Biomedical subjects

Mine Harada

Publications and source records attributed to Mine Harada.

At least 73 records · Page 4Linked to original sources

PubMed2005

Non-cardiogenic pulmonary oedema induced by salazosulfapyridine.

A 25-year-old woman received oral salazosulfapyridine, 4 g/day, for treatment of ulcerative colitis. At 10 days later, she presented with fever and respiratory symptoms. Based on physical, laboratory and radiological findings, bacterial pneumonia and non-cardiogenic pulmonary oedema was suspected. Salazosulfapyridine was immediately halted and antibiotic therapy started. Two days later, her symptoms and abnormal findings had improved rapidly. Bacteriological studies were negative. Salazosulfapyridine-induced non-cardiogenic pulmonary oedema was diagnosed. Non-cardiogenic pulmonary oedema should be considered as one of several salazosulfapyridine- induced pulmonary diseases in patients who are receiving salazosulfapyridine and who develop respiratory symptoms and an abnormal CXR.

Adult↗

PubMed2005

Characterization and distribution of bone marrow-derived cells in mouse cornea.

PURPOSE: Bone marrow (BM)-derived stem cells are thought to possess extensive differentiation capacity. The present study was conducted to investigate the characteristics and distribution of these cells in the normal mouse cornea. METHODS: BM cells and BM-derived hematopoietic stem/progenitor cells (HSCs) from enhanced GFP (eGFP) transgenic mice (lin(-), Sca-1(+)) were intravenously transplanted into irradiated wild-type C57BL/6 mice. At 4 to 6 months after transplantation, the mice were killed, and their whole corneas examined by histologic and immunohistochemical methods (CD11c, CD11b, and CD45). RESULTS: At 2 weeks after BM cell transplantation, GFP(+) cells gradually migrated into the cornea from the limbal area. At 2 to 6 months, they were distributed over the entire cornea. In cross sections of whole cornea, GFP(+) cells comprised 27.3% +/- 11.1% (BM) and 24.0% +/- 8.01% (HSC) of total cells in the peripheral corneal stroma. In the center of the corneal stroma, GFP(+) cells were 7.58% +/- 2.63% (BM) and 8.06% +/- 1.76% (HSC) of total cells. Immunohistochemistry showed that GFP(+) CD11c(+), CD11b(+), CD11c(-), and CD11b(-) cells occupied the entire corneal stroma. CONCLUSIONS: The present study provides direct evidence of the distribution of BM-derived cells in the mouse cornea. Immunohistochemical study showed that some of these cells are BM-derived antigen-presenting cells such as dendritic cells and macrophages. Some elements of BM-derived cells may continue to exist in the corneal stroma.

Animals↗

PubMed2005

Long-term results of a multicenter randomized, comparative trial of modified CHOP versus THP-COP versus THP-COPE regimens in elderly patients with non-Hodgkin's lymphoma.

In treating elderly non-Hodgkin's lymphoma (NHL) patients, it is particularly important to use drugs that have a low incidence of adverse events and high efficacy. In this multicenter study, THP (pirarubicin)-COP (cyclophosphamide, vincristine, and prednisolone) was compared to two thirds dosage of full CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen with regard to both adverse events and efficacy. For a third group, etoposide (E) was added to the THP-COP regimen (THP-COPE) in order to achieve high dose-intensity. Subjects were 486 previously untreated patients, aged 65 or older (range, 65-92 years; median, 74 years), with NHL. Subjects were randomly assigned to receive THP-COP, two thirds CHOP, or THP-COPE. Four hundred and forty-three patients were assessed for response and followed for 8 years after the last subject registered. The complete remission rates for the THP-COP, CHOP, and THP-COPE groups were 42.5%, 41.4%, and 48.0%, respectively. There was no difference in overall survival or progression-free survival among these 3 groups. In aggressive lymphoma, there was also no difference in complete response (CR) rate (45.3% in THP-COP, 44.9% in CHOP, 48.0% in THP-COPE), overall survival, and progression-free survival among these groups. The 5- and 8-year survival rates for all patients were 29.4% and 18.7%, respectively. The 5- and 8-year survival rates for patients with aggressive lymphoma were 27.4% and 17.4%, respectively. Although long-term survival for patients with aggressive lymphoma on our regimens was not worse compared to previous reports, the CR rate was lower. Because severe adverse events were not observed, higher dose chemotherapy may be directed to achieve better CR rates. In patients with T-cell-type lymphoma, the CR rate was greater after treatment with THP-COP (51.4%) or THP-COPE (57.7%) compared to treatment with CHOP (19.4%). Pirarubicin may be more useful for T-cell lymphoma than doxorubicin. Because adverse cardiac events were reported only in CHOP, adverse cardiac events might be low in the THP group.

