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Biomedical subjects

Kenji Harada

Publications and source records attributed to Kenji Harada.

At least 19 recordsLinked to original sources
PubMed2004

Kinetic evidence for remote pi-aryl participation in the BF3-catalyzed rearrangement of [2 + 2] photocycloadducts of diarylhomobenzoquinones with diphenylacetylene.

[reaction: see text] The BF(3)-catalyzed rearrangement of cyclobutene-fused m- and p-substituted diarylhomobenzoquinones exclusively gave the keto-alcohols via a Wagner-Meerwein vinyl-anion migration followed by the annulation of a delta-located endo-aryl group. The Hammett treatments for the endo/exo substituent effects, as well as the kinetic solvent effects, indicated that this reaction proceeds through the concerted S(N)2-like mechanism involving a rate-determining endo-aryl-assisted transition state.

Journal Article↗
PubMed2004

Usefulness of tissue doppler imaging for assessing aortic wall stiffness in children with the Marfan syndrome.

The purpose of this study was to assess wall motion velocities of the abdominal aorta using tissue Doppler imaging (TDI) in 12 patients with Marfan syndrome and 30 age-matched normal controls. The patients with Marfan syndrome displayed an increased aortic stiffness index in the abdominal aorta, and significant relationships were observed between wall motion velocities of the abdominal aorta and the aortic stiffness index. Thus, TDI analyzes aortic expansion and contraction velocities and allows the identification of abdominal aortic stiffness in patients with Marfan syndrome.

Adolescent↗
PubMed2004

p53 involvement in the pathogenesis of fatty liver disease.

Obesity is a major health problem in industrialized societies, and fatty liver disease (hepatic steatosis) is common in obese individuals. Oxidative stress originating from increased intracellular levels of fatty acids has been implicated as a cause of hepatocellular injury in steatosis, although the precise mechanisms remain to be elucidated. p53, widely known as a tumor suppressor, has been shown often to be activated in stressed cells, inducing cell cycle arrest or death. Here we demonstrate that p53 is involved in the molecular mechanisms of hepatocellular injury associated with steatosis. We found that p53 in the nucleus is induced in the liver from two mouse models of fatty liver disease, ob/ob and a transgenic mouse model that overexpresses an active form of sterol regulatory element-binding protein-1 in the liver (TgSREBP-1), the one with obesity and the other without obesity. This activation of the p53 pathway leads to the elevation of p21 mRNA expression, which can be considered an indicator of p53 activity, because ob/ob mice lacking p53 generated by targeting gene disruption exhibited the complete restoration of the p21 elevation to wild type levels. Consistent with these results, the amelioration of hepatic steatosis caused by Srebp-1 gene disruption in ob/ob mice lowered the p21 expression in a triglyceride content-dependent manner. Moreover, p53 deficiency in ob/ob mice resulted in a marked improvement of plasma alanine aminotransferase levels, demonstrating that p53 is involved in the mechanisms of hepatocellular injury. In conclusion, we revealed that p53 plays an important role in the pathogenesis of fatty liver disease.

Animals↗
PubMed2004

Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice.

Hormone-sensitive lipase (HSL) plays a crucial role in the hydrolysis of triacylglycerol and cholesteryl ester in various tissues including adipose tissues. To explore the role of HSL in the metabolism of fat and carbohydrate, we have generated mice lacking both leptin and HSL (Lep(ob/ob)/HSL(-/-)) by cross-breeding HSL(-/-) mice with genetically obese Lep(ob/ob) mice. Unexpectedly, Lep(ob/ob)/HSL(-/-) mice ate less food, gained less weight, and had lower adiposity than Lep(ob/ob)/HSL(+/+) mice. Lep(ob/ob)/HSL(-/-) mice had massive accumulation of preadipocytes in white adipose tissues with increased expression of preadipocyte-specific genes (CAAT/enhancer-binding protein beta and adipose differentiation-related protein) and decreased expression of genes characteristic of mature adipocytes (CCAAT/enhancer-binding protein alpha, peroxisome proliferator activator receptor gamma, and adipocyte determination and differentiation factor 1/sterol regulatory element-binding protein-1). Consistent with the reduced food intake, hypothalamic expression of neuropeptide Y and agouti-related peptide was decreased. Since HSL is expressed in hypothalamus, we speculate that defective generation of free fatty acids in the hypothalamus due to the absence of HSL mediates the altered expression of these orexigenic neuropeptides. Thus, deficiency of both leptin and HSL has unmasked novel roles of HSL in adipogenesis as well as in feeding behavior.

