Precursors to neonatal lymph nodes: LT beta+CD45+CD4+CD3- cells are found in fetal liver.
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Antigens, CD↗
Biomedical subjects
K Akashi
Publications and source records attributed to K Akashi.
Aclarubicin induces differentiation of leukemic progenitors in myelodysplastic syndrome cooperating with granulocyte colony-stimulating factor.
We have reported that low-dose aclarubicin (ACR) therapy is effective in some patients with myelodysplastic syndrome (MDS). Here, we demonstrate that a low concentration of ACR induces the in vitro differentiation of leukemic progenitor cells from patients with MDS. ACR (0.1 ng/ml) significantly increased the number of granulocyte colony-stimulating factor (G-CSF)-dependent colonies from circulating blast cells in vitro in six out of seven MDS patients with refractory anemia with excess of blast in transformation or chronic myelomonocytic leukemia, but not in all four patients with primary acute myelogenous leukemia. In these MDS patients, the effect of ACR gradually disappeared along with the progression of MDS. Interestingly, the majority of G-CSF/ACR-dependent colonies consisted of rather differentiated myeloid cells such as myelocytes and metamyelocytes, whereas colonies formed by G-CSF alone were composed mainly of immature blastic cells. The number of G-CSF-responding progenitors significantly increased during a 24-48 h incubation with ACR alone. The circulating blasts in MDS patients expressed G-CSF receptors at unchanged levels before and after the incubation with ACR. It is suggested that ACR might increase clonogenic progenitor responsiveness to G-CSF in MDS, probably through modulating downstream signaling cascades associated with G-CSF receptors, and induce these progenitors to differentiate in response to G-CSF.
Aclarubicin↗
Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes.
OBJECTIVES: The present study examined whether nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) can directly inhibit aerobic energy metabolism and impair cell function in interleukin (IL)-1beta,-stimulated cardiac myocytes. BACKGROUND: Recent reports have indicated that excessive production of NO induced by cytokines can disrupt cellular energy balance through the inhibition of mitochondrial respiration in a variety of cells. However, it is still largely uncertain whether the NO-induced energy depletion affects myocardial contractility. METHODS: Primary cultures of rat neonatal cardiac myocytes were prepared, and NO2-/NO3- (NOx) in the culture media was measured using Griess reagent. RESULTS: Treatment with IL-1beta (10 ng/ml) increased myocyte production of NOx in a time-dependent manner. The myocytes showed a concomitant significant increase in glucose consumption, a marked increase in lactate production, and a significant decrease in cellular ATP (adenosine 5'-triphosphate). These metabolic changes were blocked by co-incubation with N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis. Sodium nitroprusside (SNP), a NO donor, induced similar metabolic changes in a dose-dependent manner, but 8-bromo-cyclic guanosine 3',5'-monophosphate (8-bromo-cGMP), a cGMP donor, had no effect on these parameters. The activities of the mitochondrial iron-sulfur enzymes, NADH-CoQreductase and succinate-CoQreductase, but not oligomycin-sensitive ATPase, were significantly inhibited in the IL-1beta, or SNP-treated myocytes. Both IL-1beta and SNP significantly elevated maximum diastolic potential, reduced peak calcium current (I(Ca)), and lowered contractility in the myocytes. KT5823, an inhibitor of cGMP-dependent protein kinase, did not block the electrophysiological and contractility effects. CONCLUSIONS: These data suggest that IL-1beta-induced NO production in cardiac myocytes lowers energy production and myocardial contractility through a direct attack on the mitochondria, rather than through cGMP-mediated pathways.
Adenosine Triphosphate↗
Lymphoid precursors.
Lymphopoiesis of mature and diverse populations of T, B and NK (natural killer) cells from multipotent hematopoietic stem cells is an ideal model of tissue generation and regeneration. Identification and isolation of hematolymphoid stem and progenitor cells in several laboratories over the past several years have provided populations that can be studied biologically for lineage commitment and biochemically for receptor function, signal transduction and selective gene expression. These studies may ultimately provide candidate genes involved in lineage commitment, cell death or survival, self-renewal and migratory capacities of progenitors.
