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Biomedical subjects

K Hashimoto

Publications and source records attributed to K Hashimoto.

At least 289 records · Page 16Linked to original sources
PubMed2000

MDM2 overexpression with alteration of the p53 protein and gene status in oral carcinogenesis.

In this study, to better understand the mechanism of oral squamous cell carcinoma (SCC) carcinogenesis, alterations of the p53 gene and overexpression of MDM2 and p53 were analyzed in 38 oral SCC samples. Twelve of the 38 specimens revealed mutant-type p53. Moreover, coexpression of MDM2 and p53 was found most frequently in dysplastic lesions (P < 0.05). Expression of MDM2 and p53 was significantly increased in accordance with the histological progression of multistep carcinogenesis (P < 0.05). No significant correlation was found between the expression of MDM2 and the alteration of p53 protein or p53 gene status. MDM2 overexpression with mutant p53 was significantly associated with poorly differentiated SCCs (P < 0.05) and tumor stages III and IV of oral SCCs (P < 0.05). These results suggest that MDM2 overexpression is an early event in oral carcinogenesis through the functional inactivation of the wild-type p53, and corresponding alterations of MDM2 and p53 contribute to the oral carcinogenesis. We propose that it would be clinically more instructive to evaluate MDM2 overexpression combined with p53 gene status, compared to the evaluation of either MDM2 or p53 alteration alone.

Carcinoma, Squamous Cell↗
PubMed2000

Establishment of monoclonal anti-retroviral gp70 autoantibodies from MRL/lpr lupus mice and induction of glomerular gp70 deposition and pathology by transfer into non-autoimmune mice.

Several strains of mice, including MRL/MpJ mice homozygous for the Fas mutant lpr gene (MRL/lpr mice), F(1) hybrids of New Zealand Black and New Zealand White mice, and BXSB/MpJ mice carrying a Y-linked autoimmune acceleration gene, spontaneously develop immune complex-mediated glomerulonephritis. The involvement of the envelope glycoprotein gp70 of an endogenous xenotropic virus in the formation of circulating immune complexes and their deposition in the glomerular lesions have been demonstrated, as has the pathogenicity of various antinuclear, antiphospholipid, and rheumatoid factor autoantibodies. In recent genetic linkage studies as well as in a study of cytokine-induced protection against nephritis development, the strongest association of serum levels of gp70-anti-gp70 immune complexes, rather than the levels of antinuclear autoantibodies, with the development and severity of glomerulonephritis has been demonstrated, suggesting a major pathogenic role of anti-gp70 autoantibodies in the lupus-prone mice. However, the pathogenicity of anti-gp70 autoantibodies has not yet been directly tested. To examine if anti-gp70 autoantibodies induce glomerular pathology, we established from unmanipulated MRL/lpr mice hybridoma clones that secrete monoclonal antibodies reactive with endogenous xenotropic viral env gene products. Upon transplantation, a high proportion of these anti-gp70 antibody-producing hybridoma clones induced in syngeneic non-autoimmune and severe combined immunodeficiency mice proliferative or wire loop-like glomerular lesions. Furthermore, deposition of gp70 in glomeruli and pathological changes were observed after intravenous injection of representative clones of purified anti-gp70 immunoglobulin G, demonstrating pathogenicity of at least some anti-gp70 autoantibodies.

Animals↗
PubMed2000

Effect of orchidectomy on the age-related modulation of IL-1beta and IL-1 receptors following lipopolysaccharide treatment in the mouse.

