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K Obata

Publications and source records attributed to K Obata.

At least 109 records · Page 6Linked to original sources
PubMed1997

Function of FK506 binding protein (FKBP) in chick embryonic cardiac development.

FK506 binding protein (BP) 12, an immunophilin of FK506-binding proteins, is involved in intra-cellular signal transduction through the calcineurin-nuclear factor pathway. FKBP12 is reported to be associated with the ryanodine-receptor and IP3 Ca2+ channels, and to regulate cell proliferation via binding transforming growth factor (TGF)-beta receptor and cyclin dependent kinase (CDK). To elucidate the function of FKBP12 in cardiac development, we analyzed the temporal profile and regulation of FKBP12 expression in chick heart and in cultured cardiomyocytes. FKBP12 is expressed in embryos as early as day 4 and is predominantly associated with cardiomyocytes and osteo-chondrocytes. Tissue FKBP level in the heart increases with development. Immunohistochemically, the distribution and levels of FKBP12 appear to be related to sarco-endoplasmic reticulum Ca-ATPase 2 (SERCA2) but not to sarcomeric proteins. In proliferating cells, FKBP12 expression correlates with cellular mitosis, but not with DNA synthesis. In earlier embryos (< day 8), suppressing the activity of FKBP by FK506 administration is lethal, and induces cardiomegaly at later stages. In cultured cardiomyocytes, FK506 reduces the level of contractile proteins and inhibits cell proliferation. These results show that FKBP12 is enriched in cell types involved in dynamic Ca handling, and is likely an important molecule for cardiac development. FKBP12 most likely functions by affecting cellular Ca handling, since its effects are modified by modulators of Ca handling by sarcoplasmic reticulum.

Animals↗
PubMed1996

Mice lacking the 65 kDa isoform of glutamic acid decarboxylase (GAD65) maintain normal levels of GAD67 and GABA in their brains but are susceptible to seizures.

The gene encoding of the 65 kDa isoform of the gamma-aminobutyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase (GAD), GAD65, was targeted in mice by homologous recombination. Viable GAD65 -/- mice were obtained with the expected mendelian frequency and displayed no gross morphological defects. Despite the complete loss of GAD65 mRNA and protein in a homozygous mutant, there was no difference in GABA content in the brains of GAD65 +/+, +/-, and -/- mice. As for the other 67 kDa isoform (GAD67), the levels of mRNA and protein were largely unchanged by the GAD65 mutation. General behavior, including locomotor activity and performance in the Morris water maze task, appeared normal, but seizures were more easily induced by picrotoxin and pentylenetetrazol: the latencies to seizures induced by picrotoxin were shorter and the dose of pentylenetetrazol required for induction of seizures was lower.

Animals↗
PubMed1996

Neurochemical analysis of the tyrosine hydroxylase expression in methamphetamine-sensitized rats.

To elucidate the expression of TH mRNA in MAP-induced behavioral sensitization, rats were daily injected with MAP (5 mg/kg i.p.) or saline for 14 days. Progressive enhancement was observed in MAP-induced stereotyped behavior. After 7 days of discontinuation of MAP treatment, the rats were decapitated and the brains were prepared for either in situ hybridization or Northern blot hybridization. In situ hybridization revealed that the signals of TH mRNA were localized to the dopaminergic perikarya of substantia nigra and ventral tegmental area in the midbrain, and Northern blot analysis showed that the levels of TH mRNA in these areas decreased by 37% compared to that in the saline-treated controls. These findings indicate that MAP-induced dopaminergic hyperactivity is not associated with enhanced expression of TH gene mRNA.

Animals↗
PubMed1996

Familial Alzheimer's disease-linked mutations at Val717 of amyloid precursor protein are specific for the increased secretion of A beta 42(43).

