Publications by authors named "Takashi Ito"

677 Publications

Hoxa10 mediates positional memory to govern stem cell function in adult skeletal muscle.

Sci Adv 2021 Jun 9;7(24). Epub 2021 Jun 9.

Department of Muscle Development and Regeneration, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.

Muscle stem cells (satellite cells) are distributed throughout the body and have heterogeneous properties among muscles. However, functional topographical genes in satellite cells of adult muscle remain unidentified. Here, we show that expression of Homeobox-A (Hox-A) cluster genes accompanied with DNA hypermethylation of the Hox-A locus was robustly maintained in both somite-derived muscles and their associated satellite cells in adult mice, which recapitulates their embryonic origin. Somite-derived satellite cells were clearly separated from cells derived from cranial mesoderm in expression. inactivation led to genomic instability and mitotic catastrophe in somite-derived satellite cells in mice and human. Satellite cell-specific ablation in mice resulted in a decline in the regenerative ability of somite-derived muscles, which were unobserved in cranial mesoderm-derived muscles. Thus, our results show that Hox gene expression profiles instill the embryonic history in satellite cells as positional memory, potentially modulating region-specific pathophysiology in adult muscles.
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http://dx.doi.org/10.1126/sciadv.abd7924DOI Listing
June 2021

Specific detection of high mobility group box 1 degradation product with a novel ELISA.

Mol Med 2021 Jun 9;27(1):59. Epub 2021 Jun 9.

Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.

Background: During sepsis or sterile tissue injury, the nuclear protein high mobility group box 1 (HMGB1) can be released to the extracellular space and ultimately into systemic circulation, where it mediates systemic inflammation and remote organ failure. The proinflammatory effects of HMGB1 can be suppressed by recombinant thrombomodulin (rTM), in part through a mechanism involving thrombin-rTM-mediated degradation of HMGB1. Given that HMGB1 is proinflammatory but the HMGB1 degradation product (desHMGB1) is not, an analytical method that discriminates between these two molecules may provide a more in-depth understanding of HMGB1-induced pathogenicity as well as rTM-mediated therapeutic efficiency.

Methods: A peptide that has a shared amino-terminal structure with desHMGB1 was synthesized. C3H/lpr mice were immunized with the desHMGB1 peptide conjugate, and antibody-secreting hybridoma cells were developed using conventional methods. The reactivity and specificity of the antibodies were then analyzed using antigen-coated enzyme-linked immunosorbent assay (ELISA) as well as antibody-coated ELISA. Next, plasma desHMGB1 levels were examined in a cecal ligation and puncture (CLP)-induced septic mouse model treated with rTM.

Results: Through a series of screening steps, we obtained a monoclonal antibody that recognized desHMGB1 but did not recognize intact HMGB1. ELISA using this antibody specifically detected desHMGB1, which was significantly increased in CLP-induced septic mice treated with rTM compared with those treated with saline.

Conclusions: In this study, we obtained a desHMGB1-specific monoclonal antibody. ELISA using the novel monoclonal antibody may be an option for the in-depth analysis of HMGB1-induced pathogenicity as well as rTM-mediated therapeutic efficiency.
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http://dx.doi.org/10.1186/s10020-021-00323-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190996PMC
June 2021

GABAA Receptors and Maternally Derived Taurine Regulate the Temporal Specification of Progenitors of Excitatory Glutamatergic Neurons in the Mouse Developing Cortex.

Cereb Cortex 2021 May 17. Epub 2021 May 17.

Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.

Temporal specification of the neural progenitors (NPs) producing excitatory glutamatergic neurons is essential for histogenesis of the cerebral cortex. Neuroepithelial cells, the primary NPs, transit to radial glia (RG). To coincide with the transition, NPs start to differentiate into neurons, undergoing a switch from symmetric to asymmetric cell division. After the onset of neurogenesis, NPs produce layer-specific neurons in a defined order with precise timing. Here, we show that GABAA receptors (GABAARs) and taurine are involved in this regulatory mechanism. Foetal exposure to GABAAR-antagonists suppressed the transition to RG, switch to asymmetric division, and differentiation into upper-layer neurons. Foetal exposure to GABAAR-agonists caused the opposite effects. Mammalian foetuses are dependent on taurine derived from the mothers. GABA and taurine function as endogenous ligands for GABAARs. Ca2+ imaging showed that NPs principally responded to taurine but not GABA before E13. The histological phenotypes of the taurine transporter knockout mice resembled those of the mice foetally exposed to GABAAR-antagonists. Foetal exposure to GABAAR-modulators resulted in considerable alterations in offspring behavior like core symptoms of autism. These results show that taurine regulates the temporal specification of NPs and that disrupting the taurine-receptor interaction possibly leads to neurodevelopmental disorders.
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http://dx.doi.org/10.1093/cercor/bhab106DOI Listing
May 2021

Azathioprine Monotherapy for the Cases of Immunoglobulin G4-Related Disease With Contraindications to Glucocorticoids.

J Clin Rheumatol 2021 Feb 10. Epub 2021 Feb 10.

Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan Department of Human Pathology, Jichi medical University, Tochigi, Japan Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan Department of Rheumatology, Tokyo Kyosai Hospital, Tokyo, Japan Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan Department of Rheumatology, Chiba Nishi General Hospital, Chiba, Japan Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

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http://dx.doi.org/10.1097/RHU.0000000000001717DOI Listing
February 2021

Maintenance DNA methylation in pre-meiotic germ cells regulates meiotic prophase by facilitating homologous chromosome pairing.

Development 2021 May 17;148(10). Epub 2021 May 17.

RIKEN Center for Integrative Medical Sciences (IMS), Developmental Genetics Laboratory, Yokohama 230-0045, Kanagawa, Japan.

Heterochromatin-related epigenetic mechanisms, such as DNA methylation, facilitate pairing of homologous chromosomes during the meiotic prophase of mammalian spermatogenesis. In pro-spermatogonia, de novo DNA methylation plays a key role in completing meiotic prophase and initiating meiotic division. However, the role of maintenance DNA methylation in the regulation of meiosis, especially in the adult, is not well understood. Here, we reveal that NP95 (also known as UHRF1) and DNMT1 - two essential proteins for maintenance DNA methylation - are co-expressed in spermatogonia and are necessary for meiosis in male germ cells. We find that Np95- or Dnmt1-deficient spermatocytes exhibit spermatogenic defects characterized by synaptic failure during meiotic prophase. In addition, assembly of pericentric heterochromatin clusters in early meiotic prophase, a phenomenon that is required for subsequent pairing of homologous chromosomes, is disrupted in both mutants. Based on these observations, we propose that DNA methylation, established in pre-meiotic spermatogonia, regulates synapsis of homologous chromosomes and, in turn, quality control of male germ cells. Maintenance DNA methylation, therefore, plays a role in ensuring faithful transmission of both genetic and epigenetic information to offspring.
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http://dx.doi.org/10.1242/dev.194605DOI Listing
May 2021

Endoscopic retrieval of a migrated surgical clip in a choledochojejunal anastomosis using the rendezvous technique.

Endoscopy 2021 May 12. Epub 2021 May 12.

Kansai Medical University, The Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Hirakata, Japan.

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http://dx.doi.org/10.1055/a-1463-2618DOI Listing
May 2021

Micro- and macro-borderless surgery using a newly developed high-resolution (4K) three-dimensional video system.

PLoS One 2021 12;16(5):e0250559. Epub 2021 May 12.

Department of Organ Fabrication, Keio University School of Medicine, Tokyo, Japan.

Objective: Microsurgery using conventional optical microscopes or surgical loupes features a limited field of view and imposes a serious strain on surgeons especially during long surgeries. Here we advocate the micro- and macro-borderless surgery (MMBS) using a novel high-resolution (4K) three-dimensional (3D) video system. This study aimed to confirm the applicability of this concept in several surgical procedures.

Methods: We evaluated the possible use and efficacy of MMBS in the following experiments in porcine subjects. Experiment 1 (non-inferiority test) consisted of dissection and anastomosis of carotid artery, portal vein, proper hepatic artery, and pancreatoduodenectomy with surgical loupe versus MMBS. Experiment 2 (feasibility test) consisted of intra-abdominal and intra-thoracic smaller arteries anastomosed by MMBS as a pre-clinical setting. Experiment 3 (challenge on new surgery) consisted of orthotopic liver transplantation of the graft from a donor after circulatory death maintained by machine perfusion. Circulation of the cardiac sheet with a vascular bed in experiment 2 and liver graft during preservation in experiment 3 was evaluated with indocyanine green fluorescence imaging equipped with this system.

Results: Every procedure was completed by MMBS. The operator and assistants could share the same field of view in heads-up status. The focal depth was deep enough not to be disturbed by pulsing blood vessels or respiratory movement. The tissue circulation could be evaluated using fluorescence imaging of this system.

Conclusions: MMBS using the novel system is applicable to various surgeries and valuable for both fine surgical procedures and high-level surgical education.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250559PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115828PMC
May 2021

Fluid dynamics analyses of the intrahepatic portal vein tributaries using 7-T MRI.

HPB (Oxford) 2021 Apr 16. Epub 2021 Apr 16.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: Assessing portal vein (PV) hemodynamics is an essential part of liver disease management/liver surgery, yet the optimal methods of assessing intrahepatic PV flow have not yet been established. This study investigated the usefulness of 7-Tesla MRI with hemodynamic analysis for detecting small flow changes within narrow intrahepatic PV branches.

Methods: Flow data in the main PV was obtained by two methods, two-dimensional cine phase contrast-MRI (2D cine PC-MRI) and three-dimensional non-cine phase contrast-MRI (3D PC-MRI). Hemodynamic parameters, such as flow volume rate, flow velocity, and wall shear stress in intrahepatic PV branches were calculated before and after a meal challenge using 3D PC-MRI and hemodynamic analysis.

Results: The hemodynamic parameters obtained using 3D PC-MRI and 2D cine PC-MRI were similar. All intrahepatic PV branches were clearly depicted in eight planes, and significant changes in flow volume rate were seen in three planes. Average and maximum velocities, cross-sectional area, and wall shear stress were similar between before and after a meal challenge in all planes.

