[Anti-platelet therapy].
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Angina, Unstable↗
Biomedical subjects
M Okuma
Publications and source records attributed to M Okuma.
Malignant histiocytosis associated with autoimmune thrombocytopenia.
We describe a patient with malignant histiocytosis whose serum contained an autoantibody against platelet protein. The patient was admitted because of nasal bleeding and high-grade fever. The clinical course was fulminantly progressive and terminated with cerebral hemorrhage. Bone marrow aspirate showed the proliferation of large atypical cells, some of which exhibited phagocytic activity. At postmortem examination, there was diffuse infiltration of these atypical cells in the liver, spleen, kidney, and bone marrow. Morphological, cytochemical, immunohistochemical, and genotypic characteristics suggested that the proliferating cells were derived from the monocyte-macrophage system. Western blot analysis revealed the presence of autoantibody against an approximately 88 kd molecule of platelet proteins. Although the relationship of cause and effect remains to be clarified, this autoantibody appeared to have stimulated thrombophagocytosis of the neoplastic cells.
Autoimmune Diseases↗
Enhancement of differentiation induction of mouse myelomonocytic leukemic cells by extracellular ATP.
We examined the effect of ATP on the terminal differentiation of mouse myelomonocytic leukemic M1 cells to macrophages. Although ATP alone did not induce M1 cell differentiation, addition of ATP with the differentiation inducer, interleukin 6 (IL-6), enhanced the induction of differentiation by IL-6 about two-fold. Comparison among several adenine nucleotides revealed that the order of effectiveness on differentiation enhancement was ATP > ADP > AMP > or = adenosine. Using reactive blue 2, a P2 receptor antagonist, we confirmed that the effect of ATP on the stimulation of differentiation was mediated through the P2 purinergic receptor. Examination of cytosolic [Ca2+] elevation by ATP and comparison of potency of differentiation enhancement among several ATP analogs demonstrated that the effect of differentiation enhancement was mediated through P2y purinergic receptors expressed on M1 cell surface. Within 3 h of exposure, ATP alone slightly increased the expression of differentiation-related immediate early response genes, c-myc and JunB, and ATP also enhanced the IL-6-induced expression of these genes. Induction of JunB expression by ATP analogs correlated with their potency of differentiation enhancement, which suggested that induction of JunB by ATP is one of signaling pathways involved in the exertion of its differentiation-enhancing effect.
1-Methyl-3-isobutylxanthine↗
Simultaneous measurement of colonic ion transport and muscle contraction.
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Animals↗
A conserved epitope on H+,K(+)-adenosine triphosphatase of parietal cells discerned by a murine gastritogenic T-cell clone.
BACKGROUND/AIMS: H+,K(+)-adenosine triphosphatase (H+,K(+)-ATPase) of parietal cells is an organ-specific enzyme recognized by autoantibodies found in human and murine autoimmune gastritis (AIG). Murine AIG can be induced in BALB/c mice by thymectomy 3 days after birth and is a T cell-mediated disease. This study examined the specificity of T cells that cause AIG and the role of H+,K(+)-ATPase in this disease. METHODS: From an AIG mouse, a gastritogenic T-cell clone (II-6) was established, and its reactivity to synthetic peptides of H+,K(+)-ATPase was tested. RESULTS: II-6 cells are CD4+, V beta 14+, and interferon gamma producers. Adoptive transfer of II-6 cells to syngeneic nude mice resulted in AIG without the production of autoantibodies to parietal cells. The II-6 cells were responsive not only to murine but also to human and porcine parietal cells. Their proliferation was also induced by amino acids 891-905 (alpha 891) and 892-906 (alpha 892) of the alpha subunit of porcine and human H+,K(+)-ATPase, respectively. CONCLUSIONS: The T-cell response to a single epitope of H+,K(+)-ATPase, the amino acid sequence of which is conserved among at least three mammals tested, is sufficient to cause AIG. Autoantibodies to parietal cells are not detected in these AIG mice.
Amino Acid Sequence↗
Arg60 to Leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder.