In some pedigrees of familial Alzheimer's disease (FAD), three mutations of beta amyloid precursor protein (APP) have been found at the Val717 residue (to Ile, Phe, or Cly) and these mutations increase the secretion of A beta 42(43). To study the specificity of the effects of these mutations on APP processing, we transiently expressed APP genes with mutations of Val717 to Lys, Ser, Glu, or Cys in COS cells. The three familial AD-linked mutations increased the levels or ratios of A beta 42(43), whereas the secretion of A beta 40 was decreased. Other mutations irrelevant to FAD except Val717 to Lys had little effect on the ratio of A beta 42(43). Substitution to Lys decreased the secretion of A beta 42(43); substitution to Glu or Gly decreased the amount of intracellular C-terminal fragment produced by alpha-secretase, whereas it was increased by mutations to Phe, Cys, or Lys. However, the levels of secretion of soluble APP were constant, but a substitution to Glu reduced it. These results suggest a specific role of the Val717 residue in APP processing and, especially, in gamma-cleavage.

Alzheimer Disease↗
PubMed1996

The prognostic significance of vascular invasion by endometrial carcinoma.

BACKGROUND: Recently, invasion of vascular spaces by endometrial carcinoma has received particular attention as a prognostic factor. The goal of the current investigation was to re-examine the effect of vascular invasion on tumor recurrence and survival in patients with endometrial carcinoma. METHODS: Surgical specimens from 238 patients with endometrial carcinoma were examined for the presence of vascular invasion by tumor cells. Vascular invasion was compared with clinicopathologic features and postoperative survival. Survival curves by vascular invasion were evaluated by the Kaplan-Meier method. RESULTS: In a histopathologic review of 238 cases of endometrial carcinoma, 82 neoplasms demonstrated vascular invasion. Vascular invasion significantly correlated with the extension of primary tumor, depth of myometrial invasion, and histologic grade. Patients with lymph node metastasis had a significantly higher incidence of vascular invasion. Survival at 5 years for patients with vascular invasion was 73.4%. This was significantly lower than the survival rate of 91.5% for women without this finding (P < 0.001). Among patients with lymph node metastasis, 80.2% of the patients with vascular invasion survived for 5 years compared with 95.3% of the patients without vascular invasion (P < 0.05). Ten of 47 patients with no lymph node metastasis but with vascular invasion developed recurrent carcinoma. Nine of these ten patients apparently had extrapelvic recurrences. CONCLUSIONS: The presence of vascular invasion is a reliable prognostic indicator. Recording of tumor recurrence pattern may lead to a better selection of patients for adjuvant systemic therapy after surgery.

Endometrial Neoplasms↗
PubMed1996

Ca2+/calmodulin-dependent protein kinase II in septally kindled rat brains: changes in protein level, activity and subcellular distribution in hippocampus and cerebral cortex.

The protein level and the activity of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) in homogenate from septally kindled rat brains were quantitatively compared with those from paired controls 2 weeks after the final stimulation. The major alpha subunit level was decreased, while the activity was increased in crude homogenate from hippocampus and parietal cortex of kindled animals, indicating an apparent increase in the specific activity of CaM kinase II in these regions of the kindled brains. No such changes were observed in cerebellum. After the separation of crude homogenate into the soluble and particulate fractions, the ratio of CaM kinase II activity recovered in the soluble fraction was increased in hippocampus and parietal cortex, indicating a change in subcellular distribution of CaM kinase II in the kindled state.

Animals↗
PubMed1996

Molecular cloning of a novel basic helix-loop-helix protein from the rat brain.

In the mammalian nervous system, several basic helix-loop-helix (bHLH) proteins have been identified that may play essential roles in neurogenesis or neural development. This paper describes a novel bHLH protein in rat brain, which has a bHLH domain highly homologous with that of MATH-2 and NeuroD. On the other hand, the amino-acid sequence of the other regions had little homology with those of the known proteins. This protein consists of 381 amino acids and was detected only in neural tissue, indicating that it has an important role specific to neuronal activities.

Amino Acid Sequence↗
PubMed1996

Severe hypertension and cardiac failure associated with neuroblastoma: a case report.