Animals↗
Comparative study of perioperative management of hepatic resection.
In an attempt to identify the factors that influence outcome after hepatic resection, patient background was reviewed and operative morbidity and mortality rates were assessed during two periods: 1985-1988 (group I: N = 96) and 1995-1998 (group II: N = 109). There were no differences in patient background factors between the two groups, but intraoperative blood loss, operative morbidity, and mortality were significantly reduced in group II compared to group I. There has been a significant reduction in postoperative complications, even in cases complicated by liver cirrhosis or obstructive jaundice. As a result of appropriate surgical procedures, postoperative complications in cirrhosis have been markedly decreased. After preoperative percutaneous biliary drainage in obstructive jaundice, attempts have been made to reduce the volume of blood loss even in extensive hepatectomy, the extent of liver resection in poor risk cases has been reduced without sacrificing radicality, and, by minimizing surgical stress, perioperative management has been greatly improved.
Adult↗
Epstein-Barr virus-infected natural killer cell leukemia.
Natural killer cell leukemia (NK leukemia) is an aggressive form of lymphoproliferative disease of granular lymphocytes, and frequently complicates fulminant hemophagocytic lymphohistiocytosis. NK leukemia cells usually possess a single episomal form of Epstein-Barr virus (EBV), and therefore originate from a single EBV-infected NK cell. The NK leukemia cells lack endogenous Bcl-2 expression and are sensitive to apoptotic cell death. However, they constitutively produce interferon-gamma and maintain their survival in an autocrine fashion. The interferon-gamma released from NK leukemia cells may trigger the occurrence of hemophagocytic lymphohistiocytosis through activating macrophages/histiocytes. In the primary infection of EBV, T cells infected with the episomal form of EBV sometimes produce a high amount of interferon-gamma that may lead to the occurrence of hemophagocytic lymphohistiocytosis. Thus, it is important to determine the role of EBV in the increased production of interferon-gamma that occurs in EBV-infected T and NK cells to clarify the developmental mechanism of NK leukemia and its paraneoplastic hemophagocytic lymphohistiocytosis.
Cell Transformation, Viral↗
Hypercoagulable state following transfusions of granulocytes obtained from granulocyte colony-stimulating factor-stimulated donors.
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Blood Donors↗
[Is myocardial impairment in idiopathic dilated hypertrophic cardiomyopathy reversible by carvedilol?: a case report].
A 64-year-old woman with dilated hypertrophic cardiomyopathy was treated by beta-blocker, because of recurrent episodes of congestive heart failure. Carvedilol administration was started with a dose of 2.5 mg/day, and gradually increased to the dose of 20 mg/day 3 months later. Her functional class recovered from New York Heart Association stage IV to stage II. Thallium-201 scintigraphy demonstrated advanced myocardial damage: defect/low perfusion in the anteroseptal, infero-posterior and apical regions. Iodine-123 beta-methyl-p-iodophenyl-pentadecanoic acid scintigraphy confirmed these findings. However, the scintigraphic abnormalities had reversed to near normal perfusion and metabolism similar to those of stunned myocardium after an ischemic episode. This case demonstrates the recovery of myocardial impairment during beta-blocker therapy in a patient with dilated hypertrophic cardiomyopathy.
Adrenergic beta-Antagonists↗
[Percutaneous transluminal septal myocardial ablation combined with permanent dual-chamber pacing in hypertrophic obstructive cardiomyopathy: a case report].
A 74-year-old woman suffering from dyspnea on effort and chest pain (New York Heart Association functional class III) was admitted to our hospital. Echocardiography and left ventriculography showed severe hypertrophy of the left ventricular wall and a severe intraventricular pressure gradient of about 150 mmHg. The diagnosis was hypertrophic obstructive cardiomyopathy. The intraventricular pressure gradient was decreased from 157 to 68 mmHg by percutaneous transluminal septal myocardial ablation (PTSMA), but this reduction was not adequate. Thereafter, dual-chamber pacing was additionally performed. The intraventricular pressure gradient was decreased to 26 mmHg with no complication. PTSMA is a certain way to decrease pressure gradient, but has some complications. Permanent dual-chamber pacing also can show the same effect, but is inferior to PTSMA. Combination of these 2 methods succeeded in abolishing the intraventricular pressure gradient with no complication.
