Intrarenal renin-angiotensin system activation and macrophage infiltrations in pediatric chronic glomerulonephritis.

The data indicates that UAGT and UMCP-1 are useful biomarkers of the degree of glomerular injury during RAS blockade and immunosuppressant treatment in pediatric patients with chronic glomerulonephritis.

Baseline UAGT and UMCP-1 levels positively correlated with urinary protein levels, scores for mesangial hypercellularity, rate of crescentic formation, and expression levels of AGT and CD68 in renal tissues (p < 0.05). UAGT and UMCP-1 levels were significantly decreased after RAS blockade and immunosuppressant treatment (p < 0.01), which was accompanied by AGT and CD68 (p < 0.01), as well as the magnitude of glomerular injury. Cultured human MCs showed increased MCP-1 messenger ribonucleic acid and protein levels after Ang II treatment (p < 0.01).


Novel method utilizing bisulfite conversion with dual amplification-refractory mutation system polymerase chain reaction to detect circulating pancreatic β-cell cfDNA.

We developed a novel method for detecting unmethylated insulin DNA in circulation that can be performed using a conventional real-time PCR system. This method would be useful for analyzing dynamic profiles of β-cells in human disease such as type 1 diabetes.


Neonatal rebound hyperkalemia associated with ritodrine alone: a case report

Betamimetics have been used for tocolysis extensively in the past, and one of them, ritodrine is widely used in Japan. Various adverse events have been reported for this agent, including newborn hypoglycemia and hypokalemia, as well as maternal hypokalemia and rebound hyperkalemia; however, cases of neonatal rebound hyperkalemia are not described in the literature. A male infant born at 36 weeks of gestation by cesarean section at a local maternity clinic suddenly entered cardiopulmonary arrest with ventricular tachycardia and fibrillation due to hyperkalemia (K, 8.7 mmol/L). No monitoring, examination of blood electrolyte levels, or infusions had been performed prior to this event. Maternal infusion of ritodrine (maximum dose, 170 μg/min) had been performed for 7 weeks prior to cesarean section. After resuscitation combined with calcium gluconate, the infant died at 4 months old due to serious respiratory failure accompanied by acute lung injury following shock. No cause of hyperkalemia other than rebound hyperkalemia associated with ritodrine was identified. This case report serves as a warning regarding the potential risk of neonatal rebound hyperkalemia in association with maternal long-term ritodrine administration.


Urinary angiotensin converting enzyme 2 and disease activity in pediatric IgA nephropathy

Background : Our previous studies demonstrated that the intrarenal renin-angiotensin system (RAS) status was activated in pediatric patients with chronic glomerulonephritis. In the present study, we tested the hypothesis that angiotensin-converting enzyme 2 (ACE2) expression in the kidney is associated with the development of pediatric IgA nephropathy. Methods : We analyzed urinary ACE2 levels and ACE2 expression in the kidney tissues of pediatric patients with IgA nephropathy treated with RAS blockade. Paired tests were used to analyze changes from the first to the second biopsy. Results : Urinary ACE2 levels were significantly decreased after RAS blockade treatment, accompanied by decreased ACE2 expression levels in kidney tissues, urinary protein levels and mesangial hypercellularity scores. Urinary ACE2 levels at the first biopsy were positively correlated with the ACE2 expression levels. Conclusions : These data suggest that urinary ACE2 is associated with ACE2 expression in the diseased kidney, which correlates with the pathogenesis of IgA nephropathy in pediatric patients. J. Med. Invest. 68 : 292-296, August, 2021.

The Journal of Medical Investigation : JMI


Three-dimensional Imaging of Pulmonary Arterial Vasa Vasorum Using Optical Coherence Tomography in Patients After Bidirectional Glenn and Fontan Procedures

We evaluated pulmonary arterial (PA) vasa vasorum (VV) in Fontan candidate patients with a novel three-dimensional (3D) imaging technique using optical coherence tomography (OCT). This prospective study assessed the development of adventitial VV in the distal PA of 10 patients with bidirectional Glenn circulation (BDG group, 1.6 ± 0.3 years) and Fontan circulation (Fontan group, 3.3 ± 0.3 years), and in 20 children with normal PA haemodynamics and morphology (Control group, 1.5 ± 0.3 years). We assessed the PA VV with two-dimensional (2D) cross-sectional, multi-planar reconstruction (MPR), and volume rendering (VR) imaging. VV development was evaluated by the VV area/volume ratio, defined as the VV area/volume divided by the adventitial area/volume. Compared to the control group, the observed VV number and diameter on 3D images of MPR and VR were significantly higher, and curved and torturous-shaped VV were more frequently observed in the BDG and Fontan groups (P < 0.001, all). The median VV volume ratio was significantly greater in the BDG than in the control group (3.38% vs. 0.61%; P < 0.001). Although the VV volume ratio decreased significantly after the Fontan procedure (2.64%, P = 0.005 vs. BDG), the ratio remained higher than in the control group (P < 0.001 vs. control). 3D OCT imaging is a novel method that can be used to evaluate adventitial PA VV and may provide pathophysiological insight into the role of the PA VV in these patients.

European Heart Journal Cardiovascular Imaging


Functionally confirmed compound heterozygous ADAM17 missense loss-of-function variants cause neonatal inflammatory skin and bowel disease 1.

mEFs) exogenously expressing each of these mutants, phorbol 12-myristate 13-acetate-stimulated shedding was strongly reduced compared with wild-type ADAM17. Thus, in vitro functional assays demonstrated that both missense variants cause the loss-of-function of ADAM17, resulting in the development of NISBD1. Our study further expands the spectrum of genetic pathology underlying ADAM17 in NISBD1 and establishes functional assay systems for its missense variants.


Usefulness of individual support and medication for autism spectrum disorder traits in a boy with cyclic vomiting syndrome

自閉スペクトラム症の特性に応じた個別支援と薬物治療が有用であった周期性嘔吐症の男児例

Herein we report the case of a 7-year-old boy with cyclic vomiting syndrome (CVS) successfully treated with judicious management and medication of autism spectrum disorder (ASD) traits. Radical surgery for esophageal atresia (Gross C) was performed during the neonatal period. The patient's mother and grandmother both had migraines. The cyclic vomiting began when he was 1 year and 4 months of age, and the episodes occurred 1-3 times monthly. Various drug treatments were tested, but were not effective in controlling the vomiting events. The patient was referred to our hospital at the age of 7 years and 4 months for consultation and treatment. We arrived at a diagnosis of ASD due to observable traits including avoidance of eye contact, obsessiveness, and difficulty in communication. Subsequently, we began individual support and medication for ASD traits to alleviate the CVS. The school has begun to support for his behaviors associated with ASD. Consequently, the psychological anxiety regarding school attendance was addressed, allowing the patient to return to school. When prophylactic drug treatment was changed to the combination of risperidone, amitriptin, and sodium valproate, the vomiting attacks discontinued. The patient is now aged 9 years and 3 months, and has experienced no recurrent vomiting episodes in the past 14 months. In conclusion, it is important to consider the possible coexistence of developmental disorders in patients with intractable CVS, and to provide the reasonable accommodation and treatment for optimal outcomes.

自閉スペクトラム症 (ASD) の特性に応じた個別支援および投薬が発作消失に有用であった周期性嘔吐症の7歳男児例を経験したので報告する. 新生児期に食道閉鎖症 (Gross C) に対する根治術の既往歴あり. 母親と祖母に片頭痛の家族歴あり. 周期性嘔吐症は1歳4か月時に発症し, 以後月に1~3回の嘔吐発作が持続した. 様々な薬物治療が試みられたが, 嘔吐発作の抑制には効果がなかった. 精査加療目的で, 7歳4か月時に当科に紹介された. その際, 視線の合いにくさ, 強迫観念, コミュニケーションの困難さなどの特性があり, ASDの診断に至った. そこで, ASD特性への配慮と薬物治療を行うことで周期性嘔吐症の改善を目指した. 学校でも特性に応じた配慮が受けられるようになり, 通学に対する不安が解消され, 登校できるようになった. 予防薬は, risperidone, amitriptin, sodium valproateの3剤の組み合わせに変更した時点で, 嘔吐発作は消失した. 現在9歳3か月となったが, ここ14か月の間に嘔吐発作の再発は認めていない. 難治性の周期性嘔吐症患者においては, 発達障害の有無の精査とそれに対する支援が重要であると考えた.


Next-generation sequencing for the diagnosis of patients with congenital multiple anomalies and / or intellectual disabilities

Background : In clinical practice, a large proportion of patients with multiple congenital anomalies and/or intellectual disabilities (MCA / ID) lacks a specific diagnosis. Recently, next-generation sequencing (NGS) has become an efficient strategy for genetic diagnosis of patients with MCA/ID. To review the utility of NGS for the diagnosis of patients with MCA / ID. Patients with MCA/ID were recruited between 2013 and 2017. Molecular diagnosis was performed using NGS-based targeted panel sequencing for 4,813 genes. Promising causative variants underwent confirmation by Sanger sequencing or chromosomal microarray. Eighteen patients with MCA/ID were enrolled in this study. Of them, 8 cases (44%) were diagnosed by targeted panel sequencing. Most of diagnosed patients were able to receive better counseling and more appropriate medical management. NGS-based targeted panel sequencing seems to be an effective testing strategy for diagnosis of patients with MCA/ID. J. Med. Invest. 67 : 246-249, August, 2020.


Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial.


(Pro)renin receptor promotes crescent formation via the ERK1/2 and Wnt/β-catenin pathways in glomerulonephritis.

(Pro)renin receptor [(P)RR] has multiple functions, but its regulation and role in the pathogenesis in glomerulonephritis (GN) are poorly defined. The aims of the present study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. The anti-glomerular basement membrane nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (percent glomerular crescent: 62.1 ± 2.3%) accompanied by increased macrophage infiltration and glomerular expression of monocyte chemoattractant protein (MCP)-1, (P)RR, phospho-extracellular signal-regulated kinase (ERK)1/2, Wnt4, and active β-catenin. Treatment with DRI ameliorated proteinuria (20.33 ± 5.88 mg/day) and markedly reduced glomerular crescent formation (20.9 ± 2.6%), induction of macrophage infiltration, (P)RR, phospho-ERK1/2, Wnt4, and active β-catenin. Furthermore, primary cultured parietal epithelial cells stimulated by recombinant prorenin showed significant increases in cell proliferation. Notably, while the ERK1/2 inhibitor PD98059 or (P)RR-specific siRNA treatment abolished the elevation in cell proliferation, DRI treatment did not abrogate this elevation. Moreover, cultured mesangial cells showed an increase in prorenin-induced MCP-1 expression. Interestingly, (P)RR or Wnt4-specific siRNA treatment or the β-catenin antagonist XAV939 inhibited the elevation of MCP-1 expression, whereas DRI did not. These results suggest that (P)RR regulates glomerular crescent formation via the ERK1/2 signaling and Wnt/β-catenin pathways during the course of anti-glomerular basement membrane nephritis and that DRI mitigates the progression of crescentic GN through the reduction of (P)RR expression but not inhibition of prorenin binding to (P)RR.

American Journal of Physiology, Renal Physiology


Molecular diagnosis of an infant with TSC2/ PKD1 contiguous gene syndrome

A 1-month-old Japanese infant with cardiac rhabdomyoma was diagnosed with / contiguous gene syndrome by targeted panel sequencing with subsequent quantitative polymerase chain reaction that revealed gross monoallelic deletion, including parts of two genes: exons 19-42 of and exons 2-46 of . Early molecular diagnosis can help to detect bilateral renal cyst formation and multidisciplinary follow-up of this multisystem disease.


