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Yoshio Ikeda

Publications and source records attributed to Yoshio Ikeda.

15 recordsLinked to original sources
PubMed2006

Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8.

We previously reported that a (CTG)n expansion causes spinocerebellar ataxia type 8 (SCA8), a slowly progressive ataxia with reduced penetrance. We now report a transgenic mouse model in which the full-length human SCA8 mutation is transcribed using its endogenous promoter. (CTG)116 expansion, but not (CTG)11 control lines, develop a progressive neurological phenotype with in vivo imaging showing reduced cerebellar-cortical inhibition. 1C2-positive intranuclear inclusions in cerebellar Purkinje and brainstem neurons in SCA8 expansion mice and human SCA8 autopsy tissue result from translation of a polyglutamine protein, encoded on a previously unidentified antiparallel transcript (ataxin 8, ATXN8) spanning the repeat in the CAG direction. The neurological phenotype in SCA8 BAC expansion but not BAC control lines demonstrates the pathogenicity of the (CTG-CAG)n expansion. Moreover, the expression of noncoding (CUG)n expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and the discovery of intranuclear polyglutamine inclusions suggests SCA8 pathogenesis involves toxic gain-of-function mechanisms at both the protein and RNA levels.

Animals↗
PubMed2006

Genetic analysis of the cystatin C gene in familial and sporadic ALS patients.

Bunina bodies, small eosinophilic intraneuronal inclusions, stain positive for cystatin C and are the only specific pathological hallmark of amyotrophic lateral sclerosis (ALS). We screened the cystatin C gene (CST3) for mutations in 57 sporadic ALS patients and 12 familial ALS cases that did not possess a SOD1 mutation. We detected the known polymorphism in exon 1, a G/A transition at +73, in both familial and sporadic ALS patients. However, the allelic and genotypic frequencies of the +73 G/A polymorphism did not differ between ALS patients and control samples. No other mutation was detected in the ALS patients. The results reported here indicate that there may not be a direct genetic link between cystatin C and ALS, and it may be that deficits occur in proteins that interact with cystatin C.

Aged↗
PubMed2006

Spectrin mutations cause spinocerebellar ataxia type 5.

We have discovered that beta-III spectrin (SPTBN2) mutations cause spinocerebellar ataxia type 5 (SCA5) in an 11-generation American kindred descended from President Lincoln's grandparents and two additional families. Two families have separate in-frame deletions of 39 and 15 bp, and a third family has a mutation in the actin/ARP1 binding region. Beta-III spectrin is highly expressed in Purkinje cells and has been shown to stabilize the glutamate transporter EAAT4 at the surface of the plasma membrane. We found marked differences in EAAT4 and GluRdelta2 by protein blot and cell fractionation in SCA5 autopsy tissue. Cell culture studies demonstrate that wild-type but not mutant beta-III spectrin stabilizes EAAT4 at the plasma membrane. Spectrin mutations are a previously unknown cause of ataxia and neurodegenerative disease that affect membrane proteins involved in glutamate signaling.

Adolescent↗
PubMed2006

Increased incidence of transient left ventricular apical ballooning (so-called 'Takotsubo' cardiomyopathy) after the mid-Niigata Prefecture earthquake.

BACKGROUND: On October 23, 2004, a major earthquake, which registered 6.8 on the Richter scale, occurred in Niigata Prefecture in Japan. Emotional stress is important as a trigger of transient left ventricular apical ballooning (so-called 'Takotsubo' cardiomyopathy), but its incidence and clinical profile immediately after a natural disaster have not been fully elucidated. METHODS AND RESULTS: 'Takotsubo' cardiomyopathy was diagnosed in 16 patients (1 man, 15 women, mean age 71.5 years) within 1 month after the earthquake. Of them, 13 (81%) lived in areas where the Japan Meteorological Agency seismic intensity scale registered 6 or above, and 11 (69%) developed symptoms on the day of the earthquake. The incidence of 'Takotsubo' cardiomyopathy 1 month after the earthquake was approximately 24-fold higher near the epicenter than that before the earthquake. CONCLUSION: 'Takotsubo' cardiomyopathy can occur on the day of the earthquake in elderly women living near the epicenter.

Age Factors↗
PubMed2004

Spinocerebellar ataxia type 8: molecular genetic comparisons and haplotype analysis of 37 families with ataxia.