Aged↗
Production of soluble granulocyte colony-stimulating factor receptors from myelomonocytic cells.
It has been speculated that a soluble form of G-CSFR might be physiologically present in humans, since G-CSFR mRNA that lacks a transmembrane domain has been identified from a human myelomonocytic cell line. Here, we demonstrate human soluble G-CSFR (sG-CSFR) of two different molecular sizes (80 and 85 kDa) on an immunoblot analysis using Abs generated against the amino-terminal, extracellular domain of the full-length G-CSFR. Both isoforms of sG-CSFR were able to bind recombinant human G-CSF (rhG-CSF). RT-PCR analysis with primers targeted outside of the transmenbrane region revealed that membrane-anchored G-CSFR is expressed at all maturation stages of purified myeloid cells, including CD34+CD13+ cells (blasts), CD11b-CD15+ cells (promyelocytes or myelocytes), CD11b+CD15+ cells (metamyelocytes and mature neutrophils), and CD14+ cells (monocytes). On the other hand, sG-CSFR mRNA was detectable in CD11b-CD15+, CD11b+CD15+, and CD14+ cells, but not in the CD34+CD13+ blast population. The serum concentration of both isoforms of sG-CSFR appeared to be correlated with the numbers of neutrophils/monocytes before and after rhG-CSF treatment in normal individuals. Thus, two isoforms of sG-CSFR are physiologically secreted from relatively mature myeloid cells and might play an important role in myelopoiesis through their binding to serum G-CSF.
Amino Acid Sequence↗
Tying a molecular knot with optical tweezers.
Filamentous structures are abundant in cells. Relatively rigid filaments, such as microtubules and actin, serve as intracellular scaffolds that support movement and force, and their mechanical properties are crucial to their function in the cell. Some aspects of the behaviour of DNA, meanwhile, depend critically on its flexibility-for example, DNA-binding proteins can induce sharp bends in the helix. The mechanical characterization of such filaments has generally been conducted without controlling the filament shape, by the observation of thermal motions or of the response to external forces or flows. Controlled buckling of a microtubule has been reported, but the analysis of the buckled shape was complicated. Here we report the continuous control of the radius of curvature of a molecular strand by tying a knot in it, using optical tweezers to manipulate the strand's ends. We find that actin filaments break at the knot when the knot diameter falls below 0.4 microm. The pulling force at breakage is around 1 pN, two orders of magnitude smaller than the tensile stress of a straight filament. The flexural rigidity of the filament remained unchanged down to this diameter. We have also knotted a single DNA molecule, opening up the possibility of studying curvature-dependent interactions with associated proteins. We find that the knotted DNA is stronger than actin.
Actins↗
Interferon-gamma prevents apoptosis in Epstein-Barr virus-infected natural killer cell leukemia in an autocrine fashion.
The significant function of cytokines includes maintenance of cell survival as well as induction of cell differentiation and/or proliferation. We demonstrate here that interferon-gamma (IFN-gamma) plays a role for progression of Epstein-Barr virus (EBV)-infected natural killer cell leukemia (NK leukemia) through maintaining cell survival. NK leukemia cells obtained from 7 patients had clonal episomal forms of EBV, indicating that the leukemic cells were of clonal origin. Although normal NK cells constitutively expressed Bcl-2, the EBV-infected NK leukemia cells lacked endogenous Bcl-2 expression and were hypersensitive to apoptosis in vitro. The addition of IFN-gamma to the culture significantly inhibited their spontaneous apoptosis without inducing cell proliferation or upregulation of Bcl-2. The NK leukemia cells constitutively secreted IFN-gamma, and the patients' sera contained a high concentration of IFN-gamma, levels that were high enough to prevent NK leukemia cells from apoptosis. Bcl-XL was not involved in the IFN-gamma-induced NK leukemia cell survival. These data suggest that the acquisition of IFN-gamma-mediated autocrine survival signals, other than Bcl-2 or BCL-XL, might be important for the development of EBV-infected NK leukemia.
