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Biomedical subjects

S Nagata

Publications and source records attributed to S Nagata.

At least 55 records · Page 3Linked to original sources
PubMed2001

Processing of tumor necrosis factor by the membrane-bound TNF-alpha-converting enzyme, but not its truncated soluble form.

Tumour necrosis factor (TNF)-alpha-converting enzyme (TACE) is a membrane protein belonging to the ADAM (a disintegrin and metalloproteinase) family that cleaves various membrane proteins, including the proform of TNF-alpha. In this study, we constructed expression vectors for the membrane-bound full-length TACE (mTACE) and its truncated soluble form (sTACE). When a human TNF-alpha expression vector was introduced into human 293 cells, processing of TNF-alpha to its mature form was enhanced by coexpressing mTACE, and this processing was inhibited by a metalloproteinase inhibitor. On the other hand, coexpression of sTACE had no effect on the processing of TNF-alpha, although the culture medium of sTACE-transfected cells could cleave a peptide containing the TNF-alpha cleavage site. Fas ligand (FasL)-transfected 293 cells released a considerable amount of soluble FasL, and coexpression of neither mTACE nor sTACE enhanced this shedding. Immunoprecipitation and Western blotting analysis with cells that were cotransfected with TACE and TNF-alpha indicated that both mTACE and sTACE could interact with the proform of TNF-alpha. In the same assay, neither mTACE nor sTACE interacted with FasL. The catalytic domain-lacking TACE mutant, which could also interact TNF-alpha, showed a dominant negative effect on not only TNF-alpha secretion but also FasL secretion. These results suggest that binding of the membrane-anchored but not the soluble form of TACE to TNF-alpha results in efficient ectodomain shedding, and that FasL secretase is a metalloproteinase similar, but not identical, to TACE.

ADAM Proteins↗
PubMed2001

Overexpression of Fyn tyrosine kinase causes abnormal development of primary sensory neurons in Xenopus laevis embryos.

The expression and function of the Src family protein tyrosine kinase Fyn in Xenopus laevis embryos have been examined. In situ hybridization analysis demonstrated nervous system-specific expression of Fyn mRNA in tail-bud embryos. However, a class of primary sensory neurons; that is, Rohon-Beard (RB) neurons, which is positive for immunoglobulin superfamily cell adhesion molecules (CAM), neural cell adhesion molecule (N-CAM) and contactin, is devoid of Fyn expression. Injection of Fyn mRNA into one of the blastomeres at the 2-cell stage led to overexpression of Fyn in the injected half of the tail-bud embryos. Immunolabeling of the embryos with anti-HNK-1 antibody revealed that the peripheral axons of RB neurons were partially misguided and bound to each other to form abnormal subcutaneous fascicles. Similar abnormality was induced by injection of the Fyn overexpression vector. The incidence of abnormality appeared dose-dependent, being 68-92% of the injected embryos at 50-400 pg of mRNA. Co-injection of the contactin antisense vector depleted contactin mRNA accumulation without affecting Fyn overexpression and reduced the incidence of the abnormal RB-cell phenotype. However, the N-CAM antisense was ineffective in reducing this abnormality. These results suggest that Fyn can modify signals regulating axonal guidance or fasciculation in the developing X. laevis nervous system and that contactin may affect this action of Fyn.

Animals↗
PubMed2001

Prediction of difficult airway in school-aged patients with microtia.

BACKGROUND: Because the ear and mandible develop from the first and second branchial arches and first branchial cleft, abnormalities of the ear may be a sign that intubation will be difficult. We hypothesized that children with microtia would have a greater incidence of difficult laryngeal visualization with conventional rigid laryngoscopy compared to those with normal facial anatomy. METHODS: We enrolled 93 consecutive school-aged patients with microtia undergoing the first stage of total reconstruction of the auricle. Age-matched patients with normal facial anatomy served as controls. Each patient was examined for the presence or absence of the five dysmorphic features of hemifacial microsomia: orbital asymmetry, mandibular hypoplasia, ear deformity, nerve involvement, soft tissue deficiency (OMENS classification). After a standardized induction of anaesthesia, the laryngeal view during rigid laryngoscopy was graded. RESULTS: The incidence of difficult laryngeal view was 42% in the patients with bilateral microtia, 2% in those with unilateral microtia and 0% in the controls. CONCLUSIONS: There was a strong positive correlation between the number of involved abnormal anatomical components according to the OMENS classification and the degree of difficult visualization of the larynx in patients with both bilateral and unilateral microtia (Spearman rank order correlation coefficient=0.85 and 0.88, respectively).

