Biomedical subjects

Toshiyuki Kobayashi

Publications and source records attributed to Toshiyuki Kobayashi.

At least 19 recordsLinked to original sources

PubMed2006

Experimental demonstration of the time reversal Aharonov-Casher effect.

We demonstrate the time reversal Aharonov-Casher (AC) effect in small arrays of mesoscopic semiconductor rings. By using an electrostatic gate we can control the spin precession rate and follow the AC phase over several interference periods. We show that we control the precession rate in two different gate voltage ranges; in the lower range the gate voltage dependence is strong and linear and in the higher range the dependence in almost an order of magnitude weaker. We also see the second harmonic of the AC interference, oscillating with half the period. We finally map the AC phase to the spin-orbit interaction parameter alpha and find it is consistent with Shubnikov-de Haas analysis.

Journal Article↗

PubMed2006

Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway.

Both TSC2 (tuberin) and forkhead transcription factor FoxO1 are phosphorylated and inhibited by Akt and play important roles in insulin signaling. However, little is known about the relationship between TSC2 and FoxO1. Here we identified TSC2 as a FoxO1-binding protein by using a yeast two-hybrid screening with a murine islet cDNA library. Among FoxOs, only FoxO1 can be associated with TSC2. The physical association between the C terminus of TSC2 (amino acids 1280-1499) and FoxO1 degrades the TSC1-TSC2 complex and inhibits GTPase-activating protein activity of TSC2 toward Rheb. Overexpression of wild type FoxO1 enhances p70 S6K phosphorylation, whereas overexpression of TSC2 can reverse these effects. Knockdown of endogenous FOXO1 in human vascular endothelial cells decreased phosphorylation of p70 S6K. Prolonged overexpression of wild type FoxO1 enhanced phosphorylation of serine 307 of IRS1 and decreased phosphorylation of Akt and FoxO1 itself even in the presence of serum. These data suggest a novel mechanism by which FoxO1 regulates the insulin signaling pathway through negative regulation of TSC2 function.

Animals↗

PubMed2006

A novel tumor marker, Niban, is expressed in subsets of thyroid tumors and Hashimoto's thyroiditis.

Niban is a recently identified molecular marker of renal carcinogenesis in the Tsc2 gene-mutant Eker rat. Niban expression is most dramatically increased in the early stage of renal carcinogenesis and might decline during malignant progression. Niban is also expressed in various histologic types of human renal cell carcinoma. Therefore, Niban might be a good marker for renal carcinogenesis in both animal models and humans. In the present study, we examined Niban expression in various thyroid lesions by immunohistochemical staining using polyclonal rabbit antihuman Niban antibody. Normal thyroid tissue never stained for Niban. Niban was most frequently expressed in tumors with oxyphilic cytoplasm, including oxyphilic variants of papillary carcinoma (4/4 = 100%), oxyphilic variants of follicular adenoma (7/7 = 100%), and oxyphilic variants of follicular carcinoma (5/5 = 100%). Eighty-one percent (44/54) of papillary carcinoma cases, including microcarcinomas, and follicular variants were also positively stained for Niban at variable intensities. Follicular carcinomas were less frequently and less intensely stained. In nonneoplastic lesions, cells were rarely positively stained. In Hashimoto's thyroiditis, scattered cells with oxyphilic cell metaplasia were weakly Niban-positive. Reverse transcriptase-polymerase chain reaction and Western blot analysis of frozen tissue confirmed Niban expression at the molecular level in 4 cases of papillary carcinoma. Taken together, Niban expression is up-regulated in various types of thyroid tumors. We postulate that Niban expression may play an important role in the tumorigenic process of the thyroid in several scenarios. (1) Niban expression may be closely related to the carcinogenic process, especially from the early stage of papillary thyroid carcinoma. (2) Niban may be closely associated with altered mitochondrial functions in preneoplastic and neoplastic processes of the thyroid. (3) Niban may be a molecular marker of the oxyphilic phenotype under various conditions. Further functional studies of Niban will clarify the role of Niban in various thyroid lesions.

Biomarkers, Tumor↗

PubMed2006

Genetic and environmental factors in hereditary predisposition to tumors: a conceptual overview.

Cancer is a heritable disorder of somatic cells. Carcinogenesis at the cellular level is like an opened Japanese fan, because initiated cells grow in several directions and tumors suggest the edge of the fan by having many gene abnormalities. We discuss here the primal force and gene networks (federal headship) in renal carcinogenesis. The Eker (Tsc2 mutant) rat model of hereditary renal carcinoma (RC) is an example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. Recently, we discovered a new hereditary renal carcinoma in the rat in Japan, and the rat was named the "Nihon" rat. We suggest that its predisposing (Bhd) gene is a novel renal tumor suppressor gene. We present these unique models as part of the study of problems in carcinogenesis; e.g., multistep carcinogenesis, cancer prevention and the development of the therapeutic treatments that can be translated to human patients, as well as how environmental factors interact with cancer susceptibility gene(s).

