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Biomedical subjects

H Matsubara

Publications and source records attributed to H Matsubara.

At least 109 records · Page 6Linked to original sources
PubMed1999

Multiple spontaneous small bowel perforations due to systemic cholesterol atheromatous embolism.

A-65-year-old man was admitted for coronary and peripheral angiography to evaluate angina pectoris and peripheral vascular disease. Following angiography, he suffered from blue toes, livedo reticularis and progressive renal failure. The patient's condition continued to deteriorate, including the development of malnutrition. Four months later he suddenly developed panperitonitis, went into shock and died. The autopsy verified multiple perforations of the small bowel with disseminated cholesterol atheromatous embolism. The other organs including kidney were also invaded by atheroembolism. This was a rare case of multiple spontaneous perforations of small bowel due to systemic cholesterol atheromatous embolism.

Acute Kidney Injury↗
PubMed1999

Expression of wild-type p53 gene confers increased sensitivity to radiation and chemotherapeutic agents in human esophageal carcinoma cells.

The status of the p53 gene of tumor cells can modify the sensitivity of the tumors to radiation and anti-cancer agents. Human esophageal cancer cells (T.Tn) bearing mutated p53 gene were retrovirally transduced with wild-type p53 gene. The transduced cells (T.Tn/p53) which stably expressed wild-type p53 proliferated at the same rate as parental cells. However, the sensitivity to radiation was significantly improved by the transduction and T.Tn/p53 cells became markedly susceptible to cisplatin and etoposide compared with parental cells. Administration of cisplatin noticeably suppressed the growth of T.Tn/p53 tumors but not T.Tn tumors inoculated in nude mice. Forced expression of wild-type p53 gene thereby can increase the sensitivity to DNA damage in esophageal cells.

Animals↗
PubMed1999

Loss of tumorigenicity of human breast cancer cells engineered to produce IL-2, IL-4 or GM-CSF in nude mice.

Human breast cancer cells (OCUB-M), retrovirally transduced with granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin-2 (IL-2) or IL-4 gene were examined for their antitumor activities in nude mice. Although cell proliferation rates in vitro of these cytokine-producing cells were not significantly different from that of wild-type cells, nude mice that were subcutaneously inoculated with cytokine-producing cells did not develop tumors in contrast to mice that were injected with wild-type cells. Injection of GM-CSF-producing cells into the vicinity of growing wild-type tumors retarded subsequent growth of wild-type tumors. Histological examination of tumors which received GM-CSF-producing cells revealed marked infiltration of mononuclear cells around the tumors. Irradiation of cytokine-producing cells diminished their proliferation capacity but production of cytokine(s) was retained. Therefore, inoculation of irradiated cytokine producer cells into growing tumors can be used as a therapeutic maneuver for breast cancer.

Animals↗
PubMed1999

Differential kinetics of circulating angiotensin IV and II after treatment with angiotensin II type 1 receptor antagonist and their plasma levels in patients with chronic renal failure.

