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Biomedical subjects

K Shimada

Publications and source records attributed to K Shimada.

At least 253 records · Page 14Linked to original sources
PubMed2000

Fluvastatin upregulates inducible nitric oxide synthase expression in cytokine-stimulated vascular smooth muscle cells.

Nitric oxide (NO) production by inducible NO synthase (iNOS) may play an important role in the pathogenesis of atherosclerosis. Although fluvastatin has been shown to reduce progression of atherosclerosis, it is not known whether it regulates iNOS expression. We investigated the effects of fluvastatin on iNOS expression and subsequent NO synthesis in vascular smooth muscle cells (VSMCs) and the mechanism by which fluvastatin exerts its effects. Fluvastatin significantly increased interleukin-1ss (IL-1ss)-induced nitrite production by VSMCs in a time-dependent (0 to 24 hours) and dose-dependent (10(-)(8) to 10(-)(5) mol/L) manner. Increased nitrite production by fluvastatin was accompanied by increased iNOS mRNA and protein accumulation. IL-1ss induced nuclear factor-kappaB activation in VSMCs, which was not affected by fluvastatin. Exogenous mevalonate significantly prevented the stimulatory effect of fluvastatin on nitrite production. Cotreatment with geranylgeranyl-pyrophosphate also reversed the effect of fluvastatin. Furthermore, both Rho inhibitor C3 exoenzyme and Rho kinase inhibitor Y-27632 significantly increased IL-1ss-induced nitrite accumulation in VSMCs. These results demonstrated that fluvastatin upregulates iNOS expression and subsequent NO formation in rat VSMCs through inhibition of Rho.

Animals↗
PubMed2000

High prevalence of seropositivity for antibodies to Chlamydia-specific lipopolysaccharide in patients with acute coronary syndrome.

BACKGROUND: Results of recent studies have demonstrated that there is an association between infection with Chlamydia pneumoniae and coronary artery disease (CAD). Inflammatory response caused by chlamydial infection has been considered to contribute to the development of atherosclerosis in coronary arteries. OBJECTIVE: The aim of this study was to investigate the specific relations between chlamydial infection and coronary events in patients with CAD. METHODS: We measured serum levels of immunoglobulin A and G antibodies against Chlamydia spp.-specific lipopolysaccharide in 155 patients with CAD and 60 age-matched and sex-matched healthy controls by enzyme-linked immunosorbent assay. CAD patients were divided into groups of the patients with acute coronary syndrome [(ACS), n = 35], old myocardial infarction [(OMI), n = 60] and chronic coronary heart disease [(CCHD), n = 60]. RESULTS: Prevalence of both seropositive antibodies in the control group and CCHD group were not different. In contrast, in ACS group there were significantly higher prevalences of seropositive immunoglobulin A (46 versus 12%, P = 0.0001) and G (74 versus 45%, P = 0.005) antibodies and in OMI group there was a significantly higher prevalence of seropositive immunoglobulin A antibodies (28 versus 12%, P = 0.02). Furthermore, compared with CCHD group, in ACS group there were significantly higher prevalences of seropositive immunoglobulin A (P = 0.00006) and G (P = 0.002) antibodies and in OMI group there was a higher prevalence of seropositive immunoglobulin A (P = 0.01). Adjustment for confounding factors did not change these findings. CONCLUSIONS: Infection with Chlamydia is significantly associated with ACS and OMI, but not with CCHD. These findings suggest that chronic and reactive infection with Chlamydia can lead to disruption of vulnerable plaque in patients with ACS.

Acute Disease↗
PubMed2000

In situ estrogen synthesized by aromatase P450 in uterine leiomyoma cells promotes cell growth probably via an autocrine/intracrine mechanism.

