PubMed Health⌕ Search

Biomedical subjects

K Tobe

Publications and source records attributed to K Tobe.

At least 19 recordsLinked to original sources
PubMed2003

Hypothyroidism associated with anti-human chorionic gonadotropin antibodies secondarily produced by gonadotropin therapy in a case of idiopathic hypothalamic hypogonadism.

We report a 22-yr-old male patient with idiopathic hypothalamic hypogonadism who showed secondary resistance to gonadotropin (Gn) therapy over 3 yr after successful treatment with hCG combined with human menopausal Gn. The patient simultaneously developed subclinical hypothyroidism. Endocrine examination revealed low levels of testosterone (0.3 ng/ml), free T4 (0.91 ng/dl), and increased levels of TSH (31.1 microU/ml) in the serum. Serum autoantibodies to thyroid gland were all negative. Interestingly, thyroid function was improved after discontinuation of Gn therapy. In vitro assays by immunoprecipitation using 125I-hCG or 125I-TSH elucidated the presence of anti-hCG antibody in the serum 13 months after commencement of Gn therapy but anti-TSH antibody was not detected in the serum. Furthermore, the anti-hCG antibody specifically bound to hCG but not to other glycoproteins including TSH and FSH based on a competitive displacement assay. Bioassays using porcine thyroid cells revealed that the serum gamma-globulin fraction enables the suppression of cyclic AMP (cAMP) synthesis stimulated by TSH. Our findings suggest that anti-hCG and/or anti-idiotypic hCG antibodies induced by hCG therapy impaired TSH-dependent cAMP production through interfering with binding of TSH to its receptor, and this resulted in subclinical hypothyroidism in this patient.

Adult↗
PubMed2002

Diffusion-weighted magnetic resonance imaging of dural sinus thrombosis.

Magnetic resonance imaging (MRI) is useful to diagnose dural sinus thrombosis. However, the representative appearance of dural sinus thrombosis on diffusion-weighted MRI has not been established. This study was aimed at determining whether cytotoxic or vasogenic edema is more predominant in the affected cerebral parenchyma and assessing the time courses and prognosis of dural sinus thrombosis lesion. The studies on sixteen patients with dural sinus thrombosis who underwent diffusion-weighted MRI were retrospectively reviewed. The diagnosis was confirmed by digital subtraction angiography in 11 patients and magnetic resonance angiography in five patients. Diffusion-weighted images with echo-planar imaging were obtained using two or three b values, with the highest b value of up to 1,000 s/mm(2). A region of interest was placed on an area of abnormal signal intensity to calculate apparent diffusion coefficients (ADCs). Nine of the 16 patients had lesions with an increased ADC, whereas, three of these nine patients also had lesions with a decreased ADC. Among 11 patients who underwent initial MRI within 7 days of their last episode, eight had lesions with an increased ADC, of whom three had lesions mixed with both decreased and increased ADC areas. Follow-up studies of these three patients revealed the development of hemorrhagic infarction in two and subcortical hemorrhage in one. Vasogenic edema develops more predominantly and earlier in dural sinus thrombosis, though cytotoxic edema was also associated with the pathological changes in the early phase. Decrease of ADC value is presumed to reflect severe pathological conditions and indicate possible future development of infarction or hemorrhage.

Adult↗
PubMed2002

A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes.