BACKGROUND: Angiotensin II (Ang II) C-terminal hexapeptide (referred to as Ang IV) possesses the characteristics of a real hormone with specific receptors and biological effects. Clinical application of Ang II type 1 receptor (AT1-R) antagonists cause an increase in plasma Ang II level, which may result in enhanced production of Ang IV. PATIENTS AND METHODS: In this study, we measured plasma Ang IV and Ang II levels in patients with chronic renal failure (CRF), and also examined the changes in Ang IV and Ang II levels after administration of an ATI-R antagonist. RESULTS: Ang II and Ang IV levels in CRF patients untreated with hemodialysis (n = 16) were 15.8+/-3.6 and 6.0+/-1.1 pg/ml, respectively, which did not differ significantly from Ang II (20.6+/-2.4) and Ang IV levels (8.6+/-1.1) in normal controls (n = 23). The ratio of Ang IV to Ang II was 38%, similar to that in the controls (41%). Ang II or Ang IV levels in CRF patients treated with hemodialysis (n = 12) were also similar to the control values. Ang IV levels had a significant correlation with Ang II levels (r = 0.59). When hypertensive patients were treated with an AT1-R antagonist candesartan for 7 days, Ang II and Ang IV levels were increased 5.5- and 4.1-fold relative to the control levels, respectively. Ang II levels 28 and 56 days after treatment were significantly lower than those 7 days after treatment, whereas Ang IV levels did not differ significantly from those 7 days after treatment. Similar differential kinetics in Ang II and Ang IV levels after long-term (90 days) treatment with an AT1-R antagonist was also confirmed in experiments using rats. Significant decrease in blood pressure continued during long-term treatment with an AT1-R antagonist. CONCLUSION: These findings demonstrated that plasma Ang IV levels in patients with CRF did not differ significantly from those in normal subjects, and that treatment with an AT1-R antagonist caused marked increases in both Ang II and Ang IV levels. In contrast, during long-term treatment plasma Ang II levels were more rapidly decreased than Ang IV levels, suggesting longer-lasting enhancement of the action of Ang IV rather than that of Ang II after treatment with an AT1-R antagonist.

Aged↗
PubMed1999

[Angiotensin II receptor-mediated function unmasked by gene-engineered animals].

The receptors for angiotensin (Ang) II are classified into two subtypes (AT1-R and AT2-R) by the discovery of non-peptidic ligands and AT1-R mediates most of the cardiovascular actions of Ang II. AT2-R is expressed at very high levels in the developing fetus, whereas in the adult its expression in the cardiovascular system is very low. Cardiac myocyte- or vascular smooth muscle-specific overexpression mice of AT2-R display an inhibitory effect on Ang II-induced chronotropic or pressor actions, suggesting the role of AT2-R on the activity of cardiac pacemaker cells or maintenance of vascular resistance. AT2-R also activates the kinin/nitric oxide/cGMP system in the cardiovascular and renal system, resulting in the AT2-R-mediated cardioprotection, vasodilation and pressure natriuresis. These effects transmitted by AT2-R are mainly exerted by stimulation of protein tyrosine or serine/threonine phosphatases in Gi-protein dependent manner. The expression level of AT2-R is much higher in human hearts than in those of rodents, and the AT2-R-mediated actions are likely enhanced, especially by clinical application of AT1-R antagonists.

Adult↗
PubMed1998

Angiotensin II type 2 receptor is upregulated in human heart with interstitial fibrosis, and cardiac fibroblasts are the major cell type for its expression.

The expression pattern of angiotensin (Ang) II type 2 receptor (AT2-R) in the remodeling process of human left ventricles (LVs) remains poorly defined. We analyzed its expression at protein, mRNA, and cellular levels using autopsy, biopsy, or operation LV samples from patients with failing hearts caused by acute (AMI) or old (OMI) myocardial infarction and idiopathic dilated cardiomyopathy (DCM) and also examined functional biochemical responses of failing hearts to Ang II. In autopsy samples from the nonfailing heart group, the ratio of AT1-R and AT2-R was 59% and 41%, respectively. The expression of AT2-R was markedly increased in DCM hearts at protein (3.5-fold) and mRNA (3.1-fold) levels compared with AMI or OMI. AT1-R protein and mRNA levels in AMI hearts showed 1.5- and 2.1-fold increases, respectively, whereas in OMI and DCM hearts, AT1-R expression was significantly downregulated. AT1-R-mediated response in inositol phosphate production was significantly attenuated in LV homogenate from failing hearts compared with nonfailing hearts. AT2-R sites were highly localized in the interstitial region in either nonfailing or failing heart, whereas AT1-R was evenly distributed over myocardium at lower densities. Mitogen-activated protein kinase (MAPK) activation by Ang II was significantly decreased in fibroblast compartment from the failing hearts, and pretreatment with AT2-R antagonist caused an additional significant increase in Ang II-induced MAPK activity (36%). Cardiac hypertrophy suggested by atrial and brain natriuretic peptide levels was comparably increased in OMI and DCM, whereas accumulation of matrix proteins such as collagen type 1 and fibronectin was much more prominent in DCM than in OMI. These findings demonstrate that (1) AT2-R expression is upregulated in failing hearts, and fibroblasts present in the interstitial regions are the major cell type responsible for its expression, (2) AT2-R present in the fibroblasts exerts an inhibitory effect on Ang II-induced mitogen signals, and (3) AT1-R in atrial and LV tissues was downregulated during chronic heart failure, and AT1-R-mediated functional biochemical responsiveness was decreased in the failing hearts. Thus, the expression level of AT2-R is likely determined by the extent of interstitial fibrosis associated with heart failure, and the expression and function of AT1-R and AT2-R are differentially regulated in failing human hearts.