Adipocytes↗
PubMed2004

Losartan improves regional left ventricular systolic and diastolic function in patients with hypertension: accurate evaluation using a newly developed color-coded tissue doppler imaging technique.

BACKGROUND: Angiotensin II receptor antagonists have recently been accepted as antihypertensive therapy. Tissue Doppler imaging (TDI) has been developed as a noninvasive tool to assess quantitatively regional myocardial motion abnormalities. This study was designed to determine whether our newly developed technique of color-coded TDI may be a useful means of quantifying the improvement in regional left ventricular (LV) myocardial contractility and relaxation after treatment with losartan in patients with hypertension. METHODS AND RESULTS: Losartan (50 to 100 mg) was administered for 6 months to 37 previously untreated patients with essential hypertension. Averaged myocardial velocity profiles (MVPs) for color-coded TDI were recorded in the ventricular septum and LV posterior wall before and after treatment. Peak myocardial velocities and peak myocardial velocity gradients (MVGs) in the LV walls were determined during systole and early diastole. The plasma concentration of transforming growth factor (TGF)-beta1 also was measured in all patients. Blood pressure and plasma TGF-beta1 level decreased after initiation of losartan therapy. The LV mass index and LV meridional end-systolic wall stress also decreased after treatment with losartan. LV geometry changed from a pattern consistent with concentric hypertrophy to normal geometry in 10 patients and to a pattern consistent with concentric remodeling in 5 patients, and from concentric remodeling to normal geometry in 5 patients after treatment with losartan. The ratio of early to late diastolic filling for the transmitral flow velocity increased after losartan treatment. The peak systolic and early diastolic myocardial velocities and MVGs in the ventricular septum and LV posterior wall increased after treatment with losartan, although the values 6 months after treatment with losartan were still lower than those in normal individuals. There were good correlations between changes in plasma TGF-beta1 level and changes in systolic and early diastolic MVGs 6 months after losartan. However, there were no significant correlations between changes in the systolic blood pressure and LV end-systolic wall stress and changes in the TDI parameters. CONCLUSION: Losartan improves regional LV function in patients with hypertension. Our newly developed averaged MVP and MVG measurements may be useful for accurately evaluating regional LV myocardial contractility and relaxation in these patients.

Aged↗
PubMed2004

Quantitative assessment of right ventricular function using doppler tissue imaging in fetuses with and without heart failure.

BACKGROUND: Previous reports have established the use of Doppler tissue imaging (DTI) for noninvasive assessment of ventricular function, but the technique has not been validated for diagnosis of fetal cardiac failure. OBJECTIVE: The purpose of this study was to assess right ventricular (RV) function in fetuses with heart failure using DTI. METHODS: In all, 43 fetuses (36 control, 7 heart failure) were assessed using pulsed Doppler echocardiography combined with DTI. RV peak myocardial velocities during early diastole (Ea), atrial contraction, and systole were measured; and tricuspid peak velocities during early diastole (E) and atrial contraction. The ratio of E/Ea was used as an index of filling pressure were measured. From DTI, a Doppler-derived index of combined systolic/diastolic myocardial performance (DTI-Tei index) was measured. RESULTS: Compared with control fetuses, the mean Ea was significantly lower and the mean E was significantly higher in fetuses with heart failure, although these parameters did overlap between the 2 groups. The mean RV myocardial wall-motion velocity during atrial contraction, ratio of Ea/RV myocardial wall-motion velocity during atrial contraction, and RV myocardial wall-motion velocity during systole did not differ between the 2 groups. Compared with control fetuses, the mean E/Ea was significantly higher (9.71 +/- 0.91 vs 6.20 +/- 0.97; P <.0001) and the mean DTI-Tei index was significantly greater (0.79 +/- 0.11 vs 0.55 +/- 0.05; P <.0001) in fetuses with heart failure. In addition, the DTI-Tei index z score was >2 in all fetuses with heart failure. CONCLUSIONS: This study demonstrated a clinically important application of DTI-derived tricuspid annular velocities in fetuses with heart failure. Although DTI velocities were not sufficiently sensitive to identify fetuses with heart failure versus control fetuses, DTI-Tei index and E/Ea were useful and sensitive indicators of global RV dysfunction.

