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Biomedical subjects

S Nakao

Publications and source records attributed to S Nakao.

At least 55 records · Page 3Linked to original sources
PubMed2001

Relative increase of granulocytes with a paroxysmal nocturnal haemoglobinuria phenotype in aplastic anaemia patients: the high prevalence at diagnosis.

To clarify the pathologic significance of granulocytes exhibiting the paroxysmal nocturnal haemoglobinuria (PNH) phenotype in patients with aplastic anaemia (AA), we examined peripheral blood from 100 patients with AA for the presence of granulocytes deficient in glycosylphosphatidylinositol (GPI)-anchored proteins using a sensitive flow cytometric assay. A significant increase in the frequency of CD55-CD59-CD11b+ granulocytes (>0.003%) compared to normal individuals was observed in 31 of 35 (88.6%) patients with untreated AA at diagnosis. The proportions of patients showing increased PNH granulocytes in treated AA patients with a short (<5 yr) and long (>5 yr) disease duration were 68.6% (11/16) and 20.4% (10/49), respectively. When 19 patients showing increased frequency of PNH granulocytes before therapy were studied 6-12 months after antithymocyte globulin plus cyclosporin A therapy, the frequency decreased to 0.01-90% of pretreatment values in 15 recovering patients. These findings suggest that a relative increase in the number of PNH granulocytes is a common feature of AA at diagnosis, and that it may represent the presence of immunologic pressure to normal haematopoietic stem cells as a cause of AA.

Adult↗
PubMed2001

Decreased plasma activity of antithrombin or protein C is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation.

We investigated whether depressed plasma antithrombin and protein C activity, considered as a specific finding of disseminated intravascular coagulation (DIC), is due to consumption coagulopathy in septic patients with DIC. An analysis of hemostatic parameters was performed in 139 septic patients (68 with DIC and 71 without DIC). Plasma activity of antithrombin and protein C tended to be significantly decreased in septic patients with DIC but not in those without DIC (p < 0.001). However, when the septic patients were classified into three groups according to the albumin (or choline esterase) level, no significant differences in antithrombin activity or protein C activity were observed between the patients with and without DIC in any of the subgroups. Notably, neither the plasma activity of antithrombin nor protein C was decreased even in septic patients with DIC who had normal plasma levels of albumin (or choline esterase). No significant correlation was observed between plasma levels of thrombin-antithrombin complex (TAT) and antithrombin activity, or between plasma levels of TAT and protein C activity either in septic patients with DIC or without DIC. It is reasonable to conclude that the markedly reduced plasma activity of antithrombin and protein C is not due to consumption coagulopathy in septic patients with DIC.

Aged↗
PubMed2001

Blockade of eosinophil migration and airway hyperresponsiveness by cPLA2-inhibition.

We examined the role of a cytosolic phospholipase A2 (cPLA2) in antigen-induced eosinophil infiltration of airways and in airway hyperresponsiveness to methacholine. Inhibition of cPLA2, or blockade of the platelet-activating factor (PAF) receptor, blocked antigen-induced airway hyperresponsiveness and suppressed eosinophil infiltration. Neither cyclooxygenase nor 5-lipoxygenase inhibition had either effect. We show here that, in antigen-sensitized guinea pigs, cPLA2 inhibition prevents both eosinophilic infiltration and subsequent airway hyperresponsiveness after antigen challenge. We also show that this effect is mediated by first-step hydrolysis of membrane phospholipid into lysophospholipid rather than by prostanoid or leukotriene metabolites of arachidonate.

Animals↗
PubMed2001

Successful non-myeloablative stem cell transplantation for a heavily transfused woman with severe aplastic anemia complicated by heart failure.

