Biomedical subjects

K Takeda

Publications and source records attributed to K Takeda.

At least 109 records · Page 6Linked to original sources

PubMed2001

Exclusion of SMAD4 mutation as an early genetic change in human pancreatic ductal tumorigenesis.

Pancreatic ductal carcinoma is one of the malignant diseases with the poorest prognosis. To develop effective methods for better treatment of pancreatic cancer patients, we tried to analyze the course of multistep carcinogenesis of the pancreatic ductal cells. IPMT (intraductal papillary-mucinous tumor) is thought to be one of the premalignant lesions of the pancreas, which would transform into carcinomas. Loss of 18q at the SMAD4 locus is known to be an early genetic change in pancreatic ductal carcinomas. It is not clear, however, whether or not the target gene for inactivation is SMAD4. Using 18 IPMTs, we analyzed LOH at the SMAD4 locus and observed frequent LOH (7/14, 50%). No mutations were observed in any of the tumors. Moreover, the expression level of the SMAD4 protein did not show a reduction in IPMTs. These results suggested that (i) inactivating mutation of the SMAD4 gene is a rather late genetic change in pancreatic carcinogenesis, and (ii) there may be an unknown tumor suppressor gene in 18q, other than SMAD4, that is involved in pancreatic ductal carcinogenesis.

Carcinoma, Pancreatic Ductal↗

PubMed2001

Time course of arterial hyperintensity with fast fluid-attenuated inversion-recovery imaging in acute and subacute middle cerebral arterial infarction.

The purpose of this study was to evaluate the time course of arterial hyperintensity (AH) in acute and subacute cerebral infarctions of the middle cerebral artery (MCA) distribution by using fast fluid-attenuated inversion-recovery (FLAIR) imaging. A total of 40 FLAIR MR examinations were performed in 27 patients with MCA infarction within 13 days after ictus. Thirteen patients underwent two MR examinations during this period. Thrombotic or embolic infarctions were included in this study, but lacunar infarctions were excluded. The presence or absence of AH and the location of AH were analyzed. Overall, AH was found in 24 (60%) of 40 FLAIR examinations within 13 days after onset. AH was seen in 17 (100%) examinations less than 24 hours old, four (40%) of 10 examinations 1-4 days old, two (18%) of 11 examinations 5-9 days old, and one (50%) of two examinations 10-13 days old. AH was most frequently found at the sylvian fissure (87%), followed by the sulci (54%), and the horizontal segment of MCA (29%) in the affected MCA distribution. Although AH could be seen even at 13 days after ictus, the presence of AH declined over time. AH represented an early sign of acute embolic or thrombotic infarction. J. Magn. Reson. Imaging 2001;13:987-990.

Aged↗

PubMed2001

Pulmonary ventilation-perfusion MR imaging in clinical patients.

The purpose of this study was to evaluate the feasibility of comprehensive magnetic resonance (MR) assessment of pulmonary perfusion and ventilation in patients. Both oxygen-enhanced ventilation MR images and first-pass contrast-enhanced perfusion MR images were obtained in 16 patients with lung diseases, including pulmonary embolism, lung malignancy, and bulla. Inversion recovery single-shot fast spin-echo images were acquired before and after inhalation of 100% oxygen. The overall success rate of perfusion MR imaging and oxygen-enhanced MR imaging was 94% and 80%, respectively. All patients with pulmonary embolism showed regional perfusion deficits without ventilation abnormality on ventilation-perfusion MR imaging. The results of the current study indicate that ventilation-perfusion MR imaging using oxygen inhalation and bolus injection of MR contrast medium is feasible for comprehensive assessment of pulmonary ventilation-perfusion abnormalities in patients with lung diseases.

Adult↗

PubMed2001

Expression of tumour necrosis factor (TNF) ligand superfamily co-stimulatory molecules CD30L, CD27L, OX40L, and 4-1BBL in murine hearts with acute myocarditis caused by Coxsackievirus B3.

