Publications by authors named "Yusuke Yamashita"

34 Publications

Intramammary infection caused by Staphylococcus aureus increases IgA antibodies to iron-regulated surface determinant-A, -B, and -H in bovine milk.

Vet Immunol Immunopathol 2021 May 31;235:110235. Epub 2021 Mar 31.

Dairy Hygiene Research Division, National Institute of Animal Health, National Agriculture and Food Research Organization, 4 Hitsujigaoka, Toyohira, Sapporo, Hokkaido, 062-0045, Japan. Electronic address:

The aim of this study was to identify virulence factors that have high immunogenicity. An in vivo-expressed Staphylococcus aureus antigen was identified by probing bacteriophage expression libraries of S. aureus with antibodies in bovine mastitis milk. Eighteen clones were isolated, and their proteins were identified as 5 characterised proteins (IsdA, Protein A, IsdB, autolysin, and imidazole glycerol phosphate dehydratase) and 13 hypothetical proteins. We focused on IsdA, IsdB, and IsdH as virulence factors that have a high immunogenicity and are capable of inducing a specific humoral immune response in S. aureus-infected quarters. The optical density (OD) values of IsdA and IsdB IgA and IgG antibodies in milk affected by naturally occurring mastitis caused by S. aureus increased significantly compared to those in healthy milk. In the experimental infection study, the OD values of IsdA- and B-specific IgA and IgG antibodies were significantly increased from 2 to 4 weeks after S. aureus infection compared to day 0 (P < 0.05). On the other hand, we demonstrated that milk from natural and experimental intramammary infections caused by S. aureus are associated with significantly higher IgA levels against IsdH (P < 0.05), but no significant change in IgG levels. Our findings facilitated our understanding of the pathogenicity of S. aureus in bovine mastitis, as well as the mechanisms by which specific humoral immune responses to S. aureus infection are induced. In addition, the results obtained could provide insight into how bovine mastitis can be controlled, for example, through vaccination.
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http://dx.doi.org/10.1016/j.vetimm.2021.110235DOI Listing
May 2021

[Erdheim-Chester disease diagnosed with right atrium tumors].

Rinsho Ketsueki 2021 ;62(2):91-93

Department of Hematology/Oncology, Wakayama Medical University.

Erdheim-Chester disease (ECD) is a very rare form of the non-Langerhans histiocytic multisystem disorder. The cardiac involvement is often challenging and is associated with poor prognosis. Transthoracic echocardiography was used to detect right atrium tumors in a 62-year-old man with heart failure who was admitted to our hospital. The circumferential soft tissue sheathing of the aorta (coated aorta) and fat infiltration around the kidneys (hairy kidneys) was seen on a contrast-enhanced computed tomography strongly suspecting ECD imaging. The patient was diagnosed with ECD based on histopathology reports of the surgical resection tumor. The characteristic imaging findings of ECD may contribute to an early and accurate diagnosis.
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http://dx.doi.org/10.11406/rinketsu.62.91DOI Listing
March 2021

Progressive Massive Splenomegaly in an Adult Patient with Kabuki Syndrome Complicated with Immune Thrombocytopenic Purpura.

Intern Med 2021 Feb 1. Epub 2021 Feb 1.

Department of Hematology/Oncology, Wakayama Medical University, Japan.

Kabuki syndrome is characterized by multiple systemic anomalies and intellectual disability. It is complicated with immunodeficiencies and autoimmune disorders. The syndrome is caused by a mutation in the KMT2D gene. We herein report a case of a Kabuki syndrome with developing immune thrombocytopenic purpura (ITP) and progressive splenomegaly. Laparoscopic splenectomy was performed and the patients' symptoms quickly disappeared with platelet recovery. After this operation, the patient had no severe complications. A sequence analysis of the KMT2D gene identified a pathogenic mutation frequently associated with ITP. Laparoscopic splenectomy is therefore considered to be a good therapeutic option for recurrent ITP and symptomatic splenomegaly with Kabuki syndrome.
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http://dx.doi.org/10.2169/internalmedicine.6694-20DOI Listing
February 2021

Copy number variations in BOLA-DQA2, BOLA-DQB, and BOLA-DQA5 show the genomic architecture and haplotype frequency of major histocompatibility complex class II genes in Holstein cows.

HLA 2020 11 9;96(5):601-609. Epub 2020 Oct 9.

Hokkaido Chuo Agricultural Mutual Aid Association, Hokkaido, Japan.