Conclusion: 7-Tesla 3D PC-MRI combined with hemodynamic analysis is a promising tool for assessing intrahepatic PV flow and enables future studies in small animals to investigate PV hemodynamics associated with liver disease/postoperative liver recovery.
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http://dx.doi.org/10.1016/j.hpb.2021.04.005DOI Listing
April 2021

Puerarin blocks the aging phenotype in human dermal fibroblasts.

PLoS One 2021 22;16(4):e0249367. Epub 2021 Apr 22.

Department of Biosciences and Biotechnology, Fukui Prefectural University, Fukui, Japan.

Dermal fibroblast aging contributes to aging-associated functional defects in the skin since dermal fibroblasts maintain skin homeostasis by interacting with the epidermis and extracellular matrix. Here, we found that puerarin, an isoflavone present in Pueraria lobata (Kudzu), can prevent the development of the aging-phenotype in human dermal fibroblasts. Normal human dermal fibroblasts (NHDFs) were subcultivated and high-passage cells were selected as senescent cells, whereas low-passage cells were selected as a young cell control. Puerarin treatment increased cell proliferation and decreased the proportion of senescence-associated beta-galactosidase-positive cells in a high-passage culture of NHDFs. Moreover, puerarin treatment reduced the number of smooth muscle actin (SMA)-positive myofibroblasts and the expression of a reticular fibroblast marker, calponin 1 (CNN1), which were induced in high-passage NHDFs. Fulvestrant, an estrogen receptor antagonist, blocked the puerarin-mediated downregulation of SMA and CNN1. Our results suggest that puerarin may be a useful functional food that alleviates aging-related functional defects in dermal fibroblasts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249367PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061915PMC
April 2021

Taurine suppresses liquid-liquid phase separation of lysozyme protein.

Amino Acids 2021 May 21;53(5):745-751. Epub 2021 Apr 21.

Department of Biosciences and Biotechnology, Fukui Prefectural University, 4-1-1 Matsuokakenjojima, Eiheiji-cho, Yoshida-gun, Fukui, 910-1195, Japan.

Taurine is a compatible osmolyte that confers stability to proteins. Recent studies have revealed that liquid-liquid phase separation (LLPS) of proteins underlie the formation of membraneless organelles in cells. In the present study, we evaluated the role of taurine on LLPS of hen egg lysozyme. We demonstrated that taurine decreases the turbidity of the polyethylene glycol-induced crowding solution of lysozyme. We also demonstrated that taurine attenuates LLPS-dependent cloudiness of lysozyme solution with 0.5 or 1 M NaCl at a critical temperature. Moreover, we observed that taurine inhibits LLPS formation of a heteroprotein mix solution of lysozyme and ovalbumin. These data indicate that taurine can modulate the formation of LLPS of proteins.
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http://dx.doi.org/10.1007/s00726-021-02980-2DOI Listing
May 2021

Influence of recombinant human-soluble thrombomodulin on extracorporeal circuit clotting in septic patients undergoing blood purification: a propensity-matched cohort study.

J Artif Organs 2021 Apr 15. Epub 2021 Apr 15.

Department of Anesthesiology and Critical Care Medicine, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.

Blood purification has been widely performed for critically ill patients, even in cases without renal failure. Effective anticoagulation of the extracorporeal circuit is necessary to prevent circuit clotting. We hypothesized that administration of recombinant human-soluble thrombomodulin (rhsTM) to septic patients undergoing blood purification may prevent circuit clotting, because this agent regulates coagulation. We performed a retrospective, single-center, propensity-matched cohort study in the intensive care unit of Nishichita General Hospital. We included septic patients admitted to the intensive care unit from May 2015 to August 2020 who underwent blood purification. Patients who received rhsTM during intensive care unit admission to the end of the first blood purification (rhsTM group) were matched 1:1 with other patients (control group). The primary outcome was the occurrence of circuit clotting during the first blood purification. A total of 138 patients were included in the study [43 patients (31%) in the rhsTM group and 95 patients (69%) in the control group]. After propensity score matching, 42 pairs of patients were selected, and patients in the rhsTM group had a lower incidence of circuit clotting (21 vs. 55%, P = 0.003). One case of major bleeding occurred in the rhsTM group, but there was no difference in the incidence of major bleeding between groups (2 vs. 0%, P = 1.0). In conclusion, this propensity-matched cohort study indicated that the administration of rhsTM to septic patients undergoing blood purification may prevent extracorporeal circuit clotting.
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http://dx.doi.org/10.1007/s10047-021-01268-2DOI Listing
April 2021

A subcentimeter duodenal neuroendocrine neoplasm with a liver metastasis upgraded to G3: a case report.

Surg Case Rep 2021 Mar 19;7(1):72. Epub 2021 Mar 19.

Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: Although duodenal neuroendocrine neoplasms (DuNENs) usually have indolent phenotypes, some DuNENs exhibit aggressive clinical manifestations. Tumor size > 1 cm, lymph node metastasis, and high grade have been associated with poor prognosis. However, preoperative risk evaluation is often difficult, because Ki-67 index on biopsy is frequently underestimated due to the intratumor heterogeneity. Here, we present a case of a subcentimeter DuNEN with a low Ki-67 index on endoscopic biopsy, who developed lymph node metastasis and high-grade liver metastasis.

