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Biomedical subjects

E Azuma

Publications and source records attributed to E Azuma.

At least 37 records · Page 2Linked to original sources
PubMed1998

CD4+ and CD8+ cell cytokine profiles in neonates, older children, and adults: increasing T helper type 1 and T cytotoxic type 1 cell populations with age.

The growing body of evidence suggestive of T helper types 1 and 2 (Th1/Th2) including their counterparts T cytotoxic types 1 and 2 (Tc1/Tc2) cell responses during various human disease states necessitates determination of normal T cell subsets' cytokine profiles. We show here, using intracellular cytokine staining and flow cytometry, that in healthy subjects interferon (IFN)-gamma producing CD4+ (Th1) and CD8+ (Tc1) cell populations progressively increase with age with strong correlation to CD45RO surface antigen expression. Meanwhile populations of cells capable of producing IL-4 (Th2 and Tc2) are comparably minimal across all age groups. Collectively, these results may reflect the maturation and expansion of Th1 and Tc1 cell populations from the neonatal period to adulthood, most probably dependent on antigen exposure.

Adolescent↗
PubMed1998

Flow cytometric analysis of peripheral blood and bone marrow for tumor cells in patients with neuroblastoma.

BACKGROUND: Several sensitive surveillance tests reportedly have been used to detect occult neuroblastoma (NB) cells in peripheral blood (PB) and bone marrow (BM). They may be useful in monitoring minimal residual tumor cells. The authors report the feasibility and clinical usefulness of a sensitive flow cytometric assay that has been newly developed and evaluated to detect NB cells. METHODS: Nine NB patients and 15 healthy donors were included in the current study. Primary tumor tissues, BM, and PB were examined for the detection of NB cells using a triple-color flow cytometric assay. Tumor cells in PB and BM, isolated by fluorescence-activated cell sorting, were used for morphologic studies and differential polymerase chain reaction analysis of N-myc gene amplification. RESULTS: Neuroblastoma cells consistently showed CD9+/CD56+/CD45- phenotype. Flow cytometric analysis could detect NB cells at a level of 1 per 10(4-5) cells. The CD9+/CD56+/CD45- cell population was absent in normal PB and BM. This assay identified occult NB cells, which were not detected by conventional cytology, in PB and BM obtained from six patients (one of two with Stage II and all five with advanced disease) at diagnosis. Residual NB cells also were detected in PB and BM during therapy. Neuroblast-like morphology and N-myc gene amplification of sorted cells confirmed that CD9+/CD56+/CD45- cells were truly NB cells. CONCLUSIONS: A triple-color flow cytometric assay was a sensitive and specific method to detect occult NB cells in PB and BM. This assay could be an additional component of surveillance testing for NB patients.

Antigens, CD↗
PubMed1998

Thymic B-cell non-Hodgkin's lymphoma in a child.

A 13-year-old male developed thymic non-Hodgkin's lymphoma. Microscopically, the tumor was composed of large cells, resembling centroblasts. Immunohistochemically, the tumor demonstrated leukocyte common antigen+, L26 (B-cell)+, UCHL1 (T-cell)-, suggesting the B-cell phenotype. In contrast to the terminally differentiated phenotype (CD10-, surface immunoglobulin-) observed in adult cases, flow cytometric analysis showed that they were relatively immature: CD10+, CD19+, HLA-DR-, IgM+/-, kappa+. He was successfully treated with intensive chemotherapy. Since childhood thymic lymphomas are exclusively small non-cleaved cell lymphoma with T-cell phenotype, this case represents a unique entity in children.

Adolescent↗
PubMed1998

Thrombopoietin level is inversely related to blast count, not platelet number, in Down syndrome neonates with transient myeloproliferative disorder.

Transient myeloproliferative disorder (TMD) in neonates with Down syndrome is characterized by increased megakaryoblastic cells in the peripheral blood. Despite their spontaneous regression in weeks, prognosis is not always favorable because of fatal hepatic fibrosis. In this study, blood thrombopoietin (TPO) levels were measured by ELISA in six TMD patients and the expression of c-Mpl, a ligand for TPO, was examined on the blast cells from four patients by flow cytometer. At the onset, TPO level was undetectable in one patient and significantly lower in five patients than six neonatal controls (mean 0.52 fmol/ml, range 0.30-0.93 vs. 3.70, 1.38-8.33, P < 0.001), although platelet counts were similar (mean 321 x 10(9)/l, range 42-1,040 vs. 253 x 10(9)/l, 124-381). Two patients died of hepatic failure. TPO levels were measured in five patients after regression of the blast cells. With regression of blast cells, TPO levels were remarkably increased in four survived patients. In one patient with hepatic failure, TPO level was poorly elevated and relatively lower compared to the others. TPO levels were inversely correlated with blast numbers (r = -0.85, P < 0.001), but not with platelet counts (r = 0.426). Blast cells from four patients were all positive for c-Mpl. Our findings suggest that megakaryocyte mass is a major regulator of TPO levels and hepatic failure may affect the TPO level because liver is a major source of TPO production.