In the present study we characterized in detail the expression of aromatase P450 in leiomyomas to determine the role of in situ estrogen in the growth advantage of leiomyomas. The levels of aromatase P450 transcripts were determined by quantitative RT-PCR to be significantly higher in leiomyomas than in corresponding myometrium. The overexpression of aromatase P450 in leiomyomas was also confirmed by Western blot analysis. The estimated size of immunoreactive aromatase was 58 kDa, similar to that in placenta. To identify a cell type that express aromatase P450 in leiomyomas, histological specimens were stained for aromatase P450 using a polyclonal antibody. Strong immunoreactivity was detected in the cytoplasm of leiomyoma cells, whereas surrounding normal myometrium displayed weak or negative staining. Smooth muscle-like cells in culture obtained from leiomyomas, positive for actin D fiber, possessed immunoreactive granules of aromatase in the cytoplasm. Conversion of androgen to estrogen was effectively stimulated by phorbol myristate acetate and dexamethasone plus interleukin-1beta and was completely abolished by selective inhibitors of aromatase P450 (fadrozole and TZA-2209), but not by inhibitors of 5alpha-reductase (finasteride and flutamide). The apparent Km of androstenedione was 3 nM in the presence of dexamethasone and interleukin-1beta, corresponding to the plasma concentration of androstenedione in women of reproductive age. To determine whether endogenous aromatase P450 plays a role in the growth promotion of leiomyoma cells, we evaluated the cell growth of smooth muscle-like cells treated with various concentrations of estrogen and androgen using a WST-1 assay. Treatment with testosterone (10(-8) and 10(-7) M) and androstenedione (10(-8) and 10(-7) M) stimulated the growth of smooth muscle-like cells obtained from leiomyomas to the same extent as estradiol (10(-10)-10(-7) M), whereas dihydrotestosterone (10(-11)-10(-8) M) did not. The stimulatory effect of testosterone on cell growth was again abolished by cotreatment with fadrozole. The level of estradiol in the medium of testosterone (10(-8) M)-treated smooth muscle-like cells was 10(-11) M, which was 1 order lower than the minimum concentration of estradiol necessary to promote cell growth (10(-10) M). This indicates that estradiol synthesized in leiomyomas promotes their growth via an autocrine/intracrine mechanism. We conclude that myometrial cells of leiomyomas overexpress aromatase P450 and are able to synthesize sufficient estrogen to accelerate their own cell growth. Overexpression of aromatase P450 may play a role in the growth advantage of leiomyoma tissue over surrounding myometrium via an autocrine/intracrine mechanism.

Adult↗
PubMed2000

Evidence for the degradation of maleate moiety in chlorpheniramine maleate solution using a stability-indicating HPLC method.

The degradation phenomenon of maleate moiety of chlorpheniramine maleate in solution has been demonstrated by means of a peculiar ion-pair HPLC method developed by the authors, which permits the simultaneous determination of chlorpheniramine and maleate. A commercial cough drug containing chlorpheniramine maleate was dissolved in water with m-hydroxybenzoic acid as an internal standard, and then kept for several days at room temperature. It was recognized that the maleate content in the drug solution had gradually decreased, whereas chlorpheniramine content had not decreased. A simple solution of maleic acid was also kept for several days at room temperature, and it was also recognized that the maleate content in the solution preserved at the same concentration as the solution of the commercial cough drug had gradually decreased, and the percent of remaining maleate reached zero. The degraded peaks on HPLC chromatogram were not detected at all by UV detector, and the disappearance of maleate was ascertained by GC-MS. No detectable example of maleate of chlorpheniramine maleate in a commercial cough syrup has suggested that maleate moiety of chlorpheniramine maleate decomposed to carbon dioxide.

Chlorpheniramine↗
PubMed2000

Adenosine-induced coronary flow reserve in Watanabe heritable hyperlipidemic rabbits.

The Watanabe heritable hyperlipidemic (WHHL) rabbit develops coronary atherosclerosis and hypercholesterolemia because of a genetic deficiency of low-density lipoprotein receptors and is therefore a good animal model for studying the relationships of coronary atherosclerosis, hypercholesterolemia and coronary flow reserve. The aim of the present study was to assess myocardial perfusion at baseline and during adenosine infusion (0.2 mg x kg(-1) x min(-1)) in 8 WHHL rabbits (13.8+/-0.5 months) with 13N-ammonia, small-animal positron emission tomography (PET) and colored microspheres. Results were compared with those from 6 age-matched Japanese white rabbits. Plaque distribution was also examined in the extramural coronary arteries. All 8 WHHL rabbits had coronary plaques, with 6 showing multiple plaques. Mean global myocardial blood flow (ml x min(-1) x g(-1)) did not differ significantly between control and WHHL groups both at baseline (3.67+/-0.72 vs 4.26+/-1.12 ml x min(-1) x g(-1), p=NS) and with adenosine (7.92+/-2.00 vs 9.27+/-2.91 ml x min(-1) x g(-1), p=NS), nor did coronary flow reserve (2.16+/-0.37 vs 2.18+/-0.41, p=NS). None showed evidence of regional perfusion abnormalities by visual and semiquantitative analyses of PET images. It was concluded that WHHL rabbits preserve adenosine-induced coronary flow reserve despite coronary atherosclerosis and hypercholesterolemia, suggesting that a compensatory mechanism develops in this animal model.