Adult↗
PubMed1998

Determination of pectenotoxin-2 after solid-phase extraction from seawater and from the dinoflagellate Dinophysis fortii by liquid chromatography with electrospray mass spectrometry and ultraviolet detection. Evidence of oxidation of pectenotoxin-2 to pectenotoxin-6 in scallops.

Solid-phase extraction of pectenotoxin-2 (PTX2) and pectenotoxin-6 (PTX6) from seawater samples using a nonpolar cartridge column Sep-Pak C18 was investigated for determination of PTXs in toxic phytoplankton. PTX2 and PTX6 were almost completely recovered from the seawater samples. Determinations of PTX2 from the toxic phytoplankton and scallops were carried out by liquid chromatography (LC) on UV trace equipped with an atmospheric pressure electrospray ionization mass spectrometry (ESI-MS). PTX2 obtained from the toxic phytoplankton and scallops yielded a mass spectra exhibiting abundant [M+H]+, [M+NH4]+ and [M+Na]+ indicating that ESI-MS is useful for the identification of PTX2. Determinations of PTX6 from the toxic phytoplankton and scallops were carried out by LC fluorescence detection. A significantly higher content of PTX6 compared to PTX2 in scallops was observed, suggesting that a transformation of PTX2 to PTX6 in tissues of the scallops occurs rapidly.

Animals↗
PubMed1998

Demonstration of human T lymphotropic virus type I (HTLV-I) tax-specific CD8+ lymphocytes directly in peripheral blood of HTLV-I-associated myelopathy/tropical spastic paraparesis patients by intracellular cytokine detection.

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurologic disease caused by HTLV-I infection and has been associated with elevated levels of several proinflammatory cytokines in both serum and cerebrospinal fluid. It is unknown what kind of cells secrete these cytokines and if HTLV-I Ags are associated with this phenomenon. Here, we investigated the expression of cytokines in PBL from eight HAM/TSP patients, nine HTLV-I-infected asymptomatic carriers, and seven healthy controls by flow cytometry combined with intracellular cytokine staining. PBL were cultured with brefeldin A without mitogen and IL-2 for 14 h. Under these conditions, CD8+ cells produced proinflammatory cytokines including IFN-gamma, TNF-alpha, and IL-2, which were significantly elevated in HAM/TSP patients. The proportion of CD8+ cells producing IFN-gamma in HAM/TSP patients, asymptomatic carriers, and healthy controls were, on average, 4.9, 0.4, and 0.3%, respectively. IFN-gamma production by these CD8+ cells was suppressed by anti-HLA-class I Ab. Purified CD8+ cells from an HLA-A2 HAM/TSP patient produced IFN-gamma by cocultivation with autologous CD4 cells, the main reservoir of HTLV-I in vivo, or allogenic HLA-A2+ B cells pulsed with a known immunodominant HTLV-I tax peptide. These data suggest that high levels of circulating HTLV-I-specific CD8+ T lymphocytes have the potential to produce proinflammatory cytokines and may promote inflammatory responses to HTLV-I in HAM/TSP patients.

CD8-Positive T-Lymphocytes↗
PubMed1998

Angiotensin II type 1 receptor-induced extracellular signal-regulated protein kinase activation is mediated by Ca2+/calmodulin-dependent transactivation of epidermal growth factor receptor.