OBJECTIVE: To compare the effect of orchidectomy (ODX) in 7- and 24-week-old C57BL/6 mice on the age-related responses of the cytokine interleukin (IL)-1beta and its receptor to intraperitoneal injection of the bacterial endotoxin, lipopolysaccharide (LPS). METHODS: We measured IL-1beta concentrations in the plasma, hippocampus, hypothalamus and adrenal gland using ELISA and iodine-125-labeled recombinant human IL-1alpha ([(125)I]IL-1alpha) binding in the hippocampus following the intraperitoneal administration of saline or LPS. RESULTS: There were no significant differences in the concentrations of IL-1beta and its receptors in the brain and peripheral tissues between sham-operated and ODX mice in both age groups injected with saline. LPS induced significantly higher IL-1beta production in the plasma and hippocampus in sham-operated 24-week-old mice than in 7-week-old mice. Coincident with the heightened IL-1beta response to LPS, hippocampal [(125)I]IL-1alpha binding was lower in 24-week-old mice than in 7-week-old mice after LPS injection in the sham-operated group. The age-related differences in the IL-1beta concentrations in the plasma and hippocampus and [(125)I]IL-1alpha binding in the hippocampus in response to LPS administration were abolished by ODX. Although LPS dramatically increased IL-1beta levels in the hypothalamus, no significant age-related differences in IL-1beta concentrations were seen, and ODX did not affect IL-1beta levels. In contrast, there were no significant differences between saline- and LPS-injected 7-week-old mice in relation to concentrations in the adrenal gland. Moreover, although the adrenal IL-1beta concentrations in 24-week-old mice were significantly higher than those in 7-week-old mice, ODX did not abolish these age-related differences in concentrations in the adrenal gland. CONCLUSIONS: Our data suggest the involvement of testosterone (or gonadal product) in plasma and hippocampal IL-1beta regulation in relation to age, and demonstrate the importance of the gonadal development in mediating the effects of infectious challenge on the brain and immune function.

Adrenal Glands↗
PubMed2000

Glucocorticoid effects on the diurnal rhythm of circulating leptin levels.

It is known that circulating leptin shows diurnal variation with a nocturnal rise; however, the mechanisms generating this rhythm have not been fully elucidated. Glucocorticoids are a potent stimulator of leptin secretion, and there is a reciprocal relationship between circulating leptin and glucocorticoid levels. We hypothesized that glucocorticoids could modulate the diurnal rhythm of circulating leptin. We therefore explored the diurnal variation of leptin under situations in which subjects showed no or some shift of glucocorticoid diurnal rhythm, such as prednisolone-administered humans, and adrenalectomized and corticosterone-replaced (ADX+B) rats. The peak level of plasma cortisol immunoreactivity was shifted from early morning to noon by prednisolone administration. The nocturnal increment of plasma leptin in prednisolone-administered patients (71.2 +/- 14.2% from 08:00 h value) was significantly greater than that in normal volunteers (12.2 +/- 7.5% from 08:00 h value), but the timing of nadir and the peak of plasma leptin was not shifted. In normal rats, the plasma concentration of leptin showed the diurnal rhythm with the bottom at 16:00 h and the top between midnight and early morning. The amplitude of leptin diurnal rhythm was significantly reduced in ADX+B rats (08:00 h: 3.0 +/- 0.2, 16:00 h: 2.7 +/- 0.2, 00:00 h; 3.7 +/- 0.2 ng/ml) compared with sham operated rats (08:00 h: 3.0 +/- 0.2, 16:00 h 2.2 +/- 0.2, 00:00 h: 4.7 +/- 0.4 ng/ml); but ADX+B rats still retained similar timing of nadir and the peak of plasma leptin as observed in sham rats. These results indicate that glucocorticoids enhance the amplitude of leptin diurnal rhythm, and are consistent with previous findings showing that glucocorticoids increase leptin secretion. Glucocorticoids appear to play modulatory, but not essential roles in generating leptin diurnal rhythm.

Adrenalectomy↗
PubMed2000

Significant gene expression of insulin-like growth factor II and proliferating cell nuclear antigen in a rapidly growing recurrent pituitary acth-secreting adenoma.

BACKGROUND: We quantified the expression of various growth-related factors in an adrenocorticotropic hormone (ACTH)-secreting adenoma that had recurred very rapidly as invasive macroadenoma. METHODS/RESULTS: A 43-year-old woman underwent successful transsphenoidal surgery for Cushing's disease. Seven years later, she was admitted to our ward for further endocrine examinations. In spite of a very high plasma ACTH level, the serum cortisol level was normal. Discrepancies between ACTH and cortisol levels were detected on the basis of diurnal rhythms, dexamethasone suppression tests, and corticotropin-releasing hormone test. The patient showed no clinical features of Cushing's disease. Magnetic resonance imaging of the pituitary showed an almost empty sella, and no microadenoma was found. These results, along with those of Sephadex column gel filtration and high-performance liquid chromatography of plasma-immunoreactive ACTH, suggested that the patient's residual corticotrophs secreted biologically inactive ACTH. Two years later, the patient suddenly developed diplopia and right abducens nerve palsy. She was slightly moonfaced and centrally obese. Her plasma ACTH and serum and urinary free cortisol levels were elevated, although discrepancies between ACTH and cortisol still existed. Magnetic resonance imaging revealed a large pituitary mass with suprasellar and cavernous sinus extensions. The tumor was excised, and the proopiomelanocortin gene and the expression of growth-related factors were analyzed. No mutations were found in the ACTH-coding region of the proopiomelanocortin gene. A significant expression of insulin-like growth factor II and proliferating cell nuclear antigen mRNAs was demonstrated. A high MIB-1 antibody labeling index was also detected in the adenoma tissue, suggesting high Ki-67 expression. CONCLUSION: These growth- and proliferation-related factors might be involved in the rapid growth and aggressiveness of this patient's pituitary adenoma.

