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Biomedical subjects

Y Sato

Publications and source records attributed to Y Sato.

At least 415 records · Page 23Linked to original sources
PubMed2000

Mitochondrial myopathy and familial thiamine deficiency.

We studied two siblings with a mitochondrial myopathy, familial thiamine deficiency, and an A3243G mutation of the mitochondrial DNA (mtDNA). The elder brother (patient 1, now 36 years old) developed myopathy and beriberi heart at 20 years of age. Thiamine therapy resolved the cardiac symptoms and hyperpyruvicemia and improved the myopathy. The younger brother presented aged 19 years with a myopathy (patient 2, now 35 years old). Thiamine deficiency was present in the siblings and parents, and ragged-red fibers (RRFs) were noted in muscle biopsies from the siblings. Analysis 17 years later demonstrated thiamine malabsorption and an A3243G mutation of the mtDNA in both siblings and their mother, progressive myopathy, and an increased number of RRFs and elevated serum CKMB activity in patient 1. Thiamine treatment decreased the serum concentrations of lactate and pyruvate in patient 2, but not patient 1. The role of thiamine in mitochondrial dysfunction caused by an electron transfer disorder in the setting of A3243G mtDNA mutation is discussed.

Adult↗
PubMed2000

Angiogenesis inhibition by transdominant mutant Ets-1.

The expression of transcription factor Ets-1 is induced in endothelial cells (ECs) by angiogenic factor; and in turn Ets-1 converts ECs to angiogenic invasive phenotype. In order to control angiogenesis, we constructed a transdominant mutant Ets-1 (TMEts-1) which acts as a dominant negative molecule. This molecule inhibited the DNA binding and the transactivation activity of the wild-type Ets-1. Stable transfection of murine endothelial cell line MSS31 cells with the TMets-1 gene impaired angiogenic activities including proliferation, migration, invasion, and tube formation in type-1 collagen gel. Finally, we incorporated the TMets-1 gene into a non-proliferative adenovirus vector, designated as AdTMets-1. AdTMets-1 significantly inhibited angiogenesis in the Matrigel plugs injected into the subcutaneous tissue of C57BL mice. These results indicate that TMets-1 would be a tool for angiogenic inhibition.

3T3 Cells↗
PubMed2000

Unmethylated oligo-DNA containing CpG motifs aggravates collagen-induced arthritis in mice.

OBJECTIVE: To investigate the effects of an intradermal injection of an unmethylated oligodeoxynucleotide (ODN) containing CpG motifs on the severity of collagen-induced arthritis (CIA). METHODS: CIA was induced in DBA/1 LacJ mice by immunization with bovine type II collagen (CII) in Freund's complete adjuvant followed 3 weeks later by immunization with CII in Freund's incomplete adjuvant (yielding CIA mice). Unmethylated ODN containing a CpG motif was injected intradermally into DBA/1 LacJ mice at a dosage of 20 microg (yielding CpG-CIA mice) 1 week prior to the first immunization with CII. Unmethylated ODN containing a GpC motif instead of a CpG motif and ODN containing a methylated CpG motif were used to produce controls (GpC-CIA mice and mCpG-CIA mice, respectively). After the second immunization with CII, arthritis scores were measured weekly up to the eighth week. At the eighth week, the mice were killed, histopathologic changes in the ankle joints were examined, and titers of interferon-gamma (IFNgamma) in the supernatants of splenocytes (1 x 10(7)) stimulated in culture by CII for 3 days were determined by enzyme-linked immunosorbent assay. RESULTS: CpG-CIA mice had significantly higher arthritis scores than CIA mice. CpG-CIA mice had more severe histopathologic changes than CIA mice and mCpG-CIA mice. Moreover, splenocytes in CpG-CIA mice produced higher IFNgamma titers in response to CII than did splenocytes in CIA mice and mCpG-CIA mice. CONCLUSION: Injection of unmethylated oligo-DNA containing CpG motifs aggravated CIA through activation of the Th1-type immune response, suggesting that microbial infection could be one of the mechanisms for aggravation or exacerbation of arthritis or, alternatively, that such infection could be an adjuvant in the induction of arthritis in rheumatoid arthritis.