The signaling cascade elicited by angiotensin II (Ang II) resembles that characteristic of growth factor stimulation, and recent evidence suggests that G protein-coupled receptors transactivate growth factor receptors to transmit mitogenic effects. In the present study, we report the involvement of epidermal growth factor receptor (EGF-R) in Ang II-induced extracellular signal-regulated kinase (ERK) activation, c-fos gene expression, and DNA synthesis in cardiac fibroblasts. Ang II induced a rapid tyrosine phosphorylation of EGF-R in association with phosphorylation of Shc protein and ERK activation. Specific inhibition of EGF-R function by either a dominant-negative EGF-R mutant or selective tyrphostin AG1478 completely abolished Ang II-induced ERK activation. Induction of c-fos gene expression and DNA synthesis were also abolished by the inhibition of EGF-R function. Calmodulin or tyrosine kinase inhibitors, but not protein kinase C (PKC) inhibitors or downregulation of PKC, completely abolished transactivation of EGF-R by Ang II or the Ca2+ ionophore A23187. Epidermal growth factor (EGF) activity in concentrated supernatant from Ang II-treated cells was not detected, and saturation of culture media with anti-EGF antibody did not affect the Ang II-induced transactivation of EGF-R. Conditioned media in which cells were incubated with Ang II could not induce phosphorylation of EGF-R on recipient cells. Platelet-derived growth factor-beta receptor was not phosphorylated on Ang II stimulation, and Ang II-induced c-jun gene expression was not affected by tyrphostin AG1478. Our results demonstrated that in cardiac fibroblasts Ang II-induced ERK activation and its mitogenic signals are dominantly mediated by EGF-R transactivated in a Ca2+/calmodulin-dependent manner and suggested that the effects of Ang II on cardiac fibroblasts should be interpreted in association with the signaling pathways regulating cellular proliferation and/or differentiation by growth factors.

Animals↗
PubMed1998

Pressure overload induces cardiac hypertrophy in angiotensin II type 1A receptor knockout mice.

BACKGROUND: Many studies have suggested that the renin-angiotensin system plays an important role in the development of pressure overload-induced cardiac hypertrophy. Moreover, it has been reported that pressure overload-induced cardiac hypertrophy is completely prevented by ACE inhibitors in vivo and that the stored angiotensin II (Ang II) is released from cardiac myocytes in response to mechanical stretch and induces cardiomyocyte hypertrophy through the Ang II type 1 receptor (AT1) in vitro. These results suggest that the AT1-mediated signaling is critical for the development of mechanical stress-induced cardiac hypertrophy. METHODS AND RESULTS: To determine whether AT1-mediated signaling is indispensable for the development of pressure overload-induced cardiac hypertrophy, pressure overload was produced by constricting the abdominal aorta of AT1A knockout (KO) mice. Quantitative reverse transcriptase-polymerase chain reaction revealed that the cardiac AT1 (probably AT1B) mRNA levels in AT1A KO mice were <10% of those of wild-type (WT) mice and were not affected by pressure overload. Chronic treatment with subpressor doses of Ang II increased left ventricular mass in WT mice but not in KO mice. Pressure overload, however, fully induced cardiac hypertrophy in KO as well as WT mice. There were no significant differences between WT and KO mice in expression levels of fetal-type cardiac genes, in the left ventricular wall thickness and systolic function as revealed by the transthoracic echocardiogram, or in the histological changes such as myocyte hypertrophy and fibrosis. CONCLUSIONS: AT1-mediated Ang II signaling is not essential for the development of pressure overload-induced cardiac hypertrophy.

Angiotensin II↗
PubMed1998

Acute pressure overload could induce hypertrophic responses in the heart of angiotensin II type 1a knockout mice.

