 8-hydroxydeoxyguanosine (8-OHdG) staining were more decreased in the SHR + PIN group than SHRs. We conclude that PIN siRNA reduced PIN expression in vitro and in vivo. PIN siRNA therapy attenuates hypertension in SHRs at 12 weeks of age. Our results suggest that PIN is involved in the development of hypertension., (Copyright © 2014 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

What Is Known and Objective: Myocarditis that develops because of the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a life-threatening disease. We report a case of DRESS-associated myocarditis with cardiac failure that required extracorporeal membrane oxygenation (ECMO) for cardiovascular support., Case Summary: A 14-year-old boy experienced DRESS-associated myocarditis after anticonvulsive therapy with carbamazepine, clonazepam and phenytoin. The clinical signs included hypotension, cardiac arrhythmia and poor left ventricular (LV) performance. Laboratory investigations showed elevated levels of cardiac enzymes. Systemic corticosteroid pulse therapy for 3 days was administered for treating the DRESS syndrome. The patient required inotropic drugs including dopamine, dobutamine and milrinone because of refractory hypotension and poor LV function. He was placed on ECMO support, and intra-aortic balloon pumping was initiated because of poor response to inotropic drugs and stasis of blood flow in the ventricle on hospital day 17. Plasma exchanges for four separate times over 8 days were also performed during ECMO support on day 22. His condition stabilized 13 days after ECMO support was initiated. The patient was discharged on hospital day 50, and the seizure was controlled by the oral form clonazepam, phenobarbital, topiramate and levetiracetam. Three months later, an echocardiogram showed mild dilated cardiomyopathy., What Is New and Conclusion: Drug reaction with eosinophilia and systemic symptoms-associated fulminant myocarditis is a life-threatening disease. Traditionally, systemic corticosteroid administration, plasmapheresis, intravenous immunoglobulin infusion and ventricular assist device implantation have been used for the treatment of this disease. To our knowledge, this is the first case of DRESS-associated fulminant myocarditis treated successfully with ECMO support. However, echocardiogram should be followed regularly because dilated cardiomyopathy may be the late sequela., (© 2012 Blackwell Publishing Ltd.)

Objective: Small-bore pigtail catheters have been found to be effective in the treatment of primary spontaneous pneumothorax (PSP) in adults. The aim of this study was to compare the effectiveness of small-bore pigtail and large-bore catheters in the treatment of PSP in young adolescents., Materials and Methods: Young adolescents (<18 years) with initial PSP were treated with aspiration (control group), small-bore pigtail catheters or large-bore catheters. Treatment was determined on a case-by-case basis with parental consultation. Success rate, recurrence rate (within 12 months), duration of hospital stay, duration of catheter insertion, and complications were analysed., Main Results: There were 41 patients treated: aspiration, n=8; small-bore pigtail catheters, n=10; large-bore catheters, n=23. Demographic and baseline clinical characteristics were similar between groups. The success rates were 50.0% and 65.2% in the small-bore pigtail and large-bore catheter groups, respectively. Corresponding recurrence rates were 20.0% and 56.5%. There was no difference between the small-bore pigtail and large-bore catheter groups in the duration of hospital stay in patients for whom treatment was successful; however, the duration of catheter insertion was significantly shorter in the small-bore pigtail catheter group compared with the large-bore catheter group in patients for whom treatment was successful (p<0.05). There were no major complications in either catheter treatment group and few minor complications (small-bore pigtail catheter, n=2; large-bore catheter, n=4)., Conclusions: The findings suggest that small-bore pigtail catheters may be as effective as large-bore catheters for the initial treatment of PSP in young adolescents.

