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Biomedical subjects

Takashi Akasaka

Publications and source records attributed to Takashi Akasaka.

At least 19 recordsLinked to original sources
PubMed2006

Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

CCAAT enhancer-binding protein (CEBP) transcription factors play pivotal roles in proliferation and differentiation, including suppression of myeloid leukemogenesis. Mutations of CEBPA are found in a subset of acute myeloid leukemia (AML) and in some cases of familial AML. Here, using cytogenetics, fluorescence in situ hybridization (FISH), and molecular cloning, we show that 5 CEBP gene family members are targeted by recurrent IGH chromosomal translocations in BCP-ALL. Ten patients with t(8;14)(q11;q32) involved CEBPD on chromosome 8, and 9 patients with t(14;19)(q32;q13) involved CEBPA, while a further patient involved CEBPG, located 71 kb telomeric of CEBPA in chromosome band 19q13; 4 patients with inv(14)(q11q32)/t(14;14)(q11;q32) involved CEBPE and 3 patients with t(14;20)(q32;q13) involved CEBPB. In 16 patients the translocation breakpoints were cloned using long-distance inverse-polymerase chain reaction (LDI-PCR). With the exception of CEBPD breakpoints, which were scattered within a 43-kb region centromeric of CEBPD, translocation breakpoints were clustered immediately 5' or 3' of the involved CEBP gene. Except in 1 patient with t(14;14)(q11;q32), the involved CEBP genes retained germ-line sequences. Quantitative reverse transcription (RT)-PCR showed overexpression of the translocated CEBP gene. Our findings implicate the CEBP gene family as novel oncogenes in BCP-ALL, and suggest opposing functions of CEBP dysregulation in myeloid and lymphoid leukemogenesis.

Burkitt Lymphoma↗
PubMed2006

Effects of angiotensin II on NO bioavailability evaluated using a catheter-type NO sensor.

We investigated the acute or chronic effects of angiotensin (Ang) II on the bioavailability of NO in Ang II-infused rabbits using the catheter-type NO sensor. Male New Zealand White rabbits were infused with vehicle (sham), Ang II at a rate of 200 ng/kg per minute, either alone or in combination with hydralazine, Ang II type I receptor antagonist (valsartan), or an antioxidant (tempol) for 24 hours or 14 days. Plasma NO concentration was measured using the catheter-type NO sensor located in the aorta. We then infused saline (vehicle) and acetylcholine (ACh) into the aortic arch with or without pretreatment with N(G)-methyl-l-arginine. An increase in plasma NO levels in response to ACh was significantly attenuated in the Ang II group compared wit the control group. The decrease in the basal plasma NO concentration was significantly lower in the Ang II group than in the control group. Plasma peroxynitrite concentrations in Ang II group were significantly higher than in the control group. The negative effects of Ang II, that is, the decrease in basal and ACh-induced NO production and the increase in oxidative stress, were significantly suppressed by the cotreatment with either valsartan or tempol. Short-term treatment with Ang II significantly increased the ACh-induced increase in plasma NO concentration, as well as basal NO release. Although Ang II stimulates release of NO in the short term, chronic treatment with Ang II elicits the decreased NO bioavailability in the aorta of the Ang II-infusion rabbit model.

Angiotensin II↗
PubMed2006

The effect of senescence of endothelial progenitor cells on in-stent restenosis in patients undergoing coronary stenting.

OBJECTIVE: Restenosis after stent implantation is caused by endothelial cell damage and subsequent neointimal formation. The objective of this study is to elucidate the relevance of endothelial progenitor cells (EPCs) in the development of in-stent restenosis in patients undergoing stent implantation. PATIENTS OR MATERIALS: The subjects were 46 patients who underwent coronary stenting. Blood samples were collected at the time of follow-up coronary angiography after coronary stenting. EPCs were isolated from blood samples and cultured. Their phenotypes were confirmed by uptake of acetylated low-density lipoprotein and binding of fluorescein isothiocyanate-labeled Ulex europaeus agglutinin 1 lectin. The number of colony-forming units (CFUs) and the senescent cells, determined by acidic beta-galactosidase staining, was counted. Angiogenic growth factors secreted by EPCs, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), hepatocyte growth factor (HGF), and macrophage chemoattractant protein (MCP-1) from the culture medium were also measured by enzyme-linked immunosorbent assay. RESULTS: Patients with in-stent restenosis (defined as >40% stenosis, n=16) had a decreased number of CFUs (p<0.05), and increased senescent cells (p<0.05), compared to patients without restenosis (n=30). There was no significant difference of angiogenic growth factors (VEGF, HGF, b-FGF, and MCP-1) secreted by EPCs between the two groups. On multivariate analysis, an increased number of senescent EPCs was the indepen-dent factor associated with in-stent restenosis (OR 1.10, 95% CI 1.01 to 1.20). CONCLUSION: These data suggested that EPCs might be involved in the development of in-stent restenosis.

