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Biomedical subjects

Hiroshi Inoue

Publications and source records attributed to Hiroshi Inoue.

At least 181 records · Page 10Linked to original sources
PubMed2003

Protein phosphatase 2C is involved in the cAMP-dependent ciliary control in Paramecium caudatum.

Forward swimming of the Triton-extracted model of Paramecium is stimulated by cAMP. Backward swimming of the model induced by Ca(2+) is depressed by cAMP. Cyclic AMP and Ca(2+) act antagonistically in setting the direction of the ciliary beat. Some ciliary axonemal proteins from Paramecium caudatum are phosphorylated in a cAMP-dependent manner. In the presence of cAMP, axonemal 29- and 65-kDa polypeptides were phosphorylated by endogenous A-kinase in vitro. These phosphoproteins, however, were not dephosphorylated after in vitro phosphorylation, presumably because of the low endogenous phosphoprotein phosphatase activity associated with isolated axonemes. We purified the protein phosphatase that specifically dephosphorylated the 29- and 65-kDa phosphoproteins from Paramecium caudatum. The molecular weight of the protein phosphatase was 33 kDa. The protein phosphatase had common characteristics as protein phosphatase 2C (PP2C). The characteristics of the protein phosphatase were the same as those of the PP2C from Paramecium tetraurelia (PtPP2C) [Grothe et al., 1998: J. Biol. Chem. 273:19167-19172]. We concluded that the phosphoprotein phosphatase is the PP2C from Paramecium caudatum (PcPP2C). The PcPP2C markedly accelerated the backward swimming of the Triton-extracted model in the presence of Ca(2+). On the other hand, the PcPP2C slightly depressed the forward swimming speed. This indicates that the PP2C plays a role in the cAMP-dependent regulation of ciliary movement in Paramecium caudatum through dephosphorylation of 29- and/or 65-kDa regulatory phosphoproteins by terminating the action of cAMP.

Aniline Compounds↗
PubMed2003

Activation of cerebellum and basal ganglia on volitional swallowing detected by functional magnetic resonance imaging.

Although regions of the sensorimotor cortex, insula, and anterior cingulate gyrus are reported to be activated during swallowing, findings concerning contributions of the cerebellum and basal ganglia have been contradictory. We investigated cerebellar and basal ganglionic activation using functional magnetic resonance imaging (fMRI). In 11 subjects, single-shot gradient-echo echoplanar image volumes sensitive to BOLD contrast were acquired in block design fashion using an oblique orientation covering both cerebrum and cerebellum. Using statistical parametric mapping, regional activation upon swallowing was observed in the sensorimotor cortex, insula, cerebellum, putamen, globus pallidus, thalamus, anterior cingulate gyrus, supplementary motor area, superior temporal gyrus, and substancia nigra. The cerebellum was activated bilaterally, especially on the left; activation of the putamen and globus pallidus was also found bilaterally. Thus, volitional swallowing involves the cerebellum and basal ganglia as well as cortical structures. The method used was well tolerated by normal subjects and should also be applicable to patients with dysphagia.

Adult↗
PubMed2003

Inhibitory effect of a soluble transforming growth factor beta type II receptor on the activation of rat hepatic stellate cells in primary culture.

BACKGROUND/AIMS: Oxidative stress, including the generation of reactive oxygen species (ROS) that acts as a signaling mediator for transforming growth factor (TGF)-beta, plays a key role in hepatic fibrosis. Hepatic stellate cells (HSCs) produce and respond to TGF-beta in an autocrine manner with increased collagen expression. It has previously been reported that the adenovirus-mediated overexpression of a soluble receptor against the extracellular domain of the TGF-beta type II receptor prevents hepatofibrogenesis in vivo, although its inhibitory role and mechanism in HSC activation remains to be elucidated. METHODS: In this study, we report on an examination of the actual role of TGF-beta inhibition on oxidative stress and the activation of cultured rat HSCs, using the adenovirus-mediated soluble TGF-beta type II receptor. RESULTS: This soluble receptor secreted from the adenovirus-infected cells binds to TGF-beta. Infection of HSCs with this adenovirus attenuated intracellular levels of TGF-beta1 mRNA and protein, NADH oxidative activity, ROS generation and lipid peroxidation, and prevented HSC activation. CONCLUSIONS: These findings suggest that this adenovirus-mediated soluble TGF-beta receptor may lead to an interruption of the TGF-beta autocrine loop in activated HSC, in part, by inhibiting oxidative stress.