Improvement of epilepsy with lacosamide in a patient with ring chromosome 20 syndrome.

Although VPA and LTG are generally effective for the treatment of ring chromosome 20 syndrome, they do not completely suppress seizures. LCM can be considered an effective option for seizure control in patients with this syndrome.


Reduction in urinary angiotensinogen levels and improvement of proteinuria by renin-angiotensin system blockade in pediatric chronic kidney disease patients with very low birth weight.

Children with low birth weight (LBW) have an increased risk of developing chronic kidney disease (CKD), and no effective strategies have been established to prevent the progression of CKD in these patients. Urinary angiotensinogen (UAGT) may represent a useful marker of intrarenal renin-angiotensin system (RAS) activation, which has been suggested to play a critical role in the development of hypertension and CKD. Herein, we conducted a prospective study to determine whether RAS blockade is beneficial for suppressing the progression of CKD in children with LBW, using UAGT as a surrogate marker of renal impairment. Nine children with CKD (stages: 1-2) who had very low birth weight (VLBW; < 1500 g) were started on RAS blockade with candesartan. We measured blood pressure and laboratory parameters, including urinary concentrations of angiotensinogen, protein, albumin, creatinine (Cr), and estimated glomerular filtration rate (eGFR), before and after candesartan treatment. Birth weight was 712 g (range, 536-800 g). Age at evaluation was 11.6 years (range, 10.3-15.6 years). After candesartan treatment for 47.6 ± 25.0 months, the UAGT to urinary Cr ratio decreased from 61.9 ± 44.7 to 16.8 ± 14.4 μg/g (p = 0.015). The urinary protein to Cr and albumin to Cr ratios also decreased (p = 0.008 and p = 0.012, respectively), whereas there was no significant change in eGFR. RAS blockade reduced UAGT levels and improved proteinuria/albuminuria in children with CKD who had VLBW. Suppression of intrarenal RAS activity may slow the progression of CKD in children with LBW.


Multi-delay arterial spin labeling brain magnetic resonance imaging study for pediatric autism.

Arterial spin labeling (ASL) is a non-invasive magnetic resonance imaging (MRI) technique that can measure regional cerebral blood flow (rCBF) without radiation exposure. This study aimed to evaluate rCBF in individuals with autism and their age-matched controls, globally and regionally.

We concluded that patients with ASD showed a statistically significant decline in CBF in regions associated with the mirror neuron system. The advantages of ASL MRI include low invasiveness (no radiation exposure) and short imaging time (approximately 5 min). Studies with larger sample sizes are required to establish the diagnostic value of ASL MRI for ASD.


重篤な転帰をとったGalloway-Mowat症候群の新生児の1例

重篤な転帰をとったGalloway-Mowat症候群の新生児の1例

Journal of Japan Society for Neonatal Health and Development

日本新生児成育医学会雑誌


Assessment of Right Ventricular Function by Isovolumic Acceleration of Pulmonary and Tricuspid Annulus in Surgically Repaired Tetralogy of Fallot

Assessment of right ventricular (RV) function is quite important in patients with surgically corrected tetralogy of Fallot (TOF). However, quantitative assessment of RV function remains challenging, mainly because of the complex RV geometry. This prospective study investigated isovolumic acceleration (IVA), a parameter of myocardial systolic function not influenced by either preload or afterload, using tissue Doppler imaging. We evaluated IVA measured on pulmonary annulus (PA-IVA) and tricuspid annulus (TA-IVA), because we considered that PA-IVA and TA-IVA correspond with systolic function of the RV outflow tract (RVOT) and RV basal function, respectively. Thirty-nine patients with surgically repaired TOF (TOF group) and 40 age-matched healthy children (control group) were enrolled in this study. No significant difference was seen between TA-IVA (2.5 ± 0.8 m/s2) and PA-IVA (2.4 ± 0.8 m/s2) in the control group. In the TOF group, PA-IVA (1.0 ± 0.5 m/s2) was significantly lower than TA-IVA (1.3 ± 0.6 m/s2, p < 0.05). Both TA-IVA and PA-IVA were significantly lower in the TOF group than in the control group (p < 0.05 each). We concluded that PA-IVA offers a useful index to assess RVOT function in TOF patients. J. Med. Invest. 67 : 145-150, February, 2020.

The Journal of Medical Investigation : JMI


Serum biotin level during pregnancy is associated with fetal growth and preterm delivery

Background : Biotin is a water-soluble vitamin that plays various biological roles through histone modification, such as immune functions and fetal growth. Mammalian maternal biotin deficiency during gestation induces fetal growth restriction. Preterm infants are known to be marginal biotin deficiency. However, studies on the biotin status of pregnant women under various conditions are lacking. Method : This was a retrospective case control study to analyze serum biotin concentration during pregnancy and cord blood in normal pregnancy, preterm delivery and small-for-gestational-age (SGA). Results : Twenty pregnant women with normal term delivery, 35 with preterm delivery, 24 with SGA, and 10 non-pregnant adult women were enrolled. Serum biotin concentrations of pregnant women remained low from first to third trimester. The levels of serum biotin in cord blood showed a significant positive correlation with gestational age, and that of pregnant women showed a weak positive correlation with gestational age. The maternal serum biotin levels during second and third trimester of SGA group were significantly lower than those of normal term delivery. Conclusion : This study suggests that maternal biotin deficiency during pregnancy might be the risk of preterm labor or fetal growth restriction. Further studies are required to clarify the roles of biotin in perinatal medicine. J. Med. Invest. 67 : 170-173, February, 2020.


A novel index equivalent to the myocardial performance index for right ventricular functional assessment in children and adolescent patients.

The aims of the present study were to develop and check the utility and feasibility of a novel right ventricular (RV) functional index (RV angular velocity; RVω, s) derived from the angular velocity in harmonic oscillator kinematics obtained from the RV pressure waveform. We hypothesized that RVω reflects the myocardial performance index (MPI), which represents global RV function. A total of 132 consecutive patients, ranging in age from 3 months to 34 years with various cardiac diseases were included in this prospective study. RVω was defined as the difference between the peak derivative of pressure (dP/dt_max - dP/dt_min) divided by the difference between the maximum and minimum pressure (Pmax - Pmin). RVω showed significant negative correlations with the pulsed-wave Doppler-derived myocardial performance index (PWD-MPI) and the tissue Doppler imaging-derived MPI (TDI-MPI) (r = -0.52 and -0.51, respectively; both p < 0.0001). RVω also showed significant positive correlations with RV fractional area change (RVFAC) and RV ejection fraction (RVEF) (r = 0.41 and 0.39, respectively; both p < 0.0001), as well as a significant negative correlation with tricuspid E/e' (r = -0.19, p = 0.0283). The clinical feasibility and utility of RVω for assessing global RV performance, incorporating both systolic and diastolic function, were demonstrated.


Successful treatment with voriconazole combined with amphotericin B-liposome for fluconazole-resistant pulmonary cryptococcosis after renal transplantation.

Cryptococcosis is an invasive fungal infection that is common among organ transplant recipients, and it is challenging to treat among these patients because of their immunocompromised status. Fluconazole (FLCZ) is recommended as a first-line treatment modality for pulmonary cryptococcosis in organ transplant recipients. However, cases of FLCZ resistance among Cryptococcus neoformans isolates have been reported from the Asia Pacific region. Previous studies have reported the efficacy of voriconazole (VRCZ) in patients with FLCZ-resistant fungal infections. Herein, we report a case of FLCZ-resistant pulmonary cryptococcosis after renal transplantation that was successfully treated with VRCZ combined with amphotericin B-liposome (L-AMB). The patient was a-23-year-old woman who underwent living-donor kidney transplantation at age 20 years. She has attended our hospital since before for mental retardation, epilepsy, and dilated cardiomyopathy. At age 23 years, she presented to our hospital with fever and cough. She was diagnosed with pulmonary cryptococcosis based on positive-serum cryptococcal antigen. Chest radiography showed bilateral consolidations. Fosfluconazole (F-FLCZ) was administered, and her condition improved. However, she developed cough and fever again on day 60 of hospitalization. Cryptococcosis recurrence was suspected due to the high degree of cryptococcal antigen titers showed (1:2048) taken on the same day. Therefore, L-AMB was added, and F-FLCZ was substituted with VRCZ. Her condition improved, but L-AMB was discontinued due to hyponatremia, hypokalemia, and elevated serum creatinine. This indicates that VRCZ caused the remission. She was discharged after 6 months of admission. In conclusion, this case shows the efficacy of VRCZ combined with L-AMB for refractory pulmonary cryptococcosis.


Ovomucoid-specific IgG4 level in cord blood associates negatively with later sensitization.


A 16q22.2-q23.1 deletion identified in a male infant with West syndrome.

In partial monosomy of the distal part of chromosome 16q, abnormal facial features, intellectual disability (ID), and feeding dysfunction are often reported. However, seizures are not typical and the majority of them were seizure-free. Here we present the case of a 16q22.2-q23.1 interstitial deletion identified in a male patient with severe ID, facial anomalies including forehead protrusions and flat nose bridge, patent ductus arteriosus, bilateral vocal cord atresia treated by tracheotomy, and West syndrome, which were developed 10months after birth. Although phenobarbital, sodium valproate (VPA), and zonisamide were not effective as monotherapies or combination therapies, the patient's epileptic seizures and electroencephalogram anomalies disappeared following combined therapy with lamotrigine and VPA. Although WW Domain Containing Oxidoreductase (WWOX), which is known as a cause of autosomal recessive epileptic encephalopathy, was included within the 6.8-Mb deleted region which identified by targeted panel sequencing and validated by chromosomal microarray analysis, no pathogenic variants were detected in the other allele of WWOX. Therefore, it is possible that other genes within or outside of the long deleted region or their interactions may cause West syndrome in this patient.


Trajectories of class-switching-related egg and cow's milk allergen-specific immunoglobulin isotype formation and its modification by eczema with low- and high-affinity immunoglobulin E during early infancy

Allergen-specific immunoglobulin isotype formation associated with immunoglobulin class-switching during the lactation period is the immunological background for food allergy in infants. We analyzed the serial changes in the production of feeding type-related egg- and milk-specific immunoglobulin isotypes from birth to 6 months of age with or without eczema in 84 infants. Allergen-specific immunoglobulin G1 (IgG1), IgG2, IgG3, IgG4, IgA, and IgE levels of hen's egg and bovine milk were measured in cord blood and blood samples from infants at 2, 4, and 6 months of age by the densely carboxylated protein microarray. Formula and mixed feeding were associated with a rapid increase in cow's milk allergen-specific immunoglobulins and feeding type-related significant differences in casein-specific immunoglobulin levels were detected. Breast and mixed feeding were associated with slow but significant increase in ovalbumin-specific IgG1 and IgE levels, but not other immunoglobulins. We found two different immunoglobulin isotype formation at 6 months of age with low- or high-affinity IgE against ovalbumin. One isotype formation pattern had relatively high ovalbumin-specific IgG1 levels, detectable IgG2, and low-affinity IgE, while the other had low ovalbumin-specific IgG1 levels, undetectable IgG2, and high levels of high-affinity IgE. The incidence of eczema was significantly higher in the latter pattern (84.6%), compared with the remaining infants (42.2%). Feeding practice-related allergen sensitization and immunoglobulin isotype formation were identified during the lactation period. The development of eczema during the lactation period could potentially modify the immunoglobulin isotype formation with high levels of high-affinity IgE.