Adenoma↗
PubMed2000

Cloning, expression analysis and chromosome mapping of human casein kinase 1 gamma1 (CSNK1G1): identification of two types of cDNA encoding the kinase protein associated with heterologous carboxy-terminal sequences.

Casein kinase 1 gamma1(CK1 gamma1) is known to be involved in the growth and morphogenesis of eukaryotic cells. We have isolated two types of cDNA for human casein kinase 1 gamma1 (hCK1 gamma1). One of them (hCK1 gamma1S) was found to encode a polypeptide consisting of 393 amino acids, which is highly homologous with already reported rat CK1 gamma1 (rCK1 gamma1). The other type of cDNA (hCK1 gamma1L) encodes a polypeptide consisting of 422 amino acids, which is quite identical in the kinase domain, but different in the C-terminal sequence from hCK1 gamma1S. Namely, hCK1 gamma1L has a characteristic sequence of 50 amino acids at the C-terminal end and this motif was shown to be shared by the casein kinase gamma2 and gamma3 from rat and human, suggesting that it is a signature sequence of the gamma-isoforms. In this sense, newly isolated hCK1 gamma1L might be the original form of CK1 gamma1 subspecies rather than rCK1 gamma1 and hCK1 gamma1S. RT-PCR analysis revealed that hCK1 gamma1S mRNA is predominantly present in the testis, whereas the abundance of hCK1 gamma1L mRNA was nearly the same in the twelve tissues examined. These results suggest that novel hCK1 gamma1L may have a unique functional role different from that of hCK1 gamma1S and rCK1 gamma1. The human hCK1 gamma1 gene (CSNK1G1) was mapped to chromosome 15q22.1-->q22.31 by fluorescence in situ hybridization.

Amino Acid Sequence↗
PubMed2000

Autoantibody responses to cardiolipin and DNA in infancy: association with lymphocytic panniculitis.

We report an infant with anticardiolipin (aCL) antibodies who presented with erythematous nodular skin lesions and elevated liver enzyme levels. The cutaneous manifestation was histologically lymphocytic lobular panniculitis with vasculitic and hemorrhagic changes. The infant also had low levels of anti-double stranded DNA (dsDNA) and anti-single stranded DNA (ssDNA) antibodies. There were no detectable antibodies to small nuclear ribonucleoproteins including Ro/SSA and La/SSB. His mother was consistently seronegative for any of these antibodies. Without corticosteroid therapy, cutaneous lesions resolved and anticardiolipin antibodies, but not anti-dsDNA and ssDNA antibodies, normalized within 16 months after the onset of the disease. Our patient demonstrated an uncommon presentation of aCL related cutaneous manifestation, the presentation with panniculitis being only the third such patient reported in the literature. Of great interest was the appearance of aCL antibodies and skin lesions during very early infancy.

Adult↗
PubMed2000

Different effects of dominant negative mutants of desmocollin and desmoglein on the cell-cell adhesion of keratinocytes.

