Biomedical subjects

K Shimoda

Publications and source records attributed to K Shimoda.

At least 19 recordsLinked to original sources

PubMed2006

Physical and functional interactions between Daxx and STAT3.

Signal transducer and activator of transcription 3 (STAT3) play key roles in the intracellular signaling pathways of the interleukin (IL)-6 family of cytokines, which exhibit a diverse set of cellular responses, including cell proliferation and differentiation. Dysregulated IL-6/STAT3 signaling is involved in the pathogenesis of several diseases, for example autoimmune diseases and tumors. Type I interferon (IFN) induces the expression of proapoptotic genes and has been used in the clinical treatment of several tumors. In the present study, we found that type I IFN suppressed IL-6/STAT3-mediated transcription and gene expression. Furthermore, a type I IFN-induced protein, Daxx, also suppressed STAT3-mediated transcriptional activation, while overexpression of Daxx inhibited IL-6/STAT3-mediated gene expression. Importantly, small-interfering RNA-mediated reduction of Daxx expression enhanced IL-6/leukemia inhibitory factor (LIF)-induced STAT3-dependent transcription. Co-immunoprecipitation studies revealed a physical interaction between Daxx and STAT3 in transiently transfected 293T cells. We further found that Daxx and STAT3 were co-localized in the nucleus. These results indicate that Daxx may serve as a transcriptional regulator of type I IFN-mediated suppression of the IL-6/STAT3 signaling pathway.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Usefulness of transanal endoscopic surgery for carcinoid tumor in the upper and middle rectum.

BACKGROUND: This study evaluated the indications and outcome for transanal endoscopic surgery (TES) used to manage rectal carcinoid tumor as compared with those of conventional transanal local resection (TAR). METHODS: The retrospective study subjects were 28 patients with rectal carcinoid tumor treated by TES (n = 17) or TAR (n = 11) between January 1995 and December 2001. Patient and tumor characteristics, operative results, and postoperative outcomes were compared between the two groups. RESULTS: The distance from the anal verge to the distal tumor margin in the TES group (range, 4-12 cm; median, 6.8 cm) was significantly greater than in the TAR group (range, 3-6 cm; median, 4.5 cm) (p = 0.001). The median tumor diameter was 5.5 mm (range, 3-11 mm) in the TES group and 5.0 mm (range, 3-8 mm) in the TAR group, showing no statistical difference. Microscopically, resected specimens in both groups were typical carcinoid tumors restricted to the submucosal layer. No recurrence was noted in either group. CONCLUSION: Whereas TES is useful for patients with small rectal carcinoid tumor of typical histology within the submucosal layer in the upper and middle rectum, TAR is effective for accessing the lower rectum.

Adult↗

PubMed2005

Efficient engraftment of primary adult T-cell leukemia cells in newborn NOD/SCID/beta2-microglobulin(null) mice.

Adult T-cell leukemia (ATL) develops via multiple oncogenic steps in human T-cell leukemia virus type I (HTLV-I) carriers. To better understand pathogenesis of ATL, we developed a novel xenogeneic engraftment model in which primary ATL cells are intravenously transplanted into neonatal nonobese diabetic (NOD)/severe-combined immunodeficiency (SCID)/beta2-microglobulin(null) (NOD/SCID/beta2m(null)) mice. Acute-type ATL cells engrafted in the peripheral blood and in the lymph nodes of recipients at a high efficiency. Engrafted ATL cells were dually positive for human CD4 and CD25, and displayed patterns of HTLV-I integration identical to those of donors by Southern blot analysis. These cells infiltrated into recipients' liver, and formed nodular lesions, recapitulating the clinical feature of each patient. In contrast, in smoldering-type ATL cases, multiple clones of ATL cells engrafted efficiently in NOD/SCID/beta2m(null) mice. When smoldering-type ATL cells were retransplanted into secondary NOD/SCID/beta2m(null) recipients, single HTLV-I-infected clones became predominant, suggesting that clones with dominant proliferative activity can be competitively selected in this xenogeneic system. Taken together, the NOD/SCID/beta2m(null) newborn system is useful to understand kinetics, metastasis, and disease progression of ATL in vivo.