Case Presentation: The patient was a 52-year-old female who presented an epigastric pain. Esophagogastroduodenoscopy revealed a duodenal submucosal lesion with a size of 8 mm. The endoscopic biopsy showed DuNEN with a Ki-67 index of 3.3% (G2 categorized by the World Health Organization 2019 classification). We performed an open partial duodenectomy with adjacent lymph node dissection. Pathological examination of the resected specimens revealed a Ki-67 index of 13.5% (G2) in the "hot spot" and lymph node metastasis. A hepatic low-density area detected on preoperative contrast-enhanced computed tomography appeared to be a liver metastasis on postoperative gadoxetic acid-enhanced magnetic resonance imaging. Subsequently, we performed a laparoscopic partial hepatectomy. Pathological examination of the liver specimen showed a metastatic neuroendocrine tumor with a Ki-67 index of 27.5% (NET-G3). The patient has been alive for 14 months since the hepatectomy.

Conclusions: This case shows the possibility of high malignant potential of DuNEN even if the primary lesion is < 1 cm and has a low Ki-67 index on biopsy.
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http://dx.doi.org/10.1186/s40792-021-01155-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979845PMC
March 2021

Serum free light chain assessment in type 1 autoimmune pancreatitis.

Pancreatology 2021 Apr 6;21(3):658-665. Epub 2021 Mar 6.

Department of Internal Medicine, Kansai University Kori Hospital, Osaka, Japan. Electronic address:

Background: /Object: Some patients with type 1 autoimmune pancreatitis (AIP), the pancreatic manifestation of IgG4-related disease, have normal serum IgG4. The aim of this study is to investigate the diagnostic value of measuring serum free light chains (FLCs) in type 1 AIP.

Materials And Methods: Thirty-seven patients with type 1 AIP, and 21 healthy, 17 alcoholic chronic pancreatitis (ACP), 21 idiopathic chronic pancreatitis (ICP) and 20 pancreatic cancer (PC) patients were enrolled. Serum IgG4 and FLC concentrations were measured using sFLC Freelite assays on a nephelometric analyzer.

Results: Active AIP patients have significantly higher serum levels of κ (median 30.97 (12.3-227.0) mg/L) and λFLC (median 20.53 (12.36-102.7) mg/L)) than healthy controls (κFLC; median 12.5 (3.1-52.1) mg/L), λFLC: median 12.45 (5.4-39.5) mg/L) (p < 0.05) correlating with raised serum IgG4, and significantly higher summated FLCs (∑) (median 53.09 (25.0-218.0) mg/L) than ICP patients (median 26.77 (15.0-89.2) mg/L) and healthy controls (median 24.43 (8.5-91.6) mg/L) (p < 0.05). AIP patients (median 1.43 (0.84-3.24)) showed significantly higher κ/λ ratios than ACP (median 0.83 (0.42-1.18)), ICP (median 0.87 (0.47-2.16)), PC patients (median 0.90 (0.48-1.27)) and healthy controls (median 0.963 (0.51-1.32)). There was a correlation between increased κ and λ FLCs levels and the number of affected organs involved in IgG4 related disease.

Conclusion: Patients with type 1 AIP have increased serum k and λ FLC concentrations, Σ FLC, and κ/λ ratios. These novel biomarkers may be useful in the diagnosis of type 1 AIP and in monitoring disease activity.
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http://dx.doi.org/10.1016/j.pan.2021.03.001DOI Listing
April 2021

Direct generation of sub-picosecond pulse via multi-section gain switching.

Opt Lett 2021 Mar;46(6):1277-1280

We have directly generated optical pulses having a duration of 0.56 ps with a peak power of 25 W by gain switching of multi-section semiconductor lasers in which the optimized lengths of the absorption and gain regions were 50 and 200 µm, respectively. Even though the experiment was conducted via impulsive optical pumping at a low temperature, we observed that the multi-section gain switching suppresses the low-energy tail and chirping inherent to conventional gain switching in single-section lasers and is useful in direct short-pulse generation.
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http://dx.doi.org/10.1364/OL.409822DOI Listing
March 2021

Endotheliopathy in septic conditions: mechanistic insight into intravascular coagulation.

Crit Care 2021 03 8;25(1):95. Epub 2021 Mar 8.

Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.

Endothelial cells play a key role in maintaining intravascular patency through their anticoagulant properties. They provide a favorable environment for plasma anticoagulant proteins, including antithrombin, tissue factor pathway inhibitor, and protein C. Under septic conditions, however, the anticoagulant properties of endothelial cells are compromised. Rather, activated/injured endothelial cells can provide a scaffold for intravascular coagulation. For example, the expression of tissue factor, an important initiator of the coagulation pathway, is induced on the surface of activated endothelial cells. Phosphatidylserine, a high-affinity scaffold for gamma-carboxyglutamate domain containing coagulation factors, including FII, FVII, FIX, and FX, is externalized to the outer leaflet of the plasma membrane of injured endothelial cells. Hemodilution decreases not only coagulation factors but also plasma anticoagulant proteins, resulting in unleashed activation of coagulation on the surface of activated/injured endothelial cells. The aberrant activation of coagulation can be suppressed in part by the supplementation of recombinant antithrombin and recombinant thrombomodulin. This review aims to overview the physiological and pathological functions of endothelial cells along with proof-of-concept in vitro studies. The pathophysiology of COVID-19-associated thrombosis is also discussed.
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http://dx.doi.org/10.1186/s13054-021-03524-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938685PMC
March 2021

Attempt to Develop Rat Disseminated Intravascular Coagulation Model Using Yamakagashi () Venom Injection.