Nitric oxide (NO) deficiency contributes to hypertension and end-organ damage. Three nitric oxide synthase (NOS) isoforms have been identified: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). Whether selective nNOS or iNOS inhibition exacerbates kidney damage in spontaneously hypertensive rats (SHRs) remains unclear. Seven-week-old SHRs were randomly assigned to 4 groups (n=8 for each group): group 1, SHRs receiving no treatment; group 2 (SHR+7-NI), SHRs given 7-nitroindazole (7-NI, nNOS inhibitor) in their drinking water (10mg/kg/day); group 3 (SHR+salt), SHRs given 1% NaCl; and group 4 (SHR+AG), SHRs given 0.1% aminoguanidine (AG; iNOS inhibitor) in drinking water. The mean arterial pressure of SHRs treated with salt was significantly elevated compared with untreated controls. While AG caused a decrease of mean arterial pressure at 8 and 12 weeks of age in SHRs, both 7-NI and salt exacerbated kidney injury. In addition, AG significantly increased l-arginine levels and the l-arginine-to-asymmetric dimethylarginine (ADMA) ratio in the kidney. Salt treatment decreased renal nNOS-α protein levels and reduced dimethylarginine dimethylaminohydrolase (DDAH) activity. Salt and AG treatment increased nNOS-β and l-citrulline levels in SHR kidneys. AG attenuates hypertension development by upregulation of l-citrulline-to- l-arginine conversion and an increase in the l-arginine-to-ADMA ratio in SHR kidneys. 7-NI impairs renal function but has no effect on blood pressure, suggesting reno-protective role for the nNOS. Salt exacerbates kidney damage mainly through decreasing renal nNOS-α protein levels and DDAH activity. Our findings highlight the protective role of the nNOS/NO pathway in the development of kidney damage in SHRs., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Pupose: To determine predictive factors of spontaneous closure or size reduction in large secundum-type atrial septal defects (ASD) diagnosed in infancy prior to catheterization or surgical intervention., Methods: From June 2003 to October 2009, 59 infants diagnosed with secundum-type ASDs measuring ≥ 8 mm in the first year of life were retrospectively enrolled. We reviewed medical records, as well as electrocardiography and echocardiography findings. Patients were divided into 2 groups according to the last ASD size: group A (n = 23), ASD reduction in size to < 5 mm or spontaneous closure; group B (n = 36), size of ASD remained ≥ 5 mm., Results: The ASDs spontaneously closed in 10 (17%) patients at a median age of 26.0 ± 5.1 months (range, 15-58 months), or decreased to < 5 mm in 13 (22%) (range, 6-27 months) patients. There was a significant difference in age at diagnosis between the 2 groups (p = 0.014). Patients in group A were younger than those in group B at the time of diagnosis. Changes in ASD size (p < 0.001) and body weight percentile (p = 0.01) were also significantly different fromthe 6-month follow-up. ASD diameter of ≥ 10 mm was a negative predictive factor for size reduction (p = 0.017)., Conclusions: Spontaneous closure or size reduction of large ASDs was not uncommon in patients diagnosed during infancy. Patients with initial ASD sizes between 8 and 10 mm who were younger at the time of diagnosis and showed better weight gain were more likely to have favorable outcomes., Key Words: Infancy; Large secundum atrial septal defect; Natural course; Spontaneous closure.

Background: Conventional therapy against acute pediatric cardiopulmonary failure (APCPF) caused by a variety of disease entities remains unsatisfactory with extremely high morbidity and mortality. For refractory APCPF, extracorporeal membrane oxygenation (ECMO) is one of the last resorts., Methods: In this study, the in-hospital outcomes of pediatric patients with refractory APCPF receiving ECMO support were reviewed., Results: Between August 2006 and May 2011, a single-center cohort study was performed in pediatric patients who required ECMO support due to cardiogenic shock or severe hypoxemia. A total of 22 patients with mean age of 7.0 ± 6.3 years received ECMO (male = 11; female = 11). The indications included acute fulminant myocarditis (AFM) (n = 6), congenital diaphragmatic hernia (CDH) (n = 3), acute respiratory distress syndrome (ARDS) (n = 6), enterovirus 71 (n = 3), viral sepsis (n = 2), refractory ventricular fibrillation due to long QT syndrome (n = 1), and pulmonary edema with brain herniation (n = 1). Eighteen patients received veno-arterial (VA) mode ECMO, while another four patients undertook the veno-venous (VV) mode. The duration of ECMO use and hospitalization were 6.1 ± 3.1 and 24.4 ± 19.4 days, respectively. The survival rate in patients with AFM was 100% (n = 6). Successful ECMO weaning with uneventful discharge from hospital was noted in 14 (63.6%) patients, whereas in-hospital mortality despite successful ECMO weaning occurred in 5 patients (22.7%). Failure in ECMO weaning and in-hospital death was noted in 3 patients (13.6%)., Conclusions: ECMO resuscitation is an effective strategy in the clinical setting of APCPF.