Bovine major histocompatibility complex (MHC) class II region contains many genes. The bovine leukocyte antigen (BoLA)-DRB3 was reportedly associated with susceptibility of various phenotypes of infections including bovine leukemia virus-induced lymphoma. However, the association of the remaining genes with various phenotypes has not been clarified due to the complicated genomic structure of the MHC class II region. Thus, in this study, we elucidated the MHC class II genomic structure, including the novel alleles and copy number variations (CNVs). We determined the copy numbers of BOLA-DQA2 (DQA2), BOLA-DQB (DQB2), BOLA-DQA5 (DQA5), BLA-DQB (DQB1), LOC100848815 (DQA1), and BOLA-DRB3 (DRB3) in 127 unrelated Holstein cows by TaqMan copy number assay. The genomes were sequenced using target next-generation sequencing (NGS) based on multiplex polymerase chain reaction. Combining the results of the copy numbers and alleles, we identified the BoLA alleles directly without haplotype estimation. Pairwise linkage disequilibrium (LD) analysis between alleles and genes were performed. The CNVs of DQA2, DQB2, and DQA5 in Holstein cows were detected. The frequency of the whole gene deletion in DQA2, DQB2, and DQA5 was 35.4%, 93.7%, and 93.7%, respectively. After target NGS, we identified 37 alleles in the six genes. Fifteen novel alleles (40.5%) were not registered in the IPD-MHC Database. LD analysis showed strong LD among the DQB2*deletion, DQA5*deletion, and DRB3*27:03 alleles. Our findings will provide important insights into the identification of the BoLA genes associated with various infection-related phenotypes.
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http://dx.doi.org/10.1111/tan.14086DOI Listing
November 2020

Targeting Adaptive IRE1α Signaling and PLK2 in Multiple Myeloma: Possible Anti-Tumor Mechanisms of KIRA8 and Nilotinib.

Int J Mol Sci 2020 Aug 31;21(17). Epub 2020 Aug 31.

Department of Hematology/Oncology, Wakayama Medical University, Wakayama 641-8509, Japan.

Background: Inositol-requiring enzyme 1α (IRE1α), along with protein kinase R-like endoplasmic reticulum kinase (PERK), is a principal regulator of the unfolded protein response (UPR). Recently, the 'mono'-specific IRE1α inhibitor, kinase-inhibiting RNase attenuator 6 (KIRA6), demonstrated a promising effect against multiple myeloma (MM). Side-stepping the clinical translation, a detailed UPR phenotype in patients with MM and the mechanisms of how KIRA8 works in MM remains unclear.

Methods: We characterized UPR phenotypes in the bone marrow of patients with newly diagnosed MM. Then, in human MM cells we analyzed the possible anti-tumor mechanisms of KIRA8 and a Food and Drug Administration (FDA)-approved drug, nilotinib, which we recently identified as having a strong inhibitory effect against IRE1α activity. Finally, we performed an RNA-sequence analysis to detect key IRE1α-related molecules against MM.

Results: We illustrated the dominant induction of adaptive UPR markers under IRE1α over the PERK pathway in patients with MM. In human MM cells, KIRA8 decreased cell viability and induced apoptosis, along with the induction of C/EBP homologous protein (CHOP); its combination with bortezomib exhibited more anti-myeloma effects than KIRA8 alone. Nilotinib exerted a similar effect compared with KIRA8. RNA-sequencing identified () as a KIRA8-suppressed gene. Specifically, the IRE1α overexpression induced PLK2 expression, which was decreased by KIRA8. KIRA8 and PLK2 inhibition exerted anti-myeloma effects with apoptosis induction and the regulation of cell proliferation. Finally, PLK2 was pathologically confirmed to be highly expressed in patients with MM.

Conclusion: Dominant activation of adaptive IRE1α was established in patients with MM. Both KIRA8 and nilotinib exhibited anti-myeloma effects, which were enhanced by bortezomib. Adaptive IRE1α signaling and PLK2 could be potential therapeutic targets and biomarkers in MM.
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http://dx.doi.org/10.3390/ijms21176314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504392PMC
August 2020

[Paroxysmal nocturnal hemoglobinuria treated with eculizumab in Wakayama, Japan: a retrospective analysis].

Rinsho Ketsueki 2020 ;61(6):605-611

Department of Hematology/Oncology, Wakayama Medical University.

Currently, the humanized anti-C5 monoclonal antibody, eculizumab, is widely used for treating paroxysmal nocturnal hemoglobinuria (PNH) due to its effects on suppression of intravascular hemolysis and resulting improvement in quality of life. However, in some cases, this treatment is refractory or is associated with meningococcal meningitis. No region-specific analyses have been published, and currently, information on region specificity and genetic factors is limited. We present here the results of a retrospective study involving eight patients with PNH who were treated with eculizumab in our hospital in Wakayama, Japan. The median age of these patients was 77 (range 23-88) years. Six patients had a complication of aplastic anemia, four patients had a history of thrombosis, and two experienced hemolytic episodes. Before initiating eculizumab treatment, the median serum LDH level was 1,192 IU/l (range 755-1,525 IU/l). Serum LDH levels normalized in five patients within a month of initiating therapy and PNH-related symptoms disappeared. C5 gene mutations were identified in the three patients who did not respond to eculizumab.
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http://dx.doi.org/10.11406/rinketsu.61.605DOI Listing
July 2020

Two Episodes of Transfusion-related Acute Lung Injury (TRALI) Occurring within a Short Period.

Intern Med 2020 Oct 23;59(20):2577-2581. Epub 2020 Jun 23.

Department of Hematology/Oncology, Wakayama Medical University, Japan.

