Biomedical subjects
Publications and source records attributed to T Tsutsui.
[reaction: see text] Highly soluble and strongly blue fluorescent oligo(9,9-dihexyl-2,7-fluorene ethynylene)s (OFEs) were synthesized by a Pd/Cu-catalyzed Sonogashira coupling reaction. An organic light-emitting diode using pentamer 15 as the emitting material was successfully fabricated and emitted a bright blue light.
OBJECTIVES: This study evaluated oxidative stress in the failing ventricle in patients with dilated cardiomyopathy (DCM). BACKGROUND: Oxidative stress appears to increase in the failing myocardium and may contribute to ventricular dysfunction in patients with DCM. Tumor necrosis factor-alpha (TNF-alpha), which is expressed in the failing heart, may stimulate oxidative stress. METHODS: We measured plasma oxidized low density lipoprotein (oxLDL) by sandwich enzyme-linked immunosorbent assay using specific antibodies against oxLDL in the aortic root (AO) and the coronary sinus (CS) in control subjects (n = 8) and in 22 patients with DCM and mild congestive heart failure. We also measured the plasma levels of TNF-alpha and angiotensin II. RESULTS: There was no difference in oxLDL between the AO and CS in control subjects. In contrast, plasma oxLDL was significantly higher in the CS than the AO in patients with DCM, suggesting that the transcardiac gradient ofoxLDL reflects oxidative stress in the failing heart in these patients. Plasma TNF-alpha levels were significantly higher in the CS than the AO with a significant positive correlation of the transcardiac gradient of TNF-alpha and the transcardiac gradient of oxLDL. Moreover, a significant negative correlation existed between the transcardiac gradient of oxLDL and left ventricular ejection fraction. The transcardiac gradient of plasma oxLDL was significantly lower in 6 patients who received carvedilol than in 16 patients who did not receive carvedilol. CONCLUSIONS: These findings indicate that the transcardiac gradient of oxLDL may be a marker of oxidative stress in the heart and that left ventricular dysfunction may be partly due to the oxidative stress in patients with DCM. In addition, TNF-alpha may stimulate oxidative stress in the failing heart in patients with DCM.
OBJECTIVES: The study evaluates the effect of atrial natriuretic peptide (ANP) compared with nitroglycerin (GTN) on left ventricular (LV) remodeling after first anterior acute myocardial infarction (AMI). BACKGROUND: Compared with GTN, ANP suppresses the renin-angiotensin-aldosterone system and endothelin-1 (ET-1), which stimulate LV remodeling. METHODS: Sixty patients with a first anterior AMI were randomly divided into the ANP (n = 30) or GTN (n = 30) groups after direct percutaneous transluminal coronary angioplasty. We evaluated LV ejection fraction (LVEF), end-diastolic volume index (LVEDVI) and end-systolic volume index (LVESVI) at the acute phase and after one month. We also measured neurohumoral factors during study drug infusion. RESULTS: There was no difference in the baseline characteristics or LVEF (46.9+/-1.0 vs. 46.8+/-1.3%) between the two groups. Although there was no difference in hemodynamics during the infusion periods, the LVEF was significantly improved after one month compared with the baseline value in both groups, but it was improved more in the ANP group than in the GTN group (54.6+/-1.1%, 50.8+/-1.3%, p < 0.05). Left ventricular enlargement was prevented in the ANP group (LVEDVI, 85.8+/-3.1 ml/m2 to 87.3+/-2.7 ml/m2; p = ns, LVESVI, 45.6+/-1.8 ml/m2 to 41.0+/-2.1 ml/m2, p < 0.05) but not in the GTN group (LVEDVI, 86.2+/-4.1 to 100.2+/-3.7, p < 0.01; LVESVI, 46.3+/-2.8 ml/m2 to 51.1+/-3.0 ml/m2, p = ns). During the infusion, ANP suppressed plasma levels of aldosterone, angiotensin II and ET-1 compared with GTN. CONCLUSIONS: These findings indicate that in patients with a first anterior AMI, an ANP infusion can prevent LV remodeling better than can GTN, and effectively suppresses aldosterone, angiotensin II and ET-1.
By immobilizing fructose-modified dendrimers on a polystyrene culture plate, the number of initially adhered hepatocytes on it was increased. Moreover, increasing the number of generations of fructose-modified dendrimer (fructose-dendrimer) increased the number. Urea synthesis per unit area also was increased, corresponding to the increase in the number of initially adhered hepatocytes. This result suggests that the fructose-dendrimers do not cause a decline in cell function. On the other hand, apoptosis of hepatocytes occurs during cultivation, and results in a decrease in the number of adhered cells and a decline in cell function. Fructose-dendrimers were found to suppress apoptosis of hepatocytes. This characteristic is considered to be responsible for the increase in the number of initially adhered hepatocytes without a decline in cell function. Fructose-dendrimers are shown to be very suitable scaffolds for use in a high-performance bioartificial liver support system.