Recent advances in molecular genetics have revealed the mechanisms underlying a variety of inherited human disorders. Among them, mutations in G protein-coupled receptors have clearly demonstrated two types of abnormalities, namely loss of function and constitutive activation of the receptors. Thromboxane A2 (TXA2) receptor is a member of the family of G protein-coupled receptors and performs an essential role in hemostasis by interacting with TXA2 to induce platelet aggregation. Here we identify a single amino acid substitution (Arg60-->Leu) in the first cytoplasmic loop of the TXA2 receptor in a dominantly inherited bleeding disorder characterized by defective platelet response to TXA2. This mutation was found exclusively in affected members of two unrelated families with the disorder. The mutant receptor expressed in Chinese hamster ovary cells showed decreased agonist-induced second messenger formation despite its normal ligand binding affinities. These results suggest that the Arg60 to Leu mutation is responsible for the disorder. Moreover, dominant inheritance of the disorder suggests the possibility that the mutation produces a dominant negative TXA2 receptor.
Amino Acid Sequence↗
Color Doppler sonography of hepatic tumors with a galactose-based contrast agent: correlation with angiographic findings.
OBJECTIVE: The purpose of this study was to evaluate the clinical usefulness of a galactose-based, IV sonographic contrast agent for assessing tumor vascularity and diagnosing hepatocellular carcinoma. SUBJECTS AND METHODS: We used color Doppler sonography with the sonographic contrast agent to examine 22 patients with 26 hepatic nodules (18 hepatocellular carcinomas, four hemangiomas, two adenomatous hyperplasias, and two metastatic tumors). In all 26 lesions, intratumoral arterial flow signals were examined before and after IV injection of the sonographic contrast agent at three concentrations (200, 300, and 400 mg/ml), and the findings on color Doppler sonograms of each lesion were correlated with angiographic findings. RESULTS: Conventional color Doppler sonograms showed flow in nine hepatocellular carcinomas (50%) and one hemangioma (25%). When the contrast agent was used, color Doppler sonograms showed intratumoral arterial flow in 11 hepatocellular carcinomas (61%) and one hemangioma (25%) at a concentration of 200 mg/ml, in 14 hepatocellular carcinomas (78%) and 1 hemangioma (25%) at 300 mg/ml, and in 15 hepatocellular carcinomas (83%) and two hemangiomas (50%) at 400 mg/ml. The detectability of intratumoral arterial flow was improved by the contrast agent, especially in hepatocellular carcinomas smaller than 30 mm in diameter. Angiography revealed neovascularization or staining in 15 hepatocellular carcinomas, four hemangiomas, and none of the adenomatous hyperplasias or metastatic tumors. Among 15 angiographically hypervascular hepatocellular carcinomas, the detection rate of intratumoral arterial flow with contrast-enhanced color Doppler sonography was 73% at 200 mg/ml, 93% at 300 mg/ml, and 100% at 400 mg/ml. No intratumoral Doppler signals were depicted with the use of contrast agent in any angiographically undetected tumors. CONCLUSION: Preliminary findings on contrast-enhanced color Doppler sonograms correlate well with angiographic findings for evaluating tumor vascularity. This noninvasive technique may be useful in diagnosing hypervascular hepatocellular carcinomas.
Adenoma↗
Effects of dobutamine on hepatosplanchnic hemodynamics in patients with chronic liver disease.