Transfusion-related acute lung injury (TRALI) is a non-hemolytic adverse reaction that occurs ≤6 hours after receiving a transfusion. A 72-year-old man with leukemia developed severe hypoxemia after platelet transfusions on two occasions within a 4-day period. During the first episode, the transfused platelet preparation was positive for anti-human-leukocyte antigen antibodies. The pathogenesis of TRALI includes an antibody-mediated mechanism and a non-antibody-mediated mechanism, in which various factors combine to activate pulmonary neutrophils. In our case, it is considered that the patient's neutrophils reached the activation threshold for the development of TRALI after the accumulation of various factors besides anti-leukocyte antibodies.
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http://dx.doi.org/10.2169/internalmedicine.4700-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662060PMC
October 2020

Brentuximab vedotin for refractory anaplastic lymphoma kinase-negative anaplastic large cell lymphoma in leukemic phase with overexpression.

Hematol Rep 2020 May 15;12(1):8368. Epub 2020 May 15.

Department of Hematology/Oncology.

Anaplastic lymphoma kinase (ALK)- negative anaplastic large cell lymphoma (ALCL) is an aggressive CD30-positive non- Hodgkin lymphoma. ALK-ALCL rarely manifests with extensive bone marrow and peripheral blood involvement (known as "leukemic phase"). A 54-year-old woman was diagnosed with ALK-ALCL in leukemic phase, characterized by an extremely poor prognosis. Lymphoma cells in this case showed chromosomal translocation 1p36.1- encoded RUNX3 and overexpression of its protein. She was refractory to CHOP and salvage chemotherapy. Fortunately, she achieved complete remission with three cycles of Brentuximab vedotin (BV) and underwent umbilical cord blood transplantation. However, she died due to treatment-related mortality on day 129. The autopsy findings showed no lymphoma cells. Treatment strategy for ALK-ALCL is controversial, but the efficacy of BV in CD30-positive peripheral T-cell lymphoma not only as salvage regimens, but also in first line, has been reported in recent years. BV may be an effective option for ALK-ALCL in leukemic phase.
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http://dx.doi.org/10.4081/hr.2020.8368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256628PMC
May 2020

PKN1 kinase-negative knock-in mice develop splenomegaly and leukopenia at advanced age without obvious autoimmune-like phenotypes.

Sci Rep 2019 Sep 27;9(1):13977. Epub 2019 Sep 27.

Graduate School of Medicine, Kobe University, Kobe, 650-0017, Japan.

Protein kinase N1 (PKN1) knockout (KO) mice spontaneously form germinal centers (GCs) and develop an autoimmune-like disease with age. Here, we investigated the function of PKN1 kinase activity in vivo using aged mice deficient in kinase activity resulting from the introduction of a point mutation (T778A) in the activation loop of the enzyme. PKN1[T778A] mice reached adulthood without external abnormalities; however, the average spleen size and weight of aged PKN1[T778A] mice increased significantly compared to aged wild type (WT) mice. Histologic examination and Southern blot analyses of spleens showed extramedullary hematopoiesis and/or lymphomagenesis in some cases, although without significantly different incidences between PKN1[T778A] and WT mice. Additionally, flow cytometry revealed increased numbers in B220, CD3, Gr1 and CD193 leukocytes in the spleen of aged PKN1[T778A] mice, whereas the number of lymphocytes, neutrophils, eosinophils, and monocytes was reduced in the peripheral blood, suggesting an advanced impairment of leukocyte trafficking with age. Moreover, aged PKN1[T778A] mice showed no obvious GC formation nor autoimmune-like phenotypes, such as glomerulonephritis or increased anti-dsDNA antibody titer, in peripheral blood. Our results showing phenotypic differences between aged Pkn1-KO and PKN1[T778A] mice may provide insight into the importance of PKN1-specific kinase-independent functions in vivo.
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http://dx.doi.org/10.1038/s41598-019-50419-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764976PMC
September 2019

Relationships between expression levels of genes related to adipogenesis and adipocyte function in dogs.

Mol Biol Rep 2019 Oct 12;46(5):4771-4777. Epub 2019 Aug 12.

Division of Applied Biosciences, Kyoto University Graduate School of Agriculture, Kyoto, 606-8502, Japan.

There are three kinds of adipocytes; white adipocytes accumulate excess energy as fat, whereas brown/beige adipocytes dissipate energy through expression of uncoupling protein 1 (UCP1). Obesity, a feature of excess accumulation of white adipocytes in a body, is one of the risk factors for onset of various diseases in dogs. As the first step to explore adipose genes related to dog obesity, we examined relationships among mRNA levels of putative molecules related to adipogenesis and function of adipocytes in fat of hospitalized dogs. Gonadal adipose tissues were collected from a total of 29 dogs, and the gene expression levels were examined by quantitative RT-PCR analysis. The multicollinearity analysis revealed that body condition score (BCS), which reflects adiposity, did not correlate with expression levels of any genes but correlated with age of dog. Bone morphogenetic protein (BMP) pathway stimulates not only commitment of mesenchymal stem cells to white adipocyte-lineage cells but also brown/beige adipogenesis. Some relationships between expression levels of BMP receptors were significant; especially, expression levels of activin receptor-like kinase (Alk) 3 (a BMP type I receptor) positively related to those of Alk2 (another BMP type I receptor), activin receptor type II (ActRII) A (a type II receptor to transmit BMP signal), ActRIIB (another type II receptor to transmit BMP signal) and BMP receptor type 2 (Bmpr2). PR domain containing 16 (Prdm16) expression levels strongly correlated with expression levels of ActRIIB. Although PRDM16 is known to stimulate brown/beige adipogenesis, expression levels of Ucp1 did not correlate with those of Prdm16. On the other hand, expression levels of Ucp1 correlated with those of Alk6. The present study suggests close relationships among adipose expressions of BMP signal components, and the relationships of expression levels of BMP receptor and those of Prdm16 or Ucp1 in dogs. Further studies using more dogs with various BCS potentially lead to identification of adipose factors to relate with adiposity in dogs.
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http://dx.doi.org/10.1007/s11033-019-04923-3DOI Listing
October 2019