Cell Count↗
PubMed1998

CD4+ T-lymphocytopenia in long-term survivors following intensive chemotherapy in childhood cancers.

BACKGROUND: It is generally believed the effects of short intensive courses of therapy are rapidly reversible in childhood cancers, and immunologic function following years of maintenance treatment with chemotherapy usually returns to normal by 6 months or less when treatment is terminated. However, we previously demonstrated that dysregulation of immunoglobulins, especially IgD, was observed in long-term survivors following intensive chemotherapy in cancer patients. With regard to cellular immunity, investigators reported that antineoplastic chemotherapy significantly reduces the number of CD4+ T-lymphocytes, and production of newly developing CD4+ T-lymphocytes was inversely related to the patients' age. However, the incidence of CD4+ lymphocytopenia in long-term survivors of childhood cancers is not known. PROCEDURE: Here, we report the flow cytometric analysis of peripheral blood from long-term survivors who continue complete remission off chemotherapy for more than 5 years. RESULTS: Six out of 74 long-term survivors (8.1%), showed low CD4+ T-lymphocyte count (<300/mm3). Three of six patients showed continued CD4+ T-lymphocytopenia over a year. In spite of the persistent low levels of CD4+ T cells, these three patients were not susceptible to severe infections. COMMENT: Intriguingly, in patients with CD4+ T-lymphocytopenia there has been a tendency toward increased numbers of natural killer cells or gamma delta T cells that may be operating as a thymus-independent compensatory mechanism to defend the hosts.

Adolescent↗
PubMed1998

Suppression of alloreactivity with gamma delta T-cells: relevance to increased gamma delta T-cells following bone marrow transplantation.

Several reports have shown that an increase in T-cell receptor gamma/delta-positive T-cells (gamma delta T-cells) have been observed following bone marrow transplantation. gamma delta T-cells expanded from peripheral blood mononuclear cells from normal volunteers were used to investigate the function of gamma delta T-cells in vitro. Peripheral blood mononuclear cells were cultured with synthetic ligand of gamma delta T-cells, monoethyl phosphates (MEP), for 7 days. MEP specifically expanded gamma delta T-cells. Expanded gamma delta T-cells from subject "B" were added to an A anti-B or A anti-C mixed lymphocyte culture (MLC) containing responder cells from subject "A" and irradiated stimulator cells from subjects "B" or "C". The cultures were harvested on day 6 and tested for cytotoxicity against stimulator-type Con A blasts. gamma delta T-cells from subject "B" specifically inhibit generation of allospecific cytotoxic T lymphocytes (CTL) in A anti-B MLC. The results indicate that gamma delta T-cells exhibit veto-type suppression of alloreaction. If the current experiments are also applicable in vivo, gamma delta T-cells originating from the donor after bone marrow transplantation may inhibit graft rejection by suppressing recipient anti-donor reactivity. gamma delta T-cells may be involved in the suppression of allogeneic reaction in vivo following allogeneic bone marrow transplantation.

Bone Marrow Transplantation↗
PubMed1998

Cord blood transplantation from sibling donors in Japan. Report of the national survey.

A joint national survey on cord blood transplantation (CBT) was conducted in Japan and 18 sibling CBTs were reported. Diseases of the patients were leukemia (ten), neuroblastoma (one), bone marrow failure (four) and inborn errors of metabolism (three). A volume of 50-141 ml of cord blood containing 27-197 x 10(7) nucleated cells was collected from sibling infants soon after delivery. HLA antigens were identical in 14 and one to three antigens mismatched in four. Engraftment of donor cord blood was achieved in 17 cases. Autologous hematopoiesis was recovered in one case. Days of engraftment were 13-29 days (median 19 days) for neutrophils (500/microliter), 18-67 days (median 30 days) for reticulocytes (2%) and 21-96 days (median 46 days) for platelets (50 x 10(3)/microliter). Acute GVHD was grade 0 in seven cases, grade I in five cases and grade II in one case in HLA-identical pairs, but became grade II in two cases and grade III in two cases in HLA-mismatched pairs. Chronic GVHD of limited type developed in two out of 17 evaluable cases, however both responded to immunosuppressive therapy. Altogether, 14 out of 18 patients are currently surviving 4-27 months following transplantation. Probabilities of overall survival and disease free survival were estimated to be 77.0 and 71.8% using Kaplan-Meier tests. These findings suggest the feasibility of cord blood transplantation from sibling donors and the possibility of unrelated cord blood transplantation. A cord blood banking system is necessary for the universal use of cord blood stem cells from unrelated donors.

