記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1272/jnms.JNMS.2019_86-206

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The introduction of the Haemophilus influenzae type b (Hib) vaccine and the 7-valent pneumococcal conjugate vaccine (PCV7) has led to dramatic reductions in cases of invasive H. influenzae disease and invasive pneumococcal disease (IPD). After the introduction of the PCV7 and the 13-valent pneumococcal conjugate vaccine (PCV13), the number of children with IPD markedly decreased in our hospital. However, since 2015, three children with IPD have been admitted to our hospital. We analyzed the serotype, multilocus sequence type, and antimicrobial susceptibility of Streptococcus pneumoniae strains isolated in these newly diagnosed cases. The strains were serotypes 7F and 12F. In addition, we analyzed the incidence of invasive bacterial disease before and after the introduction of conjugate vaccines and found no change in the incidences. We found that cases of IPD and invasive H. influenzae disease clearly decreased following the introduction of the PCV7, the PCV13, and the Hib vaccine, as well as disease caused by antibiotic-resistant strains.

DOI： 10.1272/jnms.2018_85-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: We evaluated the systolic and diastolic functions of both ventricles from the early neonatal period to adolescence using color tissue Doppler imaging and 2-dimensional tissue tracking echocardiography. METHODS: We examined 100 healthy children (aged 1-5 days, n = 20; 1 month, n = 20; 1 year, n = 20; 6-7 years, n = 20; and 12-13 years, n = 20). Blood flow velocities in the mitral and tricuspid valves (E) were obtained with pulsed Doppler imaging, and longitudinal systolic (S') and early diastolic (E') peak velocities at the mid free wall segment of both ventricles were obtained with color tissue Doppler imaging. For longitudinal strain imaging, systolic peak values were obtained at the same position. In addition, peak systolic radial strain was obtained from a short-axis view of the left ventricle using the tissue tracking method. The E/E' ratio was calculated. RESULTS: Regarding systolic indices, S' increased during development and stabilized at 6 to 7 years, and longitudinal strain reached values of the 12- to 13-year-old group at 1 year of age in both ventricles. Like longitudinal strain, radial strain in the left ventricle reached values of the 12- to 13-year-old group at the age of 1 year. Similarly, the E/E' ratio was high at 1 month or younger and decreased by 1 year. CONCLUSIONS: Systolic and diastolic variables change markedly from birth to 1 year of age and show only small changes thereafter.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Congenital heart defects (CHD) are very common in patients with trisomy 18 (T18) and trisomy 13 (T13). The surgical indication of CHD remains controversial since the natural history of these trisomies is documented to be poor. To investigate the outcome of CHD in patients with T18 and T13, we collected and evaluated clinical data from 134 patients with T18 and 27 patients with T13 through nationwide network of Japanese Society of Pediatric Cardiology and Cardiac Surgery. In patients with T18, 23 (17%) of 134 were alive at this survey. One hundred twenty-six (94%) of 134 patients had CHDs. The most common CHD was ventricular septal defect (VSD, 59%). Sixty-five (52%) of 126 patients with CHD developed pulmonary hypertension (PH). Thirty-two (25%) of 126 patients with CHD underwent cardiac surgery and 18 patients (56%) have survived beyond postoperative period. While palliative surgery was performed in most patients, six cases (19%) underwent intracardiac repair for VSD. Operated patients survived longer than those who did not have surgery (P < 0.01). In patients with T13, 5 (19%) of 27 patients were alive during study period. Twenty-three (85%) of 27 patients had CHD and 13 (57%) of 27 patients had PH. Atrial septal defect was the most common form of CHD (22%). Cardiac surgery was done in 6 (26%) of 23 patients. In this study, approximately a quarter of patients underwent surgery for CHD in both trisomies. Cardiac surgery may improve survival in selected patients with T18.

DOI： 10.1002/ajmg.a.34285

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 3-year-old girl was diagnosed with restrictive cardiomyopathy (RCM) after showing symptoms of heart failure, and a 6-year-old boy was found to have RCM after abnormal electrocardiographic findings were seen during school-based heart disease screening. Both had typical clinical features of the disease. Plasma levels of brain natriuretic peptide increased significantly in both patients, allowing us to distinguish this disease from constrictive pericarditis which has similar clinical and hemodynamic features. The early diastolic mitral annular velocity recorded by tissue Doppler echocardiography was also useful to discriminate RCM from constrictive pericarditis. The former case successfully received heart transplantation, but the latter case died suddenly prior to receiving a heart transplant. The plasma level of brain natriuretic peptide and tissue Doppler echocardiography helped us to diagnose this disease earlier and follow it more carefully, which has important implications in optimal treatment and improved prognosis of RCM in children.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Here we report on a patient with multiple lentigines, hypertelorism, short stature, arachnodactyly, scoliosis, dissecting aneurysm, hypertrophic cardiomyopathy and developmental delay, and a family history of Marfan syndrome. The patient is affected with both Marfan and LEOPARD syndromes. Mutational screening of the FBN1 gene showed a c.1464T>A (p.C488X) mutation and screening of the PTPN11 gene showed a c.836A>G (p.Y279C) mutation. We conclude that each mutation contributed independently to individual features in the ocular and cardiovascular systems, although short stature was more significantly influenced by the p.Y279C change in PTPN11 rather than the mutation in FBN1. To our knowledge, this is the first report of mutations in both FBN1 and PTPN11 with combined phenotypes of Marfan and LEOPARD syndromes.