Animals↗
PubMed2000

Effects of isoflavone supplement on healthy women.

Effects of the isoflavone supplement on hormonal states in young premenopausal women were studied by cross-over study design. Administration of 20 mg or 40 mg isoflavones (IF) by tablets, of which 1 g contained 43.5 mg daidzein, 6.0 mg genistein, 24.0 mg glycitein, to 40 young female students for one month caused a prolonged menstruation in 60% of young women, shortened menstruation in 20% of young women, 17% remained unchanged and 3% became irregular. Larger dose tended to elongate more, but 17beta-estradiol levels in both follicular and luteal phages were not different between 20 mg and 40 mg isoflavone intake. Equor excreters tended to show low plasma progesteron level in the luteal phase. Detailed hormonal analysis on 3 of students by a cross over study design showed decreased level of 17beta-estradiol throughout the menstruation cycle. SHBG significantly increased about 10% in all three. DEAS, androstendione, and testosterone showed different responses according to the follicular or luteal phase. T3 and T4 increased as a result of isoflavone tablet administration in the follicular phase, but it decreased in the luteal phase. These changes suggest that isoflavones influence not only estrogen receptor-related functions but the hypothalamo-hypophysis-gonadal axis.

Androstenedione↗
PubMed2000

HGF/SF-induced spreading of MDCK cells correlates with disappearance of barmotin/7H6, a tight junction-associated protein, from the cell membrane.

Changes in expression of the two tight junction-associated proteins, barmotin/7H6 and ZO-1, as well as the adherence junction-associated protein, E-cadherin, were followed during hepatocyte growth factor/scatter factor (HGF/SC)-induced migration process of MDCK cells. Modulation of the HGF/SF-induced migration process by staurosporine, an inhibitor of protein kinase C (PKC), was also examined. Cell migration induced by HGF/SF consisted of two distinct phases, initial cell spreading between 2 and 9 h after the start of treatment, and the scattering phase which started approximately 12 h after treatment. Both ZO-1 and E-cadherin were expressed at the cell-cell border of adherent cells in the scattering phase, whereas barmotin/7H6, a barrier function-related tight junction protein, was not seen during the early spreading phase. Confluent cultures of MDCK cells, which did not spread after HGF/SF treatment, were positive for barmotin/7H6 expression at cell-cell borders. Blocking PKC activation during HGF/SF treatment with staurosporine inhibited cell spreading, and the cells retained barmotin/7H6 expression until at 6 h after HGF/SF treatment. The results indicate that disappearance of the tight junction protein, barmotin/7H6, is closely associated with cell spreading, with both barmotin/7H6 expression and cell spreading seemingly being regulated by PKC-mediated signaling.

Animals↗
PubMed2000

An antibody for macrophage migration inhibitory factor suppresses tumour growth and inhibits tumour-associated angiogenesis.

To verify the role of macrophage migration inhibitory factor (MIF) in tumourigenesis, we examined the effect of an anti-MIF antibody on tumour growth and angiogenesis. We inoculated murine colon adenocarcinoma cell line colon 26 cells subcutaneously into the flank in BALB/c mice. After nine days, we treated tumour-bearing mice with an anti-rat MIF antibody by intraperitoneal injection on days 9, 11, 13, 15, 17, 19 and 21. We found significant inhibition of tumour growth by this treatment from day 15 to day 22. Next, we implanted a chamber filled with colon 26 cells, which only passes soluble factors, in the subcutaneous fascia of the flank, and treated mice with the anti-rat MIF antibody at days 1, 3 and 5. By histological examination at day 6, angiogenesis within the subcutaneous fascia in contact with the chamber was markedly suppressed. In vitro, we added an anti-human MIF antibody to human umbilical vein endothelial cells (HUVEC) to evaluate its effect on cell growth by measurement of [3H]thymidine incorporation. We observed that the anti-MIF antibody significantly suppressed [3H]thymidine uptake by HUVEC. These results suggest the possibility that MIF is involved in tumourigenesis via promotion of angiogenesis.

Adenocarcinoma↗
PubMed2000

Cardiac-specific overexpression of calsequestrin results in left ventricular hypertrophy, depressed force-frequency relation and pulsus alternans in vivo.