Aged↗

PubMed2005

A novel mutation in the juxtamembrane intracellular sequence of the granulocyte colony-stimulating factor (G-CSF) receptor gene in a patient with severe congenital neutropenia augments GCSF proliferation activity but not through the MAP kinase cascade.

We analyzed the structure of the granulocyte colony-stimulating factor (G-CSF) receptor gene in a 6-year-old female patient with severe congenital neutropenia (SCN) who experienced severe recurrent infections since 1 month of age. There is no family history of any similar disease. When the patient was 4 months old, she began receiving treatment with recombinant human G-CSF that resulted in a small increase in the neutrophil count sufficient for the prevention and treatment of bacterial infection. An analysis of complementary DNA for the patient's G-CSF receptor revealed a 3-base pair deletion in the juxtamembrane intracellular sequence. This deletion at the beginning of exon 16 was thought to be caused by alternative splicing; analysis of the DNA revealed a G-to-A point mutation of the final nucleotide of intron 15. To evaluate the functional activity of the G-CSF receptor with this 3-base pair deletion of the juxtamembrane region, we transfected this G-CSF receptor mutant into an interleukin 3-dependent cell line, BAF/3. BAF/3 cells expressing the mutant G-CSF receptor showed augmented proliferation activity in response to G-CSF compared with cells having the wild-type G-CSF receptor. Although the proliferation signal of G-CSF in normal hematopoiesis is transduced through the activation of MAP kinases, this G-CSF receptor mutant showed decreased activation of ERKI/2 in response to G-CSF compared with the wild type, but the transduced sig-nal for Stat3 activation by G-CSF was of the same magnitude as that of the wild-type G-CSF receptor. This result means that the augmented proliferation activity in response to G-CSF that we observed in cells having the G-CSF receptor gene with the 3-base pair deletion is transduced through an intracellular signaling pathway other than MAP kinase. Because SCN patients with a mutation in the G-CSF receptor frequently develop leukemia, this 3-base pair deletion in the juxtamembrane sequence of the G-CSF receptor gene in this patient may be one step in the course of leukemic transformation.

Cell Proliferation↗

PubMed2005

Influence of interferon therapy on signal-averaged and ambulatory electrocardiograms in patients with chronic active hepatitis.

Although interferon (IFN) shows cardiotoxicity and arrhythmogenesis, the influence of IFN on signal-averaged electrocardiography remains to be clarified. The aim of this study was to test a clinical hypothesis that IFN therapy for hepatitis C virus may induce ventricular late potentials (LPs) and related arrhythmias in patients with chronic active hepatitis. Signal-averaged and ambulatory electrocardiograms were recorded sequentially in patients with chronic active hepatitis C (n = 22) throughout the entire period of IFN therapy. The filtered QRS duration (fQRS) and low amplitude (< 40 microV) signal duration (LAS40) were significantly increased (95.5 +/- 8.5 to 99.6 +/- 9.4 msec, P < 0.0001, and 32.8 +/- 3.1 to 36.3 +/- 3.0 msec, P < 0.0001, respectively), whereas the root mean square voltage in the terminal 40 msec of the fQRS (RMS40) was significantly decreased (25.5 +/- 5.4 to 22.3 +/- 5.2 microV, P < 0.005) 1 month after starting the IFN therapy. The ventricular LP was negative in all subjects before starting therapy, but became positive in 7 patients after the therapy commenced. There were no differences in clinical baseline characteristics between the LP-positive (n = 7) and LP-negative (n = 15) groups. Significant increases in mean heart rate, fQRS, and LAS40 were observed after starting the therapy, irrespective of the appearance of the ventricular LP, whereas a decrease in RMS40 was observed only in the LP-positive group. No sustained ventricular arrhythmias were documented in the ambulatory electrocardiography and no cardiac events were encountered in the follow-up period. Therefore, the results indicate a reversible and subclinical risk of IFN-induced arrhythmogenesis.