AIMS/HYPOTHESIS: Peroxisome proliferator activated receptor gamma coactivator-1 (PGC-1), a transcriptional coactivator of the nuclear receptor PPARgamma, plays a role in adaptive thermogenesis and insulin sensitivity. Plasma fasting insulin has been linked to the chromosomal region where the PGC-1 gene is located. Thus, PGC-1 can be viewed as a functional and positional candidate for the susceptibility gene for Type II (non-insulin-dependent) diabetes mellitus. METHODS: After screening the PGC-1 gene for single nucleotide polymorphisms (SNPs), we performed an association study using the newly detected SNPs in 537 Type II diabetic patients and 417 non-diabetic subjects. RESULTS: We found three relatively frequent SNPs in the PGC-1 gene (IVS4-11T > C, Thr394Thr and Gly482Ser). There were significant differences in fasting insulin (Gly/Gly; 37.7 +/- 1.43, Gly/Ser; 40.2 +/- 1.21, Ser/Ser; 44.3 +/- 1.82 pmol/l, p = 0.018) and insulin resistance index (Gly/Gly; 1.48 +/- 0.06, Gly/Ser; 1.56 +/- 0.05, Ser/Ser; 1.75 +/- 0.08, p = 0.027) according to the genotype of the Gly482Ser polymorphism. The Thr394Thr - Gly482Ser haplotype was associated with Type II diabetes (p = 0.00003). CONCLUSION/INTERPRETATION. The results of this study suggested that the PGC-1 gene might be implicated in the pathogenesis of Type II diabetes.

Base Sequence↗
PubMed2002

Regulation of circulating immune complexes by complement receptor type 1 on erythrocytes in chronic viral liver diseases.

BACKGROUND AND AIM: Complement receptor type 1 (CR1) is a transmembrane protein, and human erythrocyte CR1 (E-CR1) is involved in the transport of circulating immune complexes (IC) from the circulation to the reticuloendothelial system, including the liver and spleen. In chronic viral hepatitis, increased levels of IC containing viral particles and an association with various extrahepatic manifestations have been reported. However, regulatory mechanisms for IC levels are not fully understood. PATIENTS/SUBJECTS AND METHODS: We analysed IC, E-CR1, and quantitative polymorphism of the CR1 gene in 149 patients with chronic viral liver diseases and in 64 normal blood donors using an enzyme linked immunosorbent assay, radioimmunoassay, and polymerase chain reaction-restriction fragment length polymorphism, respectively. We also analysed the effect of CR1 gene polymorphism on IC binding to E-CR1 using molecular methods. RESULTS: E-CR1 levels in patients with chronic hepatitis and chronic viral liver diseases as a whole correlated inversely with increased levels of IC. Moreover, significantly high levels of IC were observed in patients with chronic hepatitis C (CH-C) who were homozygous for the E-CR1 low density allele. We also found low levels of E-CR1 in liver cirrhosis and CH-C but not in CH-B. Low levels of E-CR1 in CH-C were observed, even after considering the polymorphism of the CR1 gene. Finally, we demonstrated CR1 gene polymorphism dependent binding of hepatitis virus containing IC. CONCLUSIONS: Our results emphasise the important role of E-CR1 in clearance of IC from the circulation and the acquired, rather than inherited, decrease in E-CR1 in chronic viral liver diseases, especially of type C.

Adult↗
PubMed2001

Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene.

The serine/threonine kinase Akt has been implicated in the control of cell survival and metabolism. Here we report the disruption of the most ubiquitously expressed member of the akt family of genes, akt1, in the mouse. Akt1(-/-) mice are viable but smaller when compared to wild-type littermates. In addition, the life span of Akt1(-/-) mice, upon exposure to genotoxic stress, is shorter. However, Akt1(-/-) mice do not display a diabetic phenotype. Increased spontaneous apoptosis in testes, and attenuation of spermatogenesis is observed in Akt1(-/-) male mice. Increased spontaneous apoptosis is also observed in the thymi of Akt1(-/-) mice, and Akt1(-/-) thymocytes are more sensitive to apoptosis induced by gamma-irradiation and dexamethasone. Finally, Akt1(-/-) mouse embryo fibroblasts (MEFs) are more susceptible to apoptosis induced by TNF, anti-Fas, UV irradiation, and serum withdrawal.

Alleles↗
PubMed2001

The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance.

Peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-activated transcription factor and a member of the nuclear hormone receptor superfamily that is thought to be the master regulator of fat storage; however, the relationship between PPARgamma and insulin sensitivity is highly controversial. We show here that supraphysiological activation of PPARgamma by PPARgamma agonist thiazolidinediones (TZD) markedly increases triglyceride (TG) content of white adipose tissue (WAT), thereby decreasing TG content of liver and muscle, leading to amelioration of insulin resistance at the expense of obesity. Moderate reduction of PPARgamma activity by heterozygous PPARgamma deficiency decreases TG content of WAT, skeletal muscle, and liver due to increased leptin expression and increase in fatty acid combustion and decrease in lipogenesis, thereby ameliorating high fat diet-induced obesity and insulin resistance. Moreover, although heterozygous PPARgamma deficiency and TZD have opposite effects on total WAT mass, heterozygous PPARgamma deficiency decreases lipogenesis in WAT, whereas TZD stimulate adipocyte differentiation and apoptosis, thereby both preventing adipocyte hypertrophy, which is associated with alleviation of insulin resistance presumably due to decreases in free fatty acids, and tumor necrosis factor alpha, and up-regulation of adiponectin, at least in part. We conclude that, although by different mechanisms, both heterozygous PPARgamma deficiency and PPARgamma agonist improve insulin resistance, which is associated with decreased TG content of muscle/liver and prevention of adipocyte hypertrophy.

Adipocytes↗
PubMed2001

Increased expression of the sterol regulatory element-binding protein-1 gene in insulin receptor substrate-2(-/-) mouse liver.

Insulin receptor substrate (IRS)-2(-/-) mice develop diabetes because of insulin resistance in the liver and failure to undergo beta-cell hyperplasia. Here we show by DNA chip microarray analysis that expression of the sterol regulatory element-binding protein (SREBP)-1 gene, a downstream target of insulin, was paradoxically increased in 16-week-old IRS-2(-/-) mouse liver, where insulin-mediated intracellular signaling events were substantially attenuated. The expression of SREBP-1 downstream genes, such as the spot 14, ATP citrate-lyase, and fatty acid synthase genes, was also increased. Increased liver triglyceride content in IRS-2(-/-) mice assures the physiological importance of SREBP-1 gene induction. IRS-2(-/-) mice showed leptin resistance; low dose leptin administration, enough to reduce food intake and body weight in wild-type mice, failed to do so in IRS-2(-/-) mice. Interestingly, high dose leptin administration reduced SREBP-1 expression in IRS-2(-/-) mouse liver. Thus, IRS-2 gene disruption results in leptin resistance, causing an SREBP-1 gene induction, obesity, fatty liver, and diabetes.

ATP Citrate (pro-S)-Lyase↗
PubMed2001

Observation of orbital waves as elementary excitations in a solid.

A basic concept in solid-state physics is that when some kind of symmetry in a solid is spontaneously broken, collective excitations will arise. For example, phonons are the collective excitations corresponding to lattice vibrations in a crystal, and magnons correspond to spin waves in a magnetically ordered compound. Modulations in the relative shape of the electronic clouds in an orbitally ordered state could in principle give rise to orbital waves, or 'orbitons', but this type of elementary excitation has yet to be observed experimentally. Systems in which the electrons are strongly correlated-such as high-temperature superconductors and manganites exhibiting colossal magnetoresistivity-are promising candidates for supporting orbital waves, because they contain transition-metal ions in which the orbital degree of freedom is important. Orbitally ordered states have been found in several transition-metal compounds, and orbitons have been predicted theoretically for LaMnO3. Here we report experimental evidence for orbitons in LaMnO3, using Raman scattering measurements. We perform a model calculation of orbiton resonances which provides a good fit to the experimental data.

Journal Article↗
PubMed2001

Variants of neurogenin 3 gene are not associated with Type II diabetes in Japanese subjects.