A 30-year-old Japanese woman weighing 35 kg with severe hemochromatosis due to multiple transfusions was referred to our clinic for treatment of severe aplastic anemia (SAA). The patient had heart failure with an ejection fraction of 36% requiring diuretics and a severe liver dysfunction with an indocyanine green clearance rate of 18%, as well as other transfusion-related complications such as chronic hepatitis due to hepatitis C virus and diabetes mellitus. She was treated with a non-myeloablative preparative regimen that included fludarabine monophosphate (Flu, 120 mg/m(2)), cyclophosphamide (CY, 1200 mg/m(2)) and antithymocyte globulin (ATG, 15 mg/kg) followed by allogeneic peripheral blood stem cell transplantation (PBSCT) from her HLA-matched sister. The regimen was well tolerated, and engraftment rapidly occurred without any therapy-related complications. Chimerism analysis on day 14 after transplant showed reconstitution with 100% donor cells. She no longer needed transfusion after day 23 and has been well in 90% Karnofsky status at 4 months post transplant. The clinical course of this patient indicates that this preparative regimen enables SAA patients with severe organ failure to safely undergo allogeneic stem cell transplantation.

Adult↗
PubMed2001

Effects of suplatast tosilate, a new type of anti-allergic agent, on airway cough hypersensitivity induced by airway allergy in guinea-pigs.

BACKGROUND: Cough receptor hypersensitivity is a fundamental feature of some conditions presenting with chronic non-productive cough. Suplatast tosilate, an anti-allergic agent, is a T helper (Th)2 cytokine inhibitor that inhibits the synthesis of interleukin (IL)-4, IL-5, immunoglobulin (Ig)E production, and local eosinophil accumulation. OBJECTIVE: The purpose of this study was to investigate the effect of suplatast on antigen-induced airway cough hypersensitivity and eosinophil infiltration into the airway. METHODS: Number of coughs elicited by inhalation of increasing concentrations of capsaicin (10-8, 10-6 and 10-4 M) was counted 24 h after an antigen challenge in conscious guinea-pigs and then bronchoalveolar lavage was performed. We investigated the effect of single (before antigen challenge or capsaicin provocation) or repetitive treatment with intraperitoneal suplatast at a dose of 10 or 30 mg/kg on antigen-induced cough hypersensitivity. RESULTS: Twenty-four hours after antigen challenge, guinea-pigs developed an increase in cough receptor sensitivity to inhaled capsaicin and eosinophil infiltration in the airways. After a 2-week treatment with suplatast, but not after only a single treatment before antigen challenge or capsaicin provocation, the antigen-induced early phase bronchoconstriction, cough hypersensitivity, and airway eosinophilia were inhibited in a dose-dependent manner. CONCLUSION: These results indicate that suplatast inhibits airway cough hypersensitivity underlying allergic eosinophilic inflammation.

Airway Resistance↗
PubMed2001

Sensory neuropeptides are not involved in acetaldehyde-induced bronchoconstriction in guinea-pigs.

1. Alcohol-induced asthma is characterized by worsening of asthmatic symptoms after alcohol ingestion. Acetaldehyde, a metabolite of ethanol, is thought to be a main factor of alcohol-induced asthma. Although airway sensory nerves are known to be activated in asthma, there have been no studies investigating the role of tachykinins in the airway response to acetaldehyde. The purpose of the present study was to evaluate the involvement of tachykinins on acetaldehyde-induced bronchoconstriction in guinea-pigs. 2. After capsaicin desensitization or intravenous administration of 10 mg kg(-1) FK224, a NK1 and NK2 dual antagonist, airway responses to ascending doses (2.5-20 mg ml(-1)) of inhaled acetaldehyde was examined using a modified Konzett-Rössler method in guinea-pigs. 3. Inhalation of acetaldehyde induced bronchoconstriction in a dose-dependent manner. The FK224 failed to reduce the acetaldehyde-induced bronchoconstriction. Pretreatment with capsaicin did not alter the bronchoconstriction induced by acetaldehyde at a dose of 2.5-10 mg ml(-1). Pretreatment with capsaicin slightly, but significantly, inhibited bronchoconstriction induced by 20 mg ml(-1) of acetaldehyde. 4. The present results suggest that tachykinins are not involved in acetaldehyde-induced bronchoconstriction in guinea-pigs.

Acetaldehyde↗
PubMed2001

Lymphocyte collection for donor leucocyte infusion from normal donors: estimation of the minimum processed blood volume and safety of the procedure.

