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Biomedical subjects

Makoto Hirokawa

Publications and source records attributed to Makoto Hirokawa.

At least 19 recordsLinked to original sources
PubMed2006

Adrenal insufficiency complicated with antiphospholipid syndrome (APS).

We describe a 69-year-old woman with bilateral adrenal hemorrhage complicated with antiphospholipid syndrome (APS). She was hospitalized with nausea and vomiting in September 2003. Laboratory data demonstrated hyponatremia, hypoglycemia and prolongation of activated partial thromboplastin time (aPTT). Abdominal computed tomography showed bilateral adrenal enlargement. In October 2003, she demonstrated altered mental status with progressive hyponatremia, a high level of ACTH, and a low level of serum cortisol. She also showed thrombocytopenia, anti-cardiolipin IgG antibody, anti-beta2GPI antibody, and lupus anticoagulants. After four months, anti-cardiolipin IgG antibody was still positive. Based on these findings, she was diagnosed as having APS complicated with adrenal insufficiency due to hemorrhagic infarction. After treatment with corticosteroid, a low dose of aspirin and normal saline infusion, her condition quickly improved. Platelet counts and aPTT were also normalized. To our knowledge, this is the second Japanese case of APS complicated with bilateral adrenal hemorrhage. APS should be considered an important underlying cause of adrenal insufficiency.

Adrenal Gland Diseases↗
PubMed2006

Tumor-derived TGFbeta-1 induces dendritic cell apoptosis in the sentinel lymph node.

Lymphatic flux from a primary tumor initially flows into a tumor-draining lymph node (LN), the so-called sentinel LN (SLN). Carried by the lymph fluid are a variety of mediators produced by the tumor that can influence immune responses within the SLN, making it a good model with which to investigate tumor-related immunology. For instance, dendritic cell (DC) numbers are reduced in SLNs from melanoma and breast cancer patients. In the present study, we investigated the mechanism by which DC numbers were reduced within SLNs from patients with non-small cell lung cancer. We found that the incidence of apoptosis among DCs was higher in SLNs than in non-SLNs, as were levels of TGFbeta-1. In contrast, levels of TGFbeta-1 mRNA did not differ between SLNs and non-SLNs, but were 30 times higher in tumors than in either LN type. In vitro, incubation for 2 days with TGFbeta-1 induced apoptosis among both cultured DCs and DCs acutely isolated from normal thoracic LNs, effects that were blocked by the TGFbeta-1 inhibitor DAN/Fc chimera. Taken together, these results suggest that tumor-derived TGFbeta-1 induces immunosuppression within SLNs before the movement of tumor cells into the SLNs, thereby facilitating metastasis within those nodes.

Apoptosis↗
PubMed2006

Successful reduced-intensity hematopoietic stem cell transplantation in myelodysplastic syndrome with severe coronary artery disease.

A 60-year-old Japanese man with myelodysplastic syndrome (MDS) and effort angina was referred to our clinic for treatment of MDS. The patient was transfusion-dependent and displayed coronary artery disease (CAD) with 99% obstruction of the left anterior descending coronary artery. Treatment comprised reduced-intensity hematopoietic stem cell transplantation with administration of fludarabine phosphate (180 mg/m(2)) and busulfan (8 mg/kg), followed by allogeneic peripheral blood stem cell transplantation from an HLA-matched sister. The regimen was well tolerated, and engraftment occurred rapidly without any therapy-related complications, including cardiovascular attack. Sex chromosome analysis by fluorescence in situ hybridization revealed complete donor chimerism on day 29 for bone marrow cells and on day 59 for peripheral blood leukocytes. The patient became transfusion-independent on posttransplantation day 8. As of 22 months postoperatively, he remains well, with 100% Karnofsky performance status, a limited type of chronic graft-versus-host disease, and no recurrence of disease. The clinical course of the patient suggests that this preparative regimen allows safe allogeneic stem cell transplantation for MDS patients with severe CAD.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Late-onset fatal Epstein-Barr virus-associated hemophagocytic syndrome following cord blood cell transplantation for adult acute lymphoblastic leukemia.