Adolescent↗
Protrusive growth from giant liposomes driven by actin polymerization.
Development of protrusions in the cell is indispensable in the process of cell motility. Membrane protrusion has long been suggested to occur as a result of actin polymerization immediately beneath the cell membrane at the leading edge, but elucidation of the mechanism is insufficient because of the complexity of the cell. To study the mechanism, we prepared giant liposomes containing monomeric actin (100 or 200 microM) and introduced KCl into individual liposomes by an electroporation technique. On the electroporation, the giant liposomes deformed. Most importantly, protrusive structure grew from the liposomes containing 200 microM actin at rates (ranging from 0.3 to 0.7 micrometer/s) similar to those obtained in the cell. The deformation occurred in a time range (30 approximately 100 s) similar to that of actin polymerization monitored in a cuvette (ca. 50 s). Concomitant with deformation, Brownian motion of micron-sized particles entrapped in the liposomes almost ceased. From these observations, we conclude that actin polymerization in the liposomes caused the protrusive formation.
Actins↗
Cardioprotective effect of angiotensin-converting enzyme inhibition against hypoxia/reoxygenation injury in cultured rat cardiac myocytes.
BACKGROUND: Although ACE inhibitors can protect myocardium against ischemia/reperfusion injury, the mechanisms of this effect have not yet been characterized at the cellular level. The present study was designed to examine whether an ACE inhibitor, cilazaprilat, directly protects cardiac myocytes against hypoxia/reoxygenation (H/R) injury. METHODS AND RESULTS: Neonatal rat cardiac myocytes in primary culture were exposed to hypoxia for 5.5 hours and subsequently reoxygenated for 1 hour. Myocyte injury was determined by the release of creatine kinase (CK). Both cilazaprilat and bradykinin significantly inhibited CK release after H/R in a dose-dependent fashion and preserved myocyte ATP content during H/R, whereas CV-11974, an angiotensin II receptor antagonist, and angiotensin II did not. The protective effect of cilazaprilat was significantly inhibited by Hoe 140 (a bradykinin B2 receptor antagonist), NG-monomethyl-L-arginine monoacetate (L-NMMA) (an NO synthase inhibitor), and methylene blue (a soluble guanylate cyclase inhibitor) but not by staurosporine (a protein kinase C inhibitor), aminoguanidine (an inhibitor of inducible NO synthase), or indomethacin (a cyclooxygenase inhibitor). Cilazaprilat significantly enhanced bradykinin production in the culture media of myocytes after 5.5 hours of hypoxia but not in that of nonmyocytes. In addition, cilazaprilat markedly enhanced the cGMP content in myocytes during hypoxia, and this augmentation in cGMP could be blunted by L-NMMA and methylene blue but not by aminoguanidine. CONCLUSIONS: The present study demonstrates that cilazaprilat can directly protect myocytes against H/R injury, primarily as a result of an accumulation of bradykinin and the attendant production of NO induced by constitutive NO synthase in hypoxic myocytes in an autocrine/paracrine fashion. NO modulates guanylate cyclase and cGMP synthesis in myocytes, which may contribute to the preservation of energy metabolism and cardioprotection against H/R injury.
Adrenergic beta-Antagonists↗
Technetium-99m HYNIC-annexin V: a potential radiopharmaceutical for the in-vivo detection of apoptosis.
