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Biomedical subjects

Hiroshi Inoue

Publications and source records attributed to Hiroshi Inoue.

At least 145 records · Page 8Linked to original sources
PubMed2004

Tranilast attenuates myocardial fibrosis in association with suppression of monocyte/macrophage infiltration in DOCA/salt hypertensive rats.

OBJECTIVE: In order to study the association between myocardial fibrosis and inflammatory cell infiltration in the hypertensive heart, we investigated whether N(3,4-dimethoxycinnamoyl) anthranilic acid (tranilast), an anti-inflammatory drug, would suppress myocardial fibrosis via inhibition of inflammatory cell infiltration in deoxycorticosterone-acetate (DOCA) hypertensive rats. METHODS: Sprague-Dawley rats treated with DOCA combined with the addition of 1% NaCl and 0.2% KCl in the drinking water after left nephrectomy were given tranilast (100 mg/kg per day, n = 15) or vehicle (n = 15) for up to 4 weeks. Systolic blood pressure (SBP), amount of myocardial interstitial fibrosis, perivascular fibrosis and type I and III collagen, and mRNA expression of procollagen I (PI) and procollagen III (PIII), transforming growth factor (TGF)-beta1, type-1 plasminogen activator inhibitor (PAI-1), monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 were determined. RESULTS: SBP was increased significantly 2 weeks after treatment with DOCA and salt. Myocardial interstitial fibrosis, perivascular fibrosis and collagen accumulation increased significantly 4 weeks after the treatment. Two weeks after the treatment with DOCA and salt, mRNA expression of PI and PIII, TGF-beta1, PAI-1, MCP-1 and IL-6 increased significantly. Although the SBP was similar in animals treated with tranilast or vehicle, monocyte/macrophage infiltration was suppressed, mRNA expression of TGF-beta1, PAI-1, MCP-1, IL-6, PI and PIII was attenuated, and myocardial fibrosis and collagen accumulation were suppressed in hypertensive animals receiving tranilast. CONCLUSION: Myocardial fibrosis seen in DOCA/salt hypertensive rats might be associated with the inflammation/wound healing response. Tranilast suppresses both infiltration of monocytes/macrophages and myocardial fibrosis.

Animals↗
PubMed2004

Enalapril prevents perpetuation of atrial fibrillation by suppressing atrial fibrosis and over-expression of connexin43 in a canine model of atrial pacing-induced left ventricular dysfunction.

UNLABELLED: Effects of enalapril on a canine model of atrial pacing-induced atrial fibrillation (AF) with rapid ventricular responses were determined. METHODS: Four weeks of atrial rapid pacing was performed on twenty-four beagles pretreated with placebo (Group I, n = 14) or enalapril 1 mg/kg (Group II, n = 10). Atrial effective refractory period (ERP), P-wave width, duration of AF, and left ventricular ejection fraction (LVEF) were evaluated every week. AF cycle length was determined by spectral analyses of fibrillation waves. Quantitative analysis of histology was added. RESULTS: After 4 weeks of pacing, P-wave width was longer in Group I than in Group II, and the duration of induced AF was significantly longer in Group I (59.6 +/- 66.3 seconds) than in Group II (3.6 +/- 3.4 seconds, P < 0.05). AF cycle length was longer in Group I than in Group II despite similar shortening of atrial ERP. Mean ventricular rate during rapid atrial pacing was not different between the two groups. LVEF similarly decreased in both groups. Interstitial fibrosis and expression of connexin43 was greater in Group I than in Group II (interstitial fibrosis, 9.2 +/- 8.4 versus 1.9 +/- 2.1%, P < 0.05; connexin43, 5.3 +/- 2.2 versus 1.1 +/- 1.1%, P < 0.05). CONCLUSIONS: Enalapril suppressed atrial pacing-induced AF with tachycardia-mediated cardiomyopathy by suppressing interstitial fibrosis, connexin43 over-expression and conduction delay.

