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Biomedical subjects

K Itoh

Publications and source records attributed to K Itoh.

At least 145 records · Page 8Linked to original sources
PubMed2001

Strong association of a tumor necrosis factor-alpha promoter allele with cerebral malaria in Myanmar.

To investigate the host genetic factors affecting the clinical course of falciparum malaria, polymorphism of the tumor necrosis factor-alpha (TNF-alpha) promoter region was analyzed in patients with cerebral malaria. Two hundred and forty-three Myanmar patients with falciparum malaria at Mae Sot Malaria clinic and Mae Sot General Hospital located at the border between Thailand and Myanmar, were included in this study. Among the patients (128 from Karen, 115 from Burma), 200 were uncomplicated and 43 had cerebral malaria. The TNF-alpha 5'- flanking region showed biallelic polymorphic sites at -238, -308, -857, -863, -1031, and there were 7 alleles (TNFP-A, B, C, D, M1, M4, M7) found in the patients from Myanmar. We found that the TNFP-D allele was significantly associated with cerebral malaria in the populations from Karen (Pc<0.0001, OR=124.86) and Burma (Pc<0.0001, OR=34.50). TNFP-D showed no significant linkage disequilibrium with any alleles of HLA-B or HLA-DRB1, suggesting that TNFP-D was primarily associated with cerebral malaria in Myanmar.

Gene Frequency↗
PubMed2001

Human brain carboxypeptidase B, which cleaves beta-amyloid peptides in vitro, is expressed in the endoplasmic reticulum of neurons.

Intracellular localization of novel human brain carboxypeptidase B (HBCPB) was investigated in human hippocampus, using immunohistochemistry by confocal laser microscopy and biochemical purification of the homogenate by density gradient ultracentrifugation. The former revealed that the majority of HBCPB was expressed in the endoplasmic reticulum, in which the HBCPB-specific C14-module immunoreactivity was colocalized with GRP78 immunoreactivity, a stress 70 heat shock protein specifically expressed in the endoplasmic reticulum. The latter showed that anti-C14-module immunoreactivity and prepro-HBCPB immunoreactivity were both enriched in the microsome fraction, especially in that of the endoplasmic reticulum-density fraction of normal human hippocampal homogenates from various sources. However, HBCPB prepared from human hippocampus showed exopeptidase activity for synthetic beta-amyloid 1-42 peptide, in which Abeta X-42 C-terminus immunoreactivity was decreased in a fashion dose-dependent of the amount of the protease added. These findings indicate that HBCPB, which is expressed in the endoplasmic reticulum of a group of neuronal perikarya, may play an important physiological role in degradation of beta-amyloid 1-42, which is specifically generated in the endoplasmic reticulum of human and rodent neurons and is also regarded as the most pathogenic and aggregatable species among all beta-amyloid peptides.

Alzheimer Disease↗
PubMed2001

Involvement of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in the pathogenesis of granulomatous colitis in rats.

Although increased expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) has been demonstrated in inflammatory sites of various diseases, its role in colitis remains unknown. In this study, we examined whether MAdCAM-1 is involved in the pathogenesis of granulomatous colitis induced by peptidoglycan-polysaccharide (PG-PS). Experimental colitis was induced by intramural injection of PG-PS to rat colon. After 3 weeks the colon was removed and the mucosal inflammation was assessed. The area of MAdCAM-1-positive venules and the subsets of infiltrating cells were determined in colonic mucosa by immunohistochemistry. In another experiment, monoclonal antibody against MAdCAM-1 was administered intraperitoneally to examine its attenuating effect on colitis. The intramural injection of PG-PS induced significant colonic inflammation with granuloma formation. The submucosa was drastically thickened with the infiltration of CD4 positive lymphocytes and ED-1 positive macrophages. Intense MAdCAM-1 expression was observed on endothelium of the submucosal venules in inflamed mucosa. Administration of anti-MAdCAM-1 antibody significantly attenuated the PG-PS-induced colonic damage and cell infiltration. Enhanced expression of MAdCAM-1 was demonstrated in venular endothelium of the inflamed colon in PG-PS-induced colitis. The attenuating effect of anti-MAdCAM-1 suggests the importance of the MAdCAM-1-dependent process in the formation of chronic granulomatous colitis.

