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Hajime Takano

Publications and source records attributed to Hajime Takano.

At least 19 recordsLinked to original sources
PubMed2006

Random migration precedes stable target cell interactions of tumor-infiltrating T cells.

The tumor microenvironment is composed of an intricate mixture of tumor and host-derived cells that engage in a continuous interplay. T cells are particularly important in this context as they may recognize tumor-associated antigens and induce tumor regression. However, the precise identity of cells targeted by tumor-infiltrating T lymphocytes (TILs) as well as the kinetics and anatomy of TIL-target cell interactions within tumors are incompletely understood. Furthermore, the spatiotemporal conditions of TIL locomotion through the tumor stroma, as a prerequisite for establishing contact with target cells, have not been analyzed. These shortcomings limit the rational design of immunotherapeutic strategies that aim to overcome tumor-immune evasion. We have used two-photon microscopy to determine, in a dynamic manner, the requirements leading to tumor regression by TILs. Key observations were that TILs migrated randomly throughout the tumor microenvironment and that, in the absence of cognate antigen, they were incapable of sustaining active migration. Furthermore, TILs in regressing tumors formed long-lasting (>or=30 min), cognate antigen-dependent contacts with tumor cells. Finally, TILs physically interacted with macrophages, suggesting tumor antigen cross-presentation by these cells. Our results demonstrate that recognition of cognate antigen within tumors is a critical determinant of optimal TIL migration and target cell interactions, and argue against TIL guidance by long-range chemokine gradients.

Animals↗
PubMed2006

Relation between transcardiac gradient of VEGF and coronary flow response in humans.

BACKGROUND: Angiogenic growth factors, produced in the myocardium and coronary vascular bed, increase myocardial blood flow. This study examined whether plasma levels of vascular endothelial growth factor (VEGF) in coronary circulation may be related to coronary blood flow responses. METHODS: Blood flow responses in the left anterior descending coronary artery to an intracoronary infusion of acetylcholine (ACh) were measured by an intracoronary flow wire technique in 46 consecutive control subjects with normal coronary angiograms and left ventriculograms. Circulating VEGF levels were measured by ELISA in plasma obtained from the aortic root (AO) and anterior interventricular vein (AIV). RESULTS: The transcardiac gradient of VEGF, calculated by the difference in VEGF concentrations between the AIV and AO, showed a positive correlation with the coronary blood flow increase in response to ACh independently of traditional coronary risk factors. In patients with cardiac syndrome X (n=17), defined as a positive exercise stress test with a normal coronary angiograms and left ventriculogram, the transcardiac VEGF gradient was significantly lower than in the risk factors-matched control subjects (n=21). CONCLUSIONS: The transcardiac gradient of plasma VEGF was independently and positively correlated with the coronary blood flow increase in response to ACh. A reduced transcardiac VEGF gradient was present in cardiac syndrome X, a condition with a blunted coronary blood flow response.

Blood Flow Velocity↗
PubMed2006

Transcardiac adiponectin gradient is independently related to endothelial vasomotor function in large and resistance coronary arteries in humans.

Adiponectin, an adipocyte-derived protein, has been shown to have vasculoprotective effects. This study examined the possible relationship between coronary vasomotor function and the transcardiac gradient of adiponectin, reflecting adiponectin utilization and/or accumulation in the coronary vascular bed. The epicardial diameter and blood flow response of the left anterior descending coronary artery to intracoronary infusions of ACh was analyzed in 108 consecutive subjects who had a normal coronary angiogram and left ventriculogram. Adiponectin levels were measured by ELISA in plasma obtained from the aortic root (Ao) and the anterior interventricular vein (AIV). Adiponectin levels in the AIV were lower than levels in the Ao. In multivariate linear regression analysis, the transcardiac gradient of adiponectin (Ao - AIV levels) showed a positive correlation with increases in epicardial coronary diameter and coronary blood flow in response to ACh that was independent of traditional coronary risk factors. The transcardiac gradient of adiponectin was not significantly associated with the coronary dilator response to isosorbide dinitrate and the coronary flow response to sodium nitroprusside. In other groups of patients with coronary spastic angina (n = 41) or microvascular angina (n = 32) who had impaired coronary vasomotor responses, there was no significant gradient of adiponectin between the Ao and AIV. The transcardiac gradient of adiponectin may modulate endothelial vasomotor function in large and resistance coronary arteries and may play a role in the pathogenesis of diseases presenting with coronary vasomotor dysfunction.