Right Ventricular Myocardial Stiffness and Relaxation Components by Kinematic Model-Based Transtricuspid Flow Analysis in Children and Adolescents with Pulmonary Arterial Hypertension.

We hypothesized that the kinematic model-based parameters obtained from the transtricuspid E-wave would be useful for evaluating the right ventricular diastolic property in pediatric pulmonary arterial hypertension (PAH) patients. The model was parametrized by stiffness/elastic recoil k, relaxation/damping c and load x. These parameters were determined as the solution of m dx/dt + c dx/dt + kx = 0, which is based on the theory that the E-wave contour is determined by the interplay of stiffness/restoring force, damping/relaxation force and load. The PAH group had a significantly higher k and c compared with the control group (182.5 72.4 g/s vs. 135.7 49.5 g/s, p = 0.0232, and 21.9 6.5 g/s vs. 10.6 5.2 g/s, p <0.0001, respectively). These results indicate that in the PAH group, the right ventricle had higher stiffness/elastic recoil and inferior cross-bridge relaxation. The present findings indicate the feasibility and utility of using kinematic model parameters to assess right ventricular diastolic function.


Growth and neurodevelopment of small for gestational age infant

Small for gestational age児の成長および神経学的発達の予後

(Background)Small for gestational age (SGA) infants have multiple risk factors for short stature, developmental disorders, and metabolic diseases in adulthood. Our institute which plays central roles in perinatal medicine in Tokushima prefecture has many high risk pregnant women, therefore a relatively large number of SGA infants admitted to neonatal intensive care unit (NICU) and growth care unit (GCU).(Objective)To elucidate the prognosis such as short stature, neurodevelopmental disorder and mental retardation of SGA infants discharged from NICU and GCU in our hospital.(Method)SGA patients discharged from NICU and GCU in our hospital between 2012 and 2014 were enrolled in this study. Clinical data were collected from medical charts.(Results)There were 106 SGA infants (19.5%) discharged from NICU/GCU for 3 years. We excluded patients with congenital malformation syndrome, chromosomal abnormality, neuromuscular disorder, death and lost of follow-up, and finally 75 SGA infants were enrolled. Four SGA infants (5%) required growth hormone (GH) treatment for short stature and all of them were promoted growth significantly. Three SGA infants (4%) showed attention deficit hyperactivity disorder and/or autism spectrum disorder, and 5 SGA infants (6%) presented with mental retardation.(Conclusion)This study revealed the prognosis of SGA infants discharged from NICU and GCU in our hospital. Further large cohort with long-term observation is required.


Optical coherence tomography for observing development of pulmonary arterial vasa vasorum after bidirectional cavopulmonary connection in children.

Hypoxia and low pulmonary arterial (PA) blood flow stimulate the development of systemic-to-pulmonary collateral blood vessels, which can be an adverse factor when performing the Fontan operation. The aim of this study was to use optical coherence tomography (OCT) to elucidate the morphological changes in PA vasculature after creation of a bidirectional cavopulmonary connection (BCPC) in children. This prospective study evaluated PA wall thickness and development of PA vasa vasorum (VV) in the distal PA of eight patients (BCPC group, 1.3 0.3 years) and 20 age-matched children with normal pulmonary artery hemodynamics and morphology (Control group, 1.4 0.3 years). VV development was defined by the VV area ratio, defined as the VV area divided by the adventitial area in cross-sectional images. There was no significant difference in PA wall thickness between the BCPC and control groups (0.12 0.03 mm vs. 0.12 0.02 mm, respectively). The VV area ratio was significantly greater in the BCPC group than in the Control group (14.5 3.5% vs. 5.3 1.6%, respectively; p<0.0001). OCT is a promising new tool for evaluating PA pathology, including the development of VV in patients after BCPC.


Enhanced angiotensinogen expression in neonates during kidney development.

We recently demonstrated that preterm neonates have higher urinary angiotensinogen (AGT) levels than full-term neonates. Here, we tested the hypothesis that enhanced neonatal AGT expression is associated with intrarenal renin-angiotensin system (RAS) status during kidney development. We prospectively recruited neonates born at our hospital and healthy children with minor glomerular abnormalities between April 2013 and March 2017. We measured neonatal plasma and urinary AGT levels at birth and 1 year later and assessed renal AGT expression in kidney tissues from neonates and healthy children using immunohistochemical (IHC) analysis. Fifty-four neonates and eight children were enrolled. Although there were no changes in plasma AGT levels, urinary AGT levels were significantly decreased 1 year after birth. Urinary AGT levels at birth were inversely correlated with gestational age, and urinary AGT levels at birth and 1 year later were inversely correlated with estimated glomerular filtration rate 1 year after birth. IHC analysis showed that renal AGT expression in neonates was higher than that in healthy children and inversely correlated with gestational age. Enhanced AGT expression and urinary AGT excretion may reflect intrarenal RAS activation associated with kidney development in utero.


The case of an abused child with severe multiple handicaps hospitalized by legal authority

無呼吸発作を繰り返し混合性無呼吸と考えられたが, アデノイド口蓋扁桃摘出術により発作が消失した, 措置入院中の重症心身障がい (重心) 児の1例


Expression of NADPH oxidase and production of reactive oxygen species contribute to ureteric bud branching and nephrogenesis.

Ureteric bud branching and nephrogenesis are performed through large-scale proliferation and apoptosis events during renal development. Reactive oxygen species (ROS), produced by NADPH oxidase, may contribute to cell behaviors, including proliferation and apoptosis. We investigated the role of NADPH oxidase expression and ROS production in developing kidneys. Immunohistochemistry revealed that NADPH oxidase componentswere expressed on epithelial cells in ureteric bud branches, as well as on immature glomerular cells and epithelial cells in nephrogenic zones. ROS production, detected by dihydroethidium assay, was strongly observed in ureteric bud branches and nephrogenic zones, corresponding with NADPH oxidase localization. Organ culture of E14 kidneys revealed that the inhibition of NADPH oxidase significantly reduced the number of ureteric bud branches and tips, consistent with reduced ROS production. This was associated with reduced expression of phosphorylated ERK1/2 and increased expression of cleaved caspase-3. Organ culture of E18 kidneys showed that the inhibition of NADPH oxidase reduced nephrogenic zone size, accompanied by reduced ROS production, fewer proliferating cell nuclear antigen-positive cells, lower p-ERK1/2 expression, and increased expression of cleaved caspase-3. These results demonstrate that ROS produced by NADPH oxidase might play an important role in ureteric bud branching and nephrogenesis by regulating proliferation and apoptosis. J.Med. Invest. 66 :93-98, February, 2019.

The Journal of Medical Investigation : JMI


Efficacy of an elimination diet in a patient with eosinophilic gastroenteritis : a pediatric case with multiple food allergies.


Development of acquired intrapulmonary venous anastomosis contributing to establishment of Fontan circulation.

Pulmonary venous (PV) obstruction is associated with a poor prognosis, as well as a high risk of recurrence, following surgical treatment. It can also interfere with the successful completion of Fontan circulation in patients with complex congenital heart disease. A case of a patient who had right isomerism (also known as asplenia syndrome), total anomalous pulmonary venous connection (TAPVC), and a single right ventricle is presented. Although bilateral total occlusion of the inferior PVs was identified postoperatively, the formation of the anastomosis and collateral vessels into the superior and middle PVs enabled successful completion of Fontan circulation. Anastomoses and collateral flow of the PVs were found largely in the interlobar pleura and not in the lung parenchyma.


Effects of the selective chymase inhibitor TEI-F00806 on the intrarenal renin-angiotensin system in salt-treated angiotensin I-infused hypertensive mice.

What is the central question of this study? Can chymase inhibition prevent angiotensin I-induced hypertension through inhibiting the conversion of angiotensin I to angiotensin II in the kidney? What is the main finding and its importance? Treatment with TEI-F00806 decreased angiotensin II content of the kidney, renal cortical angiotensinogen protein levels and chymase mRNA expression, and attenuated the development of hypertension. The effects of the selective chymase inhibitor TEI-F00806 were examined on angiotensin I (Ang I)-induced hypertension and intrarenal angiotensin II (Ang II) production in salt-treated mice. Twelve-week-old C57BL male mice were given a high-salt diet (4% NaCl + saline (0.9% NaCl)), and divided into three groups: (1) sham + vehicle (5% acetic acid in saline), (2) Ang I (1 μg kg min , s.c.) + vehicle, and (3) Ang I + TEI-F00806 (100 mg kg day , p.o.) (n = 8-10 per group). Systolic blood pressure was measured weekly using a tail-cuff method. Kidney Ang II content was measured by radioimmunoassay. Chronic infusion of Ang I resulted in the development of hypertension (P < 0.001), and augmented intrarenal chymase gene expression (P < 0.05), angiotensinogen protein level (P < 0.001) and Ang II content (P < 0.01) in salt-treated mice. Treatment with TEI-F00806 attenuated the development of hypertension (P < 0.001) and decreased Ang II content of the kidney (P < 0.05), which was associated with reductions in renal cortical angiotensinogen protein levels (P < 0.001) and chymase mRNA expression (P < 0.05). These data suggest that a chymase inhibitor decreases intrarenal renin-angiotensin activity, thereby reducing salt-dependent hypertension.


多発性の結節病変を呈した生体腎移植後肺クリプトコッカス症の1例

多発性の結節病変を呈した生体腎移植後肺クリプトコッカス症の1例

第40回日本小児腎不全学会学術集会

第40回日本小児腎不全学会学術集会


Pulmonary Artery Wall Thickness Assessed by Optical Coherence Tomography Correlates With Pulmonary Hemodynamics in Children With Congenital Heart Disease.

Pulmonary arterial (PA) wall thickening evaluated by optical coherence tomography (OCT) has been reported in adults with PA hypertension. The purpose of this study was to evaluate the feasibility of OCT for preoperative assessment of the PA wall in children with congenital heart disease (CHD). Methods and esults: Participants comprised 39 patients with ventricular septal defect, atrial septal defect, or patent ductus arteriosus. Attempts were made to evaluate vessels of various diameters using OCT. Clearly observed vessels that were optimal for evaluation were selected and classified into 4 subgroups by diameter of the lumen. Optimal depiction was obtained in 80 of 156 vessels in total, and 25 (64.1%), 34 (87.1%), 17 (43.6%), and 4 vessels (10.3%) in each of the 1.0-<2.0 mm, 2.0-<3.0 mm, 3.0-<4.0 mm, and 4.0-5.0 mm subgroups, respectively. Arterial walls in the 2.0-<3.0 mm subgroup were the most frequently delineated, and wall thickness correlated significantly with mean PA pressure, pulmonary vascular resistance index, pulmonary-to-systemic flow ratio, and PA capacitance index (r=0.56, 0.52, 0.37, and -0.49, respectively). The 3-layered appearance was delineated in 29 of 80 vessels (36.2%). This feature had no significant correlation with pulmonary hemodynamics. OCT represents a promising tool for evaluating the PA wall in children with CHD.