The authors report on 3-year-old-girl with neuroblastoma complicated by severe hypertension and cardiac failure. She had cardiomegaly and pleural and pericardial effusions. Echocardiogram showed left ventricular hypertrophy and decrease of the left ventricular ejection fraction to 0.36 (normal > .40). Abdominal computed tomographic scan indicated a 7 x 7-cm tumor in the left suprarenal area. There was a marked increase in catecholamines and metabolites in her body fluids. After hypertension was controlled with doxazosin (a long-acting alpha 1 adrenergic blocker), her cardiac function gradually improved. A tumor was surgically removed and diagnosed as a poorly differentiated ganglioneuroblastoma. Preoperative differentiation between neuroblastoma and pheochromocytoma was not possible on the basis of catecholamine analysis or imaging studies including computed tomography scan and magnetic resonance imaging. It is important to control hypertension quickly in the patients with catecholamine-induced cardiomyopathy to facilitate surgical intervention for diagnosis and treatment.

Adrenergic alpha-Antagonists↗
PubMed1996

Primary adenocarcinoma of the renal pelvis with special reference to histochemical observations.

A case of adenocarcinoma of the renal pelvis is presented. The patient was an 84-year-old man suffering from long-standing right-sided nephrolithiasis. Surgical resection of the right kidney revealed adenocarcinoma with slight stromal invasion. A tubulovillous adenoma, which was morphologically similar to an adenoma of the large intestine, was also found adjacent to the adenocarcinoma. The pelvic epithelium neighboring the lesion revealed intestinal metaplasia. Histochemical studies revealed that the tumor in the patient and adenocarcinomas or adenomas of the large intestine have similar properties of cytoplasmic mucin. These findings suggest that the epithelium with intestinal metaplasia may have developed into the adenoma and finally transformed into the adenocarcinoma. In addition, only tumor cells with severe atypia, most of which morphologically corresponded to adenocarcinoma, demonstrated positive nuclear staining for anti-p53. This suggests that p53 may play an important role in the malignant transformation of adenomas into adenocarcinomas, as is the case in the large intestine.

Adenocarcinoma↗
PubMed1996

Pre-operative time course changes in liver function tests in biliary atresia: its usefulness in the discrimination of biliary atresia in early infancy.

In order to investigate the possibility of early discrimination of extrahepatic biliary atresia from other cholestatic diseases, a series of results of liver function tests in infants with cholestatic diseases were reviewed. The results of routine liver function tests (LFT) recorded in patients' charts were reviewed within 12 weeks after birth in 47 infants with extrahepatic biliary atresia (BA), 10 infants with neonatal hepatitis (NH) and 130 age-matched control infants (CO) without cholestatic diseases. The mean of each test value for each week after birth was derived from the actual data examined in each infant. No differences were observed between BA and CO in the levels of aminotransferases within 2 weeks after birth. Total bilirubin and direct bilirubin levels were significantly different between BA and CO within 1 week after birth (16.1 +/- 3.2 mg/dL vs 11.1 +/- 4.5 mg/dL, 4.6 +/- 2.6 mg/dL vs 0.7 +/- 0.3 mg/dL, respectively). The direct bilirubin-total bilirubin ratio exceeded 25% within the first week in BA. The individual values of direct bilirubin (DB) exceeded 2 mg/dL within the first week in all infants with BA, while none of the individual values exceeded 1.6 mg/dL in CO. Gamma-glutamyl transpeptidase levels were significantly different between BA and CO at 4 weeks (432 +/- 272 IU/L vs 79 +/- 43 IU/L) and thereafter; and were significantly different between BA and NH at 6 weeks (314 +/- 232 IU/I vs 69 +/- 58 IU/L) and thereafter. These data suggest that the determination of direct bilirubin within 1 week after birth can detect extrahepatic biliary atresia patients from those with physiologic jaundice, and gamma-glutamyl transpeptidase levels may discriminate BA from NH at no later than 6 weeks of age.

Alanine Transaminase↗
PubMed1996

Serum prostate-specific antigen values for the prediction of clinical stage and prognosis in patients with prostate cancer: an analysis of 749 cases.