Anemia, Refractory, with Excess of Blasts↗

PubMed2004

Significant effects of diacylglycerol on body fat and lipid metabolism in patients on hemodialysis.

AIMS: The long-term effects of dietary diacylglycerol (DAG) on body fat and lipid metabolism were studied in patients undergoing hemodialysis (HD). METHODS: Ten patients (seven males, three females) ranging in age from 40 to 64 years were enrolled. During the test period, 9.8 g of DAG was ingested per day for 3 months. RESULTS: Body mass index did not change throughout the study. The abdominal fat area measured by CT scan decreased significantly at 3 months, and increased significantly 3 months after completion of the DAG ingestion period. The serum composition of very low-density lipoprotein (VLDL) decreased significantly at 3 months and high-density lipoprotein (HDL) increased significantly at 3 months; these were determined using polyacrylamide gel electrophoresis. Serum lipoprotein (a) decreased significantly at 3 months. CONCLUSIONS: Our study showed that 3-month ingestion of DAG reduced the amount of abdominal fat and improved serum lipid profiles in free-living HD patients.

Abdomen↗

PubMed2003

Influence of transplanted dose of CD56+ cells on development of graft-versus-host disease in patients receiving G-CSF-mobilized peripheral blood progenitor cells from HLA-identical sibling donors.

We investigated effects of variations in the cellular composition of G-CSF-mobilized peripheral blood progenitor cell (G-PBPC) allografts on clinical outcomes of allogeneic PBPC transplantation. We retrospectively analyzed transplanted doses of various immunocompetent cells from 27 HLA-identical sibling donors in relation to engraftment, incidence of graft-versus-host disease (GVHD), and survival. Significant variability was documented in both absolute numbers and relative proportions of CD34+, CD2+, CD3+, CD4(high)+, CD4+25+, CD8(high)+, CD19+, CD56+, and CD56+16+ cells contained in these allografts. Stepwise Cox regression analysis revealed that the CD56+ cell dose was significantly inversely correlated with the incidence of GVHD. Thus, there was a significantly higher incidence of grade II acute GVHD in patients receiving a lower CD56+16+ cell dose (hazard ratio (HR) 0.0090; 95% confidence interval (CI), <0.00001-3.38; P=0.031), a higher incidence of chronic GVHD in those receiving allografts with a lower CD56+16+ to CD34+ ratio (HR <0.00001; 95% CI <0.00001-0.0007; P=0.0035), and a higher incidence of extensive chronic GVHD in those receiving allografts with a lower CD56+ to CD34+ ratio (HR <0.00001; 95% CI <0.00001-0.053; P=0.0083). These results suggest that CD56+ cells in G-PBPC allografts from HLA-identical sibling donors may play an important role in preventing the development of GVHD.

Adult↗

PubMed2002

Monitoring of cytomegalovirus reactivation after allogeneic stem cell transplantation: comparison of an antigenemia assay and quantitative real-time polymerase chain reaction.

Cytomegalovirus (CMV) antigenemia and quantitative real-time polymerase chain reaction (PCR) were compared for monitoring of CMV reactivation after allogeneic stem cell transplantation. The number of CMV antigen-positive cells by the antigenemia assay and the level of CMV DNA by real-time PCR correlated well. The sensitivity and specificity of the antigenemia assay was 55.4% and 95.5%, respectively, using real-time PCR as the reference standard. The probability of positive antigenemia at day 100 was 76.5%, with a median of first detection at day 37 in 51 patients, compared with a positive PCR of 84.3% and day 33, respectively. When HLA-identical sibling donor transplant recipients and other donor transplant recipients were analyzed separately, there was no difference between the two tests. However, temporal patterns of first detection of CMV antigen-positive cells and CMV DNA differed between HLA-identical and alternative recipients; patients without CMV (29%) or with sporadic positive PCR results (14%) were more common in HLA-identical sibling transplants, whereas patients with simultaneous antigenemia and positive PCR occurred more in alternative transplants (48%). Two of 51 patients (4%) developed CMV colitis despite antigenemia-guided prophylaxis, but both were successfully treated with ganciclovir. Although PCR is more sensitive than antigenemia, both tests are useful in the early detection of CMV after allogeneic stem cell transplantation.

