Biomedical subjects
Publications and source records attributed to M Okamoto.
Seven coumaric compounds analogous to aurapten were synthesized. Their spasmolytic activity against Ba2+, acetylcholine and histamine was evaluated to investigate their structure-activity relationship. The results of the bioassay demonstrated the important roles of the cis type of double bond at C-2' and the epoxide between c-6' and 7'.
Postprandial atrioventricular (AV) block and hypotension occurred in an 80-year-old man with a 13-year history of diabetes mellitus. Two weeks before admission, he experienced syncope on two occasions after lunch. Master's two-step test induced second degree AV block (2:1 block). Four days after admission, syncope recurred while walking 1 hour after eating; electrocardiogram (ECG) showed complete AV block following 2:1 block. PP interval analysis suggested phase 3 block as the mechanism of AV block. Electrophysiologic study revealed 2:1 HV block. Postprandial syncope ceased after permanent pacemaker implantation. Postprandial AV block and hypotension merit close attention in diabetics.
We report a case of spontaneous remission of desquamative interstitial pneumonia (DIP) in a 50-year-old male. The histological diagnosis of DIP was based on open lung biopsy. A chest X-ray revealed reticulo-nodular shadows in the bilateral lung fields, and the patient had mild dyspnea on exertion. Without treatment, these shadows decreased gradually and disappeared after several months. The patient recovered completely within one year, and recurrence of the disease has not been observed for 4 years. Recently, DIP has rarely been described, and the spontaneous remission of DIP has not been reported since Carrington et al in 1978 (1).
Mitogen-activated protein (MAP) kinase plays crucial roles in cell growth and differentiation. It has recently been shown that the MAP kinase cascade in growth factor signaling diverges and cross-talks with other signaling pathways. In the present study, we examined the effects of wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3-kinase), on the activation of Ras, Raf-1 kinase, and MAP kinase by insulin and epidermal growth factor (EGF). The effect of LY294002, a structurally distinct PI3-kinase inhibitor, on the activation of Raf-1 kinase by both ligands was also examined. In 3T3-L1 adipocytes, 25 nmol/l wortmannin inhibited the insulin-induced activation of Raf-1 kinase to the basal level, whereas the same dose of wortmannin had little effect on the EGF-induced activation of Raf-1 kinase. One hundred micromol/l LY294002 blocked insulin-induced activation of Raf-1 kinase without affecting EGF-induced activation of this kinase. Twenty-five nmol/l wortmannin inhibited the insulin-induced activation of MAP kinase to the basal level with no effect on the EGF-induced activation of this kinase. But the same dose of wortmannin did not affect the formation of guanosine 5'-triphosphate (GTP)-bound Ras stimulated by either ligand. In KB cells, results similar to those in 3T3-L1 adipocytes were obtained. In contrast, in Chinese hamster ovary cells overexpressing the human insulin receptor (CHO-HIR cells), neither wortmannin nor LY294002 inhibited the insulin-induced activation of Raf-1 kinase, and wortmannin had little effect on the activation of MAP kinase by insulin. These results indicate that 1) PI3-kinase or wortmannin-sensitive molecules are involved in the interaction between activated Ras and Raf-1 kinase in the insulin signaling in 3T3-L1 adipocytes, 2) the involvement of PI3-kinase or wortmannin-sensitive molecules in the insulin-induced activation of MAP kinase appears to be cell-type specific, and 3) differential mechanisms to activate Raf-1 kinase and MAP kinase by insulin and EGF exist.
Hypopharyngeal cancer is one of the head and neck cancers with poor prognosis. This is due to the unpredictable extension of the local disease and the high ratio of distant metastasis. To verify the morphological behavior of hypopharyngeal cancer, whole-mount horizontal serial sections were developed using the larynges obtained from total pharyngolaryngoesophagotomy. The technique of processing high-resolution three-dimensional (3D) images of the larynges using Nikon Cosmozone 2SA software is presented. Two representative surgical specimens were used and 3D images reconstructed. In these two particular cases, the cancer infiltrated superiorly through submucosal lymphatic ducts and formed separate daughter nests under the intact mucosal epithelium far above the main tumor. 3D images enhanced the morphological features of these cases. These cases also suggested the difficulty of defining the upper resecting limit in the operation of hypopharyngeal cancer. 3D reconstruction is and will be a crucial modality for studying the morphological behavior of hypopharyngeal cancer.