Adiponectin↗
PubMed2006

Atorvastatin increases plasma soluble Fms-like tyrosine kinase-1 and decreases vascular endothelial growth factor and placental growth factor in association with improvement of ventricular function in acute myocardial infarction.

OBJECTIVES: This study examined whether atorvastatin increases plasma levels of soluble Fms-like tyrosine kinase 1 (sFlt-1) and reciprocally decreases vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) levels in patients with acute myocardial infarction (AMI). BACKGROUND: Statins exert cardioprotective actions partly through anti-inflammatory actions. By capturing VEGF and PlGF in plasma, sFlt-1 acts as a natural inhibitor of VEGF and PlGF, which have proinflammatory properties. METHODS: Left ventriculography and enzyme-linked immunosorbent assay of plasma levels of sFlt-1, VEGF, and PlGF were repeated after AMI in 50 consecutive patients with a first AMI. Patients were randomized to treatment with atorvastatin (10 mg/day; n=25) or placebo (n=25) within 3 days after AMI, and therapy was continued for 6 months. RESULTS: The sFlt-1 levels were low in the acute phase, followed by an increase at 2 weeks after AMI, whereas free VEGF and PlGF levels were high in the acute phase, followed by a decrease at 2 weeks. Atorvastatin increased sFlt-1 levels and reciprocally decreased VEGF and PlGF levels at 6 months compared with placebo. The increase in sFlt-1 levels and the decrease in VEGF and PlGF levels were correlated with improvement of left ventricular ejection fraction during the follow-up period. CONCLUSIONS: There was a reciprocal relationship between changes in sFlt-1 levels and changes in VEGF and PlGF levels after AMI; and atorvastatin increased sFlt-1 levels while decreasing VEGF and PlGF levels. These changes were associated with late improvement of post-MI ventricular function, and may represent an additional benefit of statin therapy.

Atorvastatin↗
PubMed2006

Role of adiponectin receptors in endothelin-induced cellular hypertrophy in cultured cardiomyocytes and their expression in infarcted heart.

Adiponectin, an adipocyte-derived protein, has cardioprotective actions. We elucidated the role of the adiponectin receptors AdipoR1 and AdipoR2 in the effects of adiponectin on endothelin-1 (ET-1)-induced hypertrophy in cultured cardiomyocytes, and we examined the expression of adiponectin receptors in normal and infarcted mouse hearts. Recombinant full-length adiponectin suppressed the ET-1-induced increase in cell surface area and [(3)H]leucine incorporation into cultured cardiomyocytes compared with cells treated with ET-1 alone. Transfection of small interfering RNA (siRNA) specific for AdipoR1 or AdipoR2 reversed the suppressive effects of adiponectin on ET-1-induced cellular hypertrophy in cultured cardiomyocytes. Adiponectin induced phosphorylation of AMP-activated protein kinase (AMPK) and inhibited ET-1-induced ERK1/2 phosphorylation, which were also reversible by transfection of siRNA for AdipoR1 or AdipoR2 in cultured cardiomyocytes. Transfection of siRNA for alpha(2)-catalytic subunits of AMPK reduced the inhibitory effects of adiponectin on ET-1-induced cellular hypertrophy and ERK1/2 phosphorylation. Effects of globular adiponectin were similar to those of full-length adiponectin, and siRNA for AdipoR1 reversed the actions of globular adiponectin. Compared with normal left ventricle, expression levels of AdipoR1 mRNA and protein were decreased in the remote, as well as the infarcted, area after myocardial infarction in mouse hearts. In conclusion, AdipoR1 and AdipoR2 mediate the suppressive effects of full-length and globular adiponectin on ET-1-induced hypertrophy in cultured cardiomyocytes, and AMPK is involved in signal transduction through these receptors. AdipoR1 and AdipoR2 might play a role in the pathogenesis of ET-1-related cardiomyocyte hypertrophy after myocardial infarction.