BACKGROUND: It is said that catecholamines increase hepatic blood flow in patients without liver diseases, although several reports have suggested a blunted response to catecholamines in patients with liver cirrhosis. METHODS: We investigated changes in splanchnic blood flow distribution induced by the infusion of dobutamine into peripheral veins of healthy adults (NC group), patients with chronic hepatitis (CH group), and patients with liver cirrhosis (LC group), using a Doppler duplex system (protocol 1). We also investigated changes in hepatic hemodynamics induced by dobutamine infusion in patients with liver cirrhosis (cirrhosis group) and patients without liver diseases (control group), using hepatic catheterization (protocol 2). RESULTS: In protocol 1 the average increase in portal venous blood flow during dobutamine infusion was significant in the NC and CH groups but was not significant in the LC group. Changes in the blood flow in the splenic artery and vein, superior mesenteric artery and vein, and femoral artery were similar to those in the portal vein in each of the three groups. Infusion did not cause a change in the common hepatic arterial flow in any of the three groups. In protocol 2 the portal venous flow, cardiac index, and hepatic venous pressure gradient increased significantly during dobutamine infusion in both the cirrhosis and the control groups. Hepatic vascular resistance in the cirrhosis group increased slightly, whereas, in contrast, that in the control group increased significantly. The rate of change in almost all variables was lower in the cirrhosis group than in the control group. CONCLUSION: These results indicate that dobutamine has less effect on hepatic circulation in patients with liver cirrhosis than in those without liver diseases, indicating that the value of dobutamine in increasing hepatic blood flow in cirrhotic patients is very limited.
Aged↗
Inhibition of erythroid differentiation by stem cell factor in K562 cells expressing the c-kit gene.
We found a K562 subclone (K562YO) that highly expressed the c-kit gene. K562YO had a higher capability of erythroid differentiation by hemin and cytosine arabinoside (Ara-C) than its parent K562 (KIT-). We obtained the transfectant expressing c-kit by introducing c-kit cDNA into K562 (KIT-). The differentiation of the transfectant was similar to that of the parent cell. Thus the difference described above was not due to the expression of c-kit. Next, we investigated the effects of stem cell factor (SCF) on the differentiation of the K562 cell expressing c-kit. SCF did not enhance the cell growth of K562YO. On the other hand, SCF suppressed induction of benzidine-positive cells when c-kit-positive cells were treated with hemin and Ara-C, especially at a low concentration. Furthermore, c-kit mRNA and protein were down-regulated during erythroid differentiation. SCF also downregulated the c-kit proteins. Our results suggest that the SCF/c-kit signals could act negatively for erythroid differentiation of the K562 cells expressing c-kit. K562YO is also useful for studying the mechanism that controls the expression of the c-kit gene because there is a K562 counterpart cell line that does not express this gene.
Blotting, Northern↗
[A phase III trial of subcutaneous administration of rhG-CSF in aplastic anemia].
To evaluate the efficacy and safety of subcutaneous administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in aplastic anemia (AA), 21 patients were given a daily subcutaneous dose of 200 micrograms/m2 of KRN8601 for 4 weeks. When the blood neutrophil count did not reach 2,000/microliters within 2 weeks, the dose was increased to 400 micrograms/m2. A marked neutrophilic response was obtained in all 9 patients with non-severe AA and in 9 out of the 12 patients with severe AA, yielding a response rate of 85.7%. Adverse effects included lumbago in one patient and elevation of serum enzyme levels in 6 patients, but did not prohibit further treatment. These results suggest that subcutaneous administration of KRN8601 is safe and useful in improving neutropenia in AA.
Adolescent↗
[A phase III trial of subcutaneous administration of rhG-CSF in the myelodysplastic syndromes].
To evaluate the safety and efficacy of subcutaneous administration of recombinant human granulocyte colony-stimulating factor in the myelodysplastic syndromes (MDS), 20 patients were given a daily dose of 50 micrograms/m2 of KRN8601 for 4 weeks. When the blood neutrophil count did not reach 2,000/microliters within 2 weeks, the dose was increased to 100 micrograms/m2. A marked neutrophilic response was obtained in 17 of the 18 evaluable patients (94.4%), irrespective of the MDS disease type. Five patients showed a platelet increase, 3 of which also showed an erythroid improvement. To maintain neutrophil levels greater than 1,000/microliters, 12 patients were treated with KRN8601 for 4 weeks. A dose of 25 to 50 micrograms/m2 3-4 times a week served to this end in 8 patients and 100 micrograms/m2 three times a week or daily in the remaining 4 patients. One patient with RAEB progressed to acute myeloid leukemia 8 weeks after KRN8601. The treatment was well-tolerated in the majority of patients with no severe toxicities. These results suggest that subcutaneous administration of KRN8601 is safe and useful in the treatment of cytopenias in MDS.