BACKGROUND AND OBJECTIVES: To estimate the minimum volume of processed blood necessary for the purpose of donor leucocyte infusion (DLI), we determined the number of CD3+ cells harvested by apheresis from normal donors and examined adverse events during the procedure. MATERIALS AND METHODS: Leukapheresis utilizing the COBE Spectra' was performed a total of 24 times from 12 normal donors. Blood counts were obtained and the number of CD3+ cells was evaluated before and after apheresis and in the peripheral blood products. Complications associated with the procedure were documented. RESULTS: Blood products contained, on average, 51.1% CD3+ cells. A linear correlation was found between the number of CD3+ cells collected and the processed blood volume, up to 12 000 ml (r = 0.930, P < 0.001). Cytoreduction was observed in all donors after apheresis. In particular, the platelet and lymphocyte values decreased to approximately 70% of the preapheresis value. Two donors reported adverse effects: one was a mild vaso-vagal reaction and the other was citrate-related lip paresthesia. These symptoms were mild and disappeared spontaneously. CONCLUSIONS: We found a linear correlation between the number of CD3+ cells collected and the processed blood volume, which enabled us to estimate the minimum volume of processed blood necessary for DLI. The adverse events observed were acceptable.

Adolescent↗
PubMed2001

Donor leukocyte infusion for Japanese patients with relapsed leukemia after allogeneic bone marrow transplantation: indications and dose escalation.

To clarify the role of dose escalation of donor leukocyte infusion (DLI) in the treatment of relapsed leukemia after allogeneic bone marrow transplant (BMT), data from 100 patients were collected from 46 facilities in Japan and analyzed with respect to indications and infused cell dose. Complete remission (CR) was achieved in 11 of 12 (91%) patients with relapsed chronic myelogenous leukemia (CML) in the chronic phase, 3 of 11 (27%) with CML in the acute phase, 8 of 21 (38%) with acute myelogenous leukemia (AML), 6 of 23 (25%) with acute lymphoblastic leukemia (ALL), and 5 of 11 (45%) with myelodysplastic syndrome (MDS). The probability of remaining in CR at 3 years was 82% in CML patients in the chronic phase, but 0% in those with CML in the acute phase, 7% in those with AML, 0% with ALL, and 33% with MDS. Acute graft-versus-host disease (GVHD) (> or = 2) developed in 31 of 89 (34%) patients with human leukocyte antigen identical related donors and was fatal for 7 (7%). A leukocyte dose of 1 x 10(7)/kg of recipient body weight with CML in the chronic phase, 3 x 10(7)/kg of recipient body weight with MDS, and 1 x 10(8)/kg of recipient body weight with acute leukemia appeared to be optimal as an initial dose of DLI. However, the minimal dose of leukocyte developing fatal GVHD was 7 x 10(7)/kg of recipient body weight. These suggest that a relatively small dose of DLI ranging from 1 x 10(7)/kg to 5 x 10(7)/kg of recipient body weight should be administered initially then the infused escalating dose 2 or 3 months later in patients with CML in the chronic phase and MDS. However, a large number of leukocytes around 1 x 10(8)/kg are needed to induce graft versus leukemia effects in patients with acute leukemia despite a 7% fatality in GVHD.

Adolescent↗
PubMed2001

Bradykinin induces a rapid cyclooxygenase-2 mRNA expression via Ca2+ mobilization in human gingival fibroblasts primed with interleukin-1 beta.