To test the hypothesis that 1alpha-hydroxyvitamin D3 (1alpha(OH)D3) suppresses bone resorption after ovariectomy (ovx) by inhibiting osteoclastogenic potential in bone marrow cells, the bilateral tibiae of ddY mice, 8 weeks of age, subjected to ovx were obtained. 1alpha(OH)D3, at doses of 0, 0.2 (low dose), or 0.4 microg/kg body weight (high dose), was administered orally by canula three times a week for 2 or 6 weeks. Histomorphometric analysis of the proximal tibiae revealed that 1alpha(OH)D3 administration had no significant effect on trabecular bone volume of ovx limbs, which was reduced after ovx. The bone formation rate, increased by ovx, was significantly decreased by the administration of high-dose 1alpha(OH)D3. The ovx-induced increases in osteoclast number and surface at 2 weeks postsurgery were suppressed by the administration of high-dose 1alpha(OH)D3. With regard to bone marrow cells, the number of nonadherent cells per tibia obtained from ovx limbs increased, and this increase was suppressed by the administration of low- and high-dose 1alpha(OH)D3. The formation of mineralized nodules in marrow cultures obtained from ovx limbs was increased after surgery and unaltered by 1alpha(OH)D3 administration. The number of osteoclast-like multinucleated cells obtained from ovx limbs was reduced by low- and high-dose 1alpha(OH)D3 administration alike. The number of colony forming units-fibroblast and the number of colony forming units for granulocytes and macrophages was unaltered by ovx or the administration of 1alpha(OH)D3. The present study clearly demonstrates that high-dose 1alpha(OH)D3 suppresses osteoclast numbers and surface after ovx. The inhibitory effects of low- and high-dose 1alpha(OH)D3 on bone marrow cells after ovx were marked in the differentiation from osteoclast precursors to mature osteoclasts. Administration of 1alpha(OH)D3 suppressed ovx-promoted trabecular bone resorption by inhibiting osteoclastogenic potential in bone marrow cells.
OBJECTIVES: We sought to evaluate the effects of spironolactone on neurohumoral factors and left ventricular remodeling in patients with congestive heart failure (CHF). BACKGROUND: Aldosterone (ALD) promotes collagen synthesis and structural remodeling of the heart. Spironolactone, an ALD receptor antagonist, is reported to reduce mortality in patients with CHF, but its influence on left ventricular remodeling has not been clarified. METHODS: Thirty-seven patients with mild-to-moderate nonischemic CHF were randomly divided into two groups that received treatment with spironolactone (n = 20) or placebo (n = 17). We measured left ventricular volume and mass before treatment and after four months of treatment. We also measured the plasma levels of neurohumoral factors, such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), as well as plasma procollagen type III aminoterminal peptide (PIIINP), a marker of myocardial fibrosis. RESULTS: Left ventricular volume and mass were significantly decreased and ejection fraction was significantly increased in the spironolactone group, while there were no changes in the placebo group. Plasma levels of ANP, BNP and PIIINP were significantly decreased after spironolactone treatment, but were unchanged in the placebo group. There was a significant positive correlation between the changes of PIIINP and changes of the left ventricular volume index (r = 0.45, p = 0.045) as well as the left ventricular mass index (r = 0.65, p = 0.0019) with spironolactone treatment. CONCLUSIONS: These findings indicate that four months of treatment with spironolactone improved the left ventricular volume and mass, as well as decreased plasma level of BNP, a biochemical marker of prognosis and/or ventricular hypertrophy, suggesting that endogenous aldosterone has an important role in the process of left ventricular remodeling in nonischemic patients with CHF.
BACKGROUND: Cardiac natriuretic peptides may induce apoptosis in myocytes; however, the relationship between plasma levels of cardiac natriuretic peptides and those of soluble Fas (sFas) and tumor necrosis factor (TNF)-alpha remains unknown in patients with congestive heart failure (CHF). METHODS AND RESULTS: We measured plasma levels of sFas and TNF-alpha and those of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), norepinephrine, and endothelin 1 in 96 patients with CHF (ejection fraction < 45%). The patients were monitored for 3 years. Plasma levels of sFas and TNF-alpha increased with the severity of CHF. There was no significant correlation between sFas plasma levels and those of ANP and BNP. Cox proportional hazard analysis showed that high levels of sFas (P = .009) and BNP (P < .0001) and a low ejection fraction (P = .019) were independent significant prognostic predictors. CONCLUSIONS: There is no significant correlation between cardiac natriuretic peptide and sFas levels in plasma. Plasma sFas is a useful prognostic marker independent of neurohumoral factors, suggesting that immune activation and/or apoptosis play a significant role in the pathogenesis of CHF.