We reported elsewhere that an untranslated CTG expansion causes the dominantly inherited neurodegenerative disorder spinocerebellar ataxia type 8 (SCA8). SCA8 shows a complex inheritance pattern with extremes of incomplete penetrance, in which often only one or two affected individuals are found in a given family. SCA8 expansions have also been found in control chromosomes, indicating that separate genetic or environmental factors increase disease penetrance among SCA8-expansion-carrying patients with ataxia. We describe the molecular genetic features and disease penetrance of 37 different families with SCA8 ataxia from the United States, Canada, Japan, and Mexico. Haplotype analysis using 17 STR markers spanning an approximately 1-Mb region was performed on the families with ataxia, on a group of expansion carriers in the general population, and on psychiatric patients, to clarify the genetic basis of the reduced penetrance and to investigate whether CTG expansions among different populations share a common ancestral background. Two major ancestrally related haplotypes (A and A') were found among white families with ataxia, normal controls, and patients with major psychosis, indicating a common ancestral origin of both pathogenic and nonpathogenic SCA8 expansions among whites. Two additional and distinct haplotypes were found among a group of Japanese families with ataxia (haplotype B) and a Mexican family with ataxia (haplotype C). Our finding that SCA8 expansions on three independently arising haplotypes are found among patients with ataxia and cosegregate with ataxia when multiple family members are affected further supports the direct role of the CTG expansion in disease pathogenesis.

Case-Control Studies↗
PubMed2004

A family of hypokalemic periodic paralysis with CACNA1S gene mutation showing incomplete penetrance in women.

Familial hypokalemic periodic paralysis is an autosomal dominant genetic muscle disease characterized by periodic attacks of muscle weakness associated with a decrease in serum potassium. There are two major missense mutation sites in the calcium channel alpha1 subunit (CACNA1S) gene in these patients. We recently encountered a 13-year-old Japanese boy who had collapsed following exercise and was found to have a low serum potassium level. Clinical and genetic studies including exploration of his family tree proved that he and his maternal relatives had the disease with the missense mutation, Arg528His (CGC --> CAC). However, his mother and grandmother had no symptoms of the disease, indicating reduced penetrance in female carriers. Sexual difference in the penetrance of this disease and the association between the clinical symptoms and the types of genetic defects are discussed.

Arginine↗
PubMed2003

A case of mixed connective tissue disease showing a lymphoid follicle in muscle pathology.

We report a 74-year-old man suffering from mixed connective tissue disease (MCTD) accompanied by a lymphoid follicle in muscle pathology. He showed proximal muscle weakness and arthritis in finger joints. His laboratory findings were characteristic of MCTD. Prednisolone administration favorably improved his symptoms. A lymphoid follicle is a rare pathological finding in inflammatory myopathies. The immunohistochemical findings suggest that the lymphoid follicle would be involved in the specific role for the pathogenesis of MCTD.

Aged↗
PubMed2003

Myotonic dystrophy type 2: human founder haplotype and evolutionary conservation of the repeat tract.

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19 (DM1) or 3 (DM2). In 2001, we demonstrated that DM2 is caused by a CCTG expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene. To investigate the ancestral origins of the DM2 expansion, we compared haplotypes for 71 families with genetically confirmed DM2, using 19 short tandem repeat markers that we developed that flank the repeat tract. All of the families are white, with the majority of Northern European/German descent and a single family from Afghanistan. Several conserved haplotypes spanning >700 kb appear to converge into a single haplotype near the repeat tract. The common interval that is shared by all families with DM2 immediately flanks the repeat, extending up to 216 kb telomeric and 119 kb centromeric of the CCTG expansion. The DM2 repeat tract contains the complex repeat motif (TG)(n)(TCTG)(n)(CCTG)(n). The CCTG portion of the repeat tract is interrupted on normal alleles, but, as in other expansion disorders, these interruptions are lost on affected alleles. We examined haplotypes of 228 control chromosomes and identified a potential premutation allele with an uninterrupted (CCTG)(20) on a haplotype that was identical to the most common affected haplotype. Our data suggest that the predominant Northern European ancestry of families with DM2 resulted from a common founder and that the loss of interruptions within the CCTG portion of the repeat tract may predispose alleles to further expansion. To gain insight into possible function of the repeat tract, we looked for evolutionary conservation. The complex repeat motif and flanking sequences within intron 1 are conserved among human, chimpanzee, gorilla, mouse, and rat, suggesting a conserved biological function.

Adult↗
PubMed2003

Depletion and decreased function of antigen-presenting dendritic cells caused by lymphocytapheresis in ulcerative colitis.

PURPOSE: The therapeutic efficacy of lymphocytapheresis in autoimmune diseases is presumed to be caused by depletion of activated lymphocytes. However, nothing is known about the inducer of activated lymphocytes, the antigen-presenting dendritic cells, during lymphocytapheresis. BASIC PROCEDURES: Six sessions of lymphocytapheresis were done in five patients with ulcerative colitis. Dendritic cells were enriched from the buffy coat of depleted lymphocytes and also from the peripheral blood. The phenotype and function of dendritic cells were studied by dual-color flow cytometry and in allogenic mixed leukocyte reaction, respectively. The serum levels of inflammatory cytokines (interleukin-1alpha 6, 8, 10, and 12 and tumor necrosis factor-alpha and beta) were measured before and after lymphocytapheresis in all cases. MAIN FINDINGS: Lymphocytapheresis was safe and caused clinical, endoscopic or histologic improvements in all patients with ulcerative colitis. Many CD83-positive mature dendritic cells were found in the buffy coats after each session of lymphocytapheresis. The function of dendritic cells, the frequencies of CD83-positive dendritic cells and the levels of interleukin-6 and interleukin-8 were down regulated in all patients with ulcerative colitis after lymphocytapheresis compared with their levels before lymphocytapheresis. CONCLUSIONS: Depletion and down regulation of the function of dendritic cells and diminished levels of inflammatory cytokines caused by lymphocytapheresis may contribute to the therapeutic efficacy of lymphocytapheresis.