Animals↗
PubMed2001

Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription.

BACKGROUND: Nrf2 belongs to the Cap-N-Collar (CNC) transcription factor family and is essential for the antioxidant responsive element (ARE)-mediated expression of a group of detoxifying and antioxidant genes. The forced expression of Nrf2 in mammalian cells activates the expression of target genes through the ARE, with Nrf2 showing the highest transactivation activity among the CNC family of transcription factors. To elucidate the molecular mechanisms generating this potent transactivation activity, we examined the functions of the domains within Nrf2. RESULT: We found that Nrf2 contains two transcription activation domains, Neh4 and Neh5, which act synergistically to attain maximum a activation of reporter gene expression. Neh4 and Neh5 both individually and cooperatively bind to CBP (CREB (cAMP Responsive Element Binding protein) Binding Protein). In fact, the specific inhibitor of CBP, adenovirus E1A protein, significantly reduced Nrf2 activity. Importantly, the CBP-binding activity of Nrf2 deletion mutants positively correlated with their transactivation activity. Neh5 contains a motif which is commonly conserved among the CNC factors, whereas Neh4 contains the novel CBP-interacting motif recently identified in p53 and E2F. CONCLUSIONS: Our results indicate that Nrf2 exploits the cooperative binding of two independent transactivation domains to CBP in the acquisition of a potent transactivation activity.

Amino Acid Sequence↗
PubMed2001

B-cell precursors differentiated from cord blood CD34+ cells are more immature than those derived from granulocyte colony-stimulating factor-mobilized peripheral blood CD34+ cells.

Umbilical cord blood (CB) has been widely used instead of bone marrow (BM) and peripheral blood (PB) for stem cell transplantation (SCT). However, problems of sustained immunodeficiency after CB transplantation remain to be resolved. To elucidate the mechanism of immunodeficiency, we compared the characteristics of B cells differentiated in vitro from CD34+ cells of CB with those of PB. Purified CD34+ cells from CB and PB were cultured on murine stroma cell-line MS-5 with stem cell factor and granulocyte colony-stimulating factor for 6 weeks. The B-cell precursors (pre-B cells) that differentiated in this culture system, were analysed as to their immunoglobulin heavy chain (IgH) variable region gene repertoire and the expression of B-cell differentiation-related genes. CD10+ CD19+ pre-B cells were differentiated from both PB and CB. Although the usages of IgH gene segments in pre-B cells differentiated from CB and PB were similar, the N region was significantly shorter in CB-derived than PB-derived cells. Productive rearrangements were significantly fewer in cells of CB than PB in the third week. Among a number of B-cell differentiation-related genes, the terminal deoxynucleotidyl transferase (TdT) gene was not expressed in CB-derived cells during the culture. These results indicated that immature features of pre-B cells from CB, such as lack of TdT expression, and a short N region and few productive rearrangements in the IgH gene, might cause the delay in mature B-cell production.

Animals↗
PubMed2001

Adverse effect of dentine bonding agent on the oral mucosa of guinea pigs.

The purpose of present study was to determine the possibility of nebulous discoloration of the oral mucosa of guinea pigs as a result of the application of dentine bonding agents. The materials used were the Clearfil Photo Bond (CPB) system's mixture agent, universal agent and catalyst agent. Four types of experimental catalysts were used. In male albino guinea pigs weighing 300-500 g, oral mucosa irritation tests were performed in accordance with the guidelines of the Cosmetic, Toiletry and Fragrance Association (CTFA). Macroscopical findings on the oral mucosa showed that there was strong nebulous discoloration immediately after application of CPB mix and CPB catalyst and throughout the experimental periods. However, CPB without 10-methacryloxdecyl dihydrogen phosphate (MDP) did not produce noticeable nebulous discoloration and inflammation. The CPB mix caused pathological changes, such as paraketosis and hyperkeratosis on the endepidermis of the mucosa, immediately after its application.