Blood Flow Velocity↗
PubMed2004

Myocardial acceleration during isovolumic contraction as a new index of right ventricular contractile function and its relation to pulmonary regurgitation in patients after repair of tetralogy of Fallot.

BACKGROUND: Myocardial acceleration during isovolumic contraction (IVA) by Doppler tissue imaging has been proposed to be a new index of right ventricular contractile function that is unaffected by ventricular shape or loading conditions. OBJECTIVES: We sought to assess the use of IVA to evaluate right ventricular contractile function. METHODS: In all, 22 pediatric patients with pulmonary regurgitation (PR) after repair of tetralogy of Fallot (TOF) (8 +/- 3 years) and 27 age-matched children were examined. The degree of PR (mild, moderate, and severe) for patients with TOF was on the basis of pulsed and color Doppler findings. Using Doppler tissue imaging, the peak myocardial velocities during early diastole, late diastole, systole, and isovolumic contraction were recorded. RESULTS: Compared with healthy children, Doppler tissue imaging velocities for patients with TOF showed decreased myocardial velocities during early diastole (P =.007), late diastole (P <.0001), systole (P <.0001), and isovolumic contraction (P <.0001). Patients with TOF had a lower IVA when compared with healthy children (P <.0001). There was a stepwise decrease in the IVA from mild to severe PR. We found a significant relationship between the IVA and the degree of PR (r = -0.86, P <.0001). CONCLUSION: The analysis of IVA allows the assessment of right ventricular contractile function for patients with repaired TOF and various degrees of PR.

Acceleration↗
PubMed2004

Effects of coil closure of patent ductus arteriosus on left anterior descending coronary artery blood flow using transthoracic Doppler echocardiography.

Transthoracic Doppler echocardiography provides noninvasive measurements of coronary blood flow in the left anterior descending coronary artery (LAD). This method has the potential to show the effects of acute changes in loading conditions on blood flow. Coil closure of patent ductus arteriosus (PDA) is a model of acute changes in blood pressure and left ventricular (LV) preload that influences coronary blood flow. We applied this technique to assess the coronary blood flow changes for patients with PDA before and immediately after PDA coil closure. We examined 9 patients (1.8 +/- 1.1 years) with simple PDA and 8 age-matched healthy children. LV dimensions and LV mass were measured. Maximum peak flow velocity and flow volume in the LAD were measured. Pulmonary to systemic flow ratios (Qp/Qs) were obtained by cardiac catheterization. After PDA coil closure, LV end-diastolic dimension decreased, and systolic and diastolic blood pressures increased significantly. The maximum peak flow velocity, LAD flow volume, and the ratio of LAD flow volume to LV mass increased significantly. The changes in maximum peak flow velocity and the ratio of LAD flow volume to LV mass (F/M) correlated positively with the changes in diastolic pressure and Qp/Qs. In 5 patients who had Qp/Qs > 1.5, the mean F/M was significantly lower compared with control subjects, but they increased to normal values after coil closure of PDA. PDA coil closure increases diastolic pressure and decreases Qp/Qs, resulting in improvement of myocardial perfusion. These findings provide new insights into the relationship between cardiac function and coronary circulation in pediatric patients with heart diseases associated with PDA.

Blood Circulation↗
PubMed2004

Assessment of right ventricular function during exercise with quantitative Doppler tissue imaging in children late after repair of tetralogy of Fallot.

