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Biomedical subjects

T Itoh

Publications and source records attributed to T Itoh.

At least 109 records · Page 6Linked to original sources
PubMed2001

Insulin resistance induced in dairy steers by tumor necrosis factor alpha is partially reversed by 2,4-thiazolidinedione.

The aim of this study was to determine whether 2,4-thiazolidinedione (2,4-TZD) influences the effects of peripheral insulin action in steers given recombinant bovine tumor necrosis factor (TNF) alpha (rbTNF). Steers were treated once daily for 9 d (d0 - d8) with either s.c. injection of rbTNF (2.5 microg/kg), rbTNF + i.v. injection of 2,4-TZD (2.0 mg/kg), or s.c. injection of saline (control). The plasma glucose, NEFA, and insulin concentrations in the rbTNF-treated group increased compared to those in the control and rbTNF + 2,4-TZD groups, whereas glucagon concentration decreased. A single i.v. injection of insulin (0.2 U/kg), glucose (112.5 mg/kg), or growth hormone (GH)-releasing hormone (GHRH) (0.25 microg/kg) was performed on d4, d6, and d8, respectively. In the insulin challenge, the net area under the glucose curve (AUC) was smaller in the rbTNF group than in the control and rbTNF + 2,4-TZD groups. In the glucose challenge, the net insulin AUC was smaller in rbTNF + 2,4-TZD group than in rbTNF group. In the GHRH challenge, there was no difference in GH responses to GHRH between the rbTNF and rbTNF + 2,4-TZD groups, respectively. We conclude that 2,4-TZD treatment partially reverses the impairment of peripheral insulin action caused by rbTNF injection in steers.

Animals↗
PubMed2001

DNA-dependent protein kinase catalytic subunit is cleaved during UV-induced apoptosis.

Ultraviolet radiation can induce the injury of epidermal keratinocytes, resulting in sunburn cell (apoptotic cell) formation. It has been demonstrated that the protease caspase-3, a downstream molecule of the CD95 pathway, is activated in UV-exposed HaCaT cells, and that the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is cleaved by interleukin-1beta converting enzyme (ICE)-like protease during apoptosis induced by X-rays, staurosporine and etoposide. Then, we studied whether the DNA-PKcs is cleaved during UV-induced apoptosis in keratinocytes. We used the well-characterized cloned human keratinocyte cell line HaCaT, which carries p53 mutations. UVB-induced apoptotic cells were observed by TdT-mediated deoxyuridine 5'-triphosphate nick end labeling (TUNEL) assay and agarose gel electrophoresis. Western blot analysis was performed using the antibody against DNA-PKcs. The cleavage occurred during UVB-induced apoptosis in HaCaT cells. It suggests that the cleavage is associated with loss of DNA-PK activity. Thus, a functional relevance of cleavage of DNA-PKcs may be to prevent rejoining fragmented DNA during apoptosis, thereby promoting apoptotic processes. Although apoptosis was not completely blocked by the caspase-3 inhibitor, the cleavage of the DNA-PKcs was blocked. These results indicate that DNA-PKcs is cleaved by the caspase-3 for UVB-induced apoptosis in HaCaT cells.

Apoptosis↗
PubMed2001

Modulation of aromatase expression in human breast tissue.