Adolescent↗

PubMed2002

Development of rheumatoid arthritis following autologous peripheral blood stem cell transplantation.

A 51-year-old man with non-Hodgkin's lymphoma (NHL) was treated with high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT). Although he had HLA-DRB1 0405 and a positive rheumatoid factor, he was unlikely to develop rheumatoid arthritis (RA) according to diagnostic criteria. However, the patient developed RA 40 days after transplantation. Our experience suggests that the systemic autoimmune disease, RA, may occur in patients with predisposing factors after autologous PBSCT.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

GAPDH knockdown rescues mesencephalic dopaminergic neurons from MPP+ -induced apoptosis.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH; EC 1.2.1.12) has a number of diverse functions apart from glycolytic function. We explored the possible involvement of GAPDH in 1-methyl-4-phenylpyridinium (MPP+)-induced death of mesencephalic dopaminergic neurons (MDNs) in culture. MPP+ (10 and 20 microM, 24 h) exposure selectively decreased the survival of tyrosine hydroxylase positive (TH+) MDNs, which manifested apoptotic features including shrinkage of the cell body, chromatin condensation and nuclear fragmentation. Two types of GAPDH antisense oligonucleotides almost completely rescued MDNs from MPP+ toxicity. GAPDH was strongly expressed in apoptotic TH+ neurons, and MPP+ exposure significantly increased the percentage of TH+ neurons in which GAPDH is over-expressed. Confocal microscopic analysis demonstrated the nuclear accumulation of GAPDH in neurons undergoing MPP+-induced apoptosis. These results suggest that MPP+ causes apoptosis of MDNs, concomitant with the over-expression and nuclear accumulation of GAPDH.

1-Methyl-4-phenylpyridinium↗

PubMed2001

Ticlopidine-Associated thrombotic thrombocytopenic purpura with an IgG-type inhibitor to von Willebrand factor-cleaving protease activity.

A 41-year-old Japanese man complained of a left-sided visual disturbance. Imaging by magnetic resonance angiography revealed a narrowing of the left internal cervical artery. Thus, ticlopidine (Tc) administration was started at a daily dose of 300 mg. However, 2 weeks later, severe thrombocytopenia, fever, nausea, and psychiatric symptoms developed; Tc was therefore discontinued. Based on the diagnostic hallmark of 5 clinical signs, the patient's disease was diagnosed as thrombotic thrombocytopenic purpura (TTP). Daily plasmapheresis was performed for the first 4 days, and the patient's clinical signs gradually improved. Von Willebrand factor-cleaving protease (vWF-CPase) activity in his plasma was less than 3% of that of the control sample at diagnosis, but that value recovered steadily following plasmapheresis. In addition, immunoglobulin G purified from the patient plasma inhibited vWF-CPase activity in normal plasma with a specific activity of 0.8 Bethesda units/mg. No sign of TTP relapse has been noted following cessation of Tc. Thus, it was concluded that the patient developed TTP by producing an inhibitory autoantibody against vWF-CPase activity that was presumably triggered by Tc administration.

ADAM Proteins↗

PubMed2001

Effect of periodic endoscopy for gastric cancer on early detection and improvement of survival.

BACKGROUND: Increases in the detection of early gastric cancer have indisputably, improved long-term survival. The aim of this study was to establish the value of periodic gastric endoscopy and the appropriate intervals for its performance. METHODS: We compared, retrospectively, the clinicopathologic characteristics and outcomes of two groups of patients who had undergone surgical treatment for gastric cancer. Of a total of 361 patients, 106 had undergone endoscopic examination within 2 years before the detection of gastric cancer (group 1), and 255 had either undergone no endoscopic examination or had had endoscopic examination more than 2 years before the detection of gastric cancer (group 2). For the evaluation of survival rate, the patients in each group were classified into two subgroups: group 1a, endoscopic examination within 1 year before detection; group 1b, endoscopic examination more than 1 year and within 2 years; group 2a, endoscopic examination more than 2 years and within 4 years before detection; and group 2b, endoscopic examination more than 4 years before detection, or no endoscopic examination. RESULTS: Gastric cancer in group 1 was characterized by small tumor size, no tumor invasion beyond the submucosa, few instances of lymphatic and vascular permeation, and few lymph node metastases. The 5-year survival rate for group 1 patients (96.5%) was significantly higher than that for group 2 patients (71.0%; P < 0.01). The survival rates for group 1a patients and group 1b patients were not significantly different (P = 0.4595). The survival rate for patients in group 2a was significantly lower than that for those in group 1a (P < 0.05). CONCLUSION: Periodic gastric endoscopy enables early detection of cancer, thereby improving survival. The optimal interval for periodic examination appears to be 2 years.