Animals↗
PubMed2001

Expression of bone morphogenetic proteins in colon carcinoma with heterotopic ossification.

Here we report the case of a 50-year-old woman with adenocarcinoma of the colon, showing heterotopic ossification. The patient was referred to our hospital for investigation of anemia secondary to occult gastrointestinal blood loss. By colonoscopy, an irregular polypoid mass was found in the ascending colon. A biopsy of the lesion revealed moderately to poorly differentiated adenocarcinoma with heterotopic ossification. A right hemicolectomy was done and revealed areas of heterotopic bone within the tumor, but no ossification was evident in the metastatic lesions within the mesenteric lymph nodes. The formation of heterotopic bone in gastrointestinal tumors is rare and its exact mechanism is unknown. Immunohistochemical localization of bone morphogenetic proteins (BMP), known to be primary inducers of new bone formation, was determined. BMP-5 and -6 were prominent in the cytoplasm of tumor cells, and they stained weakly in osteoblast-like cells adjacent to newly formed bone. Cytoplasmic staining for BMP-2 and -4 was weak in tumor cells, osteoblast-like cells, and stromal fibroblast cells. BMP may play an important role in heterotopic ossification in colon adenocarcinoma.

Adenocarcinoma↗
PubMed2001

Changes in cellular immunity during chemotherapy for testicular cancer.

BACKGROUND: The changes in vivo in immunocyte functions during chemotherapy that is administered in combination with granulocyte colony-stimulating factor (G-CSF) in humans have not been fully investigated. This study was designed to examine neutrophil functions and the activities of natural killer (NK) cells, during the administration of chemotherapy and G-CSF for the treatment of testicular cancer. METHODS: Seven patients with germ cell tumors at stage IIA, IIB or IIIB, who were treated with bleomycin, etoposide and cisplatin (BEP), were enrolled in the study. Numbers and activities of neutrophils and NK cells were measured at various times during and after the first course of chemotherapy. Neutrophil phagocytosis was quantitated by flow cytometry with fluorescent latex beads. Bactericidal activity was measured in terms of colony-forming units. The activity of NK cells was measured by monitoring the release of 51Cr. RESULTS: After BEP chemotherapy, CD16+ and CD56+ cell counts, and neutrophil granulocyte counts decreased while there were no significant changes in the number of lymphocytes. Phagocytosis by neutrophils was enhanced after administration of G-CSF. The activity of NK cells was severely impaired after chemotherapy and did not change after administration of G-CSF. CONCLUSIONS: After BEP chemotherapy for testicular cancer with G-CSF, neutrophil function was not at all inferior to those before treatment. Natural killer cell activity was suppressed by the BEP chemotherapy and did not change after administration of G-CSF.

Adult↗
PubMed2001

Nrf2-deficient female mice develop lupus-like autoimmune nephritis.

BACKGROUND: NF-E2-related factor 2 (Nrf2) is a basic leucine zipper transcriptional activator essential for the coordinate transcriptional induction of antioxidant enzymes and phase II drug metabolizing enzymes through the antioxidant response element/electrophile response element. The Nrf2-deficient mice were found to develop normally under standard laboratory conditions. However, upon closer examination, we found that aged female Nrf2-deficient mice displayed a shortened lifespan and developed severe glomerulonephritis. The present study investigated the glomerulonephritis findings in Nrf2-deficient mice. METHODS: To evaluate glomerular lesions of Nrf2-deficient mice, histological and functional analyses were performed. The amounts of serum immunoglobulins, anti-double-stranded (ds) DNA antibody, and lipid peroxidation using thiobarbituric acid reactive substances (TBARS) also were measured. RESULTS: Nrf2-deficient female mice over 60 weeks of age developed severe nephritis characterized by cellular proliferation, lobular formation, crescent formation, and subepithelial electron-dense deposits. In immunofluorescent assays, Nrf2-deficient female mice showed mesangial deposits and massive granular deposits of IgG, IgM, and C3 along the capillary walls. Higher serum levels of IgG, anti-dsDNA antibody, lower creatinine clearance, and slight splenomegaly also were found in Nrf2-deficient female mice. A higher concentration of TBARS also was found in Nrf2-deficient female mice. CONCLUSIONS: These data indicate that the aged Nrf2-deficient female mice develop lupus-like autoimmune nephritis and suggest that nrf2 is one of the genes determining susceptibility to autoimmune disease. Analysis of nephritis in the Nrf2-deficient female mouse may clarify the mechanisms leading to the development of lupus disease.