Cardiac-specific overexpression of calsequestrin has been shown to result in significant decreases in contractile parameters and intracellular Ca(2+)transients in vitro. Therefore, the purpose of the present study was to determine the effects of calsequestrin overexpression on basal cardiac function and the force-frequency relation in vivo. Calsequestrin overexpression mice (CSQ-OE, n=20) and their isogenic controls (WT) were studied with an integrative approach using transthoracic echocardiography, stress-shortening relations, and invasive hemodynamics in intact closed-chest mice. M-mode echocardiography indicated that calsequestrin overexpression resulted in concentric hypertrophy (+52%) and an increase in LV ejection phase indices. However, mean end-systolic stress-shortening coordinates revealed that at matched end-systolic wall-stress, fractional shortening was depressed in CSQ-OE mice. This was confirmed by depressed indices of LV isovolumic contraction and relaxation in CSQ-OE v. WT mice. Furthermore, overexpression of calsequestrin resulted in a downward and leftward shift of the biphasic force-frequency relation; thus, the critical heart (HR(crit)) was significantly lower in calsequestrin-overexpression mice (264+/-15 bpm) than in wild-type controls (365+/-21 bpm). Surprisingly, calsequestrin overexpression was associated with the induction of pulsus alternans in every animal (at an average heart rate of 428+/-26 bpm), whereas none of the wild-type controls displayed this phenomenon. We conclude that: (i) although increased levels of calsequestrin result in decreased myocardial contractility and a depressed force-frequency relation, LV wall stress is reduced and chamber function is normal, and (ii) an increase in SR Ca(2+)storage capacity induces pulsus alternans in the intact anesthetized mouse.

Animals↗
PubMed2000

Topical application of amrinone (a selective phosphodiesterase III inhibitor) for relief of vasospasm.

BACKGROUND: Amrinone, a selective phosphodiesterase III inhibitor, is an agent that possesses a combination of positive inotropic and vasodilating properties as a result of preventing the degradation of cAMP, and it has recently been licensed for the treatment of heart failure. The aim of this study was to investigate the potential therapeutic application of amrinone to resolve vasospasm, which is the major problem in reconstructive surgery. In this study its effect was compared with that of lidocaine, the most commonly used topical vasodilating agent clinically. MATERIALS AND METHODS: The probe of an ultrasonic transit-time volume flowmeter was applied to the femoral artery of rats to measure blood flow. After a baseline recording was obtained, 0.03 ml of epinephrine was applied topically to induce vasospasm. The vessels were then immersed in 1 ml of amrinone (5 mg/ml), 10% lidocaine hydrochloride, or normal physiological saline solution for 1 min in an attempt to resolve the spasm. In another group of animals, no solution was used following administration of epinephrine to allow observation of spontaneous resolution of the vasospasm over time. RESULTS: The results showed an essentially immediate spasm-resolving effect in both the amrinone group and the lidocaine group. The amrinone group showed a significantly greater degree of maximum increase in blood flow than the lidocaine group. The effect of lidocaine decreased with time, whereas amrinone had a more lasting effect. CONCLUSIONS: The findings suggest that amrinone could be used as an effective topical vasodilating agent to resolve vasospasm in reconstructive surgery.

Administration, Topical↗
PubMed2000

A new model of lung metastasis for intravital studies.

We created anexperimental model of pulmonary metastasis based on subcutaneously implanted Lewis lung cancer in mice and observed in vivo the microcirculation of spontaneously metastasized tumors in the lung. The mice lung was held by a small handmade suction ring to stop cardiac and respiratory movement. Using fluorescent microscopy, tumor microcirculation and normal lung microcirculation in the same lung lobe were compared by measuring microvessel diameter and blood flow velocity [red blood cell (rbc) velocity]. In normal microcirculation, the mean values of microvessel diameter and rbc velocity were 10.4 +/- 2.7 microm and 188 +/- 63 microm/s, respectively. In tumor microcirculation, the mean values of the same were 10.6 +/- 3.3 microm and 105 +/- 40 microm/s. The rbc velocity in normal microcirculation was significantly higher (P < 0.001) than that in tumor microcirculation. The calculated shear rates of normal microcirculation and tumor microcirculation were 73.4 +/- 23.4 (/s) and 41.2 +/- 16.1 (/s), respectively. The shear rate of the tumor microcirculation was significantly slower (P < 0.001) than that of the normal microcirculation. We demonstrated a feasibility of observation and measurement of tumor microcirculation in the lung and confirmed that the physiologic data were compatible to those in the brain or in the liver reported by others. This model might be useful for studying metastatic tumor pathophysiology in the lung microcirculation.