AIMS/HYPOTHESIS: Neurogenin 3 (ngn3) is a transcription factor expressed in the endocrine precursor cells of the pancreas. It has recently been reported that ngn3-deficient mice show absence of pancreatic endocrine cells and die of postnatal diabetes. The purpose of this investigation was to screen for polymorphisms of the ngn3 gene and to test whether these polymorphisms are associated with Type II (non-insulin-dependent) diabetes mellitus in the Japanese subjects. METHODS: We screened ngn3 gene and upstream region by direct sequencing and estimated the prevalence of polymorphisms in 197 patients with Type II (non-insulin-dependent) diabetes mellitus and 216 control subjects. RESULTS: We identified four novel polymorphisms, Ser199Phe (596C/T), -43insCA, -983C/T and -1822G/A. In an association study the allelic frequencies of the major allele of these four polymorphisms were 0.721, 0.914, 0.912 and 0.530 in diabetic patients, respectively, and 0.694, 0.905, 0.917 and 0.537 in control subjects, respectively. CONCLUSION/INTERPRETATION: Mutations and polymorphisms of ngn3 gene are not significantly associated with Type II (non-insulin-dependent) diabetes mellitus in the Japanese subjects.

Aged↗
PubMed2001

The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.

Adiponectin is an adipocyte-derived hormone. Recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where the gene encoding adiponectin is located. Here we show that decreased expression of adiponectin correlates with insulin resistance in mouse models of altered insulin sensitivity. Adiponectin decreases insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. This effect results from increased expression of molecules involved in both fatty-acid combustion and energy dissipation in muscle. Moreover, insulin resistance in lipoatrophic mice was completely reversed by the combination of physiological doses of adiponectin and leptin, but only partially by either adiponectin or leptin alone. We conclude that decreased adiponectin is implicated in the development of insulin resistance in mouse models of both obesity and lipoatrophy. These data also indicate that the replenishment of adiponectin might provide a novel treatment modality for insulin resistance and type 2 diabetes.

Adiponectin↗
PubMed2001

Essential role of insulin receptor substrate 1 (IRS-1) and IRS-2 in adipocyte differentiation.

To investigate the role of insulin receptor substrate 1 (IRS-1) and IRS-2, the two ubiquitously expressed IRS proteins, in adipocyte differentiation, we established embryonic fibroblast cells with four different genotypes, i.e., wild-type, IRS-1 deficient (IRS-1(-/-)), IRS-2 deficient (IRS-2(-/-)), and IRS-1 IRS-2 double deficient (IRS-1(-/-) IRS-2(-/-)), from mouse embryos of the corresponding genotypes. The abilities of IRS-1(-/-) cells and IRS-2(-/-) cells to differentiate into adipocytes are approximately 60 and 15%, respectively, lower than that of wild-type cells, at day 8 after induction and, surprisingly, IRS-1(-/-) IRS-2(-/-) cells have no ability to differentiate into adipocytes. The expression of CCAAT/enhancer binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) is severely decreased in IRS-1(-/-) IRS-2(-/-) cells at both the mRNA and the protein level, and the mRNAs of lipoprotein lipase and adipocyte fatty acid binding protein are severely decreased in IRS-1(-/-) IRS-2(-/-) cells. Phosphatidylinositol 3-kinase (PI 3-kinase) activity that increases during adipocyte differentiation is almost completely abolished in IRS-1(-/-) IRS-2(-/-) cells. Treatment of wild-type cells with a PI 3-kinase inhibitor, LY294002, markedly decreases the expression of C/EBPalpha and PPARgamma, a result which is associated with a complete block of adipocyte differentiation. Moreover, histologic analysis of IRS-1(-/-) IRS-2(-/-) double-knockout mice 8 h after birth reveals severe reduction in white adipose tissue mass. Our results suggest that IRS-1 and IRS-2 play a crucial role in the upregulation of the C/EBPalpha and PPARgamma expression and adipocyte differentiation.

Adipocytes↗
PubMed2001

Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes.

PPARgamma is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARgamma by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPARgamma activity observed in heterozygous PPARgamma-deficient mice or the Pro12Ala polymorphism in human PPARgamma, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPARgamma/RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPARgamma antagonist decrease triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver. These inhibitors potentiated leptin's effects and increased fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, treatment of heterozygous PPARgamma-deficient mice with an RXR antagonist or a PPARgamma antagonist depletes white adipose tissue and markedly decreases leptin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggested that appropriate functional antagonism of PPARgamma/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.