Animals↗
PubMed2001

Analysis of methicillin-resistant Staphylococcus aureus isolates by proton magnetic resonance spectroscopy.

OBJECTIVES: To evaluate the stability and(1)H nuclear magnetic resonance ((1)H NMR) differences among bacterial strains, we analysed(1)H NMR spectra for 50 methicillin-resistant Staphylococcus aureus (MRSA) isolates from 42 patients. METHODS: (1)H NMR spectra for 50 MRSA isolates were obtained at 30 degrees C using a JNM-GX 270 NMR spectrometer at a field strength of 6.34 Tesla (270 MHz for(1)H). DNA fingerprints were obtained by pulsed-field gel electrophoresis (PFGE). RESULTS: Each strain had eight to nine specific resonance features in the 0.5-4.5 ppm spectral region. These features were found in all strains, but the intensity of each feature varied between strains. Six resonance features (A-F) were selected for investigation. The relative integrated intensity (mean+/-SD, normalized to feature C = 1) of each feature was: feature A, 0.49+/-0.16; feature B, 3.93+/-0.81; feature D, 0.38+/-0.22; feature E, 1.51+/-0.96; feature F, 2.18+/-0.47. Within-strain reproducibility of feature intensities for A, B, D and F was good (coefficient of variation < 10%) for replicate cultures, analyzed on separate days. Feature E showed poor within-strain reproducibility. Storage at 4 degrees C for 4 months or disintegration of the micro-organisms by ultrasound did not alter(1)H NMR spectra. Two isolates from different patients, but the same hospital, showed indistinguishable NMR spectra, and were also indistinguishable in PFGE. Five strains with distinct PFGE patterns showed differences in NMR spectra outside the range of within-strain variation. CONCLUSIONS: It is possible to analyse the whole molecular structure of MRSA by(1)H NMR. With this technique, we established that there are detectable, reproducible differences in quantitative cell composition between MRSA strains.(1)H NMR spectroscopy appears to have potential as a useful tool for epidemiological typing of bacteria.

DNA Fingerprinting↗
PubMed2001

Anxiety and pain suppress the natural killer cell activity in oral surgery outpatients.

OBJECTIVE: Psychological stress has an influence on natural killer cell (NK) activity, which plays a central role in protection against microbial infection and cancer. Anxiety concerning cancer is a typical type of psychological stress observed in patients and is associated with various diseases. In this study, we examined whether anxiety about cancer reduces the NK activity or quality of life (QOL), or both, of outpatients. PATIENTS AND METHODS: NK activity was determined by means of a 4-hour 51 chromium-release assay, and a QOL questionnaire by the World Health Organization called QOL-BRIEF was also used. One hundred forty-four patients were asked a variety of questions about anxiety with respect to cancer and pain on their first visit to the outpatient clinic of our Department of Oral Surgery. RESULTS: The NK activity in patients with anxiety about cancer was significantly lower (P < .001) than that in those with no such anxiety. In contrast, NK activity was not influenced by any other factor tested, including differences in diseases and QOL scores. CONCLUSION: Anxiety about cancer may be one of the primary factors for suppression of NK activity in oral surgery outpatients.

Adult↗
PubMed2001

Identification of the HLA-A24 peptide epitope within cytomegalovirus protein pp65 recognized by CMV-specific cytotoxic T lymphocytes.