BACKGROUND: The clinical significance of pretreatment serum prostate-specific antigen (PSA) values was studied to determine the ability to predict clinical stage and prognosis using a relatively large number of patients with prostate cancer. METHODS: Serum PSA values at diagnosis were analyzed from 749 patients with newly-diagnosed prostate cancer and registered in the Tokai Urological Cancer Registry. Correlations between the PSA value, the clinical stage and prognosis of the patients were evaluated. RESULTS: Serum PSA values at each stage of diagnosis showed positivity (> or = 3.6 ng/mL) in 23% (stage A1) to 91.2% (stage D2) of patients, and it was possible to obtain statistical differences between the stages, even between A1 and A2. Based on a cumulative study of PSA distribution, stages greater than A2 could be diagnosed using a cut-off of 7.2 ng/mL, with a 99.2% positive predictive value (PPV), and a 16.2% negative predictive value (NPV). At a PSA level of 10.8 ng/mL, stages greater than B2 could be predicted with a PPV of 95.3% but an NPV of 40.3%. Pretreatment PSA values were a significant prognostic indicator in stage D2 patients using 100 to 150 ng/mL as the cut-off values. These differences were primarily found in the poorly differentiated group, which showed a statistical difference using cut-off PSA values from 75 to 150 ng/mL. CONCLUSIONS: Serum PSA levels from a large number of patients can be used to predict the stage and prognosis of prostate cancer patients.

Aged↗
PubMed1996

Evaluation of human skin irritation by carboxylic acids, alcohols, esters and aldehydes, with nitrocellulose-replica method and closed patch testing.

Closed patch testing and the nitrocellulose-replica method are performed as useful clinical methods for the evaluation of human skin irritation by cosmetics and topical medicaments. Comparison of the sensitivity between microscopic scoring by nitrocellulose-replica method and visual scoring by closed patch test in the detection of skin irritation, however, has not been well studied with statistical analysis. Here, we evaluated human skin irritation by carboxylic acids, alcohols, esters and aldehydes, with different chain length (C8-C18), using both methods. The results of closed patch testing showed that, although the score of skin irritation for carboxylic acids (C8, C12), alcohols (C8) and aldehydes (C8), tested at a concentration of 0.5 m-2.0 m, significantly increased with increasing concentration of the test compounds, ester compounds scarcely caused any irritation on the surface of the skin occluded. In addition, an increase of carbon chain length in the test compounds made it impossible to detect skin irritation. In contrast, the nitrocellulose-replica method could evaluate skin reactions against very weak irritants that gave no macroscopic alterations on the skin surface in the closed patch test. However, the scoring system is somewhat subjective and should be improved to make the analysis more objective.

Adult↗
PubMed1996

Major risk factors for atherosclerosis are manifested in experimental Ca-deficiency.

The eggshell is the major source of Ca required during growth of chick embryos. Therefore, chick embryos placed ex ovo for long-term (SL) are rendered severe systemic calcium deficiency. We report here that SL chick embryos express Ca-deficiency related atherogenic disorders, and that in vitro Ca-deficiency induces dedifferentiation, i.e. loss of cell-type specific features and accelerated proliferative activities, in the various types of cultured cells. Systemic blood pressure is significantly higher and an accelerated weight gain of the heart is noted in SL compared to normal embryos (NL) at the incubation Day-14. Plasma cholesterol was lower, while triglyceride and glucose were higher in SL. Varying Ca in the culture medium (FCa, 1.8 mM; HCa, 2.8 mM; Ca/2, 0.9 mM) clearly affected the phenotype of the cultured cardiomyocytes and vascular cells isolated from the chick embryos. The cell number and total DNA were significantly larger and the level of LDH and proliferating cell nuclear antigen (PCNA) was elevated in Ca/2 compared to FCa. On the contrary, the level of CPK and contractile proteins were lowered in Ca/2. Thus, it is indicated that Ca-deficiency induces atherogenic disorders in vivo, and accelerates cell proliferation and decelerates sarcomeric protein expression in vitro. Taken together, it is suggested that the atherogenic, developmental disorders in SL may be the integrated result of the phenotype alteration in the various cell types directly induced by Ca-deficiency.

Animals↗
PubMed1996

Ulinastatin ameliorates acute ischemic renal injury in rats.

Effects of ulinastatin (a Kunitz-type proteinase inhibitor) administration was examined in a model of acute ischemic renal injury induced by bilateral renal artery occlusion in rats. Compared with rats administered vehicle, rats administered ulinastatin (150,000 U/kg body weight) intravenously 30 min preischemia had significantly lower serum creatinine and blood urea nitrogen, and much less injury evident by examination of kidney histologies over the course of 48 h postreperfusion. We conclude that ulinastatin exerts a protective effect against ischemic renal injury.