Aged↗
PubMed2006

Assessment of coronary arterial thrombus by optical coherence tomography.

We analyzed optical coherence tomographic (OCT) characteristics of different types of coronary thrombi that had been confirmed at postmortem histologic examination. We examined 108 coronary arterial segments of 40 consecutive human cadavers. OCT images of red and white thrombi were obtained and the intensity property of these thrombi was analyzed. Red and white thrombi were found in 16 (17%) and 19 (18%) of the 108 arterial segments, respectively. Red thrombi were identified as high-backscattering protrusions inside the lumen of the artery, with signal-free shadowing in the OCT image. White thrombi were identified as low-backscattering projections in the OCT image. There were no significant differences in peak intensity of OCT signal between red and white thrombi (130+/-18 vs 145+/-34, p=0.12). However, the 1/2 attenuation width of the signal intensity curve, which was defined as the distance from peak intensity to its 1/2 intensity, was significantly different between red and white thrombi (324+/-50 vs 183+/- 42 microm, p<0.0001). A cut-off value of 250 microm in the 1/2 width of signal intensity attenuation can differentiate white from red thrombi with a sensitivity of 90% and specificity of 88%. We present the first detailed description of the characteristics of different types of coronary thrombi in OCT images. Optical coherence tomography may allow us not only to estimate plaque morphology but also to distinguish red from white thrombi.

Aged↗
PubMed2006

Assessment of coronary arterial plaque by optical coherence tomography.

The purpose of this study was to analyze the ability of optical coherence tomography (OCT) to identify coronary arterial plaque diagnosed by histologic examination. We examined 166 sections from 108 coronary arterial segments of 40 consecutive human cadavers (24 men and 16 women; mean age 74 +/- 7 years). The plaque type was classified as fibrous (n = 43), fibrocalcific (n = 82), or lipid-rich (n = 41). The accuracy of OCT and intravascular ultrasound (IVUS) in characterizing the plaque type was studied, with the histologic consensus diagnosis serving as the gold standard. OCT, as well as IVUS, had high sensitivity and specificity for characterizing the different types of atherosclerotic plaque. OCT had a higher sensitivity for characterizing lipid-rich plaques than IVUS (85% vs 59%, p = 0.03). In conclusion, the high resolution of OCT permitted evaluation of lipid-rich plaques more accurately than IVUS.

Aged↗
PubMed2006

Sirolimus accelerates senescence of endothelial progenitor cells through telomerase inactivation.

BACKGROUND: Sirolimus-eluting stent (SES) is commonly used to prevent in-stent restenosis but is not infrequently complicated by late angiographic stent thrombosis (LAST). On the other hand, circulating endothelial progenitor cells (EPCs) play a significant role in the maintenance of endothelial integrity. AIM: We examined whether sirolimus affects differentiation, proliferative activity, senescence, colony formation, and network formation in EPCs originated from mononuclear cells (MNCs). METHODS AND RESULTS: MNCs were isolated from peripheral blood of healthy volunteers. EPCs outgrew from the culture of MNCs in the presence of vascular endothelial growth factor. When MNCs were incubated with sirolimus at 0.01, 0.1, and 1 ng/ml for 4 days, sirolimus dose-dependently reduced the number of differentiated, adherent EPCs, as assessed by an in vitro culture assay. After ex-vivo cultivation, EPCs became senescent as determined by acidic beta-galactosidase staining. When MNCs were treated with sirolimus, sirolimus dose-dependently accelerated the onset of EPCs senescence. RT-PCR analysis demonstrated that FK506-binding protein 12 (FKBP12), a receptor of sirolimus, was expressed in MNCs. To obtain an insight into the underlying downstream effects of sirolimus, we measured telomerase activity and the expression of p27(kip1). Sirolimus decreased telomerase activity dose-dependently, which was accompanied with down-regulation of the catalytic subunit, telomerase reverse transcriptase (TERT). Furthermore, sirolimus up-regulated the cell cycle inhibitor p27(kip1). Having demonstrated that sirolimus accelerated the onset of senescence, we examined whether that translated into a decrease in proliferative activity and clonal expansion. Both MTS assay and BrdU incorporation assay have shown that sirolimus treatment significantly diminished the proliferative activity in EPCs. In addition, colony forming unit assay revealed that sirolimus dramatically decreased colony formation as compared to control (no treatment). Finally, in a Matrigel assay, EPCs treated with sirolimus were shown to be less integrated into the network formation than control (no treatment). CONCLUSION: The inhibitory effects of sirolimus on circulating EPCs potently may affect re-endotheliazation after SES implantation.

