Detection of Pediatric Pulmonary Arterial Hypertension by School Electrocardiography Mass Screening.

Rationale: To detect pulmonary arterial hypertension (PAH) at any early stage is a promising approach to optimize the outcome. Objectives: To investigate the impact of school ECG-based screening on detecting idiopathic or heritable (I/H)-PAH in the general pediatric population. Methods: This was a nationwide survey of patients with I/H-PAH newly diagnosed at 3 months to 18 years of age in Japan during 2005-2012. Measurements and Main Results: Eighty-seven eligible patients (age range, 1-16 yr) were recruited. Among 68 (78%) patients diagnosed at greater than or equal to 6 years of age (the age of the first ECG-based screening), 28 (41%) were detected by the ECG-based screening (screening group) and 40 (59%) were recognized by their symptoms (n = 37) or coincidental occasions (n = 3; nonscreening group). In the screening group, the proportion of patients in World Health Organization functional class I/II at diagnosis was higher (96% vs. 60%; P < 0.001), plasma brain natriuretic peptide level was lower (149 ± 290 vs. 398 ± 559 pg/ml; P = 0.045), and 6-minute-walk distance was longer (420 ± 109 vs. 327 ± 104 m; P < 0.001) than the nonscreening group, despite similar values in mean pulmonary artery pressure (58 ± 17 vs. 61 ± 17 mm Hg; P = 0.42) and pulmonary vascular resistance index (18 ± 8 vs. 21 ± 11 Wood units ⋅ m2; P = 0.24) between groups. The proportion of patients on intravenous epoprostenol at the final visit was lower in the screening group than the nonscreening group (14% vs. 50; P = 0.004). Conclusions: These findings suggest that the ECG-based screening detects a unique subpopulation of pediatric patients with I/H-PAH that is associated with already established pulmonary hypertension but without obvious right heart failure and warrants investigating the prognostic significance of this system.

FCN1 (M-ficolin), which directly associates with immunoglobulin G1, is a molecular target of intravenous immunoglobulin therapy for Kawasaki disease.

Kawasaki disease (KD), an acute systemic vasculitis of early childhood, is of unknown etiology. High-dose intravenous immunoglobulin (IVIG) is an effective treatment, but its molecular target remains elusive. DNA microarray analysis of peripheral blood mononuclear cells (PBMCs) revealed that at least 21 genes are drastically down-regulated after IVIG treatment in most KD patients. qRT-PCR analysis confirmed that the mRNA levels of five of these genes were considerably reduced in almost all KD patients after IVIG treatment. Western blot (Wb) of PBMC extracts revealed that levels of FCN1 (M-ficolin), a protein of the complement system that defends against infectious agents, were reduced after IVIG treatment in many KD patients. In another set of KD patients, Wb confirmed that levels of both FCN1 were greatly reduced after IVIG therapy. Wb revealed that the collagen-like domain of FCN1 directly bound to IgG1 in vitro through a portion of the CH1 and CH3 domains, and synthetic peptides corresponding to these domains of IgG1 efficiently inhibited these associations. These results suggest that FCN1 is a molecular target of intravenous IVIG in KD patients. We propose that these peptides and a humanized monoclonal antibody against FCN1 could be useful in combination therapy with IVIG.

Clinical Features of Acute and Fulminant Myocarditis in Children　- 2nd Nationwide Survey by Japanese Society of Pediatric Cardiology and Cardiac Surgery.

BACKGROUND: The 1st nationwide survey by the Japanese Society of Pediatric Cardiology and Cardiac Surgery of acute or fulminant myocarditis (AMC/FMC) in children revealed that the survival rate of FMC was only 51.6%. The 2nd nationwide survey was performed to evaluate the recent outcomes of pediatric myocarditis.Methods and Results:Questionnaires regarding patients aged ≤18 years with AMC/FMC during the period from January 2006 to December 2011 were mailed. A total of 221 cases (age 6.5±5.3 years, 116 boys and 105 girls) were reported. There were 145 (65.6%) and 74 cases (33.5%) of AMC/FMC, respectively; the type of myocarditis was not reported in the remaining 2 cases (0.9%). Viruses were identified in 56 cases (25.3%), including coxsackie B in 9 and influenza A in 8. Histopathology by either endomyocardial biopsy or autopsy was obtained in 38 cases (19.2%). Intravenous immunoglobulin was effective in 49 (34.3%) of 143 cases. Steroid therapy was effective in 20 (32.8%) of 61 cases. Mechanical circulatory support was given in 54 cases (24.4%) and 94.2% of them were patients with FMC. The survival rates for the whole study population, acute myocarditis, and FMC were 75.6%, 91.0%, and 48.6%, respectively. CONCLUSIONS: The survival rate of children with myocarditis was almost identical to that of 10 years ago. (Circ J 2016; 80: 2362-2368).