Adenoviridae↗
PubMed2003

Proportion and prognosis of healthy people with coved or saddle-back type ST segment elevation in the right precordial leads during 10 years follow-up.

AIMS: The aim of this study was to investigate long-term proportion and prognosis of healthy subjects with right precordial ST segment elevation without family history of sudden death. METHODS AND RESULTS: We followed up electrocardiograms (ECGs) of 3339 healthy subjects (male/female 2646/693) who underwent periodical medical examination form 1992 to 2001 to determine the relationship between year-to-year changes of ST segment morphology and the risk of fatal arrhythmias. Inclusion criterion was defined as presenting either coved or saddle back type ST segment elevation (>0.2 mV) in the right precordial leads. The cumulative total subjects who showed Brugada-like ECG changes at least once throughout the follow-up period were 69 (male/female 67/2; age 47.9+/-8.9 years, 2.1% of total subjects). During a follow-up period, annual mean proportion of coved or saddle back type ST elevation in the right precordial leads was 1.22+/-0.23% (0.88-1.88%). The morphological pattern of ST segment elevation was saddle-back in 77.3+/-7.9% and coved in 22.7+/-7.9% of subjects. Throughout the follow-up period, 39 subjects (56.5%) showed changes in ST segment elevation pattern. Twenty-nine subjects (42.0%) showed normalization of ST segment elevation at least once. Sixty-nine subjects were followed for a period of one to 10 years (median 4 years, interquartile range 4-8 years). Only one subject with persistent saddle-back type ST elevation had episodes of ventricular fibrillation (VF). CONCLUSIONS: The average proportion of healthy subject who had coved or saddle-back type of ST elevation in the right precordial leads without family history of sudden death was 1.22% and the risk of fatal arrhythmias was low (1/393.5 subject-years).

Arrhythmias, Cardiac↗
PubMed2003

Idoxifene and estradiol enhance antiapoptotic activity through estrogen receptor-beta in cultured rat hepatocytes.

Oxidative stress plays a causative role in the development of hepatic fibrosis and apoptosis. Estradiol (E2) is an antioxidant, and idoxifene is a tissue-specific selective estrogen-receptor modulator. We have previously demonstrated that E2 inhibits hepatic fibrosis in rat models of hepatic fibrosis and that the actions of E2 are mediated through estrogen receptors (ERs). This study reports on the antiapoptotic role of idoxifene and E2, and the functions of ER subtypes ER-alpha and ER-beta in hepatocytes undergoing oxidative stress. Lipid peroxidation was induced in cultured rat hepatocytes with ferric nitrilotriacetate solution with idoxifene or E2. Oxidative stress-induced early apoptosis was linked to its ability to inhibit not only the expression of Bcl-2 and Bcl-XL but the production of antioxidant enzymes as well and to stimulate Bad expression. Hepatocytes possessed functional ER-beta, but not ER-alpha, to respond directly to idoxifene and E2. Idoxifene and E2 suppressed oxidative stress-induced reactive oxygen species generation and lipid peroxidation, and their antiapoptotic effects on the activation of activator protein-1 and nuclear factor-kappaB, the loss of antioxidant enzyme activity, and Bcl-2 family protein expression in early apoptotic hepatocytes were blocked by the pure ER antagonist ICI 182,780. Our results indicate that idoxifene and E2 could enhance antiapoptotic activity through ER-beta during oxidative damage in hepatocytes.

Animals↗
PubMed2003

Underdiagnosis and undertreatment of COPD in primary care settings.