Animals↗

PubMed2006

Neuromuscular abundance of RB1CC1 contributes to the non-proliferating enlarged cell phenotype through both RB1 maintenance and TSC1 degradation.

RB1-inducible coiled-coil 1 (RB1CC1) is a novel tumor suppressor implicated in the regulation of RB1 expression. It is abundant in post-mitotic neuromuscular cells, which are matured and enlarged, but scarce in smaller leukocytes, indicating an association between RB1CC1 status and cell size. To clarify whether RB1CC1 is involved in cell size control, we investigated the contribution of RB1CC1 to the TSC-mTOR pathway, which plays an important role in the control through translational regulation. RNAi-mediated knockdown of RB1CC1 reduced the activation of mTOR and S6K as well as the size of HEK293 and C2C12 cells. Such knockdown also suppressed RB1 expression and the population of G1-phase cells. Exogenous expression of RB1CC1 maintained S6K activity and cell size, and decreased TSC1/hamartin contents under nutritionally starved conditions, which usually inhibit the mTOR-S6K pathway. Furthermore, RB1CC1 interfered with and degraded TSC1 through the ubiquitin-proteasomal pathway. A lentiviral RNAi for RB1CC1 reduced the size of mouse leg muscles. These findings suggest that RB1CC1 is required to maintain both RB1 expression and mTOR activity. The activity of mTOR was supported by RB1CC1 through TSC1 degradation. RB1CC1 preserved cell size without cell cycle progression especially in neuromuscular tissues, and the abundance contributed to the non-proliferating enlarged cell phenotype.

Animals↗

PubMed2006

[Is the incidence of schizophrenia declining?: an investigation of the examination rates in the psychiatric clinics of a medical school hospital and a general hospital].

PURPOSE: Some researchers in Europe, America and Oceania have recently reported that the incidence of schizophrenia is declining. We investigated changes in the proportion of schizophrenic patients to the total number of patients in two Japanese hospitals during the last decade. SUBJECTS AND METHODS: The subjects were patients who first consulted the psychiatric clinic of Jichi Medical School or the psychiatric clinic of Kamitsuga General Hospital between December 1993 and November 1994 or between December 2003 and November 2004. Both clinics accepted new patients without prior appointments. Patients were classified using ICD-10 criteria (F0-F9, G40). The sex distribution of the patients and the mean age at first contact were compared for the two time periods. The proportion of schizophrenia (F2 in the ICD-10 criteria) to the total number of patients was compared for the two time periods after standardizing the populations with regard to age using the "1985 model population in Japan." RESULTS: A decade ago, 398 patients first contacted the psychiatric clinic of the medical school hospital, compared with 958 patients in the recent investigation. A decade ago, 166 patients first contacted the psychiatric clinic of the general hospital, compared with 407 patients in the recent investigation. No differences in the sex ratios of the two groups were noted. The mean age of the patients visiting the medical school significantly increased by 3.5 years (36.9 to 40.4 years), while that of the patients visiting the general hospital significantly increased by 10.0 years (46.2 to 56.2 years). The proportion of schizophrenia patients in the medical hospital decreased from 8.5% to 6.9%, while that in the general hospital decreased from 11.0% to 5.4%. Only the change in the proportion of schizophrenia patients at the general hospital was significant. CONCLUSION AND DISCUSSION: The facts that the mean age of first-contact patients has risen and that the number of first-contact patients has increased approximately 2.5-fold suggests a change in the composition of first-contact patients in the last decade. We have some reservations regarding the comparison of these two groups. Although the actual number of first-contact patients with schizophrenia increased in both clinics, we found that the proportions of schizophrenia patients decreased in both clinics after standardizing the populations with regard to age. This finding must be investigated in view of other factors, including the overall age distribution of first-contact patients, increases in the proportions of affective disorders and organic mental disorders, and so on.

Age Distribution↗

PubMed2005

Coil occlusion for patent ductus arteriosus larger than 3 mm.