Doppler tissue imaging (DTI) has been developed to assess ventricular wall-motion velocity quantitatively for patients with various types of heart disease. This technique has a possibility of assessing right ventricular (RV) function reserve during exercise. To investigate RV function during exercise using DTI, 21 patients (9.3 +/- 3.3 years) who had undergone operation for tetralogy of Fallot at 1 to 3 years of age and 19 age-matched healthy children were studied. Echocardiography combined with DTI was performed at rest and during supine bicycle submaximal exercise. DTI of tricuspid annulus movement during systole (Sa) was obtained from a 4-chamber view. RV pressure was estimated by maximal tricuspid regurgitation (TR) velocity. The peak value of the first derivation of RV pressure (peak dP/dt) was measured from the continuous wave Doppler-derived TR profile. Adequate spectral Doppler recordings of TR were obtained in all participants. However, 9 healthy children and 2 patients with tetralogy of Fallot were excluded from the study because of an inability to determine the entire spectral TR velocity envelope during exercise. Therefore, data were analyzed in 29 participants. At rest, the mean RV pressure for patients was higher than that in control subjects (27 +/- 4 vs 18 +/- 3 mm Hg, P <.01). The mean Sa and RV peak dP/dt for patients were lower than those in control subjects (6.7 +/- 1.6 vs 8.8 +/- 1.7 cm/s and 464 +/- 77 vs 550 +/- 80 mm Hg/s, P <.01, respectively). Sa and RV peak dP/dt in the two groups increased significantly during exercise. However, the magnitude of increases in Sa and peak dP/dt was significantly less for patients than in control subjects (37 +/- 16 vs 66 +/- 19% and 42 +/- 10 vs 80 +/- 13%, P <.01, respectively). The magnitude of increase in Sa correlated with that in RV peak dP/dt (r = 0.84, P <.01). Results of DTI show high correlation with RV peak dP/dt during exercise. This technique has a potential as a useful indicator of the effect of exercise on RV systolic function. An insufficient increase in Sa suggests impaired response to exercise of RV in patients with tetralogy of Fallot.

Analysis of Variance↗
PubMed2003

Molecular dissection of the alpha-dystroglycan- and integrin-binding sites within the globular domain of human laminin-10.

The adhesive interactions of cells with laminins are mediated by integrins and non-integrin-type receptors such as alpha-dystroglycan and syndecans. Laminins bind to these receptors at the C-terminal globular domain of their alpha chains, but the regions recognized by these receptors have not been mapped precisely. In this study, we sought to locate the binding sites of laminin-10 (alpha5beta1gamma1) for alpha(3)beta(1) and alpha(6)beta(1) integrins and alpha-dystroglycan through the production of a series of recombinant laminin-10 proteins with deletions of the LG (laminin G-like) modules within the globular domain. We found that deletion of the LG4-5 modules did not compromise the binding of laminin-10 to alpha(3)beta(1) and alpha(6)beta(1) integrins but completely abrogated its binding to alpha-dystroglycan. Further deletion up to the LG3 module resulted in loss of its binding to the integrins, underlining the importance of LG3 for integrin binding by laminin-10. When expressed individually as fusion proteins with glutathione S-transferase or the N-terminal 70-kDa region of fibronectin, only LG4 was capable of binding to alpha-dystroglycan, whereas neither LG3 nor any of the other LG modules retained the ability to bind to the integrins. Site-directed mutagenesis of the LG3 and LG4 modules indicated that Asp-3198 in the LG3 module is involved in the integrin binding by laminin-10, whereas multiple basic amino acid residues in the putative loop regions are involved synergistically in the alpha-dystroglycan binding by the LG4 module.

Amino Acid Sequence↗
PubMed2003

Hormone-sensitive lipase is required for high-density lipoprotein cholesteryl ester-supported adrenal steroidogenesis.

Steroid hormones are synthesized using cholesterol as precursor, with a substantial portion supplied by the selective uptake of lipoprotein-derived cholesteryl esters. Adrenals express a high level of neutral cholesteryl ester hydrolase activity, and recently hormone-sensitive lipase (HSL) was shown to be responsible for most adrenal neutral cholesteryl ester hydrolase activity. To determine the functional importance of HSL in adrenal steroidogenesis, adrenal cells were isolated from control and HSL-/- mice, and the in vitro production of corticosterone was quantified. Results show that, even though adrenal cholesteryl ester content was substantially elevated in both male and female HSL-/- mice, basal corticosterone production was reduced approximately 50%. The maximum corticosterone production induced by dibutyryl cAMP, and lipoproteins was approximately 75-85% lower in adrenal cells from HSL-/- mice compared with control. There is no intrinsic defect in the conversion of cholesterol into steroids in HSL-/- mice. Dibutyryl cAMP-stimulated conversion of high-density lipoprotein cholesteryl esters into corticosterone was reduced 97% in HSL-/- mice. An increase in low-density lipoprotein receptor expression appears to be one of the compensatory mechanisms for cholesterol delivery in HSL-/- mice. These findings suggest that HSL is functionally linked to the selective pathway and is critically involved in the intracellular processing and availability of cholesterol for adrenal steroidogenesis.