Adenosine↗
PubMed2000

Direct effects of statins on cells primarily involved in atherosclerosis.

Statins are lipid-lowering agents which act by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme is responsible for the conversion of HMG-CoA to mevalonate. Products of mevalonate metabolism are critical for several cellular processes of eukaryotic cells, and inhibition of the mevalonate pathway by statins has pleiotropic effects. It has been reported that statins inhibit the migration and proliferation of vascular smooth cells (VSMCs) and macrophages, decrease interleukin-6 and inducible nitric oxide synthase expression in VSMCs, improve endothelial function and up-regulate endothelial nitric oxide synthase expression. The above effects of statins are independent of plasma cholesterol levels, and are completely blocked by exogenous mevalonate and some isoprenoids. These findings suggest that, in addition to their effects on plasma lipids, statins exert direct antiatherosclerotic effects on the cells primarily involved in atherosclerosis.

Animals↗
PubMed2000

Is there any difference between intermediate-acting and long-acting calcium antagonists in diurnal blood pressure and autonomic nervous activity in hypertensive coronary artery disease patients?

Recently, there have been some reports indicating that calcium antagonists induce a reflex increase in sympathetic activity, triggering cardiac events, especially in coronary artery disease (CAD) patients. In this study, we assessed heart rate (HR) variability (HRV) using power spectral analysis of the 24-h RR interval in 25 hypertensive outpatients with CAD treated with nifedipine. We compared blood pressure (BP), HR, and HRV variation in the same patients substituting benidipine (long-acting) for nifedipine (intermediate-acting). There were no significant differences in 24-h, daytime, nighttime, and morning BP between the nifedipine phase and the benidipine phase. HRV parameters (LF: low frequency power, HF: high frequency power, LF/HF ratio) also showed no significant differences in 24-h, daytime, nighttime, and morning LF, HF, and LF/HF ratio between the nifedipine phase and the benidipine phase. Blood pressure, HR, and HRV parameters, except the LF component from 2 to 4 h after nifedipine administration (the most effective duration), showed no differences compared to before administration. The LF component after the nifedipine administration was lower than before administration. In conclusion, in hypertensive patients with CAD, whose BP levels were well-controlled by twice-daily use of intermediate-acting nifedipine, switching from nifedipine to a long-acting calcium antagonist, benidipine, maintained well-controlled BP levels to a similar degree, but it may not have additional benefit in sympatho-vagal balance.

Autonomic Nervous System↗
PubMed2000

Long-term survival after multimodality treatment for resectable pancreatic cancer.

BACKGROUND: The prognosis of pancreatic adenocarcinoma after radical pancreatectomy is poor, especially in advanced-stage disease. STUDY AIM: To determine the survival rates and evaluate the effectiveness of multimodality treatment for advanced pancreatic cancer. METHODS: From November 1983 to January 1993, 30 patients with pancreatic adenocarcinoma including 9 with carcinoma of the body and tail were treated by a multimodal approach consisting of extended pancreatectomy, intraoperative radiotherapy (IORT), and hepatic artery or portal vein infusion of mitomycin C (MMC) followed by systemic bolus injection. All surviving patients were followed for more than 8 yr and survival rates were calculated by the Kaplan-Meier method. RESULTS: There were no operative or hospital deaths. Eight patients survived for more than 5 yr, 3 of whom survived more than 10 yr. The 5-yr survival rate for 27 patients excluding 3 with metastasis to the liver, peritoneum, or lung was 31%, with a median survival of 31.1 mo. Among them, the 1-, 3-, and 5-yr survival rates for 19 patients with regional nodal metastasis were 95, 50, and 28%, respectively, with a median survival of 36.0 mo. CONCLUSION: The multimodality treatment combined with IORT and MMC chemotherapy appeared to have a benefit for prognosis of advanced pancreatic adenocarcinoma.