Animals↗
PubMed2004

Influence of large intrahepatic blood vessels on the gross and histological characteristics of lesions produced by radiofrequency ablation in a pig liver model.

AIMS: To determine whether the presence of large intrahepatic blood vessels (>/=3 mm) affect radiofrequency (RF)-induced coagulation necrosis, the gross and histological characteristics of RF-ablated areas proximal to or around vessels were examined in normal pig livers. METHODS: An RF ablation treatment using a two-stepwise extension technique produced 12 lesions: six contained vessels (Group A), and the other six were localized around vessels (Group B). RESULTS: Gross examination revealed that the longest and shortest diameters of the ablated lesions were significantly larger in Group B than in Group A. In Group A, patent vessels contiguous to the lesion were present in a tongue-shaped area, whereas the lesions in Group B were spherical. Staining with nicotinamide adenine dinucleotide diaphorase was negative within the ablated area; but, if vessels were present in the ablated area, the cells around the vessels in an opposite direction to the ablation were stained blue. CONCLUSIONS: Roll-off can be achieved with 100% cellular destruction within a lesion that does not contain large vessels. The ablated area was decreased in lesions that contained large vessels, suggesting that the presence of large vessels in the ablated area further increases the cooling effect and may require repeated RF ablation treatment to achieve complete coagulation necrosis.

Animals↗
PubMed2004

Expression of cancer-testis antigen (CTA) genes in intrahepatic cholangiocarcinoma.

BACKGROUND: Cancer-testis antigens (CTA), such as MAGE, are selectively expressed in various types of human neoplasms but not in normal tissues other than testis. This characteristic feature of CTA makes them promising antigens for cancer-specific immunotherapy. METHODS: We investigated the expression of five genes, including MAGE-1, MAGE-3, NY-ESO-1, SCP-1, and SSX-4, in 20 surgical samples of intrahepatic cholangiocarcinomas (IHCC) using reverse transcription-polymerase chain reaction. To visualize the localization of MAGE proteins, we performed immunohistochemical studies. Furthermore, the correlation between the CTA expression and DNA methylation status was studied in three bile duct cancer cell lines. RESULTS: Expression of MAGE-1, MAGE-3, NY-ESO-1, SCP-1, and SSX-4 was recognized in 4, 4, 2, 6, and 3 of all 20 cases, respectively. In contrast, the expressions of five genes were not recognized at all in the corresponding normal tissues. In 10 cases (50%), the tumors expressed at least one of the five CTA. An immunohistochemical analysis of MAGE proteins demonstrated homogenous or focal distributions in cytoplasm of the IHCC. Using a demethylating agent, MAGE-1, NY-ESO-1, SCP-1, and SSX-4 were induced in two of three cell lines, whereas MAGE-3 was not. CONCLUSIONS: Half of the tumor tissues of IHCC expressed at least one of the CTA. Some of the patients with IHCC, therefore, should be candidates for potentially useful cancer-specific immunotherapy.

Aged↗
PubMed2004

Nonlinear mixed effects model analysis of the pharmacokinetics of metoprolol in routinely treated Japanese patients.

This study was performed to estimate the mean pharmacokinetic parameters of routinely administered metoprolol in middle-aged and elderly Japanese patients. Whole blood concentration data (65 samples) at steady-state following repetitive administration to 34 patients were analyzed using a nonlinear mixed effects model. A one-compartment model was parameterized in terms of oral clearance (CL/F) and apparent volume of distribution (V/F). We evaluated the effect of polymorphic alleles (CYP2D6*2, CYP2D6*10, CYP2C19*2 and CYP2C19*3), age, gender, and heart failure on the pharmacokinetic parameters of metoprolol. The CL/F value in patients homozygous for the CYP2D6*10 allele was 64% lower than that in patients with a CYP2D6*1/*1 or *1/*2 genotype. The CL/F value in older (>70 years old) patients was 26% lower than that in younger (< or = 70 years old) patients. In addition, the V/F value in patients homozygous for the CYP2D6*10 allele was 25% lower than that in patients with the CYP2D6*1/*1 or *1/*2 genotype. On the other hand, the CYP2C19 genotype, gender, and heart failure showed no significant effects on the pharmacokinetics of metoprolol. The results suggest that the pharmacokinetic variability of metoprolol in Japanese extensive metabolizers of CYP2D6 is very large, probably because CYP2D6*10 is responsible not only for the decreased systemic clearance (CL) but also for the increased bioavailability (F) of the drug.