右室圧負荷は僧帽弁のtethering を増悪させる:内科的加療のみで軽快した重症僧帽弁狭窄兼閉鎖不全の1乳児例の考察

Pediatric Cardiology and Cardiac Surgery


生体腎移植後に肺クリプトコッカス症を発症し治療に難渋した1例

生体腎移植後に肺クリプトコッカス症を発症し治療に難渋した1例

第53回日本小児腎臓病学会学術集会

第53回日本小児腎臓病学会学術集会


家族性のステロイド感受性ネフローゼ症候群の原因候補遺伝子の機能解析

家族性のステロイド感受性ネフローゼ症候群の原因候補遺伝子の機能解析

第61回日本腎臓学会学術総会

第61回日本腎臓学会学術総会


小児IgA腎症における尿中アンジオテンシン変換酵素2と糸球体病変の関係

小児IgA腎症における尿中アンジオテンシン変換酵素2と糸球体病変の関係

第61回日本腎臓学会学術総会

第61回日本腎臓学会学術総会


当院NICUにおける過去10年間の晩期循環不全の検討

当院NICUにおける過去10年間の晩期循環不全の検討

第121回日本小児科学会学術集会

第121回日本小児科学会学術集会


Analysis of Right Ventricular Myocardial Stiffness and Relaxation Components in Children and Adolescents With Pulmonary Arterial Hypertension.

The rate of left ventricular pressure decrease during isovolumic relaxation is traditionally assessed algebraically via 2 empirical indices: the monoexponential and logistic time constants (τ and τ). Since the pattern of right ventricular (RV) pressure decrease is quite different from that of the left ventricular, we hypothesized that novel kinematic model parameters are more appropriate and useful to evaluate RV diastolic dysfunction. Eight patients with pulmonary arterial hypertension (age 12.5±4.8 years) and 20 normal subjects (control group; age 12.3±4.4 years) were enrolled. The kinematic model was parametrized by stiffness/restoring Ek and damping/relaxation μ. The model predicts isovolumic relaxation pressure as a function of time as the solution of dP/dt+(1/μ)dP/dt+EkP=0, based on the theory that the pressure decay is determined by the interplay of inertial, stiffness/restoring, and damping/relaxation forces. In the assessment of RV diastolic function, τ and τ did not show significant differences between the pulmonary arterial hypertension and control groups (46.8±15.5 ms versus 32.5±14.6 ms, and 19.6±5.9 ms versus 14.5±7.2 ms, respectively). The pulmonary arterial hypertension group had a significantly higher Ek than the control group (915.9±84.2 s versus 487.0±99.6 s, <0.0001) and a significantly lower μ than the control group (16.5±4.3 ms versus 41.1±10.4 ms, <0.0001). These results show that the RV has higher stiffness/elastic recoil and lower cross-bridge relaxation in pulmonary arterial hypertension. The present findings indicate the feasibility and utility of kinematic model parameters for assessing RV diastolic function.

Journal of the American Heart Association


Pulmonary annular motion velocity reflects right ventricular outflow tract function in children with surgically repaired congenital heart disease

Right ventricular (RV) dysfunction is generally evaluated using analyses of tricuspid annular motion. However, it represents only one aspect of RV performance. Whether measuring pulmonary annular motion velocity could serve as a novel way to evaluate global RV and/or RV outflow tract (RVOT) performance in pediatric congenital heart disease (CHD) patients with surgically repaired RVOT was evaluated. In this prospective study, tissue Doppler-derived pulmonary annular motion velocity was measured in children (aged 2-5 years) with RVOT reconstruction (RVOTR group, n = 48) and age-matched healthy children (Control, n = 60). The types of RVOTR procedures were as follows: pulmonary valve-sparing procedure (PVS, n = 7); transannular patch with monocusp valve reconstruction (TAP, n = 29); and RV-to-PA conduit reconstruction using a pericardial valve with expanded polytetrafluoroethylene conduit (Rastelli, n = 12). Pulmonary annular motion velocity waveforms comprised systolic bimodal (s1' and s2') and diastolic e' and a' waves in all participants. The peak velocities of s1', s2', e', and a' were significantly lower in the RVOTR group than in the control group (all p < 0.0001). Furthermore, these parameters depended significantly on the type of surgical procedure. The peak velocities of s1', s2', and e' had significant correlations with RVOT ejection fraction (RVOT-EF) (r = 0.56, 0.49, and 0.34, respectively), and RVOT fractional shortening (RVOT-FS) (r = 0.72, 0.55, and 0.41, respectively), although there were no significant correlations between pulmonary annular motion and global RV function, including RV ejection fraction (RVEF) and RV fractional area change (RVFAC) in the assessment of all RVOTR group patients. The pulmonary annular motion parameters in the PVS group had significant correlations with both global RV and RVOT performance. The TAP group showed significant correlations between RVOT function and pulmonary annular motion. The Rastelli group showed almost no significant correlations between RV/RVOT function and tissue Doppler parameters. Pulmonary annular motion velocity is a simple, rapid, reproducible, and useful method of assessing RVOT function in children with surgically repaired CHD.


Controversies of the classification of TMA and the terminology of aHUS.


Temporal Sequential Pattern of Right Ventricular Free Wall Contraction in Normal Children.

The temporal sequence of right ventricular (RV) deformation is related to RV dysfunction. The sequence of RV free wall contraction was investigated.Methods and Results:In this prospective study, strain profiles using speckle-tracking echocardiography and tissue Doppler-derived pulmonary and tricuspid annular motion were assessed in 60 normal children. Circumferential RV free wall strain of 3 individual segments (anterior, lateral, and inferior) was evaluated. Longitudinal strain was assessed in 3 individual segments (RV outflow tract [RVOT], apical, and RV inflow tract [RVIT]). The isovolumetric contraction time (ICT) and the time interval between the onset of the QRS wave to the peak s' wave were measured for pulmonary and tricuspid annular motion velocities. The time to peak circumferential strain was significantly lower in the anterior than in the lateral and inferior segments (339.1±19.5, 358.3±21.8, and 366.6±22.4 ms, respectively; P<0.0001). Longitudinal deformation of the RVOT segment occurred before the apical and RVIT segments (351.8±23.1, 366.3±20.1, and 369.2±21.3 ms, respectively; P<0.0001). The ICT and the time to peak s' were significantly shorter in pulmonary than in tricuspid annular motion (49.4±10.1 vs 58.0±13.2 ms; and 104.7±12.2 vs. 160.5±27.1 ms; P<0.0001 for each). Longitudinal deformation of RVOT precedes RVIT. Circumferential deformation occurs in the anterior segment before the lateral and posterior segments. The presence of mechanical time heterogeneity appears important for RV performance.


徳島県における小児末期腎不全患者の現況

徳島県における小児末期腎不全患者の現況

日本小児PD・HD研究会雑誌

日本小児PD・HD研究会雑誌


Re-recognition of Age-dependent Reference Range for the Serum Creatinine Level in Teenagers - A Case of Slowly Progressive Tubulointerstitial Nephritis which Occurred in an Adolescent.

For the first time, a 15-year-old boy was found to have a slight degree of proteinuria and microscopic hematuria during annual school urinalysis screening. His kidney function had already severely deteriorated. A kidney biopsy revealed tubulointerstitial nephritis (TIN) with diffuse inflammatory cell infiltration. His medical records showed his serum creatinine level to be 0.98 mg/dL two years ago, which was abnormally high considering his age. Although the etiology of slowly progressive TIN was unclear, glucocorticoid and immunosuppressant therapy improved his kidney function. This case report suggests that all doctors should recognize the reference range for the serum creatinine level in teenagers.


The first Japanese patient with mandibular hypoplasia, deafness, progeroid features and lipodystrophy diagnosed via POLD1 mutation detection.

Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome is a rare autosomal dominant disorder caused by heterozygous mutations. To date, 13 patients affected by mutation-caused MDPL have been described. We report a clinically undiagnosed 11-year-old male who noted joint contractures at 6 years of age. Targeted exome sequencing identified a known mutation [NM_002691.3:c.1812_1814del, p.(Ser605del)] that diagnosed him as the first Japanese/East Asian MDPL case.


Assessment of pulmonary arterial compliance evaluated using harmonic oscillator kinematics.

We hypothesized that K, a harmonic oscillator kinematics-derived spring constant parameter of the pulmonary artery pressure (PAP) profile, reflects PA compliance in pediatric patients. In this prospective study of 33 children (age range = 0.5-20 years) with various cardiac diseases, we assessed the novel parameter designated as Kcalculated using the pressure phase plane and the equation K = (dP/dt_max)/([Pmax - Pmin])/2), where dP/dt_max is the peak derivative of PAP, and Pmax - Pmin is the difference between the minimum and maximum PAP. PA compliance was also calculated using two conventional methods: systolic PA compliance (sPAC) was expressed as the stroke volume/Pmax - Pmin; and diastolic PA compliance (dPAC) was determined according to a two-element Windkessel model of PA diastolic pressure decay. In addition, data were recorded during abdominal compression to determine the influence of preload on K. A significant correlation was observed between Kand sPAC (r = 0.52, P = 0.0018), but not dPAC. Significant correlations were also seen with the time constant (τ) of diastolic PAP (r = -0.51, P = 0.0026) and the pulmonary vascular resistance index (r = -0.39, P = 0.0242). No significant difference in Kwas seen between before and after abdominal compression. Khad a higher intraclass correlation coefficient than other compliance and resistance parameters for both intra-observer and inter-observer variability (0.998 and 0.997, respectively). These results suggest that Kcan provide insight into the underlying mechanisms and facilitate the quantification of PA compliance.


A Proton Magnetic Resonance Spectroscopic Study in Autism Spectrum Disorder Using a 3-Tesla Clinical Magnetic Resonance Imaging (MRI) System: The Anterior Cingulate Cortex and the Left Cerebellum.

The pathophysiology of autism spectrum disorder (ASD) is not fully understood. We used proton magnetic resonance spectroscopy to investigate metabolite concentration ratios in the anterior cingulate cortex and left cerebellum in ASD. In the ACC and left cerebellum studies, the ASD group and intelligence quotient- and age-matched control group consisted of 112 and 114 subjects and 65 and 45 subjects, respectively. In the ASD group, γ-aminobutyric acid (GABA)+/ creatine/phosphocreatine (Cr) was significantly decreased in the anterior cingulate cortex, and glutamate (Glu)/Cr was significantly increased and GABA+/Cr was significantly decreased in the left cerebellum compared to those in the control group. In addition, both groups showed negative correlations between Glu/Cr and GABA+/Cr in the left cerebellum, and positive correlations between GABA+/Cr in the anterior cingulate cortex and left cerebellum. ASD subjects have hypoGABAergic alterations in the anterior cingulate cortex and hyperglutamatergic/hypoGABAergic alterations in the left cerebellum.


(Pro)renin and (pro)renin receptor expression during kidney development in neonates.

