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Kentaro Yamada

Publications and source records attributed to Kentaro Yamada.

18 recordsLinked to original sources
PubMed2007

Functional single-nucleotide polymorphisms in the secretogranin III (SCG3) gene that form secretory granules with appetite-related neuropeptides are associated with obesity.

CONTEXT: Genetic factors are important for the development of obesity. However, the genetic background of obesity still remains unclear. OBJECTIVE: Our objective was to search for obesity-related genes using a large number of gene-based single-nucleotide polymorphisms (SNPs). DESIGN AND SETTING: We conducted case-control association analyses using 94 obese patients and 658 controls with 62,663 SNPs selected from the SNP database. SNPs that possessed P < or = 0.02 were further analyzed using 796 obese and 711 control subjects. One SNP (rs3764220) in the secretogranin III (SCG3) gene showed the lowest P value (P = 0.0000019). We sequenced an approximately 300-kb genomic region around rs3764220 and discovered SNPs for haplotype analyses. SCG3 was the only gene within a haplotype block that contained rs3764220. The functions of SCG3 were studied. PATIENTS: Obese subjects (body mass index > or = 30 kg/m(2), n = 890) and control subjects (general population; n = 658, body mass index < or = 25 kg/m(2); n = 711) were recruited for this study. RESULTS: Twelve SNPs in the SCG3 gene including rs3764220 were in almost complete linkage disequilibrium and significantly associated with an obesity phenotype. Two SNPs (rs16964465, rs16964476) affected the transcriptional activity of SCG3, and subjects with the minor allele seemed to be resistant to obesity (odds ratio, 9.23; 95% confidence interval, 2.77-30.80; chi(2) = 19.2; P = 0.0000067). SCG3 mRNA and immunoreactivity were detected in the paraventricular nucleus, lateral hypothalamic area, and arcuate nucleus, and the protein coexisted with orexin, melanin-concentrating hormone, neuropeptide Y, and proopiomelanocortin. SCG3 formed a granule-like structure together with these neuropeptides. CONCLUSIONS: Genetic variations in the SCG3 gene may influence the risk of obesity through possible regulation of hypothalamic neuropeptide secretion.

Adult↗
PubMed2006

Autoimmune hypophysitis treated with intravenous glucocorticoid therapy.

A 46-year-old man presented with frontal headache, a visual field defect and general fatigue. Magnetic resonance imaging (MRI) of the brain showed symmetrical enlargement of the pituitary gland and stalk due to the presence of a mass lesion extending toward the optic chiasm. Gadolinium injection further revealed homogeneous strong enhancement with involvement of the adjacent dura (dural tail). Basal plasma levels of ACTH, free thyroxine and gonadotropins were decreased, and 24-h urinary 17-OHCS excretion was reduced. An elevated anti-thyroglobulin antibody titer indicated the presence of autoimmune thyroiditis. Under the suspicion of autoimmune hypophysitis, 60 mg/day prednisolone sodium succinate was intravenously administered for two weeks followed by a decreasing dose of oral prednisolone. Clinical symptoms and pituitary dysfunction recovered during steroid treatment and MRI showed marked shrinkage of the pituitary mass. Early initiation of an intravenous dose of glucocorticoid followed by oral steroid administration therefore seems to be an efficient treatment for autoimmune hypophysitis even in patients with visual dysfunction.

Autoimmune Diseases↗
PubMed2006

Recurrent limbic and extralimbic encephalitis associated with thymoma.