Antigen-specific T-cells infiltrate the heart and play an important role in the myocardial damage involved in acute myocarditis and dilated cardiomyopathy. To investigate the roles of the co-stimulatory molecules CD30/CD30L, CD27/CD27L, OX40/OX40L, and 4-1BB/4-1BBL, which belong to the tumor necrosis factor (TNF) receptor/ligand superfamily, in the development of acute viral myocarditis, the expression of these molecules was first analysed in the hearts of mice with acute myocarditis induced by Coxsackievirus B3 (CVB3) in vivo. Secondly, the induction of these molecules was evaluated on cultured cardiac myocytes treated with interferon (IFN)-gamma and the interleukin (IL)-6 production by cultured cardiac myocytes was analysed by stimulation with monoclonal antibodies (MAbs) against these molecules in vitro. Thirdly, the effects of in vivo administration of anti-CD30L, anti-CD27L, anti-OX40L, or anti-4-1BBL MAb on the development of acute viral myocarditis were examined. CVB3-induced myocarditis resulted in the induction of CD30L and 4-1BBL on the surface of cardiac myocytes, confirmed by treatment with IFN-gamma in vitro. CD27L and OX40L were constitutively expressed on cardiac myocytes in vivo and in vitro. Anti-CD30L and anti-4-1BBL MAbs stimulated IL-6 production by cardiac myocytes in vitro. Furthermore, in vivo anti-4-1BBL MAb treatment significantly decreased the myocardial inflammation, whereas the other MAbs did not. These findings suggest that TNF ligand superfamily co-stimulatory molecules, especially 4-1BBL, play an important role in the development of acute viral myocarditis and raise the possibility that immunotherapy with anti-4-1BBL MAb may be of benefit in acute viral myocarditis.

4-1BB Ligand↗

PubMed2001

Semantic cueing effects on word retrieval in aphasic patients with lexical retrieval deficit.

We examined lexical access in word production, focusing on lexical retrieval deficit in aphasic patients. These patients were asked to name one picture at a time and we investigated how semantic cueing affected their ability to retrieve the word. When the subjects experienced a retrieval failure, they were presented with one type of cue, and then they tried to name the target picture again. Four types of cues were used: phonological, semantic related, semantic category member, and baseline cue. Both phonological and semantically related cues improved performance. In contrast, category member cues had no effects on releasing the retrieval block. These results can be explained by an interactive activation model in word production (Dell & O'Seaghdha, 1991).

Adult↗

PubMed2001

Expression of tyrosinase-related protein 2/DOPAchrome tautomerase in the retinoblastoma.

Tyrosinase-related protein 2 (TRP-2), also known as DOPAchrome tautomerase, is an enzyme in melanin biosynthesis and may play an important role in detoxification of a metabolite derived from DOPA. TRP-2 is expressed in melanocytes of neural crest origin and retinal pigment epithelium (RPE), derived from the optic cup. TRP-2 has been established as an early differentiation marker for melanoblasts and RPE. It is therefore of significance to study the regulation of TRP-2/DOPAchrome tautomerase expression. Here we show that TRP-2 mRNA is expressed in Y79 human retinoblastoma cell line, derived from a primitive multipotential retinal cell. Retinoblastoma is the common primary intraocular tumor of childhood. Basal expression levels in Y79 retinoblastoma cells of TRP-2 mRNA and protein are comparable to those in melanoma cells, whereas mRNA for tyrosinase, the rate-limiting enzyme in melanogenesis, is undetectable in retinoblastoma cells. Transient transfection assays showed that the TRP-2 gene promoter efficiently directs the reporter gene expression in retinoblastoma cells as it does in melanoma cells. Moreover, the expression of TRP-2 mRNA was induced by retinoic acid in retinoblastoma cells but not noticeably affected by forskolin, a cAMP-elevating reagent, whereas in melanoma cells its expression was induced by forskolin but not by retinoic acid. These results suggest a difference in the regulation of TRP-2 expression between retinoblastoma and melanoma cells. Moreover, TRP-2 mRNA is expressed in the excised retinoblastoma specimens, as assessed by RT-PCR. The present study shows unexpected features of TRP-2 and may enhance our understanding of the pathophysiology of retinoblastoma.