Catechol estrogens are considered critical intermediates in estrogen-induced carcinogenesis. We demonstrated previously that 17beta-estradiol (E(2)), estrone (E(1)) and four of their catechol estrogens, 2- and 4-hydroxyestradiols (2- and 4-OHE(2)), and 2- and 4-hydroxyestrones (2- and 4-OHE(1)) induce morphological transformation in Syrian hamster embryo (SHE) fibroblasts, and the transforming abilities vary as follows: 4-OHE(1) > 2-OHE(1) > 4-OHE(2) > 2-OHE(2) vertical line E(2), E(1). To examine the involvement of catechol estrogens in the initiation of hormonal carcinogenesis, we studied the ability of E(2), E(1) and their catechol estrogens to induce DNA adducts in SHE cells by using a (32)P-post-labeling assay. DNA adducts were detected in cells treated with each of all the catechol estrogens at concentrations of 10 microg/ml for 1 h and more. 2- or 4-OHE(2) formed a single DNA adduct, which was chromatographically distinct from each other. In contrast, 2- or 4-OHE(1) produced one major and one minor adduct, and the two adducts formed by each catechol estrogen exhibited identical mobilities on the chromatograms. Neither E(2) nor E(1) at concentrations up to 30 microg/ml induced DNA adducts. The abilities of the estrogens to induce DNA adducts were ranked as follows: 4-OHE(1) > 2-OHE(1) > 4-OHE(2) > 2-OHE(2) > > E(2), E(1), which corresponds well to the transforming and carcinogenic abilities of the estrogens. In addition, the level of DNA adducts induced by the catechol estrogens was markedly decreased by co-treatment of cells with the antioxidant L-ascorbic acid. The results indicate the possible involvement of oxidative metabolites of catechol estrogens of E(2) and E(1) in the initiation of endogenous estrogen-induced carcinogenesis.
We evaluated the comparative effects of furosemide, a short-acting loop diuretic, and azosemide, a long-acting loop diuretic, on neurohumoral factors and quality of life (QOL) in patients with congestive heart failure (CHF). Twenty-five stable patients with mild chronic CHF who had been administered furosemide (n = 14) or azosemide (n = 11) orally for more than 3 months were studied. We changed furosemide to azosemide or azosemide to furosemide and followed for 3 months. Echocardiography was performed, and we also measured neurohumoral factors and assessed QOL by questionnaire. Blood pressure, body weight, renal function and echocardiographic findings were the same during the furosemide and azosemide treatments. Plasma levels of atrial natriuretic peptide and brain natriuretic peptide were not different between the two treatments. However, plasma concentrations of active renin and norepinephrine were significantly higher with furosemide treatment than with azosemide treatment. QOL score was significantly lower with azosemide than with furosemide. These findings suggest that long-acting loop diuretics may have fewer adverse effects on the neuroendocrine system and QOL than short-acting loop diuretics in patients with mild CHF.
CDC25A phosphatase promotes cell cycle progression by activating G(1) cyclin-dependent kinases and has been postulated to be an oncogene because of its ability to cooperate with RAS to transform rodent fibroblasts. In this study, we have identified apoptosis signal-regulating kinase 1 (ASK1) as a CDC25A-interacting protein by yeast two-hybrid screening. ASK1 activates the p38 mitogen-activated protein kinase (MAPK) and c-Jun NH(2)-terminal protein kinase-stress-activated protein kinase (JNK/SAPK) pathways upon various cellular stresses. Coimmunoprecipitation studies demonstrated that CDC25A physically associates with ASK1 in mammalian cells, and immunocytochemistry with confocal laser-scanning microscopy showed that these two proteins colocalize in the cytoplasm. The carboxyl terminus of CDC25A binds to a domain of ASK1 adjacent to its kinase domain and inhibits the kinase activity of ASK1, independent of and without effect on the phosphatase activity of CDC25A. This inhibitory action of CDC25A on ASK1 activity involves diminished homo-oligomerization of ASK1. Increased cellular expression of wild-type or phosphatase-inactive CDC25A from inducible transgenes suppresses oxidant-dependent activation of ASK1, p38, and JNK1 and reduces specific sensitivity to cell death triggered by oxidative stress, but not other apoptotic stimuli. Thus, increased expression of CDC25A, frequently observed in human cancers, could contribute to reduced cellular responsiveness to oxidative stress under mitogenic or oncogenic conditions, while it promotes cell cycle progression. These observations propose a mechanism of oncogenic transformation by the dual function of CDC25A on cell cycle progression and stress responses.