In the long-term observation (9-22 years) of 45 hearing-impaired children, using our own "Hearing Test Progress Table", 36(80.0%) showed fluctuation of the hearing threshold. Twenty-nine of the 36 patients had acute progression of hearing loss. Three peaks of onset of the acute loss were observed: at age 6, 10, 16 years in girls, 7, 11 and 16 years in boys. Twenty-three of the 45 (51.1%) have been able to maintain their good thresholds throughout these periods, with 14 cases of hearing loss restored by our successful treatment of acute sensorineural hearing losses (1-6 times). Twenty-two of the 45 children (48.9%) could not maintain their initial thresholds: gradual hearing deterioration in 7 of the 22, and acute hearing loss (1-10 times) in the remaining 15 cases. Although these 15 patients could not maintain their initial hearing thresholds until the end of the observation period, active treatments for their acute losses were successful in the early period, and almost all patients were able to maintain their initial hearing thresholds until graduation from elementary school. Our "Hearing Test Progress Table" is based on the results of pure tone audiometry for each frequency on every audiometry test. The management (including guidance and treatment) using the table is very effective.
Western blot analysis was carried out in order to evaluate new serodiagnostic markers, Em18 and Em16, for differentiation of alveolar echinococcosis (AE) from cystic echinococcosis (CE) using 36 serum samples from hydatid patients from Xinjiang, China, where AE and CE are both endemic and one double infection case has been reported. All AE cases except one (5/6) who exhibited a calcified lesion and a single case of double infection showed antibody responses against Em18 and Em16. Some of CE patient sera (6/22) showed antibody response against Em16 except one who showed that against Em18. Analyses of IgG subclass responses against Em18 and Em16 were carried out using all serum samples showing antibody responses against Em18 and/or Em16 (seven CE, five AE, and one AE + CE) and additional samples of three CE and 22 AE from Sichuan, China. IgG4 was the most predominant antibody subclass. Em18 and Em16 were recognized by both IgG4 and IgG1 (in most cases) or by either IgG4 or IgG1 (in minor cases) or by IgG3 (in very rare cases). Neither Em18 nor Em16 was recognized by IgG2 antibodies. The usefulness of Em18 and Em16 as potential new markers for serological differentiation of human AE and CE, respectively, is discussed.
OBJECTIVES AND METHODS: We previously reported the increased contents of group II phospholipase A2 (PLA2) in inflamed colonic mucosa of patients with Crohn's disease and ulcerative colitis (UC). However, the cellular source of the increased group II PLA2 has remained to be clarified. In the present study, we examined immunohistochemical localization of group II PLA2 in inflamed colonic mucosal biopsy samples obtained from eight patients with Crohn's disease, seven with UC, and in normal colonic mucosa of six control subjects without inflammatory bowel disease using a monoclonal antibody raised against human group II PLA2. RESULTS: and CONCLUSIONS: On immunoblot analysis using the antibody, a single band was detected on each lane containing colonic mucosal homogenates from a control subject, a Crohn's disease patient, or a UC patient at the same position as human group II PLA2 purified from ileal mucosa. The results of immunohistochemistry showed that colonic epithelial cells in inflamed mucosa obtained from all active Crohn's disease patients examined (n = 4) contained immunoreactive group II PLA2. In four of seven patients with active UC, group II PLA2 immunoreactivity was similarly positive. No apparent group II PLA2 immunoreactivity was detected in all colonic mucosal biopsy samples obtained from inactive Crohn's disease patients (n = 4) and control subjects. The present study supports the presence of group II PLA2 in colonic epithelial cells in actively inflamed mucosa of patients with Crohn's disease and UC, which suggests that epithelial cells may serve as the cellular source of increased group II PLA2 content in inflamed colonic mucosa of these patients.
We examined the effects of doxofylline, which is a new methylxanthine analog, on heart rate, respiratory rate, respiratory resistance and airway responsiveness in five beagles, and compared with those effects of theophylline. Airway responsiveness to inhaled methacholine was determined by modified Astograph (7Hz oscillation method). Theophylline (10 mg/kg, 20 mg/kg, 40 mg/kg) was orally administered one hour prior to the determination of airway responsiveness and doxofylline (20 mg/kg, 40 mg/kg, 80 mg/kg) was orally administered thirty minutes prior to determination of airway responsiveness at intervals of about one week. Heart rate increased significantly by all dose of theophylline in a dose-dependent manner and by 80 mg/kg of doxofylline. Respiratory rate increased significantly only by 40 mg/ kg of theophylline. Respiratory resistance decreased significantly after administration of 40 mg/kg of theophylline. Airway responsiveness decreased significantly by 40 mg/kg of theophylline and 40 mg/kg, 80 mg/kg of doxofylline in a dose-dependent manner. These results suggest that doxofylline decreased airway responsiveness at the dosage which dose not affect the heart rate and respiratory rate compared with theophylline.