Adult↗

PubMed2005

A unipolar coronary sinus mapping study of patients with left-sided atrioventricular accessory pathways.

So-called unipolar 'PQS pattern' is widely accepted as a hallmark of successful catheter ablation of the left-sided atrioventricular accessory pathway. However, the unipolar nature of the electrogram and the site-dependent appearance of this characteristic pattern are poorly understood. Therefore, unipolar coronary sinus (CS) mapping was performed using a multipolar fine electrode in patients with Wolff-Parkinson-White (WPW) syndrome associated with an antegrade left-sided accessory pathway (case group) and those with a concealed left-sided accessory pathway or atrioventricular nodal reentrant tachycardia (control group) under sinus rhythm and fixed high right atrial, CS ostial, and distal pacing. In both groups, the unipolar CS atrial electrogram showed intrinsic negative deflection (initial positive followed by negative parts) with considerable variation depending on the recording site. This unipolar configuration of the atrial electrogram was not influenced by different activation sequences during pacing at various sites. The case group exhibited a unipolar 'PQS pattern' at successful ablation sites for the left lateral to anterolateral accessory pathway. However, this was not true for the left posteroseptal accessory pathway, possibly because the negative part of the atrial electrogram distorted the 'PQS pattern' as an intervening dip. In conclusion, the site-dependent variations of the unipolar CS atrial electrogram underlie the limited usefulness of the 'PQS pattern' in left posteroseptal accessory pathway localization.

Adolescent↗

PubMed2005

Roles of Stat3 and ERK in G-CSF signaling.

G-CSF specifically stimulates the proliferation and differentiation of cells that are committed to the neutrophil-granulocyte lineage. Although Stat3 was thought to be essential for the transduction of G-CSF-induced cell proliferation and differentiation signals, mice deficient for Stat3 in hematopoietic cells show neutrocytosis and infiltration of cells into the digestive tract. The number of progenitor cells in the neutrophil lineage is not changed, and G-CSF-induced proliferation of progenitor cells and prolonged neutrophil survival were observed in Stat3-deficient mice. In hematopoietic cells from Stat3-deficient mice, trace levels of SOCS3, a negative regulator of granulopoiesis, were observed, and SOCS3 expression was not induced by G-CSF stimulation. Stat3-null bone marrow cells displayed a significant activation of extra-cellular regulated kinase 1 (ERK1)/ERK2 under basal conditions, and the activation of ERK was enhanced and sustained by G-CSF stimulation. Furthermore, the augmented proliferation of Stat3-deficient bone marrow cells in response to G-CSF was dramatically decreased by addition of a MEK1 inhibitor. These results indicate that Stat3 functions as a negative regulator of G-CSF signaling by inducing SOCS3 expression and that ERK activation is the major factor responsible for inducing the proliferation of hematopoietic cells in response to G-CSF.

Animals↗

PubMed2005

Human cord blood--derived cells generate insulin-producing cells in vivo.

Here we report the capacity of human cord blood (CB)-derived cells to generate insulin-producing cells. To investigate in vivo capacity of human CB-derived cells, T cell-depleted mononuclear cells were intravenously transplanted into nonobese diabetic/severe combined immunodeficient/beta2-microglobulinnull mice within 48 hours of birth. At 1-2 months post-transplantation, immunofluorescence staining for insulin and fluorescence in situ hybridization (FISH) analysis using a human chromosome probe indicated that human CB-derived cells generated insulin-producing cells at a frequency of 0.65%+/-0.64% in xenogeneic hosts. Reverse transcription-polymerase chain reaction analysis confirmed the transcription of human insulin in the pancreatic tissue of the recipient mice. To clarify the mechanism underlying CB-derived insulin-producing cells, double FISH analysis using species-specific probes was performed. Almost equal proportions of human chromosome+ murine chromosome- insulin+ cells and human chromosome+ murine chromosome+ insulin+ cells were present in recipient pancreatic islets. Taken together, human CB contains progenitor cells, which can generate insulin-producing cells in recipient pancreatic tissues across a xenogeneic histocompatibility barrier by fusion-dependent and -independent mechanisms.