Aromatase plays an important role in breast cancer development through its role in the synthesis of estrogen. Aromatase expression in breast tissue can be regulated by several mechanisms. The major promoter usage for aromatase expression in breast tumors (i.e. cAMP-stimulated promoters I.3 and II) is different from that in normal breast tissue (i.e. glucocorticoid-stimulated promoter I.4). Recent characterization of transcription factors that interact with the two important regulatory elements near promoters I.3 and II, i.e. S1 and CREaro, helps us better understand the mechanism of the switch of promoter usage between normal breast tissue and cancer tissue. It is thought that in normal breast tissue, the function of promoters I.3 and II is suppressed through the binding of EAR-2, COUP-TFI, and EARgamma to S1, and through the binding of Snail/Slug proteins to their binding site that quenchs the CREaro activity. In cancer tissue, the expression levels of EAR-2, COUP-TFI, EARgamma, Snail, and Slug decrease, and aromatase expression is then up regulated through the binding of ERRalpha-1 to S1 and the binding of CREB or related factors to CREaro. Results from this and other laboratories reveal that aromatase activity in aromatase expressing cells can also be modified by treatment with aromatase inhibitors and the antiestrogen ICI 182, 780. While aromatase inhibitors are used to treat breast cancer, the treatment has been found to increase the level of aromatase in the breast tissue of some patients. The enhancement of aromatase activity by aromatase inhibitors is thought to be due to a decrease of aromatase protein degradation by enzyme-inhibitor complex formation, up-regulation of the aromatase gene transcription through a cAMP-mediated mechanism, and an induction of aromatase expression by gonadtropins that are released from the pituitary in response to a reduction of estrogen levels in circulation in premenopausal women. Antiestrogen ICI 182, 780 has been found to suppress aromatase expression, but the mechanism has not yet been determined. In addition, aromatase activity and expression can be affected by environmental chemicals. A detailed structure-function study has revealed that flavones, but not isoflavones, are inhibitors of aromatase. It was found that flavones bind to the active site of aromatase in an orientation in which their rings-A and -C mimic rings-D and -C of the androgen substrate. The modulation of aromatase expression by endocrine disrupting chemicals is exemplified by two organochlorine pesticides (i.e. toxaphene and chlordane) that have been found to be antagonists of ERRalpha-1 orphan receptor. These compounds reduce ERRalpha-1 activity, resulting in a suppression of aromatase expression.

Aromatase↗
PubMed2001

The impact of ischaemic preconditioning on spinal cord blood flow and paraplegia.

PURPOSE: We investigated the effect of ischaemic preconditioning (IP) on ischaemic spinal cord injury in a rabbit model. METHODS: Fourteen rabbits were divided into IP and control groups of seven rabbits each. We repeated 3-min clamping of the infrarenal abdominal aorta and 3-min reperfusion twice (preconditioning), followed by 15 min clamping in the IP group. In the control group, the aorta was clamped for 15 min without preconditioning. Lumbar cord blood flow and systemic blood pressure were measured until 3 h of reperfusion. Another 14 rabbits underwent the same procedures with or without IP and neurologic status was assessed on the second postoperative day. RESULTS: The percent change in lumbar cord blood flow after reperfusion was significantly greater (P=0.013) in the IP group despite lower mean blood pressure. There was no significant difference in overall neurologic status (P=0.461) but the incidence of spastic paraplegia in the IP group was lower (14%, 1/7) than that of control group (43%, 3/7). CONCLUSION: IP increased postischaemic lumbar cord blood flow and contributed to lower incidence of spastic paraplegia.

Animals↗
PubMed2001

Coronary endothelial damage during off-pump CABG related to coronary-clamping and gas insufflation.

OBJECTIVE: Although off-pump coronary artery bypass grafting (CABG) has been recognized less invasive than conventional CABG on cardiopulmonary bypass, off-pump CABG may be partly invasive especially to the coronary endothelium. The present study was designed to evaluate the adverse effects of coronary snaring with looped sutures and gas insufflation on the coronary endothelium. The protective efficacies on the coronary endothelium of coronary snaring with elastic sutures or humidified gas insufflation with/without heparin and dipyridamole-added were also tested. METHODS: Thirty-six mongrel dogs were used. After systemic heparinization (150 U/kg), a 5 mm longitudinal coronary incision was made with looped non-elastic monofilament sutures or elastic sutures applied proximally and distally. The incised coronary artery was exposed to non-humidified carbon dioxide, humidified carbon dioxide with lactated Ringer solution, or humidified carbon dioxide with heparin and dipyridamole-added lactated Ringer solution for 10 or 20 min in each group. After gas insufflation, the incised coronary artery was repaired, then, the coronary was reperfused. Perfusion-fixation was done for observation of the coronary endothelium by scanning electron microscopy. The adverse effect on the endothelium was graded as follows: grade 1, appeared normal; grade 2, few blood cells deposited; grade 3, many blood cells deposited; grade 4, few endothelial cells delaminated with blood cells deposited; grade 5, many endothelial cells delaminated with blood cells deposited. RESULTS: Non-elastic looping caused much more endothelial tears than elastic looping (P<0.00001). Non-humidified gas blowing for 20 min caused more endothelial cell damage than humidified gas blowing (P=0.00005). Non-humidified gas blowing for 10 min caused less damage than for 20 min (P=0.00326), but still caused more damage than humidified gas blowing (P=0.00253). Heparin and dipyridamole-added humidification reduced coronary endothelial area mottled by the deposited cells when compared with simple humidification (P=0.00120). CONCLUSIONS: Coronary snaring resulted in coronary endothelial injury, which was ameliorated by using elastic sutures instead of non-elastic sutures. Non-humidified gas insufflation made blood cells deposited and endothelial cells delaminated with time. Humidified gas insufflation attenuated these adverse effects. Heparin and dipyridamole-added humidification had potential advantage in terms of reducing deposited blood cells on the endothelium over simple humidification.