Increasing evidence has suggested that locally produced angiotensin II (Ang II) plays an important role in the development of cardiac hypertrophy through the Ang II type 1 receptor (AT1). We and others have recently reported that Ang II is critical for mechanical stress-induced hypertrophic responses in vitro. Using AT1a knockout (KO) mice, we examined whether Ang II is indispensable for pressure overload-induced cardiac hypertrophy in the present study. Reverse-transcriptase polymerase chain reaction analysis revealed that AT1 mRNA levels were <10% in the heart of KO mice compared with wild-type (WT) mice, but the Ang II type 2 receptor gene was expressed at almost the same levels in the hearts of both mice. Intravenous infusion of subpressor dose of Ang II induced c-fos gene expression in the hearts of WT mice but not KO mice. Acute pressure overload, however, induced expressions of immediate-early response genes and activations of mitogen-activated protein kinases in the hearts of KO mice as well as WT mice. Both basal and activated levels of all these responses were significantly higher in KO mice than in WT mice. Pressure overload markedly increased the heart weight-to-body weight ratio in both mice strains at 14 days after aortic banding. These results suggest that acute hypertrophic responses could be induced by pressure overload in the in vivo heart without AT1 signaling.

Angiotensin II↗
PubMed1998

Cardiac-specific overexpression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects.

Angiotensin (Ang) II has two major receptor isoforms, AT1 and AT2. Currently, AT1 antagonists are undergoing clinical trials in patients with cardiovascular diseases. Treatment with AT1 antagonists causes elevation of plasma Ang II which selectively binds to AT2 and exerts as yet undefined effects. Cardiac AT2 level is low in adult hearts, whereas its distribution ratio is increased during cardiac remodeling and its action is enhanced by application of AT1 antagonists. Although in AT2 knock-out mice sensitivity to the pressor action of Ang II was increased, underlying mechanisms remain undefined. Here, we report the unexpected finding that cardiac-specific overexpression of the AT2 gene using alpha-myosin heavy chain promoter resulted in decreased sensitivity to AT1-mediated pressor and chronotropic actions. AT2 protein undetectable in the hearts of wild-type mice was overexpressed in atria and ventricles of the AT2 transgenic (TG) mice and the proportions of AT2 relative to AT1 were 41% in atria and 45% in ventricles. No obvious morphological change was observed in the myocardium and there was no significant difference in cardiac development or heart to body weight ratio between wild-type and TG mice. Infusion of Ang II to AT2 TG mice caused a significantly attenuated increase in blood pressure response and the change was completely blocked by pretreatment with AT2 antagonist. This decreased sensitivity to Ang II-induced pressor action was mainly due to the AT2-mediated strong negative chronotropic effect and exerted by circulating Ang II in a physiological range that did not stimulate catecholamine release. Isolated hearts of AT2 transgenic mice perfused using a Langendorff apparatus also showed decreased chronotropic responses to Ang II with no effects on left ventricular dp/dt max values, and Ang II-induced activity of mitogen-activated protein kinase was inhibited in left ventricles in the transgenic mice. Although transient outward K+ current recorded in cardiomyocytes from AT2 TG mice was not influenced by AT2 activation, this study suggested that overexpression of AT2 decreases the sensitivity of pacemaker cells to Ang II. Our results demonstrate that stimulation of cardia AT2 exerts a novel antipressor action by inhibiting AT1-mediated chronotropic effects, and that application of AT1 antagonists to patients with cardiovascular diseases has beneficial pharmacotherapeutic effects of stimulating cardiac AT2.

Angiotensin II↗
PubMed1998

Reduced tumorigenicity of human gastric carcinoma cells engineered to produce IL-2 in SCID mice reconstituted with peripheral blood cells from cancer patients.

We have examined the validity of a humanized immune system with an animal model to assess cytokine gene therapy for cancer patients. For that purpose, we prepared hematologically-reconstituted severe combined immunodeficiency mice by transferring patient's peripheral blood cells containing CD34+ cells. These animals were inoculated subcutaneously with human gastric cancer lines transduced with cytokine genes. Tumorigenicity of interleukin-2-producing cells was significantly reduced in reconstituted but not in non-reconstituted mice, whereas that of wild-type and interleukin-6 producer cells was not affected irrespective of the reconstitution status. An inability to induce protective immunity in the reconstituted mice, which had rejected interleukin-2-producers, suggested that the effector cells mediating the antitumor response were non-T cells of donor origin. The experimental system presented in this study seems to be a feasible model to investigate applicable cytokines for patients.