Toxins (Basel) 2021 02 18;13(2). Epub 2021 Feb 18.

Emergency and Critical Care Medicine St. Luke's International Hospital Tokyo 104-8560, Japan.

Disseminated intravascular coagulation, a severe clinical condition caused by an underlying disease, involves a markedly continuous and widespread activation of coagulation in the circulating blood and the formation of numerous microvascular thrombi. A snakebite, including that of the Yamakagashi (), demonstrates this clinical condition. Thus, an animal model using Yamakagashi venom was constructed. Yamakagashi venom was administered to rats, and its lethality and the changes in blood coagulation factors were detected after venom injection. When 300 μg venom was intramuscularly administered to 12-week-old rats, (1) they exhibited hematuria with plasma hemolysis and died within 48 h; (2) Thrombocytopenia in the blood was observed in the rats; (3) irreversible prolongation of prothrombin time in the plasma to the measurement limit occurred; (4) fibrinogen concentration in the plasma irreversibly decreased below the measurement limit; and (5) A transient increase in the plasma concentration of D-dimer was observed. In this model, a fixed amount of venom injection resulted in the clinical symptom similar to the human pathology with snakebite. The use of the rat model is very effective in validating the therapeutic effect of human disseminated intravascular coagulation condition due to snakebite.
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http://dx.doi.org/10.3390/toxins13020160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922536PMC
February 2021

Chimeric Measles Virus (MV/RSV), Having Ectodomains of Respiratory Syncytial Virus (RSV) F and G Proteins Instead of Measles Envelope Proteins, Induced Protective Antibodies against RSV.

Vaccines (Basel) 2021 Feb 16;9(2). Epub 2021 Feb 16.

Laboratory of Viral Infection I, Ōmura Satoshi Memorial Institute, Kitasato University, Tokyo 108-8641, Japan.

In our previous study, fusion (F) or glyco (G) protein coding sequence of respiratory syncytial virus (RSV) was inserted at the P/M junction of the measles AIK-C vector (MVAIK), and the recombinant measles virus induced protective immune responses. In the present study, the ectodomains of measles fusion (F) and hemagglutinin (HA) proteins were replaced with those of RSV F and G proteins, and a chimeric MV/RSV vaccine was developed. It expressed F and G proteins of RSV and induced cytopathic effect (CPE) in epithelial cell lines (Vero, A549, and HEp-2 cells), but not in lymphoid cell lines (B95a, Jurkat, and U937 cells). A chimeric MV/RSV grew similarly to AIK-C with no virus growth at 39 °C. It induced NT antibodies against RSV in cotton rats three weeks after immunization through intramuscular route and enhanced response was observed after the second dose at eight weeks. After the RSV challenge with 10 PFU, significantly lower virus (10 PFU of RSV) was recovered from lung tissue in the chimeric MV/RSV vaccine group than in the MVAIK control group with 10 PFU ( < 0.001) and no obvious inflammatory pathological finding was noted. The strategy of ectodomain replacement in the measles virus vector is expected to lead to the development of safe and effective vaccines for other enveloped viruses.
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http://dx.doi.org/10.3390/vaccines9020156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920054PMC
February 2021

Multicenter 1-month follow-up study of the patch-test reaction to the gold sodium thiosulfate of the TRUE Test and its association with piercings and dental metal history.

Contact Dermatitis 2021 Mar 3. Epub 2021 Mar 3.

Japanese Contact Dermatitis Research Group, Nagoya, Japan.

Background: There is controversy over late and long-lasting reactions to gold sodium thiosulfate (GST).

Objectives: To study the GST patch-test reaction by observing the application site after 1 month, and to clarify the relevance of GST sensitization by piercings and dental metals.

Patients: A retrospective analysis was performed on 746 patients (143 male; 603 female) who were patch tested using GST of the TRUE Test. We conducted a questionnaire on the presence of piercings or dental metals in these patients.

Results: The GST positive rate was 27.9% at day (D)3 and/or D7 and 40.3% up to the 1-month reading. The positive rate was significantly higher in female patients and increased with age. Sixty-two percent of cases with a positive reaction at D7 continued to show a positive reaction after 1 month. Eleven percent of cases with a negative reaction at D3 and D7 showed a late reaction. Both piercings and dental metals were related to gold sensitization.

Conclusions: The GST of the TRUE Test had a high positive and low false-negative rate. The 1-month reading after the patch test was important for identifying late reactions. Piercing history and dental metal were associated with gold sensitization.
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http://dx.doi.org/10.1111/cod.13827DOI Listing
March 2021

Histological changes in the human esophagus following triamcinolone injection to prevent esophageal stricture after endoscopic submucosal dissection.

Esophagus 2021 Jul 2;18(3):594-603. Epub 2021 Mar 2.

Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences (Medicine), Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

Background: Locoregional steroid injection prevents post-endoscopic submucosal dissection (ESD) esophageal stricture, but histological changes that occur following steroid injection in the human esophagus are unclear. This study investigated the histopathological characteristics caused by locoregional triamcinolone acetonide (TA) injection using human esophagectomy specimens.

Methods: From January 2014 to December 2019, among 297 patients (373 lesions) who underwent esophageal ESD, 13 patients who underwent additional esophagectomy after ESD were examined. Seven patients (TA group) with wide excisions were injected with TA after ESD and another six patients (Non-TA group) with smaller tumors were not injected with TA. The clinical background of these patients and histopathological features of ESD ulcer scar obtained from esophagectomy specimens were retrospectively investigated.

Results: The circumferential rate of ESD excision was more than three-quarters in all cases in the TA group, whereas it was less than three-quarters in the Non-TA group. No other statistical difference in the clinical background was found between the two groups. The subepithelial fibrous tissue of the ESD ulcer scar in the TA group was significantly thinner than that in the Non-TA group (P < 0.05). There was no significant difference in the thickness of the regenerated epithelium and muscularis propria layer of the ESD ulcer scar.

Conclusions: Histological finding of thinning of the subepithelial fibrous tissue of ESD ulcer scar in the human esophagus after TA injection was obtained. This suggests that TA suppresses the proliferation of the fibrous tissue of the subepithelial layer to help prevent esophageal stricture after widespread ESD in the human esophagus.
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http://dx.doi.org/10.1007/s10388-021-00818-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172396PMC
July 2021

The Edible Brown Seaweed (Turner) C. Agardh Ameliorates High-Fat Diet-Induced Obesity, Diabetes, and Hepatic Steatosis in Mice.

Nutrients 2021 Feb 8;13(2). Epub 2021 Feb 8.

Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Ishikawa 9218836, Japan.

(Turner) C. Agardh () is edible brown seaweed that grows along the coast of East Asia and has been traditionally used as a folk medicine and a local food. In this study, we evaluated the effects of on the development of obesity and related metabolic disorders in C57BL/6J mice fed a high-fat diet. was freeze-dried, fine-powdered, and mixed with a high-fat diet at a weight ratio of 2% or 6%. Feeding a high-fat diet to mice for 13 weeks induced obesity, diabetes, hepatic steatosis, and hypercholesterolemia. Supplementation of mice with suppressed high-fat diet-induced body weight gain and the accumulation of fat in adipose tissue and liver, and the elevation of the serum glucose level. In addition, improved insulin resistance. An analysis of the feces showed that stimulated the fecal excretion of triglyceride, as well as increased the fecal polysaccharide content. Furthermore, extracts of inhibited the activity of pancreatic lipase in vitro. These results showed that can ameliorate diet-induced metabolic diseases, and the effect may be partly associated with the suppression of intestinal fat absorption.
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http://dx.doi.org/10.3390/nu13020551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915656PMC
February 2021

Fluorescence Microscopic Investigations of Molecular Dynamics in Self-Assembled Nanostructures.

Chem Rec 2021 Jun 3;21(6):1417-1429. Epub 2021 Feb 3.

Department of Chemistry, Kansas State University, 213 CBC Building, Manhattan, KS 66506-0401, USA.

Many analytical methods employ self-assembled nanostructured materials as chemical recognition media. Molecular permeation through these materials exhibits unique selectivity owing to nanoconfinement-induced enhancement of permeant-nanostructure interactions. This Personal Account introduces our efforts to investigate the detailed dynamics of single or a small number of molecules in nanostructured materials. We developed new experimental and analysis approaches built upon laser-based fluorescence microscopy to measure the detailed translational and orientational dynamics of molecules diffusing in horizontally-oriented, cylindrical nanostructures, including surfactant micelles, silica mesopores, block copolymer microdomains, and bolaamphiphile-based organic nanotubes. Our studies clarified nanoscale details on the structural/chemical heterogeneity of the nanostructures, and their impacts on molecular mass transport dynamics.
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http://dx.doi.org/10.1002/tcr.202000173DOI Listing
June 2021

Endoscopic retrieval of a migrated biliary stent into intrahepatic bile duct by using fine-gauge biliary balloon dilation catheter.

Dig Endosc 2021 Mar 11;33(3):e39-e40. Epub 2021 Jan 11.

Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan.

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http://dx.doi.org/10.1111/den.13915DOI Listing
March 2021

A structured summary of a study protocol for a multi-center, randomized controlled trial (RCT) of COVID-19 prevention with Kampo medicines (Integrative Management in Japan for Epidemic Disease by prophylactic study: IMJEDI P1 study).

Trials 2021 Jan 6;22(1):23. Epub 2021 Jan 6.

Akashi Clinic Kanda, 3-8, Kandaogawamachi, Chiyodaku, Tokyo, 101-0052, Japan.

Objective: We aimed to test our hypothesis that traditional Japanese (Kampo) medicine, hochuekkito (Hochu-ekki-to: HET) has a preventive effect for the symptoms on COVID-19.

Trial Design: The study is designed as a multi-center, interventional, parallel-group, randomized (1:1 ratio), investigator sponsored, two-arm study.