Although a recent study demonstrated that the (pro)renin receptor ((P)RR) was highly expressed in the developing kidney during the mouse embryonic development, the mechanism by which (P)RR supports renal development in humans is not fully understood. In this study, we examined the plasma levels of (pro)renin and soluble (P)RR (s(P)RR) in cord blood and neonates as well as (P)RR expression in human kidney tissues. Samples were collected from 57 preterm and 67 full-term human neonates. (Pro)renin and s(P)RR levels were measured using enzyme-linked immunosorbent assays. Additionally, we performed an immunohistochemical (IHC) analysis of kidney tissues from neonates and minor glomerular abnormalities in order to assess (P)RR expression in the kidney. Plasma (pro)renin and s(P)RR levels in cord blood were significantly higher in preterm neonates than in full-term neonates. Four weeks after birth, these differences were no longer evident for either plasma (pro)renin or s(P)RR levels between the two groups. Importantly, plasma (pro)renin and s(P)RR levels in cord blood were inversely correlated with gestational age. Furthermore, IHC indicated that renal expression levels of (P)RR in neonates were stronger than those in minor glomerular abnormalities. (P)RR may play a pivotal role in prenatal renal development in humans. What is Known: · Renal renin-angiotensin system (RAS) has several pathophysiologic functions not only in blood pressure regulation but also in pediatric renal disease. · Renal RAS activation plays a key role of renal development during gestation. What is New : · Plasma (pro)renin and soluble (pro)renin receptor (s(P)RR) levels in cord blood were significantly higher in preterm neonates than in full-term neonates. · Immunohistochemical analysis of kidney tissue indicated that renal expression levels of (P)RR in neonates were stronger than in minor glomerular abnormalities.


Assessment of Anterior Cingulate Cortex (ACC) and Left Cerebellar Metabolism in Asperger's Syndrome with Proton Magnetic Resonance Spectroscopy (MRS).

Proton magnetic resonance spectroscopy (1H MRS) is a noninvasive neuroimaging method to quantify biochemical metabolites in vivo and it can serve as a powerful tool to monitor neurobiochemical profiles in the brain. Asperger's syndrome (AS) is a type of autism spectrum disorder, which is characterized by impaired social skills and restrictive, repetitive patterns of interest and activities, while intellectual levels and language skills are relatively preserved. Despite clinical aspects have been well-characterized, neurometabolic profiling in the brain of AS remains to be clear. The present study used proton magnetic resonance spectroscopy (1H MRS) to investigate whether pediatric AS is associated with measurable neurometabolic abnormalities that can contribute new information on the neurobiological underpinnings of the disorder. Study participants consisted of 34 children with AS (2-12 years old; mean age 5.2 (±2.0); 28 boys) and 19 typically developed children (2-11 years old; mean age 5.6 (±2.6); 12 boys) who served as the normal control group. The 1H MRS data were obtained from two regions of interest: the anterior cingulate cortex (ACC) and left cerebellum. In the ACC, levels of N-acetylaspartate (NAA), total creatine (tCr), total choline-containing compounds (tCho) and myo-Inositol (mI) were significantly decreased in children with AS compared to controls. On the other hand, no significant group differences in any of the metabolites were found in the left cerebellum. Neither age nor sex accounted for the metabolic findings in the regions. The finding of decreased levels of NAA, tCr, tCho, and mI in the ACC but not in left cerebellar voxels in the AS, suggests a lower ACC neuronal density in the present AS cohort compared to controls.


Coil occlusion of aberrant arteries to pulmonary sequestration in a case with pulmonary atresia with intact ventricular septum: successful treatment of repetitive myocardial ischaemic attacks

In this study, we describe an infant case of pulmonary atresia with intact ventricular septum associated with ventriculo-coronary arterial communication for which a modified Blalock-Taussig shunt operation was performed. He experienced repeated myocardial ischaemic attacks. Further examination revealed pulmonary sequestration in the right lower lobe. He therefore underwent a bidirectional Glenn operation and coil occlusion of the feeding arteries. His myocardial ischaemic attacks subsequently improved.


Exome-first approach identified a novel gloss deletion associated with Lowe syndrome.

Lowe syndrome (LS) is an X-linked disorder affecting the eyes, nervous system and kidneys, typically caused by missense or nonsense/frameshift OCRL mutations. We report a 6-month-old male clinically suspected to have LS, but without the Fanconi-type renal dysfunction. Using a targeted-exome sequencing-first approach, LS was diagnosed by the identification of a deletion involving 1.7 Mb at Xq25-q26.1, encompassing the entire OCRL gene and neighboring loci.


Differential regulation of angiotensin II-induced extracellular regulated kiase-1/2 and -5 in progressive glomerulonephritis.

Extracellular signal regulated kinase (ERK)1/2 and ERK5 are key kinases of the signalling pathways involved in various cellular responses to kidney injury; however, the mechanistic links between those kinase and renin-angiotensin system (RAS) activations in glomerulonephritis (GN) have not been fully elucidated. In this study, we sought to clarify the potential roles of ERK1/2 and ERK5 via RAS activation in the pathogenesis of GN. A rat model of progressive GN was induced by anti-glomerular basement membrane (GBM) injection and the signal transduction pathway in angiotensin II (Ang II)-induced glomerular pathologic alterations were investigated in primary cultured mesangial cells (MCs). Rats developed typical cellular crescents in glomeruli on day 7 that progressed to severe fibrocellular crescents and glomerulosclerosis on day 28. Strong expression of phospho-ERK1/2 was observed on day 7 and phospho-ERK5 expression was markedly increased on day 28 of GN. An angiotensin II type 1 receptor blocker (ARB) suppressed those augmentations. Moreover, ARB treatment attenuated the increases in macrophage infiltration and PCNA-positive cells observed on day 7 in GN rats, as well as the increase in collagen type 1 expression on day 28. Consistently, MCs stimulated by Ang II showed significant increases in proliferation and the expression of MCP-1 and collagen type 1. Interestingly, while the ERK1/2 inhibitor PD98059 abolished the elevations in MCP-1 expression and cell proliferation, the ERK5 inhibitor BIX02189 abrogated the elevation in collagen type 1 expression. Altogether, these data suggest that ERK1/2 regulates acute inflammatory reactions, while ERK5 promotes the development of RAS-induced chronic glomerular fibrosis activation in GN.


Survival of mature T cells depends on signaling through HOIP.

T cell development in the thymus is controlled by a multistep process. The NF-B pathway regulates T cell development as well as T cell activation at multiple differentiation stages. The linear ubiquitin chain assembly complex (LUBAC) is composed of Sharpin, HOIL-1L and HOIP, and it is crucial for regulating the NF-B and cell death pathways. However, little is known about the roles of LUBAC in T-cell development and activation. Here, we show that in T-HOIP(linear) mice lacking the ubiquitin ligase activity of LUBAC, thymic CD4(+) or CD8(+) T cell numbers were markedly reduced with severe defects in NKT cell development. HOIP(linear) CD4(+) T cells failed to phosphorylate IB and JNK through T cell receptor-mediated stimulation. Mature CD4(+) and CD8(+) T cells in T-HOIP(linear) mice underwent apoptosis more rapidly than control T cells, and it was accompanied by lower CD127 expression on CD4(+)CD24(low) and CD8(+)CD24(low) T cells in the thymus. The enforced expression of CD127 in T-HOIP(linear) thymocytes rescued the development of mature CD8(+) T cells. Collectively, our results showed that LUBAC ligase activity is key for the survival of mature T cells, and suggest multiple roles of the NF-B and cell death pathways in activating or maintaining T cell-mediated adaptive immune responses.


A novel missense mutation of COL5A2 in a patient with Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders characterized by hyperextensible skin, joint hypermobility and soft tissue fragility. For molecular diagnosis, targeted exome sequencing was performed on a 9-year-old male patient who was clinically suspected to have EDS. The patient presented with progressive kyphoscoliosis, joint hypermobility and hyperextensible skin without scars. Ultimately, classical EDS was diagnosed by identifying a novel, mono-allelic mutation in COL5A2 [NM_000393.3(COL5A2_v001):c.682G>A, p.Gly228Arg].


Noninvasive assessment of pulmonary arterial capacitance by pulmonary annular motion velocity in children with ventricular septal defect.

We hypothesized that longitudinal pulmonary arterial deformation during the cardiac cycle reflects pulmonary arterial capacitance. To examine this hypothesis, we assessed whether tissue Doppler-derived pulmonary annular motion could serve as a novel way to evaluate pulmonary arterial capacitance in pediatric patients with ventricular septal defect (VSD). In this prospective study, pulmonary annular velocity was measured in children (age, 6 months-5 years) with a preoperative VSD (VSD group, n = 35) and age-matched healthy children (Control group, n = 23). Pulmonary artery capacitance was calculated by two methods. Systolic pulmonary arterial capacitance (sPAC) was expressed as the stroke volume/pulmonary arterial pulse pressure. Diastolic pulmonary arterial capacitance (dPAC) was determined according to a two-element windkessel model of the pulmonary arterial diastolic pressure profile. Pulmonary annular velocity waveforms comprised systolic bimodal (s1' and s2') and diastolic e' and a' waves in all participants. The peak velocities of s1', s2', and e' were significantly lower in the VSD group than in the Control group. On multiple regression analysis, sPAC was an independent variable affecting the peak velocities of the s1', s2', and e' waves (β = 0.41, 0.62, and 0.35, respectively). The dPAC affected the s1' wave peak velocity (β = 0.34). The time durations of the s1' and e' waves were independently determined by the sPAC (β = 0.49 and 0.27). Pulmonary annular motion velocity evaluated using tissue Doppler is a promising method of assessing pulmonary arterial capacitance in children with VSD.


Role of the intrarenal renin-angiotensin system in the progression of renal disease.

The intrarenal renin-angiotensin system (RAS) has many well-documented pathophysiologic functions in both blood pressure regulation and renal disease development. Angiotensin II (Ang II) is the major bioactive product of the RAS. It induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation. In addition, Ang II regulates the gene expression of bioactive substances and activates multiple intracellular signaling pathways that are involved in renal damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, intracellular formation of reactive oxygen species, cell proliferation, and extracellular matrix synthesis, which in turn facilities renal injury. Involvement of angiotensinogen (AGT) in intrarenal RAS activation and development of renal disease has previously been reported. Moreover, studies have demonstrated that the urinary excretion rates of AGT provide a specific index of the intrarenal RAS status. Enhanced intrarenal AGT levels have been observed in experimental models of renal disease, supporting the concept that AGT plays an important role in the development and progression of renal disease. In this review, we focus on the role of intrarenal RAS activation in the pathophysiology of renal disease. Additionally, we explored the potential of urinary AGT as a novel biomarker of intrarenal RAS status in renal disease.


Detection of 1p36 deletion by clinical exome-first diagnostic approach.

Although chromosome 1p36 deletion syndrome is considered clinically recognizable based on characteristic features, the clinical manifestations of patients during infancy are often not consistent with those observed later in life. We report a 4-month-old girl who showed multiple congenital anomalies and developmental delay, but no clinical signs of syndromic disease caused by a terminal deletion in 1p36.32-p36.33 that was first identified by targeted-exome sequencing for molecular diagnosis.


A novel frameshift mutation of CHD7 in a Japanese patient with CHARGE syndrome.

CHARGE syndrome is a rare autosomal dominant developmental disorder involving multiple organs. CHD7 is a major causative gene of CHARGE syndrome. We performed targeted-exome sequencing using a next-generation sequencer for molecular diagnosis of a 4-month-old male patient who was clinically suspected to have CHARGE syndrome, and report a novel monoallelic mutation in CHD7, NM_017780.3(CHD7_v001):c.2966del causing a reading frameshift [p.(Cys989Serfs*3)].


Differential response in allergen-specific IgE, IgGs and IgA levels for predicting outcome of oral immunotherapy.

The response to OIT was associated with significant increases in serum allergen-specific IgG1 levels after rush phase and high baseline IgA levels, compared with small changes in immunoglobulin response in low-responders. The characteristic IgG1 changes and IgA levels in the responders could be potentially useful biomarkers for the prediction of positive clinical response to OIT. This article is protected by copyright. All rights reserved.