Anemia, Aplastic↗
PubMed1998

Late-onset unilateral renal dysfunction combined with non-insulin-dependent diabetes mellitus and bronchial asthma following allogeneic bone marrow transplantation for acute lymphoblastic leukemia in a child.

We report a child with T cell acute lymphoblastic leukemia who developed late-onset multiple complications after allogeneic bone marrow transplantation from an HLA-matched sibling. The preparative regimen consisted of total body irradiation (TBI, 12 Gy), splenic irradiation (6 Gy) and cytosine arabinoside (3 g/m2 x 10). Splenic irradiation was added because of persistent splenomegaly in spite of intensive chemotherapy. He developed bronchial asthma 1 1/2 years post transplant. He presented with microhematuria and proteinuria 4 1/2 years post-transplant, which were due to unilateral left renal dysfunction. He developed type II, non-insulin-dependent diabetes mellitus 8 years post-transplant. A biopsy from the left kidney was not compatible with diabetic nephropathy. All these complications appear to be independently related to BMT, particularly TBI and/or splenic irradiation.

Adolescent↗
PubMed1998

Cytokine-enhanced mixed lymphocyte reaction (MLR) in cord blood.

Although in cord blood (CB) transplantation graft-versus-host disease (GVHD) is reported to be less severe, GVHD may occur even in patients with HLA-identical sibling donors. This result shows that HLA typing can not entirely predict GVHD. The standard MLR with CB cells was either normal or slightly reduced compared with adult peripheral blood (PB) cells. We used two manipulations to increase the responses of CB cells to allo-antigens. The first was to treat the stimulator cells with cytokines, and the second to amplify weak proliferative responses by adding exogenous cytokines to MLR cultures (modified MLR). The stimulator cells were treated with both interferon-gamma (IFN-gamma) and IL-4. The responder cells were treated with both IL-2 and tumour necrosis factor-alpha (TNF-alpha). It is still to be determined whether or not this cytokine-enhanced MLR could be a possible predictor of GVHD. However, using these cytokines, 90% of CB could recognize allo-antigens, even if the standard MLR was negative.

Adult↗
PubMed1998

[Factors aggravating bronchial asthma in urban children (I)--The involvement of indoor air pollution].

The aggravation of bronchial asthma in today's urban child population was studied by an epidemiological study in order to elucidate the involvement of indoor air pollution in relation to housing style. The asthma group consisted of 210 children under 12 years old who had been recently diagnosed as having bronchial asthma and under the care of Osaka Prefectural Habikino Hospital. The non-asthma group consisted of 180 children under 12 years old who had been under care at Osaka Prefectural Hospital but had no present history of allergic symptom. The individual atmospheric environment and housing style were surveyed by questionnaire. Also, the amount of mite allergen (Dp: Dermatophagoides pteronyssinus, Df: Dermatophagoides farinae) in room and bedding dust and the concentration of cotinine in urine were examined as objective indicators for the load of environmental allergen and the indoor air pollution by tobacco smoke, respectively. In this study, bronchial asthma was classified into two types: atopic/non-atopic, according to whether Dp-specific immunoglobulin E (Dp-IgE) was present/absent (positive/negative). Thus, for the risk factors given above, their involvement in each type of asthma was examined by comparing the proportion of the exposed subjects between the three groups of atopic asthma, non-atopic asthma and non-asthma. As atopy is an important factor of child asthma, the relative risk (odds ratio) of Dp-IgE increase (atopy) was also determined for the same factors by logistic regression analysis in each of the asthma and non-asthma groups. The results are as follows: 1. Reinforced concrete housing material, which results in mal-ventilation, increased the load of indoor air pollutants such as tobacco smoke. 2. A higher amount of mite allergen in bedding dust increased Dp-IgE. 3. Heating with stove, which results in a higher room humidity as well as temperature, enhanced Dp proliferation and appeared to be involved in increasing the risk of atopic asthma. 4. Reinforced concrete housing material appeared to be involved in suppressing Dp-IgE and increasing the risk of non-atopic asthma. But some air pollutants such as tobacco smoke and mite allergen showed no relationship to these involvements.