Participants: Six thousand participants will be recruited from healthy hospital workers in 7 Japanese University Hospitals.

Inclusion Criteria: 1. Age from 20 to 75 years old at the time of registration 2. Asymptomatic and body temperature below 37°C at the time of registration 3. Capable of eating orally Exclusion criteria: 1. Previous upper respiratory inflammation due to viral infection (including suspected COVID-19) 2. Taking immunosuppressants 3. Allergic to the Kampo medicines used in this study 4. History of hypokalaemia, severe hypertension, severe liver dysfunction, and interstitial pneumonia 5. Regularly taking other Kampo medicines 6. Pregnant or possibly pregnant 7. Participating in other research 8. Judged to be unsuitable for this study by the doctor in charge INTERVENTION AND COMPARATOR: Kampo group: participants receive HET in 9 tablets 2 times per day for 8 weeks.

Control Group: participants receive placebo in the same dosage as the Intervention group - 9 tablets 2 times per day for 8 weeks. Placebo tablets are identical in appearance and package to HET. Taste of placebo is different from that of HET. The Ohsugi Pharmaceutical Co. Ltd, Osaka, Japan manufactured the placebo and HET.

Main Outcomes: Primary outcome: Number of patients with a SARS-CoV-2 RNA by ploymerase chain reaction (PCR) positive result with at least one symptom (fever, cough, sputum, malaise, shortness of breath) during the 12-week study period (including the 4-week observation period after oral administration).

Secondary Outcomes: 1. Period from infection to onset 2. Period from the appearance of symptoms to the disappearance of PCR positive 3. Number of days until the appearance or improvement of symptoms 4. Severe stage: presence of hospitalization 5. Shock stage: ICU management required for mechanical ventilation, shock vitals or failure of organ(s) other than lungs Safety endpoints include numbness in the hands and/or feet, edema, skin rash or other allergic symptoms, and gastric discomfort.

Randomisation: Patients are randomized (1:1 ratio) to each group using minimization implemented with the Electric data capture system (DATATRAK Enterprise Cloud), with balancing of the arms with age range (under 50 years of age or not) and having a history of risk factors for COVID-19 (cardiovascular disease, hypertension, diabetes, respiratory diseases).

Blinding (masking): Only participants will be randomized.

Numbers To Be Randomised (sample Size): The main research hypothesis of this study is that Kampo medicines significantly prevent the onset of COVID-19. It is assumed that the infection rate before the administration of the drug under consideration will be 0% and that the incidence of COVID-19 thereafter will be 2- 3%, of which 70%-80% will show symptoms of COVID-19. Assuming that the pharmaceutical effect of the drug will be effective in 50% of patients and that the incidence rates in the placebo and drug groups will be 1.4%-2.4% and 0.7%-1.2%, respectively, the placebo is calculated at 2%, and the study drug at 1%. Since the frequency of verification is low and the number of cases will be large, we set a total of 10 analyses (9 interim analyses and a final analysis). Since the number of cases at the time of the final analysis will be 4,986 under the conditions of α = 0.05 and a power of 80% by the Peto method. We set at 600 cases in each interim analysis with an estimated dropout rate of 16.9%. Finally, the total number of cases is set to 6,000 with 3,000 in the placebo group and 3,000 in the HET group.

Trial Status: Protocol version 1.3 of October 23rd , 2020. Recruitment start (expected): December 1, 2020. Recruitment finish (expected): December 31, 2022.

Trial Registration: This trial is registered in the Japan Registry of Clinical Trials (jRCT) ( jRCTs031200150 ) on 14 October 2020.

Full Protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-020-04939-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787232PMC
January 2021

Catalytically inactive Cas9 impairs DNA replication fork progression to induce focal genomic instability.

Nucleic Acids Res 2021 01;49(2):954-968

Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

Catalytically inactive Cas9 (dCas9) has become an increasingly popular tool for targeted gene activation/inactivation, live-cell imaging, and base editing. While dCas9 was reported to induce base substitutions and indels, it has not been associated with structural variations. Here, we show that dCas9 impedes replication fork progression to destabilize tandem repeats in budding yeast. When targeted to the CUP1 array comprising ∼16 repeat units, dCas9 induced its contraction in most cells, especially in the presence of nicotinamide. Replication intermediate analysis demonstrated replication fork stalling in the vicinity of dCas9-bound sites. Genetic analysis indicated that while destabilization is counteracted by the replisome progression complex components Ctf4 and Mrc1 and the accessory helicase Rrm3, it involves single-strand annealing by the recombination proteins Rad52 and Rad59. Although dCas9-mediated replication fork stalling is a potential risk in conventional applications, it may serve as a novel tool for both mechanistic studies and manipulation of genomic instability.
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http://dx.doi.org/10.1093/nar/gkaa1241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826275PMC
January 2021

Disseminated Varicella zoster infection with abdominal pain and periarterial fat stranding in a patient taking pomalidomide.

Acute Med Surg 2020 Jan-Dec;7(1):e494. Epub 2020 Mar 6.

Department of Critical Care Medicine and Trauma National Hospital Organization Disaster Medical Center Tokyo Japan.