Animals↗
PubMed2001

Inhibition of matrix metalloproteinases blocks lethal hepatitis and apoptosis induced by tumor necrosis factor and allows safe antitumor therapy.

Acute and fulminant liver failure induced by viral hepatitis, alcohol or other hepatotoxic drugs, are associated with tumor necrosis factor (TNF) production. In a mouse model of lethal hepatitis induced by TNF, apoptosis and necrosis of hepatocytes, but also lethality, hypothermia and influx of leukocytes into the liver, are prevented by a broad-spectrum matrix metalloproteinase (MMP) inhibitor, BB-94. Mice deficient in MMP-2, MMP-3 or MMP-9 had lower levels of apoptosis and necrosis of hepatocytes, and better survival. We found induction of MMP-9 activity and fibronectin degradation. Our findings suggest that several MMPs play a critical role in acute, fulminant hepatitis by degrading the extracellular matrix and allowing massive leukocyte influx in the liver. BB-94 also prevented lethality in TNF/interferon-gamma therapy in tumor-bearing mice. A broad-spectrum MMP inhibitor may be potentially useful for the treatment of patients with acute and perhaps chronic liver failure, and in cancer therapies using inflammatory cytokines.

Animals↗
PubMed2001

Role of the epithelium in opposing H(2)O(2)-induced modulation of acetylcholine-induced contractions in rabbit intrapulmonary bronchiole.

1. The role played by the epithelium in H(2)O(2)-induced modulation of the mechanical responses induced by acetylcholine (ACh) in rabbit intrapulmonary bronchioles was investigated in epithelium-intact and -denuded strips. 2. When ACh (3 microM) was applied intermittently, H(2)O(2) (30 microM) enhanced the ACh-induced contractions in epithelium-intact strips. In contrast, in epithelium-denuded strips H(2)O(2) (30 microM) inhibited such contractions. At higher concentrations, H(2)O(2) concentration-dependently attenuated the ACh-induced contractions in both epithelium-intact and -denuded strips, its action being more potent in the latter strips than in the former. 3. Diclofenac (a cyclo-oxygenase inhibitor; 3 microM) reduced the H(2)O(2)-induced enhancement of ACh-contractions in epithelium-intact strips but had no effect on the H(2)O(2)-induced inhibition in epithelium-denuded strips. N(G)-nitro-L-arginine did not alter the effect of H(2)O(2) on ACh-induced contractions in epithelium-intact strips. 4. Catalase (500 u ml(-1)) completely blocked both H(2)O(2)-induced effects on ACh-contractions (enhancement and inhibition). Neither superoxide dismutase (200 u ml(-1)) nor deferoxamine (0.5 mM) had any effect on H(2)O(2)-induced inhibition in epithelium-denuded strips. 5. Aminotriazole (an inhibitor of catalase; 50 mM) significantly potentiated the H(2)O(2)-induced inhibition of ACh-contractions in epithelium-intact strips but not in epithelium-denuded strips. 6. The density ratio for catalase (epithelium-intact over -denuded strips) analysed by Western blot was about 2.1, suggesting that epithelium contains more catalase than smooth muscle. 7. It is concluded that in rabbit intrapulmonary bronchioles, H(2)O(2) has dual actions on ACh-contractions. It is suggested that the epithelium may act as a powerful biochemical barrier via both the action of catalase (scavenging H(2)O(2)) and the release of bronchoconstrictor prostaglandins, thus attenuating the H(2)O(2)-induced modulation of ACh-contractions.