A 43-year-old Japanese woman underwent unrelated cord blood transplantation (CBT) during remission for acute lymphoblastic leukemia with t(4; 11)(q21;q23). Tacrolimus was given for prophylaxis of graft-versus-host disease. The posttransplantation clinical course was mostly uneventful, and the leukemia remained in remission. Fourteen months after CBT, the patient developed pancytopenia and hepatic dysfunction with persistent high-grade fever. The bone marrow was hypocellular with increased numbers of macrophages and hemophagocytes. The numbers of Epstein-Barr virus (EBV) copies in peripheral blood samples were remarkably high. Although the patient showed complete donor-type hematopoiesis, the titer of viral capsid antigen immunoglobulin G was low, and the results of a test for EBV nuclear antigen were negative. There was no clinical response to the reduction of immunosuppressive therapy or to the administration of high-dose methylprednisolone, human immunoglobulin, or acyclovir. The patient died 466 days after CBT of massive gastrointestinal hemorrhage due to bone marrow and hepatic failures. This case demonstrates that fatal EBV-associated hemophagocytic syndrome (HPS) can occur more than 1 year after CBT. This report is the first of a case of late-onset EBV-associated HPS following CBT.

Acyclovir↗
PubMed2006

Successful autologous peripheral blood stem cell transplantation using thiotepa in a patient with systemic sclerosis and cardiac involvement.

A 19-year-old man with systemic sclerosis (SSc) was hospitalized for autologous peripheral blood stem cell transplantation (auto-PBSCT) due to progressive scleroderma and cardiac involvement despite conventional treatment. During the administration of cyclophosphamide (60 mg/kg/day for 2 days) for mobilization and collection of CD34+ selected peripheral blood stem cells, he developed congestive heart failure. Echocardiogram showed hypokinetic asynergy from the septum to posterior wall, which might indicate underlying cardiac damage. We were also concerned about the risk of high-dose cyclophosphamide-induced cardiotoxicity. Since the dose-limiting toxicity of thiotepa, an alkylating agent, is myelosuppression, and cardiac toxicity due to thiotepa is less common, we used a conditioning regimen consisting of thiotepa (10 mg/kg/day, day -5) and low-dose cyclophosphamide (50 mg/kg/day, days -3 and -2), instead of the conventional high-dose cyclophosphamide (50 mg/kg/day x 4 days/course). The post-transplant course was uneventful, and the modified Rodnan skin thickness score improved from 32 to 15. The present case report demonstrates that thiotepa can be employed as a conditioning regimen for auto-PBSCT in SSc patients with cardiac involvement in order to reduce cyclophosphamide-induced cardiotoxicity.

Adult↗
PubMed2006

[Acute monoblastic leukemia with tetrasomy 8].

Tetrasomy 8 is a rare chromosomal abnormality in acute leukemia, and it has recently been considered as a poor prognostic factor. A 20-year-old woman was admitted because of purpura on the upper and lower limbs in February 2002. On admission, her leukocyte count was 6.5 x 10(9)/l with 66% of blasts, the hemoglobin level was 11.2 g/dl, and the platelet count was 101 x 10(9)/l. The bone marrow aspirate contained 85.6% of peroxidase-negative, alpha-naphthyl-butyrate esterase-positive, and CD4+ CD56+ blast cells. Karyotypic analysis of the bone marrow cells showed 48, XY, + 8, + 8[17]/47, XY, +8[3]. The patient was diagnosed as having AML (M5a), and treatment with daunorubicin (70 mg x 5 days) and cytosine arabinoside (150 mg x 7 days) resulted in a complete remission. She relapsed four months later, however, with an extramedullary tumor in T12. Remission could not be achieved, and the patient underwent allogeneic peripheral blood stem cell transplantation from her HLA-identical mother. Her clinical course was almost uneventful except for a phlegmon in the right leg, but on day 49 a relapse occurred, and she died of acute renal failure on day 73. This case strongly illustrates the characteristic of tetrasomy 8 as a poor prognostic factor in acute leukemia.

Adult↗
PubMed2006

Oligoclonal T cell expansion in blood but not in the thymus from a patient with thymoma-associated pure red cell aplasia.

Despite the well-known association between thymoma and PRCA, the role of thymoma remains uncertain. There is accumulating evidence that clonal T cells are involved in acquired PRCA. We examined T cell receptor repertoires in blood and thymus from a patient with PRCA associated with thymoma and myasthenia gravis. Oligoclonal expansions of Vdelta1- and Vbeta1-expressing T cells were found in peripheral blood, whereas the repertoires of Vdelta1+ and Vbeta1+ T cells in thymoma were not skewed. Oligoclonal expansion of Vdelta1-expressing T cells remained unchanged after thymectomy. Thymus may not be the site of clonal T cell expansion in thymoma-associated PRCA.

Clone Cells↗
PubMed2005

Phagocytosis of codeveloping megakaryocytic progenitors by dendritic cells in culture with thrombopoietin and tumor necrosis factor-alpha and its possible role in hemophagocytic syndrome.