[The algorithms of acute phase treatment for patients with Kawasaki disease].

Approximately one decade has passed when the original version of "Guidelines for Medi cal Treatment of Acute Kawasaki Disease" was published. Since then, many clinical stud ies have investigated and new evidences regarding diagnosis and acute phase treatment have been piled up. Based upon the background, Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery revised the guideline in December 2012. The revised guideline proposed new therapeutic algorithm for acute Kawasaki disease patients. The present review overviews the revised guideline especially focused on the algorithm, and explains how to treat acute phase Kawasaki disease patients.

[Anti TNF-α (infliximab) treatment for intravenous immunoglobulin (IVIG) resistance patients with acute Kawasaki disease the effects of anticytokine therapy].

Among the patients with acute Kawasaki disease treated with intravenous immunoglobulin (IVIG), 10-20 % demonstrate resistance or incomplete effects. Cardiac complication such as the coronary arterial aneurysm is frequent in these patients. For patients with IVIG-resistance, we have surveyed the efficacy and safety of anti-cytokine therapy with use of infliximab (Remicade), chimera type anti TNF-α agent, for children. After May, 2005, Remicade has been used in >500 pediatric patients in whom IVIG and intravenous methylprednisolone pulse therapy did not show significant effects. The efficacy and safety of Remicade on patients with IVIG-resistant Kawasaki disease has been observed but 10~20 % of patients was Remicade-resistant. Re-treatment with IVIG or steroids was also effective. The efficacy of Remicade for reducing the fever duration, CRP, WBC counts was promising, but reduction of the incidence of coronary aneurysm was not confirmed. Randomized clinical trial will be needed.

Risks and prevention of severe RS virus infection among children with immunodeficiency and Down's syndrome.

By the age of two years, almost all infants are infected with the Respiratory syncytial virus (RSV). One of the main causes of hospitalizations for bronchiolitis and pneumonia at this age is RSV infection. In addition to well-known risks for severe RSV disease, such as prematurity, bronchopulmonary dysplasia and congenital heart disease, immunodeficiencies, chromosomal abnormalities such as Down's syndrome or neuromuscular diseases have also been identified as risks. While the medical needs for RSV prevention in these risk groups are high, clinical evidence to support this is limited. Palivizumab was recently approved in Japan for prophylaxis in children with immunodeficiency or Down's syndrome. A clinical guidance protocol for the prevention of RSV infection using Palivizumab in these risk groups is provided here on the basis of a review of the available literature and on expert opinion. Thus, the present article reviews the published literature related to RSV infections in infants and children with immunodeficiencies or Down's syndrome in order to outline the risks, pathology and physiology of severe RSV disease in these patient groups. The purpose of this article is to facilitate understanding of the medical scientific bases for the clinical guidance.

Unexpected pulmonary hypertensive crisis after surgery for ocular malignant melanoma.

AIMS: To report a case of unexpected pulmonary hypertensive crisis caused by endothelin release from melanoma cells after surgery for choroidal melanoma. MAIN METHODS: A 56-year-old man suddenly developed dyspnea after resection of choroidal melanoma. Worsening hypoxia required intensive treatment, including percutaneous cardiopulmonary support, after which a series of tests were immediately performed. The tentative diagnosis was idiopathic pulmonary arterial hypertension. KEY FINDINGS: Previous studies noted a significant association between melanoma and endothelin (ET)-1. We hypothesized that a substantial amount of ET-1 had been released from malignant melanoma cells during resection, thus triggering the pulmonary hypertensive crisis in our patient. The patient fully recovered after intensive treatment and administration of the endothelin receptor antagonist bosentan. SIGNIFICANCE: The success of bosentan treatment, along with the extremely high level of ET-1 on pathologic analysis, confirmed our hypothesis regarding the increase in plasma ET-1 level.

The role of TNF-α in a murine model of Kawasaki disease arteritis induced with a Candida albicans cell wall polysaccharide.