Adrenal Glands↗
PubMed2003

Quantum Monte Carlo algorithm for softcore boson systems.

An efficient quantum Monte Carlo algorithm for the simulation of bosonic systems on a lattice in a grand canonical ensemble is proposed. It is based on the mapping of bosonic models to the spin models in the limit of the infinite total spin quantum number. It is demonstrated how this limit may be taken explicitly in the algorithm, eliminating the systematic errors. The efficiency of the algorithm is examined for the noninteracting lattice boson model and compared with the stochastic series expansion method with the heat-bath-type scattering probability of the random walker.

Journal Article↗
PubMed2003

Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice.

To elucidate the role of hormone-sensitive lipase (HSL) in diet-induced obesity, HSL-deficient (HSL-/-) and wild-type mice were fed normal chow or high-fat diets. HSL-/- mice were resistant to diet-induced obesity showing higher core body temperatures. Weight and triacylglycerol contents were decreased in white adipose tissue (WAT) but increased in both brown adipose tissue (BAT) and liver of HSL-/- mice. Serum insulin levels in the fed state and tumor necrosis factor-alpha mRNA levels in adipose tissues were higher, whereas serum levels of adipocyte complement-related protein of 30 kDa (ACRP30)/adiponectin and leptin, as well as mRNA levels of ACRP30/adiponectin, leptin, resistin, and adipsin in WAT, were lower in HSL-/- mice than in controls. Expression of transcription factors associated with adipogenesis (peroxisome proliferator-activated receptor-gamma, CAAT/enhancer-binding protein-alpha) and lipogenesis (carbohydrate response element-binding protein, adipocyte determination- and differentiation-dependent factor-1/sterol regulatory element-binding protein-1c), as well as of adipose differentiation markers (adipocyte lipid-binding protein, perilipin, lipoprotein lipase), lipogenic enzymes (glycerol-3-phosphate acyltransferase, acyl-CoA:diacylglycerol acyltransferase-1 and -2, fatty acid synthase, ATP citrate lyase) and insulin signaling proteins (insulin receptor, insulin receptor substrate-1, GLUT4), was suppressed in WAT but not in BAT of HSL-/- mice. In contrast, expression of genes associated with cholesterol metabolism (sterol-regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA:cholesterol acyltransferase-1) and thermogenesis (uncoupling protein-2) was upregulated in both WAT and BAT of HSL-/- mice. Our results suggest that impaired lipolysis in HSL deficiency affects lipid metabolism through alterations of adipose differentiation and adipose-derived hormone levels.

Adipose Tissue↗
PubMed2003

Early embryonic lethality caused by targeted disruption of the 3-hydroxy-3-methylglutaryl-CoA reductase gene.

The endoplasmic reticulum (ER) enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which converts HMG-CoA to mevalonate, catalyzes the ratelimiting step in cholesterol biosynthesis. Because this mevalonate pathway also produces several non-sterol isoprenoid compounds, the level of HMG-CoA reductase activity may coordinate many cellular processes and functions. We used gene targeting to knock out the mouse HMG-CoA reductase gene. The heterozygous mutant mice (Hmgcr+/-) appeared normal in their development and gross anatomy and were fertile. Although HMG-CoA reductase activities were reduced in Hmgcr+/- embryonic fibroblasts, the enzyme activities and cholesterol biosynthesis remained unaffected in the liver from Hmgcr+/- mice, suggesting that the haploid amount of Hmgcr gene is not rate-limiting in the hepatic cholesterol homeostasis. Consistently, plasma lipoprotein profiles were similar between Hmgcr+/- and Hmgcr+/+ mice. In contrast, the embryos homozygous for the Hmgcr mutant allele were recovered at the blastocyst stage, but not at E8.5, indicating that HMG-CoA reductase is crucial for early development of the mouse embryos. The lethal phenotype was not completely rescued by supplementing the dams with mevalonate. Although it has been postulated that a second, peroxisome-specific HMG-CoA reductase could substitute for the ER reductase in vitro, we speculate that the putative peroxisomal reductase gene, if existed, does not fully compensate for the lack of the ER enzyme at least in embryogenesis.