Desmosomes contain two types of cadherin: desmocollin (Dsc) and desmoglein (Dsg). In this study, we examined the different roles that Dsc and Dsg play in the formation of desmosomes, by using dominant-negative mutants. We constructed recombinant adenoviruses (Ad) containing truncated mutants of E-cadherin, desmocollin 3a, and desmoglein 3 lacking a large part of their extracellular domains (EcaddeltaEC, Dsc3adeltaEC, Dsg3deltaEC), using the Cre-loxP Ad system to circumvent the problem of the toxicity of the mutants to virus-producing cells. When Dsc3adeltaEC Ad-infected HaCaT cells were cultured with high levels of calcium, E-cadherin and beta-catenin, which are marker molecules for the adherens junction, disappeared from the cell-cell contact sites, and cell-cell adhesion was disrupted. This also occurred in the cells infected with EcaddeltaEC Ad. With Dsg3deltaEC Ad infection, keratin insertion at the cell-cell contact sites was inhibited and desmoplakin, a marker of desmosomes, was stained in perinuclear dots while the adherens junctions remained intact. Dsc3adeltaEC Ad inhibited the induction of adherens junctions and the subsequent formation of desmosomes with the calcium shift, while Dsg3deltaEC Ad only inhibited the formation of desmosomes. To further determine whether Dsc3adeltaEC directly affected adherens junctions, mouse fibroblast L cells transfected with E-cadherin (LEC5) were infected with these mutant Ads. Both Dsc3adeltaEC and EcaddeltaEC inhibited the cell-cell adhesion of LEC5 cells, as determined by the cell aggregation assay, while Dsg3deltaEC did not. These results indicate that the dominant negative effects of Dsg3deltaEC were restricted to desmosomes, while those of Dsc3adeltaEC were observed in both desmosomes and adherens junctions. Furthermore, the cytoplasmic domain of Dsc3adeltaEC coprecipitated both plakoglobin and beta-catenin in HaCaT cells. In addition, beta-catenin was found to bind the endogenous Dsc in HaCaT cells. These findings lead us to speculate that Dsc interacts with components of the adherens junctions through beta-catenin, and plays a role in nucleating desmosomes after the adherens junctions have been established.

Animals↗
PubMed2000

Degradation products generated by sonication of benzyl alcohol, a sample preparation solvent for the determination of residual solvents in pharmaceutical bulks, on capillary gas chromatography.

Benzyl alcohol used as the sample preparation solvent in the determination of residual solvents in pharmaceutical bulks yielded benzene, toluene, and benzaldehyde on capillary gas chromatography (GC) by sonication. The factors responsible for compounds generated are discussed. The quality of benzyl alcohol and the type of sonicator were not involved in the generation of benzene, toluene, and benzaldehyde, whereas matrix contributions were observed. The degradation profiles of benzyl alcohol and its analogous compounds obtained by pyrolysis-GC/mass spectrometric analysis were similar to those obtained by sonication, suggesting that benzyl alcohol is degraded by the high local heat generated by sonication. Consequently, no matter how long it may take to dissolve bulk substances in benzyl alcohol completely, we do not recommend the use of a sonicator in sample preparation for the determination of residual solvents in pharmaceutical bulks.

Benzyl Alcohols↗
PubMed2000

A new gluco indole alkaloid, 3, 4-dehydro-5-carboxystrictosidine, from Peruvian Uña de Gato (Uncaria tomentosa).

A new gluco indole alkaloid, 3,4-dehydro-5-carboxystrictosidine, was obtained from Peruvian Uña de Gato (Cat's Claw, original plant: Uncaria tomentosa) together with two known gluco indole alkaloids. This compound was the first example of isolation of a gluco monoterpenoid indole alkaloid having a 3,4-dihydro-beta-carboline ring system from nature. A characteristic feature of the compound was the quick replacement of the methylene hydrogens on C-14 with deuterium that was observed when it was dissolved in CD3OD. We demonstrated a similar proton-deuterium exchange on a model compound, 1-methyl-3,4-dihydro-gamma-carboline, in CD3OD solution.

Alkaloids↗
PubMed2000

Determination of residual solvents in bulk pharmaceuticals by thermal desorption/gas chromatography/mass spectrometry.

Thermal desorption (TD) techniques followed by capillary GC/MS were applied for the analysis of residual solvents in bulk pharmaceuticals. Solvents desorbed from samples by heating were cryofocused at the head of a capillary column prior to GC/MS analysis. This method requires a very small amount of sample and no sample pretreatment. Desorption temperature was set at the point about 20 degrees C higher than the melting point of each sample individually. The relative standard deviations of this method tested by performing six consecutive analyses of 8 different samples were 1.1 to 3.1%, and analytical results of residual solvents were in agreement with those obtained by direct injection of N,N-dimethylformamide solution of the samples into the GC. This novel TD/GC/MS method was demonstrated to be very useful for the identification and quantification of residual solvents in bulk pharmaceuticals.