Animals↗

PubMed2005

Cyclophosphamide-induced cardiomyopathy in a patient with seminoma and a history of mediastinal irradiation.

A 17-year-old man with mediastinal seminoma was treated with chemotherapy and mediastinal irradiation therapy. Then he received high-dose chemotherapy containing cyclophosphamide (CY) followed by autologous peripheral blood stem cell transplantation. He suffered from CY-induced cardiomyopathy beginning six days after the administration of high-dose CY. The predictable factors associated with the onset of CY-induced cardiomyopathy are not precisely known. It is suggested that the history of mediastinal irradiation was responsible for the onset of cardiomyopathy.

Adolescent↗

PubMed2005

[B cells as key contributors in determining the level of immune responses -B-cell-targeted therapy in patients with autoimmune diseases].

The levels and types of immune responses are determined dependent on the extent of pathogen invasion, reactions to antigens mediated by macrophage-dendritic cells, T cells and antibodies. Recently, accumulating evidence suggests that B cells also play an important role in the regulation of immune responses. Here we have made a review to present a role of B cells in determining the level of immune responses and discussed about the clinical significance of B cell-targeted therapy in patients with autoimmune diseases. Type 1 diabetes is a T cell-mediated autoimmune disease characterized by the destruction of insulin-producing pancreatic beta cells. We and other groups have elucidated that B cells play a critical role in the development of insulitis and diabetes, as B-cell-deficient NOD mice are protected from developing type 1 diabetes. B cells are essential for the T cell receptor clonotype spreading of islet-infiltrating T cells, indicating that B cells may play a role in determining the level of immune responses by antigen presentation to antigen specific T cells. There are now numerous case reports and small series of clinical trials regarding rituximab therapy in autoimmune diseases, such as refractory autoimmune hemolytic anemia, IgM antibody-associated polyneuropathy, systemic lupus erythematosus and rheumatoid arthritis. Rituximab is a genetically engineered chimeric anti-CD 20 monoclonal antibody that is approved for the treatment of lymphoma. CD20 is a B-cell surface antigen that is expressed only on pre- B and mature B cells. Thus, rituximab causes a selective transient depletion of the CD20+ B -cell subpopulation. Rationale and strategy for targeting B cells in the treatment of autoimmune diseases consist of the inhibition of antigen-presentation and co-stimulation that induces T cell expansion and activation. Further careful mechanistic studies are required to develop therapies in patients with autoimmune diseases.

Animals↗

PubMed2005

Synergistic interaction between oxaliplatin and SN-38 in human gastric cancer cell lines in vitro.

The interaction between CPT-11 and oxaliplatin, a new platinum derivative that has a great antitumor activity against colon cancer, has not been determined in gastric cancer cells. In this study, we investigated in vitro cytotoxic activity of oxaliplatin alone or in combination with SN-38, an active metabolite of CPT-11, using different exposure schedules in three human gastric cancer cell lines (AZ-521, MKN-45, and NUGC-4). Cytotoxicity was determined by WST-1 assay. Different treatment schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay. Cell cycle perturbation was evaluated by flow cytometry. In 24-h exposure, simultaneous administration of oxaliplatin and SN-38 showed a synergistic effect in AZ-521 and NUGC-4 cells, and an additive effect in MKN-45 cells. Greater than additive effects were observed in all of the cell lines when cells were treated with oxaliplatin followed by SN-38, whereas such effects were observed only in NUGC-4 cells in the reverse sequence. Flow cytometric analyses at IC(50) indicated that apoptosis was most prominent in simultaneous exposures with accumulation of cells in both G(0)/G(1) and S phases. These results suggest that SN-38 may kill the cells recovering from the G(1) block produced by oxaliplatin as they progress into the S phase. Simultaneous administration appears most active in gastric cancer cell lines. These results may provide important information for a clinical trial of oxaliplatin and CPT-11 combination for patients with gastric cancer.