Adolescent↗
PubMed2001

Dialysis patients' preferences regarding cardiopulmonary resuscitation and withdrawal of dialysis in Japan.

The aim of this study is to show the preferences of Japanese dialysis patients for receiving cardiopulmonary resuscitation (CPR) in their current health status, if they were severely demented, or if they had terminal cancer and to determine their desires about continuing dialysis if they were severely demented or had terminal cancer. A questionnaire survey including the three scenarios was administered to 450 dialysis patients in 15 hospitals in JAPAN: Three hundred ninety-eight patients completed the questionnaires for a response rate of 88%. The majority of responding patients were men and were undergoing hemodialysis. Only 5% of the patients had discussed their preferences regarding CPR with their physicians, and 29%, with their family members. Forty-two percent of the patients answered that they would want to receive CPR if they experienced cardiopulmonary arrest in their current health status, and 12% answered in the affirmative if they were seriously demented or had terminal cancer. Eighteen percent of the patients would want to continue dialysis if they were demented, and 45%, if they had terminal cancer. Statistical analysis showed that more patients who were working tended to want to continue dialysis if they had terminal cancer than those who were not (53% versus 37%; P < 0.014). Patients' age and preferences did not statistically correlate. Preferences of Japanese dialysis patients for CPR and dialysis vary according to differences in health status, and only a minority would want to receive CPR for cardiopulmonary arrest even in their current health status.

Adult↗
PubMed2001

Psychosocial factors as a potential trigger of oxidative DNA damage in human leukocytes.

Although numerous studies have been carried out on the stress-cancer linkage, the results are still inconclusive. One of the useful, but rarely applied, methods to assess this linkage is to examine the relationship between psychosocial stress and cancer-predisposing genetic alterations simultaneously. We investigated whether various psychosocial factors can be associated with the levels of 8-hydroxydeoxyguanosine (8-OH-dG), a biomarker of cancer-related oxidative DNA damage, in peripheral blood leukocytes in 362 healthy workers (276 males and 86 females). After adjustments for age, body mass index, cigarette smoking, and alcohol use, female subjects showed positive relationships between the amount of 8-OH-dG and the Tension-Anxiety, Depression-Rejection, Anger-Hostility, Fatigue, and Confusion scores of the Profile of Mood States, respectively. The levels of 8-OH-dG also increased reliably in the female subjects who had poor stress-coping behaviors, particularly wishful thinking strategy, in the NIOSH general job stress instrument. There were positive relationships of the 8-OH-dG levels to average working hours, a self-blame coping strategy, and recent loss of a close family member in male subjects. These findings in a nonclinical sample of healthy adults not only provide evidence of a stress-cancer linkage, but also suggest possible sex differences in the mechanisms of stress-related cancer initiation.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

Identification and characterization of two distinct GnRH receptor subtypes in a teleost, the medaka Oryzias latipes.

We report the identification and characterization of two distinct GnRH receptor (GnRH-R) subtypes, designated GnRH-R1 and GnRH-R2, in a model teleost, the medaka Oryzias latipes. These seven-transmembrane receptors of the medaka contain a cytoplasmic C-terminal tail, which has been found in all other nonmammalian GnRH-Rs cloned to date. The GnRH-R1 gene is composed of three exons separated by two introns, whereas the GnRH-R2 gene has an additional intron and therefore consists of four exons and three introns. The GnRH-R1 and GnRH-R2 genes, both of which exist as single-copy genes in the medaka genome, were mapped to linkage groups 3 and 16, respectively. Inositol phosphate assays using COS-7 cells transfected with GnRH-R1 and GnRH-R2 demonstrated that they had remarkably different ligand sensitivities, although both receptors showed highest preference for chicken-II-type GnRH. Phylogenetic analysis showed the presence of three paralogous lineages for vertebrate GnRH-Rs and indicated that neither GnRH-R1 nor GnRH-R2 is the medaka ortholog to mammalian GnRH-Rs that lack a cytoplasmic tail. This, together with an observation that medaka-type GnRH had low affinity for GnRH-R1 and GnRH-R2, suggests that a third GnRH-R may exist in the medaka.

