経動脈的化学塞栓術における予防的抗菌薬と肝膿瘍発症の関連 : 後方視的コホート研究

Objectives: Clinical evidence on prophylactic antibiotics for transarterial chemoembolization (TACE) to prevent liver abscess is limited because liver abscess is a rare event. This study aimed to analyse the association between prophylactic antibiotic use for TACE and the occurrence of liver abscess after TACE. Methods: Using the nationwide Diagnosis Procedure Combination database in Japan, we retrospectively identified patients who underwent TACE for hepatic cancer between July 2010 and March 2017. The primary outcome was liver abscess requiring procedural intervention within 30 days of TACE. Secondary outcomes included 30-day in-hospital mortality and length of stay. Propensity score matching was performed to adjust for potential confounding factors and compare outcomes between patients with and without prophylactic antibiotics. Results: Among 167 544 eligible patients, 134 712 received antibiotics and 32 832 did not. In the matched cohort of 29 211 pairs, the proportion of patients with liver abscess requiring procedural intervention was significantly lower in the antibiotics group than in the no-antibiotics group (0.08% vs. 0.22%, p 0.001; relative risk (95% confidence interval), 0.35 (0.22-0.57); absolute risk reduction, 0.0014 (0.0008-0.0021); and number needed to treat, 696 (476-1223)). There was no significant difference in 30-day in-hospital mortality between the groups. The length of stay was longer in the antibiotics group than in the no-antibiotics group (median, 10 vs. 9 days, p < 0.001). Conclusions: Prophylactic antibiotic use in patients undergoing TACE was associated with a reduced occurrence of liver abscess requiring procedural intervention.博士（医学）・甲第794号・令和3年6月25日Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved

心室中隔欠損症に対する小児心臓カテーテル検査における麻酔方法と重症合併症の関連

Pediatric cardiac catheterization requires unconsciousness and immobilization through general anesthesia or sedation. This study aimed to compare the occurrence of severe complications in pediatric diagnostic cardiac catheterization for ventricular septal defect between general anesthesia and sedation performed under similar institutional environments. Using the Japanese Diagnosis Procedure Combination database, we retrospectively identified pediatric patients (aged <2 years) who underwent diagnostic cardiac catheterization for ventricular septal defect between July 2010 and March 2019. The composite outcome was the occurrence of severe complications, including catecholamine use and intensive care unit admission, within seven days after catheterization. Overlap weighting based on propensity scores was used to adjust for patient- and hospital-level confounding factors. We identified 3159 patients from 87 hospitals, including 930 under general anesthesia and 2229 under sedation. The patient- and hospital-level baseline characteristics differed between the groups. After adjustment, the proportion of patients with severe complications was significantly higher in the general anesthesia group than in the sedation group (2.4% vs. 0.6%; risk difference, 1.8% [95% confidence interval, 0.93–2.6%]). Severe complications occurred more frequently in the general anesthesia group than in the sedation group. Further research on anesthetic methods is necessary to assess the safety and accuracy of pediatric diagnostic cardiac catheterization.博士（医学）・甲第867号・令和5年3月15

Global Gene Expression Profiling in PPAR-γ Agonist-Treated Kidneys in an Orthologous Rat Model of Human Autosomal Recessive Polycystic Kidney Disease

Kidneys are enlarged by aberrant proliferation of tubule epithelial cells leading to the formation of numerous cysts, nephron loss, and interstitial fibrosis in polycystic kidney disease (PKD). Pioglitazone (PIO), a PPAR-γ agonist, decreased cell proliferation, interstitial fibrosis, and inflammation, and ameliorated PKD progression in PCK rats (Am. J. Physiol.-Renal, 2011). To explore genetic mechanisms involved, changes in global gene expression were analyzed. By Gene Set Enrichment Analysis of 30655 genes, 13 of the top 20 downregulated gene ontology biological process gene sets and six of the top 20 curated gene set canonical pathways identified to be downregulated by PIOtreatment were related to cell cycle and proliferation, including EGF, PDGF and JNK pathways. Their relevant pathways were identified using the Kyoto Encyclopedia of Gene and Genomes database. Stearoyl-coenzyme A desaturase 1 is a key enzyme in fatty acid metabolism found in the top 5 genes downregulated by PIO treatment. Immunohistochemical analysis revealed that the gene product of this enzyme was highly expressed in PCK kidneys and decreased by PIO. These data show that PIO alters the expression of genes involved in cell cycle progression, cell proliferation, and fatty acid metabolism