BACKGROUND: Coil occlusion of patent ductus arteriosus (PDA) is now widely accepted as the first-line treatment, but there are few reports of age-dependent differences in the complications associated with this technique. METHODS AND RESULTS: Sixteen patients (11 adults, 5 children) with a PDA larger than 3 mm, who underwent coil occlusion at Sapporo Medical University Hospital between September 1995 and August 2004, were enrolled. Immediate and intermediate outcomes and complications were analyzed. Procedural success rate was 72.7% (8/11) in the children and 100% (5/5) in the adults. Coil migration occurred in 4 children and 1 adult, and 3 adult patients had hemolysis. CONCLUSION: Hemolysis was more frequent in adults than in children even though the residual shunt was trivial.

Aged↗

PubMed2005

[Remarkably low blood pressure induced by combination of SSRI and a small dose of TCA].

Recently, selective serotonin reuptake inhibitors (SSRI) have been frequently used as the first choice of antidepressants because of their safety in comparison with tricyclic antidepressive agents (TCA). On the other hand, when SSRIs are not effective, they are frequently replaced with another antidepressant. In that case, a small dose of a TCA is often added without cross tapering. We report two elderly patients with depression who exhibited markedly low blood pressure when a small dose of a TCA was added to a SSRI. The combination of a SSRI and a TCA can be hazardous because it can cause unexpected adverse effects especially in elderly patients.

Aged↗

PubMed2004

Prepro-orexin mRNA expression in the rat brain is increased during pregnancy.

The purpose of this study was to investigate whether orexin expression in the rat brain was changed during pregnancy. Brain samples were obtained from 5 nonpregnant rats and 10 pregnant rats (5; day 10 of gestation, and 5; day 20 of gestation). Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed to investigate the expression of prepro-orexin mRNA and the housekeeping gene in the rat brain. The signals were quantified by the densitometric analysis. The distribution and expression of orexin-A and orexin-B were determined using immunohistochemistry. The ratio of the prepro-orexin mRNA expressions to the housekeeping gene expression in pregnant rat brain were significantly higher than that in nonpregnant control. There was no significant difference between prepro-orexin mRNA levels of day 10 and day 20 of gestation. Immunohistochemical staining for orexin-A and orexin-B was present in neurons within and around the lateral and posterior hypothalamic areas in both nonpregnant and pregnant rats. These results suggest that increased prepro-orexin mRNA levels at early gestational age in the maternal rat has a role on energy metabolism during pregnancy.

Actins↗

PubMed2004

Niban gene is commonly expressed in the renal tumors: a new candidate marker for renal carcinogenesis.

Functional inactivation of tuberous sclerosis 2 gene (Tsc2) leads to renal carcinogenesis in the hereditary renal carcinoma Eker rat models. Recent studies revealed a role of tuberin, a TSC2 product, in suppressing the p70 S6 kinase (p70S6K) activity via inhibition of mammalian target of rapamycin (mTOR). Phosphorylated S6 protein, a substrate of p70S6K, was expressed in the early lesions in Eker rats, and this expression was suppressed by the treatment of rapamycin, an inhibitor of mTOR. We previously isolated the novel gene Niban expressed in renal carcinogenesis of Eker rats. In this study, we demonstrated that the expression of Niban was detected from early preneoplastic lesions in Eker rats. Interestingly, in contrast to the phosphorylated S6 protein, the expression of Niban was unchanged and early lesions still remained even after treatment with rapamycin. These results might suggest the existence of another pathway independent of mTOR-S6K pathway in Tsc2 mutant renal carcinogenesis. In addition, Niban was also expressed in other renal carcinoma models, including Tsc1 and Tsc2 knockout mice, and various types of human renal cell carcinomas. Thus, Niban was commonly expressed in renal carcinomas and might be a new marker for renal carcinogenesis.

Amino Acid Sequence↗

PubMed2004

A germ-line insertion in the Birt-Hogg-Dubé (BHD) gene gives rise to the Nihon rat model of inherited renal cancer.

A rat model of hereditary renal carcinoma (RC) was found in a rat colony of the Sprague-Dawley strain in Japan and named the "Nihon" rat. In heterozygotes, RCs, predominantly the clear cell type, develop from early preneoplastic lesions, which began to appear as early as 3 weeks of age, to adenocarcinomas by the age of 6 months. The Nihon rat is an example of a Mendelian dominantly inherited predisposition for development of RCs like the Eker (Tsc2 gene mutant) rat. We have previously shown that the Nihon mutation was tightly linked to genes that are located on the distal part of rat chromosome 10. The order of the genes is the Eker (Tsc2 gene (human 16p13.3)-Il3 gene-Nihon gene-Llgl1 locus- Myhse gene. We now describe a germ-line mutation in the Birt-Hogg-Dubé gene (Bhd) (human 17p11.2) caused by the insertion of a single nucleotide in the Nihon rat, resulting in a frameshift and producing a stop codon 26 aa downstream. We found that the homozygous mutant condition was lethal at an early stage of fetal life in the rat. We detected a high frequency of loss of heterozygosity (LOH) in primary RCs (10/11) at the Bhd locus and found a point mutation (nonsense) in one LOH-negative case, fitting Knudson's "two-hit" model. The Nihon rat may therefore provide insights into a tumor-suppressor gene that is related to renal carcinogenesis and an animal model of human BHD syndrome.