[Refractory ascites developing in late-phase of cord blood transplantation improving with CART].

Rinsho Ketsueki 2019;60(2):130-133

Department of Hematology/Oncology, Wakayama Medical University.

We managed a patient with acute myeloid leukemia (AML) who showed refractory ascites that developed in late-phase cord blood transplantation (CBT). The ascites obverted 5 months after CBT. The liver was atrophic, and serum hyaluronic acid was elevated at the onset, suggesting fibrotic changes in the liver. The ascites were transiently improved by cell-free and concentrated ascites reinfusion therapy (CART) and corticosteroid administration; however, the patient died from anasarca and recurrent AML 378 d after CBT. The etiology of the ascites is not well understood; therefore, additional studies on similar patients should be explored for proper management.
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http://dx.doi.org/10.11406/rinketsu.60.130DOI Listing
August 2019

[Cytomegalovirus meningoencephalitis in a diffuse large B-cell lymphoma patient undergoing salvage chemotherapy].

Rinsho Ketsueki 2019;60(2):124-129

Department of Hematology/Oncology, Wakayama Medical University.

A 63-year-old woman was admitted to our hospital to receive a fourth course of modified rituximab-ESHAP chemotherapy for relapsed primary breast diffuse large B-cell lymphoma. She developed hemophagocytic lymphohistiocytosis (HLH) 20 days after admission. Polymerase chain reaction (PCR) detected cytomegalovirus (CMV) DNA in her peripheral blood; therefore, she was diagnosed with CMV-associated HLH and consequently treated with foscarnet (FCN). Her general condition and pancytopenia soon improved, and the antiviral drug was stopped for 1 week. However, she suddenly became disoriented 10 days later, and this condition rapidly worsened. Cerebrospinal fluid (CSF) examination revealed an elevated white blood cell count with lymphocytic predominance and a high CMV DNA load, prompting a final diagnosis of CMV meningoencephalitis. We began intravenous combination therapy with FCN and ganciclovir (GCV), and her conscious state gradually improved. CMV DNA sequencing did not reveal drug resistance associated with mutations, and intravenous GCV was stopped for 1 week. FCN treatment was then continued until CMV DNA was no longer detected in her CSF samples via PCR. CMV meningoencephalitis is a rare neurological infection complicated with hematological malignancy in non-transplant patients and can be serious and life-threatening with a high mortality rate. This infection requires a differential diagnosis of consciousness impairment that develops in a patient with lymphoid malignancy during chemotherapy.
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http://dx.doi.org/10.11406/rinketsu.60.124DOI Listing
August 2019

Identification of a novel CCDC22 mutation in a patient with severe Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis and aggressive natural killer cell leukemia.

Int J Hematol 2019 Jun 31;109(6):744-750. Epub 2019 Jan 31.

Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan.

Aggressive natural killer cell leukemia (ANKL) is a rare neoplasm characterized by the systemic infiltration of Epstein-Barr virus (EBV)-associated NK cells, and rapidly progressive clinical course. We report the case of a 45-year-old man with intellectual disability who developed ANKL, and describe the identification of a novel genetic mutation of coiled-coil domain-containing 22 (CCDC22). He presented with persistent fever, severe pancytopenia, and hepatosplenomegary. Following bone marrow aspiration, numerous hemophagocytes were identified. High EBV viral load was detected in NK cells fractionation by qPCR. The initial diagnosis was EBV-related hemophagocytic lymphohistiocytosis (EBV-HLH). A combination of immunosuppressive drugs and chemotherapy was administered, but was unsuccessful in controlling the disease. Therefore, he was treated with HLA-matched related allogeneic hematopoietic stem cell transplantation. However, his condition deteriorated within 30 days, resulting in fatal outcome. Autopsy revealed many EBV-infected NK cells infiltrating major organs, consistent with ANKL. Furthermore, whole-exome sequencing identified a novel missense mutation of the CCDC22 gene (c.112G>A, p.V38M), responsible for X-linked intellectual disability (XLID). CCDC22 has been shown to play a role in NF-κB activation. Our case suggests that CCDC22 mutation might be implicated in pathogenesis of EBV-HLH and NK-cell neoplasms as well as XLID via possibly affecting NF-κB signaling.
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http://dx.doi.org/10.1007/s12185-019-02595-0DOI Listing
June 2019

Effects of Neostigmine and Sugammadex for Reversal of Neuromuscular Blockade on QT Dispersion Under Propofol Anesthesia: A Randomized Controlled Trial.