Adenocarcinoma↗
PubMed2000

Quenching of bacteriochlorophyll fluorescence in chlorosomes from Chloroflexus aurantiacus by exogenous quinones.

The quenching of bacteriochlorophyll (BChl) c fluorescence in chlorosomes isolated from Chloroflexus aurantiacus was examined by the addition of various benzoquinones, naphthoquinones (NQ), and anthraquinones (AQ). Many quinones showed strong quenching in the micromolar or submicromolar range. The number of quinone molecules bound to the chlorosomes was estimated to be as small as one quinone molecule per 50 BChl c molecules. Quinones which exhibit a high quenching effect have sufficient hydrophobicity and one or more hydroxyl groups in the alpha positions of NQ and AQ. Chlorobiumquinone has been suggested to be essential for the endogenous quenching of chlorosome fluorescence in Chlorobium tepidum under oxic conditions. We suggest that the quenching effect of chlorobiumquinone in chlorosomes from Chl. tepidum is related to the 1'-oxo group neighboring the dicarbonyl group.

Bacteriochlorophylls↗
PubMed2000

Structure and chromosomal localization of the RAE28/HPH1 gene, a human homologue of the polyhomeotic gene.

The Polycomb group of (Pc-G) genes and trithorax group of genes are known to play a crucial role in the maintenance of the transcriptional repression state of Hox genes, probably through modification of the chromatin configuration. The rae28/mph1 gene is a mammalian homologue of the Drosophila polyhomeotic gene, which belongs to the Pc-G genes. As reported previously, we established mice deficient in the rae28/mph1 gene and showed that these homozygous animals displayed the developmental defects compatible with a human congenital disorder, CATCH22 syndrome. In this study we analyzed the structural organization of the human counterpart of the rae28/mph1 gene (RAE28/HPH1) and its processed pseudogene (psiPH), which are located on, respectively, human chromosome 12p13 and 12q13. The HPH1 gene consists of 15 exons spanning approximately 26 kb and its structural organization is well conserved between mouse and human. These genetic information of the RAE28/HPH1 gene may provide an important clue for further examination of its involvement in human congenital disorders related to CATCH22 syndrome.

Animals↗
PubMed2000

[Determinants of endothelial cell damage in the elderly hypertension: assessment by plasma von Willebrand factor].

To investigate the determinants of endothelial cell damage in hypertensive elderly patients, we measured the plasma von Willebrand factor (vWF) levels by a recently developed enzyme-linked immunosorbent assay using monoclonal antibody for the functional epitope. Plasma vWF level was markedly increased in the elderly normotensive subjects (n = 42) than in younger normotensive subjects (n = 39) (127 vs 88%, p < .0001), and was further increased in elderly hypertensive subjects (n = 68) (148%, p < .05 vs elderly normotensives). The vWF level was positively correlated with body mass index in younger normotensive subjects (r = 0.41, p < .01), with systolic blood pressure (BP) in elderly normotensive subjects (r = 0.41, p < .01), and with age (r = 0.44, p < .001) and fibrinogen level (r = 0.37, p < .01) in elderly hypertensive subjects. In elderly hypertensive subjects (n = 150), vWF level had a stronger positive correlation with 24-hr systolic BP measured (r = 0.41, p < .0001) by ambulatory BP monitoring than with clinic systolic BP (r = 0.33, p < .0001). In conclusion, in hypertensive elderly patients, endothelial cell damage increases with systolic BP and fibrinogen levels, indicating a prethrombotic condition.

Age Factors↗
PubMed2000

Troglitazone improves endothelial dysfunction in patients with insulin resistance.