Animals↗

PubMed2004

Near-fatal cerebral edema associated with adenovirus type 2 infection in a previously healthy infant.

We report a near-fatal case of cerebral edema associated with adenovirus type 2 infection in a previously healthy 19-month-old boy. After 3 to 4 d of high fever and a series of seizures, he developed persistent loss of consciousness and irreversible respiratory arrest. Adenovirus type 2 infection was diagnosed by virus isolation from his stool and serology.

Adenovirus Infections, Human↗

PubMed2004

A clinical study on serum prostaglandin E2 with low-level laser therapy.

METHODS: The subjects of this investigation consisted of 83 female patients that were treated in this department during the 2-year period from January 1999 to December 2002. Laser irradiation was applied for 3 min either every day or every other day for a total of 10 times. A diode semi-conductor laser with a wavelength of 830 nm and a photointensity of 1 W was used. Evaluations were performed before and after the series of 10 exposures to laser irradiation. The evaluation included the measurement of pain using the visual analog scale (VAS) and serum prostaglandin E(2) (pg/mL) measured by RIA-PEG. RESULTS: The analgesic effects were observed in 67 of 83 cases, or 80.7%. The VAS scores for the effective cases decreased after the irradiation series from 8.5 +/- 0.2, to 2.8 +/- 0.2 ( p < 0.001). The post-irradiation PGE(2) levels were lower than the pre-irradiation PGE(2) levels in the effective cases, which were 5.8 +/- 0.3 and 7.1 +/- 0.4 pg/mL, respectively ( p < 0.05). The postirradiation PGE(2) levels for the effective cases were lower than those for the ineffective cases, which were 5.8 +/- 0.3 and 7.3 +/- 0.9 pg/mL, respectively ( p < 0.05). CONCLUSIONS: Based on the above findings, the analgesic effects of LLLT were found to be valid. The serum PGE(2) levels are therefore considered to directly reflect nociceptive pain.

Adult↗

PubMed2004

Psychopathology and outcome of first-admission schizophrenic patients: hypochondriac-cenestopathic symptoms as predictors of an unfavorable outcome.

The outcome of first-admission schizophrenic patients at Jichi Medical School Hospital was investigated to identify outcome predictors of schizophrenia among the symptoms at the time of the first hospitalization. The subjects were 62 schizophrenic patients, 29 females and 33 males, consecutively discharged from the Department of Psychiatry, Jichi Medical School Hospital, between June 1983 and May 1988. The mean interval between first admission and follow-up was 13 years. Eguma's Social Adjustment Scale was used to measure social outcome. The subjects were divided into two groups according to their rating on Eguma's Scale; a favorable outcome group and an unfavorable outcome group. Information on premorbid status and psychopathology at the time of the first hospitalization was obtained from clinical records and analyzed by comparing them between the two groups. Of the 62 patients, 56 were followed-up. Nine of the 56 patients followed-up had died. While 47 patients were alive; 39 were receiving psychiatric treatment and eight were not. The 47 patients who were still living were divided into two groups; a favorable outcome group (n = 22), and an unfavorable outcome group (n = 25). No significant differences in premorbid status were found. Comparison of psychopathology at the time of the first hospitalization between the outcome groups revealed significant differences in lack of spontaneity and hypochondriac-cenestopathic symptoms. Lack of spontaneity may reflect negative symptomatology, while hypochondriac-cenestopathic symptoms may reflect a serious disturbance of ego function. There is a strong possibility that evaluation of body-related symptoms in schizophrenia will be helpful in predicting outcome.

Activities of Daily Living↗

PubMed2004

Natural history of the Nihon rat model of BHD.