In dogs, embryo transfer (ET) techniques such as induciton of excessive ovulation and synchronization of estrus have not progressed well. Therefore, using embryos at various developmental stages, ET was investigated in dogs from a beagle colony in which the ovulation days were close, as estimated by the progesterone level. Embryos were, recovered 8-11 days after ovulation (4-9 days after mating) by excising the oviducts and uteri (excision method) in 16 animals and by surgical flushing of the uteri at laparotomy (surgical method) in 3 animals. In 24 dogs with -4 to +2 days of difference in the timing of ovulation between donor and recipient dogs, 1-10 embryos at the 8-cell to blastocyst stages were transferred per animal. The mean embryo recovery rate by the excision method (97.1%) was significantly higher than that by the surgical method (42.5%) (p<0.01). Twelve (57.1%) of 21 animals with -1 to +2 days difference in ovulation day became pregnant after the transfer of 8-cell to blastocyst stage embryos. Although 3 dogs with -4 to -2 days of difference of ovulation day underwent ET of morula or compacted morula, none of these dogs became pregnant. The mean ratio of the number of newborns to the number of transferred embryos was only 51.9%. The mean duration of the period between ovulation and delivery in the pregnant recipients was 65.8 days, which tended to be longer than that in natural mating. These results demonstrate that pregnancy can be induced by ET at the 8-cell to blastocyst stage in dogs with -1 to +2 days difference in ovulation day.
The semen quality of 22 dogs (4 to 7 years old) with benign prostatic hyperplasia (BPH) was examined at the hospital of our university, and 4 of the 22 BPH dogs were diagnosed as azoospermic. The mean peripheral plasma estradiol-17beta (E2) level (17.3 pg/ml) of the 18 BPH dogs with spermatogenic function was higher than that of 5 normal male dogs and their mean T level (1.7 ng/ml) was lower. The mean E2 level (27.3 pg/ml) of the 4 BPH dogs with azoospermia was significantly higher than the value in the BPH dogs with spermatogenic function (P<0.01), and the mean T level (1.1 ng/ml) was significantly lower (P<0.05). Five normal male dogs were given 10 intramuscular injections of estradiol benzoate (E2B) 5 microg/kg, at 3-day intervals to investigate the relationship between high plasma E2 levels and the cause of the BPH and azoospermia. Their testes and prostates were measured and biopsied both before and 30 days after the start of E2B injections. At 30 days after the start of the E2B injections, the mean peripheral plasma T levels had decreased by half, and the mean testicular volume had decreased to 88% of original volume. The numbers of spermatocytes, spermatids, and spermatozoa in the seminiferous tubules of all of the dogs were significantly lower (P<0.05, 0.01). In addition, the mean prostatic volume increased to 130%, the mean height of the glandular epithelium decreased, and the glandular lumen became increased in diameter. These findings indicate that both BPH and serious spermatogenic dysfunction may be simultaneously induced by protracted high plasma E2 levels in dogs.
The effects of osaterone acetate (OSA), which is an anti-androgen agent being developed as a therapeutic drug for benign prostatic hypertrophy (BPH) in dogs, on the degree of prostatic regression and semen qualities were investigated. Prostatic regression was compared between dogs with and without orchidectomy. Five male beagles aged 5-9 years were used in the experiment. OSA was orally administered at doses of 0.2 mg/kg and 0.5 mg/kg for one week. The prostatic regression rate one week after the end of administration was 62.6% on average. In the orchidectomized group, the mean regression rate one week after orchidectomy was 60.1%. However, the prostate became enlarged 6 months after administration, compared to the size prior to administration. The above findings suggested that OSA is clinically applicable as a therapeutic drug for BPH in dogs, and inhibits prostatic hypertrophy during the early phase.
Testicular Transferrin (Tf) and peripheral plasma estradiol-17beta (E2) concentrations were measured in 3 dogs with azoospermia (AZ dogs), 3 dogs with Sertoli cell tumors (SC dogs), and 5 normal male Beagles. The mean Tf concentrations in the testes of the AZ dogs and the affected testes of the SC dogs, and the plasma E2 concentrations in both these groups of dogs were significantly higher than the values in normal dogs (P<0.05, 0.01 and 0.01, respectively). Therefore, excessive E2 secretion by hyperfunctioning Sertoli cells is thought to have caused the azoospermia in the 3 dogs.