Background: Nitric oxide (NO) is involved in hypertension and chronic kidney disease (CKD). NO synthase can metabolize L-arginine (ARG) to generate NO and L-citrulline (CIT). Two methylated ARG derivatives, asymmetric and symmetric dimethylarginine, are also involved in NO deficiency. Thus it was hypothesized that their combined ratios relate to blood pressure (BP) abnormalities in children with early CKD., Methods and Results: The relationship between these ARG metabolites in plasma was examined using 24-h ambulatory BP monitoring (ABPM) profile in children and adolescents with CKD stages 1-3 (n=44). Approximately 20.4% (9/44) of children with CKD stages 1-3 were diagnosed with hypertension on clinical BP measurement, and 77.3% (33/44) had BP abnormalities on ABPM, including increased BP load, nocturnal BP non-dipping, and nocturnal hypertension. Children with CKD stages 2-3 were more prevalent with abnormal BP on ABPM, and had a higher level of CIT and CIT-to-ARG ratio than those with stage 1. Furthermore, high CIT-to-ARG ratio was significantly correlated with abnormal ABPM profile, including nocturnal hypertension, increased diastolic BP load, and nocturnal BP non-dipping. Higher CIT level was significantly correlated with increased diastolic BP load and overall ABPM profile., Conclusions: Plasma CIT-to-ARG ratio may serve as a useful marker of cardiovascular outcome in children with early CKD.

Arginine (ARG) metabolites are interrelated and are involved in chronic kidney disease (CKD) and cardiovascular disease. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) appears to correlate with cardiovascular outcomes. We investigated the relationship between ARG metabolites, and their combined ratios in urine, and the ABPM profiles of children and adolescents with CKD. This cross-sectional study included 45 children and adolescents (age, 5-18 years) with stage 1 to 4 CKD. Each child underwent office blood pressure (BP) measurements, 24-hour ABPM, and urinary ARG metabolite determinations. Seventy percent of children with CKD had abnormal 24-hour ABPM profiles, including nocturnal hypertension, increased BP load, and nondipping nocturnal BP. The urinary ARG-to-asymmetric dimethylarginine (ADMA) ratio was lower, and the ADMA-to-symmetric dimethylarginine (SDMA) ratio was higher in children with advanced CKD (stages 2-4) than those with stage 1 CKD. CKD patients with BP abnormalities also had reduced urinary ARG and dimethylamine (DMA) levels. The higher urinary (ADMA+SDMA)-to-ARG ratios were correlated to ABPM abnormalities, including increased systolic BP load and non-dipping nocturnal BP. ABPM abnormalities were significantly associated with a high urinary (ADMA+SDMA)-to-ARG ratio, suggesting the possible involvement of methylated ARG in the development of hypertension among children with CKD., (Copyright © 2012 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Background: Kawasaki disease (KD) of unknown immunopathogenesis is an acute febrile systemic vasculitis and the leading cause of acquired heart diseases in childhood. To search for a better strategy for the prevention and treatment of KD, this study compared and validated human KD immunopathogenesis in a mouse model of Lactobacillus casei cell wall extract (LCWE)-induced coronary arteritis., Methods: Recruited subjects fulfilled the criteria of KD and were admitted for intravenous gamma globulin (IVIG) treatment at the Kaohsiung Chang Gung Memorial Hospital from 2001 to 2009. Blood samples from KD patients were collected before and after IVIG treatment, and cardiovascular abnormalities were examined by transthoracic echocardiography. Wild-type male BALB/c mice (4-week-old) were intraperitoneally injected with LCWE (1 mg/mL) to induce coronary arteritis. The induced immune response in mice was examined on days 1, 3, 7, and 14 post injections, and histopathology studies were performed on days 7 and 14., Results: Both human KD patients and LCWE-treated mice developed coronary arteritis, myocarditis, valvulitis, and pericarditis, as well as elevated plasma levels of interleukin (IL)-2, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α in acute phase. Most of these proinflammatory cytokines declined to normal levels in mice, whereas normal levels were achieved in patients only after IVIG treatment, with a few exceptions. Toll-like receptor (TLR)-2, but not TLR4 surface enhancement on circulating CD14+ monocytes, was augmented in KD patients before IVIG treatment and in LCWE-treated mice, which declined in patients after IVIG treatment., Conclusion: This result suggests that that not only TLR2 augmentation on CD14+ monocytes might be an inflammatory marker for both human KD patients and LCWE-induced CAL mouse model but also this model is feasible for studying therapeutic strategies of coronary arteritis in human KD by modulating TLR2-mediated immune activation on CD14+ monocytes.