A 33-year-old woman, with a 7-year clinical history of invasive thymoma treated at ages 26 and 30 years by thymectomy and radiation, presented with a generalized convulsion and loss of consciousness. Following the seizure there was no neurological deficit and normal tendon reflexes. Magnetic resonance imaging (MRI) of the brain without gadolinium enhancement revealed multiple small lesions of high signal intensity on T2 and diffusion weighted images located in the cortical area beyond the temporal lobes. Brain biopsy demonstrated encephalitis with activated microglias and activated T-cell infiltration. Within 4 months of treatment with nothing other than anticonvulsant therapy, the lesions visible on the original MRI had completely disappeared and the patient was discharged with no neurological symptoms. The patient subsequently had two more episodes with a variety of symptoms such as incontinence, confusion, aphasia, apallial syndrome, and motor paresis. MRI following these episodes again revealed multiple lesions of similar appearance to those of the first episode, although in different locations, and much larger and more numerous. The patient had steroid pulse therapy after both episodes and the lesions noted on brain MRI disappeared within a few months with minimal neurological complications.

Administration, Oral↗
PubMed2006

Involvement of nucleoprotein, phosphoprotein, and matrix protein genes of rabies virus in virulence for adult mice.

Rabies virus Ni-CE strain causes nonlethal infection in adult mice after intracerebral inoculation, whereas the parental Nishigahara strain kills mice. In this study, to identify viral gene(s) related to the difference in pathogenicity between Ni-CE and Nishigahara strains, we generated chimeric viruses with respective genes of the virulent Nishigahara strain in the background of the avirulent Ni-CE genome. Since chimeric viruses, which had the N, P, or M genes of the Nishigahara strain, respectively, killed adult mice after intracerebral inoculation, it became evident that the N, P, and M genes are related to the difference in pathogenicity between Ni-CE and Nishigahara strains. Previously, we showed that the G gene is a major contributor to the difference in pathogenicity between another avirulent strain, RC-HL, and the parental Nishigahara strain. These results imply that the attenuation mechanism of the Ni-CE strain is different from that of the RC-HL strain, thus suggesting that rabies virus can be attenuated by diverse mechanisms. This is the first report of changes in viral genes other than the G gene of rabies virus causing the reversion of pathogenicity of an avirulent strain.

Animals↗
PubMed2006

Interleukin-12B gene polymorphism does not confer susceptibility to Graves' ophthalmopathy in Japanese population.

Graves' disease (GD) is an autoimmune disorder with genetic predisposition and frequently associated with Graves' ophthalmopathy (GO). Interleukin 12 (IL-12) is an important mediator of inflammatory immune responses and is expressed in the thyroid and orbit. IL-12B gene, which encodes the p40 subunit of IL-12, is located at chromosome 5q31-33. The aim of the present study was to investigate whether IL-12B gene polymorphism is associated with the development of GD or GO. IL-12B gene polymorphism was studied in Japanese GD patients (n = 329) and healthy control subjects without anti-thyroid autoantibodies or a family history of autoimmune disorders (n = 226). The A/C polymorphism at position 1188 of the 3' untranslated region (3'UTR) of the IL-12B gene was analyzed using the polymerase chain reaction--restriction fragment length polymorphism method. There was no difference in allele or genotype frequency of the IL-12B gene polymorphism (1188A/C) between GD patients and control subjects. There was no association of the IL-12B gene polymorphism with ophthalmopathy, severity of hyperthyroidism or serum IgE levels. There was no association of the IL-12B gene polymorphism with serum IL-12 levels, which were significantly elevated in hyperthyroid phase of GD. In conclusion, IL-12B gene 1188A/C polymorphism is not associated with GD or GO susceptibility in Japanese.

Adolescent↗
PubMed2006

Sequential activation of caspases and synergistic beta-cell cytotoxicity by palmitate and anti-Fas antibodies.