Colforsin↗

PubMed2001

Binding rate constant of Tc-99m DTPA galactosyl human serum albumin measured by quantitative dynamic SPECT--clinical evaluation as a total and regional liver function test.

To evaluate the clinical utility of a new method with dynamic single photon emission computed tomography (SPECT) and scatter and attenuation compensation to estimate both total and regional liver function quantitatively. Five controls, 20 patients with chronic liver disease, and 2 patients with Budd-Chiari syndrome were studied. Dynamic liver SPECT data were acquired during 20 minutes after injection of Technetium (Tc)-99m diethylenetriaminepentaacetic acid (DTPA) galactosyl human serum albumin (GSA) with scatter and attenuation compensation. The binding rate constant of Tc-99m GSA (Ku) was derived quantitatively from the Patlak plot based on kinetic models for GSA receptor binding. The mean Ku was obtained by dividing the Ku value (total Ku) by the liver volume. Both total and mean Ku were significantly lower in patients with chronic liver disease than in controls (302 +/- 112 vs. 523 +/- 78 ml/min; p < 0.001, 0.26 +/- 0.11 vs. 0.43 +/- 0.03 ml/min/cm3; p < 0.001). In the patient group, both total and mean Ku were significantly correlated with the results of conventional liver function tests and the histological severity of chronic liver disease. In 2 patients with Budd-Chiari syndrome, the mean Ku was lower in the right lobe, where the hepatic veins were occluded, than in the left lobe, where draining veins were patent. In conclusion, this method is a reliable diagnostic technique for estimating total and regional liver function.

Adult↗

PubMed2001

Very late antigen-5 and leukocyte function-associated antigen-1 are critical for early stage hematopoietic progenitor cell homing.

Interactions of adhesion molecules among hematopoietic progenitor cells (HPC), bone marrow microvascular endothelial cells (BMMEC), and stromal cells are critical for hematopoiesis. However, most of the identified HPC receptors mediate interactions between HPC and stromal cells in the extravascular space. In order to study the interaction between HPC and BMMEC in the early period of homing, we preincubated mouse bone marrow mononuclear cells with blocking monoclonal antibodies against very late antigen-4 (VLA-4), VLA-5, leukocyte function-associated antigen-1 (LFA-1), and L-selectin before transplantation into irradiated splenectomized mice. Colony-forming units of granulocyte-macrophage (CFU-GM) seeding efficiency after preincubation with anti-VLA-5 resulted in a 54%, 67%, and 65% reduction, while that after preincubation with anti-LFA-1 resulted in a 37%, 25%, and 56% reduction, as compared with control, at 0.5, 2, and 24 h following transplantation, respectively. Similarly, the seeding efficiency was reduced by 12%, 13%, and 71% after preincubation with anti-VLA-4, and by -1%, 0%, and 18% after preincubation with anti-L-selectin. Thus, antibody blockade of VLA-5 and LFA-1 on HPC caused a significant decrease in CFU-GM seeding efficiency in the early period of homing. These observations suggest that VLA-5 and LFA-1 may play an important role in the recognition of BMMEC by HPC.

Animals↗

PubMed2001

Dose escalation study of irinotecan combined with carboplatin for advanced non-small-cell lung cancer.