Animals↗
PubMed1996

Determination of stromelysin-1, 72 and 92 kDa type IV collagenase, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 in synovial fluid and serum from patients with rheumatoid arthritis.

OBJECTIVE: To investigate the correlation between serum and synovial fluid (SF) concentrations of stromelysin-1 (MMP-3), gelatinases (MMP-2 and MMP-9), tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in patients with rheumatoid arthritis (RA) and to assess the role of these proteins in cartilage destruction and their clinical value as indicators of disease activity. METHODS: Enzyme linked immunoassays (ELISA) were used. SF and serum samples were collected simultaneously from 55 patients with RA. Radiographic (Larsen grade) and clinical evaluations were also done. RESULTS: There was significant correlation between SF concentrations of MMP-3 and MMP-9. In addition, there was significant negative correlation between SF concentrations of TIMP-2 and MMP-2, 3, and 9. The only correlation observed among MMP and TIMP in serum was that of MMP-3 with MMP-2. Significant correlation was also found between MMP-3 concentrations in the serum and SF. There were no significant correlations between radiological grade and concentrations of these proteins. Patients with mild to moderate functional disability showed significantly higher serum TIMP-1 concentrations than patients with severe disability. CONCLUSION: Extremely high concentrations of MMP-3 in SF of the patients with RA may contribute to its elevation in serum. It would seem that regulation of TIMP production depends upon the disease state and not the concentration of MMP. Discrepancies between concentrations of TIMP and MMP in SF may be responsible for cartilage destruction in RA.

Aged↗
PubMed1996

Effects of indomethacin on the production of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinases-1 by human articular chondrocytes.

OBJECTIVE: To study the action of indomethacin on cartilage catabolic activity by comparing the production of a matrix degrading proteinase and its inhibitor in human articular chondrocyte cultures. METHODS: Matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in conditioned medium from human articular chondrocyte cultures were measured using a one-step sandwich enzyme immunoassay. TIMP-1 mRNA expression was analyzed by Northern blotting using a 0.6 kb cDNA probe for human TIMP-1. RESULTS: Human recombinant interleukin 1 beta (IL-1 beta) increased MMP-3 levels in primary chondrocyte cultures. Indomethacin at 10(-5) M inhibited this IL-1 beta stimulation, but had no effect in the therapeutic range (10(-6)-10(-7) M). Low levels of indomethacin (10(-7) M) significantly increased the production of TIMP-1 by chondrocytes. Synthesis of TIMP-1 appeared to be inhibited by prostaglandin E2 (PGE2), since exogenously added PGE2 reversed the stimulating effect of indomethacin on TIMP-1 production. Northern blot analysis showed that 10(-7) M indomethacin increased TIMP-1 mRNA levels in chondrocytes. CONCLUSION: Our findings indicate that low levels of indomethacin can benefit matrix metabolism by affecting the balance of proteinases to their inhibitors in human articular cartilage.

Blotting, Northern↗
PubMed1995

Methamphetamine-induced dopaminergic hyperactivity is not accompanied with increase in tyrosine hydroxylase mRNA of the rat midbrain.

Tyrosine hydroxylase (TH) mRNA was measured in the midbrain of rats treated repeatedly with methamphetamine (MAP). Male Sprague-Dawley rats were daily injected with MAP (5 mg/kg, i.p., once daily) or saline for 14 days. Progressive augmentation was observed in MAP-induced stereotyped behaviors. After one week of abstinence, the rats were decapitated and the brains were prepared for either in situ hybridization using non-radioactive cRNA probes or Northern blot analysis using 32P-labeled cDNA probes. In situ hybridization showed that the signals of TH mRNA were localized to the dopaminergic perikarya in the midbrain and were reduced in MAP-treated animals compared to the controls. Northern blot analysis revealed that the level of TH mRNA in the midbrain of MAP-treated rats was decreased by 37% compared to the controls, which was close to the statistical significance (P = 0.053). These results indicate that the dopaminergic hyperactivity caused by repeated MAP treatment is not associated with enhanced transcription of the TH gene.

Animals↗