Amino Acid Sequence↗
PubMed2001

Molecular and pharmacokinetic properties of 222 commercially available oral drugs in humans.

This study was performed to determine the exclusion criteria that differentiate poorly absorbed drugs from good drug candidates, and to accelerate drug development by exclusion of unnecessary assessment. The molecular and pharmacokinetic properties of 222 commercially available oral drugs were tabulated and their correlations were analyzed. The exclusion criteria obtained were 1) a molecular weight of more than 500, and 2) a ClogP value of more than 5. Exceptions to molecular weight criteria were compounds with a sugar moiety, high atomic weight, and large cyclic structure. It was also suggested that being a substrate for MDRI (P-glycoprotein) does not always result in poor bioavailability, and that drug development by chemical modification of a seed or lead compound with quantitative structure activity relationship analysis can result in lower bioavailability, higher bound fraction and lower urinary excretion, which would hamper later development processes and might result in considerable drug-drug interaction. The criteria should be adjusted according to the pharmacological profiles of the agents in question and depending on the estimated profit, but ignoring these criteria may result in a significant waste of time and money during drug development.

Administration, Oral↗
PubMed2001

Abnormal myocardial free fatty acid utilization deteriorates with morphological changes in the hypertensive heart.

The left ventricle's morphological adaptation to high blood pressure is classified into 4 patterns based on mass and wall thickness. The geometric changes caused by maladaptation to pressure overload possibly relate to progression of contractile dysfunction with abnormal energy metabolism. The present study assessed whether the geometric adaptation of the left ventricle (LV) to high blood pressure relates to changes in myocardial energy metabolism, especially free fatty acid (FFA) utilization. Thirty-five patients with essential hypertension underwent echocardiography and dual isotopes myocardial scintigraphy using iodine-123 labeled 15-p-iodophenyl-3-(R,S)-methylpentadecanoic acid (BMIPP, an analogue of a FFA) and thallium-201 (Tl-201). Systolic (endocardial fractional shortening; %FS) and diastolic indices (the ratio of early to atrial filling waves; E/A) of LV function were also assessed. Quantitative myocardial BMIPP uptake was evaluated by the BMIPP/TI-201 myocardial uptake ratio (B/T). The subjects were divided into 4 groups based on LV mass and wall thickness: (1) concentric hypertrophy (CH), (2) eccentric hypertrophy (EH), (3) concentric remodeling (CR), and (4) normal geometry (N). The %FS was lower in the EH group than in the other groups. The mitral E/A ratio in the CH group was lowest. B/T was significantly decreased in the EH group compared with the N group (p < 0.05). B/T correlated with the mitral E/A ratio significantly (p < 0.05, r = 0.42), whereas there was no relationship between %FS and B/T. These results indicate that the geometric changes occurring in hypertensive hearts strongly correlate with alternations in cardiac function and with abnormal myocardial FFA metabolism, and that the latter is associated with diastolic abnormality, but not with systolic function.

Aged↗
PubMed2001

Determination of coronary zero flow pressure by analysis of the baseline pressure-flow relationship in humans.