Age Factors↗
PubMed2004

Prolonged activation of hemostatic markers following conversion of atrial flutter to sinus rhythm.

BACKGROUND: It remains controversial whether prophylactic anticoagulation for embolism is required in patients with atrial flutter (AFL) prior to and following cardioversion as in patients with atrial fibrillation. To evaluate the potential prothrombotic state following cardioversion of AFL, concentrations of hemostatic markers were determined before and after conversion to sinus rhythm (SR). METHODS AND RESULTS: In 12 patients (mean age 68 years) with AFL who underwent transesophageal echocardiography in the plasma concentrations of markers for platelet activity (platelet factor 4 (PF4) and beta-thromboglobulin (beta-TG)), thrombotic status (thrombin-antithrombin III complex (TAT) and prothrombin fragments 1 and 2 (F1+2)) and fibrinolytic status (D-dimer and plasmin-alpha(2)-plasmin inhibitor complex (PIC)) were determined during AFL, and 3 days and 7 days after restoration of SR. Left atrial appendage (LAA) blood flow velocity was lower immediately after than before restoration of SR (29+/-11 vs 41+/-23 cm/s, p<0.05). Three patients developed left atrial spontaneous echo contrast immediately after restoration of SR. Although the concentrations of the markers of platelet activity did not change after restoration of SR, those of TAT and PIC increased 7 days after restoration of SR as compared with during AFL (p<0.05). CONCLUSIONS: AFL patients have a potential risk for thromboembolism after restoration of SR and therefore anticoagulation might be required in selected patients.

Aged↗
PubMed2004

Drug-induced changes in fibrillation cycle length and organization index can predict chemical cardioversion of long-lasting atrial fibrillation with bepridil alone or in combination with aprindine.

BACKGROUND: The aim of this study was to investigate whether drug-induced changes in fibrillation wave characteristics can predict pharmacological conversion of long lasting persistent atrial fibrillation (AF). METHODS AND RESULTS: The study group comprised 23 consecutive patients with AF lasting > or =1 month. Patients first received bepridil (200 mg/day) for 2-4 weeks. When sinus rhythm was not restored with bepridil, oral aprindine (40 or 60 mg/day) was added to bepridil. Fast Fourier transform analysis of fibrillation waves using lead V1 was performed to calculate the fibrillation cycle length (FCL). The spectral areas were measured and the maximum area divided by the total area was termed the fibrillation organization index (FOI). Sinus rhythm was restored in 16 of 23 patients (70%); 8 of these 16 patients received only bepridil (Group I) and the other 8 responders received bepridil and aprindine (Group II). In Group I bepridil increased both FCL (p<0.001) and FOI (p<0.01) and terminated AF after 20+/-12 days. In Group II bepridil increased FCL (p<0.001), but did not change FOI. The addition of aprindine terminated AF in association with an increase in both FCL (p<0.005) and FOI (p<0.005) within 19+/-8 days. In the remaining 7 patients who did not have restoration of sinus rhythm, bepridil increased both FCL and FOI significantly, but less than in Group I, and the addition of aprindine did not further increase either of them. Chemical cardioversion of AF occurred in all patients with FCL > or =190 ms and FOI > or =45% after drug administration. CONCLUSION: Bepridil alone or in combination with aprindine converted long lasting persistent AF in association with an increase in both FCL and FOI. The combination of FCL and FOI after drug administration is helpful in predicting chemical cardioversion of persistent AF.