Despite the abundance of reports describing adult cases of t(8;21) acute myelocytic leukemia (AML), childhood cases have received little attention. We retrospectively investigated 14 childhood cases of t(8;21) AML, and compared their clinical characteristics with those of adult cases, focusing on the risk factors for poor prognosis. Seventy-one percent of the patients had fever. Their mean leukocyte count was 12,700/microliter, and they showed decreased NAP activity. The cell surface showed positivity for CD13, 33, 19, 34, and HLA-DR. The complete remission rate was 100%, and relapse was observed in three of the patients. Bone marrow eosinophilia was present in a smaller proportion of the childhood cases than in the adult cases. Although an increased leukocyte count, tumor formation, and other risk factors have been reported in adults, there was no correlation between these factors and prognosis in our childhood cases. As children who showed AML relapse had TdT-positive blasts, detectable blast TdT activity may be a risk factor for relapse in childhood cases of t(8;21) AML. However, to confirm this, a study with a larger subject base should be conducted.
PURPOSE: The power density values of high (HF; 0.15 to 0.4 Hz) and low frequency (LF; 0.04 to 0.15 Hz) components of arterial pressure were adopted for evaluation of stress on the autonomic nervous system of patients supported by mechanical circulatory assist. METHODS: Power spectral analysis (PSA) of arterial pressure signals was carried out, and trends in changes in the spectral components were observed in 12 patients on mechanical circulatory support (IABP and/or PCPS) and without the support (n=10). RESULTS: The normalized LF was depressed initially and increased gradually in both groups of patients except for four patients on mechanical circulatory assist. Three patients among them consequently died. CONCLUSIONS: Depressed LF represented marked stress on ANS and prolongation of the depression was related to poor outcome of patients. PSA of systemic blood pressure offers a reasonable tool for evaluation of stress on the ANS and for prediction of the prognosis of patients with circulatory assist devices.
We experienced a case of convulsion following the combination of single oral administration of enoxacine before an emergency operation and single postoperative intravenous administration of flurbiprofen axetil. The patient was an 87-year-old female referred to our hospital for severe abdominal pain. She was diagnosed as having the strangulation ileus, then underwent the emergent operation of partial resection of the necrotic small intestine under general anesthesia. Unfortunately we did not know that she had temporarily received oral enoxacine 200 mg, a new quinolone, administered by the previous doctor on the day before the operation. After the operation, flurbiprofen axetil 50 mg, a nonsteroidal anti-inflammatory drug, was given intravenously in thirty seconds due to postoperative pain. One minute after administration of the drug, she immediately developed a convulsive fit, severe disturbance of consciousness and apnea. We then administered at once, a single dose of diazepam intravenously for convulsion treatment, kept her airway open and controlled her ventilation. Convulsion disappeared in a minute and her condition improved gradually. We suspect that convulsive seizure may have been induced by the drug interaction between single oral dose of enoxacine before the operation and single intravenous dose of flurbiprofen axetil after the operation. We also suspect that the serum concentration of enoxacine was kept high because of metabolic disturbance and renal dysfunction resulting from her old age and dehydration. This case suggests that medication before the emergency operation must be considered in anesthetic management because of the possible side effect such as convulsion induced by the drug interaction between neuquinolones and anti-inflammatory drugs.
We used Trachlight for blind orotracheal intubation (ordinary tracheal tube or Portex Blueline in 305 cases, and reinforced tube or Mallinckrodt Safety-Flex in 206 cases) for general anesthetic procedures, and evaluated its technical features along with related complications. With ordinary tubes, 93% of the patients could be intubated successfully at the first attempt. Unsuccessful intubation even at the third attempt occurred in 3 patients (1%). One patient was complicated with a long epiglottis and the cause was unknown in the other patients. With reinforced tubes, 83% of the patients could be intubated at the first attempt but 8 patients (4%) could not. Of them, four patients received too large reinforced tubes straightening the bending of the stylet. Each of the three patients had a narrow larynx, mandibular retraction or obese neck making transillumination difficult. In the remaining one patient, the cause was unknown. Complication found in 30% of the patients was sore throat that seemed severer than that caused by laryngoscope. One patient developed minor tracheal bleeding probably due to injury of the mucosa. The elevation of the blood pressure at intubation with this device was not as high as that by direct laryngoscopy. We conclude that Trachlight leads to intubation with a high success rate, and that care should be taken not to damage the tracheal mucosa by blind insertion.