Tricuspid valve detachment has been used for decades in the repair of type II ventricular septal defects (VSDs); however, the procedure can damage the tricuspid valve and conduction system. We retrospectively reviewed 177 consecutive type II VSD repairs performed at our hospital from 1997 through 2004. Patients were included if they had symptoms, pulmonary hypertension, or a Qp/Qs ratio>1.5: 86 underwent tricuspid valve detachment (TVD group) and 84 underwent VSD repair without this detachment (non-TVD group). There was no significant difference between groups in age, body weight, VSD size, Qp/Qs ratio, follow-up duration, or incidence of residual shunting. Cross-clamp times (109.6±42.6 vs 92.2±38.1 min) and cardiopulmonary bypass times (155.1±53.8 vs 137±47 min) were longer in the TVD group. No patients developed tricuspid stenosis or heart block. After excluding patients who underwent tricuspid repair, we found similar grades of postoperative tricuspid regurgitation in both groups. In applying our novel criterion (last postoperative regurgitation grade minus preoperative regurgitation grade) to evaluate changes between preoperative and postoperative tricuspid regurgitation, we found significant deterioration in the non-TVD group (P=0.018). Had conventional evaluation methods been used, severity in the groups would not have differed significantly. Our method enables additional evaluation of late tricuspid function in individual patients. Tricuspid valve detachment is safe for type II VSD repair and has no adverse effect on late tricuspid valve function. In addition, we recommend the interrupted-suture technique for leaflet reattachment.

Objective: A transpulmonary arterial approach to repair type I ventricular septal defect is the standard. However, the possible adverse effect on the pulmonary valve by this technique has not been investigated., Methods: A retrospective study reviewing type I ventricular septal defect repair from January 1991 to May 2010 was conducted. Of the 142 cases, the ventricular septal defect was repaired via the transpulmonary arterial route in 77 patients (54.2%, PA group) and via the subpulmonic route in 65 patients (45.8%, SP group). All patients received serial annual transthoracic color Doppler echocardiographic evaluation of pulmonary valve function., Results: The age at operation ranged from 1.2 to 272 months (median, 35.0 months; mean, 50.4 months). The mean follow-up period was 96.2 months (range, 2-234 months). Between the PA and SP groups, there was no significant difference in age, body weight, ventricular septal defect size, left to right shunt amount, mean pulmonary arterial pressure, and preoperative pulmonary stenosis or regurgitation. Postoperatively, there was no significant difference in the ejection fraction or incidence of residual ventricular septal defect, right bundle branch block, and pulmonary stenosis. However, the incidence of postoperative pulmonary regurgitation of more than moderate and the total scale of postoperative pulmonary regurgitation were both significantly higher in the PA group (16.9% vs 4.6% and 1.7 ± 0.1 vs 1.4 ± 0.1, P = .031 and .019, respectively)., Conclusions: Although the transpulmonary arterial approach for type I ventricular septal defect repair has been advocated for decades, considering the adverse effect on pulmonary valve competency, the subpulmonic approach may be an alternative., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

