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Biomedical subjects

I Tanaka

Publications and source records attributed to I Tanaka.

At least 19 recordsLinked to original sources
PubMed2007

Clinical and prognostic significance of cytokine receptor expression in adult acute lymphoblastic leukemia: interleukin-2 receptor alpha-chain predicts a poor prognosis.

We quantitatively assessed the expression of cytokine receptors (interleukin-2 receptor (IL-2R), IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, granulocyte-macrophage colony-stimulating factor R (GM-CSFR), G-CSFR, c-fms, c-mpl, c-kit and FLT3) in cells from 211 adults with acute lymphoblastic leukemia (ALL) by flow cytometry and determined their prevalence and clinical significance. Although all cytokine receptors were expressed to various degrees, the levels of IL-3R alpha-chain (IL-3Ralpha), IL-2Ralpha, IL-2Rbeta, IL-7Ralpha, common-Rgamma(gammac), c-mpl, c-kit and FLT3 exhibited a wide spectrum > or =2000 sites/cell. Among them, IL-3Ralpha, IL-2Ralpha and FLT3 were highly expressed in B-lineage ALL, whereas IL-7Ralpha, gammac and c-kit predominated in T-lineage ALL. Higher levels of IL-3Ralpha, IL-2Ralpha, c-kit and FLT3 correlated with the expression of CD13/33. Increased IL-2Ralpha levels related to the presence of Philadelphia chromosome (Ph), leukocytosis and shorter event-free survival (EFS). C-kit preferred in male. Elevated FLT3 levels correlated with age > or =60 years. Multivariate analysis in B-lineage ALL revealed only IL-2Ralpha (P=0.028) and Ph (P=0.020) as independent factors for EFS. These findings suggest that several cytokine receptors associated with certain cellular and clinical features, but IL-2Ralpha solely had a prognostic value and should be considered as a major prognostic factor for adult ALL that is comparable with Ph.

Adult↗
PubMed2006

Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice.

AIMS/HYPOTHESIS: Brain natriuretic peptide (BNP) is a potent vasorelaxing and natriuretic peptide that is secreted from the heart and has cardioprotective properties. We have previously generated hypotensive transgenic mice (BNP-Tg mice) that overproduce BNP in the liver, which is released into the circulation. Using this animal model, we successfully demonstrated the amelioration of renal injury after renal ablation and in proliferative glomerulonephritis. Glomerular hyperfiltration is an early haemodynamic derangement, representing one of the key mechanisms of the pathogenesis of diabetic nephropathy. Based on the suggested involvement of increased endogenous natriuretic peptides, the aim of this study was to investigate their role in the development and progression of diabetic nephropathy. MATERIALS AND METHODS: We evaluated the progression of renal injury and fibrogenesis in BNP-Tg mice with diabetes induced by streptozotocin. We also investigated the effect of BNP on high glucose-induced signalling abnormalities in mesangial cells. RESULTS: After induction of diabetes, control mice exhibited progressively increased urinary albumin excretion with impaired renal function, whereas these changes were significantly ameliorated in BNP-Tg mice. Notably, diabetic BNP-Tg mice revealed minimal mesangial fibrogenesis with virtually no glomerular hypertrophy. Glomerular upregulation of extracellular signal-regulated kinase, TGF-beta and extracellular matrix proteins was also significantly inhibited in diabetic BNP-Tg mice. In cultured mesangial cells, activation of the above cascade under high glucose was abrogated by the addition of BNP. CONCLUSIONS/INTERPRETATION: Chronic excess of BNP prevents glomerular injury in the setting of diabetes, suggesting that renoprotective effects of natriuretic peptides may be therapeutically applicable in preventing the progression of diabetic nephropathy.

Animals↗
PubMed2006

Distribution and medullary projection of respiratory neurons in the dorsolateral pons of the rat.