Animals↗
PubMed2000

Signal transduction and transcriptional regulation of angiogenesis.

When quiescent endothelial cells (ECs) are exposed to angiogenic factor such as VEGF; ECs express proteases to degrade extracellular matrices, migrate, proliferate and form new vessels. However, the molecular mechanism of these events is not fully characterized yet. We are studying the signal transduction and transcriptional regulation of angiogenesis. We investigated the properties of two VEGF receptors, Flt-1 and KDR, by using two newly developed blocking monoclonal antibodies (mAbs), i.e., anti-human Flt-1 mAb and anti-human KDR mAb. VEGF elicited induction of transcription factor Ets-1 in human umbilical vein endothelial cells (HUVECs). This induction was mediated by the KDR/Flt-1 heterodimer and the KDR homodimer. The role of transcription factor Ets-1 in angiogenesis was further clarified. We established both high and low Ets-1 expressing EC lines, and compared angiogenic properties of these cell lines with a parental murine EC line, MSS31. The growth rate was almost identical among three cell lines. It appeared that gene expressions of matrix metalloproteinases (MMP-1, MMP-3, and MMP-9) as well as integrin beta 3 were correlated with the level of Ets-1 expression. As a result, the invasiveness was enhanced in high Ets-1 expressing cells and reduced in low Ets-1 expressing cells compared with parental cells, and high Ets-1 expressing cells made more tube-like structures in type 1 collagen gel. These results indicate that Ets-1 is a principle transcription factor converting ECs to the angiogeneic phenotype.

Animals↗
PubMed2000

Induction of acute-phase reactive substances during open-heart surgery and efficacy of ulinastatin. Inhibiting cytokines and postoperative organ injury.

OBJECTIVE: A systemic inflammatory response after open-heart surgery using cardiopulmonary bypass may be responsible for postoperative organ dysfunction. Ulinastatin, a protease inhibitor, plays an important role in host defense under periods of stress. METHODS: We studied the efficacy of ulinastatin on changes in acute-phase reactive substances during and after open-heart surgery. Patients undergoing open-heart surgery were divided into an ulinastatin group (Group U) and a control group (Group C). In Group U, we introduced 600,000 units of ulinastatin into a priming solution for cardiopulmonary bypass, 300,000 units into a cardiopulmonary bypass circuit at the removal of aortic cross-clamping, and 300,000 units a day for 5 days following surgery. RESULTS: Immediately after cardiopulmonary bypass, alpha 1-antitrypsin levels decreased significantly in both groups, and increased significantly on the second day after surgery. Ulinastatin levels decreased after cardiopulmonary bypass in Group C. Significantly high levels of ulinastatin were obtained in Group U. Interleukin-6, interleukin-8, and polymorphonuclear elastase were markedly induced, and high levels of plasma concentration continued for several days after surgery. At all sample points, these concentrations in Group U tended to be lower than those in Group C. A significantly positive correlation was seen between the maximum levels of interleukin-8 and polymorphonuclear elastase, but these cytokine and polymorphonuclear elastase levels did not correlate with parameters such as the duration of anesthesia, surgery, cardiopulmonary bypass, or aortic cross-clamping. CONCLUSIONS: Our study suggests that high-dose ulinastatin administration to maintain a sufficient concentration of circulating protease inhibitors may suppress overinduction of cytokines and polymorphonuclear elastase in open-heart surgery.

Aged↗
PubMed2000

Single-fiber analysis of mitochondrial A3243G mutation in four different phenotypes.