Adiponectin↗
PubMed2006

Bidirectional astrocyte-neuron communication: the many roles of glutamate and ATP.

Glutamatergic and purinergic signalling play key roles in synaptic transmission and modulation in the CNS. Here, we review recent evidence showing that glial cells, and in particular astrocytes, are active players in ATP and glutamate signalling in the brain. ATP and glutamate coordinately activate astrocytes, through the mobilization of their internal Ca2+, which in turn triggers the release from astrocytes of several neuroactive molecules including ATP and glutamate themselves. These 'gliotransmitters' signal either to astrocytes, where they generate Ca2+ waves, or to neurons, where they modulate synaptic transmission and neuronal excitability. By using microfabricated lanes of adhesive substrate, we provide further evidence for a diffusible factor-mediated propagation of Ca2+ waves and, through flash photolysis experiments in hippocampal slices, we show that glutamate and ATP cooperate in the generation of the astrocytic Ca2+ signal. Once astrocytes are activated they provide both excitatory and inhibitory effects on neighbouring neurons. Through the Ca2+-dependent release of glutamate, which acts on extrasynaptic neuronal NMDA receptors, astrocytes excite neurons while, in contrast, ATP released from astrocytes, after the delayed conversion to adenosine, causes neuronal suppression.

Action Potentials↗
PubMed2006

Region-directed phototransfection reveals the functional significance of a dendritically synthesized transcription factor.

Multiple nuclear transcription factors including E-26-like protein 1 (Elk-1) have been found in neuronal dendrites, yet the functional significance of such localization has not yet been explained. Here we use a focal transfection procedure, 'phototransfection', to introduce Elk1 mRNA into specific regions of live, intact primary rat neurons. Introduction and translation of Elk1 mRNA in dendrites produced cell death, whereas introduction and translation of Elk1 mRNA in cell bodies did not produce cell death. Elk-1 translated in dendrites was transported to the nucleus, and cell death depended upon transcription, supporting the dendritic imprinting hypothesis and highlighting the importance of the dendritic environment on protein function. Our demonstration of the utility of phototransfection for spatially controlled introduction of mRNAs opens the broader opportunity to use this method to introduce selected quantities of small molecules into discrete regions of live cells to assess their biological functions.

Active Transport, Cell Nucleus↗
PubMed2005

Astrocytic purinergic signaling coordinates synaptic networks.

To investigate the role of astrocytes in regulating synaptic transmission, we generated inducible transgenic mice that express a dominant-negative SNARE domain selectively in astrocytes to block the release of transmitters from these glial cells. By releasing adenosine triphosphate, which accumulates as adenosine, astrocytes tonically suppressed synaptic transmission, thereby enhancing the dynamic range for long-term potentiation and mediated activity-dependent, heterosynaptic depression. These results indicate that astrocytes are intricately linked in the regulation of synaptic strength and plasticity and provide a pathway for synaptic cross-talk.

Adenosine↗
PubMed2005

Endothelial vasomotor dysfunction in the brachial artery is associated with late in-stent coronary restenosis.