Hereditary cancer was first described in the rat by Eker and Mossige in 1954 in Oslo. The Eker rat model of hereditary renal carcinoma (RC) was the first example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal, and has been contributing to the elucidation of renal carcinogenesis. Recently, we found a second hereditary RC model in the Sprague-Dawley (SD) rat, in Japan in 2000, which was named the Nihon rat. The Nihon rat is also an example of a Mendelian dominantly inherited predisposition for development of RCs like the Eker rat, which are predominantly of the clear cell type (this type represents approximately 75 % of human RCC), and develop from earlier preneoplastic lesions than the Eker rat. We performed a genetic linkage analysis of the Nihon rat using 113 backcross animals, and found that the Nihon mutation was tightly linked to genes, which are located on the distal part of rat chromosome 10. Finally, we identified a germline mutation in the Birt-Hogg-Dubé gene (Bhd) (rat chromosome 10, human chromosome 17p11.2) caused by the insertion of a single nucleotide in the Nihon rat gene sequence, resulting in a frame shift and producing a stop codon 26 amino acids downstream. Thus, the Nihon rat will contribute to understanding the BHD gene function and renal carcinogenesis.

Animals↗

PubMed2004

Cloning of the Cav 1.3 (alpha1D) L-type Ca2+ channel from mouse and its expression in the liver.

Dihydropyridine (DHP) type Ca2+ channel blocker (CCB) is effective in treatment of hepatitis in man. L-type Ca2+ channel is a target of DHP-CCB, and basic studies suggest that L-type Ca2+ channel alpha1D-subunit (Cav 1.3) seems to be a target of drug development for the treatment of hepatitis. Mouse hepatitis model is useful to study the effect of DHP-CCB on hepatitis. In order to use mouse hepatitis model to screen DHP-CCB specific for Cav 1.3, Cav 1.3 expressed in the mouse liver should have enough structural homology with that of human Cav 1.3. cDNA of the Cav 1.3 was cloned from mouse brain by reverse transcription polymerase chain reaction. The primary structure of the mouse Cav 1.3 comprises an open reading frame of 6540 bp encoding 2180 amino acids. Liver transcript lacked 60 and 45 bases from 1497 to 1556, and from 3949 to 3993 of the sequence, respectively, due to results of an alternative splicing. The present results indicated that mouse Cav 1.3 exhibited 96% homology with human Cav 1.3 and was expressed in the liver. Thus, mouse hepatitis model seemed to be useful to screen DHP-CCB specific for Cav 1.3.

Alternative Splicing↗

PubMed2003

Ets protein Elf-1 bidirectionally suppresses transcriptional activities of the tumor suppressor Tsc2 gene and the repair-related Nth1 gene.

Alterations in the rat tuberous sclerosis gene (Tsc2) cause renal cell carcinomas (RCCs) with complete penetrance. In this study, it was shown that the minimal core promoters of the rat Tsc2 and endonuclease III 1 (Nth1) genes, lying in a 5'-to-5' arrangement, were localized in a 0.11-kb region containing two Ets binding sites (EBSs). This region worked as a bidirectional promoter in a single reporter plasmid. Mutational inactivation of each of the two EBSs significantly reduced promoter activity. Moreover, gel shift assays revealed the presence of specific EBSs-protein complexes. These results demonstrate that some members of the Ets family positively regulate the promoter activities of the Tsc2/Nth1 genes by binding to the EBSs. We identified Elf-1 as a binding factor for EBSs through super-shift assays, and detected approximately 35 kDa bands with an EBSs-containing DNA probe by Southwestern blot analysis. Forced expression of Elf-1 in cells, however, bidirectionally suppressed the activities of the Tsc2/Nth1 promoters. Elf-1 may be a negative regulator of Tsc2/Nth1 gene expression and may compete against positive regulators for binding to the EBSs. Our observations suggest that mechanisms that inactivate Tsc2 gene expression, such as promoter suppression, may exist.

Animals↗

PubMed2003

Renal carcinogenesis: genotype, phenotype and dramatype.

Cancer is a heritable disorder of somatic cells. Environment and heredity are both important in the carcinogenic process. The Eker rat model of hereditary renal carcinoma (RC) is an example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. Forty years after the discovery of the Eker rat in Oslo, we and Knudson's group independently identified a germline retrotransposon insertion in the rat homologue of the human tuberous sclerosis (TSC2) gene. To our knowledge, this was the first isolation of a Mendelian dominantly predisposing cancer gene in a naturally occurring animal model. Recently, we discovered a new hereditary renal carcinoma in the rat. This rat was named the "Nihon" rat and its predisposing (Nihon) gene could be a novel renal tumor suppressor gene. This article will review the utility of these unique models for the study of problems in carcinogenesis; e.g., species-specific differences in tumorigenesis, cell stage and tissue/cell-type specific tumorigenesis, multistep carcinogenesis, modifier gene(s) in renal carcinogenesis, cancer prevention and the development of therapeutic treatments which can be translated to human patients, as well as how environmental factors interact with cancer susceptibility gene(s).

Animals↗