Insulin resistance is a possible major metabolic cause of atherosclerosis. Endothelial dysfunction is commonly found in patients with insulin resistance, and primary treatment of insulin resistance with troglitazone should improve such endothelial dysfunction. Thus, the effects of troglitazone on endothelial function were investigated. Thirteen non-diabetic male subjects with hyperinsulinemic response to oral glucose load (n = 7) and normal (n = 6) subjects were investigated. Flow-mediated dilatation (FMD) of the brachial artery was examined by high resolution ultrasonography before and after the administration of troglitazone of 400 mg for 4 weeks. In insulin resistant subjects, fasting glucose (4.9+/-0.3 to 4.7+/-0.3 mmol/L, p<0.05), insulin (45+/-30 to 25+/-15 pmol/L, p<0.05) and response to oral glucose load (AUC glucose: 15.0+/-3.5 to 13.0+/-2.2 mmol x h/L, p<0.05; AUC insulin: 965+/-560 to 475+/-275 pmol x h/L, p<0.05) were significantly reduced. FMD was significantly improved in insulin resistant subjects. A significant negative correlation was observed between FMD and AUC insulin (r=-0.64, p<0.05). The present study demonstrates that FMD is impaired in insulin resistant subjects, and troglitazone improves the blunted vascular response and impaired insulin response. This finding suggests that primary treatment of insulin resistance could prevent the development of atherosclerosis by improving endothelial dysfunction.

Adult↗
PubMed2000

[Congenital hydronephrosis detected by prenatal ultrasonography: the effect of pyeloplasty on renal function].

PURPOSE: Prenatal detection of congenital hydronephrosis has raised new questions with regard to the need of management and the indications for operation. Moreover, there is considerable controversy whether or not pyeloplasty improves long-term renal function. We evaluated the operative results of this entity under the setting of well defined indications for surgery. MATERIALS AND METHODS: The indications for pyeloplasty included Society for Fetal Urology-grade (SFU-grade) 3 and grade 4 hydronephrosis on ultrasonogram together with obstructive pattern on modified "Well Tempered" diuretic renogram. We analysed the postoperative changes of ultrasonographic findings, differential renal function, and renogram patterns in 28 children with unilateral hydronephrosis detected prenatally. RESULTS: Of the patients, 27 had grade-4 hydronephrosis on preoperative ultrasonogram. Pyeloplasty was effective in decreasing the grade of dilatation in all kidneys except one. Of the involved renal units, 14 (50%) had reduced differential renal function less than 45% on the preoperative renogram. Differential renal function increased significantly by absolute value of 5% or greater in 8 kidneys (29%), but decreases in 5 kidneys (18%). In the remaining 15 kidneys (54%) there was no significant differences between pre- and post-operative differential renal function. Postoperative diuretic renogram changed to non-obstructive pattern in 26 kidneys (93%). Another 2 kidneys showed hypofunctioning pattern. CONCLUSIONS: The results suggest that, although pyeloplasty decreases ultrasonographic dilatation of hydronephrosis and improves excretory pattern of diuretic renogram, significant increase of differential renal function is expected in only one third of the involved kidneys.

Humans↗
PubMed2000

Endogenously generated nitric oxide by nitric-oxide synthase gene transfer inhibits cellular proliferation.

We investigated whether endothelial nitrite oxide synthase (NOS) gene transfer inhibited cellular proliferation. Endothelial NOS and endothelin type A receptor genes were transferred into 293 cells, a human embryonic kidney cell line, by calcium-phosphate coprecipitation. The cytosolic free Ca(2+) levels ([Ca(2+)](i)) of transfected cells were estimated with fura-2 fluorescence. Thymidine incorporation was increased by endothelin-1 in type A receptor-transfected cells. The endothelial NOS gene transfer did not affect endothelin-1-induced increase in [Ca(2+)](i) of type A receptor-transfected cells, but markedly inhibited mitogen-activated protein kinase and c-fos promoter activities. The endothelial NOS gene transfer also inhibited thymidine incorporation into type A receptor-transfected cells in response to endothelin-1, which was abolished in the presence of the NOS inhibitor N(G)-monomethyl-L-arginine acetate. The endothelin-1-induced increase in cell number was significantly suppressed by endothelial NOS gene transfer as well as by the mitogen-activated protein kinase inhibitor PD98059. These results indicate that endothelial NOS gene transfer inhibits cellular proliferation via inhibition of the mitogen-activated protein kinase cascade.

Calcium↗
PubMed2000

Uptakes and images of 38K in rabbit heart, kidney, and brain.