DOI： 10.1002/ajmg.a.32735

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: It was investigated whether edaravone, a potent free radical scavenger, would protect against anthracycline-induced cardiotoxicity and prevent cardiac function deterioration. METHODS AND RESULTS: Cultured neonatal rat cardiomyocytes were stimulated by daunorubicin 1 mumol/L either with or without edaravone or superoxide dismutase mimetic Mn (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP). Cell viability was estimated by measuring the amount of lactate dehydrogenase (LDH) released into the culture medium. Apoptosis was determined by a caspase-3 activity assay and a histone - DNA complex fragment assay. To investigate whether edaravone interfered with daunorubicin's anti-tumor effect, daunorubicin and edaravone were added to human leukemia K562 cells, and the surviving cells were counted. In addition, edaravone's in vivo effect was evaluated using Sprague - Dawley rats. A total of 15 mg/kg doxorubicin was injected intraperitoneally either with or without simultaneous edaravone injection. Two and 6 weeks after the final injection, left ventricular diastolic diameter and left ventricular fraction shortening were assessed echocardiographically. The LDH assay showed that edaravone significantly inhibited LDH release from cardiac myocytes (p=0.0428). The caspase-3 activity and histone - DNA complex fragment assays demonstrated that edaravone's apoptosis suppression effect was much weaker than that of MnTMPyP. The in vivo study showed that edaravone prevented doxorubicin-induced cardiac deterioration. Finally, edaravone was found to not affect daunorubicin's anticancer effect on K562 cells. CONCLUSIONS: Edaravone protects cardiomyocytes from anthracycline-induced cardiotoxicity via an anti-necrotic rather than an anti-apoptotic effect.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Noonan syndrome is characterized by short stature, facial dysmorphia and a wide spectrum of congenital heart defects. Mutations of PTPN11, KRAS and SOS1 in the RAS-MAPK pathway cause approximately 60% of cases of Noonan syndrome. However, the gene(s) responsible for the remainder are unknown. We have identified five different mutations in RAF1 in ten individuals with Noonan syndrome; those with any of four mutations causing changes in the CR2 domain of RAF1 had hypertrophic cardiomyopathy (HCM), whereas affected individuals with mutations leading to changes in the CR3 domain did not. Cells transfected with constructs containing Noonan syndrome-associated RAF1 mutations showed increased in vitro kinase and ERK activation, and zebrafish embryos with morpholino knockdown of raf1 demonstrated the need for raf1 for the development of normal myocardial structure and function. Thus, our findings implicate RAF1 gain-of-function mutations as a causative agent of a human developmental disorder, representing a new genetic mechanism for the activation of the MAPK pathway.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Kawasaki disease (KD) causes coronary artery disease (CAD) in children. In addition, a history of KD is suspected to be a risk factor for the development of atherosclerotic heart disease in the future. Histological senescence changes are a common denominator in atherosclerotic lesions in adults, so the present study investigated whether histological senescence changes had already occurred in KD aneurysm. METHODS AND RESULTS: KD coronary aneurysms and internal mammary arteries retrieved from 5 children with KD (3, 4, 5, 6, and 11 years old, respectively) who underwent coronary artery bypass grafting, as well as giant coronary aneurysm size-reducing operations, were analyzed. Senescence-associated strong beta-galactosidase activity was observed in KD aneurysms, but not in the internal mammary arteries. An immunohistochemical analysis of the KD aneurysm using anti-CD31, anti-endothelial nitric oxide synthetase (eNOS), anti-vascular adhesion molecule-1 (VCAM-1), and anti-monocyte chemoattractant protein-1 (MCP-1) showed vascular endothelium CD31 staining, decreased staining of eNOS and strong staining of MCP-1 and VCAM-1. cDNA microarray gene expression profiling revealed increased MCP-1 expression in the KD aneurysm, a finding confirmed by quantitative polymerase chain reaction. CONCLUSIONS: Histological features of senescence and active remodeling gene expression show that the KD aneurysm is not a silent vasculitis terminal. The future fate of KD aneurysms, including atherosclerosis, should be monitored carefully.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hypertrophic pyloric stenosis (HPS) is the principal disease to consider in neonates presenting with frequent projectile vomiting and poor weight gain. Ramstedt pyloromyotomy is commonly used for the surgical treatment of HPS. The present study investigated the efficacy of nonsurgical medical treatment using intravenous administration of atropine and the examined the clinical course and results of ultrasonography and a contrast upper gastrointestinal series. A 34-day-old girl was admitted with chief complaints of projectile vomiting and poor weight gain. HPS was diagnosed on the basis of the clinical course and results of imaging studies. After intravenous administration of atropine, projectile vomiting resolved and weight increased without complications. On imaging studies, barium introduced into the stomach by tube rapidly entered the duodenum after atropine administration. Ultrasonography initially showed no reductions in hypertrophic muscle in the pyloric region, but gradual reductions were identified in subsequent months.