Tumor necrosis factor-alpha (TNF-alpha) and thrombopoietin (TPO) have been shown to induce the differentiation and proliferation of CD34+ cells toward dendritic cells (DCs) in the presence of multiacting cytokines. We hypothesized that the costimulation of TPO and TNF-alpha generates megakaryocytic progenitors and DCs together from human CD34+ cells and that the interaction of these cells may indicate a physiologic and/or a pathologic role of DCs in megakaryopoiesis. When highly purified human CD34+ cells were cultured for 7 days with TPO alone, the generated cells expressed megakaryocytic markers, such as CD41, CD42b, and CD61. The addition of TNF-alpha with TPO remarkably decreased the number of megakaryocytic progenitor cells without affecting the cell yield. Almost half of the cells thus generated expressed CD11c, and most of them were positive for CD4 and CD123. Furthermore, CD11c+ cells were found to capture damaged CD61+ cells and to induce autologous T-cell proliferation, although the cytokine productions were low. We also confirmed an engulfment of CD61+ cells and their fragment by CD11c+ cells in bone marrow cells from patients with hemophagocytic syndrome. These findings suggest that DCs generated under megakaryocytic and inflammatory stimuli are involved in megakaryopoiesis and the subsequent immune responses to self-antigens.

Aged↗
PubMed2005

TCRalphabeta repertoire diversity of human naturally occurring CD4+CD25+ regulatory T cells.

We examined the alphabeta T cell receptor (TCR) repertoire of naturally occurring CD4+CD25+ regulatory T (Treg) cells isolated from healthy human blood. Three-color FACS analysis demonstrated that the usage of variable region segments of TCRbeta chains by CD4+CD25+ cells did not differ from those of CD4+CD25- cells. Complementarity-determining region 3 (CDR3) size distribution analyses demonstrated that the repertoire diversity of CDR3beta was almost identical between CD4+CD25+ and CD4+CD25- T cell subsets, and that there was no skewing of the CDR3beta repertoire of CD4+CD25+ T cells. In contrast, in vitro activated CD4+CD25+ T cells by cytomegalovirus-derived antigens showed a skewed CDR3 size distribution pattern. These findings support the hypothesis that naturally occurring CD4+CD25+ T cell subset in humans is 1argely composed of a T cell lineage positively selected in the thymus as a consequence of the interaction between self-peptides and TCRs and not derived from recent activation by a limited array of antigens.

CD4 Antigens↗
PubMed2005

Cytogenetic features of de novo CD5-positive diffuse large B-cell lymphoma: chromosome aberrations affecting 8p21 and 11q13 constitute major subgroups with different overall survival.

De novo CD5-positive diffuse large B-cell lymphoma (CD5(+)DLBCL) is regarded as a different clinicopathological entity from CD5-negative DLBCL (CD5(-)DLBCL) and mantle cell lymphoma (MCL). Because only a few published cytogenetic studies of de novo CD5(+)DLBCL are available, we investigated chromosomal changes in 23 Japanese patients who had de novo CD5(+)DLBCL. A characteristic of cytogenetic abnormalities in de novo CD5(+)DLBCL was a high incidence of chromosomal aberrations affecting 8p21 and 11q13. Major chromosomal breakpoints were concentrated at 8p21, 11q13, and 3q27. Patients with 8p21 aberrations showed aggressive clinical features, including advanced stage of disease, elevated serum LDH level, poor performance status, and an inferior survival curve compared with patients who had 11q13 changes (P = .043). Chromosomal abnormalities of both 8p21 and 11q13 were not observed in the same patient, and each abnormality showed different chromosomal gains and losses. These results indicate that de novo CD5(+)DLBCL may occur in previously unidentified subgroups that differ in their chromosomal abnormalities. The conflicting results of previous studies on prognosis may thus be explained in part by the differences in chromosomal changes.

Adult↗
PubMed2005

Allogeneic haematopoietic stem cell transplantation as a promising treatment for natural killer-cell neoplasms.

The efficacy of allogeneic haematopoietic stem-cell transplantation (allo-HSCT) for natural killer (NK)-cell neoplasms is unknown. We investigated the results of allo-HSCT for NK-cell neoplasms between 1990 and 2003 through questionnaires. After reclassification by a haematopathologist, of 345 patients who underwent allo-HSCT for malignant lymphoma, 28 had NK-cell neoplasms (World Health Organization classification): extranodal NK/T-cell lymphoma (n=22), blastic NK-cell lymphoma (n=3), and aggressive NK-cell leukaemia (n=3). Twelve were chemosensitive and 16 chemorefractory. Twenty-two had matched-related donors. Stem-cell source was bone marrow in eight and mobilised peripheral blood in 20. Conditioning regimens were myeloablative (n=23) and non-myeloablative (n=5). Grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD developed in 12 and 8 respectively. Eight died of disease progression, three of infection, two of acute GVHD, one of veno-occlusive disease, one of interstitial pneumonitis, and one of thrombotic microangiopathy. Two-year progression-free and overall survivals were 34% and 40% respectively (median follow-up, 34 months). All patients who did not relapse/progress within 10 months achieved progression-free survival (PFS) during the follow-up. In multivariate analysis, stem cell source (BM versus peripheral blood; relative risk 3.03), age (>or=40 years vs. <40 years; relative risk 2.85), and diagnoses (extranodal NK/T-cell lymphoma versus others; relative risk 3.94) significantly affected PFS. Allo-HSCT is a promising treatment for NK-cell neoplasms.