OBJECTIVES: This study examined whether endothelial dysfunction in the brachial artery might be associated with late in-stent restenosis (ISR) after percutaneous coronary intervention (PCI). BACKGROUND: Simple and noninvasive identification of late ISR might help to select patients who require further angiographic evaluation. METHODS: Endothelium-dependent flow-mediated dilation (FMD) of the brachial artery was measured before (initial FMD) and at six months (follow-up FMD) after PCI in 141 consecutive patients who had elective and successful PCI with bare metal stents in de novo lesions of native coronary arteries for symptomatic coronary artery disease. Follow-up angiography was performed at six months after PCI in all patients. RESULTS: With multivariate logistic regression analysis, the impairment (< or = 4.8% dilation from baseline diameter) of FMD at follow-up showed the strongest association with late ISR (defined as > 50% diameter stenosis, n = 46) independently of other clinical and angiographic variables known to be associated with ISR (odds ratio 7.4, 95% confidence interval 2.8 to 19.2, p < 0.001), whereas the initial FMD did not have the association. The sensitivity of impaired FMD at follow-up (69%) in detecting ISR was higher than chest pain during the follow-up period (45%), with comparable specificity. The impaired FMD in combination with the chest pain increased the sensitivity to 90%. CONCLUSIONS: The impairment of FMD in the brachial artery at the time of follow-up was independently and closely associated with late ISR in native coronary arteries. The noninvasive assessment of FMD at the time of follow-up might be useful for identification of late ISR.

Aged↗
PubMed2005

Increased ambulatory pulse pressure is a strong risk factor for coronary endothelial vasomotor dysfunction.

OBJECTIVES: This study was aimed to determine the relationship between pulse pressure (PP) and coronary vasomotor dysfunction, a predictor of coronary events. BACKGROUND: Pulse pressure is a strong risk factor for coronary artery disease (CAD). However, the mechanisms by which an increase in PP affects the pathogenesis of CAD are unclear. METHODS: Ambulatory blood pressure (BP) monitoring for 24 h was performed in 103 consecutive patients with normal coronary angiograms (51 hypertensive and 52 normotensive; age 42 to 70 years). The relationship between changes in coronary arterial diameter and blood flow during an intracoronary infusion of acetylcholine (ACh) (5, 10, 50 microg/min), and BP parameters, and other traditional risk factors was evaluated using univariate and multivariate linear regression analyses. RESULTS: With multivariate analyses, the 24-h PP showed an inverse correlation with the epicardial coronary dilator response to ACh independently of other covariates including age, smoking, and 24-h systolic BP in normotensive as well as hypertensive patients. Furthermore, multivariate analysis showed that the 24-h PP was inversely and independently correlated with the increase in coronary blood flow in response to ACh. The dilator response of epicardial coronary arteries to nitrate was not significantly correlated with 24-h PP. CONCLUSIONS: Increased 24-h PP is independently associated with endothelial vasomotor dysfunction in conduit and resistance coronary arteries irrespective of the presence of hypertension. Increased ambulatory PP may have an intimate relation to coronary endothelial vasomotor dysfunction.

Acetylcholine↗
PubMed2005

Remnant lipoproteinemia is a risk factor for endothelial vasomotor dysfunction and coronary artery disease in metabolic syndrome.

This study aimed to determine whether elevated levels of remnant lipoprotein, an atherogenic triglyceride-rich lipoprotein, might be associated with coronary artery disease (CAD) and endothelial vasomotor dysfunction in metabolic syndrome. The fasting serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method in 210 patients with metabolic syndrome meeting ATP III criteria. Flow-mediated endothelium-dependent dilatation (FMD) in the brachial artery during reactive hyperemia was examined by high-resolution ultrasound technique. This study found that elevated RLP-C levels were a significant and independent risk factor for impaired FMD and angiographically proven coronary artery disease (CAD). Treatment with bezafibrate (n = 20) or atorvastatin (n = 20) for 4 weeks significantly reduced RLP-C levels, with a concomitant improvement in FMD. The % reduction in RLP-C levels from baseline after the treatment was independently correlated with the magnitude of improvement in FMD after adjustment for the % changes in levels of triglyceride, hsCRP, and IL-6, and HOMA index. Thus, elevated levels of RLP-C are a risk factor for CAD and endothelial vasomotor dysfunction, a predictor of coronary events, in metabolic syndrome. Measurement of RLP-C is useful for assessment of CAD risk and therapeutic effects in metabolic syndrome.

Aged↗
PubMed2004

Correlation of plasma concentrations of B-type natriuretic peptide with infarct size quantified by tomographic thallium-201 myocardial scintigraphy in asymptomatic patients with previous myocardial infarction.