Acetylcholine↗
PubMed2001

Novel gene delivery systems: complexes of fusigenic polymer-modified liposomes and lipoplexes.

We have previously developed the succinylated poly(glycidol)-modified liposome which becomes fusigenic under weakly acidic condition. In this report, we describe that complexation of this pH-sensitive, fusigenic liposome with a lipoplex consisting of 3beta-(N-(N',N'-dimethylaminoethane) carbamoyl)cholesterol, dioleoylphosphatidylethanolamine and plasmid DNA gives efficient gene delivery systems. In this study, we prepared the complexes, which are termed SucPG-complexes, with a positively or negatively charged surface by mixing the lipoplex with varying amounts of the SucPG-modified liposomes. The positively charged SucPG-complexes either bearing or not bearing a cell-specific ligand, transferrin, could transfect HeLa cells efficiently. In contrast, the negatively charged complexes hardly transfected the cells when transferrin was not conjugated to them. However, the negatively charged SucPG complexes bearing transferrin exhibited high transfection ability against HeLa and K562 cells, indicating that this gene delivery was achieved through their binding to the cellular receptors. These transferrin-attached, negatively charged complexes retained the high transfection ability in the presence of serum. Thus, this negatively charged complex may be useful as nonviral vectors in vivo.

Blood↗
PubMed2001

Therapeutic effects on intestinal Behçet's disease of an intravenous drug delivery system using dexamethasone incorporated in lipid emulsion.

Recurrent intestinal ulcer is a frequent problem in the management of Behçet's disease. However, no standard therapy for intestinal Beheçt's disease has been established. We report two patients with intestinal Behçet disease and recurrent ileal ulcers who were treated successfuly with a lipid emulsion of dexamethasone. In one patient, the cecal ulcer did not relapse after the intravenous administration initiation of a lipid emulsion of dexamethasone once a week, despite the discontinuation of prednisolone. In the other patient, the cecal ulcer showed a healing tendency, and oral administration of prednisolone was reduced from 40 to 15 mg/day after intravenous administration of a lipid emulsion of dexamethasone. Both patients experienced no complications associated with the administration of the emulsion. These results suggest that an intravenous drug delivery system using a lipid emulsion of dexamethasone is useful for treatment of intestinal Behçet's disease.

Anti-Inflammatory Agents↗
PubMed2001

Adult T-cell lymphoma involving the leptomeninges associated with a spinal cord schwannoma.

Adult T-cell lymphoma (ATL-L) developing initially in the meninges is rare. An autopsy case of ATL-L with an acute onset of meningitis and generalized lymphadenopathy in association with a cervical cord schwannoma is reported here. A 78-year-old woman with sensori-motor weakness of both arms over a 1-year period, developed febrile episodes and drowsiness with neck stiffness. Lumbar puncture revealed an increased protein content (161 mg/dL) and increased cell count (463/3) consisting of 99% of lymphocytes which contained atypical lymphocytes with multilobulated nuclei ('flower cells'), which are characteristic of ATL-L. Viral titers were positive only for HTLV-I antibodies (serum X 640: CSF X 16). Biopsy of an enlarged retroperitoneal lymph node revealed malignant lymphoma of the T-cell type. Brain MRI was negative, whereas an intradural extramedullary mass was found at the C4 level. With a diagnosis of ATL-L stage IV, chemotherapy was commenced, which was effective in reducing the generalized lymphadenopathy as well as the cervical mass and restoring the CSF findings to normality. The cervical cord mass was verified to be a solitary schwannoma, and ATL-L involvement was found not only in the leptomeninges, but also within the cervical cord schwannoma.