Adult↗
PubMed1998

Ventricular pressure-volume area (PVA) accounts for cardiac energy consumption of work production and absorption.

We briefly review that ventricular systolic pressure-volume area (PVA) can predict changes in myocardial O2 consumption (VO2) associated with cardiac work production (positive work) and absorption (negative work). PVA represents the total mechanical energy of cardiac contraction as it is an integral of mechanical energy generated during systole in the cardiac chamber. We have shown that PVA linearly correlates with VO2 under varied pre- and afterload conditions in the left ventricle of the excised cross-circulated canine heart preparation as well as other heart preparations of different species. PVA is the sum of external mechanical work (EW) and mechanical potential energy (PE) which is almost fully convertible to mechanical work without affecting VO2. To compare the energetic effects of cardiac work production and absorption, we varied the timing of the servo pump motion relative to left ventricular (LV) contraction. When the pump fills the LV during diastole and sucks (allows ejection) during systole, cardiac work is produced by the heart, and hence EW > 0. When the pump fills the LV during systole and sucks during diastole, work is absorbed by the heart, and hence EW < 0. The pressure-volume loop rotates counterclockwise when EW > 0. It rotates clockwise when EW < 0. As the result, PVA (= PE + EW) > PE when EW > 0; PVA < PE when EW < 0. We found that VO2 always linearly correlated with PVA regardless of the polarity of EW. Therefore, PVA is the unique determinant of VO2 in a cardiac chamber in a stable contractility.

Animals↗
PubMed1998

Benign esophageal stricture caused by diffuse severe esophagitis presenting as ascending fibrosis: report of a case.

A 46-year-old Japanese man was referred to our hospital for treatment of an esophageal stricture. Esophageal cancer was suspected after detailed investigations, and a right transthoracic esophagectomy was performed. The resected specimen showed only nonspecific esophagitis with severe fibrous thickening in the submucosa, but no evidence of malignancy. Between 1906 and 1993, only 19 similar cases of benign esophageal strictures with fibrous thickening, excluding congenital and iatrogenic strictures, have been reported in Japan. These lesions occurred in the middle to lower third of the esophagus in 15 of 19 cases (78.9%), and 8 of the 19 patients (42.1%) were aged between 30 and 50 years. The interval between onset and hospital admission was short, being less than 1 year in 8 of the 12 patients for whom this information was available. Our patient demonstrated a disorder resembling the diffuse severe esophagitis described by Roth in 1974.

Biopsy↗
PubMed1998

Sleep improvement by light in a demented aged individual.

We administered daily morning bright light exposure in two separate periods to a demented aged subject in a nursing home and analyzed the sleep pattern changes from the sleep diary over 6 months. In the first light exposure period, the ratio of sleep time in night hours increased and maintained a higher value throughout the period than the previous baseline. After stopping the light exposure, the sleep pattern of the subject deteriorated. Resuming the light exposure reproduced similar sleep pattern changes. These results suggest that morning bright light exposure provides a better environment for aged persons to maintain a regular sleep-wake pattern.

Aged↗
PubMed1998

Effects of short duration morning bright light in healthy elderly subjects. I: subjective feeling and ophthalmological examinations.

Seven aged subjects aged 61-78 years were exposed to 6000 lx bright light for 30 min during morning hours at their homes for 1 week. Visual analog scale was recorded before bedtime and after rising to assess subjective feelings. Ophthalmological examinations were made before and after light exposure, to exclude pre-existing ocular disorders and to detect ocular damage. Furthermore, ocular fatigue was self-evaluated immediately before and after exposure. Visual analog scale results indicated that alertness reduced significantly before bedtime. Ophthalmological abnormalities were not found after exposure. These findings suggest that short duration morning bright light exposure reduces night-time vigilance.

Aged↗