Aged↗

PubMed2001

Phototoxic retinal degeneration and toxicokinetics of sitafloxacin, a quinolone antibacterial agent, in mice.

We examined drug concentrations and the incidence of retinal degeneration in the eyes of albino BALB/c mice after a single intravenous administration of sitafloxacin plus a 4 h period of UVA irradiation. Retinal degeneration was induced at 40 mg/kg or more plus UVA irradiation, and there was little decrease in ocular sitafloxacin concentration under UVA irradiation. We then examined the incidence of retinal degeneration with various periods of UVA irradiation in BALB/c mice given a single intravenous administration of 40 mg/kg sitafloxacin. Retinal degeneration occurred in all the groups receiving UVA irradiation immediately after sitafloxacin administration, whereas no retinal degeneration occurred in the groups receiving UVA irradiation starting 30 min or later after administration. In addition, we examined both the retinal degeneration and auricular inflammation in BALB/c mice given a 7-day repeated administration of sitafloxacin at 1, 3.3 and 10 mg/kg per day, which never induce retinal or auricular change by a single administration. Retinal degeneration was not induced at any dose level, although auricular skin inflammation was augmented by repeated administration. These results suggest that the occurrence of retinal degeneration depends on maximum ocular sitafloxacin concentration during UVA irradiation, whereas the severity of auricular inflammation is directly proportional to the total decrease in area under the drug concentration curve for auricular sitafloxacin under UVA irradiation. This difference between retinal degeneration and auricular inflammation may derive from their respective mechanisms of pathogenesis.

Animals↗

PubMed2001

Immunosuppressive therapy for patients with refractory anemia.

Trials of immunosuppressive therapy have been reported in some case reports of hypoplastic myelodysplastic syndrome (MDS). In this study, we gave immunosuppressive therapies to eight patients with normo- or hyperplastic MDS of refractory anemia subtype without karyotypic abnormalities and analyzed the HLA-DRB1 type or the presence of paroxysmal nocturnal hemoglobinuria (PNH) neutrophils in these patients. Cyclosporin A (CyA) therapy was effective for improving cytopenia in four of the eight MDS patients. While the side effects of CyA were mostly mild and transient, one patient demonstrated karyotypic abnormality following CyA therapy and accelerated to refractory anemia with an excess of blasts. Additional antithymocyte globulin (ATG) therapy was effective in one of three nonresponders to CyA therapy. One patient died due to leukemic transformation after ATG therapy. When we analyzed the correlation between the response to CyA therapy and the HLA-DRB1 type, there were more responders with DRB1*1501 (three of four patients) than without (one of four patients), but a statistically significant difference was not evident between the two groups. In addition, the presence of PNH neutrophils was not correlated with the response to CyA and/or ATG therapy. These results indicate the usefulness of immunosuppressive therapies even for normo- or hyperplastic MDS patients. Further trials using more patients with a long follow-up period would be worthwhile in order to clarify the possibility of disease progression and in order to predict the response of patients.

Adult↗

PubMed2001

Frequent presence of HBV in the sera of HBsAg-negative, anti-HBc-positive blood donors.

BACKGROUND: Recent studies have revealed that HBV may not be cleared even after the disappearance of serum HBsAg. The purpose of this study was to investigate whether the replication of HBV persists in HBsAg-negative blood donors who lack apparent liver disease. STUDY DESIGN AND METHODS: Serum HBV was examined by using PCR coupled with Southern blotting in 50 blood donors who were identified to be HBsAg negative but anti-HBc positive. RESULTS: HBV DNA was detected in the sera from 19 (38%) of 50 donors. In 11 of the 19, HBV existed exclusively as immune complexes, while HBV presumably did not exist as immune complexes in the remaining eight. The levels of HBV DNA were similar to those in patients who had recovered from acute HBV. Some nucleotide substitutions, which did not confer amino acid changes in the major epitope of HBsAg, were found in the preS-S regions. CONCLUSION: The replication of HBV is ongoing in a substantial proportion of healthy blood donors who have anti-HBc. Blood from such donors may contain very low levels of HBV free of immune complex formation and should be excluded for transfusion. The fact that such blood donors apparently lacked liver disease suggests no pathogenicity of such "occult" HBV.