Blotting, Western↗
PubMed2006

Measurement of the thickness of the fibrous cap by optical coherence tomography.

BACKGROUND: Identification of the fibrous cap is important because its thickness is a major determinant of plaque vulnerability in lipid-rich plaque. Thus, a high-resolution imaging technique may be a promising method for the identification of the fibrous cap within lipid-rich plaque. The purpose of this study was to investigate the feasibility of using optical coherence tomography (OCT) to measure the thickness of the fibrous cap within lipid-rich plaque. METHODS AND RESULTS: We examined 35 lipid-rich plaques from 102 coronary arterial segments of 38 human cadavers (22 men and 16 women; mean ages, 74 +/- 7 years). Optical coherence tomography and corresponding histological images were digitized for measurement of the thickness of fibrous cap, and the results between OCT and histological examination were compared. There was good correlation of the thickness of the fibrous cap between OCT and histological examination (y = 0.97x + 28.49; r = 0.90; P < .001). A Bland-Altman test showed good agreement of the thickness of the fibrous cap between OCT and histological examination (mean difference, -24 +/- 44 microm). CONCLUSIONS: Optical coherence tomography provides an accurate representation of the thickness of the fibrous cap and may prove useful in assessing plaque vulnerability in lipid-rich plaque.

Aged↗
PubMed2006

Geometric differences of the mitral valve tenting between anterior and inferior myocardial infarction with significant ischemic mitral regurgitation: quantitation by novel software system with transthoracic real-time three-dimensional echocardiography.

We sought to investigate the 3-dimensional geometric differences of mitral leaflet tenting in ischemic mitral regurgitation, comparing inferior and anterior myocardial infarction (MI). Using real-time 3-dimensional echocardiography, we obtained transthoracic volumetric images for patients with significant ischemic mitral regurgitation (9 inferior and 7 anterior). With our novel software system, 3-dimensional images of the leaflets were reconstructed for quantitation. Mitral leaflet configuration was then represented in contour in which the degree of the tenting could be observed. Calculated percent of tethered leaflet area (>5-mm tenting from the annular level) was compared in inferior and anterior MI. Percent of tethered leaflet area was significantly smaller in inferior than anterior MI, reflecting the localized leaflet tenting in inferior MI (16.7 +/- 18.8% vs 38.9 +/- 9.7%, P = .01). In anterior MI, mitral valve leaflets were widely tethered toward the left ventricle, in contrast with inferior MI showing localized tenting of the leaflet.

Aged↗
PubMed2006

Heterogeneity of myocardial perfusion in distal coronary embolism with different particle sizes.

BACKGROUND: We hypothesized that altered myocardial perfusion distribution patterns could be seen with coronary distal emboli of different particle sizes using myocardial contrast echocardiography. METHODS: In 16 open-chest anesthetized dogs, microsphere suspensions of 9 or 500 microm in diameter were injected into the left anterior descending coronary artery until the mean left anterior descending coronary artery flow rate was reduced to less than 30% of baseline flow. During baseline conditions and after maximal embolization, real-time myocardial contrast echocardiography was performed by intravenous infusion of an echocontrast agent. RESULTS: In animals infused with 9-microm microspheres, a transmural perfusion defect was seen at the time of maximal embolization. In contrast, in animals infused with 500-microm microspheres, a subendocardial perfusion defect was observed. CONCLUSIONS: The particle size of coronary distal emboli affects myocardial perfusion distribution.

Animals↗
PubMed2006

Coronary flow velocity pattern assessed noninvasively by transthoracic color Doppler echocardiography serves as a predictor of adverse cardiac events and left ventricular remodeling in patients with acute myocardial infarction.

BACKGROUND: Quantitative assessment of microvascular injury is possible in patients with reperfused anterior myocardial infarction by invasive method. Coronary flow velocity patterns can also be assessed by transthoracic color Doppler echocardiography (TTCDE). OBJECTIVES: The purpose of this study was to determine whether the coronary flow velocity pattern assessed by TTCDE serves as a predictor of adverse cardiac events and left ventricular remodeling. METHODS: The study population consisted of 64 consecutive patients. We could analyze coronary flow velocity patterns by TTCDE in 59 of 64 patients (92%) after coronary intervention. The patients were followed up for the occurrence of complications and underwent serial measurement of left ventricular volumes. RESULTS: In patients with a short deceleration time of diastolic flow velocity, the frequency of adverse cardiac events and left ventricular remodeling was higher. CONCLUSION: It is possible to predict clinical outcome by assessing coronary flow velocity pattern by TTCDE.

