Biomedical subjects
Publications and source records attributed to T Manabe.
After protection of the two sugar hydroxyl groups of 8-bromoadenosine, the products were converted to the arabinoside or xyloside, which were treated with diethy laminosulfur trifluoride (DAST) and acid to afford 2'-deoxy-2'-fluoro- or 3'-deoxy-3'-fluoro-8-bromoadenosine. 8-OH and 8-SH derivatives were obtained from 8-bromo congener.
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Subtype 2 of the metabotropic glutamate receptor (mGluR2) is expressed in the presynaptic elements of hippocampal mossy fiber-CA3 synapses. Knockout mice deficient in mGluR2 showed no histological changes and no alterations in basal synaptic transmission, paired-pulse facilitation, or tetanus-induced long-term potentiation (LTP) at the mossy fiber-CA3 synapses. Long-term depression (LTD) induced by low-frequency stimulation, however, was almost fully abolished. The mutant mice performed normally in water maze learning tasks. Thus, the presynaptic mGluR2 is essential for inducing LTD at the mossy fiber-CA3 synapses, but this hippocampal LTD does not seem to be required for spatial learning.
Long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength may underlie learning and memory in the brain. The induction of LTP occurs in postsynaptic cells in the hippocampal CA1 region but is presynaptic in CA3. LTD is also well characterized in CA1 but not in CA3. Low-frequency stimulation of mouse hippocampal slices caused homosynaptic LTD at the mossy fiber-CA3 synapse, which may be induced presynaptically by activation of metabotropic glutamate receptors. Thus, the efficacy of mossy fiber-CA3 synapses can be regulated bidirectionally, which may contribute to neuronal information processing.
The adhesion of cancer cells to vascular endothelium is an important step in the hematogenous metastasis of cancer. The authors investigated the alteration of integrin expression in human esophageal cancer cells, following the selectin-mediated initial adhesion to endothelial cells. The expression of alpha2 beta1 and alpha3 beta1 integrins in esophageal cancer cells (TE-1 and T.Tn), strongly expressing EGF-receptors, were markedly increased by the addition of the heparin-binding EGF like growth factor (HB-EGF). The increase of integrin expression in esophageal cancer cells was inhibited by the addition of the tyrosine kinase inhibitor, genistein. HB-EGF treatment of esophageal cancer cells resulted in the augmentation of cancer cell adhesion to immobilized collagen. When esophageal cancer cells were co-cultured with endothelial cells, similar levels of augmentation of cancer cell adhesion to collagen were observed. The augmentation of cancer cell adhesion to collagen was inhibited by the addition of anti-HB-EGF neutralizing antibody. Our interpretation of the results described above is that the cancer cells receive stimulation from cytokines, such as HB-EGF, produced by endothelial cells, following initial adhesion of cancer cells via selectins. This results in a secondary increase in the expression of cell adhesion molecules, such as the beta1 integrin family, and leads to augmentation in the adhesive activities of cancer cells at vessel walls. We postulate that this sequence of events involves the enhanced transmigration of cancer cells to extravascular tissues, following the selectin-mediated adhesion to the endothelium.
PURPOSE: The results of high-dose intraoperative radiotherapy (IORT) and/or external beam radiotherapy (EBRT) for unresectable pancreatic cancer were analyzed to evaluate the possible advantages of IORT in combination with EBRT. METHODS AND MATERIALS: Between 1983 and 1993, 115 patients with unresectable adenocarcinoma of the pancreas (53 with non-Stage IV disease and 62 with Stage IV disease) were treated with EBRT + IORT (55 patients), EBRT alone (44 patients), or IORT alone (16 patients). In non-Stage IV patients, the use of EBRT alone was due to the unavailability of IORT and the use of IORT alone was due to refusal of EBRT. The IORT dose was 30-33 Gy and the EBRT dose was 40-60 Gy. A historical control group comprised of 101 patients undergoing palliative surgery alone was also analyzed. RESULTS: Both non-Stage IV and Stage IV patients receiving EBRT with or without IORT had a better prognosis than the nonirradiated historical controls. Among non-Stage IV patients, the median survival of the EBRT + IORT group (8.5 months) and the EBRT group (8 months) was similar, although survival from 12 to 18 months was higher in the former group (38% vs. 10% at 12 months, p = 0.018, and 19% vs. 0% at 18 months, p = 0.023). In Stage IV patients, the prognosis was not influenced by the type of radiotherapy. Multivariate analysis revealed that a pretreatment carbohydrate antigen (CA) 19-9 level < 1000 U/ml was associated with better survival. In non-Stage IV patients with a CA 19-9 level < 1000 U/ ml, EBRT + IORT appeared to produce a better survival than EBRT alone (p = 0.047). This was supported by multivariate analysis. CONCLUSION: High-dose IORT + EBRT may be more effective than EBRT alone in patients with unresectable but localized pancreatic cancer and a low CA 19-9 level.