OBJECTIVE: The aim of this study was to improve the detection of COPD in a primary care setting and to evaluate the subsequent management of these patients by general practitioners. METHODOLOGY: A two-step protocol was followed: patients were screened for airway obstruction and their subsequent management status reviewed. Screening spirometry was performed in 56 primary care settings (23 hospitals and 33 general practices). Inclusion criteria for screening subjects were: (i) > or =40-year-old smokers (both current and past smokers) and/or (ii) > or =40-year-old patients with respiratory symptoms of chronic cough and sputum. Patients with a previously diagnosed respiratory disease were excluded. In the second part of the study, the diagnosis and the subsequent management status of subjects with airway obstructive changes (FEV1/FVC <70%) were sought from their physician using a questionnaire 2 months after detection. RESULTS: A total of 1168 patients were screened, with 128 not analysed because of incomplete data, leaving 1040 patients. The percentages of current smokers, ex-smokers, and non-smokers among all analysed subjects were 41.7%, 29.8% and 28.5%, respectively. Airway obstructive changes (FEV1/FVC <70%) were found in 27.0% (n = 281) of all analysed subjects. Questionnaires for 194 subjects (with positive screening tests) were sent back by the participating physicians. Eighty-one per cent (n = 158) of the 194 subjects had COPD and 13.4% (n = 26) had asthma. Sixty-one per cent (n = 96) of the subjects with moderate to severe COPD according to international guidelines (FEV1 <80% predicted). However, 31.3% (n = 30) did not receive any clinical intervention (smoking cessation advice and/or drug administration). CONCLUSIONS: Screening spirometry in outpatients in a primary care setting can identify many COPD patients. However, COPD management appears to be poor in Japan.

Aged↗
PubMed2003

Angiotensin-converting enzyme-gene polymorphism is associated with collagen I synthesis and QT dispersion in essential hypertension.

AIM: This study tested the hypothesis that abnormal QT dispersion, an indicator of arrhythmogenic risk, is associated with angiotensin-converting enzyme (ACE) gene polymorphism and abnormalities of collagen metabolism. METHODS: A total of 132 patients with untreated essential hypertension (EHT) were recruited. QT dispersion corrected by heart rate (QTc) on a 12-lead electrocardiogram, ACE genotype, left ventricular mass index (LVMI) and E/A ratio using echocardiogram, plasma ACE activity and serum propeptide type I C-terminal procollagen (PICP) concentration, a marker of myocardial fibrosis, were determined. A normal control group (NC) of 200 normotensive subjects was used for comparison of QT dispersion. RESULTS: Number of EHT patients with ACE genotype I/I, I/D and D/D was 61, 52 and 19, respectively. LVMI and E/A ratio were similar in the three groups. Compared with subjects with I/I or I/D genotype, subjects with D/D showed higher plasma ACE activity (I/I: 13 +/- 0.6, I/D: 17 +/- 0.9, and D/D: 21 +/- 1.1 nmol/min per ml, mean +/- SE, P05) and serum PICP concentration (I/I: 106 +/- 5.4, I/D: 106 +/- 4.9, D/D: 140 +/- 12.1 ng/ml, P < 0.01). QTc dispersion was larger in the three hypertensive subgroups than in NC, and was the largest in EHT with D/D (NC: 0.037 +/- 0.001, I/I: 0.056 +/- 0.003, I/D: 0.055 +/- 0.002, D/D: 0.069 +/- 0.004 s, P < 0.05). CONCLUSION: ACE D/D genotype could be associated with an elevation of serum PICP concentration possibly leading to myocardial fibrosis and increased QT dispersion.

Adult↗
PubMed2003

Parametric system identification of arterial baroreflex with random perturbation of blood pressure in normal subjects.

The purpose of the study was to evaluate the dynamic nature of heart rate baroreflex under closed-loop conditions. We applied pressure perturbation with a random-interval cuff inflation to parametric system identification of the baroreflex. In 10 healthy men (six young, 27 +/- 3.9 years old, and four older, 50 +/- 3.8 years old), blood pressure variations were produced by a random-interval (0.06-0.50 Hz) cuff inflation around bilateral thighs to identify characteristics of the baroreflex with an autoregressive moving average model with exogenous input. The model faithfully described the dynamic relationship between mean blood pressure and RR interval. A theoretical 1 mmHg step input of mean blood pressure caused a rapid increase in RR intervals toward the steady state within 10 s in younger subjects. In older subjects, however, the step response showed a delayed and gradual increase in RR interval over 20 s. The steady-state gain obtained from the autoregressive moving average model with exogenous input was significantly greater than that determined from the slope of the pressure-RR relationship. The conclusion was that the dynamic baroreflex gain was quantified using a parametric system identification technique and blood pressure perturbation by means of a random-interval cuff inflation. This method would potentially be of great use in helping us gain insights into a closed-loop system of complex and dynamic cardiovascular regulation in humans.