Chemistry, Pharmaceutical↗
PubMed2000

Influence of cardiopulmonary bypass temperature on circulatory pathophysiology and clinical outcomes.

This study was designed to investigate the effects of cardiopulmonary bypass (CPB) perfusion temperature. Forty-four patients who had undergone elective coronary bypass surgery were randomly divided into 2 groups (22 patients each) according to their perfusion temperature (N group=36 degrees C; L group=30 degrees C). The concentrations of endogenous catecholamines, complements, elastase, serotonin, arachidonic acid metabolites and endothelin underwent various changes throughout the CPB but did not exhibit any statistical differences in either group. None of the substances measured correlated with systemic vascular resistance at any time. The temperature of the perfusion appears to be a major determinant of vascular tone. The postoperative PO2 was better, and postoperative pulmonary vascular resistance lower in the N group (p<0.05), most likely because of a much larger water balance during hypothermic CPB (p<0.01). The postoperative blood loss was statistically less in the N group (p<0.05). Although apparent brain damage, evidenced by the leakage of creatine kinase-BB, was not seen, the jugular bulb venous hemoglobin saturation levels (<50% in 27% of the N group, p<0.05) and higher lactate levels suggested that normothermic perfusion was relatively disadvantageous. It is concluded that normothermic CPB was relatively safe and advantageous with regard to hemostasis and pulmonary function.

Aged↗
PubMed2000

Effect of magnesium sulfate on the haloperidol-induced QT prolongation assessed in the canine in vivo model under the monitoring of monophasic action potential.

Haloperidol has been reported to induce polymorphic ventricular arrhythmias associated with QT prolongation. The present study examined the effects of magnesium sulfate on the cardiovascular system suffering from haloperidol overdose. Beagle dogs were anesthetized with halothane inhalation under the monitoring of monophasic action potential (n=6). After intravenous administration of an intentionally high dose of haloperidol (3 mg/kg), the heart rate (HR), left ventricular contraction and mean blood pressure (BP) decreased, and the ventricular repolarization phase and effective refractory period (ERP) were prolonged, the increment in the former being than in the latter, indicating an increase in electrical vulnerability. However, preload of the left ventricle, cardiac output (CO) and cardiac conduction were hardly affected. An additional intravenous dose of 100 mg/kg of magnesium sulfate increased the preload of the left ventricle, and decreased the HR, mean BP, left ventricular contraction and CO, suppressed atrioventricular as well as intraventricular conduction, and prolonged the ventricular repolarization phase and ERP, in which the increment of the repolarization phase was similar to that of ERP. These results suggest that magnesium sulfate hardly affects the electrical vulnerability of the heart during haloperidol overdose, but may block the calcium, potassium and sodium channels, which may explain its antiarrhythmic action.

Action Potentials↗
PubMed2000

Comparison of the electropharmacological effects of verapamil and propranolol in the halothane-anesthetized in vivo canine model under monophasic action potential monitoring.

The cardiovascular profile of verapamil was assessed in the halothane-anesthetized canine model and compared with that of propranolol. Verapamil was infused at the rates of 1, 3 and 10 microg x kg(-1) x min(-1) (n=6), whereas propranolol was administered at a fixed rate of 10 microg x kg(-1) x min(-1) (n=6). Each infusion was performed over 30 min, and the parameters were assessed for 20-30 min after the start of each infusion. Verapamil in a dose of 10 microg x kg(-1) x min(-1) significantly suppressed atrio-ventricular (AV) node conduction and slightly decreased the mean blood pressure, but no significant change was detected in the left ventricular end-diastolic pressure, maximum upstroke velocity of the left ventricular pressure, sinus automaticity, double product, cardiac output, intraventricular conduction, and ventricular repolarization phase and refractoriness. Propranolol suppressed AV node conduction to an extent similar to that of verapamil, but it also inhibited intraventricular conduction, sinus automaticity and ventricular contraction, increased the ventricular refractoriness, and decreased the double product and cardiac output, without any significant change in the other variables measured. These results suggest that verapamil can selectively affect the AV node, and that the greater part of the suppressive action of propranolol on the multiple cardiovascular performance is through a beta-blocking action and direct membrane effect, although the halothane inhalation itself might have modified each of the drug's effects. The abbreviation of the relative refractory period of the ventricle by propranolol may show its potential utility for re-entry type ventricular tachycardia.