As an extension of our study aiming to discover a novel compound with dual activities against histamine and slow-reacting substance (SRS), we synthesized two types of indolylpiperidine derivatives, 3 and 4-20. Testing for in vivo antianaphylactic activity and for in vitro anti-SRS activity revealed that (2E,4E)-5-(3,5-dimethoxy-4-hydroxyphenyl)-N-(2-(4-(1H-indol-3-yl)+ ++piperidin-1- yl)ethyl)-2,4-pentadienamide (11) exhibited potent dual activities with ED50 = 0.89 mg/kg and IC50 = 1.43 microM, respectively. However, the plasma concentration of unchanged 11 was very low when administered orally in guinea pigs. This result can be explained by fast formation of a glucuronic acid conjugate.
We experienced three cases of right ventricular perforation that were induced by transvenous pacing electrodes. The patients were a 72-year-old man who underwent percutaneous transluminal coronary recanalization and angioplasty, an 80-year-old woman who had temporary transvenous pacing for a complete atrioventricular block induced by acute valvular heart failure, and a 44-year-old man who had received a permanent pacemaker. All three patients were treated surgically. The first and second patients demonstrated either cardiac tamponade or hemopericardium necessitating pericardial drainage. Spontaneous hemostasis did not occur in cases 1 and 2, due to either anticoagulant therapy or myocardial degeneration. Such patients require surgical closure of the perforation and pericardial drainage as soon as pericardial effusion is confirmed. In contrast, middle-aged individuals without myocardial damage, such as patient 3, need only a simple removal and repositioning of the electrode followed by serial echocardiography.
The object of this study was to define the pattern of gastrointestinal myoelectrical activity before and after cholecystectomy. After surgery, on the first postoperative day, the mean and maximal activities of the gastrointestinal tracts decreased significantly, but there was no significant change in the pattern and the duration of the nonreactive period. A dyskinetic effect and/or weakness of electrical activity was observed in all patients before operation, and the same pattern persisted after operation for one month. This suggests the future onset of the so-called postcholecystectomy syndrome, which may result from the fundamental pathological effect of gallstones.
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Multiple epsilon subunits are major determinants of the NMDA receptor channel diversity. Based on their functional properties in vitro and distributions, we have proposed that the epsilon 1 and epsilon 2 subunits play a role in synaptic plasticity. To investigate the physiological significance of the NMDA receptor channel diversity, we generated mutant mice defective in the epsilon 2 subunit. These mice showed no suckling response and died shortly after birth but could survive by hand feeding. The mutation hindered the formation of the whisker-related neuronal barrelette structure and the clustering of primary sensory afferent terminals in the brainstem trigeminal nucleus. In the hippocampus of the mutant mice, synaptic NMDA responses and longterm depression were abolished. These results suggest that the epsilon 2 subunit plays an essential role in both neuronal pattern formation and synaptic plasticity.
In general, hepatocytes lack basement membrane structures and therefore no laminin expression is seen around hepatic cords. To determine whether or not laminin expression appears when hepatic tissue becomes carcinomatous, we carried out immunohistochemical staining of hepatic tissues excised surgically from 35 patients with hepatocellular carcinoma, 18 with metastatic colon carcinoma, two with adenomatous hyperplasia, and 10 without any nodular lesions. Among the various conditions of hepatic tissue, laminin expression was detected only in hepatocellular carcinoma with 86% positivity. The result was not dependent on the degree of differentiation. Therefore, it was confirmed that immunohistochemical detection of laminin provides a useful adjunct for the diagnosis of hepatocellular carcinoma, and this was verified by a study using needle biopsy samples. In addition, our results suggested that the basement membranes are derived from endothelial cells of either portal veins or hepatic arteries.
We report a case of adenosquamous carcinoma of the stomach which involved only the mucosa and submucosa, but was found to have already metastasized to a regional lymph node and the liver at surgery. Adenosquamous carcinomas of the stomach are rare and usually invade deeply into the muscular layer. Those limited to the mucosa and submucosa are extremely rare, and only seven cases have been reported to date. It was interesting that in our case, 80% of the tumor in the stomach and lymph node was composed of squamous cell carcinoma and 20% consisted of adenocarcinoma, whereas the metastases in the liver consisted entirely of adenocarcinoma. The literature on this type of gastric carcinoma is reviewed and the possible histogenesis of this tumor is discussed.