BACKGROUND: Secretion of A-type (atrial) and B-type (brain) natriuretic peptides (ANP and BNP) increases in relation to left ventricular (LV) dysfunction in patients with myocardial infarction (MI). However, it is unknown what determines the concentrations of ANP and BNP in asymptomatic MI patients with preserved LV function, so the aim of the present study was to examine if they are associated with MI size. METHODS AND RESULTS: Plasma concentrations of ANP and BNP in the peripheral blood were measured in 88 asymptomatic (New York Heart Association class I) patients with previous MI. The infarct size was quantitatively calculated from rest thallium-201 myocardial single photon emission computed tomography. In multivariate linear regression analysis that included MI size, hemodynamic parameters, and age as covariables, only BNP concentrations had a significant association with MI size (p=0.0001). In contrast, ANP concentrations were not significantly correlated with MI size in either the univariate or multivariate analysis. CONCLUSIONS: BNP but not ANP concentrations increased in proportion to the scintigraphic MI size despite the lack of heart failure in asymptomatic patients with previous MI. Thus, the increase in plasma BNP concentrations reflects the MI size, an important determinant of prognosis, in asymptomatic patients with MI.

Adult↗
PubMed2004

Blunted reduction of pulse pressure during nighttime is associated with left ventricular hypertrophy in elderly hypertensive patients.

Increased pulse pressure (PP) is recognized as a risk factor for cardiovascular disease, especially in elderly patients. However, blood pressure (BP) is known to have a circadian variation. Therefore, this study asked whether or not PP has a circadian variation and, if so, whether a circadian variation of PP has clinical importance. Ambulatory BP monitoring (every 30 min for 48 h) was performed in 255 patients with untreated essential hypertension (24 to 82 years old; mean: 52+/-12 years). Left ventricular mass index (LVMI) was estimated from M-mode echocardiography. PP was decreased during nighttime (10+/-11% reduction from daytime PP). Multivariate linear regression analysis showed that, among four variables-the degree of nighttime PP reduction, daytime PP, 48-h systolic BP, and nondipper hypertension-the degree of nighttime PP reduction had the strongest (inverse) correlation with LVMI in a subgroup of elderly patients (> or =60 years old, n =67) (standardized regression coefficient=-0.32, p =0.02), whereas this association was not significant in the whole patient population unclassified by age. Furthermore, a blunted reduction of nighttime PP in combination with nondipper hypertension was an incremental risk for increase in LVMI in the elderly patients. In conclusion, PP is reduced during nighttime, but the degree of reduction varies among patients. The blunted reduction of nighttime PP is a risk for left ventricular hypertrophy, an established predictor of hypertension-induced cardiovascular events, and it may thus play a role in cardiovascular complications, especially in elderly patients with nondipper hypertension.

Adult↗
PubMed2004

[Therapeutic angiogenesis by autologous transplantation of bone-marrow cells in a patient with progressive limb ischemia due to arteriosclerosis obliterans: a case report].

A 78-year-old woman with arteriosclerosis obliterans was admitted with complaints of progressive ischemic change and resting pain of the left leg. She had severe ischemic limb in stage IV of the Fontaine classification. Angiography showed total occlusion of the three main arteries with poor collateral flow at the left crus. Autologous transplantation of bone-marrow mononuclear cell to her left leg was performed to achieve therapeutic angiogenesis. One month later, follow-up angiography showed excellent angiogenesis of collateral vessels at the left crus. Her pain was relieved and leg amputation was not necessary. Recently, the TACT study in Japan showed the efficacy of angiogenesis by autologous bone-marrow transplantation for peripheral artery disease. This case illustrates the efficacy of this therapy.

Aged↗
PubMed2004

Relationship between the visiting birds and nectar secretion in the cherry tree.