UNLABELLED: The purpose of this study was to evaluate the kinetics and image quality of positron-emitting 38K (half-life, 7.6 min) and high-resolution small-animal PET in the heart, kidney, and brain of rabbits. METHODS: Studies were performed with 18 closed-chest anesthetized rabbits at baseline and during infusions of adenosine (0.2 mg/kg/min) and propranolol (0.5-1.0 mg/kg intravenously) using high-resolution small-animal PET. 38K was injected intravenously and dynamic PET imaging of the heart, kidney, or brain was performed for 3 min. Colored microspheres were injected into the left ventricle to measure organ blood flow. Arterial blood was withdrawn directly from the femoral artery, and, after the animals were killed, 38K activities in each organ were measured directly with a well counter. Uptake of 38K was calculated by dividing the 38K activities in each organ by the integral of the input function. The extraction fraction of 38K was estimated by dividing the uptake of 38K in each organ by the organ blood flow, measured by microspheres. RESULTS: The left ventricular myocardium and kidney were clearly visualized, but there was no visual 38K uptake in the brain. For the heart, kidney, and brain, respectively, average blood flow was 2.91 +/- 1.29, 5.49 +/- 0.71, and 0.57 +/- 0.11 mL/min/g, and the extraction fraction of 38K at baseline was 0.55 +/- 0.13, 0.48 +/- 0.13, and 0.022 +/- 0004. The Renkin-Crone model fit the relation between myocardial extraction and flow under a wide range of myocardial blood flow (r = 0.89). CONCLUSION: 38K is a suitable tracer for noninvasively showing the potassium kinetics of the heart, kidney, and brain by PET imaging.

Animals↗
PubMed2000

[Absence of cross resistance between an irinotecan plus cisplatin combination and raltitrexed (ZD1694) in two patients with advanced colorectal cancer].

Two patients with advanced colorectal cancer were consecutively administered two different chemotherapeutic regimens. The first patient showed an initial response to combination treatment with irinotecan plus cisplatin, but then progressed. He subsequently responded to treatment with a novel thymidylate synthase (TS) inhibitor, raltitrexed. The second patient, who progressed after exhibiting a response to raltitrexed, subsequently responded to irinotecan/cisplatin combination therapy. In conclusion, no clinical cross resistance between the regimens of irinotecan/cisplatin combination therapy and raltitrexed was observed in these patients with advanced colorectal cancer.

Antimetabolites, Antineoplastic↗
PubMed2000

[Prediction of restenosis after percutaneous transluminal coronary angioplasty using coronary flow reserve. Kansai Doppler Guide Wire Study Group].

This multi-center prospective study attempted to predict restenosis after percutaneous transluminal coronary angioplasty(PTCA) using coronary flow reserve. Intracoronary blood flow velocity was measured in 47 patients(37 males, 10 females, mean age 66 +/- 9 years) with a Doppler guide wire, following successful PTCA. Twenty-four patients had prior myocardial infarction. After successful PTCA, a Doppler guide wire was placed at the distal portion of the target lesion, and coronary blood flow velocity was measured before and during intravenous administration of adenosine triphosphate. Follow-up coronary angiography was performed 154 +/- 69 days after PTCA, and the diameter stenosis of the target lesion was measured using quantitative coronary angiography. Follow-up angiography showed restenosis in 13 patients(28%). Sensitivity and specificity for predicting restenosis were low(50%, 45%, respectively) with a post-PTCA% diameter stenosis cut-off point of 27%. Sensitivity and specificity were 67% and 61% with a minimal lumen diameter cut-off of 1.8 mm. The reference coronary artery diameter(cut-off point 2.5 mm) was better for predicting restenosis(sensitivity 78% and specificity 76%). Sensitivity and specificity were 62% and 67%, respectively, using coronary flow reserve(cut-off point 2.0). The restenosis rate of patients with a reference diameter of more than 2.5 mm was 10%, but 54% for those with less than 2.5 mm(p < 0.05). In patients with a reference diameter of less than 2.5 mm, coronary flow reserve was useful for predicting restenosis(cut-off point 1.9, sensitivity 71% and specificity 83%). Coronary flow reserve is useful for predicting restenosis after PTCA, when combined with reference coronary artery diameter.

Aged↗