The dorsolateral pons around the parabrachial nucleus including the Kölliker-Fuse nucleus is closely linked with the medullary respiratory center and plays an important role in respiratory control. We aimed to elucidate the firing properties, detailed distributions, and medullary projections of pontine respiratory neurons in pentobarbitone-anesthetized, paralyzed, and artificially ventilated rats with intact vagi. A total of 235 respiratory neurons were recorded from the dorsolateral pons in and around the Kölliker-Fuse nucleus. Six types of firing patterns were identified: inspiratory, expiratory-inspiratory phase spanning, inspiratory-expiratory phase spanning, decrementing expiratory, augmenting expiratory, and whole-phase expiratory patterns. Of these, the inspiratory neurons and the expiratory-inspiratory phase spanning neurons, which constituted the largest population (61%), were characterized most carefully by changing lung inflation levels, since under some conditions both showed similar firing patterns. Many (58%) of the 133 respiratory neurons examined were antidromically activated by electrical stimulation of the medulla. They were activated from the ventrolateral medulla around the ventral respiratory group and the Bötzinger complex and from the dorsomedial medulla around the nucleus tractus solitarii and the hypoglossal nucleus. The projections to the dorsomedial medulla were bilateral in many cases, and those to the ventrolateral medulla were unilateral. Of these medullary projections, two specific projections could be characterized in detail. First, many expiratory-inspiratory phase spanning neurons projected to the hypoglossal nucleus, suggesting that these pontine neurons are important premotor neurons of the hypoglossal motoneurons. This projection explains well the hypoglossal inspiratory activity, which is often dissociated from the phrenic inspiratory activity. Second, most whole-phase expiratory neurons that were distributed medially to the KF nucleus sent their axons toward the spinal cord via the midline medulla. These findings provide a new insight into the pontine control of medullary and spinal respiratory function.

Action Potentials↗
PubMed2006

Recent results on hydrogen and hydration in biology studied by neutron macromolecular crystallography.

Neutron diffraction provides an experimental method of directly locating hydrogen atoms in proteins, a technique complimentary to ultra-high-resolution [1, 2] X-ray diffraction. Three different types of neutron diffractometers for biological macromolecules have been constructed in Japan, France and the United States, and they have been used to determine the crystal structures of proteins up to resolution limits of 1.5-2.5 A. Results relating to hydrogen positions and hydration patterns in proteins have been obtained from these studies. Examples include the geometrical details of hydrogen bonds, H/D exchange in proteins and oligonucleotides, the role of hydrogen atoms in enzymatic activity and thermostability, and the dynamical behavior of hydration structures, all of which have been extracted from these structural results and reviewed. Other techniques, such as the growth of large single crystals, the preparation of fully deuterated proteins, the use of cryogenic techniques, and a data base of hydrogen and hydration in proteins, will be described.

Biology↗
PubMed2006

The measurement of low levels of factor VIII or factor IX in hemophilia A and hemophilia B plasma by clot waveform analysis and thrombin generation assay.

BACKGROUND: Precise assessment of clotting function is essential for monitoring of hemostatic treatment for hemophilias A and B. MATERIALS AND METHODS: Clot waveform analysis and thrombin generation assays were performed on factor (F) VIII- and FIX-deficient plasmas, which had been reconstituted with known amounts of recombinant FVIII (rFVIII) and affinity-purified FIX respectively. Clot waveforms were assessed qualitatively and quantitatively by measuring the parameters clotting time, maximum coagulation velocity (Min1), and maximum coagulation acceleration (Min2). The thrombin generation assay was also assessed qualitatively and measurements made of time to peak and peak height. RESULTS: Overall results obtained with both assays showed good correlation for both clotting factors confirming that the changes in clotting waveform reflected changes in thrombin generation. Both assays demonstrated a predictable dose response to the addition of FVIII or IX. However, clot waveform analysis was more sensitive than the thrombin generation assay, particularly in detecting very low levels (0-0.1 IU dL(-1)) of both factors. CONCLUSIONS: These data suggest that the application of clot waveform analysis to the routine management of the hemophiliacs could increase our understanding of the clinical significance of low levels of FVIII and FIX that cannot be measured by assays in current use. This may be particularly useful in the management of hemophiliacs with inhibitors or undergoing gene therapy.

