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S Ichihara

Publications and source records attributed to S Ichihara.

At least 37 records · Page 2Linked to original sources
PubMed2000

Evidence for angiotensin II type 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload

The pathophysiological roles of the angiotensin II type 2 receptor (AT(2)) in cardiac hypertrophy remain unclear. By the targeted deletion of mouse AT(2) we were able to prevent the left ventricular hypertrophy resulting from pressure overload, while cardiac contractile functions remained normal. This implies that AT(2) is a mediator of cardiac hypertrophy in response to increased blood pressure. The effects of AT(2) deletion were independent of activation of embryonic genes for cardiac hypertrophy. However, p70(S6k), one of the key factors in cardiac hypertrophy, was markedly and specifically reduced in the ventricles of Agtr2(-)/Y mice. We propose that p70(S6k) plays a major role in AT(2)-mediated ventricular hypertrophy. This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

Journal Article↗
PubMed1998

Association of a G994-->T missense mutation in the plasma platelet-activating factor acetylhydrolase gene with genetic susceptibility to nonfamilial dilated cardiomyopathy in Japanese.

BACKGROUND: Although several genes or genetic loci that are responsible for or confer susceptibility to familial dilated cardiomyopathy (DCM) have been identified, genetic defects that underlie nonfamilial DCM remain to be characterized. Mice lacking manganese superoxide dismutase exhibit DCM, suggesting that impairment of the defense mechanisms against oxidative stress is an important susceptibility factor for DCM. Plasma platelet-activating factor (PAF) acetylhydrolase also acts as a key defense against oxidative stress by hydrolyzing PAF and oxidized phospholipids. Thus, abnormalities in the activity of this enzyme may result in predisposition to myocardial damage. METHODS AND RESULTS: The possible association of a G994 (M allele)-->T (m allele) missense mutation in the plasma PAF acetylhydrolase gene with genetic susceptibility to nonfamilial DCM has now been investigated in 122 Japanese individuals with this condition and 226 healthy control subjects. PAF acetylhydrolase activity in plasma was significantly associated with plasma PAF acetylhydrolase genotype in both DCM patients and healthy control subjects. The frequency of the mutant m allele was significantly higher in DCM patients than in control subjects. Left ventricular mass (LVM) and the LVM index in DCM patients with Mm or mm genotypes were significantly greater than those in patients with the MM genotype. CONCLUSIONS: The G994-->T mutation in the plasma PAF acetylhydrolase gene is associated with nonfamilial DCM in Japanese subjects. Although the mutation is unlikely to be a causative factor, it may contribute to genetic susceptibility to or progression of nonfamilial DCM.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1998

Association of a polymorphism of the endothelial constitutive nitric oxide synthase gene with myocardial infarction in the Japanese population.

We investigated the association between variations in the endothelial constitutive nitric oxide synthase (ecNOS) gene and the presence of myocardial infarction. The results indicate that the mutant allele (ecNOS'4a) is an independent risk factor for myocardial infarction in the Japanese population, especially in those lacking other conventional risk factors.

Aged↗
PubMed1998

Different distributions of immunoreactive S100-alpha and S100-beta protein expression in human breast cancer.

BACKGROUND AND OBJECTIVES: Although the localization of S100 protein in breast carcinoma has previously been studied, the immunohistochemical expression of the S100-alpha and -beta subunits has not been examined. METHODS: Immunohistochemical staining for S100-alpha and S100-beta proteins was performed on 72 benign breast lesions and 72 infiltrating ductal carcinoma of the breast. Noncross-reactive anti-S100-alpha and anti-S100-beta antibodies purified by affinity chromatography were used in the studies. RESULTS: More than 30% of the epithelial cells comprising all the benign lesions were either S100-alpha or S100-beta positive. In breast carcinoma cases, however, >30% of malignant cells were S100-alpha positive in 70/72 cases (97.2%), whereas the number of S100-beta positive cells exceeded 30% in only 3/72 cases (4.0%). CONCLUSIONS: Immunohistochemical staining for S 100-alpha and S100-beta proteins may help to differentiate benign proliferative breast lesions from breast cancers in difficult cases.