Adult↗
PubMed2003

Microsatellite instability is often observed in esophageal carcinoma patients with allelic loss in the FHIT/FRA3B locus.

We have previously reported a significant correlation between the progression of colorectal carcinoma and the loss of Fhit and Msh2 expression. This observation led us to investigate the effect of an allelic loss of the FHIT gene on esophageal cancer when coupled with a deficient mismatch repair system. In this study, 8 of 42 patients with esophageal cancer had microsatellite instability (MSI), and 29 cases demonstrated allelic loss (loss of heterozygosity or homozygous deletion) at the FHIT/FRA3B locus. All 8 MSI-positive cases showed allelic loss, while 13 of 34 MSI-negative cases retained both alleles, and a significant correlation was found between the incidence of MSI and allelic loss (p < 0.05). On the other hand, only 1 of the 8 MSI-positive patients exhibited neither Msh2 nor Fhit protein expression in both normal and carcinoma epithelial tissues, but neither a relationship between Msh2 expression and Fhit expression nor with the incidence of MSI was noted. This result indicated that the disruption of the mismatch repair system of Msh2 does not mainly lead to allelic loss of the FHIT/FRA3B locus as well as MSI in esophageal cancer. We concluded that MSI is significantly related to the allelic loss in the FHIT/FRA3B region, but Msh2 might be unrelated to the progression or oncogenic process in esophageal cancer.

Acid Anhydride Hydrolases↗
PubMed2003

Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms.

Signal transducer and activator of transcription-3 (Stat3) is one of the most important molecules involved in the initiation of liver development and regeneration. In order to investigate the hepatoprotective effects of Stat3, we examined whether Stat3 protects against Fas-mediated liver injury in the mouse. A constitutively activated form of Stat3 (Stat3-C) was adenovirally overexpressed in mouse liver by intravenous injection, and then a nonlethal dose of Fas agonist (Jo2) was injected intraperitoneally into the mouse (0.3 microg/g body wt). Stat3-C dramatically suppressed both apoptosis and necrosis induced by Jo2. In contrast, liver-specific Stat3-knockout mice failed to survive following Jo2 injection. Stat3-C upregulated expression of FLICE inhibitor protein (FLIP), Bcl-xL, and Bcl-2, and accordingly downregulated activities of FLICE and caspase-3 that were redox-independent. Interestingly, Stat3-C also upregulated the redox-associated protein redox factor-1 (Ref-1) and reduced apoptosis in liver following Jo2 injection by suppressing oxidative stress and redox-sensitive caspase-3 activity. These findings indicate that Stat3 activation protects against Fas-mediated liver injury by inhibiting caspase activities in redox-dependent and -independent mechanisms.

Animals↗
PubMed2003

PKClambda in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity.

PKClambda is implicated as a downstream effector of PI3K in insulin action. We show here that mice that lack PKClambda specifically in the liver (L-lambdaKO mice), produced with the use of the Cre-loxP system, exhibit increased insulin sensitivity as well as a decreased triglyceride content and reduced expression of the sterol regulatory element-binding protein-1c (SREBP-1c) gene in the liver. Induction of the hepatic expression of Srebp1c and of its target genes involved in fatty acid/triglyceride synthesis by fasting and refeeding or by hepatic expression of an active form of PI3K was inhibited in L-lambdaKO mice compared with that in control animals. Expression of Srebp1c induced by insulin or by active PI3K in primary cultured rat hepatocytes was inhibited by a dominant-negative form of PKClambda and was mimicked by overexpression of WT PKClambda. Restoration of PKClambda expression in the liver of L-lambdaKO mice with the use of adenovirus-mediated gene transfer corrected the metabolic abnormalities of these animals. Hepatic PKClambda is thus a determinant of hepatic lipid content and whole-body insulin sensitivity.

Animals↗
PubMed2003

Platelet-derived endothelial cell growth factor mediates Rho-associated coiled-coil domain kinase messenger RNA expression and promotes cell motility.