Biometry↗
PubMed2006

Factor V C2 domain contains a major thrombin-binding site responsible for thrombin-catalyzed factor V activation.

Factor (F)V is converted into its active form, FVa, by limited proteolysis. Thrombin-catalyzed activation of FV is essential for its full cofactor activation. Previously, we reported that thrombin was bound to the C2 domain in the light chain of FVIII. As FV has a similar domain structure to FVIII, we focused on the FV C2 domain as a possible binding region for thrombin. Kinetic parameters, measured by surface plasmon resonance, revealed that the K(d) values of anhydro-thrombin for FV, FVa, and the FV C2 domain were 66, 240, and 670 nmol L(-1), respectively. FV activation was increased by approximately 9-fold by the addition of thrombin. In the presence of the FV C2 domain, this increase of the FV activation was inhibited. However, FV activation was not inhibited by the addition of the FVIII C2 domain. FV was cleaved into a 105-kDa heavy chain and a 71/74-kDa light chain by thrombin-catalyzed proteolysis at Arg709, Arg1018 and Arg1545. In the presence of the FV C2 domain, the cleavage was inhibited at all sites. Proteolysis was not affected by the addition of the FVIII C2 domain. These results indicated that the FV C2 domain contains a major binding site for thrombin and that this domain is necessary for the proteolysis at all cleavage sites. Furthermore, the present results also suggested that thrombin has an independent binding site for FV different from that for FVIII.

Binding, Competitive↗
PubMed2005

Implantation of primary cultured adipocytes that secrete insulin modifies blood glucose levels in diabetic mice.

AIM/HYPOTHESIS: In type 1 diabetic patients, basal insulin supplementation plays a central role in tight glycaemic control. Therefore, safe and steady supplementation of basal insulin is strongly desirable, despite the need for multiple injections. The aim of this study was to investigate a procedure for supplementation using genetically engineered, primary-cultured adipocytes in diabetic mice. METHODS: Furin-cleavable human proinsulin cDNA was transferred into murine primary-cultured adipocytes using a retroviral vector. The cells were implanted subcutaneously into streptozotocin-induced diabetic mice. RESULTS: The transfected cells secreted substantial amounts of mature insulin, as well as C-peptide, into conditioned medium. Syngeneic implantation of the cells significantly improved hyperglycaemia and blood HbA(1)c concentrations in a manner that was dependent on cell number, without causing hypoglycaemia. The plasma insulin concentration was dependent on the implanted cell number, and the systemic effect of the circulating insulin was confirmed by marked improvement of body weight reduction and liver glycogen content. Additionally, surgical resection of the implants, in which the insulin secretion was immunologically confirmed after transplantation, diminished the glucose-lowering effect, suggesting that in vivo expression could be eliminated if necessary. CONCLUSIONS/INTERPRETATION: These results indicate that the autotransplantation of functionalised adipocytes may lead to a clinical application in the treatment of diabetes.

Adipocytes↗
PubMed2005

General rule for displacive phase transitions in perovskite compounds revisited by first principles calculations.

A recent high pressure experiment on LaAlO3 has revealed that the compound is an exception for the "general rule" of displacive phase transition associated with zone-boundary phonons. In the present study, the experimental result is successfully confirmed by first principles calculations. The pressure dependence of phonon frequencies as well as the phase transition pressure is quantitatively well reproduced. We found that the behavior is not peculiar to LaAlO3 but rather ubiquitous. RAlO3 (R = La, Nd, Sm, and Gd) and LaGaO3 can be classified in the same group.

Journal Article↗
PubMed2005

Efficacy of auxiliary partial orthotopic liver transplantation for cure of hemophilia in a canine hemophilia A model.