Aged↗
PubMed2004

Complex atrial reentrant circuits evaluated by entrainment mapping using a multielectrode basket catheter.

Atrial tachycardias after open heart surgery sometimes have complex reentrant circuits. A patient with a dual-loop atrial reentrant circuit occurring after mitral valve replacement was evaluated by entrainment mapping with a basket catheter. The position of the catheter was adjusted to obtain atrial electrograms of the anterior and posterior septal areas, the crista terminalis, the free wall, and the tricuspid annular region. Entrainment mapping identified a dual-loop reentry consisting of one circuit around the tricuspid annulus and another around the septal atriotomy scar. The reentrant circuit around the septal incision was eliminated by ablating the area between the septal incision and the inferior vena cava, and the circuit around the tricuspid annulus was terminated with an additional linear ablation between the tricuspid annulus and the inferior vena cava. Entrainment mapping using a multielectrode basket catheter is very useful for identifying complex atrial reentrant circuits.

Catheter Ablation↗
PubMed2004

Effects of anticoagulation intensity on hemostatic markers in patients with non-valvular atrial fibrillation.

BACKGROUND: Elevation of hemostatic markers may account for the increased risk of ischemic stroke in patients with non-valvular atrial fibrillation (NVAF). The aim of this study was to determine the effects of anticoagulation intensity on hemostatic markers in patients with NVAF. METHODS AND RESULTS: In 509 patients with NVAF, comprising 263 patients treated with warfarin and 246 patients without warfarin, the hemostatic markers of prothrombin fragment F1.2 (F1.2), fibrin D-dimer, platelet factor 4 (PF4), and beta-thromboglobulin were determined and compared with those in 111 patients with sinus rhythm. F1.2 was inversely related with anticoagulation intensity and D-dimer increased with age. All hemostatic markers, except F1.2, were greater in patients with NVAF than in patients with sinus rhythm. F1.2 and D-dimer were significantly lower in patients with international normalized ratio (INR) > or =1.5 than in NVAF patients without warfarin and were not different between NVAF patients with INR of 1.5-1.9 and with INR > or =2.0. CONCLUSIONS: Low intensity of anticoagulation (INR 1.5-1.9) suppresses the elevated concentration of F1.2 and D-dimer in patients with NVAF, and might be favorable in Japanese patients with NVAF in view of the balance between prevention of thromboembolism and the adverse effect by warfarin (ie, bleeding).

Adult↗
PubMed2004

Attitudes of Japanese cardiologists toward anticoagulation for nonvalvular atrial fibrillation and reasons for its underuse.

BACKGROUND: Although warfarin reduces embolic events in patients with nonvalvular atrial fibrillation (NVAF), it is used less frequently in Japan and so the aim of the present study was to determine the attitudes of Japanese cardiologists toward antithrombotic therapy for NVAF patients. METHODS AND RESULTS: Subjects were NVAF patients enrolled in a prospective study in 1999. Clinical characteristics, type of NVAF and antithrombotic therapy, risk factors for embolism, and contraindications to warfarin were analyzed. Risk factors included advanced age (>75 years), hypertension, diabetes mellitus, congestive heart failure, and prior embolic events. Contraindications to warfarin included bleeding tendency, malignant tumors and others. Among 509 patients (66.6+/-10.3 years old), 359 had at least one risk factor for embolism and of these 359 patients, 200 (55.7%) received warfarin (ie, modest adherence to the guideline for antithrombotic therapy). There were 159 patients who had at least one risk factor but did not receive warfarin; 70.4% of these received antiplatelet drugs. Contraindications were found in only 22.6% and paroxysmal nature of NVAF seemed a possible reason for non-use of warfarin in 47.2% of 159 patients. CONCLUSIONS: In Japan warfarin is not used extensively for treatment of NVAF patients having risk factors and the reasons for not using antithrombotic therapy seemed inappropriate in most of patients.