Adolescent↗
PubMed2002

Generation of amyloid beta protein from a presenilin-1 and betaAPP complex.

Presenilin-1 (PS1) is a causative gene in early onset familial Alzheimer's disease (FAD). FAD-linked mutant PS1s significantly increased Abeta40 and Abeta42(43) levels (P < 0.001) and decreased the production of an 11.4 kD (beta-stub) and an 8.7 kD (alpha-stub) carboxyl-terminal fragment of amyloid beta precursor protein (betaAPP-CTFs) (P < 0.01). In the 2% CHAPS extracted lysates, the complex containing the amino-terminal fragment of PS1 (PS1-NTF), the carboxyl-terminal fragments of PS1 (PS1-CTF), and betaAPP-CTFs was identified. Incubation of this isolated complex at pH 6.4 showed the direct generation of Abeta40 and gamma-stub from this complex. This reaction was inhibited by a gamma-secretase inhibitor. The degrading rate of a co-precipitated beta-stub was facilitated under the presence of FAD-linked mutant PS1s. This findings suggest that the direct generation of Abeta from the complex may play an important role in the pathogenesis of Alzheimer's disease.

Amyloid Precursor Protein Secretases↗
PubMed2002

Antigen-presenting dendritic cells in ulcerative colitis.

BACKGROUND: Antigen-presenting dendritic cells are the inducers and regulators of immune responses. Here, we have discussed the phenotype and function of dendritic cells in situ and their alteration during lymphocytapheresis in patients with ulcerative colitis. METHODS: Dendritic cells were enriched from the peripheral blood mononuclear cells by culturing with granulocyte-macrophage colony-stimulating factors and interleukin 4 for 8 days. The function of dendritic cells was evaluated in an allogenic mixed leukocyte reaction. Flow cytometry was employed to study the phenotype of dendritic cells. Lymphocytapheresis was done by a continuous flow centrifugation technique using a CS-3000 separator. Immunohistochemical methodology was employed to detect dendritic cells at the colonic mucosa. RESULTS: Peripheral blood dendritic cells had increased functional capacity, and these cells were matured and activated compared to dendritic cells from normal controls. CD83-positive activated and mature dendritic cells were found at the colonic mucosa from patients with ulcerative colitis. Lymphocytapheresis induced decreased function of peripheral blood dendritic cells in patients with ulcerative colitis. Also, the levels of inflammatory cytokines were reduced by lymphocytapheresis. CONCLUSIONS: Increased function of dendritic cells may be related to the inflammatory mucosal milieu found in patients with ulcerative colitis. Depletion of dendritic cells during lymphocytapheresis may downregulate the exacerbated immune response in patients with ulcerative colitis.

Antigen-Presenting Cells↗
PubMedDate not supplied

Combination therapy with interferon alpha and beta to chronic hepatitis C.

To increase the sustained response (SR) rate in chronic hepatitis C (CHC), we tried a combination therapy with interferon (IFN) alpha and beta. Fifty patients were grouped into 4 groups: group 1H (n=9), HCV serotype 1 and high HCV-RNA titer (over 6 log copies/ml); group 1L (n=11), HCV serotype 1 and low HCV-RNA titer (less than 6 log copies/ml); group 2H (n=23), HCV serotype 2 and high HCV-RNA titer; group 2L (n=7), HCV serotype 2 and low HCV-RNA titer. They were given a total dose of 768 MIU which included natural IFN beta (6 MIU) once daily for 28 consecutive days and then natural IFNalpha (10 MIU) three times a week for 20 weeks. Forty-nine patients with CHC receiving IFN alpha at total dose of 480 MIU served as single therapy group. In combination group, SR rate was achieved in 62%, 44% in 1H, 45% in 1L, 70% in 2H, and 86% in 2L, respectively. In single group, SR rate was achieved in 45, 14, 58, 60, and 82%, respectively. There was no significant difference for SR rate between combination group and single group. However, in patients with HCV-RNA titer between 6-7 log copies/ml of 1H group, SR rate in combination group (67%, 4/6) was significantly higher than that of single group (18%, 3/17) (p<0.05). These data suggest the usefulness of combination therapy with IFN alpha and beta in CHC with serotype 1 having moderately high HCV-RNA titer.

Adult↗