OBJECTIVES: Various inflammatory cytokines, including tumor necrosis factor-α (TNF-α), have been reported to play roles in Kawasaki disease (KD). Recently, anti-TNF-α therapy was reported to show efficacy in patients who do not respond to high-dose intravenous immunoglobulin therapy. However, there are many gaps in our understanding of the role that TNF-α plays in the development of KD arteritis as well as whether anti-TNF-α therapy causes any histological changes in the arteritis. Accordingly, the present histopathological study was carried out to elucidate the inhibitory effect of anti-TNF-α therapy on vasculitis as well as the role of TNF-α in the development of vasculitis in a murine model of KD vasculitis. METHODS: We used two anti-TNF-α drugs (etanercept and infliximab) to treat a Candida albicans-induced murine model of KD vasculitis. We investigated the histopathological changes in terms of the incidence of vasculitis, the scope of lesions and the degree of inflammation. RESULTS: Administration of etanercept to the mice reduced not only the incidence of vasculitis but also the scope of lesions and the degree of inflammation. CONCLUSION: Based on the histological findings, TNF-α is deeply involved in the development of vasculitis.

Comprehensive analyses of imprinted differentially methylated regions reveal epigenetic and genetic characteristics in hepatoblastoma.

BACKGROUND: Aberrant methylation at imprinted differentially methylated regions (DMRs) in human 11p15.5 has been reported in many tumors including hepatoblastoma. However, the methylation status of imprinted DMRs in imprinted loci scattered through the human genome has not been analyzed yet in any tumors. METHODS: The methylation statuses of 33 imprinted DMRs were analyzed in 12 hepatoblastomas and adjacent normal liver tissue by MALDI-TOF MS and pyrosequencing. Uniparental disomy (UPD) and copy number abnormalities were investigated with DNA polymorphisms. RESULTS: Among 33 DMRs analyzed, 18 showed aberrant methylation in at least 1 tumor. There was large deviation in the incidence of aberrant methylation among the DMRs. KvDMR1 and IGF2-DMR0 were the most frequently hypomethylated DMRs. INPP5Fv2-DMR and RB1-DMR were hypermethylated with high frequencies. Hypomethylation was observed at certain DMRs not only in tumors but also in a small number of adjacent histologically normal liver tissue, whereas hypermethylation was observed only in tumor samples. The methylation levels of long interspersed nuclear element-1 (LINE-1) did not show large differences between tumor tissue and normal liver controls. Chromosomal abnormalities were also found in some tumors. 11p15.5 and 20q13.3 loci showed the frequent occurrence of both genetic and epigenetic alterations. CONCLUSIONS: Our analyses revealed tumor-specific aberrant hypermethylation at some imprinted DMRs in 12 hepatoblastomas with additional suggestion for the possibility of hypomethylation prior to tumor development. Some loci showed both genetic and epigenetic alterations with high frequencies. These findings will aid in understanding the development of hepatoblastoma.

Bidirectional Glenn procedure for an infected modified Blalock-Taussig shunt.

A 1-month-old girl underwent right modified Blalock-Taussig shunt (mBTS) for pulmonary atresia with hypoplastic right ventricle. Five months after palliation, she suffered from sepsis and progressive desaturation following otitis media. Computed tomography and angiography revealed a pseudoaneurysm surrounding the mBTS graft. After stabilization of the infection, we performed pseudoaneurysm resection, shunt-graft removal, and the bidirectional Glenn (BDG) procedure under cardiopulmonary bypass. Her condition improved, and she was discharged on the 17th day after surgery. When parameters for the partial right heart bypass should permit, the BDG procedure can be a beneficial recovery procedure for the cases of infected pseudoaneurysm after mBTS in Fontan candidates.

Trends in the prevalence of invasive fungal infections from an analysis of annual records of autopsy cases of Toho University.

Clinical diagnosis of invasive fungal infections (IFIs) is sometimes difficult, and obtaining an accurate assessment of trends concerning the prevalence of IFIs is a challenge. The aim of this study was to determine trends in the prevalence of IFIs from an autopsy survey. The retrospective review of autopsy records stored in Toho University was performed on all documented cases with fungal infection from 1955 to 2006. A total of 411 cases of IFIs were detected among 10 297 autopsies. The prevalence of candidiasis decreased from 3.6% (1981-93) to 2.0% (1994-2006), and that of aspergillosis increased throughout the 52-year period and reached 2.0% (1994-2006). The prevalence of IFIs in the patient group comprising haematological disorders was significantly higher (19.9%) than in other patient groups (2.9%), of which the odds ratio was 18.4 for mucormycosis and 10.0 for aspergillosis. The lung was the most common organ involved irrespective of major fungal species, and most cases with candidiasis showed multiple-organ infection. Results confirmed the increasing prevalence of aspergillosis and high risk of IFIs in the patient group with haematological disorders. IFIs were also detected in an immunocompromised state caused not only by primary disease but also by treatment with anti-tumour drugs and corticosteroids.

Serum adipokine profiles in Kawasaki disease.