Alleles↗
PubMed2003

Néel and Spin-Peierls ground states of two-dimensional SU(N) quantum antiferromagnets.

The two-dimensional SU(N) quantum antiferromagnet, a generalization of the quantum Heisenberg model, is investigated by quantum Monte Carlo simulations. The ground state for N or=5 with broken lattice translational invariance. Our computation of the magnetization and the dimerization order parameter shows the absence of the intermediate spin-liquid phase.

Journal Article↗
PubMed2003

The efficacy of using pulmonary vein wedge pressure for the estimation of pulmonary artery pressure in children with congenital heart disease.

The objectives of this study were to assess the accuracy of pulmonary vein wedge pressure (PVWP) in estimating pulmonary artery pressure (PAP) in various types of congenital heart disease, including single-ventricle physiology. The systolic, diastolic, and mean values of both PAPs and PVWPs were measured in 30 patients (a total of 46 points). Pulmonary artery pressure ranged from 13 to 74 (34 +/- 15) mm Hg in systole, 5 to 25 (13 +/- 6) mm Hg in diastole, and 6 to 48 (18 +/- 10) mm Hg in mean. As a whole, good correlations between PAPs and PVWPs were observed (systole, r = 0.70; diastole, r = 0.85; mean, r = 0.82; P < 0.0001). However, with an increase in PAP, the discrepancy between PAPs and PVWPs increased. When the mean PVWP was more than 18 mm Hg, the mean PVWP in 14 of 24 (58%) underestimated the mean PAP by up to 22 mm Hg (mean difference, -1.7 +/- 5.8 mm Hg). On the other hand, all of the patients with mean PVWPs less than 18 mm Hg (n = 22) had mean PAPs less than 18 mm Hg (r = 0.86; PAP = 1.11 x PVWP - 1.41; P < 0.0001), and the mean difference was -0.2 +/- 1.8 mm Hg. The mean PVWP can accurately estimate the mean PAP in children with congenital heart disease who have a mean PVWP less than 18 mm Hg.

Cardiac Catheterization↗
PubMed2003

Comparison of gastric peristalsis inhibition by scopolamine butylbromide and glucagon: evaluation by electrogastrography and analysis of heart rate variability.

BACKGROUND: Activation of glucagon receptors of the smooth muscle membrane suppresses gastric peristalsis. We evaluated autonomic nervous activity by two methods, electrogastrography (EGG) and analysis of heart rate variability, to compare the inhibiting effects of glucagon and scopolamine butylbromide on gastric peristalsis. METHODS: Heart rate variability, EGG, and blood catecholamine levels were measured before and after administration of glucagon (G group), scopolamine butylbromide (SB group), or physiological saline (C group). Autonomic nervous function was evaluated using spectral analysis of heart rate variability, and low frequency (LF) and high frequency (HF) power; the LF/HF ratios were also determined. RESULTS: After administration of scopolamine butylbromide, HF power, an index of parasympathetic nervous activity, decreased; and the LF/HF ratio, an index of sympathetic nervous activity, increased. In contrast, no significant change was observed in autonomic nervous activity after administration of glucagon. The peak power amplitudes of the EGG decreased significantly in the G and SB groups after intramuscular injection, but the difference between the groups was not significant. Furthermore, the dominant frequency increased significantly in the G and SB groups after injection. Serum catecholamine levels showed no significant changes after administration of scopolamine butylbromide or glucagon. CONCLUSIONS: Inhibition of gastric peristalsis by glucagon via glucagon receptors on smooth muscles did not influence autonomic nervous activity, unlike the results obtained after administration of scopolamine butylbromide. Therefore, glucagon may be safe for use with elderly patients and those with cardiopulmonary complications.

Adult↗