The flying birds to cherry tree, Prunus campanulata, are well known. However since their relationship has not yet been examined, then the present study elucidated their relationship at Tama Forestry and Forest Product Research Institute. The observation of flying birds was carried out on their species, number, attitude and visiting time, with naked eye, a video camera, and a camera from the blind. The observations were carried out every 15 minutes during 5 to 12 hours per day. The efflorescence grade was divided into 4 stages. Bulbul visited most frequently to the tree among visiting birds, on the other hand white-eye visited hardly due to the disturbance by bulbul. The nectar grade gradually increased together with the efflorescence grade, then reached 30% at the 4th stage.

Animals↗
PubMed2002

Micropatterned substrates: approach to probing intercellular communication pathways.

Intercellular signaling is critical for the normal development and physiology of the central nervous system (CNS). To study such signaling, it is vital to control where and when the cells make contact with one another. It is also important to determine whether the process used for cell localization has an impact on signaling. This paper describes a technique that controls the location for cell growth in vitro and demonstrates that the technique has minimal (if any) impact on intercellular signaling. By using photolithographic methods, poly(dimethylsiloxane) molds were fabricated to function as templates for micrometer-level patterning of a nonadhesive agar (agarose) onto glass coverslips coated with a cell adhesive film (poly(L-lysine)). This process yields a surface composed of well-defined adhesive and nonadhesive microdomains. When endothelia or astrocytes are plated onto these substrates, confluent domains of endothelia or astrocytes grow on the poly(L-lysine) domains. Cocultures of astrocytes and neurons can also successfully be used to form interwoven networks on the adhesive domains. Moreover, studies of calcium signaling revealed that astrocytes grown on such patterns retain their native physiological activity. This conclusion is based on the observed propagation rate for calcium waves within individual astrocyte domains and across neighboring, but spatially disconnected, astrocyte domains. The potential to apply these micropatterned substrates as platforms for interrogating communication pathways in key components of the CNS is discussed.

Astrocytes↗
PubMed2002

Methylenetetrahydrofolate reductase genotype, vitamin B12, and folate influence plasma homocysteine in hemodialysis patients.

Hyperhomocysteinemia, a well-recognized cardiovascular risk factor, is frequent in hemodialysis (HD) patients. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, C-->T substitution at nucleotide 677, is associated with homocysteine (Hcy) level elevation. We examined whether three factors involved in the methionine cycle could influence plasma Hcy concentrations in HD patients: MTHFR polymorphism; vitamin B12, an essential cofactor; and folate, the substrate. In a cross-sectional study, serum vitamin B12, folate, and plasma Hcy were measured and MTHFR genotyping was performed in 534 HD patients. Effects of MTHFR genotypes, vitamin B12, and folate on plasma Hcy levels were examined in 450 HD patients not administered vitamin B12 or folate. To examine the effect of vitamin B12 on plasma Hcy concentrations, we compared plasma Hcy concentrations in HD patients with and without vitamin B12 supplementation. To examine whether functional vitamin B12 deficiency exists even in HD patients with normal vitamin B12 concentrations, 15 HD patients (serum vitamin B12 concentrations, 250 to 2,100 pg/mL) were treated with vitamin B12 (mecobalamin, 1.5 mg/d) for 8 weeks. Serum concentrations of methylmalonic acid (MMA) and vitamin B12 were measured. Hcy levels were higher and folate levels were lower in patients with the TT and CT genotypes compared with patients with the CC genotype. Analysis of covariance to determine independent predictors of high Hcy levels identified low serum vitamin B12 and folate levels and high albumin (Alb) levels in CC-genotype patients, low folate levels and high Alb levels in CT-genotype patients, and low folate levels in TT-genotype patients. Plasma Hcy levels were lower in CC- and CT-genotype patients with vitamin B12 supplementation than in those without supplementation. Vitamin B12 supplementation for 8 weeks significantly reduced MMA concentrations in HD patients with normal serum vitamin B12 concentrations. These results indicate that MTHFR genotype influences the correlation of Hcy level with vitamin B12 and folate levels in HD patients. Functional vitamin B12 deficiency may exist, even in HD patients with normal vitamin B12 concentrations. The efficacy of vitamin B12 and folate supplementation on plasma Hcy levels may depend on MTHFR genotype.

Cross-Sectional Studies↗