Choroidal Structure of CSC on OCT Image

Purpose To determine the structural changes of the choroid in eyes with central serous chorioretinopathy (CSC) by enhanced depth imaging optical coherence tomography (EDI-OCT). Methods A retrospective comparative study was performed at two academic institutions. Forty eyes with CSC, their fellow eyes, and 40 eyes of age-matched controls were studied. Subfoveal cross sectional EDI-OCT images were recorded, and the hypo reflective and hyperreflective areas of the inner and outer choroid in the EDI-OCT images were separately measured. The images were analyzed by a binarization method to determine the sizes of the hyporeflective and hyperreflective areas. Results In the inner choroid, the hyperreflective area was significantly larger in the CSC eyes (35,640±10,229 μm2) than the fellow eyes (22,908±8,522 μm2) and the control eyes (20,630±8,128 μm2; P<0.01 vs control for both, Wilcoxon signed-rank test). In the outer choroid, the hyporeflective area was significantly larger in the CSC eyes (446,549 ±121,214 μm2) than the control eyes (235,680±97,352 μm2, P<0.01). The average ratio of the hyporeflective area to the total choroidal area was smaller in the CSC eyes (67.0%) than the fellow eyes (76.5%) and the control eyes (76.7%) in the inner choroid (P<0.01, both). However, the ratio was larger in the CSC eyes (75.2%) and fellow eyes (71.7%) than in the control eyes (64.7%) in the outer choroid (P<0.01, both). Conclusions The larger hyperreflective area in the inner choroid is related to the inflammation and edema of the stroma of the choroid in the acute stage of CSC. The larger hyporeflective areas in the outer choroid is due to a dilatation of the vascular lumens of the larger blood vessels. These are the essential characteristics of eyes with CSC regardless of the onset

Clinical Outcomes and Genetic Analyses of Restrictive Cardiomyopathy in Children

BACKGROUND: Restrictive cardiomyopathy in children is rare and outcomes are very poor. However, little information is available concerning genotype-outcome correlations. METHODS: We analyzed the clinical characteristics and genetic testing, including whole exome sequencing, of 28 pediatric restrictive cardiomyopathy patients who were diagnosed from 1998 to 2021 at Osaka University Hospital in Japan. RESULTS: The median age at diagnosis (interquartile range) was 6 (2.25-8.5) years. Eighteen patients received heart transplantations and 5 patients were on the waiting list. One patient died while waiting for transplantation. Pathologic or likely-pathogenic variants were identified in 14 of the 28 (50%) patients, including heterozygous TNNI3 missense variants in 8 patients. TNNT2, MYL2, and FLNC missense variants were also identified. No significant differences in clinical manifestations and hemodynamic parameters between positive and negative pathogenic variants were detected. However, 2- and 5-year survival rates were significantly lower in patients with pathogenic variants (50% and 22%) compared with survival in patients without pathogenic variants (62% and 54%; P=0.0496, log-rank test). No significant differences were detected in the ratio of patients diagnosed at nationwide school heart disease screening program between positive and negative pathogenic variants. Patients diagnosed by school screening showed better transplant-free survival compared with patients diagnosed by heart failure symptoms (P=0.0027 in log-rank test). CONCLUSIONS: In this study, 50% of pediatric restrictive cardiomyopathy patients had pathogenic or likely-pathogenic gene variants, and TNNI3 missense variants were the most frequent. Patients with pathogenic variants showed significantly lower transplant-free survival compared with patients without pathogenic variants.Ishida H., Narita J., Ishii R., et al. Clinical Outcomes and Genetic Analyses of Restrictive Cardiomyopathy in Children. Circulation: Genomic and Precision Medicine 16, 382 (2023); https://doi.org/10.1161/CIRCGEN.122.004054

Pathogenic Roles of Cardiac Fibroblasts in Pediatric Dilated Cardiomyopathy

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure in children. Despite intensive genetic analyses, pathogenic gene variants have not been identified in most patients with DCM, which suggests that cardiomyocytes are not solely responsible for DCM. Cardiac fibroblasts (CFs) are the most abundant cell type in the heart. They have several roles in maintaining cardiac function; however, the pathological role of CFs in DCM remains unknown. METHODS AND RESULTS: Four primary cultured CF cell lines were established from pediatric patients with DCM and compared with 3 CF lines from healthy controls. There were no significant differences in cellular proliferation, adhesion, migration, ap-optosis, or myofibroblast activation between DCM CFs compared with healthy CFs. Atomic force microscopy revealed that cellular stiffness, fluidity, and viscosity were not significantly changed in DCM CFs. However, when DCM CFs were cocultured with healthy cardiomyocytes, they deteriorated the contractile and diastolic functions of cardiomyocytes. RNA sequencing revealed markedly different comprehensive gene expression profiles in DCM CFs compared with healthy CFs. Several hu-moral factors and the extracellular matrix were significantly upregulated or downregulated in DCM CFs. The pathway analysis revealed that extracellular matrix receptor interactions, focal adhesion signaling, Hippo signaling, and transforming growth factor-β signaling pathways were significantly affected in DCM CFs. In contrast, single-cell RNA sequencing revealed that there was no specific subpopulation in the DCM CFs that contributed to the alterations in gene expression. CONCLUSIONS: Although cellular physiological behavior was not altered in DCM CFs, they deteriorated the contractile and diastolic functions of healthy cardiomyocytes through humoral factors and direct cell–cell contact.Tsuru H., Yoshihara C., Suginobe H., et al. Pathogenic Roles of Cardiac Fibroblasts in Pediatric Dilated Cardiomyopathy. Journal of the American Heart Association 12, e029676 (2023); https://doi.org/10.1161/JAHA.123.029676