Either inadequate or excessive apoptosis (programmed cell death) is associated with many diseases. A method to image apoptosis in vivo, rather than requiring histologic evaluation of tissue, could assist with therapeutic decision making in these disorders. Programmed cell death is associated with a well-choreographed series of events resulting in the cessation of normal cell function, and the ultimate disappearance of the cell. One component of apoptosis is signaling adjacent cells that this cell is committing suicide by externalizing phosphatidylserine to the outer leaflet of the cell membrane. Annexin V, a 32-kDa endogenous human protein, has a high affinity for membrane-bound phosphatidylserine. We have coupled annexin V with the bifunctional hydrazinonicotinamide reagent (HYNIC) to prepare technetium-99m HYNIC-annexin V and demonstrated localization of radioactivity in tissues undergoing apoptosis in vivo. In this report we describe the results of a series of experiments in mice and rats to characterize the biologic behavior of (99m)Tc-HYNIC- annexin V. Biodistribution studies were performed in groups of rats at 10-180 min after intravenous injection of (99m)Tc-HYNIC-annexin V. In order to estimate the degree of apoptosis required for localization of (99m)Tc-annexin V in vivo, mice were treated with dexamethasone at doses ranging from 1 to 20 mg/kg, 5 h prior to (99m)Tc-HYNIC-annexin V administration, to induce thymic apoptosis. Thymus was excised 1 h after radiolabeled HYNIC-annexin V injection; thymocytes were isolated, incubated with Hoechst 33342 followed by propidium iodide, and analyzed on a fluorescence-activated cell sorter. Each sorted cell population was counted in a scintillation counter. To test (99m)Tc-HYNIC-annexin V as a tracer for external radionuclide imaging of apoptotic cell death, radionuclide imaging of Fas-defective mice (lpr/lpr mice) and wild-type mice treated with the antibody to Fas (anti-Fas) was carried out 1 h post injection. Rat biodistribution studies demonstrated a blood clearance half-time of less than 10 min for (99m)Tc-HYNIC-annexin V. The kidneys had the highest concentration of radioactivity at all time points. Studies in the mouse thymus demonstrated a 40-fold increase in (99m)Tc-HYNIC-annexin V concentration in apoptotic thymocytes compared with the viable cell population. A correlation of r=0.78 was found between radioactivity and flow cytometric and histologic evidence of apoptosis. Imaging studies in the lpr/lpr and wild-type mice showed a substantial increase of activity in the liver of wild-type mice treated with anti-Fas, while there was no significant change, irrespective of anti-Fas administration, in lpr/lpr mice. Excellent images of hepatic apoptosis were obtained in wild-type mice 30 min after injection of (99m)Tc-HYNIC-annexin V. The imaging results were consistent with histologic analysis in these animals. In conlusion, these studies confirm the value of (99m)Tc-HYNIC-annexin V uptake as a marker for the detection and quantification of apoptotic cells in vivo.
Animals↗
Induction of germline transcription in the TCRgamma locus by Stat5: implications for accessibility control by the IL-7 receptor.
IL-7 receptor (IL-7R) plays critical roles in lymphocyte development by promoting survival and proliferation and by inducing V(D)J recombination in TCR and Ig loci. Here, we demonstrate that IL-7R-activated Stat5 binds to consensus motifs in the 5' regions of Jgamma segments and induces germline transcripts. We also show that a constitutively active form of Stat5 restores V-J recombination of TCRgamma genes and partially rescues T cell development from IL-7R(-/-) T cell precursors, especially in favor of gammadelta T cells. Therefore, this study reveals a potential role of Stat5 in T cell development and also implies that IL-7R may control the accessibility of the TCRgamma locus through Stat5-induced germline transcription.
Animals↗
Multiple autoimmune haemopoietic disorders and insidious clonal proliferation of large granular lymphocytes.
We report a patient with clonal proliferation of CD3+8+TCRalphabeta+ large granular lymphocytes (LGL) presenting multiple episodes of autoimmune cytopenia, including autoimmune neutropenia, idiopathic thrombocytopenic purpura, autoimmune haemolytic anaemia, and pure red cell aplasia. Each disorder appeared separately or as a combination during an 11-year clinical course. The increase of blood CD3+8+TCRalphabeta+ LGL was detected 6 years after the initial diagnosis of cytopenia, but the absolute number of LGL cells was always < 1.0 x 109/l. LGL cells were of monoclonal origin and had a chromosomal abnormality. LGL cells transiently responded to cyclosporine A therapy, which was also effective on all of these autoimmune cytopenias. Accordingly, an undetectable level of proliferation of a clonal LGL population could cause various autoimmune haemopoietic disorders.
Adolescent↗
Lymphoid development from stem cells and the common lymphocyte progenitors.
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Animals↗