We have previously demonstrated that bradykinin potentiates prostaglandin E(2)release in human gingival fibroblasts pretreated with interleukin-1 beta (priming). In this study, we demonstrate a potentiating effect of bradykinin on cyclooxygenase-2 mRNA expression in the interleukin-1 beta-primed fibroblasts. Interleukin-1 beta (200 pg/ml) induced cyclooxygenase-2 mRNA expression, but not bradykinin (1 microM). However, bradykinin rapidly and markedly increased the cyclooxygenase-2 mRNA expression in the fibroblasts primed with interleukin-1 beta. In the primed fibroblasts, ionomycin and thapsigargin mimicked the potentiating effect of bradykinin on the cyclooxygenase-2 mRNA expression. Dexamethasone and actinomycin D completely suppressed not only the interleukin-1 beta-induced cyclooxygenase-2 mRNA expression, but also the bradykinin-induced cyclooxygenase-2 mRNA expression in the interleukin-1 beta-primed fibroblasts, although cycloheximide did not inhibit the effects of interleukin-1 beta and bradykinin. These results suggest that bradykinin-induced prostaglandin E2 synthesis is regulated at the level of the transcription of cyclooxygenase-2 mRNA via Ca2+ mobilization in the interleukin-1 beta-primed human gingival fibroblasts.

Bradykinin↗
PubMed2001

Effect of a cysteinyl leukotriene antagonist, pranlukast hydrate, on acetaldehyde-induced bronchoconstriction in asthmatic patients.

Acetaldehyde is a main factor of alcohol-induced asthma. We previously reported that the cysteinyl leukotriene (cys-LT) receptor antagonist, pranlukast hydrate, inhibits acetaldehyde-induced airway hyperresponsiveness in guinea pigs. The purpose of this study was to evaluate the involvement of cys-LT on bronchial responsiveness to acetaldehyde in asthmatic patients. We investigated the bronchial response to inhalation of acetaldehyde in 10 asthmatic patients, who were treated with placebo or pranlukast hydrate (225.5 mg), a cys-LT receptor antagonist, twice a day for 1 wk using a double-blind, randomized, placebo-controlled, cross-over design. Although a remarkable improvement of acetaldehyde bronchoconstriction was observed in 3 out of 10 subjects, PC(20)-AcCHO values were identical between placebo [12.0 (GSEM, 1.192) mg/ml] and pranlukast [14.7 (GSEM, 1.245) mg/ml] groups. The changes in bronchial responsiveness to acetaldehyde were similar in the six patients who had never experienced alcohol-induced asthma and the four who had. In conclusion, cys-LTs are not involved in acetaldehyde-induced bronchoconstriction.

Acetaldehyde↗
PubMed2001

Propofol depressed neutrophil hydrogen peroxide production more than midazolam, whereas adhesion molecule expression was minimally affected by both anesthetics in rats with abdominal sepsis.

The treatment of sepsis may require mechanical ventilation of the lungs and sedation. Because neutrophils are the most important effector cells for protecting against sepsis, and propofol and midazolam are the most widely used anesthetics for sedation, we studied the effects of these two anesthetics on the neutrophil function during sepsis. Sepsis was induced in rats by cecal ligation and puncture. At either 4 h or 24 h after cecal ligation and puncture, blood and peritoneal neutrophils were obtained, incubated with the test anesthetics, and the hydrogen peroxide (H(2)O(2)) production and CD11b/c expression were determined by flow cytometry. In both early (at 4 h) and late (at 24 h) sepsis, propofol and midazolam depressed H(2)O(2) production by blood and peritoneal neutrophils at clinical concentrations. Propofol caused more depression than midazolam (P < 0.005). In both early and late sepsis, the effect of the anesthetics on the up-regulation of the stimulation-induced CD11b/c expression on blood neutrophils was minimal at clinical concentrations. If these results ultimately become clinically relevant, midazolam may be preferable to propofol for sedation during sepsis.

Anesthetics, Intravenous↗
PubMed2001

Elevated levels of free tissue factor pathway inhibitor antigen in cases of disseminated intravascular coagulation caused by various underlying diseases.