Air Pollution, Indoor↗
PubMed1998

[Factors aggravating bronchial asthma in urban children (II)--The involvement of atopy and serum fatty acids, and their interaction with urban living environment].

The aggravation of bronchial asthma in today's urban child population was studied by an epidemiological study in order to elucidate the involvement of food habits as well as individual factors such as age, sex, and history of atopic dermatitis, and the interaction with urban living environments. The asthma group consisted of 202 children under 12 years old who had been recently diagnosed as having bronchial asthma and under the care of Osaka Prefectural Habikino Hospital. The non-asthma group consisted of 81 children under 12 years old who had been under care at Osaka Prefectural Hospital but had no present history of allergic symptom. The individual factors and the urban living environments (atmospheric environment, housing style) were surveyed by questionnaire. Also, the mite (Dp: Dermatophagoides pteronyssinus, Df: Dermatophagoides farinae) specific immunoglobulin E (Dp-IgE, Df-IgE) and the composition of serum fatty acid were examined as objective indicators for atopy and dietary habits, respectively. In this study, bronchial asthma was classified into two types: atopic/non-atopic, according to whether Dp-IgE was present/absent (positive/negative). Thus, for the risk factors given above, their involvement in each type of asthma was examined. As atopy is an important factor of child asthma, the relative risk (odds ratio) of Dp-IgE increase (atopy) was also examined by logistic regression analysis in each of the asthma and non-asthma groups. The results are as follows: 1. As age increased, the risk of atopy increased but the risk of asthma decreased. 2. The risk of asthma increased as Dp-IgE rather than Df-IgE increased. 3. For the composition of serum fatty acid, the lower quartile ranking (LQR) group for a saturated fatty acid, stearic acid, and the upper quartile ranking (UQR) group for a mono-unsaturated fatty acid, oleic acid, had a higher risk of nonatopic asthma. 4. The LQR group for omega 6-poly-unsaturated fatty acid such as linoleic acid, had a lower risk of atopy. 5. The UQR group for a omega 3-poly-unsaturated fatty acid, eicosapentaenoic acid, had a higher risk of nonatopic asthma. The UQR of eicosapentaenoic acid and living environments within 25 m from a major road or housing of reinforced concrete structure showed involvement in synergistic increase in the risk of non-atopic asthma.

Asthma↗
PubMed1997

Inhibition of interleukin-2 receptor (CD25) expression induced on T cells from children with acute lymphoblastic leukemia.

Peripheral blood lymphocytes obtained from children with acute lymphoblastic leukemia (ALL) at onset were studied for the expression of interleukin-2 (IL-2) receptor alpha-chain (CD25) by two-color flow-cytometric analysis. Stimulated with anti-CD3 monoclonal antibody (mAb) alone. CD25 expression was significantly suppressed in CD4+ T cells from 27 of 48 (56.3%) cases and in CD8+ T cells from 29 of 48 (60.4%) cases. When stimulated with anti-CD3 mAb plus phorbol 12-myristate 13-acetate (PMA), CD25 expression was clearly restored in certain cases of ALL. When PMA plus ionomycin were used for stimulation of T cells. CD25 was inducible in a majority of cases. Interestingly CD25 expression upon anti-CD3 mAb stimulation was recovered after complete remission had been achieved. These observations suggest the presence in ALL children at onset of an in vitro defect in the signal transduction pathway of the T-cell-receptor/CD3 complex, resulting in inefficient CD25 expression. However, immune-staining analysis indicated that protein kinase C was normally translocated from the cytosol fraction to the cell membrane fraction. The mobilization of cytoplasmic free calcium is also normal.

Antibodies, Monoclonal↗
PubMed1997

Salvage therapy for relapsed or refractory childhood acute lymphocytic leukemia by alternative administration a lymphoid- and myeloid-directed chemotherapeutic regimen consisting of dual modulation of ara-C, hydroxyurea, and etoposide.