Five unrelated patients harboring the A3243G mutation in the mitochondrial DNA (mtDNA) but presenting with different clinical phenotype were studied for their percentage of mutation at the single muscle fiber levels. One patient had a clinically and pathologically defined Leigh syndrome (LS), two showed mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), another showed progressive external ophthalmoplegia (PEO), and the other showed mitochondrial diabetes mellitus (MDM). The mutation load was greater in the muscle from the patient with LS (92%), who showed more than 80% even in the non-ragged red fibers (RRF) and also presented the highest proportion of RRF. The patients with MELAS had lower mutation levels as well as a lower proportion of RRF, and these two parameters were even lower in the PEO and MDM patients. These results were consistent with the concept that differences in the mutation load and in the somatic distribution of the mutation among different cells and tissues are responsible for the differences in phenotypical expression of the disease.

Adenine↗
PubMed2000

Juvenile fulminant adnexal tuberculosis caused by gastrointestinal tuberculosis immediately after ovarian cystectomy.

Genital fulminant tuberculosis is rarely a primary site of infection. We report a case of juvenile adnexal tuberculosis possibly related to tuberculosis immediately after cystectomy in the ileocecal region in a virginal girl. A 13-year-old virginal girl visited our clinic because of a huge ovarian tumor, which was resected by cystectomy. On postoperative day 39, fever episodes were noted, and she received antibiotics, which were not effective. An abscess developed in the region of the cecum and the right adnexa. Laparotomy revealed chronic abscess formation, especially in the right adnexa. Resection of the abscess was done. The pathological diagnosis was tuberculosis with caseation, although bacterial culture and molecular biological diagnosis for Mycobacterium tuberculosis were negative in sputum, vaginal discharge, urine, and stool of the patient and her family. She was placed on anti-tuberculosis drugs, including isoniazid, rifampicin, and ethambutol, and this regimen was effective. This patient represents a rare case of fulminant adnexal tuberculosis without pulmonary disease.

Adnexa Uteri↗
PubMed2000

Human CD8 and CD4 T cell epitopes of epithelial cancer antigens.

Recent human tumor immunology research has identified several genes coding immunogenic peptides recognized by CD8 cytotoxic T lymphocytes (CTLs) in melanoma tumors. Very recently, CD4 T cell antigenic epitopes were also determined in certain melanoma tumors. The use of these peptides in conjunction with human immunotherapy could prove to be of great benefit. However, such peptides in clinically common tumors of epithelial cell origin, such as of the stomach, colon, lung, etc., have not yet been determined extensively. We describe for the first time an HLA-A31 (A*31012)-restricted natural antigenic peptide recognized by the CD8 CTL TcHST-2 of gastric signet ring cell carcinoma cell line HST-2. We also identified the HLA-DRB1*08032-restricted peptide recognized by the CD4 T cell line TcOSC-20 of squamous cell carcinoma OSC-20 derived from the oral cavity. The antigenic peptide of HST-2, designated F4.2, is composed of 10 amino acid residues with two anchor motif residues necessary for binding to HLA-A31 molecules. The synthetic F4.2 peptide enhanced the reactivity of TcHST-2 against HST-2 cells. Furthermore, introduction of an expression minigene coding F4.2 peptide to HLA-A31(+) cells conferred cytotoxic susceptibility to TcHST-2 on the cells. Some stomach cancer lines into which the HLA-A31 gene had been introduced, such as MKN28-A31-2, were lysed by TcHST-2, suggesting the presence of F4.2 peptide in at least some HLA-A31(+) stomach cancers. Furthermore, F4.2 peptide induced an F4.2 peptide-specific CTL response in at least 30-40% of HLA-A31(+) peripheral blood lymphocytes from gastric cancer patients, suggesting that F4.2 peptide could be used as a cancer vaccine for gastric tumors. The natural antigenic peptide of OSC-20 was also determined using acid extraction and biochemical separation and by mass spectrometry. Consequently, OSC-20 peptide was designated as the 6-1-5 peptide, an HLA-DRB1*08032-restricted 16-mer peptide with two possible anchor motifs. It has an amino acid sequence identical to that of human alpha-enolase, suggesting that it was derived from the processed parental alpha-enolase protein. We are presently attempting to determine the genes that code tumor rejection antigens recognized by HLA-A24- and A26-restricted T cells, including those of pulmonary and pancreatic carcinomas. The search for these antigenic peptides may lead to the identification of immunogenic peptide antigens that would be suitable for clinical use in commonly occurring epithelial cancers.