Adult↗
PubMed2005

Fluorescence in situ hybridization monitoring of BCR-ABL-positive neutrophils in chronic-phase chronic myeloid leukemia patients during the primary stage of imatinib mesylate therapy.

We describe a method for monitoring chronic myeloid leukemia (CML) patients treated with imatinib that uses fluorescence in situ hybridization (FISH) to detect BCR-ABL in peripheral blood (PB) granulocytes. First, we compared this method, termed Neutrophil-FISH, with interphase FISH (i-FISH) analysis of bone marrow (BM), i-FISH analysis of PB mononuclear cells, and conventional cytogenetic analysis (CCA) of BM in 30 consecutive CML patients. We found the percentage of BCR-ABL-positive neutrophils as determined by Neutrophil-FISH to correlate best with the percentage of Philadelphia chromosome-positive metaphases in the BM determined by CCA (y = 0.8818x + 5.7249; r(2) = 0.968). We then performed a serial Neutrophil-FISH study of 10 chronic-phase CML patients treated with imatinib and found that the technique could clearly separate imatinib responders from nonresponders within 12 weeks of drug administration. There was a significant difference in the percentages of BCR-ABL-positive neutrophils between responder (mean 3 SD, 18.2% 3 11.8%) and nonresponder (82.4% 3 5.1%) groups at 12 weeks (P < .0001, Student t test).Together with real-time quantitative polymerase chain reaction analysis, Neutrophil-FISH represents another useful method for monitoring CML patients during the primary myelosuppressive stage of imatinib therapy because it is a quick, simple, and reliable method for assessing cytogenetic response.

Antineoplastic Agents↗
PubMed2004

Codevelopment of dendritic cells along with erythroid differentiation from human CD34(+) cells by tumor necrosis factor-alpha.

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) inhibits erythropoiesis and enhances nonerythroid colony formation. The present study examines the nature of these nonerythroid cells and investigates their physiologic role in relation to erythroid progenitor cells. MATERIALS AND METHODS: Highly purified human CD34(+) cells underwent erythroid differentiation in the presence of multiple cytokines, including stem cell factor (SCF), interleukin-3 (IL-3), and erythropoietin (EPO), with and without TNF-alpha. We enumerate colony-forming unit-erythroid (CFU-E) and glycophorin A (GPA; a specific marker for erythroid lineage) positive cells in semisolid phase as well as in liquid suspension culture. The character and roles of codeveloping nonerythroid cells in the presence of TNF-alpha were analyzed using fluorescent activating cell sorter, enzyme immunohistochemistry, and confocal microscopy. RESULTS: TNF-alpha inhibited the generation of GPA(+) cells and conversely enhanced the generation of GPA(-) cells. The GPA(-) cells were comprised of cells with excentric cell shape and were positive for HLA class I, HLA class II, CD1a, CD4, CD11c, CD14, CD40, CD80, CD83, and CD86, but not for CD3, CD8, CD19, CD20, and CD56, indicating the codevelopment of dendritic cells (DC) along with erythroid differentiation. Developing DC/DC precursors were detected within 3 days of culture. Only in the presence of TNF-alpha did CD34(+) cells proliferate by forming aggregates where both GPA(+) and CD11c(+) DC/DC precursors were present. During culture period, immature CD11c(+) DC were capable of endocytosing damaged GPA(+) cells. CONCLUSIONS: GPA(-) cells cogenerated from human CD34(+) cells during erythroid differentiation in the presence of IL-3/SCF/EPO and TNF-alpha express DC phenotypes. The CD11c(+) DC subset physically and selectively associates with developing immature erythroid cells and damaged self-GPA(+) cells and then obtains and captures self-substances.

Antigens, CD34↗
PubMed2004

Monitoring the expression profiles of doxorubicin-resistant K562 human leukemia cells by serial analysis of gene expression.