Antineoplastic Agents↗

PubMed2005

Decreased expression of interleukin-21 receptor on peripheral B lymphocytes in systemic lupus erythematosus.

Interleukin-21 (IL-21) is the most recent member of the common gamma-chain-dependent cytokine family. We studied the expression of the IL-21 receptor (IL-21R) on peripheral B lymphocytes in patients with systemic lupus erythematosus (SLE) or primary Sjögren's syndrome (pSjS), and healthy controls. Naive B lymphocytes expressed higher levels of IL-21R than memory B lymphocytes and plasmablasts, both in SLE patients and healthy controls. The proportion of IL-21R+ cells in the total peripheral B lymphocytes, as well as those in the respective B lymphocyte subsets, was significantly lower in SLE compared with those of pSjS or healthy controls (p=0.0002 and p<0.0001, respectively, in total B lymphocytes). The decreased expression of IL-21R in SLE was significantly associated with nephritis and high titer anti-double-strand DNA antibody. In some SLE patients, IL-21-induced proliferation of CD19+ B lymphocytes, in the presence of CD40 stimulation, was impaired. The abnormalities of IL-21R signaling might contribute to the pathological features of SLE, such as B lymphocytopenia.

Adult↗

PubMed2005

[A case of metabolic syndrome with coronary artery disease advanced over 13 years. Case report].

A 61-year-old man was diagnosed with obesity, diabetes mellitus, and hyperlipidemia associated with insulin resistance in 1988. His condition was complicated with asymptomatic coronary artery disease in 1992. His coronary artery disease gradually progressed during the subsequent 13 years of observation, and he underwent percutaneous coronary intervention four times and also received a coronary artery bypass graft. This is a case of metabolic syndrome with multiple risk factors for arteriosclerosis as visceral obesity, insulin resistance, diabetes, hypertension and hyperlipidemia, in which the recent rapid progression of coronary artery disease might be associated with the discontinuation of statin after coronary artery bypass graft, accompanied with hyper-LDL-choleterolemia. Patients with metabolic syndrome require most comprehensive and strict therapies against multiple risk factors.

Coronary Disease↗

PubMed2004

Human cord blood- and bone marrow-derived CD34+ cells regenerate gastrointestinal epithelial cells.

In the present study, we aimed to clarify the capacity of human cord blood- and bone marrow-derived progenitor cells to generate gastrointestinal epithelial cells in clinical and experimental transplantation settings. First, in a clinical transplantation setting, gastrointestinal tissues derived from female pediatric or juvenile recipients of allogeneic sex-mismatched bone marrow and cord blood transplantation were examined for the presence of donor-derived epithelial cells. Gastrointestinal specimens of allogeneic recipients included Y chromosome+ cytokeratin+ epithelial cells at a frequency of 0.4-1.9%. To further determine the capacity of purified human progenitor cells, human cord blood- or bone marrow-derived CD34+ cells were transplanted into newborn NOD/SCID/beta2-microglobulin(null) mice as an experimental transplantation assay. When gastrointestinal tissues derived from recipient mice were subjected to FISH and immunofluorescence analyses, human epithelial cells were identified at a frequency of 0.24-0.58% at 3 months posttransplantation. Finally, double FISH analyses using species-specific probes revealed that human chromosome+ epithelial cells did not possess any murine chromosomes, indicating that donor-derived epithelial cells were not generated only by cell fusion. On the basis of these findings, it is concluded that purified human cord blood and bone marrow CD34+ progenitor cells can generate gastrointestinal epithelial cells across allogeneic and xenogeneic histocompatibility barriers.

Animals↗

PubMed2004

Spred-1 negatively regulates interleukin-3-mediated ERK/mitogen-activated protein (MAP) kinase activation in hematopoietic cells.