Adult↗

PubMed2001

The effect of CYP2C19 and CYP2D6 genotypes on the metabolism of clomipramine in Japanese psychiatric patients.

In this study, the authors investigated the relationship between the metabolism of clomipramine (C) and the genotypes of cytochrome P450 (CYP) CYP2C19 and CYP2D6. Fifty-one Japanese patients (18 men and 33 women) were administered 10 to 250 mg/day of C by mouth and maintained on the same daily dose of C for at least 2 weeks to obtain steady-state concentrations. Plasma levels of C and its metabolites N-desmethylclomipramine (DC), 8-hydroxyclomipramine, and 8-hydroxy-N-desmethylclomipramine (HDC) were determined by high-performance liquid chromatography. The allele frequencies of CYP2C19*2, CYP2C19*3, CYP2D6*5, and CYP2D6*10 were 27.5%, 12.8%, 2.9%, and 43.1%, respectively. Subjects who were homozygous for mutated alleles of CYP2C19 showed approximately 75% higher concentrations of C corrected by dose and body weight compared with those who were homozygous for wild-type alleles. Also, subjects who were homozygous for mutated alleles of CYP2C19 showed an approximately 68% higher value of C/DC compared with those who were homozygous for wild-type alleles. No significant difference in the ratio of DC/HDC was observed between subjects who were homozygous for mutated alleles of CYP2D6 and those who were homozygous for wild-type alleles. These results suggest that genotyping CYP2C19 is useful for grossly predicting the risk of getting high plasma concentrations of C and the low individual capacity to demethylate C because there is marked interindividual variability within each genotype. However, the genotyping of CYP2D6 is not useful for predicting the individual capacity to hydroxylate DC.

Adolescent↗

PubMed2001

Establishment of enzyme immunoassay for measuring serum sultopride levels.

Measurement of serum sultopride levels was performed using an enzyme immunoassay. Little or no cross-reactivity with metabolites of sultopride and other drugs was found. The results of reproducibility, recovery, and dilution testing were all good enough for clinical use. A comparison between the measurement values of this method (y) with that of high-performance liquid chromatography (x) showed high correlation (n = 211, r = 0.991, p < 0.0001, y = 0.99x + 107.5). In a comparison between the sultopride dose and serum levels in 161 patients, interindividual differences were large (19 times for same doses), implying that the serum level cannot be predicted from the dosage. The method was found to be reliable for serum level measurements of sultopride and useful for monitoring compliance and assessing the optimal dose.

Adult↗

PubMed2001

Importance of the cytochrome P450 2D6 genotype for the drug metabolic interaction between chlorpromazine and haloperidol.

The authors studied the interactive effects of the coadministration of haloperidol and chlorpromazine on plasma concentrations of haloperidol and reduced haloperidol. The subjects were 43 Japanese male schizophrenic inpatients who were concomitantly treated with chlorpromazine before or after monotherapy with haloperidol. Coadministration of chlorpromazine produced significant increases in the plasma concentrations of haloperidol (P < 0.01) and reduced haloperidol (P < 0.001) by an average of 28.5% +/- 83.3% and 160.8% +/- 288.9%, respectively. However, there were marked interindividual variations in the interactive effects of chlorpromazine. The authors analyzed the importance of five CYP2D6 genotypes, *1/ *1, *1/ *10, *10/ *10, *1/*5, and *5/*10 on the percentage of change in plasma concentrations of haloperidol and reduced haloperidol. Patients with the CYP2D6*5 allele (n = 4) showed a significantly smaller increase in plasma concentrations of haloperidol (P < 0.05) and a slightly smaller increase in those of reduced haloperidol (P = 0.074) in response to the coadministration of chlorpromazine compared than those with the CYP2D6*1/*1 genotype (n = 8). Those with the CYP2D6*1/*1 genotype (n = 8) showed a trend toward greater increases in plasma concentrations of haloperidol than those with other genotypes (P = 0.087).