From December 1994 to July 1997, we conducted a dose escalation study of irinotecan combined with carboplatin in 17 patients with advanced non-small-cell lung cancer (NSCLC) to determine the maximum tolerated dose and the dose-limiting toxicities. Irinotecan was administered intravenously over 90 min on days 1, 8 and 15, with carboplatin given at an area under the concentration-time curve dose of 5 mg/ml x min (calculated using Calvert's formula) on day 1. The starting dose of irinotecan was 30 mg/m2 and dose escalation was done in 10-mg/m2 increments. Treatment was repeated at 28-day intervals for at least two cycles. The dose-limiting toxicities were neutropenia and thrombocytopenia, since three out of five patients given 60 mg/m2 of irinotecan developed grade 4 neutropenia and thrombocytopenia. The overall response rate was 35.3%. The median survival time and the 1-year survival rate were 10.5 months and 35.3%, respectively. The maximum tolerated dose of irinotecan with this regimen was 60 mg/m2, while 50 mg/m2 can be recommended for future use. Further studies of this combination in advanced NSCLC are warranted.

Adult↗

PubMed2001

Japanese experience with second-line chemotherapy with low-dose (60 mg/M2) docetaxel in patients with advanced non-small-cell lung cancer.

PURPOSE: To assess the efficacy and toxicity of relatively low-dose docetaxel (60 mg/m2) for previously treated advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced (clinical stage IIIA-IV) NSCLC who had previously undergone at least one series of chemotherapy were enrolled. Previous paclitaxel use was allowed, but docetaxel was not. Docetaxel was administered at an initial dose of 60 mg/m2 intravenously on day 1 over 90 min every 3 weeks. RESULTS: From June 1997 to November 1999, 22 patients were entered into this study. The total number of cycles delivered to 22 patients was 53, with a median per patient of 2. Four patients achieved a partial response (PR), and the overall response rate was 18.2% (95% confidence interval 5.1-40.3%). The median time to progression was 13.7 weeks. The median survival time was 7.8 months, and the 1-year survival rate was 25%. About 73% of patients experienced grade 3 or 4 neutropenia. Neutropenic fever was observed in four patients (18%). Non-hematologic toxicities were generally mild. No treatment-related deaths occurred. CONCLUSIONS: Although the validity of the results of this study is limited due to the small and monoracial study population examined, low-dose (60 mg/m2) docetaxel for previously treated advanced NSCLC appears to yield antitumor activity and survival benefit comparable to those obtained with the conventional dose (100 mg/m2).

Adult↗

PubMed2001

Cytokine modulation in acute pancreatitis.

The clinical manifestations of acute pancreatitis (AP) vary significantly from mild to lethal in form, the severity of the disease being largely determined by the actions of various kinds of inflammatory mediators, including cytokines, reactive oxygen species, proteolytic enzymes, and lipids, as well as gaseous mediators. Despite increasing knowledge implicating the involvement of cytokines in the progression of AP, no clinical trials pertaining to cytokine modulation have been performed so far. Progress in intensive care technologies has contributed to the improvement of mortality and morbidity rates in severe AP in the past decade; however, it appears to be reasonable for clinicians to "line up their sights" on the modulation of cytokines as a direct treatment. In contrast to the large body of experimental studies demonstrating the beneficial effects of cytokine modulation on the amelioration of the disease, direct extrapolation from these successful experiments to the clinical situation seems to be extremely difficult.

Acute Disease↗

PubMed2001

Continuous regional arterial infusion (CRAI) therapy reduces the mortality rate of acute necrotizing pancreatitis: results of a cooperative survey in Japan.

We evaluated the usefulness of continuous regional arterial infusion (CRAI) of protease inhibitors and antibiotics in 156 patients with acute necrotizing pancreatitis (ANP) collected in a cooperative survey carried out in 1997 in Japan. The overall mortality rate was 18.6%, and the frequency of infected pancreatic necrosis was 12.8%. There was no significant difference in mortality rates between patients who received the protease inhibitor via CRAI and the antibiotics intravenously (group A) and patients who received both the protease inhibitor and the antibiotics via CRAI (group B), but the frequency of infected pancreatic necrosis was significantly lower in group B (7.6%) than in group A (23.5%). The mortality rate in patients in whom CRAI therapy was initiated within 48 h after the onset of ANP (11.9%) was significantly lower than that in patients in whom CRAI therapy was initiated more than 48 h after the onset (23.6%). These results suggested that CRAI of both protease inhibitors and antibiotics was effective in reducing mortality and preventing the development of pancreatic infection in ANP when initiated within 48 h after the onset of ANP.