Adipokines are cytokines derived from adipose tissue. Recently it has been established that adipokines are closely linked to the pathophysiology of not only metabolic diseases, such as diabetes mellitus, obesity, and atherosclerosis, but also to inflammation and immune diseases. In this study we measured serum levels of adipokines in patients with acute Kawasaki disease to investigate the role of adipokines in the pathophysiology of Kawasaki disease. Serum resistin, high-molecular-weight (HMW) adiponectin, leptin, and visfatin levels were measured by enzyme-linked immunosorbent assay in a total of 117 subjects: 56 patients with acute Kawasaki disease, 30 healthy children, and 31 patients with acute infectious diseases. Serum resistin levels in patients with Kawasaki disease were significantly higher than those of healthy children and patients with acute infectious diseases. In contrast, mean serum HMW adiponectin, leptin, and visfatin levels in patients with Kawasaki disease exhibited no statistically significant differences compared with those in healthy children and patients with infectious diseases. Serum resistin levels decreased significantly after administration of intravenous immune globulin. Serum resistin levels on admission were significantly higher in nonresponders compared with responders to intravenous immune globulin therapy. A multivariate model revealed that C-reactive protein was a factor that was significantly related to elevated serum resistin level in patients with Kawasaki disease. In patients with Kawasaki disease, serum resistin levels were elevated, but decreased to nearly normal after intravenous administration of immune globulin. In contrast, serum HMW adiponectin, leptin, and visfatin levels showed no statistically significant changes. These findings suggest that resistin plays an important role, while other adipokines do not play a major role, in the pathogenesis of Kawasaki disease.

Fontan conversion with novel direct ablation after childbirth: report of a case.

A 38-year-old woman underwent atriopulmonary Fontan surgery at age 18 years and subsequently successfully delivered a girl by cesarean section at age 34. Her condition later deteriorated due to atrial tachyarrhythmia and progressed to New York Heart Association (NYHA) class IV heart failure. Her treatment, at age 36, comprised total cavopulmonary connection conversion, direct right atrial ablation with bipolar radiofrequency devices, the creation of an atrial septal defect, and placement of a dual-chamber permanent pacemaker. Three years after the conversion, her condition has improved to NYHA class I.

Pharmacokinetics of bosentan in routinely treated Japanese pediatric patients with pulmonary arterial hypertension.

We evaluated the pharmacokinetics of routinely administered bosentan in 46 Japanese pediatric patients with pulmonary arterial hypertension. Plasma samples were taken twice at times corresponding to the peak and trough concentrations following repetitive oral administration. The population pharmacokinetic parameters of bosentan were estimated by use of the NONMEM program, in which a one-compartment model with repetitive bolus dosing was parameterized in terms of the oral clearance (CL/F) and elimination rate constant (k). Polymorphisms of CYP3A5, SLCO1B1, SLCO1B3, and SLCO2B1 had no significant effect on the disposition of bosentan. In addition, the pharmacokinetics of bosentan was not altered by heart failure or coadministration of sildenafil. In contrast, weight (WT)-normalized values of CL/F were correlated negatively with age (AGE). The final population mean values of CL/F and k were estimated to be 0.409 · (1 - 0.0377 · (AGE - 3.81)) · WT L/h and 0.175 h(-1), respectively.

Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG.

BACKGROUND: The International Neuroblastoma Pathology Classification (INPC) was the first to clearly define prognostic subgroups in ganglioneuroma (GN) and ganglioneuroblastoma (GNB). PROCEDURE: Histopathology and tumor resectability of 552 GN/GNB cases from the Children's Cancer Group (CCG) and Children's Oncology Group (COG) neuroblastoma studies were reviewed. The results were analyzed along with clinical information and biological data of the cases. RESULTS: According to the INPC, 300 tumors were classified into the Favorable Histology (FH) group and 252 were into the Unfavorable Histology (UH) group. Tumors in the FH group included 43 ganglioneuroma-maturing (GN-M), 198 ganglioneuroblastoma-intermixed (GNB-I), and 59 ganglioneuroblastoma-nodular, favorable subset (GNB-N-FS), and were often (91%) resected completely by single or multiple surgical procedures. Patients with the FH tumors had an excellent prognosis with no tumor-related deaths. The UH group included ganglioneuroblastoma-nodular, unfavorable subset (GNB-N-US) tumors. Patients with the UH tumors had a high incidence (53%) of distant metastasis at the time of diagnosis, and their prognosis significantly depended on clinical stage (5-year EFS: 80.1% for non-stage 4 patients; 16.7% for stage 4 patients): Complete primary tumor resection was not beneficial to those GNB-N-US patients, regardless of whether metastasis was present or not. MYCN amplification was detected in four tumors in the FH group and six tumors in the UH group. The majority (160/191, 84%) of GN-M and GNB-I tumors had a diploid pattern determined by flow cytometry. CONCLUSIONS: Stringent application of the INPC along with clinical staging was critical for prognostic evaluation of the patients with this group of tumors.