Tissue factor pathway inhibitor (TFPI) is primarily synthesized by vascular endothelial cells and is found in vivo in association with endothelial cells, lipoproteins, or in free form. Free TFPI is the most potent and important type, because it is released from endothelial cells following an injection of heparin, or as a result of pathological stimuli. In order to study the role of TFPI in disease, the concentration of free form TFPI was measured in the plasma of 114 patients suffering from disseminated intravascular coagulation (DIC), as the result of several underlying diseases. Plasma antigen levels of free TFPI were significantly higher even in those patients not exhibiting DIC than in normal healthy subjects. These levels were even higher among patients exhibiting DIC, especially those with acute promyelocytic leukemia or cancer, receiving continuous heparin drip infusions. A significant correlation was observed between the plasma antigen levels of free form TFPI and those of fibrin/fibrinogen degradation products, and free form TFPI and plasmin inhibitor complex (r = 0.428, P < 0.0001 and r = 0.329, P < 0.0001, respectively) among 114 DIC patients. There were no significant differences between the plasma levels of free TFPI in DIC patients with or without multiple organ failure. It has been suggested that the plasma levels of free TFPI are closely related to the levels of fibrinolysis occurring in DIC patients, although further study is required to clarify the degree to which TFPI is expressed by endothelial cells during DIC.

Case-Control Studies↗
PubMed2001

Depressed plasma activity of plasminogen or alpha2 plasmin inhibitor is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation.

We have attempted to determine whether depressed plasma plasminogen and alpha2 plasmin inhibitor (or alpha2 antiplasmin) activity is, as a result of consumption coagulopathy, a specific finding of disseminated intravascular coagulation (DIC) in septic patients. The hemostatic parameters of 139 septic patients (68 with DIC and 71 without DIC) were analyzed. Among the group as a whole, plasma activities of plasminogen and alpha2 plasmin inhibitor were significantly depressed in septic patients with DIC relative to those without DIC (P < 0.01 and P < 0.05, respectively). Notably, a significant correlation was observed between plasma levels of albumin and plasminogen activity, as well as between plasma levels of albumin and alpha2 plasmin inhibitor activity both in septic patients with DIC and those without DIC. However, no significant correlation was observed between plasma levels of plasmin-alpha2 plasmin inhibitor complex (PIC) and plasminogen activity, nor between PIC and alpha2 plasmin inhibitor activity either in septic patients with DIC or those without DIC. We concluded that depressed activity of plasminogen or alpha2 plasmin inhibitor is not as a result of consumption coagulopathy, but rather a result of low synthetic function of the liver in septic patients with DIC.

Aged↗
PubMed2001

All-trans retinoic acid is partially effective against lipopolysaccharide-induced but not against tissue-factor-induced disseminated intravascular coagulation in rat models.

All-trans retinoic acid (ATRA) has been introduced to the management of acute promyelocytic leukemia (APL) as a differentiation treatment. This drug not only causes complete remission, but also improves disseminated intravascular coagulation (DIC) without adding anticoagulants in APL. We have attempted to determine whether ATRA is effective against DIC in rat models induced by tissue factor (TF) or lipopolysaccharide (LPS), because the anticoagulant effect of ATRA has been considered to induce thrombomodulin upregulation and TF downregulation on endothelial cells as well as on APL cells. In male Wistar rats, DIC was induced by a 4-h infusion of thromboplastin (3.75 U/kg) or lipopolysaccharide (30 mg/kg). The rats were given ATRA orally each day at a dose of 100 mg/kg per day for 1 week before the injection of TF or LPS in ATRA treatment groups, or given low molecular weight heparin (LMWH) 10 min before the injection of TF or LPS (200 U/kg, bolus intravenously) in LMWH treatment groups. No significant changes in hemostatic parameters or markers of organ dysfunction were caused by the ATRA administration, while DIC was significantly improved by LMWH in the TF-induced model. DIC was significantly improved by both ATRA and LMWH in the LPS-induced model. These findings suggested that ATRA was useful for treating DIC only in the LPS-induced model, and that drug efficacy should be carefully assessed because the agents used to induce DIC considerably influenced the outcome.

Animals↗
PubMed2001

An enhanced fibrinolysis prevents the development of multiple organ failure in disseminated intravascular coagulation in spite of much activation of blood coagulation.