The present study seeks to estimate the difference between coronary zero flow pressure (Pzf) by analysis of the baseline pressure-flow relationship and the Pzf calculated during a long diastole in humans. Although Pzf is likely to provide meaningful information about the characteristics of coronary circulation, there are no available data on Pzf in humans because Pzf is overestimated when it is calculated during normal cardiac cycles. Actual Pzf was determined in 15 subjects by analyzing the coronary pressure-flow relationship during a long cardiac cycle induced by an intracoronary adenosine triphosphate (ATP) infusion, and it was compared with the Pzf calculated during a normal cardiac cycle in order to estimate the difference. Pzf calculated during a normal cardiac cycle was 47 +/- 15 mmHg, which decreased to 36 +/- 9mmHg after intracoronary administration of ATP (0.05 mg) whereas actual Pzf was 21 +/- 7 mmHg. Pzf calculated in a pressure-flow relationship during a normal cardiac cycle under vasodilation correlated well with that during a long diastole (r = 0.75, p < 0.01), although it was 15 +/- 6 mmHg greater than the actual Pzf. It was concluded that Pzf during a normal cardiac cycle could be used to anticipate Pzf.

Adenosine Triphosphate↗
PubMed2001

Serial assessment of left and right ventricular filling in patients with congestive heart failure.

Serial changes in the diastolic filling of both ventricles were studied using Doppler echocardiography in 19 patients with congestive heart failure from the acute to the convalescent stage. During the acute stage, left ventricular early filling velocity (E) was high (88 +/- 17 cm/s) and atrial filling velocity (A) was low (44 +/- 23 cm/s), whereas the right ventricular E was depressed (17 +/- 8 cm/s) and A was enhanced (40 +/- 9 cm/s). As the condition improved, left ventricular E decreased (43 +/- 11 cm/s, p < 0.01) and A increased (59 +/- 24 cm/s, p < 0.01) along with a decrease in the left ventricular and atrial dimensions. In contrast to the changes in left ventricular filling, right ventricular E increased (31 +/- 10 cm/s, p < 0.01) and A decreased (32 +/- 5 cm/s, p < 0.05). There are opposite directional changes in left and right ventricular filling with clinical improvement from the acute to the convalescent stage of congestive heart failure, which suggest that the changes are related to improvement of the hemodynamic conditions of both ventricles. The changes in the right ventricular filling pattern was likely to be related to changes in right ventricular afterload, ventricular interaction and external constraint rather than a change in right ventricular filling pressure.

Adult↗
PubMed2001

Accumulation of ectoine in the halotolerant Brevibacterium sp. JCM 6894.

The optimum conditions for the intracellular synthesis of the cyclic amino acid ectoine (1,4,5,6-tetrahydro-2-methyl-4-pyridine carboxylic acid) were determined using the halotolerant Brevibacterium sp. JCM 6894. The amount of ectoine synthesized in cells was quantitatively determined after extraction from cells grown under various conditions, such as different external osmolarities, incubation times, and types and concentrations of nutrients in the medium. The optimum condition for the synthesis of ectoine was confirmed to be consecutive cell transfers accompanied with the changes in the medium osmolarity as follows; cells grown in the presence of 0.3 M NaCl were transferred to medium containing 1.5-2 M NaCl. After incubation for 18-24 h a second transfer of the cells to fresh medium containing 2-3 M NaCl was carried out and the cells were incubated for a further 12-24 h. The addition of 50-100 mM glucose or a high concentration of yeast extract in the medium resulted in an increase in the intracellular concentration of ectoine as well as of the cell yield. The growth medium affording the highest ectoine productivity of strain JCM 6894 consisted not only of 2 M NaCl but also Polypepton (10.0 g/l), yeast extract (5.0 g/l), and glucose (9.0 g/l) as nutrients. The highest yield of ectoine, 800 mg/l culture, was obtained using the optimum medium and one osmotic upshock. This yield corresponded to about an 8-fold increase compared to that obtained using standard medium (2 M NaCl) without an osmotic shift. In addition, the ectoine which was synthesized in cells grown at high osmolarity was released well from the cells by osmotic downshock.

Journal Article↗
PubMed2001

Growth of Escherichia coli ATCC 9637 through the uptake of compatible solutes at high osmolarity.