Adult↗
A clinicopathological analysis of early gastric cancer: retrospective study with special reference to lymph node metastasis.
We reviewed 217 cases of early gastric cancer (EGC) resected from 1978 through 1988. To determine the indications for curative resection by endoscopic mucosectomy (EM) for EGC, we paid special attention to lymph node metastasis examined after gastrectomy. The overall incidence of lymph node metastasis was 12.4%. It was 3.4% for mucosal (m-) cancer and 23.5% for submucosal (sm-) cancer. The maximum diameter of the lesion, depth of cancerous invasion, and location of the lesion showed positive correlations with lymph node involvement (p < 0.05). EGCs less than 20 mm in diameter had no lymph node metastasis. Pieces of mucosa about 20 mm in diameter on the average could be obtained with a single EM procedure. EGC with ulceration had a higher incidence of lymph node involvement than did that without ulceration. We conclude that if EM reveals an intramucosal gastric carcinoma less than 20 mm in diameter without ulceration, curative resection by EM is indicated.
Adenocarcinoma↗
Mechanism of leukemic cell lysis by activated human macrophages: leukemic cells can be lysed without direct contact.
We recently reported that human macrophages effectively destroyed leukemic cells. In this study, we investigated the mechanism of leukemic cell lysis by human macrophages. Human peripheral blood monocyte-derived macrophages were activated with interferon-gamma and lipopolysaccharide. Activated macrophages exhibited lytic activity against leukemic cells (K562 and HL-60 cells) by cocultivation. When macrophages and these leukemic cells were separated by a microporous membrane, activated macrophages did not show any lytic activity against these leukemic cells. However, activated macrophages interacting with leukemic cells under the microporous membrane exhibited lytic activity against leukemic cells that were placed on the microporous membrane. Different kinds of leukemic cells were also effective to induce such lytic activity in the macrophages, but normal lymphocytes could not. Culture supernatants of activated macrophages incubated with leukemic cells did not have cytolytic activity against leukemic cells. The leukemic cells used in this study were confirmed to be resistant to tumor necrosis factor (TNF), but the activated macrophage-mediated cytolytic activity was significantly inhibited by the anti-TNF antibody. These findings suggested that the contact between macrophages and leukemic cells triggered the secretion of lytic factor(s), and that TNF and other labile factor(s) co-operatively functioned to lyse leukemic cells.
Cytotoxicity, Immunologic↗
Successful bone marrow transplantation with rabbit anti-human thymocyte globulin in aplastic anemia. Report of a case previously treated with equine anti-human lymphocyte globulin.
Bone marrow transplantation is widely accepted as the first line therapy for patients with severe aplastic anemia. Patients with less severe forms of aplastic anemia are treated with immunosuppressive agents, hematopoietic growth factors or androgenic steroids. The use of rabbit anti-human thymocyte globulin allowed us to successfully transplant in a patient with a moderately severe form who once failed to respond to all conservative treatment including equine anti-human lymphocyte globulin. We propose that, given the availability of rabbit anti-human thymocyte globulin, marrow transplantation should be considered in non-severe aplastic anemia patients who are refractory to equine anti-human lymphocyte globulin.
Adult↗
Infection in myelodysplastic syndromes before evolution into acute non-lymphoblastic leukemia.
The frequencies, kinds, pathogens, and risk factors of infections in the myelodysplastic syndromes (MDS) were analysed in 430 cases. The overall tendency was for one infectious episode per 1023.5 patient days. The frequency of infectious episodes was highest just after diagnosis of MDS when more than 4 episodes per 1000 patient days occurred. Thereafter, the rate declined rapidly to about 0.3 episodes per 1000 patient days within 4 years. The most frequent infection was that of the respiratory tract followed by sepsis and fever of unknown origin (FUO). Among the types of infection resulting in death, sepsis and FUO comprised the highest proportion (40%) followed by respiratory tract infections (39%). The most frequent pathogen observed was Staphylococcus bacteria. The significant multivariate risk factors for fatal infections were subtype, hemoglobin, dependence on red blood cell transfusion, age, and sex. A staging system was created using these five simple variables at diagnosis.