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We describe an uncircumcised male infant treated for urinary tract infection who exhibited multiple hormonal and electrolyte abnormalities consistent with a diagnosis of transient pseudohypoaldosteronism. Successful treatment of the urinary tract infection was accompanied by the resolution of all hormonal and electrolyte abnormalities, including hyperaldosteronemia, hyperreninemia, hyponatremia and hyperkalemia. Radiographic examination revealed marked left dilatation of the renal pelvis and hydroureter but no vesicoureteral reflux. Owing to the possibilities of future renal scarring, decreased renal function, and hypertension, evaluation of urinary tract malformation and appropriate hormonal studies should be performed in infants with urinary tract infection and hyperkalemia.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 6-year-old boy was hospitalized because of dark feces and facial pallor of 1 weeks duration. Other gastrointestinal symptoms, including vomiting and abdominal pain, were absent, but he felt dizziness when standing and fatigue on effort. Hematologic studies revealed iron-deficiency anemia, and endoscopy showed gastric erosions and a duodenal ulcer. All test results for Helicobacter pylori infection, including H. pylori antigen in stool, anti-H. pylori IgG immunoassay in serum, and the (13)C-urea breath test, were positive. Because an H. pylori-associated gastric ulcer had been diagnosed with endoscopy in the patients father 3 years earlier, father-son transmission was suspected. The patient was treated with triple-agent eradication therapy (proton pump inhibitor [lansoprazol], amoxicillin, and clarithromycin) for 2 weeks. One month after therapy was completed, eradication of H. pylori was confirmed by negative results on the stool antigen test. Peptic ulcer disease can occur in young children, as in this case. The stool antigen test kit is a useful and reliable method that can be used even in preschool children to diagnose H. pylori infection.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Inherited human cardiomyopathies often lead to heart failure. A common feature of these conditions is that affected individuals can express the disease causing mutations for many years without showing clinical signs of the disease. Previous studies have demonstrated that sarcomere protein gene mutations can cause either dilated cardiomyopathy or hypertrophic cardiomyopathy. Here we demonstrate that the Arg442His missense mutation in beta-cardiac myosin heavy chain (betaMHC) causes dilated cardiomyopathy, endocardial fibroelastosis and heart failure at a very early age. Using standard genetic engineering tools we and others have made murine models by introducing human disease causing mutations into mice. The central hypothesis of these studies has been that by identifying the pathophysiological pathways activated by these mutations we can define enzymatic activities that are modified during the disease process and which may be involved in pathways that involve more common forms of cardiac disease. Murine models bearing different mutant myosins are being used to address whether each disease causing mutant betaMHC activates the same or different cellular pathways. Dissecting the molecular pathways modulated by mutations in sarcomere protein genes as well as other genes has already demonstrated that there are multiple pathways leading to cardiac remodelling and heart failure. Defining the mechanisms by which mutations in the same genes activate different cellular pathways remains an important question.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, GATA4 and NKX2.5 were reported as the disease genes of atrial septal defect (ASD) but the relationship between the locations of their mutations and phenotypes is not clear. We analyzed GATA4 and NKX2.5 mutations in 16 familial ASD cases, including four probands with atrioventricular conduction disturbance (AV block) and two with pulmonary stenosis (PS), by PCR and direct sequencing, and examined their phenotypes clinically. Five mutations, including two GATA4 and three NKX2.5 mutations, were identified in 31.3% of the probands with ASD, and three of them were novel. The two GATA4 mutations in the probands without AV block were S52F and E359Xfs (c.1075delG) that was reported previously, and three NKX2.5 mutations in the probands with AV block were A88Xfs (c.262delG), R190C, and T178M. Additionally, we observed some remarkable phenotypes, i.e., dextrocardia with E359Xfs (c.1075delG) and cribriform type ASD with R190C, both of which are expected to be clues for further investigations. Furthermore, progressive, most severe AV block was closely related with a missense mutation in a homeodomain or with a nonsense/frame-shift mutation of NKX2.5 for which classification has not been clearly proposed. This pinpoints essential sites of NKX2.5 in the development of the conduction system.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