Breast Neoplasms↗
PubMed1998

Identification of the G994--> T missense in exon 9 of the plasma platelet-activating factor acetylhydrolase gene as an independent risk factor for coronary artery disease in Japanese men.

Platelet-activating factor (PAF) acetylhydrolase may play important roles in the pathophysiology of thrombosis and atherosclerosis related to its catalytic action in the degradation of PAF and oxidized phospholipids. A missense mutation (G--> T transversion at nucleotide 994) in the plasma PAF acetylhydrolase gene results in a Val--> Phe substitution at amino acid 279 of the mature protein and a consequent loss of catalytic activity. However, the role of a deficiency or low activity of this enzyme caused by the missense mutation in the etiology of coronary artery disease (CAD) has not been determined. The relation between this mutation and the incidence of CAD in the Japanese population is investigated herein. The genotype of plasma PAF acetylhydrolase (MM, normal; Mm, heterozygote; and mm, deficient homozygote) was determined with a polymerase chain reaction (PCR) assay for 454 patients with myocardial infarction (MI) and 602 control subjects. The frequency of the m allele was significantly higher in male patients with MI (odds ratio, 1.8) than in controls, an association that was more marked in a low-risk subgroup (odds ratio, 2.3). In contrast, the m allele was not associated with MI in women. These results indicate that the G994--> T missense mutation in exon 9 of the plasma PAF acetylhydrolase gene is an independent risk factor for CAD in Japanese men, especially low-risk individuals, but not in women.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1998

Nonadditive effects of double mutations at the flexible loops, glycine-67 and glycine-121, of Escherichia coli dihydrofolate reductase on its stability and function.

The structure, stability, and enzymatic function of dihydrofolate reductase (DHFR) from Escherichia coli are influenced by point mutations at sites 67 and 121 in two flexible loops [Gekko et al. (1994) J. Biochem. 116, 34-41; Ohmae et al. (1996) J. Biochem. 119, 703-710]. In the present study, eight double mutants at sites 67 and 121 (G67V/G121S, G67V/G121A, G67V/G121C, G67V/G121D, G67V/G121V, G67V/G121H, G67V/G121L, and G67V/G121Y) were constructed in order to identify interactions between the two sites of DHFR. The far-ultraviolet circular dichroism spectra of double mutants were clearly different from those of the respective single mutants, with significant changes being observed for three mutants, G67V/G121A, G67V/G121L, and G67V/G121S. The Gibbs free energy change of urea unfolding of double mutants could not be expressed by the sum of those of the respective single mutants except for G67V/G121H. The steady-state kinetic experiments showed that the effect of double mutations manifests itself not in Km but in k(cat), and the transition-state stabilization energy for G67V/G121A, G67V/G121C, and G67V/G121L is not equal to the sum of those for the single mutants. These results indicate that the additivity rule essentially does not hold for these double mutants, and that long-range interactions occur between sites 67 and 121, even though they are separated by 27.7 A. This is evidence that the flexible loops play important roles in the stability and function of this enzyme through structural perturbations, in which a small alteration in local atomic packing due to amino acid substitution is cooperatively magnified over almost the whole molecule.

Circular Dichroism↗
PubMed1998

Pulmonary hypertension associated with systemic lupus erythematosus: predominantly thrombotic arteriopathy accompanied by plexiform lesions.

We report an autopsy case of pulmonary hypertension associated with systemic lupus erythematosus in a 48-year-old woman. After 8-year follow-up under a definite diagnosis of systemic lupus erythematosus, she experienced gradually developing exertional dyspnea with palpitation. Her chest x-ray showed clear lung fields with marked cardiac enlargement. A right cardiac catheterization revealed a pulmonary arterial pressure of 74/30 mm Hg (mean: 47). She was treated with repeated plasmapheresis, oral corticosteroid, and immunosuppressant without improvement, and she died suddenly, 23 days after admission. Pathological examination revealed that small pulmonary arteries and arterioles were diffusely involved by florid thrombotic lesions, which were characterized by intimal eccentric fibrous thickening, luminal occlusion with recanalization, and occasional fresh thrombi. In addition, some arteries showed plexiform lesions coexistent with intimal thrombotic lesions. Concentric laminar intimal fibrosis was not seen. No significant parenchymal change was seen. Our study not only adds a rare case of thrombotic pulmonary hypertension associated with systemic lupus erythematosus, but also suggests that plexiform lesions can occur in association with thrombotic arteriopathy.