Background: Disseminated Varicella zoster virus infection (DVI) is a severe infection associated with severe abdominal pain of unknown cause. We report a case in which periarterial (the celiac artery and superior mesenteric artery) fat stranding (PFS) on computed tomography (CT) was the presumed cause of abdominal pain in a patient taking pomalidomide.

Case Presentation: A 62-year-old woman was admitted to our hospital with abdominal pain. Her medical history was multiple myeloma treated with pomalidomide. Computed tomography showed no remarkable findings on admission, but 1 day later, a contrast-enhanced CT showed PFS. A skin eruption appeared on day 4 and we started acyclovir. On day 10, Varicella zoster virus antigen and antibody tests were positive, confirming the diagnosis of DVI. The abdominal pain subsequently improved, together with the PFS, and she was discharged.

Conclusion: When patients present with severe abdominal pain and PFS, DVI and acyclovir must be considered.
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http://dx.doi.org/10.1002/ams2.494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774293PMC
March 2020

Development of Severe Acute Pancreatitis Following Uncovered Metallic Stent Placement: A Rare Case Report.

Intern Med 2021 Jun 29;60(11):1703-1707. Epub 2020 Dec 29.

The Third Department of Internal Medicine, Kansai Medical University, Japan.

Self-expandable metallic stents (SEMSs) are widely used for malignant biliary stricture (MBS). Acute pancreatitis is an early complication following SEMS placement. In the present case, the patient developed severe acute pancreatitis after SEMS placement for MBS because of metastatic lymph nodes. Endoscopic retrograde cholangiopancreatography, endoscopic sphincterotomy and an endoscopic nasobiliary drainage tube placement were performed. After seven days, an uncovered SEMS was placed; however, severe acute pancreatitis occurred, and the SEMS was drawn out emergently. In SEMS placement for patients with MBS caused by non-pancreatic cancer, SEMS should be selected carefully while considering each patient's case.
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http://dx.doi.org/10.2169/internalmedicine.6394-20DOI Listing
June 2021

Analysis of bevacizumab treatments and metastatic sites of lung cancer.

Cancer Treat Res Commun 2021 26;26:100290. Epub 2020 Dec 26.

Division of Pulmonary Medicine, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan. Electronic address:

Introduction: Liver metastasis has not been sufficiently evaluated in lung cancer so far. We retrospectively analyzed the distant metastasis of Non-squamous non-small cell lung cancer (NSQ-NSCLC), including liver metastasis, and association between prognosis and therapeutic effect of bevacizumab treatment.

Patients And Methods: Clinical data were collected from 1954 patients with lung cancer admitted in our hospital between 1st April 2011 and 31 March 2019. Information is extracted from the electronic medical record. Main collection data was the age, gender, smoking history, performance status, histology and driver mutation, distant metastasis site. Efficacy data of treatment including treatment duration and survival time were obtained from medical record, image data and local registry.

Results: Total 366 patients receiving any chemotherapy with NSQ-NSCLC were eligible for this study. Most frequent extrathoracic metastasis is bone (N = 59) followed by brain (37), liver (18), adrenal gland (23), and OS analysis showed liver metastasis was worse prognosis compared to brain and bone metastasis (median OS: 11.6, 18.9, 15.0, respectively). Bevacizumab treatment was tend to have favorable efficacy in patients with each metastatic sites, especially, induced significant longer OS for patients with liver metastasis. CONCLUSION;: Though this study was retrospective study for small sized metastatic patients, the study suggested that liver metastasis was refractory, and that bevacizumab treatment might improve the worse prognosis.
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http://dx.doi.org/10.1016/j.ctarc.2020.100290DOI Listing
December 2020

Adenocarcinoma arising in the multiple heterotopic submucosal glands of the intestine in a Satoyoshi syndrome patient: A case report.

Pathol Int 2021 Feb 17;71(2):147-154. Epub 2020 Dec 17.

Department of Comprehensive Pathology, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan.

Satoyoshi syndrome is a rare multisystemic disorder of unknown etiology characterized by progressive muscle spasms, alopecia and diarrhea. Multiple protruding lesions with cystic glands, namely gastroenterocolitis cystica polyposa, manifest in the gastrointestinal tract. Since the first report of these lesions in 1977, which was unique to Satoyoshi syndrome, few studies have focused on their role, and the associated clinicopathological features are not well understood. Here, we report a 64-year-old Japanese woman with Satoyoshi syndrome who presented with multiple polypoid lesions in the stomach, duodenum, jejunum, ileum and colon. Histologically, the polypoid lesions in the intestine comprised multiple heterotopic submucosal glands containing cystically dilated glands and smooth muscle fibers in the lamina propria mucosa and/or submucosa. Additionally, we observed stromal changes, such as fibrosis, discontinuous and thinning muscularis mucosae, and diffuse neural fiber proliferation in the entire intestinal tract. Furthermore, multiple foci of adenocarcinomas were identified within several heterotopic submucosal glands. We hypothesized that multiple heterotopic submucosal glands in the present case corresponded to previously reported gastroenterocolitis cystica polyposa, suggesting that these lesions are essential in the histopathology and are a unique manifestation of Satoyoshi syndrome.
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http://dx.doi.org/10.1111/pin.13053DOI Listing
February 2021