The growth rate of Escherichia coli ATCC 9637 was determined in a chemically defined (CD) medium with high osmolarity, 1-1.2 M. The addition of ectoine or glycine betaine to the medium resulted in a significant stimulation of growth rate for this strain. In the presence of ectoine derivatives, hydroxyectoine and homoectoine, cell growth was not stimulated to the same extent as when ectoine was added, but it was improved slightly. The acceleration of growth rate of E. coli ATCC 9637 at elevated osmolarity was ascribed to the accumulation in the cells of ectoine or glycine betaine added to the medium, both of which were proved to be genuine osmolytes in cells. Rapid uptake of ectoine by cells was confirmed when ectoine was available in the CD medium with high osmolarity. Since strain ATCC 9637 did not accumulate ectoine in the absence of an energy source, ectoine uptake might take place not only through cellular sensing of the external high osmolarity but through cellular functioning via energization.

Journal Article↗
PubMed2001

Grazing-exit X-ray spectrometry for surface and thin-film analyses.

Electron-probe x-ray micro analysis (EPMA) and particle-induced x-ray emission analysis (PIXE) were performed under grazing-exit conditions. To control the exit angle (take-off angle), a new sample holder having a stepping motor was developed for grazing-exit EPMA. A carefully polished surface of a stainless-steal sample was measured. The surface of stainless steel is normally covered with a thin native oxide layer. The intensity ratio of Cr K(alpha) to Fe K(alpha) increases significantly at the grazing angle, becoming about 5-times larger at 0.2 degrees than at 40 degrees. This result indicates that grazing-exit EPMA is useful for surface analysis. In addition, a new PIXE equipment was developed for grazing-exit x-ray measurements. The sample is fixed and the x-ray detector is moved by applying a linear stage. Preliminary experimental results of grazing-exit PIXE are also shown.

Journal Article↗
PubMed2001

Polymyositis, pulmonary fibrosis and malignant lymphoma associated with hepatitis C virus infection.

Polymyositis has been associated with various viral infections, and a spectrum of immune-related diseases may occur with hepatitis C (HCV) infection. Both polymyositis and HCV infection may be accompanied by pulmonary fibrosis. An association between polymyositis and malignancy has also been reported. We report a 55-year-old woman accompanied cryoglobulinemia with HCV infection and manifesting polymyositis, pulmonary fibrosis and malignant lymphoma. Steroid therapy was effective to improve interstitial pneumonia, polymyositis, and liver function.

Cryoglobulinemia↗
PubMed2001

Tumoral calcinosis in the upper cervical spine causing progressive radiculomyelopathy--case report.

A 54-year-old woman with chronic renal failure presented with tumoral calcinosis manifesting as progressive radiculomyelopathy. Magnetic resonance imaging revealed a spinal epidural mass in the C-2 to C-4 levels. The clinical and radiological findings suggested malignant tumor. Resection of the lesion was performed with total C-2 laminectomy and C-3 and C-4 laminoplasty. The symptoms totally disappeared after surgery. The histological diagnosis was tumoral calcinosis. Tumoral calcinosis is a rare tumoral calcium pyrophosphate dihydrate crystal deposition disease which presents as periarticular soft tissue calcification. Tumoral calcinosis should be considered in patients with a mass lesion involving the upper cervical spine and associated with metabolic abnormalities. Surgical excision is the treatment of choice, because this is completely curative without known recurrence.

Calcinosis↗
PubMed2001

MUC1 and cathepsin D expression in early colorectal carcinoma showing V type pit pattern.

