Kouji Masumoto

Incidence and prediction of outcome in hypoxic–ischemic encephalopathy in Japan

Hypoxic–ischemic encephalopathy (HIE) is one of the most critical pathologic conditions in neonatal medicine due to the potential for neurological deficits in later life. We investigated the incidence of term infants with moderate or severe HIE in Japan and identified prognostic risk factors for poor outcome in HIE.

Identification of a KEAP1 Germline Mutation in a Family with Multinodular Goitre

Background The familial clustering of multinodular goitres (MNGs) with a dominant mode of inheritance has been repeatedly reported. Linkage studies have revealed several genetic loci responsible for familial MNG; however, most of the causative variants remain unknown. Methods and Results Through linkage analysis using single-nucleotide polymorphism markers, we identified a new MNG locus on 19p13.2-q12 in a five-generation Japanese MNG family. Subsequent mutation searches focusing on the candidate 25-Mb region of chromosome 19 identified a heterozygous mutation, c.879_880delinsA, p.Asp294Thr, fs*23, in exon 3 of the KEAP1, which plays a central role in the cytoprotection pathway against oxidative stress. Reverse transcriptase-PCR analysis showed low expression of wild type KEAP1 accompanied by no transcription product of mutant allele in the normal and goitre region of thyroid tissues obtained from the proband. In agreement with previous studies showing that KEAP1 negatively regulates NFE2L2, the NFE2L2 target genes GSTA4 and GCLC were up-regulated in the thyroid tissues of the patient. Conclusions This study identified the first KEAP1 mutation in MNG. The results provide insights into the pathogenesis of goitre which develops in the organ continuously exposed to oxidative stress during hormone synthesis.

Pancreatic complications in pediatric choledochal cysts

BACKGROUND/PURPOSE The aim of this study is to clarify the clinical features and risk factors of pre- and postoperative pancreatic complications in pediatric choledochal cysts. METHODS A retrospective chart review was carried out on pediatric patients with choledochal cysts who underwent radical operation at our department. RESULTS Twenty-one, 24, and 24 patients were classified into the Todani Ia, Ic, and IV-A choledochal cyst, respectively. Preoperative acute pancreatitis and protein plugs were observed in 31 (43.7%) and 11 (15.5%) patients, respectively. Patients with preoperative pancreatitis were more likely to have fusiform dilatation of choledochal cysts (79.3% vs. 35.0%) and a dilated common channel (53.9% vs. 23.1%) compared to those without preoperative pancreatitis. Compared to patients without preoperative protein plugs, those with protein plugs were more likely to have fusiform dilatation (90.9% vs. 46.5%) and pancreatic divisum with communicating ducts and a dilated ductal system (60.0% vs. 2.5%). Postoperatively, three patients (4.2%) experienced acute pancreatitis. One of these and all 3 had protein plugs and preoperative pancreatitis, respectively. CONCLUSIONS Fusiform-type choledochal cyst is a significant risk factor for preoperative pancreatic complications in choledochal cysts. While postoperative pancreatic complications were relatively rare, preoperative pancreatic complications might be risk factors for postoperative pancreatitis.

Impact of deletion of envelope-related genes of recombinant Sendai viruses on immune responses following pulmonary gene transfer of neonatal mice

We demonstrated previously that the additive-type recombinant Sendai virus (rSeV) is highly efficient for use in pulmonary gene transfer; however, rSeV exhibits inflammatory responses. To overcome this problem, we tested newly developed non-transmissible constructs, namely, temperature-sensitive F-deleted vector, rSeV/dF (ts-rSeV/dF) and a rSeV with all the envelope-related genes deleted (rSeV/dFdMdHN), for pulmonary gene transfer in neonatal mice, by assessing their toxicity and immune responses. The gene expression in the lungs of neonatal ICR mice peaked on day 2, then gradually decreased until almost disappearing at 14 days after infection in all constructs. Loss of body weight and mortality rate, however, were dramatically improved in mice treated with SeV/dFdMdHN (mortality=0%, n=41) and ts-rSeV/dF (24.2%, n=33) compared with additive rSeV (70.7%, n=58). Although the deletion of envelope-related genes of SeV had a small impact on the production of antibody and cytotoxic T-lymphocyte activity in both adults and neonates, a dramatic reduction was found in the events related to innate responses, including the production of proinflammatory cytokines, particularly in the case of neonates. These results indicate that pulmonary gene transfer using SeV/dFdMdHN warrants further investigation for its possible use in developing safer therapeutics for neonatal lung diseases, including cystic fibrosis.