BACKGROUND: Platelet-derived endothelial cell growth factor (PD-ECGF), whose expression is increased in several cancers, is an endothelial cell mitogen and has chemotactic activity in vitro and angiogenic activity in vivo. Tumors with high PD-ECGF expression tend to have frequent lymph node metastasis and are associated with poor outcome. METHODS: We screened genes transduced by PD-ECGF transfection to the colon cancer cell line DLD-1 by using a complementary DNA microarray. Cell motility was evaluated by in vitro migration assay. Actin fiber polymerization was visualized by immunofluorescent detection of phalloidin. RESULTS: Rho-associated coiled-coil domain kinase (ROCK1) was found to be significantly overexpressed in PD-ECGF transfectants compared with mock cells. PD-ECGF transfectants showed higher cell motility than mock cells. The parental cell, DLD-1, with recombinant PD-ECGF showed higher cell motility than that without recombinant PD-ECGF, in which motility was blocked by the neutralizing antibody of PD-ECGF or Y-27632, a specific inhibitor of ROCK1. Moreover, the actin fiber polymerization, which is a marker of activation of ROCK1, was higher in PD-ECGF transfectants than in mock cells. CONCLUSIONS: PD-ECGF expression may be associated with cancer cell migration via activation of ROCK1. This may explain one mechanism by which tumors with high expression of PD-ECGF show aggressive behavior.

Acute-Phase Proteins↗
PubMed2003

Role of fibrillation cycle length in spontaneous and drug-induced termination of human atrial fibrillation.

The aim of this study was to investigate the mechanism of spontaneous termination of atrial fibrillation (AF) by comparing it with drug-induced termination on the basis of changes in fibrillation cycle length (FCL). Fast Fourier transform analysis was carried out on the electrocardiogram (ECG) records of 27 patients with paroxysmal AF without organic heart disease. In 8 patients with drug-induced termination of AF, spectral analysis of the data from surface ECG lead V1 was performed before and after class I antiarrhythmic drug infusion for 10 min. In 19 patients with spontaneous termination of AF, the analysis used the Holter ECG recordings at 10 min before the spontaneous termination and at the termination. FCL was calculated from the peak frequency of each epoch and the mean FCL and the coefficient of variation (CV) of FCL were determined from the data of 20 epochs. In the 8 episodes of drug-induced AF termination, the mean FCL increased significantly with class I drugs (from 151+/-17 to 203+/-21 ms, p<0.001), whereas in the 19 episodes of spontaneous termination, the mean FCL and CV of FCL at termination did not differ from those at 10 min before the termination. Of the 19 episodes, 10 episodes terminating in the morning showed a significant increase in the FCL of the last epoch of the termination period (from 158 +/-22 to 172+/-17 ms, p<0.05). In the 9 episodes terminating in either the afternoon or the evening, the FCL of the last epoch did not change significantly. Although drug-induced termination of paroxysmal AF may depend on a gradual increase in FCL, the pattern of spontaneous termination may depend on the time of day. Spontaneous termination in the morning may be caused by an abrupt increase in FCL related to vagolytic autonomic balance.

Anti-Arrhythmia Agents↗
PubMed2003

Investigation of the optimal treatment strategy for atrial fibrillation in Japan.

The Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM study) is a randomized comparative evaluation of rate control and rhythm control, both combined with antithrombotic therapy, as therapeutic strategies for the treatment of atrial fibrillation (AF). This study differs from the earlier AFFIRM and RACE studies in that it has a composite primary end-point representing mortality and also physical/psychological disablement (total mortality, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for heart failure requiring intravenous administration of diuretics, and patient disablement). Patients' will to change the therapeutic strategy to the other is also considered as an end-point representing disablement under the assigned strategy. The secondary end-point includes quality of life scores and the efficacy and safety of drugs used in treating AF. The J-RHYTHM study emphasizes patient-reported experience and perception of AF-specific disablement, and the safety of antiarrhythmics available in Japan; it will follow 2600 patients treated at more than 150 sites in Japan for a 3-year period.

Anti-Arrhythmia Agents↗
PubMed2003

Supersensitive response to isoproterenol in patients with marked global reduction of cardiac metaiodobenzylguanidine uptake.