The relation between MUC1, cathepsin D expression, and histologic features in early colorectal carcinomas (CRCs) with V type pit pattern was examined in 78 patients. We classified V type pit pattern into two grades (VA, VN) and we subclassified the VN type pit pattern into three subtypes (Grade A, B, and C) according to the degree of appearance of VN type pit pattern. At the tumor surface, the status of desmoplastic reaction and pit disorder or destruction were subclassified histologically into three grades (-, +, ++). MUC1 and cathepsin D expression were examined immunohistochemically at a superficial level and at the deepest part of the tumor invasion. MUC1 expression showed a significant correlation with high grade carcinoma, desmoplastic reaction (+) levels in VA type pit pattern (P<0.05), and high grade carcinoma, sm2 and sm3 lesions, desmoplastic reaction (+) and (++) levels, pit disorder or destruction (+) and (++) levels in VN type pit pattern (P<0.05). Cathepsin D expression had a significant correlation with m and sm1 lesions and desmoplastic reaction (-) levels in VN type pit pattern (P<0.05). In VA type pit pattern, a significant correlation between cathepsin D expression and histologic findings was absent. The incidence of MUC1 expression in VN.Grade B and C type pit pattern was significantly higher than that in VA and VN.Grade A type pit pattern (P<0.05). The incidence of cathepsin D expression in VA, VN.Grade A and B type pit pattern was significantly higher than that in VN.Grade C type pit pattern (P<0.05). MUC1 expression (+) or (++) levels at the deepest part of a tumor was identical to that (+) or (++) levels at the superficial part except for one case. Cathepsin D expression at the deepest part of a tumor differed from that at the superficial part. Desmoplastic reaction may be related to MUC1 and cathepsin D expression; however, pit disorder or destruction may be related to only MUC1 expression in V type pit pattern. MUC1 expression at the superficial part of a tumor may be related to expression at the deepest part; however, cathepsin D expression at the superficial part may not be related to expression at the deepest part in submucosal CRCs with V type lesions.

Cathepsin D↗
PubMed2001

The active molecular form of plasma adrenomedullin is extracted in the pulmonary circulation in patients with mitral stenosis: possible role of adrenomedullin in pulmonary hypertension.

Adrenomedullin (AM), a novel hypotensive peptide, preferentially dilates pulmonary vessels rather than systemic vessels. This suggests the possibility that AM is a circulating hormone which participates in regulation of the pulmonary circulation. A recent study revealed that two molecular forms of AM, i.e. a mature, active form of AM (AM-m) and an intermediate, inactive, glycine-extended form of AM (AM-Gly), circulate in human plasma. In the present study we investigated the production and clearance sites and pathophysiological significance of the two molecular forms of AM in the pulmonary circulation in patients with mitral stenosis. We measured the plasma levels of AM-m and total AM (AM-T; AM-m+AM-Gly) using a recently developed specific immunoradiometric assay, and thus calculated plasma AM-Gly levels, in blood samples obtained from the femoral vein, pulmonary artery, left atrium and aorta of 28 consecutive patients with mitral stenosis (20 females and eight males; age 53+/-10 years). Patients with mitral stenosis had significantly higher venous concentrations of AM-T, AM-Gly and AM-m than age-matched normal controls (AM-T, 15.9+/-2.5 and 10.6+/-2.1 pmol/l respectively; AM-Gly, 14.0+/-2.1 and 9.8+/-1.9 pmol/l respectively; AM-m, 1.9+/-0.6 and 1.1+/-0.3 pmol/l respectively; each P<0.001). There was a significant decrease in the concentrations of AM-m and AM-T between the pulmonary artery and the left atrium (AM-T, 16.1+/-2.7 and 14.0+/-2.4 pmol/l respectively; AM-m, 2.0+/-0.6 and 0.7+/-0.2 pmol/l respectively; each P<0.001); however, there were no differences in plasma AM-Gly levels between the pulmonary artery and the left atrium (14.1+/-2.3 and 13.5+/-2.3 pmol/l respectively). The venous concentrations of AM-m, AM-Gly and AM-T showed similar correlations with mean pulmonary artery pressure (AM-T, r=0.67; AM-Gly, r=0.63; AM-m, r=0.59; each P<0.001) and total pulmonary vascular resistance (AM-T, r=0.77; AM-Gly, r=0.70; AM-m, r=0.75; each P<0.001). These results suggest that the plasma concentration of AM-m is increased in parallel with those of AM-Gly and AM-T, and that the main site for clearance of AM-m from the plasma is the lung; the extracted AM-m in the lungs may help to attenuate the increased pulmonary arterial resistance in secondary pulmonary hypertension due to mitral stenosis.

Adrenomedullin↗