Aged↗
PubMed2001

Primary extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type in the CNS.

Extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type has been reported in various internal organs. Here a case is reported of MALT lymphoma developing in the cerebellopontine (CP) angle in a patient with Sjogren syndrome, and the concept of MALT lymphoma of the CNS is introduced. Pathologically, the tumor showed inflammatory features of reactive lymphocytic infiltration with follicle formation, but there were slightly atypical lymphocytes and plasmacytes with B-cell markers. These cells invaded reactive follicles, showing follicular colonization, and showed aberrant expression indicating their neoplastic nature. A review of the literature revealed eight cases of MALT lymphoma originating from the dura mater and one from the CP angle. The average age of patients was 50 years (range 28-66 years), and all patients were female. The tumors were slow to develop and the patients were cured after surgical removal and/or additional therapies. It is proposed that MALT lymphoma should be considered as a differential diagnosis of inflammatory pseudotumor of the CNS.

Adult↗
PubMed2001

Secondary tumors of the pancreas: clinicopathological study of 103 autopsy cases of Japanese patients.

To investigate the clinicopathological features of patients with secondary tumors of the pancreas, we reviewed autopsy records and pathological features of 103 cases with pancreatic secondary tumors from 690 cases of malignant tumors (excluding cases of primary pancreatic cancer) over a 10-year period. There were 67 men and 36 women in the study, ranging in age from 2 to 94 years (mean: 61 years). The incidence of pancreatic secondary tumors was 15% in the autopsy cases of malignant tumors, and the majority of the secondary tumors were carcinomas. The stomach was the most common primary tumor site (20%), followed by the lung (18%) and extrahepatic bile duct (13%). Because the total number of each primary carcinoma differed, we paid specific attention to the incidence of pancreatic metastasis in each primary carcinoma. We found that carcinoma of the papilla of Vater showed the highest rate of incidence (75%) of pancreatic metastasis in each type of primary carcinoma. Approximately half of the metastatic lesions were solitary, but the metastatic lesions in the pancreas could not be identified macroscopically in 34 cases (33%). Histologically, the most common carcinoma was adenocarcinoma, followed by large cell carcinoma, small cell carcinoma and neuroendocrine carcinoma. The most common non-epithelial tumor was leukemia, followed by malignant lymphoma. Undifferentiated carcinoma and neuroendocrine carcinoma were often found in cases of extrahepatic bile duct or urinary bladder carcinoma with pancreatic metastasis. As for the microscopic infiltration patterns of tumor cells, 73% of cases showed an interlobular and intralobular infiltration. Fat necrosis was most frequently seen as an associated pathological finding (19%). Our study indicates that secondary tumors of the pancreas can be found in approximately one out of six to seven autopsy cases of malignant tumors, and in Japan, the most common of these is adenocarcinoma of the stomach.

Adolescent↗
PubMed2001

Intraglandular necrotic debris in gastric biopsy and surgical specimens.

To clarify whether intraglandular necrotic debris (IND) is a diagnostic clue to noninvasive high-grade neoplasia or invasive neoplasia of the stomach, we reviewed 135 gastric biopsy specimens and 55 surgical materials. Intraglandular necrotic debris is defined as an eosinophilic material with necrotic epithelial fragments within the lumen of a dilated atypical gland. Using the Vienna classification, the incidence of IND in category 4 (noninvasive high-grade neoplasia) and category 5 (invasive neoplasia) was significantly higher than that of category 1 (negative for neoplasia/dysplasia), category 2 (indefinite for neoplasia/dysplasia), and category 3 (noninvasive low-grade neoplasia). The incidence of IND was much higher in category 5 than in category 4 in biopsy specimens. In addition, cases with IND in category 4 in biopsy specimens turned out to be either carcinoma in situ or invasive carcinoma in the surgical specimens. According to the histologic classification of surgically removed invasive carcinoma, moderately differentiated adenocarcinoma showed the highest incidence of IND. Intraglandular necrotic debris was not found in either signet-ring cell carcinoma or mucinous adenocarcinoma. Our results indicate that IND in biopsy specimens is a diagnostic clue to noninvasive high-grade neoplasia or invasive carcinoma, and the origin of IND may be associated with necrotic atypical epithelium.