Cardiol Ther 2018 Dec 14;7(2):163-172. Epub 2018 Sep 14.

Department of Anesthesiology, Dokkyo Medical University, School of Medicine, Mibu, Tochigi, Japan.

Introduction: Reversal of non-depolarizing neuromuscular blocking agent neostigmine is associated with QT prolongation under general anesthesia. To clarify the effects of neostigmine and sugammadex on hemodynamic status, the QT interval and QT dispersion after reversal of neuromuscular blockade were evaluated with a 12-lead electrocardiogram. To exclude QT prolongation due to sevoflurane, the present study was performed under propofol anesthesia.

Methods: After receiving approval from the ethics committee of Dokkyo Medical University Hospital, 40 patients with American Society of Anesthesiologists physical status I or II were randomly allocated to group N (n = 20) or group S (n = 20). Group N was administered neostigmine (40 μg/kg) and atropine (20 μg/kg), while Group S was administered sugammadex (4 mg/kg) for reversal of neuromuscular blockade after surgery. The changes in RR interval, QT interval (QT), corrected QT interval (QTc), QT dispersion (QTD), and corrected QT dispersion (QTcD) before and after administration of reversal agents were recorded using computerized measurements. Statistical analysis was performed using two-way analysis of variance.

Results: The RR interval significantly decreased after reversal of the neuromuscular blockade in group N, compared with group S (p < 0.05). Compared with group S, the QT decreased, whereas QTc and QTcD increased, in group N (p < 0.05). Sugammadex was not found to alter QT, QTc, QTD, or QTcD throughout the study.

Conclusion: In the present study, a mixture of neostigmine and atropine, but not sugammadex, increased QTc and QTcD under propofol anesthesia. Thus, neostigmine may cause electrocardiogram abnormalities that could precede the development of fatal arrhythmias.
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http://dx.doi.org/10.1007/s40119-018-0119-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251823PMC
December 2018

Visual Evoked Potential Recovery by Subretinal Implantation of Photoelectric Dye-Coupled Thin Film Retinal Prosthesis in Monkey Eyes With Macular Degeneration.

Artif Organs 2018 Aug 6;42(8):E186-E203. Epub 2018 Apr 6.

Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama City, Japan.

Retinal prosthesis or artificial retina is a promising modality of treatment for outer retinal degeneration, caused by primary and secondary loss of photoreceptor cells, in hereditary retinal dystrophy and age-related macular degeneration, respectively. Okayama University-type retinal prosthesis (OUReP) is a photoelectric dye-coupled polyethylene film which generates electric potential in response to light and stimulates nearby neurons. The dye-coupled films were implanted by vitreous surgery in the subretinal space of monkey eyes with macular degeneration which had been induced by cobalt chloride injection from the scleral side. A pilot 1-month observation study involved 6 monkeys and a pivotal 6-month observation study involved 8 monkeys. Of 8 monkeys in 6-month group, 3 monkeys underwent dye-coupled film removal at 5 months and were observed further for 1 month. The amplitude of visual evoked potential which had been reduced by macular degeneration did recover at 1 month after film implantation and maintained the level at 6 months. Optical coherence tomography showed no retinal detachment, and full-field electroretinograms maintained a-wave and b-wave amplitudes, indicative of no retinal toxicity. Pathological examinations after 6-month implantation showed structural integrity of the inner retinal layer in close apposition to dye-coupled films. The implanted films which were removed by vitrectomy 5 months later showed light-evoked surface electric potentials by scanning Kelvin probe measurement. The photoelectric dye-coupled film (OUReP), which serves as a light-receiver and a displacement current generator in the subretinal space of the eye, has a potential for recovering vision in diseases with photoreceptor cell loss, such as retinitis pigmentosa and age-related macular degeneration.
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http://dx.doi.org/10.1111/aor.13120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175213PMC
August 2018

[Successful cord blood transplantation in a patient with adult-onset common variable immunodeficiency].

Rinsho Ketsueki 2018;59(3):293-299

Department of Hematology/Oncology, Wakayama Medical University.

Common variable immunodeficiency (CVID) is the most frequently diagnosed congenital immunodeficiency and is characterized by dysfunctional antibody production. It often occurs at the age of ≥10 years. Here we reported a case of a 46-year-old man confirmed with adult-onset CVID. He was effectively treated with cord blood transplant (CBT). The patient was observed with repeated upper respiratory infection a few years back and was referred to our department owing to a marked decrease in neutrophil counts and progression of anemia. Laboratory tests confirmed hypogammaglobulinemia, but no autoantibodies were detected. Bone marrow aspiration showed a hypocellular marrow with predominantly mature lymphocytes. T-cell receptor excision circle assay revealed a reduction in T-cell neogenesis. Further, multicolor flow cytometry analysis revealed a low differentiation of B cells; subsequently, CVID was confirmed in the patient. The patient had a severe clinical course and therefore, received CBT for the treatment. After the transplantation, the hematopoiesis was restored and the serum immunoglobulin levels returned to normal. The patient exhibited a favorable clinical course. Nevertheless, there is no precise definition to establish the disease concept of CVID. Also, most of the potential cases are predominantly reported in adults. Therefore, further data on cases with CVID should be accumulated to establish the diagnostic criteria as well as treatment modalities.
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http://dx.doi.org/10.11406/rinketsu.59.293DOI Listing
July 2019

AUTOMATIC ACQUISITION OF CT RADIATION DOSE DATA: USING THE DIAGNOSTIC REFERENCE LEVEL FOR RADIATION DOSE OPTIMIZATION.