OBJECTIVES: To investigate the relationship between fibrinolytic enhancement and the development of multiple organ failure (MOF) in disseminated intravascular coagulation (DIC). To detect the useful prognostic index for outcome in DIC. DESIGN: Case-control study. SETTING: A department of internal medicine in a university hospital, a clinical division for diagnosis and treatment, mainly of respiratory diseases, hematologic diseases, DIC, and other diseases requiring critical care medicine. PATIENTS: A total of 69 DIC patients, 31 with MOF. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: The DIC patients with MOF had more elevated levels of tissue plasminogen activator antigen (t-PA) and plasminogen activator inhibitor antigen (PAI), and more depressed levels of plasmin-alpha2 plasmin inhibitor complex (PIC) and fibrin/fibrinogen degradation products than those without MOF, although no significant difference in thrombin-antithrombin complex (TAT) levels was observed. A fibrinolytic enhancement (shown by PIC) was parallel to an activation of blood coagulation (shown by TAT) in DIC patients without MOF, although no such fibrinolytic enhancement was provoked even by much activation of blood coagulation in DIC patients with MOF. Whereas all the patients without MOF were restored from DIC, 14 of 31 patients with MOF were unable to be restored from DIC and died. A significant increase in plasma levels of t-PA and PAI under the condition of sustained hemostatic activation was observed in the patients who died. CONCLUSION: Enhanced fibrinolysis was considered to be the important defense mechanism in preventing the development of MOF in DIC. The increases in plasma levels of t-PA and PAI were poor prognostic markers in DIC. Further careful study may be useful to clarify whether the fibrinolytic therapy is beneficial in clinical DIC patients with MOF.

Antifibrinolytic Agents↗
PubMed2001

[Low dose melphalan therapy was effective in an elderly patient with MDS-AML].

An 80-year-old man with MDS-refractory anemia (RA) suffered transformation to a leukemic state after 18 months. The karyotype of the bone marrow cells was 47, XY, +8 in 8 cells among 20 dividing cells analyzed. Combination therapy of 150 micrograms of granulocyte colony-stimulating factor (G-CSF) and 250 mg of cytarabine ocfosfate (SPAC) for 3 weeks had no beneficial effect. Then, the patient was subjected to low-dose (2 mg daily) melphalan therapy. Gradual and concurrent improvement in anemia, thrombocytopenia, and neutropenia occurred, and the patient became free of transfusions at 2 weeks after the treatment began. Since then, his performance status has improved from grade 4 on his diagnosis of AML to grade 2. Cytogenetic analysis was normal in all 20 dividing cells in the bone marrow examination and melphalan had no adverse effect. Recently, several reports of low dose chemotherapy for elderly patients or high risk leukemia have been described, and have sustained for the QOL therapy. In the present case, low-dose melphalan therapy was effective and, moreover the abnormal karyotype of trisomy eight had disappeared.

Aged↗
PubMed2001

Beneficial effect of the active form of vitamin D3 against LPS-induced DIC but not against tissue-factor-induced DIC in rat models.

1Alpha,25-dihydroxyvitamin D3 (active form of vitamin D3; vitamin D3) has been reported to induce the upregulation of thrombomodulin and downregulation of tissue factor (TF) on monocytes. The possibility exists that vitamin D3 prevents the development of disseminated intravascular coagulation (DIC). In particular, monocyte TF production plays an important role in the pathophysiology of DIC in septic patients. We have attempted to determine whether vitamin D3 is effective against DIC in a rat model induced by lipopolysaccharides (LPS) (30 mg/kg, 4 h) or TF (3.75 U/kg, 4 h) using selective hemostatic parameters, markers of organ dysfunction and pathological findings (assessment of glomelular fibrin deposition). Vitamin D3 was administered orally each day at a dose of 2.0 mg/kg/day for 3 days, or low molecular weight heparin (LMWH 200 u/kg; i.v.) was given 10 min before the injection of TF or LPS in each treatment group. Vitamin D3 was effective against DIC in the rat model induced by LPS only, whereas LMWH was effective against DIC in both rat models induced by either TF or LPS. The anti-DIC effect of vitamin D3 was equal to (or more potent than) that of LMWH. The results suggested that vitamin D3 was useful for the treatment of LPS-induced DIC, and that the assessment of a drug's efficacy should be done carefully given the markedly different results obtained according to the agents used to induce DIC.

Administration, Oral↗