Metabolic liver disease can be cured by orthotopic liver transplantation. Some successful cases of whole or partial liver transplantation have been reported. Because liver function in these recipients is normal save for the production of the responsive metabolic factor, auxiliary partial orthotopic liver transplantation (APOLT) may produce a benefit. However, no experimental model of APOLT for metabolic liver diseases has been reported. We established a canine APOLT model to evaluate the clinical feasibility and efficacy of APOLT to cure hemophilia. The donor normal beagle dog was used to establish an APOLT model. A left lobe partial liver graft taken from the donor was orthotopically transplanted to the recipient after resection of the native left lobe preserving the native right lobe. Recipients showed no atrophy and comparable blood flow in both the graft and the native liver at the time of exploration after APOLT. Thus, APOLT was performed from a normal donor to a recipient with hemophilia A. In this recipient, blood factor VIII activity markedly increased after APOLT and was maintained for 7 weeks. No episode of bleeding was seen during the observation. In conclusion, a canine APOLT model was successfully established as evidenced by sustained production of factor VIII in a hemophilia recipient. These findings suggest the clinical feasibility and efficacy of APOLT for metabolic liver diseases.

Animals↗
PubMed2005

Involvement of transforming growth factor-beta and thrombopoietin in the pathogenesis of myelodysplastic syndrome with myelofibrosis.

We investigated the cause of myelofibrosis and proliferation of megakaryocytes in myelodysplastic syndrome with myelofibrosis (MDS-MF (+)). Plasma-transforming growth factor-beta1 (PTGF-beta1) concentrations closely correlated with myelofibrosis grade in MDS-MF (+) and were higher than those in idiopathic myelofibrosis (IMF), essential thrombocythemia (ET), idiopathic thrombocytopenic purpura (ITP), MDS-without MF (MDS-MF (-)) or healthy volunteers (HV). Peripheral blood mononuclear cells from MDS-MF (+) patients expressed more TGF-beta1 mRNA than those from IMF, MDS-MF (-) or HV. When we immunostained bone marrow specimens of MDS-MF (+) for TGF-beta, the intensity of blasts was apparently higher than that of megakaryocytes, while in MDS-MF (-), megakaryocytes were immunostained with a similar intensity as that in MDS-MF (+), but blasts were negative for staining. In IMF, megakaryocytes, monocytes and small mononuclear cells representing CD34+ cells were all similarly stained with a much lower intensity than that of blasts in MDS-MF (+). The number of bone marrow megakaryocytes were increased the most in MDS-MF (+), followed by ET, ITP, MDS-MF (-) and NHL and correlated with plasma thrombopoietin (TPO) levels or with plasma TGF-beta1 levels, respectively, in each disease. Thus, in MDS-MF (+), both myelofibrosis and the increased megakaryocytes were ascribed to overproduction of TGF-beta1 from blasts.

Adult↗
PubMed2004

GABA, in some cases together with glycine, is used as the inhibitory transmitter by pump cells in the Hering-Breuer reflex pathway of the rat.

The Hering-Breuer reflex is one of the fundamental respiratory reflexes and is mediated by second-order relay neurons of the slowly adapting lung stretch receptors. These neurons, which are called pump cells, are located in the nucleus tractus solitarii and include a population of inhibitory neurons. We aimed to determine which transmitter, GABA or glycine, the inhibitory pump cells use. In addition, we examined whether or not second-order relay neurons of the rapidly-adapting lung stretch receptors (RAR-cells), whose excitatory or inhibitory nature is not known, use these inhibitory neurotransmitters. In Nembutal-anesthetized, neuromuscularly blocked and artificially ventilated rats, we labeled pump cells (n=33) and RAR-cells (n=26) with Neurobiotin and processed the tissues for detection of mRNA encoding either glutamic acid decarboxylase isoform 67 (GAD67) or glycine transporter 2 (GLYT2) using in situ hybridization. The pump cells were located in the interstitial nucleus and its vicinity and the RAR-cells in the commissural subnucleus. The majority (64%) of the pump cells examined for GAD67 mRNA and many (26%) of the pump cells examined for GLYT2 mRNA expressed respective mRNAs. Of the eight pump cells in which both mRNAs were double-detected, three expressed both mRNAs and one expressed GAD67 mRNA but not GLYT2 mRNA, the other four expressing neither mRNAs. On the other hand, RAR-cells expressed neither GAD67 mRNA nor GLYT2 mRNA. The results suggest that the inhibitory pump cells are basically GABAergic and some of them may corelease GABA and glycine, and that RAR-cells are neither GABAergic nor glycinergic. These findings expand our understanding of the networks of lung receptor-mediated reflexes including the Hering-Breuer reflex.