Musculoskeletal abnormalities in congenital diaphragmatic hernia survivors: Patterns and risk factors: Report of a Japanese multicenter follow-up survey

The aim of this study was to investigate the natural history and associated predictors of musculoskeletal deformities in congenital diaphragmatic hernia (CDH) survivors.

A case of unusual histology of infantile lipoblastoma confirmed by PLAG1 rearrangement

Lipoblastoma, a relatively rare benign adipose neoplasm, predominantly affects children younger than 3 years of age. We herein report the case of a 7-month-old girl with an unusual myxomatous histology of lipoblastoma. A rapidly growing mass was detected in the subcutaneous area of the left buttock. Histologically, the tumor consisted of abundant myxoid stroma exhibiting cellular atypia and a high mitotic activity. Although the histological findings were unusual, the tumor was diagnosed as a lipoblastoma according to both PLAG1 immunohistochemistry and the presence of PLAG1 rearrangement on fluorescence in situ hybridization.

Prenatal administration of neuropeptide bombesin promotes lung development in a rat model of nitrofen-induced congenital diaphragmatic hernia

BACKGROUND/PURPOSE Fetal medical treatment to improve lung hypoplasia in congenital diaphragmatic hernia (CDH) has yet to be established. The neuropeptide bombesin (BBS) might play an important role in lung development. The present study aims to determine whether prenatally administered BBS could be useful to promote fetal lung development in a rat model of nitrofen-induced CDH. METHODS Pregnant rats were administered with nitrofen (100mg) on gestation day 9.5 (E9.5). BBS (50mg/kg/day) was then daily infused intraperitoneally from E14, and fetal lungs were harvested on E21. The expression of PCNA was assessed by both immunohistochemical staining and RT-PCR to determine the amount of cell proliferation. Lung maturity was assessed as the expression of TTF-1, a marker of alveolar epithelial cell type II. RESULTS The lung-body-weight ratio was significantly increased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.05). The number of cells stained positive for PCNA and TTF-1 was significantly decreased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.01). The TTF-1 mRNA expression levels were significantly decreased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.05). CONCLUSIONS Prenatally administered BBS promotes lung development in a rat model of nitrofen-induced CDH. Neuropeptide BBS could help to rescue lung hypoplasia in fetal CDH.

The accumulation of regulatory T cells in the hepatic hilar lymph nodes in biliary atresia

PurposeA proposed etiopathogenesis of biliary atresia (BA) involves T-cell-mediated inflammatory bile duct damage and progressive hepatic fibrosis. Pediatric surgeons often observe swelling of the hepatic hilar lymph nodes during the Kasai procedure. Given the importance of regulatory mechanisms in immune responses, the present study was designed to analyze the quantitative changes of regulatory T cells (Treg cells) in the hepatic hilar lymph nodes (hepatic hilar LNs) and peripheral blood (PB) in BA.MethodsThe hepatic hilar LNs and PB obtained during the Kasai procedure were analyzed by flow cytometry. The ratios of total and active Tregs to the total CD4+ cells in the PB and the hepatic hilar LNs were compared.ResultsIn patients with BA, the ratios of both the total and active Treg cells in the hepatic hilar LNs were higher than those in the PB (total Treg cells: PB vs. LN; P < 0.001; active Treg cells: PB vs. LN; P = 0.001). In BA patients, the increase in the ratio of active Treg cells to the CD4 + cells in the LNs in comparison to the PB was greater than that in control patients. The ratio observed in the BA patients was almost double the ratio observed in the control patients. The median LN/PB ratio in the BA patients was 3.1, while that in controls was 1.6 (P = 0.03).ConclusionThe present study showed that the ratios of both total Treg cells and active Treg cells were higher in the hepatic hilar lymph nodes of BA patients. This finding could shed light on the pathogenesis of BA.

Co-morbidity and quality of life in childhood cancer survivors treated with proton beam therapy

The rate of childhood cancer survival has recently reached >80%. Various adverse events among childhood cancer survivors (CCS) have been reported. Proton beams are able to avoid unnecessary irradiation to normal/vital organs. We conducted a quality of life (QOL) study for CCS who were treated with proton beam therapy (PBT).

Suppressed erythropoietin expression in a nitrofen‐induced congenital diaphragmatic hernia

Erythropoietin (EPO), an essential stimulator of erythropoiesis produced by the fetal liver, is important both in vascular remodeling and modulation of the endothelial response in the pulmonary vasculature. In addition, EPO guides alveolar development, along with retinoic acid (RA). EPO is a direct target of RA, and the retinoid pathway is altered in the nitrofen‐induced congenital diaphragmatic hernia (CDH) model. In the present study, we tested the hypothesis that the synthesis of EPO is suppressed in a rat model of CDH.