Adenocarcinoma↗
PubMed2001

Control of non-malignant chronic pain conditions in Japan and the possible future role of tramadol.

Pharmacological treatment is the most common treatment for non-malignant chronic pain diseases such as lumbar and/or cervical spondylosis and osteoarthritis of the knee or hip joint. In Japan, opioid analgesics cannot be used for non-malignant chronic pain syndromes because of the strict regulations for opioid use by the Ministry of Health and Welfare. Non-steroidal anti-inflammatory drugs (NSAIDs) do not have sufficient effect as analgesics for some painful conditions as well as having possible serious side-effects on the gastrointestinal tract and kidneys. According to the Japanese Rheumatism Foundation report on NSAID-induced gastrointestinal lesions in 1991, gastric ulcers were found in 15.5% of 1008 patients who underwent endoscopic examinations. In multicentric questionnaire research, it was discovered that 63% received NSAIDs for longer than 3 months. New drugs having stronger effects for chronic pain and less severe adverse side-effects are expected within the decade. Tramadol hydrochloride controlled-release is a long- and centrally-acting analgesic without serious side-effects for which we are currently going on to the phase II trial in collaborative studies between Japan and the United States for non-malignant chronic pain diseases.

Analgesics, Opioid↗
PubMed2001

Method to detect substitutions in the interferon-sensitivity-determining region of hepatitis C virus 1b for prediction of response to interferon therapy.

Substitutions deduced by direct sequencing in the interferon-sensitivity-determining region (ISDR) of hepatitis C virus (HCV) are related to patients' responses to interferon (IFN), but sequencing is time consuming and results are only for the dominant virus. We developed a rapid method to detect such changes. With serum from 50 patients with chronic hepatitis C (genotype 1b) given IFN-alpha, a way to detect changes in ISDR by hybridization with oligonucleotide probes that had a prototype nucleotide sequence of HCV-J was established. Hybridization intensity was expressed as optical density (OD(NS5A)). The method was checked with serum from 100 more patients. In the study of 50 patients, all 21 with the prototype sequences had a high OD(NS5A) (> or = 0.4), and all 8 patients with a mutant-type sequence had low values (< or = 0.2). Twelve (95% confidence interval, 36-81%) of 20 patients with OD(NS5A) of <0.4 and 2 (1%-22%) of 30 patients with OD(NS5A) > or = 0.4 had complete responses (CR). All nine (66%-100%) patients with OD(NS5A) <0.4 and little HCV RNA (<100 kIU/mL) had CR, but none (0%-14%) of the 24 patients with high values from both predictors had CR. In the study of 100 patients, OD(NS5A) and the HCV RNA level were independent predictors of the effects of IFN. By multivariate analysis, the odds ratio for a CR in patients with OD(NS5A) of > or = 0.4 was 0.015 (0. 001-0.190) compared with the other patients (P =.001). In conclusion, our method should be useful in identification of prototype strains, which generally resist IFN therapy.

Amino Acid Substitution↗
PubMed2001

Repetitive administration of tetrabenazine induces irreversible changes in locomotion and morphology of the substantia nigra in rats.

We investigated the effects of a 7 day repetitive administration of tetrabenazine (TBZ), which depletes monoamines, on both locomotor behavior and histomorphometrial findings of substantia nigra in rats. These results were compared with the effects of a single dose of TBZ, which is a common paradigm in animal models of depression. A single dose of TBZ causes reversible decrease of voluntary movement and no histological changes. In contrast, as for repetitive administration, this experiment demonstrated irreversible and significant decrease in spontaneous locomotion, as well as histological changes in the neurons of the substantia nigra pars compacta. These results have led us to propose that prolonged TBZ administration could provide a novel and useful model for the behavioral characteristics and anatomical pathology of Parkinson's disease as one of the oxidative stress models induced by abnormal dopamine metabolism.

Adrenergic Uptake Inhibitors↗