We investigated immunohistochemical localization of P-glycoprotein (P-gp) on paraffin-embedded sections from 103 cases of previously untreated pancreatic tumors and also analyzed multidrug resistance-1 (MDR1) gene expression by polymerase chain reaction after reverse transcription in 35 cases. High positive staining for P-gp was observed in 72.8% of pancreatic tumors and in 73.2% of ductal adenocarcinoma. In ductal adenocarcinoma, immunoreactivity of P-gp was inversely correlated with biological aggressiveness of tumors determined by histologic grading (P<0.01), tumor size (P < 0.01), retroperitoneal invasion (P < 0.01) and portal invasion (P < 0.05). Expression of the MDR1 gene was detected in all the pancreatic tumors examined and was significantly higher than that in normal pancreas (P < 0.05). The levels of MDR1 mRNA showed a moderate correlation with those of P-gp (r=0.62, P<0.0001). Higher expression levels of MDR1/P-gp significantly correlated with better prognosis of patients with ductal carcinoma (P < 0.05). Among patients with ductal carcinoma, the high staining group for P-gp revealed a 3.5-fold better prognosis compared with the low staining group (HR=3.47, 95% CI=1.62, 7.45; P=0.0016). In conclusion, MDR1 gene/P-gp expression in pancreatic cancer without chemotherapy inversely correlates with biological aggressiveness and is an independent indicator of favorable prognosis.
Epstein-Barr (EB) virus-associated primary smooth muscle tumors have been reported in immunosuppressed young patients with acquired immunodeficiency syndrome (AIDS) and young people who have undergone liver transplantation. An autopsy case of EB virus-associated smooth muscle cell tumor in a 21 year old female who received immunosuppressive therapy following renal transplantation is reported. Multiple tumor nodules were present in the liver, but no primary lesion was found in any other organ. Histologically, the nodules were composed of spindle cells, positive for alpha-smooth muscle actin, which were arranged in fascicles and closely associated with vascular channels, thereby suggesting a vascular smooth muscle cell origin. EB virus infection of the tumor cells was clearly demonstrated by in situ hybridization with an EB virus-encoded RNA 1 (EBER-1) probe. The present case illustrates that EB virus infection may play some role in the development of smooth muscle tumors not only in immunocompromised young patients with liver allografts, but also in those with renal allografts.
A 18-year-old male was admitted to another hospital complaining of his chest X-ray. After transfer to our hospital, increased serum antibody titers to simultaneous M. pneumoniae and C. psittaci were noted. These antibody titers decreased after about four months. Positive results for M. pneumoniae was obtained by Polymerase chain reaction in the right pleural effusion. Based on these findings, this case was diagnosed as M. pneumoniae and C. psittaci pneumonia. A transbronchial lung biopsy and a bronchial biopsy revealed rare histological findings, including histiocytic intra-alveolar pneumonia with palisaded granuloma and small foci of necrosis in the left upper lobe and eosinophilic bronchitis in the right middle bronchus. His chest X-ray and chest CT showed a nodular shadow, obstructive pneumonia and pleural effusion which are rare in M. pneumoniae and C., psittaci pneumonia.
The usefulness of the serial section method was investigated in four bone marrow aspirates, four biopsies and nine autopsy specimens obtained from patients with miliary tuberculosis who were admitted to our hospital between 1974 and 1994. In original sections, granulomas consistent with tuberculosis were found in two out of four aspirate specimens (50%) but in none of the four bone marrow biopsies. By using serially out sections, however, granulomas were detected in two more aspirate specimens and two biopsies which were negative in original sections. Consequently four of four aspirates (100%) and two of four biopsies ((50%) became positive. In addition, the distribution of granulomas was investigated using vertebral bone marrows obtained from 12 autopsy cases. We divided the vertebral bone marrows obtained from 12 autopsy cases. We divided the vertebra into the peripheral and central portions. Granulomas were more frequently found in the peripheral portions than in the central. The higher detection rate of granulomas in the peripheral bone marrow when the biopsy and aspiration needles easily reach, suggests that bone marrow aspiration and/or biopsy would be a useful procedure for the diagnosis miliary tuberculosis. Therefore if serial sections were utilized for such samples in the miliary tuberculosis patients, the detection rate is expected to became much higher.