Amino Acid Transport Systems, Neutral↗
PubMed2004

Effectiveness of factor VIII infusions in haemophilia A patients with high responding inhibitors.

We report here the efficacy of factor VIII (FVIII) infusions in two haemophiliacs with inhibitors using clot waveform analysis on the MDA II system, which was possible to detect very low levels of FVIII activity < 1.0 U dL(-1). In the presence of type 1 inhibitors at the level of 6.2 (patient 1) and 14.4 (patient 2) Bethesda Units mL(-1), 3.2 and 6.5 U dL(-1) of FVIII:C remained 30 min after the infusion of FVIII (100 U kg(-1)), respectively. Moreover, 0.9 U dL(-1) of FVIII:C remained 24 h after infusion in patient 2. In both cases, these changes were reflected by qualitative improvement in the aPTT clot waveform and quantitative changes in the minimum value of the second derivative of the aPTT waveform (Min2) that reflects clot acceleration. These results suggest that FVIII infusion may be continued with clinical benefit in some haemophiliacs with high responding inhibitors. Furthermore, the haemostatic response may be monitored accurately and efficiently by clot waveform analysis.

Child↗
PubMed2004

Unresponsiveness to factor VIII inhibitor bypassing agents during haemostatic treatment for life-threatening massive bleeding in a patient with haemophilia A and a high responding inhibitor.

We report a case of haemophilia A with a high responding inhibitor of factor VIII (FVIII) who had a serious retroperitoneal haematoma caused by penetration of a duodenal ulcer. Inhibitor-bypassing therapy was commenced immediately on admission. On the 17th day of treatment with activated prothrombin complex concentrate (APCC; FEIBA, re-bleeding occurred and thrombelastography (TEG) demonstrated resistance to therapy. Treatment was changed to recombinant activated factor VII (rFVIIa; NovoSeven and resulted in clinical improvement together with an improvement in TEG parameters. On the 10th day of continuous infusion with NovoSeven, however, TEG again showed resistance to therapy. FEIBA infusions were re-introduced and TEG results remained satisfactory for 7 days. On day 34, however, further retroperitoneal bleeding was evident and a decline in the haemostatic efficiency of FEIBA was recorded by TEG. NovoSeven was again successfully administered for 7 days. There were no laboratory findings to indicate disseminated intravascular coagulation (DIC), hypercoagulability or abnormal fibrinolysis. The plasma-based clotting tests did not show any additional prolongation on the occasions when the TEG demonstrated unresponsiveness to FEIBA or NovoSeven. These findings suggested that some component of whole blood, other than plasma might have governed the TEG data. The long-term use of APCC such as FEIBA or rFVIIa, requires careful monitoring in terms of FVIII inhibitor bypassing activity as well as the tendency to DIC.

Adolescent↗
PubMed2003

Crystallization of a large single crystal of cubic insulin for neutron protein crystallography.

The growth of a large single crystal of cubic porcine insulin for characterization of hydrogen and hydration in cubic insulin crystals by neutron diffraction analysis is reported. Growth in D2O was investigated based on the phase diagram for cubic insulin to determine appropriate growth conditions, and a large single crystal was then successfully grown by a dialysis method to a size of 4.0 x 4.0 x 1.3 mm3. Neutron diffraction analysis of the cubic insulin crystals was carried out using a single-crystal diffractometer at the JRR-3M reactor of the Japan Atomic Energy Research Institute. In preliminary analysis, Npi appears to be protonated and Ntau deprotonated in His5 in the B-chain, whereas both Npi and Ntau are protonated in His10.