[Clinical utility of ulinastatin, urinary protease inhibitor in acute Kawasaki disease].

Ulinastatin, a trypsin inhibitor, is useful as a first-line or a second-line treatment regimen including alternative therapy for IVIG-resistant or IVIG nonresponder Kawasaki disease (KD) patients. Mechanisms involving protections against tissue organs and endthelial cell and anti-inflammatory effects by ulinastatin, are dependent on the inhibition of PMN-derived elastase, tumor necrosis factor alpha (TNFalpha), and other proinflammatory cytokines/interleukins(IL-1, IL-6, IL-8). Ulinastatin also suppresses the activation of PMN cells, macrophages, and platelets. Although almost no statistical data related to the definitive effect in acute stage of KD, ulinastatin have shown possible effects, but not always, in a part of KD patients. The indications of clinical use include shock and pancreatitis. Off-label uses of ulinastatin have been reported in hematological, hepatic, renal, OB/Gy diseases and cardiovascular diseases including vasculitis syndromes. The efficacy of ulinastatin in aKD remained to be investigated.

Long-term effects of recombinant human insulin-like growth factor I treatment on glucose and lipid metabolism and the growth of a patient with congenital generalized lipodystrophy.

Congenital generalized lipodystrophy (CGL) is a disease characterized by generalized lack of body fat, insulin resistance, hypertriglyceridemia, and fatty liver. We studied the long-term effects of recombinant human insulin-like growth factor I (rhIGF-I) treatment on glucose and lipid metabolism and the growth in a patient with CGL. During rhIGF-I treatment, the serum triglyceride level was maintained almost within the normal range, and the plasma glycosylated hemoglobin A1c (HbA1c) levels were maintained under 8.0% (5.8%-7.9%). Thus, rhIGF-I treatment was effective in lowering glucose and triglyceride levels over the long-term in a CGL patient. However, it was difficult to suppress the patient's voracious appetite. Although serum total IGF-I levels were extremely high (1000-1700 ng/ml), growth was not accelerated after the start of rhIGF-I treatment, likely because of normal IGF binding protein 3 (IGFBP-3) levels. During rhIGF-I treatment, the patient developed a recurrence of mild hypertrophic cardiomyopathy and a mild elevation of intraocular pressure.

Lack of human herpesvirus 8 infection in lungs of Japanese patients with primary pulmonary hypertension.

Samples of lung tissue, taken at autopsy, from 10 Japanese patients with primary pulmonary hypertension (PPH) and samples of lung tissue from 12 Japanese patients with secondary pulmonary hypertension were tested for the presence of human herpesvirus 8 (HHV-8). All samples from patients with PPH contained plexiform lesions around pulmonary arterial vessels, but immunohistochemistry failed to detect the HHV-8-encoded latency-associated nuclear antigen. HHV-8 DNA could not be amplified by polymerase chain reaction for the HHV-8-encoded K1 and KS330(233) genes in any sample. These data suggest that HHV-8 infection is not associated with PPH in Japanese patients.

CD40 ligand gene and Kawasaki disease.

Kawasaki disease (KD) is an acute systemic vasculitis syndrome of infants and young children. Although its etiology is largely unknown, epidemiological findings suggest that genetic factors play a role in the pathogenesis of KD. To identify genetic factors, affected sib-pair analysis has been performed. One of the identified peaks was located on the Xq26 region. A recent report of elevated expression of CD40 ligand (CD40L), which maps to Xq26, during the acute-phase KD, and its relationship to the development of coronary artery lesions (CAL) prompted us to screen for polymorphism of CD40L and to study the association of the gene to KD. A newly identified SNP in intron 4 (IVS4+121 A>G) is marginally over-represented in KD patients as compared to controls (109/602, 18.1 vs 111/737, 15.1%). When male KD patients with CAL were analyzed as a patient group, the SNP was significantly more frequent than in controls (15/58, 25.9%, vs 111/737, 15.1%, OR=2.0, 95% CI=1.07-3.66; P=0.030). Interestingly, this variation was extremely rare in a control Caucasian population (1/145, 0.7%). Our results suggest a role of CD40L in the pathogenesis of CAL and might explain the excess of males affected with KD.