ACE I/D and AT1R 1166A/C polymorphisms are considered to comprise individual risk factors for the development of coronary disease. We sought to demonstrate that the ACE I/D and AT1R 1166A/C polymorphisms affect coronary artery stenosis in patients with Kawasaki disease (KD). We examined 147 healthy controls and 281 Japanese children with KD. The patients were further divided into group N (n = 246, no ischemia) and group I (n = 35, severe coronary artery stenosis with myocardial ischemia), and we studied the genotype of ACE I/D and AT1R 1166A/C polymorphisms. We also examined ACE activity in patients with acute KD. We did not detect any prevalent genotypes of the ACE and AT1R polymorphisms between controls and KD patients. However, the prevalence of the D allele in the ACE polymorphism and of the C allele in the AT1R polymorphism tended to be higher in group I than in group N (odds ratios, 2.00 and 2.32, respectively). In addition, the presence of the D and/or C alleles significantly increased the relative risk of developing myocardial ischemia (odds ratio, 2.71; p = 0.038). During the convalescent phase of KD, ACE activity was increased despite significant attenuation during the acute phase. These results suggested that the renin-angiotensin system is associated with the formation of severe coronary artery stenosis and myocardial ischemia.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: We used myocardial fractional flow reserve (FFR(myo)) and coronary flow reserve (CFR) to estimate cut-off values for assessment of the functional severity of coronary stenosis and myocardial ischemia, and we tested the usefulness of coronary blood hemodynamic measurements before and after plain old balloon angioplasty (POBA) and coronary artery bypass graft surgery (CABG). BACKGROUND: Fractional flow reserve and CFR are useful for assessing the functional severity of coronary artery stenosis, coronary microvascular dysfunction, and myocardial ischemia during cardiac catheterization in adults. However, there have been no reports on the use of these measurements in children with Kawasaki disease (KD). METHODS: The study group included 128 patients with 314 coronary branches. The subjects were classified into three groups: normal coronary group, with 206 branches; abnormal coronary artery without ischemia group, with 58 branches; and ischemia group, with 50 branches. RESULTS: In each branch, CFR and FFR(myo) were significantly lower in the ischemia group than in the other groups. Cut-off values for assessing the functional severity of coronary stenosis and CFR were approximately equal to those obtained for adults (CFR: <2.0; FFR(myo): <0.75). We obtained very high sensitivity and specificity for estimating myocardial ischemia using CFR and FFR(myo) (CFR: 94.0% and 98.5%, respectively; FFR(myo): 95.7% and 99.1%, respectively). Both CFR and FFR(myo) were reliable indicators of coronary hemodynamics before and after POBA and CABG. CONCLUSIONS: Together, CFR and FFR(myo) provide a useful index for assessing the functional severity of coronary artery stenosis and myocardial ischemia and estimating the effectiveness of POBA and CABG in children with KD, the same as they do for adults.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Molecular etiologies of heart failure, an emerging cardiovascular epidemic affecting 4.7 million Americans and costing 17.8 billion health-care dollars annually, remain poorly understood. Here we report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban (PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular Ca2+-adenosine triphosphatase (SERCA2a) pump. Transgenic PLN(R9C) mice recapitulated human heart failure with premature death. Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit SERCA2a. Rather, PLN(R9C) trapped protein kinase A (PKA), which blocked PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of calcium transients in myocytes. These results indicate that myocellular calcium dysregulation can initiate human heart failure-a finding that may lead to therapeutic opportunities.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Terminal deletions of chromosome 4q are commonly associated with cardiovascular malformations (CVMs). The dHAND gene (HAND2 heart and neural crest derivative express 2), a basic helix-loop-helix transcription factor expressed in the developing heart, maps to 4q33. A targeted deletion in mouse shows that dHAND plays an important role in heart development, suggesting that haploinsufficiency of in patients with 4q deletions may be causal for CVMs. The purpose of this study is to examine the possible association between dHAND haploinsufficiency with the CVMs that occur in patients with 4q terminal deletions. METHODS: Fluorescence in situ hybridization (FISH) was performed with a dHAND human genomic probe on five patients with terminal deletion at 4q33 or 4q34. RESULTS: Of the three patients with a deletion of the dHAND locus, two had CVM (both valvar pulmonic stenosis). Of the two patients without a deletion of the dHAND gene, one had a small atrial septal defect noted on autopsy. In one of the patients with breakpoint on chromosome 4 assigned to 4q34.2 by GTG-banding, FISH revealed deletion of the dHAND gene. CONCLUSION: The results suggest that cardiac phenotypes are very variable in patients with the terminal deletion of chromosome 4q and that haploinsufficiency of the dHAND is not necessarily associated with CVMs. The correct cytogenetic interpretation of terminal chromosome deletions might be augmented by FISH.

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