Radiat Prot Dosimetry 2018 Oct;181(2):156-167

National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inaga-ku, Chiba-shi, Chiba.

The present work describes that we try to construct a system that collects dose information that performed CT examination from multiple facilities and unified management. The results of analysis are compared with other National diagnostic reference level (DRL), and the results are fed back to each facility and the cause of the abnormal value is investigated for dose optimization. Medical information collected 139 144 tests from 33 CT devices in 13 facilities. Although the DRL of this study is lower than that of Japan DRL, it was higher than the DRL of each country. When collecting all the examination, it is thought that the variation of the dose due to the error other than the intended imaging site is large. In future, we should continue to collect information in order to DRL renewal and we also think that it is desirable to collect information on physique and detailed scan region as well.
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http://dx.doi.org/10.1093/rpd/ncy003DOI Listing
October 2018

Enforced expression of MIR142, a target of chromosome translocation in human B-cell tumors, results in B-cell depletion.

Int J Hematol 2018 Mar 25;107(3):345-354. Epub 2017 Oct 25.

Hematology/Oncology, Wakayama Medical University, 811-1 Kimi-idera, Wakayama, 641-8510, Japan.

MicroRNA142 (MIR142) is a target of chromosome translocations and mutations in human B-cell lymphomas. We analyzed an aggressive B-cell lymphoma carrying t(8;17)(q24;q22) and t(6;14)(p21;q32), and sought to explore the role(s) of MIR142 in lymphomagenesis. t(8;17)(q24;q22) involved MYC on 8q24 and pri-MIR142 on 17q22. MYC was activated by a promoter substitution by t(8;17)(q24;q22). t(8;17)(q24;q22) was an additional event after t(6;14) (p21;q32), which caused the over-expression of CCND3. Southern blot analyses revealed that the MIR142 locus was deleted from the affected allele, whereas Northern analyses showed over-expression of MIR142 in tumor cells. Although previous studies reported an over-expression of mutations in MIR142 in B-cell lymphomas, limited information is available on the functions of MIR142 in lymphomagenesis. Therefore, we generated bone marrow transplantation (BMT) and transgenic (Eμ/mir142) mice, which showed enforced expression in hematopoietic progenitor cells and B cells, respectively. BMT mice showed decreased numbers of all lineage-positive cells, particularly B cells, in peripheral blood. Eμ/mir142 mice showed decreased numbers of IgM-positive splenocytes, and exhibited altered B-cell phenotypic changes induced by lipopolysaccharide. Our results suggest that over-expression of MIR142 alters B-cell differentiation, implying multi-step lymphomagenesis together with MYC activation and CCND3 over-expression.
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http://dx.doi.org/10.1007/s12185-017-2360-8DOI Listing
March 2018

sepsis in a methotrexate-treated patient with rheumatoid arthritis.

IDCases 2017 5;10:18-21. Epub 2017 Aug 5.

Department of Internal Medicine, Kinan Hospital, Japan.

is a gram-negative rod that can be transmitted primarily by dog bites. This life-threatening organism commonly causes sepsis in patients with splenectomy or alcoholism. A 53-year-old rheumatoid arthritis male treated with methotrexate (MTX) for 5 years was admitted for a 4-day history of fever and dyspnea. He had been bitten on a finger by the family dog 4 days before onset. Laboratory tests revealed pancytopenia, acute renal failure, and evidence of disseminated intravascular coagulation, and he subsequently developed acute respiratory distress syndrome. Furthermore, blood cultures grew gram-negative bacilli and despite intensive treatment, he died 5 days after admission. Later, was identified from his culture samples using a species-specific polymerase chain reaction. infections should be considered in the differential diagnosis of sepsis for immunocompromised hosts following animal bites.
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http://dx.doi.org/10.1016/j.idcr.2017.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554928PMC
August 2017

Successful Intrathecal Chemotherapy Combined with Radiotherapy Followed by Pomalidomide and Low-Dose Dexamethasone Maintenance Therapy for a Primary Plasma Cell Leukemia Patient.

Hematol Rep 2017 Feb 23;9(1):6986. Epub 2017 Feb 23.

Department of Hematology/Oncology, Wakayama Medical University , Wakayama, Japan.