Crystallization↗
PubMed2003

Characteristics of t(8;21) acute myeloid leukemia (AML) with additional chromosomal abnormality: concomitant trisomy 4 may constitute a distinctive subtype of t(8;21) AML.

t(8;21)(q22;q22) is the most frequently observed karyotypic abnormality associated with acute myeloid leukemia (AML), especially in FAB M2. Clinically, this type of AML often shows eosinophilia and has a high complete remission rate with conventional chemotherapy. t(8;21) AML is also frequently associated with additional karyotypic aberrations, such as a loss of the sex chromosome; however, it is unclear whether these aberrations change the biological and clinical characteristics of t(8;21) AML. To investigate this issue, 94 patients with t(8;21) AML were categorized according to their additional karyotypic aberrations, which were detected in more than three cases, and then morphologic features, phenotypes, expression of cytokine receptors, and clinical features were compared to t(8;21) AML without other additional aberrant karyotypes. t(8;21) AML with loss of the sex chromosome and abnormality of chromosome 9 were found in 27 cases (29.3%) and 10 cases (10.6%), respectively; however, no differences were observed from the t(8;21) AML without other additional karyotypes in terms of morphological and phenotypic features. There was also no significant difference in the clinical outcome among these three groups. On the other hand, trisomy 4 was found in three cases (3.2%) and these cells showed low expressions of CD19 (P=0.06) and IL-7 receptor (P=0.05), and high expressions of CD33 (P=0.13), CD18 (P=0.03), and CD56 (P=0.03) when compared to t(8;21) AML without additional karyotypes. Moreover, all three t(8;21) AML cases with trisomy 4 did not show eosinophilia in their bone marrow and died within 2.4 years. These observations suggest that additional karyotypic aberration, t(8;21) with trisomy 4 is rare, but it may constitute a distinctive subtype of t(8;21) AML.

Adolescent↗
PubMed2001

Immunological characterization of factor VIII autoantibodies in patients with acquired hemophilia A in the presence or absence of underlying disease.

The development of a factor VIII autoantibody results in a severe hemorrhagic diathesis known as acquired hemophilia A. Underlying pathologies, such as autoimmune disease or chronic inflammatory disease, are observed in about half of the patients. We have investigated a total of 16 cases with acquired hemophilia A and divided the patients into two groups according to the presence or absence of other clinical conditions. Group A comprised nine cases with no detectable associated pathology. Group B consisted of seven cases with other clinical diagnoses. Significant levels of factor VIII activity (FVIII:C) and factor VIII antigen (FVIII:Ag) were detected in Group A and the pattern of FVIII:C inactivation was characteristic of Type 2 inhibitors. In contrast, no FVIII:C was detected in Group B and, in five of seven cases, the inhibitory pattern was Type 1. IgG(4) antibody subclass specificity was dominant in both groups. IgG1 antibody reactivity was higher in Group B than in Group A. Our results suggested a close relationship between the presence of underlying disease and immunological and coagulation characteristics in acquired hemophilia A.

Adult↗
PubMed2001

Crystallization and preliminary X-ray diffraction studies of monomeric isocitrate dehydrogenase by the MAD method using Mn atoms.

NADP(+)-dependent isocitrate dehydrogenase (E.C. 1.1.1.42; IDH) is an enzyme of the Krebs cycle and catalyzes the oxidative decarboxylation reaction from DL-isocitrate to alpha-ketoglutarate, with a concomitant reduction of the coenzyme NADP(+) to NADPH. Single crystals of monomeric IDH from Azotobacter vinelandii in complex with DL-isocitrate and Mn(2+) were obtained by the hanging-drop vapour-diffusion method at room temperature. One crystal diffracted to a resolution of 2.9 A and was found to belong to the orthorhombic system; the space group was determined to be P2(1)2(1)2(1), with unit-cell parameters a = 108.4, b = 121.7, c = 129.7 A. The asymmetric unit contains two molecules of monomeric IDH, corresponding to a V(M) value of 2.66 A(3) Da(-1). The crystals were frozen in a capillary by a flash-cooling technique and MAD data were collected using Mn atoms as anomalous scatterers on beamline BL41XU at SPring-8, Japan. The positions of two Mn atoms binding to two independent IDH molecules were located from Bijvoet difference Patterson maps.

Azotobacter vinelandii↗