胎児期から類洞交通を確認できた純型肺動脈閉鎖の一例

胎児期から類洞交通を確認できた純型肺動脈閉鎖の一例

Journal of Japan Society of Perinatal and Neonatal Medicine

日本周産期・新生児医学会雑誌


補体の沈着を認めなかったPLA2R陽性特発性膜性腎症の1例

補体の沈着を認めなかったPLA2R陽性特発性膜性腎症の1例

Japanese Journal of Pediatric Nephrology


シクロスポリンが有効であったブドウ膜炎に伴う尿細管間質性腎炎の女児例

シクロスポリンが有効であったブドウ膜炎に伴う尿細管間質性腎炎の女児例


Ifosfamide and etoposide chemotherapy may interact with warfarin, enhancing the warfarin-induced anticoagulant response

To report a case of warfarin-response enhancement during administration of ifosfamide and etoposide chemotherapy. A 15-yearold boy with rhabdomyosarcoma was treated with a regimen of alternating cycles of vincristine, doxorubicin, and cyclophosphamide (VDC) chemotherapy and ifosfamide and etoposide (IE) chemotherapy. During VDC chemotherapy, occlusion of the left middle cerebral artery occurred, and warfarin was started. On day 3 of IE chemotherapy, the patient's international normalized ratio (INR) transiently increased from baseline 2.61 to 5.45. The INR returned to normal within 3 days after warfarin discontinuation. An increase in INR was observed between days 1 and 3 of subsequent cycles of IE chemotherapy but not during VDC chemotherapy. This INR increase was also observed during concomitant use of aprepitant, an inducer of the CYP2C9. There are no reports describing the interaction between warfarin and IE chemotherapy because coadministration of warfarin and IE chemotherapy is unusual. The Drug Interaction Probability Scale score of this interaction was 7, and it is probable that the enhancement of the warfarin response was caused by an interaction with IE chemotherapy. Moreover, in the present case, the enhancement of warfarin response was observed during concomitant use of aprepitant, which has been reported to weaken the warfarin response. Therefore, this interaction may be quite powerful and may increase the risk of warfarin toxicity. A patient who was administered both warfarin and IE chemotherapy experienced a rapid increase in INR, suggesting that INR should be closely monitored in patients receiving warfarin with IE chemotherapy.

International Journal of Clinical Pharmacology and Therapeutics


Pulmonary annular motion velocity assessed using Doppler tissue imaging - Novel echocardiographic evaluation of right ventricular outflow tract function-

We assessed whether measuring pulmonary annular motion velocity could serve as a novel method of evaluating right ventricular outflow tract (RVOT) performance in pediatric patients with heart disease. Tissue Doppler-derived pulmonary annular motion velocity was determined from the parasternal long-axis view of the RVOT. Pulmonary annular velocity was measured in children (age, 5-10 years) with an atrial septal defect (ASD), pulmonary arterial hypertension (PAH), surgically repaired tetralogy of Fallot (TOF) and healthy children (control). Pulmonary annular velocity waveforms comprised systolic bimodal (s1' and s2') and diastolic e' and a' waves in all groups. The peak velocity of s1' and s2' was significantly higher in the ASD group than in the controls (15.0±2.4 vs. 11.2±2.1 and 6.0±0.9 vs. 4.4±1.2 cm/s; P<0.01 and P<0.001, respectively). The s1' and s2' peak velocities were significantly lower in the PAH group (8.5±1.2 and 3.2±0.4 cm/s; P<0.05 for both), and in the group with TOF (5.3±2.2 and 3.4±1.4 cm/s; P<0.001 and P<0.05, respectively). The peak velocity of e' was significantly decreased in the PAH and TOF, compared with the control group (6.8±1.6 and 8.2±2.9 vs. 11.9±1.9 cm/s; P<0.001 for both). Pulmonary annular motion velocity determined using tissue Doppler imaging is a promising method of assessing RVOT function. (Circ J 2016; 80: 168-176).


正常肺組織を犠牲にすることを前提としてコイル塞栓術を施行した両側肺全区域びまん性肺動静脈瘻の1 例

Pediatric Cardiology and Cardiac Surgery


Optical coherence tomography can visualize the pulmonary artery in Williams-Beuren syndrome

European Heart Journal Cardiovascular Imaging


Aortic forward flow in aortic atresia via ventriculo-coronary arterial connections.


Right ventricular myocardial deformation patterns in children with congenital heart disease associated with right ventricular pressure overload.

Longitudinal wall motion of the right ventricle (RV) has been thoroughly studied in patients with RV dysfunction. However, circumferential strain of the RV free wall has yet to be investigated. Therefore, this study was conducted to assess the utility of RV free wall circumferential strain. Strain profile curves were obtained using speckle tracking echocardiography from the subcostal left ventricular (LV) short-axis view in 30 normal children (normal group) and 25 patients with RV pressure overload (RVO group). The time-strain curves of three individual segmental (anterior, lateral, and inferior segments) and global circumferential deformations were evaluated. RV ejection fraction (RVEF), RV systolic pressure (RVSP), and RV fractional area change obtained in the four-chamber view and LV short-axis view [RVFAC (4CH) and RVFAC (SAX), respectively] were measured, and their relationships with RV free wall deformation were assessed. In the normal group, circumferential strain was significantly lower in the anterior segment than in the other segments. The inferior segment had a significantly larger strain than the other segments in the RVO group. Circumferential strain was predominant over longitudinal RV free wall strain in the RVO group (-18.4 ± 3.9 vs. -14.2 ± 3.8%, respectively; P < 0.005), whereas no significant difference between them was observed in the normal group (-23.0 ± 3.9 vs. -22.4 ± 4.7%, respectively). Global circumferential strain had a significantly higher correlation with RVFAC (4CH), RVFAC (SAX), RVEF, and RVSP than global longitudinal strain (P < 0.05 for all). RV free wall circumferential strain provides better information about RV function than longitudinal strain in children with RVO.


Bronchogenic cyst compressing the pulmonary artery and the left atrium.


Changes in urinary angiotensinogen posttreatment in pediatric IgA nephropathy patients.

Recently, we demonstrated that urinary angiotensinogen (AGT) levels are increased and reflect intrarenal renin-angiotensin system (RAS) status in pediatric patients with chronic glomerulonephritis. Therefore, this study was performed to test the hypothesis that urinary AGT (UAGT) levels provide a specific index of intrarenal RAS status associated with RAS blockade treatment in pediatric IgA nephropathy (IgAN) patients. We measured plasma and UAGT levels and urinary transforming growth factor beta (TGF-β) levels, after which we performed immunohistochemical analysis of AGT, angiotensin II (Ang II), and TGF-β in 24 pediatric IgAN patients treated with RAS blockades for 2 years. Paired tests were used to analyze the changes from baseline to study end. Although there was no change in plasma AGT levels, UAGT and TGF-β levels were significantly decreased after RAS blockade, which was accompanied by the expression levels of AGT, Ang II, and TGF-β, as well as the magnitude of glomerular injury. Baseline UAGT levels positively correlated with diastolic blood pressure, urinary protein levels, scores for mesangial hypercellularity, and the expression levels of AGT, Ang II, and TGF-β in renal tissues. These data indicate that UAGT is a useful biomarker of intrarenal RAS activation, which is associated with glomerular injury during RAS blockade in pediatric IgAN patients.


Hydrogen peroxidase-inducible clone-5 regulates mesangial cell proliferation in proliferative glomerulonephritis in mice

Hydrogen peroxide-inducible clone-5 (Hic-5) is a transforming growth factor (TGF)-β1-inducible focal adhesion protein. We previously demonstrated that Hic-5 was localized in mesangial cells and its expression was associated with glomerular cell proliferation and matrix expansion in human and rat glomerulonephritis (GN). In the present study, we first assessed the role of Hic-5 in mesangioproliferative GN by injecting Habu venom into heminephrectomized wild type (Hic-5+/+) and Hic-5-deficient (Hic-5-/-) mice. Hic-5+/+ GN mice exhibited glomerular cell proliferation on day 7. Surprisingly, glomerular cell number and Ki-67-positive cells in Hic-5-/- GN mice were significantly greater than those in Hic-5+/+ GN mice on day 7, although the number of glomerular apoptotic cells and the expression of growth factors (platelet-derived growth factor-BB and TGF-β1) and their receptors were similarly increased in both Hic-5+/+ and Hic-5-/- GN mice. In culture experiments, proliferation assays showed that platelet-derived growth factor-BB and TGF-β1 enhanced the proliferation of Hic-5-/- mesangial cells compared with Hic-5+/+ mesangial cells. In addition, mitogenic regulation by Hic-5 was associated with altered and coordinated expression of cell cycle-related proteins including cyclin D1 and p21. The present results suggest that Hic-5 might regulate mesangial cell proliferation in proliferative GN in mice. In conclusion, modulation of Hic-5 expression might have a potential to prevent mesangial cell proliferation in the acute mitogenic phase of glomerulonephritis.


Are the equations for the creatinine-based estimated glomerular filtration rate applicable to the evaluation of renal function in Japanese children and adult patients receiving chemotherapy?

Equations for the creatinine-based estimated glomerular filtration rate (eGFR) were recently established for Japanese adults (>18 years old) and children (2-11 years old), respectively, but it is unclear whether eGFR can be as useful as 24-h creatinine clearance (CCr) for assessing renal function in patients receiving chemotherapy. This study examined the degree of concordance between eGFR and CCr and the risk factors leading to the overestimation of renal function by eGFR. A total of 53 data points of 19 children and 56 data points of 16 adults who received chemotherapy were analyzed retrospectively. Body mass index, serum creatinine concentration, 24-h urinary creatinine excretion (UCr), and nephrectomy were considered as risk factors for overestimation by eGFR. In the pediatric part of the study, 7 data points from 3 patients who underwent nephrectomy were included. The eGFR in patients with bilateral kidneys overestimated renal function to a greater degree than in patients with a unilateral kidney. In 45.7 % of pediatric patients with bilateral kidneys and in 19.6 % of adult patients, eGFR overestimated renal function. The risk factor for overestimation was lower UCr in pediatric patients with bilateral kidneys and adult patients. Concordance between eGFR and CCr in pediatric patients with a unilateral kidney should be assessed separately from that in patients with bilateral kidneys. In restricting calculation of eGFR to pediatric patients with bilateral kidneys and adult patients without little muscle mass, eGFR may be useful regardless of whether patients are receiving chemotherapy.


Urinary angiotensinogen level is increased in preterm neonates.

All components of the renin-angiotensin system (RAS) are abundantly synthesized in the developing kidney, suggesting that the RAS plays an important role in renal development. To examine this system in human neonates, we measured urinary angiotensinogen levels in preterm and full-term neonates and examined the relationship between urinary angiotensinogen levels and gestational age. Urine and plasma samples were collected from 20 preterm and 18 full-term neonates at birth. Angiotensinogen levels were measured using enzyme-linked immunosorbent assay. Plasma angiotensinogen concentrations were not increased in preterm neonates compared with that in full-term neonates (P = 0.7288). However, the urinary angiotensinogen-to-creatinine ratio was significantly higher in preterm neonates compared with that in full-term neonates (P = 0.0011). Importantly, the urinary angiotensinogen-to-creatinine ratio dropped significantly with increasing gestational age (P = 0.0010), whereas the plasma angiotensinogen concentration was not correlated with gestational age (P = 0.7814). These results suggest that urinary angiotensinogen levels may indicate the involvement of intrarenal RAS activation in prenatal renal development.