Primary plasma cell leukemia (PPCL) is a rare aggressive variant of plasma cell disorder and frequently presents with extramedullary disease. Central nervous system (CNS) involvement with PPCL has an extremely poor prognosis. We describe a 46-year-old man with PPCL treated with a combination of lenalidomide, bortezomib, and dexamethasone as induction therapy following upfront allogeneic stem cell transplantation (allo-SCT). Despite achieving a very good partial response, the patient suffered from an isolated CNS relapse 12 months after allo-SCT. He was immediately started on concurrent intrathecal chemotherapy (IT) and cranial irradiation (RT). Subsequently, pomalidomide and low-dose dexamethasone (Pd) were given as maintenance therapy. He has been without CNS recurrence for more than 18 months. Our case suggests that concurrent IT and RT followed by Pd maintenance therapy may be an effective option to control CNS relapse of PPCL after allo-SCT.
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http://dx.doi.org/10.4081/hr.2017.6986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337827PMC
February 2017

Double-Strand Breaks in Genome-Sized DNA Caused by Ultrasound.

Chemphyschem 2017 Apr 14;18(8):959-964. Epub 2017 Mar 14.

Faculty of Life and Medical Sciences, Doshisha University, Tatara-Miyakodani, Kyotanabe, Kyoto, 610-0321, Japan.

DNA double-strand breaks (DSBs) caused by ultrasound were evaluated in a quantitative manner by single-molecule fluorescence microscopy. We compared the effect of time-interval (or pulse) sonication to that of continuous wave (CW) sonication at a fixed frequency of 30 kHz. Pulses caused fewer DSBs than CW sonication under the same total input ultrasound energy when the pulse repetition period was above the order of a second. In contrast, pulses caused more DSBs than CW sonication for pulse widths shorter than a second. These effect of ultrasound on DNA were interpreted in terms of the time-dependent decay in the probability of breakage during the duration of a pulse. We propose a simple phenomenological model by considering a characteristic decay in the probability of DSBs during single-pulse sonication, which reproduces the essence of the experimental trend. In addition, a data analysis revealed a characteristic scaling behavior between the number of pulses and the number of DSBs.
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http://dx.doi.org/10.1002/cphc.201601325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413823PMC
April 2017

An Epstein-Barr virus susceptible immature T-cell line, WILL4, established from a patient with T-lymphoblastic lymphoma bearing CD21 and a clonal EBV genome.

Leuk Res 2017 04 15;55:1-5. Epub 2017 Jan 15.

Hematology/Oncology, Wakayama Medical University, Japan. Electronic address:

We managed a patient with an Epstein-Barr virus-associated T-cell lymphoblastic lymphoma. Mediastinal tumor cells at initial admission were positive for CD4, CD8, and TdT. Interestingly, a lymph node at necropsy was compatible for a CD4-positive peripheral T-cell lymphoma without CD8 and TdT expression, suggesting a different phenotype from the mediastinal tumor. Tumor cells in pleural effusion continued to proliferate in in vitro and were designated as WILL4. WILL4 cells were positive for CD3, CD4, CD8, CD21, T-cell receptor (TcR) αβ, and TdT, indicating a similar phenotype to thymocytes. Southern blot analyses showed that the pleural tumor and WILL4 cells shared a TcR gene rearrangement, and that both contained a clonal EBV genome in an episomal form. RT-PCR showed that EBNA1 and LMP1 were expressed in the fresh tumor and WILL4 cells. Southern blot analyses revealed that WILL4 cells were susceptible to EBV infection in vitro using B95-8 supernatant. Anti-CD21 antibody inhibited in vitro infection of EBV, suggesting that CD21 plays a role in EBV infection into WILL4 cells. In vitro infection of EBV did not affect latent gene expression in WILL4 cells. WILL4 is a useful tool for analyzing the roles of EBV in onocogenesis in immature T-lymphoid malignancies.
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http://dx.doi.org/10.1016/j.leukres.2017.01.022DOI Listing
April 2017

Effect of oral γ-aminobutyric acid (GABA) administration on sleep and its absorption in humans.

Food Sci Biotechnol 2016 30;25(2):547-551. Epub 2016 Apr 30.

Pharma Foods International Co., Ltd., Kyoto, 615-8245 Japan.

The effects of γ-aminobutyric acid (GABA) on sleep and its levels in blood after oral administration were investigated in humans. A randomized, single-blind, placebo-controlled crossover-designed study was conducted to evaluate the effect of GABA on sleep. Sleep was evaluated by electroencephalography (EEG) after oral GABA administration. GABA significantly shortened sleep latency and increased the total non-rapid eye movement (non-REM) sleep time. Questionnaires showed that subjects receiving GABA realized its effects on sleep. In addition, the blood level of GABA after administration was investigated, and the absorption and metabolism rates of GABA were determined. GABA was quickly absorbed, and the blood level of GABA was the highest 30 min after oral administration, with a subsequent decrease in concentration. As GABA strongly affected the early stage of sleep, the effect of GABA on sleep may be connected to its levels in blood.
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http://dx.doi.org/10.1007/s10068-016-0076-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049207PMC
April 2016

Anti-oxidative effect of AST-120 on kidney injury after myocardial infarction.

Br J Pharmacol 2016 Apr 5;173(8):1302-13. Epub 2016 Mar 5.

Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan.

Background And Purpose: Chronic kidney disease (CKD) is a crucial risk factor for cardiovascular disease (CVD), and combined CKD and CVD further increases morbidity and mortality. Here, we investigated effects of AST-120 on oxidative stress and kidney injury using a model of myocardial infarction (MI) in rats.