Adolescent↗
Involvement of the BCL3 gene in two patients with chronic lymphocytic leukemia.
The t(14;19)(q32;q13) is a recurring translocation found in some patients with chronic lymphocytic leukemia (CLL), and the t(14;19) juxtaposes the BCL3 gene on chromosome 19 with the immunoglobulin heavy chain gene (IGH) locus on chromosome 14. Genomic DNAs from 49 patients with chronic B-cell leukemia and the related lymphomas were examined by Southern blot hybridization using 2 separate probes, named p alpha 1.4P and p alpha .5B, from the BCL3 gene locus. None of the 18 patients with leukemic manifestations of non-Hodgkin's lymphomas had detectable BCL3 rearrangements. Of 31 patients with CLL, 2 had the BCL3 rearrangements. A comigration study using the C alpha and C epsilon constant gene probe from IGH indicated that the t(14;19) translocation occurred in these 2 patients, and they were diagnosed with CLL/prolymphocytic (PL) according to the French-American-British (FAB) classification. Probes for the IGH locus revealed that leukemia cells of the 2 patients each were clonal, indicating that both small lymphocytes and prolymphocytoid cells found in the peripheral blood of one patient had the t(14;19), as well as a major population of the small lymphocytes in the peripheral blood of a second patient. It thus appears that tumor cells carrying the t(14;19) constitute a distinct disease entity in a group of chronic B-cell leukemia, that has a converting potential to more aggressive forms.
Aged↗
A new method for quantitative estimation of the degree of DNA fragmentation utilizing agarose gel electrophoresis.
We designed a new method for quantitative analysis of the degree of DNA fragmentation, a characteristic feature of apoptosis. A photograph of an agarose gel electrophoresis of fragmented DNA was incorporated by an optical density scanner or equivalent equipment, and the integrations of middle molecular size area (10,000 to 300 bp), single nucleosomal size area (smaller than 300 bp) and total lane area were calculated. We defined fragmentation rate or (%)FR as the amount of fragmented DNA expressed as the percentage of the total amount of DNA, assigning the coefficients of 1 and 0.5, respectively, to the fragments completely digested into single nucleosomal length and to those partially digested (between 10 k to 300 bp). A standard calibration curve was constructed from triplicate experiments of target nuclei digestion by micrococcal nuclease, which revealed that this method covered a wide range of nuclease activity. We also confirmed that our method was applicable to an autodigestion assay of isolated nuclei which represented endogenous endonuclease activities. This method may be a useful tool for quantitative analysis of endonuclease activities capable of producing nucleosomal-size DNA fragmentation.
Apoptosis↗
Marked apoptosis of human myelomonocytic leukemia cell line P39: significance of cellular differentiation.
Myelodysplastic syndrome (MDS)-derived leukemia cell line P39/Tsugane could be induced to apoptosis by a variety of agents including metabolic inhibitors, a calcium ionophore and differentiation-inducing agents. As evaluated by characteristic morphological changes and oligonucleosomal lengths DNA ladder, the levels of apoptosis in P39 cells induced by actinomycin D, or A23187, were far greater than in other myeloid lines examined in this study. When 22-oxa-1 alpha, 25(OH)2D3 (D3), dimethyl sulfoxide (DMSO) and all-trans retinoic acid (RA) were used as differentiation-inducers, varying degrees of apoptosis were seen. D3 induced monocytoid differentiation, but not apoptosis above the control level. On the other hand, RA induced profound apoptosis concomitant with the progressive expression of differentiation markers. Studies on morphology, functions and phenotypes of P39 cells exposed to differentiation inducers suggest that the incidence of apoptosis was not affected by the process of differentiation, but cells in the process of varying degrees of differentiation may die via apoptosis. Moreover, RA-treated P39 cells are unique in the simultaneous occurrence of profound apoptosis and differentiation. We propose that RA-treated P39 differentiation model is ideally suited for the study of MDS.
Apoptosis↗