Blood Flow Velocity↗
PubMed2006

Rate of progression of valvular aortic stenosis in patients undergoing dialysis.

BACKGROUND: In patients undergoing dialysis, aortic valve calcification and aortic stenosis are frequently found. However, the rate of progression of aortic stenosis is still unclear. METHODS: In all, 55 consecutive patients undergoing dialysis were followed up by echocardiography for a period of 12 months. Patients were divided into two groups: noncalcification (no or mildly calcified aortic valve) and calcification (moderate or heavily calcified aortic valve). RESULTS: The rate of progression of maximum aortic jet velocity and degression of aortic valve area were more rapid in calcification group than in noncalcification group (0.37 +/- 0.36 m/s and 0.17 +/- 0.29 m/s, P = .027; 0.17 +/- 0.15 cm2 and 0.04 +/- 0.07 cm2, P < .001, respectively). CONCLUSIONS: The degree of aortic stenosis progressed more rapidly in patients undergoing dialysis with aortic valve calcification than without aortic valve calcification.

Aged↗
PubMed2006

Chromosomal translocations fusing the BCL6 gene to different partner loci are recurrent in primary central nervous system lymphoma and may be associated with aberrant somatic hypermutation or defective class switch recombination.

Primary central nervous system lymphomas (PCNSLs) are diffuse large B cell lymphomas confined to the brain. Only minimal data exist on chromosomal aberrations underlying PCNSLs. We studied 41 PCNSLs by fluorescence in situ hybridization for breakpoints affecting the BCL6 locus in chromosomal band 3q27. Of 37 cases evaluable, 14 (38%) carried a breakpoint in the BCL6 locus. Two of these showed juxtaposition of BCL6 to the IGH locus. In 4 cases, the BCL6 breakpoints were cloned using long-distance inverse polymerase chain reaction. All breakpoints were located within the BCL6 major translocation cluster. The translocation partners were the IGH gene in 14q32.33, the IGL gene in 22q11.22, and the histone 1 H4I gene in 6p22.1. In the fourth case, a deletion in 3q leads to loss of an 837-kb fragment extending from the first intron of BCL6 to the third intron of the lipoma-preferred partner (LPP) gene. This deletion may bring the BCL6 gene under the control of regulatory elements of the LPP gene or the miRNA-28 gene located in intron 4 of LPP. DNA sequence analysis of the junctional sequences provided evidence that aberrant class switch recombination or somatic hypermutation may be involved in the generation of BCL6 translocations.

Base Sequence↗
PubMed2006

Hyperglycemia accelerated endothelial progenitor cell senescence via the activation of p38 mitogen-activated protein kinase.

BACKGROUND: Both the number and function of bone marrow-derived endothelial progenitor cells (EPCs) have been shown to be impaired in patients with diabetes mellitus. Therefore, we investigated the effect of glucose on the senescence of EPCs. METHODS AND RESULTS: EPCs were isolated from human peripheral blood and characterized to evaluate the effect of glucose (in 5-12.5 mmol/L) on the rate of senescence by acidic beta-galactosidase staining. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) level was analyzed by ELISA. The exposure of cultured EPC to high glucose (HG; 12.5 mmol/L) significantly accelerated the rate of senescence compared with that in osmolar control (L-glucose) during 10 days culture. An inhibitory effect of HG on EPC proliferation disclosed by an MTS assay. The phosphorylation of p38 MAPK in EPCs was also increased by glucose compared with control in a dose-dependent manner. HG-induced EPC senescence was significantly inhibited by the addition of an inhibitor of the p38 MAPK, SB203580. CONCLUSIONS: HG accelerates the onset of EPCs senescence leading to the impairment of proliferative activity, which might be related to the phosphorylation of p38 MAPK.

Cell Differentiation↗
PubMed2006

Endothelial progenitor cell differentiation and senescence in an angiotensin II-infusion rat model.