Anticoagulants↗
PubMed2004

Maintenance of sinus rhythm and recovery of atrial mechanical function after cardioversion with bepridil or in combination with aprindine in long-lasting persistent atrial fibrillation.

BACKGROUND: The aim of this study was to evaluate pharmacological cardioversion of long-lasting persistent atrial fibrillation (AF) using bepridil in terms of recovery of atrial mechanical function and maintenance of sinus rhythm. Bepridil alone or in combination with aprindine is effective for termination of persistent AF. METHODS AND RESULTS: The study group comprised 38 consecutive patients (24 men, 58.8+/-9.3 years) with successful conversion of persistent AF lasting >1 month either pharmacologically (Group I) or electrically (Group II). Fast Fourier transform analysis of fibrillation waves was performed and fibrillation cycle length (FCL) was calculated from the peak frequency. In Group I, sinus rhythm was pharmacologically restored in 22 patients after an average 30 days (7-49 days) of bepridil administration, either alone (11) or in combination with oral aprindine (11); they were followed up while using the same drugs. In Group II, electrical conversion restored sinus rhythm in 16 patients, and they were followed up with conventional antiarrhythmic drugs other than bepridil and aprindine. After bepridil treatment FCL increased and became significantly longer in Group I than in Group II (190+/-39 vs 150+/-29 ms, p<0.001). Atrial peak velocity in transmitral flow within the first week after cardioversion was greater in Group I than in Group II (68+/-35 vs 32+/-20 cm/s, p<0.05). By Kaplan-Meier analysis, 83% of Group I patients were free of AF recurrence at the 12-month follow-up, compared with 36% in Group II (p<0.005). CONCLUSIONS: In patients with long-lasting AF, pharmacological conversion with bepridil alone or in combination with aprindine recovered atrial mechanical function better and maintained sinus rhythm longer than electrical conversion.

Anti-Arrhythmia Agents↗
PubMed2004

Prothrombotic activity is increased in patients with nonvalvular atrial fibrillation and risk factors for embolism.

STUDY OBJECTIVES: The aim of this study was to investigate whether risk factors for embolism would promote thrombus formation in patients with nonvalvular atrial fibrillation (NVAF). METHODS: Hemostatic markers for platelet activity (ie, platelet factor-4 and beta-thromboglobulin [TG]), thrombotic status (ie, prothombin fragments 1 and 2), and fibrinolytic status (ie, d-dimer) were determined in 246 patients with NVAF (mean age, 66.1 years) and 111 control subjects without NVAF (68.3 years). RESULTS: The beta-TG level was higher in NVAF patients than in control subjects. D-dimer levels were higher in NVAF patients having risk factors (mean [+/- SE] d-dimer level, 158.6 +/- 9.2 ng/mL) than in those without risk factors (mean d-dimer level, 92.1 +/- 6.7 ng/mL; p < 0.01) and in control subjects (mean d-dimer level: control subjects with risk factors, 79.1 +/- 10.3 ng/mL; control subjects without risk factors, 31.0 +/- 7.4 ng/mL; p < 0.01). NVAF (odds ratio [OR], 3.94; 95% confidence interval [CI], 1.87 to 8.30; p = 0.0003) and age of >/= 75 years (OR, 5.68; 95% CI, 2.87 to 11.23; p < 0.0001) emerged as predictors of elevated levels of d-dimer, and only NVAF (OR, 10.30; 95% CI, 5.67 to 18.72; p < 0.0001) emerged as a predictor of elevated levels of beta-TG. CONCLUSIONS: NVAF patients whose conditions were complicated with risk factors for embolism could be in the prothrombotic state. Advanced age is a strong predictor of the prothrombotic state in NVAF patients.

Aged↗
PubMed2004

Morphological changes in capillaries in the ischemic brain in Wistar rats.