Sprouty/Spred family proteins have been identified as negative regulators of growth factor-induced ERK/mitogen-activated protein (MAP) kinase activation. However, it has not been clarified whether these proteins regulate cytokine-induced ERK activity. We found that Spred-1 is highly expressed in interleukin-3 (IL-3)-dependent hematopoietic cell lines and bone marrow-derived mast cells. To investigate the roles of Spred-1 in hematopoiesis, we expressed wild-type Spred-1 and a dominant negative form of Spred-1, DeltaC-Spred, in IL-3- and stem cell factor (SCF)-dependent cell lines as well as hematopoietic progenitor cells from mouse bone marrow by retrovirus gene transfer. In IL-3-dependent Ba/F3 cells expressing c-kit, forced expression of Spred-1 resulted in a reduced proliferation rate and ERK activation in response to not only SCF but also IL-3. In contrast, DeltaC-Spred augmented IL-3-induced cell proliferation and ERK activation. Wild-type Spred-1 inhibited colony formation of bone marrow cells in the presence of cytokines, whereas DeltaC-Spred-1 expression enhanced colony formation. Augmentation of ERK activation and proliferation in response to IL-3 was also observed in Spred-1-deficient bone marrow-derived mast cells. These data suggest that Spred-1 negatively regulates hematopoiesis by suppressing not only SCF-induced but also IL-3-induced ERK activation.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Myeloid/natural killer cell blast crisis representing an additional translocation, t(3;7)(q26;q21) in Philadelphia-positive chronic myelogenous leukemia.

We encountered a patient in blast crisis (BC) with chronic myelogenous leukemia (CML) who showed immunophenotypic features similar to those previously described in acute myeloid/natural killer (NK) cell precursor leukemia. The blasts were positive for CD7, CD33, CD34, and CD56. Cytogenetic analysis disclosed a Philadelphia chromosome (Ph) and t(3;7)(q26;q21). Molecular analysis did not detect any EVI1/CDK6 chimeric transcript generated by t(3;7)(q26;q21), but did indicate overexpression of EVI1, which occurs frequently in progression to myeloid BC in CML. Three cases of myeloid/NK cell precursor BC in CML have been reported, but this case is the first to present with Ph and EVI1 abnormality. These observations suggested that a myeloid/NK cell precursor might have been involved in the Ph-positive clone and have been a target for blastic transformation of CML, although EVI1 expression is not specific for transformation to BC from myeloid/NK lineage.

Adolescent↗

PubMed2004

Association between IFNA genotype and the risk of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by multisystem inflammation and production of autoantibodies, which can generate immune complexes and may cause tissue damage through the recognition of an autoantigen. Although many factors have been proposed, such as genetic factors, environmental factors, hormonal action, viruses, and dysregulation of cytokine production, the cause of this disease is not well understood. It has been reported that the levels of interferon (IFN)-alpha in the sera of some SLE patients are elevated and that IFN-alpha induces maturation of monocytes into highly active antigen-presenting dendritic cells (DCs). We analyzed the association between IFN-alpha genotype and the risk of SLE to clarify whether IFN-alpha plays a central role in susceptibility to SLE. The results showed that no IFN-alpha genotype was significantly associated with the risk of SLE.

Adolescent↗

PubMed2004

Tyrosine kinase 2 interacts with and phosphorylates receptor for activated C kinase-1, a WD motif-containing protein.

Receptor for activated C kinase (Rack)-1 is a protein kinase C-interacting protein, and contains a WD repeat but has no enzymatic activity. In addition to protein kinase C, Rack-1 also binds to Src, phospholipase Cgamma, and ras-GTPase-activating proteins. Thus, Rack-1 is thought to function as a scaffold protein that recruits specific signaling elements. In a cytokine signaling cascade, Rack-1 has been reported to interact with the IFN-alphabeta receptor and Stat1. In addition, we show here that Rack-1 associates with a member of Jak, tyrosine kinase 2 (Tyk2). Rack-1 interacts weakly with the kinase domain and interacts strongly with the pseudokinase domain of Tyk2. Rack-1 associates with Tyk2 via two regions, one in the N terminus and one in the middle portion (aa 138-203) of Rack-1. Jak activation causes the phosphorylation of tyrosine 194 on Rack-1. After phosphorylation, Rack-1 is translocated toward the perinuclear region. In addition to functioning as a scaffolding protein, these results raise the possibility that Rack-1 functions as a signaling molecule in cytokine signaling cascades.

Amino Acid Motifs↗