To assess the mechanism of beta-cell lipotoxicity in comparison with Fas-mediated cell death, we used a mouse beta-cell clone stably transfected with human Fas. Palmitate induced beta-cell death in correlation with medium glucose levels between 5 and 20 mmol/l, while Fas-mediated cytotoxicity was observed irrespective of glucose concentration. At the glucose level of 10 mmol/l, palmitate induced caspase-6 activity within 3 h, and caspase-3 activity after a lag period of 6 h. The activities of caspases were correlated with glucose concentration. A caspase-6 inhibitor attenuated caspase-3 activation and cell death induced by palmitate. Oxfenicine, an inhibitor of carnitine palmitoyltransferase-1, attenuated both palmitate-induced cytotoxicity and activation of caspases. Finally, beta-cell cytotoxicity caused by the combination of anti-Fas and palmitate at 25 mmol/l of glucose was greater than the sum of those induced by each. These observations suggest that palmitate induces sequential activation of caspase-6 and caspase-3 through a mitochondrial signal(s), and caspase-6 plays a primary role in the mechanism. Fas-mediated beta-cell death and lipotoxicity may share common mechanisms involving caspase activation, and thereby synergistically inducing beta-cell death, although upstream signaling pathways are distinct.

Animals↗
PubMed2006

Multigenic relation to the attenuation of rabies virus.

Rabies virus Nishigahara strain causes lethal infection in adult mice after intracerebral inoculation. On the other hand, the RC-HL strain, derived from the Nishigahara strain, does not cause lethal infection in adult mice. We previously demonstrated that a chimeric virus, R(G), with the open reading frame of the G gene (G-ORF) from the Nishigahara strain in the background of the RC-HL genome, is virulent. Reversely, in order to demonstrate that the G gene of the RC-HL strain is related to the attenuated phenotype, we established a reverse genetics system of the Nishigahara strain and generated a chimeric virus, Ni(G), with the G-ORF from RC-HL in the background of the Nishigahara genome. Contrary to our prediction, Ni(G) killed adult mice after intracerebral inoculation with neuropathic symptoms like those of Nishigahara strain infection. Therefore, the G-ORF of the RC-HL strain is not the sole determinant of the attenuated phenotype. In additional investigation, we examined other genes, including N, P, M and L genes, and generated chimeric viruses exhaustively. We found that chimeric viruses with a single gene from the RC-HL were not attenuated and that chimeric viruses with the G-ORF and at least one other ORF from the RC-HL were attenuated. In conclusion, attenuation from the Nishigahara to RC-HL strain is multigenic.

Animals↗
PubMed2006

Characterization of recombinant rabies virus carrying double glycoprotein genes.

A recombinant rabies virus carrying double glycoprotein (G) genes, R(NPMGGL) strain, was generated by a reverse genetics system utilizing cloned cDNA of the RC-HL strain, and the biological properties of the virus were compared to those of the recombinant RC-HL (rRC-HL) strain. The extents of virus growth in cultured cells and virulence for adult mice of the R(NPMGGL) strain were almost same as those of the rRC-HL strain, while G protein content of the purified R(NPMGGL) virion and G protein expression level in R(NPMGGL)-infected cells were 1.5-fold higher than those of the rRC-HL strain. As a result of serial passages of the R(NPMGGL) strain in cultured cells, the expression level of G protein in cultured cells infected with the passaged R(NPMGGL) strain was maintained and virus titers rose with adaptation to the cultured cells. Furthermore, analysis of neutralization titers in mice immunized with UVinactivated virus suggested that the R(NPMGGL) strain had higher immunogenicity than that of the rRC-HL strain. The results suggest that the R(NPMGGL) strain carrying double G genes might be a useful candidate for development of a new inactivated rabies vaccine.

Animals↗
PubMed2005

Multiple amino acids in the glycoprotein of rabies virus are responsible for pathogenicity in adult mice.