Experimental Approach: At 10 weeks, male spontaneously hypertensive rats (SHR) were divided into three groups: SHR (n = 6), MI (n = 8) and MI + AST-120 (n = 8). AST-120 administration was started at 11 weeks after MI. At 18 weeks, the rats were killed, and blood and urine, mRNA expression and renal histological analyses were performed. Echocardiography was performed before and after MI.

Key Results: At 18 weeks, the BP was significantly lower in the MI and MI+AST-120 groups than in the SHR group. Elevated levels of indoxyl sulfate (IS), one of the uremic toxins, in serum and urine were reduced by AST-120 treatment, compared with the MI group. Markers of oxidative stress in urine and serum biomarkers of kidney injury were decreased in the MI+AST-120 group compared with the other two groups. Renal expression of mRNAs for kidney injury related-markers were decreased in the MI+AST-120 group, compared with the MI group. In vitro data also supported the influence of IS on kidney injury. Immunohistological analysis showed that intrarenal oxidative stress was reduced by AST-120 administration.

Conclusions And Implications: Serum IS was increased after MI and treatment with AST-120 may have protective effects on kidney injury after MI by suppressing oxidative stress.
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http://dx.doi.org/10.1111/bph.13417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940817PMC
April 2016

Effects of N-Acetylcysteine on Cognitive Functions in Subjects With an At-Risk Mental State: A Case Series.

J Clin Psychopharmacol 2016 Feb;36(1):87-8

Department of Neuropsychiatry St. Marianna University School of Medicine Kawasaki, Japan Department of Neuropsychiatry St. Marianna University School of Medicine Kawasaki, Japan.

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http://dx.doi.org/10.1097/JCP.0000000000000445DOI Listing
February 2016

The Improvement of Sleep by Oral Intake of GABA and Apocynum venetum Leaf Extract.

J Nutr Sci Vitaminol (Tokyo) 2015 ;61(2):182-7

Pharma Foods International Co., Ltd.

The effects of two food materials, γ-aminobutyric acid (GABA) produced by natural fermentation and Apocynum venetum leaf extract (AVLE), on the improvement of sleep were investigated in humans. The electroencephalogram (EEG) test revealed that oral administration of GABA (100 mg) and AVLE (50 mg) had beneficial effects on sleep. GABA shortened sleep latency by 5.3 min and AVLE increased non-rapid eye movement (REM) sleep time by 7.6%. Simultaneous intake of GABA and AVLE shortened sleep latency by 4.3 min and increased non-REM sleep time by 5.1%. The result of questionnaires showed that GABA and AVLE enabled subjects to realize the effects on sleep. These results mean that GABA can help people to fall asleep quickly, AVLE induces deep sleep, and they function complementarily with simultaneous intake. Since both GABA and AVLE are materials of foods and have been ingested for a long time, they can be regarded as safe and appropriate for daily intake in order to improve the quality of sleep.
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http://dx.doi.org/10.3177/jnsv.61.182DOI Listing
February 2016

New absorbed dose measurement with cylindrical water phantoms for multidetector CT.

Phys Med Biol 2015 Jun 20;60(11):4517-31. Epub 2015 May 20.

Department of Health Sciences, Faculty of Life Sciences, Kumamoto University, 4-24-1 Kuhonji, Kumamoto, Japan.

The aim of this study was to develop new dosimetry with cylindrical water phantoms for multidetector computed tomography (MDCT). The ionization measurement was performed with a Farmer ionization chamber at the center and four peripheral points in the body-type and head-type cylindrical water phantoms. The ionization was converted to the absorbed dose using a (60)Co absorbed-dose-to-water calibration factor and Monte Carlo (MC) -calculated correction factors. The correction factors were calculated from MDCT (Brilliance iCT, 64-slice, Philips Electronics) modeled with GMctdospp (IMPS, Germany) software based on the EGSnrc MC code. The spectrum of incident x-ray beams and the configuration of a bowtie filter for MDCT were determined so that calculated photon intensity attenuation curves for aluminum (Al) and calculated off-center ratio (OCR) profiles in air coincided with those measured. The MC-calculated doses were calibrated by the absorbed dose measured at the center in both cylindrical water phantoms. Calculated doses were compared with measured doses at four peripheral points and the center in the phantom for various beam pitches and beam collimations. The calibration factors and the uncertainty of the absorbed dose determined using this method were also compared with those obtained by CTDIair (CT dose index in air). Calculated Al half-value layers and OCRs in air were within 0.3% and 3% agreement with the measured values, respectively. Calculated doses at four peripheral points and the centers for various beam pitches and beam collimations were within 5% and 2% agreement with measured values, respectively. The MC-calibration factors by our method were 44-50% lower than values by CTDIair due to the overbeaming effect. However, the calibration factors for CTDIair agreed within 5% with those of our method after correction for the overbeaming effect. Our method makes it possible to directly measure the absorbed dose for MDCT and is more robust and accurate than the CTDIair measurement.
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http://dx.doi.org/10.1088/0031-9155/60/11/4517DOI Listing
June 2015