Fatal Outcome↗
PubMed1997

Lack of association between variants of the angiotensinogen gene and the risk of coronary artery disease in middle-aged Japanese men.

The renin-angiotensin system is important in cardiovascular remodeling. Although a variant of the angiotensinogen gene is associated with an increased generation of angiotensinogen, it is unclear how this genetic variant might influence the activity of the renin-angiotensin system and thereby contribute to the predisposition to coronary artery disease (CAD). The relation between genetic polymorphisms in the gene-encoding angiotensinogen and the risk of CAD in middle-aged Japanese men was investigated. Two polymorphisms in exon 2 of the angiotensinogen gene, M235T and T174M, were analyzed in 327 patients with CAD and 352 matched control subjects. The genotype distribution of both polymorphisms did not differ between patients with CAD and control subjects. No combination of genotypes of the two polymorphisms was associated with CAD. Results indicate that the M235T and T174M variants of the angiotensinogen gene are not associated with CAD in Japanese men.

Angiotensinogen↗
PubMed1997

Lack of association of polymorphisms of the angiotensin converting enzyme and angiotensinogen genes with nonfamilial hypertrophic or dilated cardiomyopathy.

Although several genes or genetic loci that are either responsible for or confer susceptibility to familial hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) have been identified, genetic defects that underlie nonfamilial HCM or DCM remain to be characterized. An allelic association study for the angiotensin converting enzyme (ACE) and angiotensinogen genes has now been performed with 71 patients with nonfamilial HCM, 88 patients with nonfamilial DCM, and 122 healthy control subjects in the Japanese population. The distribution of ACE genotypes for an insertion/deletion (I/D) polymorphism in intron 16 did not differ significantly among control subjects and patients with HCM or DCM. Similarly, the distributions of angiotensinogen genotypes for methionine-235-threonine (M235T) and threonine-174-methionine (T174M) polymorphisms did not differ significantly among the three groups. Echocardiographic parameters that are indicators of the severity or progression of disease did not differ significantly among ACE I/D or angiotensinogen M235T and T174M genotypes in the two patient groups. Finally, no additive or synergistic effect of any combined genotypes or haplotypes of the ACE and angiotensinogen polymorphisms on the association with HCM or DCM was detected. Results indicate that the ACE I/D and angiotensinogen M235T and T174M polymorphisms are not related to HCM or DCM in the Japanese population, and that variants of these polymorphisms do not contribute to the genesis or progression of these cardiomyopathies.

Angiotensinogen↗
PubMed1997

Epithelial hyperplasia of usual type expresses both S100-alpha and S100-beta in a heterogeneous pattern but ductal carcinoma in situ can express only S100-alpha in a monotonous pattern.

Immunohistochemical identification of myoepithelial cells using alpha-smooth muscle actin provides little information about the nature of solid or quasi-solid portions of epithelial hyperplasia and ductal carcinoma in situ (DCIS) because actin-rich myoepithelial cells are usually demonstrated only in the stromal-epithelial junction of both lesions. We studied the differential distribution of alpha-subunit (S100-alpha) and beta-subunit (S100-beta) of S100 protein in actin-negative areas of usual epithelial hyperplasia and DCIS by employing the streptavidin method with monospecific rabbit antibodies against each subunit. All usual epithelial hyperplasias (n = 17) were composed of heterogeneous epithelial cell types; cells expressing S100-alpha and/or S100-beta were intermingled with non-expressing cells, resulting in a mosaic-like pattern. On the contrary, DCIS (n = 32) uniformly lacked immunoreactive S100-beta; S100-alpha was diffusely expressed in 24 (68.8%) DCIS (three solid/comedo, 13 cribriform, four endocrine, one micropapillary, three papillary variants) and negative in the remaining eight (31.2%) DCIS (one cribriform, two micropapillary, four papillary and one apocrine variants). In conclusion, in contrast to usual epithelial hyperplasia that expresses both S100-alpha and S100-beta in a heterogeneous pattern, DCIS can express only S100-alpha in a monotonous pattern, possibly signifying unidirectional differentiation toward secretory glandular epithelium.