We have reported that the region between amino acids 164 and 303 in the glycoprotein of rabies Nishigahara strain is important for lethality in adult mice. The region contains nine amino acid substitutions between the virulent Nishigahara and the avirulent RC-HL strains. In order to determine key residues for the pathogenicity, two chimeric strains and seven mutants were generated and examined for pathogenicities. The R(G 242/255/268) strain, in which amino acids at positions 242, 255, and 268 were replaced by those from the Nishigahara strain in the genomic backbone of the RC-HL strain, showed the same lethality as that of the Nishigahara strain in mice. Mutants in which one or two of these three amino acids were replaced by those from the Nishigahara strain did not revert to the lethality of the R(G 242/255/268) strain. These results demonstrate that at least these three amino acids are related to enhancement of pathogenicity. It is thought that multiple amino acids of the G protein are related to the pathogenicity of rabies viruses.

Amino Acid Substitution↗
PubMed2005

Characterization of M gene-deficient rabies virus with advantages of effective immunization and safety as a vaccine strain.

Matrix (M) protein of rabies virus is known to play an important role in assembly and budding of the progeny virus. We generated an M gene-deficient rabies virus, RC-HLDeltaM, using a reverse genetics system of rabies virus RC-HL strain to develop a novel type of vaccine. RC-HLDeltaM infection was confined within a single cell in mouse neuroblastoma cells. This deficient virus failed to generate the progeny virus in the cells. In contrast, RC-HLDeltaM propagated in BHK cells inductively expressing M protein. Suckling and adult mice inoculated intracerebrally with the parental RC-HL strain showed lethal infection and transient body weight loss, respectively, whereas both suckling and adult mice inoculated with RC-HLDeltaM showed no symptoms. The neutralizing antibody against rabies virus was successfully induced by intramuscular immunization with 10(5) focus-forming units of RC-HLDeltaM but not UV-inactivated RC-HL. Intranasal immunization with RC-HLDeltaM resulted in almost the same antibody titer to rabies virus as that in the case of immunization with live RC-HL strain. These findings indicate that RC-HLDeltaM is a candidate for a novel rabies vaccine that is safer and more effective than are current vaccines.

Administration, Intranasal↗
PubMed2005

A C/T polymorphism in the 5' untranslated region of the CD40 gene is associated with later onset of Graves' disease in Japanese.

Graves' disease (GD) is an autoimmune disorder with genetic predisposition. CD40, which stimulates lymphocyte proliferation and differentiation, is an important immunomodulator and is expressed in the thyroid follicular cells as well as antigen-presenting cells. A single nucleotide polymorphism (SNP) at position -1 of the Kozak sequence of the CD40 gene has been reported to be associated with the development of GD. The aim of the present study was to investigate whether CD40 gene polymorphism confers susceptibility to GD in Japanese. CD40 gene polymorphisms were studied in Japanese GD patients (n = 324) and healthy control subjects without anti-thyroid autoantibodies or a family history of autoimmune disorders (n = 229). A C/T polymorphism at position -1 of the CD40 gene was measured using the polymerase chain reaction restriction fragment length polymorphism. There was no significant difference in allele or genotype frequency of the CD40 SNP between GD and control subjects. There was a significant decrease in the TT genotype frequency in the GD patients, who developed GD after 40 years old, than those under 40 year of age. These data suggest that the SNP of CD40 gene is associated with susceptibility to later onset of GD in Japanese.

5' Untranslated Regions↗
PubMed2005

"A girdle-like tightening sensation" misapprehended as abdominal splanchnopathy in a sarcoidosis patient.

We describe a 53-year-old man with the isolated manifestation of girdle-like tightening sensation of the trunk due to polyradiculopathy at the beginning of sarcoidosis which was first misapprehended as abdominal splanchnopathy. Late development of other neurological and systemic symptoms led to the final diagnosis of sarcoidosis. Segmental dysesthesia at the trunk in neurosarcoidosis is unique and may mimic a splanchnic pain. Such a dysesthesia may be solely manifested at the beginning of sarcoidosis and may continue for days without other symptoms. When patients complain of a girdle-like tightening with unknown etiology, sarcoidosis should be suspected as the possible cause.

Abdomen↗
PubMed2004

Region at amino acids 164 to 303 of the rabies virus glycoprotein plays an important role in pathogenicity for adult mice.