Action Potentials↗
PubMed2000

Effects of sphingosine 1-phosphate, a naturally occurring biologically active lysophospholipid, on the rat cardiovascular system.

Recent studies have indicated that sphingosine 1-phosphate (Sph-1-P) is released into the blood flow from activated platelets upon stimulation to exhibit a wide spectrum of biological functions. The purpose of the present study was to assess the acute cardiovascular effects of circulating Sph-1-P in the in vivo rat model. Intravenous administration of Sph-1-P decreased the heart rate, ventricular contraction and blood pressure, while it hardly affected the atrioventricular and intraventricular conduction. Sph-1-P did not affect the adenylate cyclase activities of the membrane preparations made from the right atrium and left ventricle. These results suggest that functional receptors like lysophospholipid receptor Edg-1, which can inhibit adenylate cyclase via Gi protein, are lacking in the rat heart. Moreover, these observations will provide a clue to better understand the various types of Sph-1-P-related pathophysiological processes.

Adenylyl Cyclases↗
PubMed2000

Electrophysiological and cardiohemodynamic effects of AH-1058, a new type calcium channel blocker, assessed by the in vivo canine model.

AH-1058 (4-(5H-dibenzo[a, d]cyclohepten-5-ylidene)- 1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-propenyl]piperidine hydrochloride) is a novel calcium channel blocker whose chemical structure is quite different from those of typical calcium channel blockers. In this study, electrophysiological and hemodynamic effects of AH-1058 were assessed in the halothane-anesthetized, closed-chest canine model. Intravenous administration of a canine antiarrhythmic dose of 100 microg/kg of AH-1058 (n = 6) did not affect the cardiovascular variables, except that the cardiac output was decreased at 30 min after the drug administration. Additional administration of 200 microg/kg of AH-1058 (n = 6) suppressed the sinus nodal automaticity, AV nodal conduction and ventricular contraction and decreased the mean blood pressure, cardiac output and double product. The effects gradually appeared, while no change was detected in the intraventricular conduction, ventricular repolarization period, ventricular effective refractory period, preload to the left ventricle and total peripheral vascular resistance during the observation period of 30 min. The cardiosuppressive effects of AH-1058 can be explained by its calcium channel blocking action demonstrated in a previous in vitro experiment, while the lack of the effect on the vascular resistance would suggest that AH-1058 may become a slow-acting cardioselective calcium channel blocker.

Animals↗
PubMed2000

Effects of mexiletine on the canine cardiovascular system complicating cisapride overdose: potential utility of mexiletine for the treatment of drug-induced long QT syndrome.

The purpose of this study was to test the potential utility of mexiletine for the treatment of drug-induced long QT syndrome in vivo. Beagle dogs were anesthetized with halothane inhalation (n =7). Monophasic action potential (MAP) of the right ventricle, ECG, systemic and left ventricular pressure, cardiac output and effective refractory period (ERP) of the right ventricle were measured. The electrically vulnerable period was estimated by the difference between MAP duration and ERP. An intentionally high dose of 1 mg/kg, i.v. of cisapride decreased the heart rate, mean blood pressure, left ventricular contraction and cardiac output and prolonged the ventricular repolarization phase and ERP, in which the increment was greater in the former than in the latter, indicating the increase of electrical vulnerability. The left ventricular end-diastolic pressure and atrioventricular as well as intraventricular conduction were hardly affected. Additional administration of an antiarrhythmic dose of 3 mg/kg, i.v. of mexiletine increased the heart rate, decreased the left ventricular contraction and cardiac output, suppressed the atrioventricular as well as intraventricular conduction, and prolonged the ERP, but shortened the ventricular repolarization phase. There was no change in the afterload and preload of the left ventricle. Thus, mexiletine decreased the electrical vulnerability of the heart during cisapride overdose, suggesting that it may become a potential pharmacological strategy for drug-induced long QT syndrome.

Action Potentials↗