Adult↗

PubMed2001

Early microcirculatory derangement in mild and severe pancreatitis models in mice.

An in vivo microscopic technique was used to clarify the increase in microvascular permeability and enhanced leukocyte-endothelium interaction of pancreatic microcirculation in experimental pancreatitis of differing severity. Using bovine albumin fluorescein isothiocyanate (FITC) and carboxyfluorescein diacetate succinimidyl ester (CFDASE) as tracers, the change in permeability and the behavior of leukocytes in the acinar microcirculation were quantified during the initial 1, 2, 6, and 12h after the induction of caerulein pancreatitis in mice. Cold stress was added to produce the severe model. It was revealed that the early microcirculatory changes in the pancreas of caerulein pancreatitis included the increased permeability of endothelial lining and an accumulation of extravasated fluid in the perilobular space, which were more severe if cold stress was added. A decrease in flow velocity was also noted 2h after the onset of severe pancreatitis. Leukocyte adherence to the endothelial cells was not observed during the first 12h in either model of severity. In contrast, observation of the hepatic microcirculation revealed a significant number of adherent leukocytes 2h after the induction of severe pancreatitis. These results suggest that during the early course of acute pancreatitis, leukocyte adherence in the pancreatic microcirculation is a secondary event following the increase in pancreatic vascular permeability.

Acute Disease↗

PubMed2001

A malonylated anthocyanin and flavonols in blue Meconopsis flowers.

The structures of the major anthocyanin and two flavonols from the blue flowers of Meconopsis were identified by NMR spectroscopy as being cyanidin 3-O-[(6-O-malonyl-2-O-B-D-xylopyranosyl)-beta-D-glucopyranoside]-7-O-beta-D-glucopyranoside, kaempferol 3-O-(6-O-beta-D-glucopyranosyl)-beta-D-glucopyranoside and kaempferol 3-O-(6-O-beta-D-glucopyranosyl)-beta-D-galactopyranoside respectively.

Anthocyanins↗

PubMed2001

Radiation therapy for loco-regionally recurrent esophageal cancer after surgery.

PURPOSE: To evaluate the treatment outcome of radiation therapy for 33 loco-regionally recurrent esophageal cancer patients. METHODS: Between 1988 and 1997, 33 patients with loco-regional recurrence of esophageal cancer after curative surgery received radiation therapy at an average total dose of 61 Gy. The site of recurrence was the supraclavicular region in 14 patients, the mediastinal region in 13 patients, and both the supraclavicular and mediastinal regions in six patients. If patients had ether distant metastasis or malignant pleural effusion, they were excluded from analysis. Patients who received prophylactic postoperative irradiation were also excluded from analysis. RESULTS: The median survival period was 7 months. The survival rates at 1, 2, and 3 years were 33, 15, and 12%, respectively. In univariate analysis, patients with a short time interval between surgery and recurrence (P=0.0098) and patients with recurrence in both the supraclavicular and mediastinal regions (P=0.036) had a worse prognosis. In multivariate analysis, the time interval between surgery and recurrence (P<0.001) and age (worse prognosis in younger patients, P=0.019) were the significant prognostic factors. Complete or partial responses were observed in nine (27%) and 21 (64%) of the patients, respectively. Changes in clinical symptoms, such as dysphagia, chest pain and back pain, could be evaluated in 11 patients, and improvement in symptoms was obtained in eight (73%) patients. CONCLUSIONS: The prognosis of patients who received radiation therapy for postoperative loco-regional recurrence of esophageal cancer is poor. However, there is symptomatic relief in a significant proportion of such patients, and long-term survival is possible in some patients.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

Reduction of white coat effect by cilnidipine in essential hypertension.