3T3 Cells↗
PubMed2001

Japanese family with glucocorticoid-remediable aldosteronism diagnosed by long-polymerase chain reaction.

We report a Japanese family with glucocorticoid-remediable aldosteronism (GRA) in whom gene abnormality was identified by the long-polymerase chain reaction (PCR) method. The proband was a 21-year-old female incidentally found to have high blood pressure (173/107 mmHg). Laboratory tests showed hypokalemia (3.7 mmol/l), and high plasma aldosterone concentration (PAC, 234 pg/ml) with suppressed plasma renin activity (PRA, <0.1 ng/ml/h). The circadian rhythm pattern and the results of a rapid adrenocorticotrophic hormone (ACTH) test indicated ACTH-dependent changes in PAC. Imaging studies showed no adrenal mass on either side. A dexamethasone (Dexa) suppression test (1.0 mg/day orally for 7 days) showed a marked decrease of PAC 2 days after administration, and this decreased level was maintained throughout Dexa administration. High blood pressure and hypokalemia also improved during Dexa treatment. The proband's younger sister was 19 years old and had hypertension, PAC of 231 pg/ml, and PRA <0.1 ng/ml/h. The mother was 53 years old and had hypertension, PAC of 98.5 pg/ml, and PRA <0.1 ng/ml/h. The proband's elder sister was a 22-year-old normotensive with PAC of 110 pg/ml and PRA of 0.1 ng/ml. Long-PCR was performed for detection of the chimeric gene associated with GRA, using DNA samples from all four cases and two normal control subjects. Although the aldosterone synthase gene was expressed among all DNA samples, the chimeric gene was detected only in the proband, her younger sister and her mother. Our clinical data and genetic investigation confirmed the presence of GRA in this Japanese family.

Adult↗
PubMed2001

Serum total cholesterol of new students enrolled at Okayama University: trend during 1989-1998.

To clarify the trend of hypercholesterolemia in Japanese adolescents, we investigated the serial changes in body mass index (BMI) and serum total cholesterol (TC) concentrations among 5,700 new students enrolled at Okayama University in 1989, 1993, and 1998. After confirming the stability of the TC assay of serum samples stored at -80 degrees C, we measured serum TC levels in stored serum samples using an automated assay system. Although serum TC levels were higher in females than in males, these levels correlated weakly and positively with BMI (r = 0.21, P < 0. 001) in males but not in females. Serum TC concentrations progressively increased from 1989-1998 in both sexes, irrespective of changes in BMI. In subjects with normal BMI (> or = 19 and < 23 kg/m2), a significant increase in serum TC was noted from 1989-1998 in both males (157.2 +/- 1.0 to 163.6 +/- 0.9 mg/dl) and females (172.0 +/- 1.1 to 175.6 +/- 1.0 mg/dl). Our results indicate on increased incidence of hypercholesterolemia even in nonobese young Japanese adolescents. A concerted effort by health and education officials together with parents is necessary to prevent a further rise in the incidence of hypercholesterolemia among young Japanese.

Adolescent↗
PubMed2001

Subcellular localization of insulin receptor substrate family proteins associated with phosphatidylinositol 3-kinase activity and alterations in lipolysis in primary mouse adipocytes from IRS-1 null mice.