The type 1 fimbriae of uropathogenic Escherichia coli (UPEC) have been described as important for the establishment of bladder infections and urinary tract infections (UTI). Urinary prostaglandin (PG) levels and cyclooxygenase (COX)-2 expression in urine particulates may increase with infectious and inflammatory processes, including UTIs. We investigated the mechanisms underlying the modulation of COX-2 expression through the invasion of type 1 fimbriated UPEC strain J96 (J96-1) in human bladder 5637 cells. Bladder 5637 cells infected with J96-1 induced increases in the expression of COX-2 and secretion of PGE(2) . By using specific inhibitors and short hairpin RNA (shRNA), we have demonstrated that the activation of extracellular signal-related kinase (ERK), c-Jun-NH(2) -terminal kinase (JNK) and p38 MAPK pathways is critical for J96-1-induced COX-2 expression. Luciferase reporters and chromatin immunoprecipitation assays suggest that J96-1 invasion increases NF-κB- and AP-1-DNA-binding activities in 5637 cells. Inhibition of NF-κB and AP-1 activations blocked the J96-1-induced COX-2 promoter activity and expression. The effect of J96-1 on 5637 cell signalling and COX-2 expression is mediated by Toll-like receptor (TLR)-4. In summary, our findings provide the molecular pathways underlying type 1 fimbriated J96-dependent COX-2 expression in 5637 cells, providing insight into the function of UPEC invasion in bladder epithelial cells., (© 2011 Blackwell Publishing Ltd.)

E-selectin expression by endothelial cells (ECs) is crucial for leukocyte recruitment during the inflammatory response. Macrophage accumulation and serum E-selectin elevation are features of type 2 diabetes mellitus. However, the interactions between macrophages and ECs in regulating vascular endothelial function are not clearly understood. We investigated the mechanisms underlying the modulation of EC E-selectin expression by high glucose (HG)-treated macrophages. Macrophage-conditioned media (MCM) were prepared from HG-treated macrophages. EC stimulation with HG-MCM induced increases the expression and secretion of E-selectin. By using specific inhibitors and small interfering RNAs, we demonstrate that the activation of the JNK and p38 MAPK pathways are critical for HG-MCM-induced E-selectin expression. Transcription factor ELISA and chromatin immunoprecipitation assays further showed that HG-MCM increases the NF-κB- and AP-1 DNA-binding activities in ECs. The inhibition of NF-κB and AP-1 activation by specific siRNAs blocks the HG-MCM-induced E-selectin promoter activity and expression. Protein arrays and blocking assays using neutralizing antibodies demonstrated that macrophage inflammatory protein 1α and 1β in HG-MCM are major mediators for the induction of EC E-selectin expression. These data support the hypothesis that E-selectin up-regulation stimulated by macrophages may play an active role in atherogenesis in the HG condition and suggest a new mechanism by which arterial disease is accelerated in diabetes.

Background/purpose: Pediatric patients with atrial septal defect (ASD) may have failure to thrive. This study aimed to investigate body weight changes in pediatric patients after transcatheter closure of ASD., Methods: From June 2003 to September 2008, we enrolled 60 pediatric patients who underwent transcatheter closure of ASD. Changes in body weight percentile, heart rate, and resolution of right ventricular hypertrophy were compared before and after ASD closure. Patients were divided into two groups according to initial weight percentile: group A, <50(th) percentile (n = 39) and group B, ≥50(th) percentile (n = 21). Echocardiography and routine weight measurements were performed before the procedure and at 3, 6, and 12 months during follow-up. Clinical presentations, laboratory data, and outcomes were measured., Results: Increased body weight percentile (41±4 vs. 48±4, p<0.01), lower heart rate (100±2 beats/min vs. 89±2beats/min, p<0.01), and resolution of right ventricular hypertrophy (59/60 vs. 1/60, p<0.01) were achieved after ASD closure at the 12-month follow-up. Patients in group A were significantly younger (4.6±0.5 years vs. 7.0±0.9 years, p = 0.016), had a higher pulmonary/systemic blood flow ratio (2.2±0.1 vs. 1.8±0.l, p = 0.044), a largerratio of ASD diameter/body surface area (25.0±1.4 vs. 16.4±1.9, p<0.01), and higher percentage of weight gain increase ≥ 5 percentile compared with patients in group B (22/39 vs. 6/21, p = 0.039)., Conclusion: Transcatheter closure of ASD positively affects weight gain. An increase of 7 percentile weight was observed at 1 year of follow-up. Patients with a younger age, higher pulmonary/systemic blood flow ratio, and a larger ratio of ASD diameter/body surface area may have better weight gain after ASD closure., (Copyright © 2011 Formosan Medical Association & Elsevier. Published by Elsevier B.V. All rights reserved.)