Assessment of the Helical Ventricular Myocardial Band Using Standard Echocardiography

The purpose of this study was to assess the feasibility of morphological and functional evaluation of the helical ventricular myocardial band using standard echocardiographic images. Echocardiographic data were obtained from 132 normal children. We attempted to identify the echogenic bright line serving as the boundary between the ascending and descending segments in the ventricular septum, and between the left and ascending segments in the left ventricular inferior wall in the helical myocardial band model proposed by Torrent-Guasp. Myocardial deformations on both sides of the bright line were compared using speckle tracking echocardiography. The bright line separating the ascending from descending segment was visible in the mid-ventricular septum in the four-chamber view in all subjects. This echogenic boundary was observed obliquely in the parasternal short-axis view in 116 subjects (87.9%). There was no significant difference in peak longitudinal or circumferential strain between the ascending and descending segments. However, the time from the QRS onset to peak circumferential strain was significantly lower in the descending than ascending segment (394.5 ± 37.0 vs. 432.7 ± 33.1 ms, P < 0.0001), whereas there was no significant difference in the time to peak longitudinal strain (394.4 ± 26.4 vs. 393.2 ± 24.1 ms). The bright line between the left and ascending segment was detected in the short-axis view from the subcostal region in 86 subjects (65.2%). The time to peak circumferential strain was significantly lower in the left than ascending segment (380.1 ± 32.0 vs. 435.7 ± 37.9 ms, P < 0.0001). There is a helical ventricular myocardial band that can be observed in standard echocardiographic images.


Fibromyxoid excrescence of the aortic valve that manifested after catheterisation and required resection.

A 2-year-old boy developed fibromyxoid excrescence of the aortic valve 2 years after balloon dilatation for simple coarctation. Transthoracic echocardiography showed a mobile mass on the non-coronary cusp of the aortic valve. Definitive diagnosis was achieved after operative resection. This pathology was attributed to injury during catheter manipulation. Catheterised patients should be followed up carefully to avoid missing morphological changes.


Neuroimaging in autism spectrum disorders: 1H-MRS and NIRS study

Using proton magnetic resonance spectroscopy ((1)H-MRS), we measured chemical metabolites in the left amygdala and the bilateral orbito-frontal cortex (OFC) in children with autism spectrum disorders (ASD). The concentrations of N-acetylaspartate (NAA) in these regions of ASD were significantly decreased compared to those in the control group. In the autistic patients, the NAA concentrations in these regions correlated with their social quotient. These findings suggest the presence of neuronal dysfunction in the amygdala and OFC in ASD. Dysfunction in the amygdala and OFC may contribute to the pathogenesis of ASD. We performed a near-infrared spectroscopy (NIRS) study to evaluate the mirror neuron system in children with ASD. The concentrations of oxygenated hemoglobin (oxy-Hb) were measured with frontal probes using a 34-channel NIRS machine while the subjects imitated emotional facial expressions. The increments in the concentration of oxy-Hb in the pars opercularis of the inferior frontal gyrus in autistic subjects were significantly lower than those in the controls. However, the concentrations of oxy-Hb in this area were significantly elevated in autistic subjects after they were trained to imitate emotional facial expressions. The results suggest that mirror neurons could be activated by repeated imitation in children with ASD.

The Journal of Medical Investigation : JMI


Developmental changes in the left ventricular diastolic wall strain on M-mode echocardiography

The diastolic wall strain (DWS) of the left ventricle has been proposed as an indicator of left ventricular (LV) wall stiffness. The DWS is calculated as follows using M-mode echocardiography:[Formula: see text]Although this index is simple and clinically useful, normal values for children, including neonates, have not been reported. The DWS was measured in 235 healthy people, ranging from neonates to adults. They were classified into 8 subgroups according to their age. The DWS was compared with conventional echocardiographic parameters for left ventricle function, including shortening fraction of the left ventricle, the Tei index, E/A of mitral flow, mitral annular tissue Doppler velocity during systole (s') and during early diastole (e'), and the E/e' ratio. The DWS in the just after birth group was 0.28 ± 0.11, which was significantly lower than that of the remaining groups (p < 0.05), except for the neonate group at 5-10 days after birth. The DWS was highest in the 1-9 years of age group, and then gradually decreased with age. Stepwise regression of various echocardiographic parameters showed that e' was the most relevant parameter for the DWS (β = 0.64). Normal values for the DWS of the left ventricle change with age. The data reported in this study can be used as normal values for the DWS of the left ventricle determined by M-mode echocardiography.


Continuing medical education activity in echocardiography.


Assessment of Two-Component Ventricular Septum: Functional Differences in Systolic Deformation and Rotation Assessed by Speckle Tracking Imaging.

The purpose of this study was to elucidate functional differences in the right and left components of the ventricular septum (Rt and Lt, respectively). Strain, strain rate, rotation, and rotation rate profile curves of Rt and Lt were obtained using speckle tracking echocardiography in 38 normal children and adolescents. The echogenic bright line serving as the boundary separating Rt from Lt was consistently visible in the middle of the ventricular septum. There was no significant difference in peak strain or peak strain rate during systole between Rt and Lt. However, the time interval from the onset of QRS-wave to peak strain and peak strain rate were significantly lower in Lt than in Rt in terms of radial and circumferential deformation (P < 0.005, all), whereas there was no significant difference in longitudinal deformation in the time to peak strain or peak strain rate between Rt and Lt. Lt showed counterclockwise rotation, whereas Rt showed clockwise rotation (10.4 ± 2.9° vs. -10.2 ± 2.6°, P < 0.0001). Time to peak rotation was significantly lower in Lt than in Rt (201.7 ± 32.7 msec vs. 370.4 ± 31.2 msec, P < 0.0001). Morphologically and functionally the ventricular septum is a two-component structure. Evaluation of deformation and rotation of the 2 components would help in evaluating septal performance.


Assessment of Pulmonary Artery Morphology by Optical Coherence Tomography in a Patient with Idiopathic Pulmonary Arterial Hypertension

光干渉断層像(Optical Coherence Tomography)で肺血管病変を観察した特発性肺動脈性肺高血圧症

Pediatric Cardiology and Cardiac Surgery


Right ventricular thrombosis in two patients with pulmonary atresia with intact ventricular septum


Echocardiographic assessment of anomalous origin of the left coronary artery from the pulmonary artery


Age-related changes in a patient with Pelizaeus-Merzbacher disease determined by repeated 1H-magnetic resonance spectroscopy.

A boy with Pelizaeus-Merzbacher disease underwent repeated evaluations by 3-Tesla (1)H-magnetic resonance spectroscopy (MRS). The patient showed overlap of the PLP1. Individuals selected as normal controls for (1)H-magnetic resonance spectroscopy consisted of healthy age-matched children. For (1)H-magnetic resonance spectroscopy, the center of a voxel was positioned in the right parietal lobe. (1)H-magnetic resonance spectroscopy was performed when the patient was 2, 6, 14, and 25 months old. γ-Aminobutyric acid concentration in early childhood was increased compared with that in normal controls. However, the γ-aminobutyric acid concentration in the Pelizaeus-Merzbacher disease patient was normalized at 14 and 25 months. No remarkable changes were observed in choline-containing compounds concentration at any time. These results suggest that the changes in metabolite concentrations during growth can reflect the pathological condition of Pelizaeus-Merzbacher disease. Furthermore, the lack of change in the choline-containing compounds concentration can be useful for differentiating Pelizaeus-Merzbacher disease from other white matter disorders.


Nitrosonifedipine ameliorates the progression of type 2 diabetic nephropathy by exerting antioxidative effects

Diabetic nephropathy (DN) is the major cause of end-stage renal failure. Oxidative stress is implicated in the pathogenesis of DN. Nitrosonifedipine (NO-NIF) is a weak calcium channel blocker that is converted from nifedipine under light exposure. Recently, we reported that NO-NIF has potential as a novel antioxidant with radical scavenging abilities and has the capacity to treat vascular dysfunction by exerting an endothelial protective effect. In the present study, we extended these findings by evaluating the efficacy of NO-NIF against DN and by clarifying the mechanisms of its antioxidative effect. In a model of type 2 DN (established in KKAy mice), NO-NIF administration reduced albuminuria and proteinuria as well as glomerular expansion without affecting glucose metabolism or systolic blood pressure. NO-NIF also suppressed renal and systemic oxidative stress and decreased the expression of intercellular adhesion molecule (ICAM)-1, a marker of endothelial cell injury, in the glomeruli of the KKAy mice. Similarly, NO-NIF reduced albuminuria, oxidative stress, and ICAM-1 expression in endothelial nitric oxide synthase (eNOS) knockout mice. Moreover, NO-NIF suppressed urinary angiotensinogen (AGT) excretion and intrarenal AGT protein expression in proximal tubular cells in the KKAy mice. On the other hand, hyperglycemia-induced mitochondrial superoxide production was not attenuated by NO-NIF in cultured endothelial cells. These findings suggest that NO-NIF prevents the progression of type 2 DN associated with endothelial dysfunction through selective antioxidative effects.


Hemodynamic activities in children with autism while imitating emotional facial expressions: a near-infrared spectroscopy study

自閉症における表情模倣時の脳血流変化 -NIRSによる検討-

Objective: To examine the hemodynamic activities in the frontal lobe, children with autistic disorder and matched controls underwent near-infrared spectroscopy (NIRS) while imitating emotional facial expressions. Methods: The subjects consisted of 10 boys with autistic disorder without mental retardation (9∼14 years) and 10 normally developing boys (9∼14 years). The concentrations of oxyhemoglobin (oxy-Hb) were measured with frontal probes using a 34-channel NIRS machine while the subjects imitated emotional facial expressions. Results: The increments in the concentration of oxy-Hb in the pars opercularis of the inferior frontal gyrus in autistic subjects were significantly lower than those in the controls. However, the concentrations of oxy-Hb in this area were significantly elevated in autistic subjects after they were trained to imitate emotional facial expressions. The increments in the concentration of oxy-Hb in this area in autistic subjects were positively correlated with the scores on a test of labeling emotional facial expressions. Conclusions: The pars opercularis of the inferior frontal gyrus is an important component of the mirror neuron system. The present results suggest that mirror neurons could be activated by repeated imitation in children with autistic disorder.

【目的】近赤外線スペクトロスコピー (NIRS) を用い, 顔表情の模倣課題を施行中の前頭葉活動について, 自閉症と定型発達の小児例で比較検討する. 【方法】対象は定型発達の男児10例, 知的障害を有さない自閉性障害の男児10例. NIRS測定のため左右前頭部にそれぞれ17チャンネルのプローブを装着した. 【結果】自閉症群において初回検査時, 両側下前頭回弁蓋部 (Broca野) での酸素化ヘモグロビン (oxy-Hb) 濃度の上昇は, 定型発達児に比べ有意に低かったが, 同じ課題を複数回練習してから, 再度, NIRSを施行したところ, 同部でoxy-Hb濃度の有意な上昇が認められた. 自閉症群におけるoxy-Hb濃度の変化量と感情ラベリング成績の間には正の相関関係が認められた. 【結論】自閉症においても模倣運動を繰り返すことによりミラーニューロンを賦活できる可能性が示唆された.