To clarify the roles of insulin receptor substrate (IRS) family proteins in phosphatidylinositol (PI) 3-kinase activation and insulin actions in adipocytes, we investigated the intracellular localization of IRS family proteins and PI 3-kinase activation in response to insulin by fractionation of mouse adipocytes from wild-type and IRS-1 null mice. In adipocytes from wild-type mice, tyrosine-phosphorylated IRS-1 and IRS-2, which were found to associate with PI 3-kinase in response to insulin, were detected in the plasma membrane (PM) and low-density microsome (LDM) fractions. By contrast, tyrosine-phosphorylated IRS-3 (pp60), which was found to associate with PI 3-kinase, was predominantly localized in the PM fraction. In adipocytes from IRS-1-null mice, insulin-stimulated PI 3-kinase activity in anti-phosphotyrosine (alphaPY) immunoprecipitates in the LDM fraction was almost exclusively mediated via IRS-2 and was reduced to 25%; however, insulin-stimulated PI 3-kinase activity in the PM fraction was primarily mediated via IRS-3 and was reduced to 60%. To determine the potential functional impact of the distinct subcellular localization of IRSs and associating PI 3-kinase activity on adipocyte-specific metabolic actions, we examined lipolysis in IRS-1 null mice. The level of isoproterenol-induced lipolysis was increased 5.1-fold in adipocytes from IRS-1 null mice as compared with wild-type mice. Moreover, hormone-sensitive lipase (HSL) protein was increased 4.3-fold in adipocytes from IRS-1-null mice compared with wild-type mice, and HSL mRNA expression was also increased. The antilipolytic effect of insulin in IRS-1 null adipocytes, however, was comparable to that in wild-type mice. Thus, discordance between these two insulin actions as well as the transcriptional and translational effect (HSL mRNA and protein regulation) and the PM effect (antilipolysis) of insulin may be explained by distinct roles of both PI 3-kinase activity associated with IRS-1/IRS-2 and PI 3-kinase activity associated with IRS-3 in insulin actions related to their subcellular localization.

Adipocytes↗
PubMed2000

Constitutive tyrosine phosphorylation of ErbB-2 via Jak2 by autocrine secretion of prolactin in human breast cancer.

Overexpression of the oncogene for ErbB-2 is an unfavorable prognostic marker in human breast cancer. Its oncogenic potential appears to depend on the state of tyrosine phosphorylation. However, the mechanisms by which ErbB-2 is constitutively tyrosine-phosphorylated in human breast cancer are poorly understood. We now show that human breast carcinoma samples with ErbB-2 overexpression have higher proliferative and metastatic activity in the presence of autocrine secretion of prolactin (PRL). By using a neutralizing antibody or dominant negative (DN) strategies or specific inhibitors, we also show that activation of Janus kinase Jak2 by autocrine secretion of PRL is one of the significant components of constitutive tyrosine phosphorylation of ErbB-2, its association with Grb2 and activation of mitogen-activated protein (MAP) kinase in human breast cancer cell lines that overexpress ErbB-2. Furthermore, the neutralizing anti-PRL antibody or erbB-2 antisense oligonucleotide or DN Jak2 or Jak2 inhibitor or DNRas or MAP kinase kinase inhibitor inhibits the proliferation of both untreated and PRL-treated cells. Our results indicate that autocrine secretion of PRL stimulates tyrosine phosphorylation of ErbB-2 by Jak2, provides docking sites for Grb2 and stimulates Ras-MAP kinase cascade, thereby causing unrestricted cellular proliferation. The identification of this novel cross-talk between ErbB-2 and the autocrine growth stimulatory loop for PRL may provide new targets for therapeutic and preventive intervention of human breast cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Horizontal transmission of hepatitis B virus among players of an American football team.

Eleven cases of hepatitis B virus (HBV) infection (5 cases of acute hepatitis B and 6 of subclinical infection) were detected among 65 members of our university's American football team during a period of 19 months. All tested positive for antibody to the hepatitis B surface antigen (HB(s)Ag) or core antigen (HB(c)Ag). The incidence of HBV infection among team members (20.4%) was significantly higher (P<.001) than among students who tested positive for antibody to HB(s)Ag throughout the university (1.8%). We also detected a single carrier of hepatitis B e antigen (HB(e)Ag) on the team. Analysis of HB(s)Ag subtypes in 3 of 5 players with acute hepatitis B indicated that their subtype (adr) was identical to that of the HB(e)Ag carrier. All players with acute hepatitis B belonged to the same training group, which also included the HB(e)Ag carrier. Our analysis suggests that horizontal transmission of HBV can occur even in a sports team, probably due to contact with open wounds during training.

Acute Disease↗