We examined the expression profiles of doxorubicin-resistant K562 cells by serial analysis of gene expression (SAGE) to identify novel and/or partially characterized genes that might be related to drug resistance in human leukemia. SAGE complementary DNA (cDNA) libraries were constructed from K562 and doxorubicin-resistant K562 (K562/ADM) cells, and concatamer sequences were analyzed with SAGE 2000 software. We used 9792 tags in the identification of 1076 different transcripts, 296 of which were similarly expressed in K562 and K562/ADM cells. There were 343 genes more actively expressed in K562/ADM than in parental K562 cells and 437 genes expressed less often in K562/ADM cells. K562/ADM cells showed increased expression of well-known genes, including the genes for spectrin beta, eukaryotic translation initiation factor 1A (EIF1A), RAD23 homolog B, laminin receptor 1, and polyA-, RAN-, and PAI-1 messenger RNA-binding proteins. K562/ADM cells showed decreased expression of the genes for fatty acid desaturase 1 (FADS1), hemoglobin epsilon 1, N-myristoyltransferase 1, hemoglobin alpha 2, NADH dehydrogenase Fe-S protein 6, heat shock 90-kDa protein, and karyopherin beta 1. Quantitative reverse transcription-polymerase chain reaction analysis confirmed the increased expression of EIF1A and the decreased expression of FADS1 in K562/ADM cells. Prior to this investigation, such differences in the expression of these genes in doxorubicin-resistant leukemia cells were unknown. Although we do not provide any evidence in the present report for the potential roles of these genes in drug resistance, SAGE may provide a perspective into our understanding of drug resistance in human leukemia that is different from that provided by cDNA microarray analysis.

Delta-5 Fatty Acid Desaturase↗
PubMed2004

Contribution of Complementarity-Determining Region 3 of the T-Cell Receptor Vδ2 Chain to the Recognition of Aminobisphosphonates by Human γδ T-Cells.

Human gammadelta T-lymphocytes expressing Vgamma2Vdelta2 T-cell receptors (TCRs) can be stimulated by aminobisphosphonates and can kill certain tumor cells. Although germline-encoded lysine residues on the Jgamma1.2 segment have been demonstrated to be essential for the recognition of nonpeptide antigens by human gammadelta T-cells, the role of the junctional sequences of the TCR delta chain in the recognition of aminobisphosphonates by Vgamma2Vdelta2+ T-cells remains unknown. We examined the structure of complementarity-determining region 3 (CDR3) of Vdelta2 chains expressed by aminobisphosphonate-stimulated human gammadelta T-cells. CDR3 size-spectratyping analysis of Vdelta2 chains revealed that risedronate did not induce a CDR3 size distribution pattern of Vdelta2 cells that was distinct from that of Vdelta2 cells cultured without risedronate. The clonality of risedronate-expanded Vdelta2 T-cells was also determined by sequencing analysis, with the result that no particular consensus sequences were observed. However, most Vdelta2 T-cells freshly isolated from peripheral blood carried a distinctive junctional motif consisting of a hydrophobic amino acid residue (valine, leucine, or isoleucine [Val/Leu/Ile]) at conserved position 97, and this feature was not altered by risedronate stimulation. A significant proportion of Vdelta1 T-cells from the same individual had Leu at position 97, but Vdelta1 T-cells did not expand in response to risedronate. Moreover, Vdelta2 T-cells from the nonresponder against risedronate also carried a Val/Leu/Ile amino acid residue at position 97. These results suggest that the presence of a hydrophobic amino acid residue at position 97 in CDR3 of the TCR delta chain is not sufficient to account for the recognition of aminobisphosphonate by human gammadelta T-cells.

Amino Acid Sequence↗
PubMed2004

Gene expression profiling of human erythroid progenitors by micro-serial analysis of gene expression.

We compared the expression profiles of highly purified human CD34+ cells and erythroid progenitor cells by micro-serial analysis of gene expression (microSAGE). Human CD34+ cells were purified from granulocyte colony-stimulating factor-mobilized blood stem cells, and erythroid progenitors were obtained by cultivating these cells in the presence of stem cell factor, interleukin 3, and erythropoietin. Our 10,202 SAGE tags allowed us to identify 1354 different transcripts appearing more than once. Erythroid progenitor cells showed increased expression of LRBA, EEF1A1, HSPCA, PILRB, RANBP1, NACA, and SMURF. Overexpression of HSPCA was confirmed by real-time polymerase chain reaction analysis. MicroSAGE revealed an unexpected preferential expression of several genes in erythroid progenitor cells in addition to the known functional genes, including hemoglobins. Our results provide reference data for future studies of gene expression in various hematopoietic disorders, including myelodysplastic syndrome and leukemia.

Antigens, CD34↗