Among cytomegalovirus (CMV) tegument proteins, phosphoprotein 65 (pp65) has been identified as the important target antigen of the cytotoxic T lymphocyte (CTL) response against the virus. We synthesized seven CMV-pp65-derived peptides carrying an HLA-A24-binding motif, and investigated the ability of these peptides to induce CMV-specific CTL. We identified one nonamer peptide (pp65113-121; VYALPLKML) able to bind HLA-A24 and induce CTL responses in vitro in peripheral blood mononuclear cells (PBMC) from CMV-seropositive individuals. The peptide-specific CTLs generated were capable of recognizing pp65 expressed on CMV-infected fibroblasts as well as pp65113-121 peptide bound to the surface of C1R-A*2402 cells in an HLA-A24-restricted manner. The pp65113-121 peptide thus might be considered a synthetic peptide vaccine in HLA-A24-positive individuals.

Antigens, Viral↗
PubMed2001

Clinical effect of irinotecan in advanced and metastatic breast cancer patients previously treated with doxorubicin- and docetaxel-containing regimens.

BACKGROUND: Previous phase II trials in Japan suggested that irinotecan was a promising agent for advanced or metastatic breast cancer pretreated with anthracycline. However, irinotecan has not yet been evaluated in the salvage setting for breast cancer pretreated with both anthracycline and taxane, which are two active agents for breast cancer. METHODS: The efficacy and safety of irinotecan were retrospectively evaluated in patients with breast cancer who had previously been treated with both doxorubicin and docetaxel. From 1996 to 1999, irinotecan was administered to 20 patients, all with a performance status of <2. Irinotecan treatment was repeated in approximately 6 week cycles consisting of the administration of irinotecan once weekly for 4 weeks followed by a 2 week rest. The median dose of irinotecan administered was 100 mg/m(2) weekly. The median number of irinotecan cycles given was 1 (range: 1-8 cycles). The median total dose was 388 mg/m(2) (range: 50-2400 mg/m(2)). RESULTS: Performance status declined to >3 after treatment with irinotecan in four patients. Two patients had grade 3 leukopenia; three had grade 3 anemia and one had a creatinine elevation of grade 4. The objective response rate for all patients was 5.0% (95% CI: 0-15.5%). The median time to progression and overall survival were 35 days (range: 17-285 days) and 124 days (range: 17-667 days), respectively, since the start of the administration of irinotecan. CONCLUSIONS: Salvage chemotherapy with irinotecan may be inactive against advanced and metastatic breast cancer pretreated with doxorubicin and docetaxel. We will evaluate irinotecan for advanced and metastatic breast cancer patients as first- or second-line chemotherapy combined with anthracycline or taxane.

Adult↗
PubMed2001

Increased expression of queuosine synthesizing enzyme, tRNA-guanine transglycosylase, and queuosine levels in tRNA of leukemic cells.

Queuosine is a modified nucleoside located at the first position of the tRNA anticodon, which is synthesized by tRNA-guanine transglycosylase (TGT). Although the levels of queuosine in cancer cells have been reported to be lower than those in normal cells, the expression levels of TGT remain to be determined. We determined the expression levels of a subunit of TGT (TGT60KD). Contrary of our expectations, the results revealed higher levels of expression of TGT60KD than that in normal cells, and the level of queuosine in the tRNA fraction corresponded with that of TGT60KD expression. These results suggest the possibilities that the expression levels of TGT60KD regulate TGT activity and the levels of queuosine, and that TGT60KD plays significant roles in carcinogenesis. To our knowledge, this is a first report of increased expression levels of TGT60KD in human cancer cells.

Humans↗
PubMed2001

High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes.