The microvasculature in the brain plays a vital role in the maintenance of brain perfusion, and fulfills the dynamic requirements of normal brain functions. It is well known that collateral circulation can be induced by ischemia in cerebral infarctions, but it is not known whether cerebral ischemia affects microvasculatures in the ischemic region. In the present study, we examined quantitatively serial changes in capillaries following bilateral common carotid artery ligation in Wistar rats. After the animals were perfused with tetramethylrhodamine isothiocyanate-labeled gelatin 3 h (n = 9), 1 day (n = 9), 7 days (n = 9) and 28 days (n = 9) after the ligation, capillary diameters in the brain sections were measured with a confocal laser-scanning microscope. Capillary diameters of the cerebellum did not differ among all groups, while those in the ischemic regions decreased significantly 3h after the ligation (p<0.01), thereafter gradually returned toward the baseline level, and became significantly larger (168% of the control) 28 days after the ligation (p< 0.01). The density of capillaries in the frontal and parietal cortices increased approximately to 1.3-fold of those of the control level 28 days after the ligation. Transmission electron microscopy showed that the mean ratio of the inner diameter to the outer diameter of capillaries in the frontal cortex became significantly greater 28 days after the ligation (p<0.05). Our data indicate that capillaries dilate in the ischemic brain region in the chronic phase of cerebral ischemia. It is also suggested that neovascularization occurs in the ischemic brain region.

Animals↗
PubMed2004

Control of the ciliary beat by cyclic nucleotides in intact cortical sheets from Paramecium.

The locomotor behavior of Paramecium depends on the ciliary beat direction and beat frequency. Changes in the ciliary beat are controlled by a signal transduction mechanism that follows changes in the membrane potential. These events take place in cilia covered with a ciliary membrane. To determine the effects of second messengers in the cilia, cortical sheets were used with intact ciliary membrane as a half-closed system in which each cilium is covered with a ciliary membrane with an opening to the cell body. Cyclic nucleotides and their derivatives applied from an opening to the cell body affected the ciliary beat. cAMP and 8-Br-cAMP increased the beat frequency and the efficiency of propulsion and acted antagonistically to the action of Ca(2+). cGMP and 8-Br-cGMP increased the efficiency of propulsion accompanying clear metachronal waves but decreased the beat frequency. These results indicate that the cyclic nucleotides affect target proteins in the ciliary axonemes surrounded by the ciliary membrane without a membrane potential and increase the efficiency of propulsion of the ciliary beat. In vitro phosphorylation of isolated ciliary axonemes in the presence of cyclic nucleotides and their derivatives revealed that the action of cAMP was correlated with the phosphorylation of 29-kDa and 65-kDa proteins and that the action of cGMP was correlated with the phosphorylation of a 42-kDa protein.

Animals↗
PubMed2004

Occult neoplastic cells in the lymph node sinuses and recurrence of primary breast, lung, esophageal, and gastric cancer.

The correlation between detection of occult neo-plastic cells (ONCs) in lymph node sinuses and the recurrence/metastasis of primary breast, lung, esophageal, and gastric cancer was examined. Among patients with Stage I-III cancer treated by radical resection with dissection of at least 10 lymph nodes, 40 patients who suffered recurrence/metastasis within 5 years post-operatively and 94 patients who did not have recurrence within 5 years were randomly selected. A total of 1,340 lymph nodes were subjected to immunohistochemical staining for cytokeratin to identify ONCs. Then the sensitivity, specificity, positive predictive value, and negative predictive value of ONCs were determined for predicting the recurrence of each cancer. These parameters were respectively 40.0, 75.9, 62.4, and 55.8% for breast cancer, while the respective values were 50.0, 77.4, 68.9, and 60.8% for lung, 57.1, 64.3, 61.5, and 60.0% for esophageal, and 68.8, 65.0, 66.3, and 67.5% for gastric cancer. All of the parameters exceeded 65% for gastric cancer. ONCs also showed a high specificity for breast and lung cancer, but both the sensitivity and specificity were low for esophageal cancer.

Breast Neoplasms↗