The ability of endothelial progenitor cells (EPCs) to participate in endothelial repair is impaired by angiotensin II (Ang II) and other atherogenic factors. Therefore, we investigated the effects of Ang II on the differentiation and senescence of EPCs derived from bone marrow (BM-EPCs) in an Ang II-infusion rat model. Wistar rats (n=40) were infused with Ang II or vehicle, either alone or in combination with an Ang II type 1 receptor (AT(1)R) blocker (valsartan). Bone marrow cells were obtained from the tibias and femurs. Rats of the Ang II treatment group had a significantly lower number of differentiated, adherent BM-EPCs than those of the non-treated control group. Addition of valsartan restored the level of attached, differentiated BM-EPCs to the level in the non-treated controls. The number of senescent BM-EPCs, as assessed by acidic beta-galactosidase staining, was significantly greater in the Ang II-alone group than the control group, and addition of valsartan dramatically delayed the senescence of BM-EPCs in the Ang II-alone group. A polymerase chain reaction (PCR)-ELISA-based assay revealed that telomerase activity was significantly lower in BM-EPCs from the Ang II-alone group than in those from the control group, and addition of valsartan significantly augmented this activity. An MTS assay revealed that Ang II treatment significantly decreased the functional activity in BM-EPCs, and this effect was significantly reversed by valsartan. In conclusion, Ang II decreased the differentiation and accelerated the senescence of BM-EPCs via AT(1)R.

Angiotensin II↗
PubMed2006

[Mechanisms of coronary plaque formation and disruption].

We review here the evolutional understanding of the pathophysiology of chronic and acute phase of coronary artery disease (CAD). Although we previously considered CAD as a cholesterol storage disease, we currently understand that atherosclerosis is an inflammatory disorder and inflammation plays a major role in all stages of atherogenesis. We formerly focused our attention on luminal narrowing due to the atheroma. However, we now recognize the need to attend to non-obstructive lesions and their biological attributes as well. Moreover, plaque disruption is thought to occur due to, not only local changes in the plaque itself, but also systemic changes in the patient. Thus, treatment of CAD should involve the approach of mechanical revascularization and systemic preventive intervention.

Blood Coagulation↗
PubMed2005

Comparison of high-frequency two-dimensional transthoracic echocardiography versus intravascular ultrasound for evaluation of the left anterior descending coronary artery.

The purpose of this study was to evaluate the feasibility of high-frequency transthoracic echocardiography for measuring the wall thickness and luminal area of the left anterior descending coronary artery (LAD). Fifteen patients underwent simultaneous high-frequency transthoracic echocardiography and intravascular ultrasound (IVUS) examinations. There were good agreements for wall thickness (0.38 +/- 0.05 vs 0.38 +/- 0.06 mm, p = 0.0004) and luminal area (3.24 +/- 1.05 vs 3.32 +/- 1.34 mm2, p <0.0001) between high-frequency transthoracic echocardiography and IVUS measurements. High-frequency transthoracic echocardiography was reliable in the measurement of the wall thickness and luminal area of the LAD.

Angina Pectoris↗
PubMed2005

Mitral annulus flattens in ischemic mitral regurgitation: geometric differences between inferior and anterior myocardial infarction: a real-time 3-dimensional echocardiographic study.

BACKGROUND: New surgical strategies to restore the saddle shape of the mitral annulus are expected to increase annuloplasty effectiveness. Preoperative and postoperative configuration of the curved annulus, however, is difficult to quantify with 2-dimensional echocardiography. We sought to investigate the geometric deformity in the mitral annulus in ischemic mitral regurgitation (MR), comparing inferior and anterior myocardial infarction (MI) with the use of a custom quantitation software system with transthoracic 3-dimensional echocardiography. METHODS AND RESULTS: We performed real-time 3-dimensional echocardiography in 23 patients with ischemic MR attributable to inferior MI or anterior MI and in 10 controls. Three-dimensional data were cropped into 18 radial planes, and we manually marked the annulus in mid systole. Three-dimensional annular images were reconstructed, and annular circumferences, areas, and heights were quantified. Annulus was significantly more dilated and flattened in ischemic MR than in controls and was further deformed in anterior MI as compared with inferior MI (control: circumference 9.9+/-0.7 cm, area 9.6+/-0.5 cm2, height 5.0+/-0.7 mm; inferior MI: circumference 11.5+/-1.2 cm [P<0.01 compared with control], area 11.4+/-2.0 cm2 [P<0.05 compared with control], height 3.5+/-1.6 mm [P<0.05 compared with control]; anterior MI: circumference 14.2+/-2.4 cm [P<0.0001 compared with control, P<0.05 compared with inferior MI], area 13.7+/-2.8 cm2 [P<0.01 compared with control, P<0.05 compared with inferior MI], height 1.7+/-1.5 mm [P<0.0001 compared with control, P<0.05 compared with inferior MI]). CONCLUSIONS: Mitral annulus flattens in ischemic MR. Deformity of the mitral annulus was greater in anterior MI group than in the inferior MI group.

Aged↗