Stress elevates blood pressure (BP) by increased sympathetic nerve activity. Cilnidipine, a novel dihydropyridine calcium antagonist that has inhibitory actions on N-type as well as L-type voltage-dependent calcium channels, has been reported to attenuate the cold stress-induced increase in plasma norepinephrine and BP in rats. Because white coat effect is associated with an enhanced pressor response to mental stress, we postulated that cilnidipine would attenuate white coat effect in patients with essential hypertension. Sixty-one consecutive outpatients (50 men, 11 women) with essential hypertension were studied prospectively. Twenty-nine patients were treated with either cilnidipine (n = 15) or nifedipine, a representative L-type voltage-dependent calcium antagonist (n = 14). Gender, age, body mass index, duration of hypertension, target organ damage of hypertension, and BP and heart rate (HR) were not significantly different between cilnidipine and nifedipine groups, and both systolic (SBP) and diastolic BP (DBP) were significantly decreased after treatment in both groups. White coat effects on systolic and DBP and HR were not significantly different between groups before antihypertensive treatment. Cilnidipine, but not nifedipine, significantly reduced white coat effects on SBP and HR. Furthermore, white coat effects on systolic BP and HR were significantly lower after treatment in the cilnidipine group compared with the nifedipine group. These data suggest that cilnidipine may reduce white coat effect in hypertensive patients by N-type calcium channel antagonism.

Blood Pressure↗

PubMed2001

Activated brain regions in musicians during an ensemble: a PET study.

As in visual processing, we speculated that, in music processing, different brain regions would activate according to the mode of music listening. Using motets by a famous composer, we studied changes in regional cerebral blood flow (rCBF) with positron emission tomography associated with concentrating on the alto-part within the harmony (alto-part-listening condition) compared to listening to the harmony as a whole (harmony-listening condition). The alto-part-listening condition was associated with bilateral increases of rCBF in superior parietal lobules, precunei, premotor areas and orbital frontal cortices. Superior parietal lobules are likely to be responsible for auditory selective attention to the alto part within the harmony and the analysis of tone pitch on a mental score. The precuneus possibly participated in writing tones of the alto part on a mental score. Based on our findings, we propose that both auditory selective attention and analytic processing play an important role in concentrating on a certain vocal part within a harmony. During the harmony-listening condition, temporal poles, the anterior portion of the cingulate gyrus, occipital cortex and the medial surface of the cerebellum were bilaterally activated. Further studies are necessary to clarify the difference in music processing between musicians and nonmusicians.

Adult↗

PubMed2001

Alternations in hepatic expression of fatty-acid metabolizing enzymes in ArKO mice and their reversal by the treatment with 17beta-estradiol or a peroxisome proliferator.

We generated aromatase gene knockout mice (ArKO mice) by targeting disruption of Cyp19, which encodes an enzyme responsible for conversion of androgens to estrogens. We found that ArKO males developed hepatic steatosis spontaneously with aging, indicating that the function of Cyp19 is required to maintain constitutive lipid metabolism in male mice. Plasma lipoprotein analysis using a gel permeation chromatography revealed that high density lipoprotein (HDL)-cholesterol levels were slightly higher in ArKO males than in wild-type males, whereas no other obvious alternations in the profiles were detected. Nevertheless, analysis of lipoprotein compositions by SDS-polyacrylamide gel electrophoresis demonstrated apparent reduction in the amounts of apolipoprotein E, functioning in receptor-mediated clearance of lipoproteins in the liver, in the IDL/LDL fraction of ArKO males as compared with that of wild-type males. Biochemical analysis on the ArKO livers revealed suppression of mRNA expression and activity of enzymes involved in fatty acid beta-oxidation. The impairment was reversed to the wild-type levels by treatment with 17beta-estradiol or bezafibrate, the latter is a synthetic peroxisome proliferator. These findings indicated a pivotal role of estrogen in supporting constitutive hepatic expression of genes involved in fatty acid beta-oxidation and in maintaining lipid homeostasis.

Acyl-CoA Dehydrogenase↗