Amino Acid Sequence↗
PubMed2000

Motor dynamics encoding in the rostral zone of the cat cerebellar flocculus during vertical optokinetic eye movements.

The complex spike (CS) and simple spike (SS) activities of Purkinje cells in the rostral zone of the cerebellar flocculus were recorded in alert cats during optokinetic responses (OKR) elicited by a stimulus sequence consisting of a constant-speed visual pattern movement in one direction for 1 s and then in the opposite direction for 1 s. The quick-phase-free trials were selected. Ninety-eight cells were identified as rostral zone cells by the direction-selective CS activity that was modulated during vertical but not horizontal stimuli. In most of the majority population (88 cells), with an increasing CS firing rate during upward OKR and an increasing SS rate during downward OKR, the inverse dynamics approach was successful and the time course of the SS rate was reconstructed (mean coefficient of determination, 0.70 and 0.72 during upward and downward stimuli, respectively) by a linear weighted superposition of the eye acceleration, velocity, position, and constant terms, at a given time delay (mean 10 ms) from the unit response to the eye-movement response. Standard regression coefficient (SRC) analysis revealed that the contribution of the velocity term (mean SRC 0.98 for upward and 0.80 for downward) to regression was dominant over acceleration (mean SRC 0.018 and 0.058) and position (-0.14 and -0.12) terms. The velocity coefficient during upward stimuli (6.6 spikes/s per degree/s) was significantly (P<0.01) larger than that during downward stimuli (4.9 spikes/s per degree/s). In most of the minority population (10 cells), with both CS and SS firing rates increasing during upward OKR, the inverse dynamics approach was not successful. It is concluded that 1) in the cat rostral zone Purkinje cells, in which the preferred direction is upward for CS and downward for SS, eye velocity and acceleration information is encoded in SS firing to counteract the viscosity and inertia forces, respectively, on the eye during vertical OKR; 2) the eye position information encoded in SS firing is inappropriate for counteracting the elastic force; 3) encoding of eye velocity information during upward OKR is quantitatively different from that during downward OKR: SS firing modulation is larger for upward than for downward OKR of the same amplitude; and 4) encoding of motor dynamics is obscure in cells in which the preferred direction is upward for both CS and SS.

Acceleration↗
PubMed2000

Degradation of the metal-cyano complex tetracyanonickelate (II) by Fusarium oxysporum N-10.

A fungus with the ability to utilize a metalcyano compound, tetracyanonickelate (II) ¿K2[Ni (CN)4]; TCN¿, as its sole source of nitrogen was isolated from soil and identified as Fusarium oxysporum N-10. Both intact mycelia and cell-free extract of the strain catalyzed hydrolysis of TCN to formate and ammonia and produced formamide as an intermediate, thereby indicating that a hydratase and an amidase sequentially participated in the degradation of TCN. The enzyme catalyzing the hydration of TCN was purified approximately ten-fold from the cell-free extract of strain N-10 with a yield of 29%. The molecular mass of the active enzyme was estimated to be 160 kDa. The enzyme appears to exist as a homotetramer, each subunit having a molecular mass of 40 kDa. The enzyme also catalyzed the hydration of KCN, with a cyanide-hydrating activity 2 x 10(4) times greater than for TCN. The kinetic parameters for TCN and KCN indicated that hydratase isolated from F. oxysporum was a cyanide hydratase able to utilize a broad range of cyano compounds and nitriles as substrates.

Amino Acid Sequence↗
PubMed2000

Treatment of erectile dysfunction: what should we do next?

Because sildenafil (Viagra) is scheduled to be clinically available in the near future, urologists in Japan must prepare for changes in the treatment of erectile dysfunction. The drug will surely influence our current clinical style of diagnosis and treatment of the dysfunction. We herein discuss this issue, referring to favorable and unfavorable effects that will be brought about by the drug. We also propose several future studies that we should do, including those on testosterone replacement therapy. We present results of our experiment using testosterone replacement therapy in aged rats and speculate about the mechanism by which the hormone replacement works in the sex center of the brain.

3',5'-Cyclic-GMP Phosphodiesterases↗