Risk-directed chemotherapeutic regimens in recent use have improved the prognosis of children with acute lymphocytic leukemia (ALL). However, many patients relapse during or shortly after cessation of the initial continuation chemotherapy. Since achievement of a second complete remission (CR) is the initial step in successful retreatment effort, it is important to develop salvage protocols for children with relapsed or refractory ALL. In the present study, we developed a new salvage protocol (MLL-93) and applied the concept of dual chemical modulation of cytarabine, hydroxyurea, and etoposide with the alternative administration of high doses of myeloid- and lymphoid-directed agents. We also planned to perform allogeneic bone marrow transplantation (BMT) following a CR if patients had HLA-identical donor(s). The six patients treated with the MLL-93 protocol achieved a second CR. One patients in CR died of interstitial pneumonia after an unrelated allogeneic BMT. The other five patients have been in CR for 12-41 months. We suggest that the concepts of alternative administration of lymphoid- and myeloid-directed drugs and biochemical modulation are useful in the treatment of children with relapsed or refractory ALL.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Treatment of multidrug-resistant murine leukemia with antisense mdr1 oligodeoxynucleotides.

To overcome multidrug resistance in a P-glycoprotein-overexpressing P388/ADR murine leukemia cell line, antisense mdr1 phosphorothioate-oligodeoxynucleotide (AS-oligomer) was constructed. AS-oligomer inhibited P-glycoprotein expression and mdr1 mRNA in vitro in a dose-dependent manner, whereas sense mdr1 oligomer (SE-oligomer) had no effect at the doses used. When P388/ADR was treated in vitro with AS-oligomer and doxorubicin (ADR), ADR-resistance was reduced by approximately 2 logs. Furthermore, a single injection of AS-oligomer plus ADR intraperitoneally into B6D2F1 mice with P388/ADR significantly prolonged mean survival time in a dose-dependent fashion. Again, sense mdr1 oligomer had no effect in vivo. No side effects, either acute or chronic, were found with this treatment during the observation period. These results show that antisense mdr1 oligomer could be a useful tool to overcome multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Apoptotic cell death of human T lymphoblastoid cells induced by arginine deiminase.

A growth-inhibitory substance found in the culture of a B-precursor leukemia cell line, NALM-20, was purified from the serum-free culture medium and identified as arginine deiminase derived from Mycoplasma arginini (EC 3.5.3.6). Arginine deiminase strongly inhibited, in a dose-dependent manner, the growth of human T cells and T lymphoblastoid cell lines, but not that of B-precursor and myeloid cell lines. The addition of L-arginine completely restored the growth of T lymphoblastoid cells that had been inhibited by arginine deiminase. The addition of L-ornithine also partially restored it. This enzyme suppressed interleukin-2 (IL-2) production and IL-2 receptor expression in T cells stimulated by non-specific mitogens. The morphologic features of dying cells and DNA fragmentation indicated that arginine deiminase induced apoptotic cell death in T lymphoblasts. Cell cycle analysis revealed that G1-->S transition was blocked in cell treated with arginine deiminase, accompanied by the increase of apoptotic nuclei in the sub-G1 fraction. In conclusion, the deletion of the essential nutrient L-arginine by arginine deiminase significantly inhibited cell growth and activation in T lymphoblasts, accompanied by the induction of apoptotic cell death.

Apoptosis↗
PubMed1997

Successful hematopoietic reconstitution by transplantation of umbilical cord blood cells in a transfusion-dependent child with Diamond-Blackfan anemia.

A 4-year-old boy with Diamond-Blackfan anemia and a history of multiple transfusions underwent umbilical cord blood transplantation from his HLA-identical female sibling born by vaginal delivery at 38 weeks. The patient was prepared with busulfan, cyclophosphamide and antilymphocyte globulin. Methotrexate and cyclosporin A were given for the prophylaxis of GVHD. Regimen-related toxicity was not observed and successful engraftment occurred, including the erythroid series. No evidence of acute or chronic GVHD has been observed for 14 months after transplantation. This is the first case of successful umbilical cord blood transplantation to a patient with Diamond-Blackfan anemia.

Blood Transfusion↗
PubMed1997

Conditioning with cyclophosphamide/antithymocyte globulin for allogeneic bone marrow transplantation from HLA-matched siblings in children with severe aplastic anemia.

Graft rejection has been a problem after bone marrow transplantation for patients with severe aplastic anemia (SAA). Ten children with SAA were conditioned for bone marrow transplantation from HLA-identical siblings, using cyclophosphamide (CY, 50 mg/kg) plus antithymocyte globulin (ATG, 15 mg/kg) for 4 successive days. Marrow was infused 36 h after the last dose of CY. Cyclosporin A and methotrexate were administered as graft-versus-host disease (GVHD) prophylaxis. All patients achieved durable engraftment at follow-up of 7-41+ months (mean, 25) without significant GVHD. Since investigators have used different sources, doses, and time schedules of ATG, we compared our results with other published reports. We conclude that CY/ATG conditioning is well tolerated and effective in children with SAA.

Adolescent↗