Thirty-two adults (median age 48 years) with acute myelogenous leukemia (excluding M3) have been treated with short-term intensive therapy (M90 therapy). After induction therapy with daunorubicin, cytosine arabinoside (araC), 6-mercaptopurine, prednisolone, mitoxantrone (MIT) and etoposide (VP16), three regimens of post-induction chemotherapy were conducted as short an intercycle time as possible. The first regimen was with MIT and VP16, the second with behenoyl-araC and aclarubicin and the third with VP16, araC, vincristine and vinblastine. No further therapy was given. Complete remission was achieved in 24 (75%) of 32 patients and 24% of all patients were projected to remain free of disease at 5 years. The median duration of the entire therapy was 120 days with a range of 95 to 157 days. Post-induction regimens resulted in severe myelosuppression and their toxicity included treatment-related death in one patient. The treatment results of this short-term therapy were comparable to a former treatment protocol, M84 therapy with a median duration of the entire treatment therapy of 515 days. To confirm the advantages of such short-term therapy, prospective randomized comparisons with conventional post-induction therapy may be required.
A 62-year-old female who had a complaint of palpitation was diagnosed as bicuspid aortic stenosis and left single coronary artery by the echocardiographic examination, cardiac catheterization study and coronary artery angiography. Aortic valve replacement was performed and the patient was discharged 22 days after surgery with good post-operative course. Preoperative coronary artery angiography was important in the case of aortic valvular disease.
We studied the effects of SDZ ISQ 844, a cyclic nucleotide phosphodiesterase (PDE) isozyme type III/IV inhibitor, and salbutamol on the release of histamine from activated human peripheral leukocytes. We stimulated the leukocyte suspensions with calcium ionophore A23187 (Ca-I, 10(-6 M) accompanied with SDZ ISQ 844 (10(-7) M, 10(-6) M, 10(-5) M), salbutamol (10(-7) M, 10(-6) M, 10(-5) M) and combination of SDZ ISQ 844 and salbutamol (10(-7) M, 10(-6) M, 10(-5) M), and measured the levels of histamine in the supernatant fluid and total cyclic AMP levels in the leukocyte suspensions. The increase of histamine levels induced by Ca-I was significantly inhibited by SDZ ISQ 844 (10(-6) M, 10(-5) M) in a dose-dependent manner (p < 0.05, p < 0.01). Salbutamol at the concentration until 10(-5) M did not inhibit the increase of histamine levels. Combination of SDZ ISQ 844 and salbutamol significantly inhibited the increase of histamine levels (10(-6) M, 10(-5) M) in a dose-dependent manner (p < 0.05, p < 0.01). The inhibition of the histamine release by SDZ ISQ 844 (10(-5) M was enhanced significantly by salbutamol (10(-5) M) (p < 0.05). Total cyclic AMP levels in the leukocytes suspensions increased significantly by SDZ ISQ 844 (10(-5) M) and combination of SDZ ISQ 844 and salbutamol (10(-6) M, 10(-5) M) in a dose-dependent manner (p < 0.05, p < 0.01). The increase of cyclic AMP levels by SDZ ISQ 844 (10(-5) M) was enhanced by salbutamol significantly (p < 0.01). These results suggest that selective inhibition of PDE isozyme type III/IV protects the release of histamine from human activated leukocytes in connection with intracellular cyclic AMP levels and the protection is enhanced by beta-agonist.
OBJECTIVE: To investigate the effects of thymulin (serum thymic factor + Zn2+) in collagen induced arthritis (CIA) in rats. METHODS: SD rats were immunized with bovine type II collagen plus Freund's incomplete adjuvant, and thymulin was administered intraperitoneally on the first day of first immunization. We determined the level of serum thymulin by rosette inhibition assay. Effects of thymulin on CIA rats were estimated by measuring the extent of hind paw edema, the level of serum anti-type II collagen antibody, and changes in histopathological features of the affected joints. RESULTS: Serum thymulin levels in CIA rats were significantly lower than in untreated rats. Thymulin diminished hind paw swelling and onset of arthritis compared with control rats. The serum anti-type II collagen antibody level was also reduced by thymulin. Histopathological examination showed inhibition of granulation tissue and new bone formation after injection of thymulin. CONCLUSION: Our results suggest thymulin plays a significant role in the onset and development of CIA in rats. Our data indicate thymulin may be therapeutically effective in preventing the development of rheumatoid arthritis.
Transforming growth factor beta1 (TGF-beta1), a potent growth inhibitor of bladder carcinoma cells, elicits its effects by binding to cell surface receptors. LMC19, a highly invasive and metastatic rat bladder carcinoma cell line, was insensitive to the growth-suppressive effect of TGF-beta1, and it expressed undetectable levels of TGF-beta type I receptor (TbetaRI) mRNA by reverse transcription-PCR and its protein by Western blot analysis. To evaluate the effect of TbetaRI in reducing the malignant phenotype, we transfected LMC19 with an expression vector containing human TbetaRI cDNA. Stable transfection with the expression vector yielded five transfectants that expressed the introduced TbetaRI mRNA. The binding activity of TGF-beta1 to TbetaRI was restored in all of the transfectants. The growth of the transfectants on a plastic surface was markedly inhibited in the presence of TGF-beta1 in the culture medium (P < 0.001), whereas the control cells (parental and transfectant with only neo gene) remained TGF-beta1 insensitive. The colony-forming efficiency of the transfectants was strongly reduced in soft agar medium containing 5% FCS (P < 0.001) and was restored by the addition of a neutralizing anti-TGF-beta antibody. Furthermore, none of the transfectants tested formed tumors in athymic nude mice, whereas the control cells did so in all mice tested. These findings indicate that introduction of TbetaRI can revert a malignant phenotype to a less aggressive (even benign) phenotype in a rat bladder carcinoma cell line that lacks TbetaRI, and that reduced expression of TbetaRI may be associated with the development and progression of bladder carcinomas.