Adult↗
PubMed1997

Does local or global orientation determine the McCollough effect?

In this research, the McCollough effect was observed by using an ambiguous test pattern of coarse gratings made out of fine gratings. Coarse gratings meet at right angles to fine gratings. The global features (coarse gratings) in the test pattern became more salient if the test pattern was blurred, and the frequency of the McCollough effect, corresponding to the global orientation of the test pattern, increased with the increase of the extent of blur. The McCollough effects corresponding to the local orientation of the test pattern occurred frequently if the subjects adapted to fine gratings before viewing the test pattern, whereas the McCollough effects corresponding to the global orientation of the test pattern occurred frequently if the subjects adapted to coarse gratings. Our results indicate that the perceptual organization is an important determinant in the McCollough effect.

Adult↗
PubMed1997

Depressed mechanoenergetics and compensatory responses in idiopathic dilated cardiomyopathy.

The aim of this study was to clarify that the depressed mechanoenergetics in patients with idiopathic dilated cardiomyopathy (DCM) resulted from compensation for the decreased contractility. The study population consisted of eight control subjects, with normal left ventricular size and ejection fraction and 31 patients with DCM. Left ventricular end-systolic elastance (Ees), effective arterial elastance (Ea), external work (EW), and the pressure-volume area (PVA) were measured, using a dual-field volume conductance catheter equipped with a micromanometer-tipped catheter. Ea/Ees was evaluated as ventriculoarterial coupling. Normal hearts worked at almost optimal condition (defined as Ea/Ees = 1/2), while ventriculoarterial coupling was far from the optimum (Ea > Ees) in patients with DCM. Ees in patients with DCM was less than that in control subjects; however, Ea was similar in the two groups. The mismatch of Ea/Ees observed in DCM leads to depressed mechanoenergetics as a result of the compensatory response to maintain adequate blood pressure. Volume enlargement plays an important role in maintaining adequate blood pressure and cardiac output in the course of chronic deterioration of contractility.

Blood Pressure↗
PubMed1996

MR lmaging of the Primary Breast Lymphoma: A Case Report.

Recently magnetic resonance (MR) imaging has been investigated for the detection and differentiation of benign and malignant breast lesions. Dynamic scan using the contrast material has been shown to increase the specificity of breast MR imaging. Primary breast lymphoma (PBL) is a rare disease and its MR imaging finding has not been described before. We recently experienced a case of PBL that was demonstrated on MR imaging as an early enhancing mass similar to common carcinomas. Other imaging findings including sonography, mammography were also non-specific. Furthermore, lymphoma cells had spread beyond the early enhanced area. Thus the precise delineation of the tumor extent was impossible. However, features such as a quite unclear border on pre-contrast T2-weighted image, and increased uptake of gallium-67-citrate may allow diagnosis of such lesions as malignant lymphoma.

Journal Article↗
PubMed1996

Nimodipine improves brain energy metabolism and blood rheology during ischemia and reperfusion in the gerbil brain.