Adult↗

PubMed2001

Light induced apoptosis is accelerated in transgenic retina overexpressing human EAT/mcl-1, an anti-apoptotic bcl-2 related gene.

BACKGROUND/AIM: EAT/mcl-1 (EAT), an immediate early gene, functions in a similar way to bcl-2 in neutralising Bax mediated cytotoxicity, suggesting that EAT is a blocker of cell death. The aim of this study was to determine the effect of overexpression of the human EAT gene on light induced retinal cell apoptosis. METHODS: EAT transgenic mice incorporating the EF-1alpha promoter were utilised, and expression of human EAT was detected by RT-PCR. Light damage was induced by raising mice under constant illumination. Two groups of animals, EAT transgenic mice (n=14) and littermates (n=13), were examined by ERG testing and histopathology at regular time points up to 20 weeks of constant light stimulation. Electrophysiological and histopathological findings were evaluated by established systems of arbitrary scoring as scores 0-2 and scores 0-3, respectively. RESULTS: The mean score (SD) of ERG response was significantly lower in EAT transgenic mice (0.79 (0.89)) than in littermates (1.69 (0.48)) (p<0.01). Although the differences between the two survival curves did not reach statistical significance (p=0.1156), the estimated incidence of electrophysiological retinal damage was higher in EAT mice (0.0495/mouse/week; 95% confidence interval (CI) 0.0347-0.0500) than in littermates (0. 0199/mouse/week; 95% CI 0.0035-0.0364). The mean scores (SD) for histopathological retinal degeneration were 2.31 (0.63) in littermates and 1.43 (1.22) in EAT transgenic mice (p=0.065). However, Kaplan-Meier curves for histopathological failure in two groups of mice showed that retinal photoreceptor cells were preserved significantly against constant light in the littermate compared with transgenic mice (p=0.0241). The estimated incidence of histopathological retinal damage was 0.0042/mouse/week in the littermates (95% CI 0-0.0120) and 0.0419/mouse/week in the EAT mice (95% CI 0.0286-0.0500). CONCLUSION: Retinal photoreceptor cell apoptosis under constant light stimulation is likely to be accelerated in transgenic retina overexpressing EAT.

Animals↗

PubMed2000

Involvement of EAT/mcl-1, an anti-apoptotic bcl-2-related gene, in murine embryogenesis and human development.

Apoptosis plays an important regulatory role in mammalian embryogenesis and development. EAT/mcl-1 (EAT), an anti-apoptotic bcl-2-related gene, was isolated during the early differentiation of a human embryonal carcinoma cell line, an event which serves as a model of early embryogenesis. EAT is involved in apoptotic regulation and is believed to also function as an immediate-early gene. Thus it was hypothesized that EAT would be expressed during early embryogenesis and would be involved in the regulation of apoptosis during this critical period. To clarify this early expression, two antibodies to EAT were generated by use of immunizing oligopeptide (aa 37-55) and recombinant protein (aa 31-229) for use in immunohistochemistry and immunoblotting, respectively. With these antibodies, we then determined EAT expression during murine embryogenesis and in human development, using human fetal tissue of 6 to 23 gestational weeks. During murine embryogenesis, the EAT protein was found to be rapidly induced after fertilization, to peak at the 2-cell stage, to remain constant until the 8-cell stage, and then to decrease to below unfertilized egg levels in blastocysts. EAT expression patterns in early human development were found to essentially overlap those observed in adult tissues which suggest that EAT expression continues until adulthood in terminally differentiated tissues. Among tissues distinct to fetal development, EAT was detected in the mesonephric (Wolffian) duct and paramesonephric (Müllerian) duct. It is also noteworthy that prominent EAT immunoreactivity was also observed in large primary oocytes in 21-week fetal ovary, but was not detected in primordial germ cells in 23-week fetal testis. In summary, EAT expression was detected in hematopoietic, epithelial, neural, endocrine, and urogenital cells; this provides evidence that EAT, as an anti-apoptotic molecule, possibly functions to regulate apoptosis during development in these systems.

Amino Acid Sequence↗