Nrf2, which belongs to the basic leucine zipper (bZip) transcription factor family, has been implicated as a key molecule involved in antioxidant-responsive element (ARE)-mediated gene expression. In order to examine the role of Nrf2 in protection against xenobiotic toxicity, the sensitivity of nrf2 knockout mice to acetaminophen (N-acetyl-4-aminophenol (APAP)) was analyzed. The saturation of detoxification pathways after high levels of exposure to APAP is known to induce hepatotoxicity. Two factors important in its detoxification are UDP-glucuronosyltransferase (UDP-GT), an ARE-regulated phase-II drug-metabolizing enzyme, and glutathione (GSH), an antioxidant molecule whose synthesis depends on ARE-regulated gamma-glutamylcysteine synthetase (gammaGCS). Two- to 4-month-old male mice were orally administered a single dose of APAP at 0, 150, 300, or 600 mg/kg. Doses of 300 mg/kg APAP or greater caused death in the homozygous knockout mice only, and those that survived showed a greater severity in hepatic damage than the wild-type mice, as demonstrated by increased plasma alanine aminotransferase activity, decreased hepatic non-protein sulfhydryl (NPSH) content, and centrilobular hepatocellular necrosis. The high sensitivity of Nrf2-deficient mice was confirmed from observations made at 0, 2, 8, and 24 h after dosing with 300 mg/kg APAP; increased anti-APAP immunoreactivity was also noted in their livers at 2 h. Untreated homozygous knockout mice showed both a lower UDP-GT activity and NPSH content, which corresponded to decreased mRNA levels of UDP-GT (Ugt1a6) and the heavy chain of gammaGCS, respectively. These results show that Nrf2 plays a protective role against APAP hepatotoxicity by regulating both drug metabolizing enzymes and antioxidant genes through the ARE.

Acetaminophen↗
PubMed2001

Pancreaticobiliary arteriovenous malformation with common bile duct dilation in a patient with hemobilia.

Arteriovenous malformation of the pancreas is a very rare entity. We describe a case involving the head of the pancreas associated with progressive hemobilia bleeding from the lower part of the common bile duct. The patient was a 50-year-old man with acute epigastralgia. Endoscopic retrograde cholangiopancreatography revealed hemobilia and cystic dilation of the common bile duct. Angiography demonstrated increased blood volume in the head of the pancreas and early filling of the superior mesenteric and portal veins. Abdominal pain and progressive anemia caused by hemobilia required surgical treatment. Histologic examination of the resected specimen revealed marked proliferation of the blood vessels in the pericholedochal area and the exact point of bleeding from the pancreaticobiliary arteriovenous malformation.

Angiography↗
PubMed2001

Phase I study of intravenous PSC-833 and doxorubicin: reversal of multidrug resistance.

PSC-833 reverses multidrug resistance by P-glycoprotein at concentrations < or = 1000 ng / ml. A phase I study of PSC-833 and doxorubicin was conducted to determine the maximum tolerated dose and to investigate pharmacokinetics. PSC-833 was intravenously infused as a 2-h loading dose (LD) and a subsequent 24-h continuous dose (CD). Doxorubicin was infused over 5 min, 1 h after the LD. The starting dose was 1 mg / kg for both LD and CD with 30 mg / m(2) doxorubicin; these dosages were increased to 2 and 10 mg / kg and 50 mg / m(2), respectively. Thirty-one patients were treated. Nausea / vomiting was controllable with granisetron and dexamethasone. Neutropenia and ataxia were dose limiting. Steady-state concentrations of PSC-833 > 1000 ng / ml were achieved at a 2 mg / kg LD and a 10 mg / kg CD. Ex-vivo bioassay revealed that activity in serum for reversing multidrug resistance was achieved in all patients; IC(50) of P-glycoprotein expressing 8226 / Dox(6) in patients' serum was decreased from 5.9 to 1.3 microg / ml (P < 0.0001) by PSC-833 administration. Doxorubicin clearance was 24.3 +/- 13.7 (mean +/- SD) liter / h/m(2), which was lower than the 49.0 +/- 16.9 liter / h/m(2) without PSC-833 (P < 0.0001). The relationship between doxorubicin exposure and neutropenia did not differ between patients treated and not treated with PSC-833. The recommended phase II dose of PSC-833 was 2 and 10 mg / kg for LD and CD, respectively, which achieved a sufficient concentration in serum to reverse drug resistance, as confirmed by bioassay. The dose of doxorubicin should be reduced to 40 mg / m(2), not because of the pharmacodynamic interaction between PSC-833 and doxorubicin affecting hematopoiesis, but because of pharmacokinetic interaction.

Adult↗