Whether nimodipine improves cerebral blood flow (CBF) and metabolism in cerebral ischemia remains a controversial issue. We investigated the effect of nimodipine on CBF, brain energy metabolism, using a laser-Doppler flowmeter and in vivo 31phosphorus nuclear magnetic resonance (31P NMR) spectroscopy, and blood rheology during forebrain ischemia and reperfusion in gerbils. Eighty-three adult gerbils received nimodipine (1 micrograms/kg/min), or an equal volume of the vehicle, or saline, over 60 min prior to a transient forebrain ischemia for 60 min. We measured sequential changes in phosphocreatine (PCr) / inorganic phosphate (Pi) ratio, beta-ATP/Pi ratio, and intracellular pH (pHi) during ischemia and reperfusion by 31P NMR spectroscopy, and the measurement of whole blood viscosity (WBV) at 60 min after reperfusion. CBF was measured continuously throughout the study by a laser-Doppler flowmeter. During forebrain ischemia, PCr/Pi and beta-ATP/Pi ratios were higher significantly in the nimodipine-treated group (p < 0.05 and 0.01) than in the vehicle- or saline-treated groups. During reperfusion, PCr/Pi and beta-ATP/Pi ratios recovered significantly only in the nimodipine-treated group (p < 0.05 and 0.01). The WBV at high shear rate (562.5 s-1) lowered significantly in the nimodipine-treated group (p < 0.05) compared with the vehicle- or saline-treated group. CBF was higher significantly only during administration of nimodipine in the nimodipine-treated group (p < 0.01) than other groups. Nimodipine improved brain energy metabolism and blood rheology during forebrain ischemia and reperfusion in the gerbil brain.

Animals↗
PubMed1996

Effects of point mutations at the flexible loop glycine-67 of Escherichia coli dihydrofolate reductase on its stability and function.

To elucidate the role of a flexible loop (residues 64-72) in the stability and function of Escherichia coli dihydrofolate reductase, glycine-67 in this loop was substituted by site-directed mutagenesis with seven amino acids (Ala, Cys, Asp, Leu, Ser, Thr, and Val). The circular dichroism spectra suggested that the confirmation of the native structure was affected by the mutations in both the presence and absence of NADPH. The free energy change of unfolding by urea decreased in the order of G67A > G67S > or = wild-type > or = G67D > G67T > G67C > or = G67L > G67V. The steady-state kinetic parameters for the enzyme reaction, Km and kcat, were only slightly influenced, but the rate of the hydride transfer reaction was significantly changed by the mutations, as revealed by the deuterium isotope effect on the enzyme activity. These results suggest that site 67 in the flexible loop, being very far from the active site, plays an important role in the stability and function of this enzyme. The characteristics of the mutations were discussed in terms of the modified flexibility of the native structure, compared with the results of mutations at site 121 in another flexible loop.

Base Sequence↗
PubMed1996

Effects of defibrination on hemorheology, cerebral blood flow velocity, and CO2 reactivity during hypocapnia in normal subjects.

BACKGROUND AND PURPOSE: Plasma fibrinogen is reported to be an independent risk factor for stroke and cardiovascular diseases. The effects of defibrination on hemorheology, middle cerebral artery (MCA) blood flow velocity, and CO2 reactivity during hypocapnia were evaluated in normal subjects. METHODS: Twenty-five healthy subjects (mean age, 31.8 +/- 5.7 years) were included in the study. Measurements were done at rest and repeated 24 hours after administration of 10 batroxobin units. Plasma fibrinogen, plasma viscosity, and whole blood viscosity were measured as hemorheological factors. MCA blood flow velocity was measured with a transcranial Doppler flowmeter. Blood flow velocity was corrected to 40 mm Hg of end-tidal CO2 partial pressure (PETCO2), and expressed as CV40. CO2 reactivity was measured as percent change in mean blood flow velocity per millimeter of mercury PETCO2. RESULTS: Plasma fibrinogen (from 7.04 to 2.29 mumol/L; P < .001), whole blood viscosity, and plasma viscosity decreased after administration of batroxobin. Mean MCA blood flow velocity at rest, CV40. and CO2 reactivity during hypocapnia increased significantly (from 67.4 to 73.6 cm/s, from 71.7 to 77.7 cm/s, and from 2.9%/mm Hg to 3.2%/mm Hg, respectively; P < .01) after defibrination. Mean arterial blood pressure and PETCO2 at rest were constant before and 24 hours after administration of batroxobin. There was a significant positive correlation between CV40 and CO2 reactivity (r = .623, P < .0001). CONCLUSIONS: The increase in MCA blood flow velocity was associated with improved CO2 reactivity and reduced blood viscosity after defibrination. The data may suggest that defibrination increases cerebral blood flow by reducing blood viscosity.

Adult↗