It is unknown whether the non-transplanted, denervated human heart is supersensitive to beta-adrenergic agonist in terms of inotropism and chronotropism. In the present study, 36 patients with normal left ventricular (LV) wall motion were divided into 3 groups according to the cardiac metaiodobenzylguanidine (MIBG) scintigrams: group I with normal MIBG uptake, group II with regionally reduced MIBG uptake, and group III with globally reduced MIBG uptake (heart-to-mediastinum ratio <1.6). Before isoproterenol (IP) infusion, heart rate (HR), blood pressure (BP) and echocardiographic indices were similar among the groups. There was a trend toward a greater increase in HR with IP (0.01 microg x kg (-1) x min(-1)) in group III (27+/-18 beats/min) than in groups I (20+/-8) and II (17+/-8) despite the lack of a significant difference in BP reduction by IP. During IP infusion, increases in posterior wall motion amplitude and LV fractional shortening were significantly greater in group III (4.5+/-1.8 mm and 16.4+/-5.4%, respectively) than in groups I (1.5+/-2.5 mm and 8.7+/-6.4%) and II (2.6+/-1.7 mm and 8.9+/-7.9%). The present results suggest that the sympathetically denervated human heart is supersensitive to IP and the exaggerated responses may be caused, at least in part, by a postsynaptic mechanism.

3-Iodobenzylguanidine↗
PubMed2003

Left atrial appendage function and abnormal hypercoagulability in patients with atrial flutter.

STUDY OBJECTIVES: The prevalence of thromboembolism might be higher than previously recognized in patients with atrial flutter (AFL) based on findings of transesophageal echocardiography (TEE). To evaluate the potential prothrombotic state in patients with AFL, TEE findings and hemostatic markers were compared among patient groups with AFL, normal sinus rhythm (NSR) and chronic nonvalvular atrial fibrillation (AF). DESIGN AND SETTINGS: Cross-sectional study at a university hospital. METHODS: In 28 patients (mean age, 63 years) with AFL, 58 patients (mean age, 66 years) with AF, and 27 patients (mean age, 61 years) with NSR who underwent TEE, plasma levels of markers for platelet activity (platelet factor 4 and beta-thromboglobulin [beta-TG]), thrombotic status (thrombin-antithrombin III complex and prothrombin fragments 1 and 2) and fibrinolytic status (d-dimer and plasmin-alpha(2)-plasmin inhibitor complex) were determined. RESULTS: Left atrial appendage (LAA) blood flow velocity in patients with AFL was higher (p < 0.05) than that in patients with AF, but was lower (p < 0.05) than that in patients with NSR (AF, 25 +/- 2; AFL, 44 +/- 4; NSR, 60 +/- 4 cm/s). Dense left atrial spontaneous echo contrast (SEC) was found in 4 patients (14%) with AFL and 16 patients (28%) with AF. There was no significant difference in plasma levels of hemostatic markers between the AFL group and the NSR group. AFL patients with impaired LAA function (LAA flow < 30cm/s, dense SEC, or both), however, showed higher level of d-dimer and beta-TG than those without impaired LAA function (d-dimer, 1.9 +/- 0.6 microg/mL vs 0.4 +/- 0.1 microg/mL; beta-TG, 73 +/- 17 ng/mL vs 33 +/- 5 ng/mL, p < 0.05). CONCLUSIONS: Patients with AFL as a whole are not in the prothrombotic state as compared with those with AF. However, patients with AFL and impaired LAA function are at potentially high risk for thromboembolism and might require anticoagulation.

Aged↗
PubMed2003

Pulmonary lymphangioleiomyomatosis: a case report with immunohistochemical details and DNA analysis.

A 47-year-old woman is presented with pulmonary lymphangioleiomyomatosis (PLAM) involving the bilateral lung and slight pulmonary function abnormality. Computed tomography scan showed bilateral microcyst formation in the lung. Histologically, proliferating spindle shaped cells with centrilobular emphysema were main findings. Immunohistochemically, these proliferating spindle shaped cells were positive for alpha-smooth muscle actin, desmin, vimentin, HMB45, estrogen receptor and progesterone receptor, but negative for S-100, cytokeratin. Single strand conformation polymorphism (SSCP) and DNA analysis for tuberous sclerosis 1 and 2 showed no significant abnormality.

Actins↗