Background: To evaluate the feasibility of echocardiography after transcatheter closure of patent ductus arteriosus (PDA) with coils., Methods: Between April 1998 and December 2006, 131 patients had transcatheter coil occlusion of their PDA using Gianturco coils. We hypothesized that post-procedural hemolysis would not occur if a residual shunt < 1 mm or if no continuous waveform was detected by echocardiography. Immediately after coil implantation, patients without and with a residual shunt as detected by echocardiography were designated to groups A and B, respectively. The clinical presentations, laboratory data and outcomes were compared between the two groups., Results: There were 101 patients in group A and 30 patients in group B. Patients in group B had larger ductal diameter (2.8 +/- 0.9 mm vs. 1.6 +/- 0.8 mm; p < 0.001), larger Qp/Qs (1.9 +/- 0 .9 vs. 1.3 +/- 0.4; p = 0.001), higher frequency of more than one coil used (14/30 vs. 11/101; p < 0.001), and female predominance (22/30 vs. 53/101; p = 0.043) compared with group A. Trivial residual shunt was noted in 6 patients in group A and 20 patients in group B on the day after embolization. All shunts spontaneously closed within 6 months in patients of group A, while five patients in group B had a persistent shunt at the 1-year follow-up and thereafter. Although the patients in group B had higher residual shunt rate than group A during follow-up (p < 0.001), none of these patients suffered from hemolysis., Conclusion: Echocardiography is a feasible tool to assess residual shunt after PDA closure. If a residual shunt < 1 mm or if no continuous waveform is detected by echocardiography, the risk of developing hemolysis is low.

Background: Balloon angioplasty (BA) is an alternative to surgical repair for coarctation of the aorta (CoA) in children. However, its role in the treatment of native CoA in neonates and infants remains controversial. The purpose of this study was to report the midterm outcomes of BA for native CoA in neonates and infants with congestive heart failure (CHF)., Methods: Between July 2000 and March 2007, 18 neonates and infants with native CoA and CHF who underwent BA were enrolled. Patients without recoarctation were designated as group A, while those with recoarctation or CHF were designated as group B. The clinical presentations, laboratory data, and outcomes were compared between groups., Results: There were 10 patients in group A and eight in group B. The mean age was 2.8 +/- 3.1 months (range, 0.7-11 months). Mean body weight was 4.0 +/- 1.9 kg (range, 2.1-8.0kg). CHF improved markedly in all patients immediately after BA, with a reduction in systolic pressure gradient from 36.4 +/- 12.0 to 5.6 +/- 6.0 mmHg (p < 0.001). The recoarctation rate was 44% (8/18). The risk factors for restenosis were post-BA systolic pressure gradient >10 mmHg (p = 0.007) and CoA diameter <3 mm (p = 0.013)., Conclusions: The outcomes of BA for native CoA in neonates and infants with CHF remain poor. The incidence of recoarctation is high in neonates and patients whose post-BA systolic pressure gradient is >10 mmHg or whose CoA diameter is <3 mm.