The authors have previously reported that the glycoprotein of the pathogenic Nishigahara strain of rabies virus is required to lethality for adult mice. A cluster region of amino acid substitutions exists at the positions 164 to 303 on the glycoprotein between avirulent and virulent strains. In this study, the authors generated a chimeric strain having the region at the positions 164 to 303 of the glycoprotein derived from the pathogenic Nishigahara strain in the genetic background of the avirulent RC-HL strain. The chimeric R(G 164-303) strain restores the lethality for adult mice. This result clearly shows that the region at the position 164 to 303 of glycoprotein plays an important role in the lethality for adult mice. Moreover, the authors observed that the lethality for adult mice correlated well with the viral growth in a brain but not with the pH-dependent fusion activity in vitro.

Age Factors↗
PubMed2004

A polymorphism of interferon-gamma gene associated with changes of anti-thyrotropin receptor antibodies induced by antithyroid drug treatment for Graves' disease in Japanese patients.

Graves' disease (GD) is an autoimmune disorder with genetic predisposition. Interferon-gamma (IFN-gamma) is an important mediator of inflammatory and immune responses. The aim of the present study was to investigate whether the polymorphism of IFN-gamma gene is associated with the development of GD or with clinical course during the antithyroid drug therapy. We have studied the CA repeat polymorphisms in the first intron of IFN gamma gene in Japanese patients with GD (n = 162) and healthy control subjects without antithyroid autoantibodies or family history of autoimmune disorders (n = 133). There was no difference in allele frequency of IFN-gamma gene polymorphism between patients with GD and control subjects. However, the allele 4 (15 CA repeats) frequency was significantly greater in patients whose antithyrotropin receptor antibody (TRAb) became negative within 3 years by antithyroid drug treatment than those with consistently positive TRAb for more than 3 years (34.1% vs. 15.7%, chi2 = 8.545, p = 0.0035, pc = 0.049). The in vitro production of IFN-gamma by concanavalin A-stimulated peripheral blood mononuclear cells was significantly smaller in control subjects with the allele 4 compared to those with the other alleles. In conclusions, the CA repeat polymorphism of the IFN-gamma gene might be associated with the outcome of anti-thyroid drug treatment.

Adenine↗
PubMed2003

Improved recovery of rabies virus from cloned cDNA using a vaccinia virus-free reverse genetics system.

To improve efficiency of recovery of rabies virus from cloned cDNA, we established a BHK cell clone that stably expresses T7 RNA polymerase, which we named BHK/T7-9. We also constructed new helper plasmids for expression of nucleoprotein and RNA polymerase of the RC-HL strain using the pTM1 plasmid vector, which makes the T7 RNA polymerase-transcripts from the plasmid cap-independent for translation. After co-transfection of these helper plasmids and the previously constructed full-length genome plasmid of the RC-HL strain to BHK/T7-9 cells, recombinant rabies virus was efficiently recovered from the cloned cDNA.

Cell Line↗
PubMed2003

[Pharmacological treatment of postprandial hyperglycemia in hypertensive patients with type 2 diabetes mellitus].

Several epidemiological studies have shown an association between postprandial hyperglycemia and mortality from cardiovascular disease. Postprandial hyperglycemia is frequently associated with visceral obesity which plays a key role in metabolic abnormalities such as dyslipidemia and hypertension. Inhibitors of alpha-glucosidase and nateglinide have beneficial effects on the metabolic syndrome associated with visceral obesity. Voglibose in combination with diet therapy reduces visceral fat deposition and ameliorates insulin resistance. Acarbose slightly reduces blood pressure of hypertensive diabetic patients. Nateglinide, a rapidly acting insulin secretagogue, lowers postprandial glucose levels without significant body weight gain. These drugs may protect pancreatic beta-cells from postprandial glucose toxicity and prevent the progression of diabetes.

Acarbose↗