Chronic inflammation is a significant risk factor for the development of urinary bladder cancer. We showed previously that inflammation induced by killed Escherichia coli strikingly enhanced N-methyl-N-nitrosourea (MNU)-initiated rat bladder carcinogenesis. We also demonstrated a marked increase in several cytokines, including TNF-alpha, in aspirates from bladders treated with killed E. coli. In the present investigation, we tested the hypothesis that TNF-alpha released during inflammation was causally related to the development of bladder cancer. Using growth in soft agar and tumorigenicity in athymic nude mice as indices of transformation, we examined the effect of TNF-alpha on the enhancement of H2O2-initiated transformation of MYP3 cells; MYP3 is an anchorage-dependent nontumorigenic rat urothelial cell line. We have already demonstrated that H2O2 is a potent transforming agent which is released during the inflammatory process. MYP3 cells pretreated with H2O2 were exposed to TNF-alpha (0 to 100 ng/ml) for 1 week in monolayer culture and were then subjected to growth in soft agar. A marked increase in the number of colonies was observed in the cells that were first treated with H2O2 and subsequently exposed to TNF-alpha, as compared with the untreated control (p < 0.001). In addition, treatment with TNF-alpha alone caused colony formation and was associated with a 6.5- to 8.7-fold increase in intracellular H2O2 (p < 0.001). Addition of an antioxidant, alpha-tocopherol, resulted in a significant reduction in the number of colonies induced by TNF-alpha (p < 0.001). The transformants induced by TNF-alpha have acquired the potential of anchorage-independent growth and tumorigenicity in athymic nude mice. Our results suggest that TNF-alpha-induced transformation in urothelial cells is due to induction of H2O2, and that this may be one of the mechanisms involved in the carcinogenesis in vivo associated with chronic urinary tract infection.
We studied the chemotactic activity of isolated human peripheral eosinophils toward leukotriene (LT) E4. We obtained eosinophil suspensions by the method of CD16 negative selection. Eosinophil chemotactic activities toward platelet activating factor (PAF, 10(-6) M) and LTE4 (10(-7) M, 10(-6) M, 10(-5) M) were studied using a modified Boyden Chamber method. Eosinophils migrated significantly toward PAF and LTE4 (10(-7) M, 10(-6) M). The chemotactic activity toward LTE, was most potential at 10(-6) M. These results suggest that LTE4 is an eosinophil chemoattractant.
We report a case of severe aplastic anemia (SAA) treated with granulocyte colony-stimulating factor (G-CSF), cyclosporin A and danazole, in which myelodysplastic syndrome (MDS) with monosomy 7 developed eight months later. A 24-year-old woman was diagnosed as having SAA and was initially treated with G-CSF, cyclosporin A and danazole. At initial presentation, bone marrow aspirate revealed marked hypocellularity with a normal karyotype (46, XX [20]) and no MDS features. Eight months after initial treatment, leukocytosis and reticulocytosis were observed and bone marrow aspirate showed hypercellular marrow with morphological and cytogenetic features (45, XX, -7 [16]/46, XX [4]) characteristic of MDS (refractory anemia). A total of 75 mg (1.25 mg/kg) of G-CSF had been administered during the preceding eight months. Among seven previous reports published in Japan since 1992, in which MDS/acute myelogenous leukemia (AML) developed from SAA treated with G-CSF, six showed monosomy 7. Careful observation for leukemic transformation is therefore indicated in patients with SAA who are treated with G-CSF.
The effects of OK-432 and/or MMC on host immunity were studied in patients with advanced colorectal cancer. OK-432 was administered to the portal vein, and MMC was dispersed into the peritoneal cavity for prevention of liver metastasis. In the MMC group, NK activity was significantly reduced at 7 days postoperatively, while such a reduction was not seen in the OK and OK + MMC groups. The administration of OK-432 decreased the postoperative proportion of suppressor T cells in the lymphocyte subsets more than that of MMC group. Our results strongly suggest that intraoperative administration of BRM to the patients with advanced colorectal cancer can significantly prevent postoperative immunosuppression.