Background: Myocarditis complicated with complete atrioventricular block (CAVB) is rare in children. The purpose of this study was to report the outcome of myocarditis with CAVB in our institution., Methods: Between June 1998 and June 2007, nine pediatric patients (aged from 1.5 to 16 years) were admitted, presenting with acute myocarditis with CAVB. We analyzed their clinical presentations, biochemistry and serology studies, chest X-rays, electrocardiograms, echocardiography, complications and outcomes., Results: Hypotension and Stokes-Adams seizures occurred in five and four of our patients, respectively. Cardiomegaly of chest X-ray was common in eight (89%) of our patients. Echocardiography revealed impaired left ventricular performance in three patients. Six patients suffered ventricular tachycardia (VT). Three cases of VT occurred before pacemaker implantation and the others occurred afterwards. Eight patients survived. Six of them regained sinus rhythm within 12 days (range 1-12 days), and two had a right bundle branch block at follow-up. Two patients had persistent CAVB, and one received permanent pacemaker implantation; the other received supportive care. One patient died due to persistent low cardiac output and a new onset of VT on the 4th admission day. During a follow-up period of 56+/-27 months, all eight surviving patients remained asymptomatic., Conclusions: The outcome of CAVB complicated with myocarditis is variable. Most of our patients resumed normal heart function. The incidence of persistent CAVB was 22%. VT is a common and serious complication, but it can be effectively treated medically. Persistent low cardiac output after pacemaker implantation and late onset VT should be considered as risk factors of mortality.

Background/purpose: To evaluate the outcome of transcatheter closure of atrial septal defects (ASD) with superior-anterior (SA) rim deficiency using Amplatzer septal occluder (ASO)., Methods: Between June 2003 and March 2007, 84 patients with secundum type ASD attempted transcatheter insertion of ASO in our institution. According to the transesophageal echocardiographic findings, patients were divided into two groups: group A, with deficient SA rim (< 3 mm); group B, with sufficient SA rim (> or = 3 mm). There were 43 children and 41 adults (age range, 2.0-79.4 years; mean age, 22.0 +/- 20.2 years). The failure rate, complications and the presence of residual shunt were compared between the two groups., Results: There were 34 patients in group A and 50 patients in group B. Failure of ASO implantation occurred in six patients, three in each group. One patient had two ASOs implanted for two separate ASDs. Therefore, the study cohort consisted of 78 patients with 79 ASO placed. Among 78 patients with successful implantation, five (6.4%) had persistent small residual shunt during follow-up (range, 1-46 months; mean, 21.6 +/- 12.0 months). There was no statistically significant difference between group A and group B in the procedures failure rate (p = 0.682), complications (p = 1.0) and the presence of residual shunt (p = 0.381) during the follow-up period., Conclusion: ASD with deficient SA rim is a common variation. Similar to ASD with sufficient rims, transcatheter closure of secundum type ASD is also effective for ASD with SA rim deficiency.

Ehlers-Danlos syndrome (EDS) includes a group of connective tissue disorders with abnormal collagen metabolism and a diverse clinical spectrum. We report two siblings with EDS who both presented with congenital diaphragmatic hernia (CDH). The elder sister suffered from recurrent diaphragmatic hernia twice and EDS was overlooked initially. Echocardiography as well as contrast-enhanced magnetic resonance angiography (MRA) showed dilatation of the pulmonary artery, and marked elongation and tortuosity of the aorta and its branches. A diagnosis of EDS was eventually established when these findings were coupled with the clinical features of hyperelastic skin. Her younger brother also had similar features. This report emphasizes that EDS may present as CDH in a small child which could easily be overlooked. Without appropriate surgery, diaphragmatic hernia might occur. Echocardiographic screening is recommended in patients with CDH. Contrast-enhanced MRA can be helpful in delineation of abnormally tortuous aortic great vessels that are an important clue to the early diagnosis of EDS.

We present a rare case of a central venous catheter-malposition-induced life-threatening cardiac tamponade as a result of computed tomography (CT) with contrast enhancement in an infant with a ventricular septal defect and pulmonary atresia after a modified Blalock-Taussig shunt. The diagnosis was confirmed by chest radiographs and CT study with catheter perforation through the right atrial wall and extravasation of the contrast medium into the pericardium, leading to cardiac tamponade and subsequent circulatory collapse. Two hours after successful cardiopulmonary resuscitation, the patient gradually resumed normal hemodynamic status.