簡易版就学前幼児(4-6歳)用発達障害チェック・リスト(BCD46) -5歳児検診での有用性の検討-


Sept-optic dysplasiaの末期腎不全に対して維持血液透析を導入した1例


Glomerular angiotensin-converting enzyme 2 in pediatric IgA nephropathy

Angiotensin-converting enzyme (ACE) 2 is a homolog of ACE and is thought to be a potent counter-regulator against ACE activity. However, the role of ACE2 has not been investigated in pediatric patients with IgA nephropathy (IgAN). This study was performed to examine the relationship between ACE2 expression and the development of pediatric IgAN. We performed immunohistochemical analysis of ACE2 and ACE in 39 patients with pediatric IgAN and 14 patients with minor glomerular abnormalities, and elucidated the effects of various cytokines on ACE2 expression in cultured human mesangial cells. ACE2 expression levels in glomeruli and tubules were positively correlated with the mesangial hypercellularity score, while ACE expression levels in glomeruli and tubules are not. Multiple regression analysis showed that the mesangial hypercellularity score correlated with the ACE2 expression level in glomeruli and the urinary protein-creatinine ratio. In IgAN patients not treated with a renin-angiotensin system blocker, ACE2 expression levels in glomeruli were significantly increased compared to patients with minor glomerular abnormalities. IgAN patients treated with a renin-angiotensin system blocker did not show this increase in ACE2 expression. Furthermore, cultured human MC showed increased ACE2 mRNA and protein after treatment with IL-1β, a pro-inflammatory cytokine in IgAN. In fact, glomerular expressions of IL-1β were remarkably increased in patients with IgAN. These data indicate that ACE2 expression in glomeruli is associated with mesangial hypercellularity in early lesions of pediatric IgAN.


Effective treatment of a 13-year-old boy with steroid-dependent ocular myasthenia gravis using tacrolimus

Over the past several years, tacrolimus has attracted attention as a new therapeutic drug for myasthenia gravis (MG), but few reports have considered its use for MG in pediatric patients, and most of these have focused on severe systemic MG. In this case report, we used tacrolimus to successfully treat a 13-year-old boy with ocular MG who had suffered from severe steroid complications, including a failure of thrive and osteoporosis. He first showed symptoms of ocular MG at age 2 years 3 months. At age 13 years, he was receiving PSL (3.75 mg/day), but the symptoms of ocular MG recurred. We increased the dosage of oral PSL up to 30 mg/day, and three courses of mPSL pulse therapy were applied, but these therapies had only limited effect, and his symptoms worsened. Tacrolimus was started at 0.4 mg/day (0.011 mg/kg/day), and every 2 weeks the dose was gradually increased by 0.2 mg/day. His symptoms of MG began to improve 3 weeks after the initial administration of tacrolimus. Approximately 3 months after the start of tacrolimus administration, PSL was discontinued. Currently, at 1 year and 4 months after the start of tacrolimus administration, while slight ptosis is observed in the evening, it does not influence his daily life, and his condition remains comparable to that when he stopped taking PSL. No adverse effects of tacrolimus have been recognized. In pediatric patients with steroid-dependent ocular MG without thymectomy, tacrolimus may be a safe and effective alternative to steroid and thymectomy.


Ratio of early diastolic tricuspid inflow to tricuspid lateral annulus velocity reflects pulmonary regurgitation severity but not right ventricular diastolic function in children with reparied terralogy of Fallot

The current study assessed relationships between the ratio of early diastolic tricuspid inflow to tricuspid lateral annular velocity (tricuspid E/e') and right ventricular (RV) function in children after tetralogy of Fallot (TOF) repair. The RV function of 25 asymptomatic children with surgically repaired TOF (age 3.3 ± 2.0 years) was assessed by echocardiography and cardiac catheterization. Right ventricular end-diastolic pressure and volume (RVEDP and RVEDV), systolic pressure, and ejection fraction, as well as mean pulmonary arterial pressure, mean right atrial pressure (RAP), and the severity of both pulmonary regurgitation (PR) and tricuspid regurgitation (TR) were assessed in terms of the contribution to tricuspid E/e'. Univariate analysis discovered a relationship between tricuspid E/e' and RVEDV (R(2) = 0172), pressure half-time of PR (PR-PHT) (R(2) = 0.173), and TR grade (R(2) = 0.145) (p < 0.01 for each). After multivariate adjustment, PR-PHT was significantly associated with tricuspid E/e' (β = 0.210; p < 0.001). Tricuspid E/e' was not significantly associated with RVEDP or RAP. In conclusion, tricuspid E/e' does not indicate RV diastolic function but reflects the severity of PR in asymptomatic children after TOF repair.


Committee for standardization of renal Pathological diagnosis; Committee for kidney disease registry; Japanese society of nephrology: Japan renal biopsy registry and japan kidney disease registry: Committee report for 2009 and 2010.

The Japan Renal Biopsy Registry (J-RBR) was started in 2007 and the Japan Kidney Disease Registry (J-KDR) was then started in 2009 by the Committee for Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to describe and summarize the registered data from 2009 and 2010. For the J-KDR, data were collected from 4,016 cases, including 3,336 (83.1 %) by the J-RBR and 680 (16.9 %) other cases from 59 centers in 2009, and from 4,681 cases including 4,106 J-RBR cases (87.7 %) and 575 other cases (12.3 %) from 94 centers in 2010, including the affiliate hospitals. In the J-RBR, 3,165 native kidneys (94.9 %) and 171 renal grafts (5.1 %) and 3,869 native kidneys (94.2 %) and 237 renal grafts (5.8 %) were registered in 2009 and 2010, respectively. Patients younger than 20 years of age comprised 12.1 % of the registered cases, and those 65 years and over comprised 24.5 % of the cases with native kidneys in 2009 and 2010. The most common clinical diagnosis was chronic nephritic syndrome (55.4 % and 50.0 % in 2009 and 2010, respectively), followed by nephrotic syndrome (22.4 % and 27.0 %); the most frequent pathological diagnosis as classified by the pathogenesis was IgA nephropathy (31.6 % and 30.4 %), followed by primary glomerular diseases (except IgA nephropathy) (27.2 % and 28.1 %). Among the primary glomerular diseases (except IgA nephropathy) in the patients with nephrotic syndrome, membranous nephropathy was the most common histopathology in 2009 (40.3 %) and minor glomerular abnormalities (50.0 %) were the most common in 2010 in native kidneys in the J-RBR. Five new secondary and longitudinal research studies by the J-KDR were started in 2009 and one was started in 2010.


Subclavian and pulmonary artery steal phenomenon in a patient with isolated left subclavian artery and right aortic arch.

We describe a patient with an isolated left subclavian artery associated with right aortic arch, patent ductus arteriosus, and ventricular septal defect. As the isolated left subclavian artery is supplied by the left vertebral artery in which blood flows in the retrograde direction, this anomaly is usually responsible for a congenital subclavian steal phenomenon. Atrophy of the left cerebral hemisphere and inverted left vertebral arterial flow were clearly depicted by echoencephalography in this patient, whose subclavian artery was connected to the main pulmonary artery by a patent ductus arteriosus.


Left atrial volume change throughout the cardiac cycle in children with congenital heart disease associated with increased pulmonary blood flow: evaluation using a novel left atrium-tracking method.

There is a paucity of data regarding the significance of left atrial (LA) volume and its changes throughout the cardiac cycle in pediatric patients with heart disease. The recently developed LA volume-tracking (LAVT) method can automatically construct the LA volume curve. The study group consisted of 48 pediatric patients with ventricular septal defect (n = 34) or patent ductus arteriosus (n = 14) and age-matched healthy controls. Maximum and minimum LA volumes (LAVmax and LAVmin, respectively) were measured. The total LA emptying volume (LAVtotal) was defined as LAVmax--LAVmin. Volume parameters were standardized by dividing by body surface area (BSA). The total LA emptying fraction (%LAVtotal) was defined as the ratio of LAVtotal to LAVmax. In the patient group, there was a positive correlation between the ratio of pulmonary to systemic blood flow (Qp/Qs) and LAVmax/BSA, LAVmin/BSA, and LAVtotal/BSA (r = 0.42, 0.44, and 0.34, respectively). LAVmin/BSA was positively correlated with the ratio of early mitral inflow velocity to early mitral annular diastolic tissue Doppler velocity (E/E') (r = 0.32). The %LAVtotal had a negative correlation with left-ventricular (LV) end-diastolic pressure (r = -0.32). There were significant correlations between serum B-type natriuretic peptide level and LAVmax/BSA, LAVmin/BSA, and %LAVtotal (r = 0.38, 0.49, and -0.35, respectively). The LAVT method is useful in the evaluation of LV diastolic function in pediatric patients with chronic LV volume overload.


A proton magnetic resonance spectroscopic study in autism spectrum disorders: amygdala and orbito-frontal cortex.

We previously reported neural dysfunction in the anterior cingulate cortex and dorsolateral prefrontal cortex in autistic patients using proton magnetic resonance spectroscopy ((1)H-MRS). In this investigation, we measured chemical metabolites in the left amygdala and the bilateral orbito-frontal cortex (OFC), which are the main components of the social brain. We also examined the association between these metabolic findings and social abilities in subjects with autism. The study group included 77 autistic patients (3-6years old; mean age 4.1; 57 boys and 20 girls). The control subjects were 31 children (3-6years old; mean age 4.0; 23 boys and 8 girls). Conventional proton MR spectra were obtained using the STEAM sequence with parameters of TR=5 sec and TE=15 msec by a 1.5-tesla clinical MRI system. We analyzed the concentrations of N-acetylaspartate (NAA), creatine/phosphocreatine (Cr), and choline-containing compounds (Cho) using LCModel (Ver. 6.1). The concentrations of NAA in the left amygdala and the bilateral OFC in autistic patients were significantly decreased compared to those in the control group. In the autistic patients, the NAA concentrations in these regions correlated with their social quotient. These findings suggest the presence of neuronal dysfunction in the amygdala and OFC in autism. Dysfunction in the amygdala and OFC may contribute to the pathogenesis of autism.


Developmental changes in facial expression recognition in Japanese school-age children.

Facial expressions hold abundant information and play a central part in communication. In daily life, we must construct amicable interpersonal relationships by communicating through verbal and nonverbal behaviors. While school-age is a period of rapid social growth, few studies exist that study developmental changes in facial expression recognition during this age. This study investigated developmental changes in facial expression recognition by examining observers' gaze on others' expressions. 87 school-age children from first to sixth grade (41 boys, 46 girls). The Tobii T60 Eye-tracker(Tobii Technologies, Sweden) was used to gauge eye movement during a task of matching pre-instructed emotion words and facial expressions images (neutral, angry, happy, surprised, sad, disgusted) presented on a monitor fixed at a distance of 50 cm. In the task of matching the six facial expression images and emotion words, the mid- and higher-grade children answered more accurately than the lower-grade children in matching four expressions, excluding neutral and happy. For fixation time and fixation count, the lower-grade children scored lower than other grade children, gazing on all facial expressions significantly fewer times and for shorter periods. It is guessed that the stage from lower grades to middle grades is a turning point in facial recognition.

The Journal of Medical Investigation : JMI


A case of infantile systemic lupus erythematosus with severe lupus nephritis and EBV infection


日本の小児科学研究の現況

日本の小児科学研究の現況

The Journal of the Japan Pediatric Society