Neuronal glutathione loss leads to neurodegeneration involving gasdermin activation

Accumulating evidence suggests that glutathione loss is closely associated with the progression of neurodegenerative disorders. Here, we found that the neuronal conditional-knockout (KO) of glutamyl-cysteine-ligase catalytic-subunit (GCLC), a rate-limiting enzyme for glutathione synthesis, induced brain atrophy accompanied by neuronal loss and neuroinflammation. GCLC-KO mice showed activation of C1q, which triggers engulfment of neurons by microglia, and disease-associated-microglia (DAM), suggesting that activation of microglia is linked to the neuronal loss. Furthermore, gasdermins, which regulate inflammatory form of cell death, were upregulated in the brains of GCLC-KO mice, suggesting the contribution of pyroptosis to neuronal cell death in these animals. In particular, GSDME-deficiency significantly attenuated the hippocampal atrophy and changed levels of DAM markers in GCLC-KO mice. Finally, we found that the expression of GCLC was decreased around amyloid plaques in AppNL-G-F AD model mice. AppNL-G-F mouse also exhibited inflammatory events similar to GCLC-KO mouse. We propose a mechanism by which a vicious cycle of oxidative stress and neuroinflammation enhances neurodegenerative processes. Furthermore, GCLC-KO mouse will serve as a useful tool to investigate the molecular mechanisms underlying neurodegeneration and in the development of new treatment strategies to address neurodegenerative diseases

Double photon emission coincidence imaging with GAGG-SiPM Compton camera

Compton imaging is a promising gamma-ray imaging method based on the Compton scattering kinematics due to high Compton scattering probability for sub-MeV to MeV gamma-rays. A conventional Compton camera has a disadvantage of low signal-to-background ratio (SBR), which is caused by drawing of multiple Compton cones. A method to solve this fundamental problem is the double-photon emission computed tomography (DPECT), which uses the coincidence detection for cascade gamma-rays and significantly increases the SBR using intersections of two Compton cones. In this study, we demonstrated the DPECT method by using 134Cs radio isotope, which is one of important radioisotopes for the imaging of fuel debris, with two Ce:Gd(Al,Ga)O12 (GAGG) scintillator Compton cameras

Deregulation of DUX4 and ERG in acute lymphoblastic leukemia

Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL).1,2 Here, we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG are hallmarks of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases, and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion. ERGalt utilizes a non-canonical first exon whose transcription was initiated by DUX4 binding. ERGalt retains the DNA-binding and transactivating domains of ERG, but inhibits wild-type ERG transcriptional activity and is transforming. These results illustrate a unique paradigm of transcription factor deregulation in leukemia, in which DUX4 deregulation results in loss-of-function of ERG, either by deletion or induction of expression of an isoform that is a dominant negative inhibitor of wild type ERG function

On the origin and evolution of the asteroid Ryugu: A comprehensive geochemical perspective

Presented here are the observations and interpretations from a comprehensive analysis of 16 representative particles returned from the C-type asteroid Ryugu by the Hayabusa2 mission. On average Ryugu particles consist of 50% phyllosilicate matrix, 41% porosity and 9% minor phases, including organic matter. The abundances of 70 elements from the particles are in close agreement with those of CI chondrites. Bulk Ryugu particles show higher δ18O, Δ17O, and ε54Cr values than CI chondrites. As such, Ryugu sampled the most primitive and least-thermally processed protosolar nebula reservoirs. Such a finding is consistent with multi-scale H-C-N isotopic compositions that are compatible with an origin for Ryugu organic matter within both the protosolar nebula and the interstellar medium. The analytical data obtained here, suggests that complex soluble organic matter formed during aqueous alteration on the Ryugu progenitor planetesimal (several 10’s of km), <2.6 Myr after CAI formation. Subsequently, the Ryugu progenitor planetesimal was fragmented and evolved into the current asteroid Ryugu through sublimation