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Y Sakiyama

Publications and source records attributed to Y Sakiyama.

At least 37 records · Page 2Linked to original sources
PubMed2000

A PET study of adenosine A1 receptor in anesthetized monkey brain.

We demonstrated the distribution of adenosine A1 receptors in the anesthetized monkey brain with positron emission tomography (PET) using [(11)C]KF15372 ([1-propyl-(11)C]8-dicyclopropylmethyl-1, 3-dipropylxanthine). [(11)C]KF15372 was injected intravenously. The regional standardized uptake values and the distribution volume were calculated. We also investigated the effect of carrier on the uptake and regional brain distribution of [(11)C]KF15372. The use of [(11)C]KF15372 with dynamic PET scanning could be an appropriate method to analyze the regional binding potential of adenosine A1 receptors in living brain.

Anesthesia↗
PubMed2000

Genetic studies of three Japanese patients with p22-phox-deficient chronic granulomatous disease: detection of a possible common mutant CYBA allele in Japan and a genotype-phenotype correlation in these patients.

Chronic granulomatous disease (CGD) is a disorder caused by defects in the NADPH oxidase responsible for superoxide generation in phagocytes. Cytochrome b558, an essential component of this enzyme, is a heterodimer formed by a 91 kDa glycoprotein (gp91-phox) and a 22 kDa polypeptide (p22-phox). Mutations in the p22-phox gene (CYBA) locus in 16q24 result in one of the rare autosomal recessive forms of CGD. We performed mutation analysis in three female CGD patients suspected of having this form of the disease and found two novel mutations in CYBA. Whereas patient 1 with severe phenotype had a homozygous nonsense mutation in exon 1 (C-35 --> T, Gln-3 --> stop), patients 2 and 3 with mild phenotype shared the same homozygous missense mutation in exon 2 (G-98 --> A, Gly-24 --> Arg). None of the parents of patients 2 and 3 is related. Therefore, this mutation could be a hot-spot or a common mutation in the Japanese population. Patients 2 and 3, but not patient 1, were demonstrated to have detectable p22-phox expression and significant granulocyte respiratory burst (ROB) activity. In this study, we were able to demonstrate an excellent correlation between genotype, p22-phox expression, ROB activity and clinical phenotype in these patients.

Adult↗
PubMed2000

Cerebral vasculitis in chronic mucocutaneous candidiasis: autopsy case report.

An autopsy case of chronic mucocutaneous candidiasis (CMCC) is reported here, in which cerebral vasculitis developed in the final stage. A 32-year-old man who had suffered from superficial candidial infection since his childhood was diagnosed as having CMCC. During the past 7 years the patient had developed various associated disorders including insulin-dependent diabetes mellitus (IDDM), common variable immunodeficiency (CVID), candidial esophagitis, multiple digestive tract ulcers and pyothorax. In 1998, at the age of 32, he developed convulsions that were accompanied by impairment of consciousness, and which were temporarily treated with steroid pulsed-medication. Epileptic status associated with widespread cerebral infarctions occurred subsequently, however, and the patient died of sepsis 2 months later. At autopsy, multiple cerebral infarctions and arterial thrombosis were evident. These were histologically proven to be primary vasculitis which was confined solely to the brain, and this was verified by general pathological examination. Thus, some as yet unknown cerebrovascular factors might be involved in the onset of an autoimmune-related vasculitis in patients with a longstanding immunodeficiency state such as CMCC.

Adult↗
PubMed2000

Adenosine deaminase deficiency as the first target disorder in gene therapy.

In the past decade, the advent of gene therapy has been acclaimed as a revolutionary medical intervention, embraced with great enthusiasm. However, recent disappointing results of the considerable clinical trials have also clearly demonstrated that such an initial expectation was an overestimation of gene therapy. There are only a few successful cases despite the 3000 patients who have been treated with various forms of gene therapy. Gene therapy for severe combined immunodeficiency (SCID) caused by adenosine deaminase (ADA) deficiency is one of the few such cases where results have been promising. In particular, peripheral T-lymphocytes-directed gene therapy provides further immunological improvements for patients with ADA-SCID receiving the PEG-ADA treatment whereas gene therapy targeting haematopoietic stem cell has so far proved insufficient for clinical benefits. This report will review crucial problems elucidated in the past five clinical trials for ADA-SCID and gives an outline of the next generation of stem cell gene therapy in Japan.

Adenosine Deaminase↗
PubMed2000

[Genetic analysis of two patients with adenosine deaminase (ADA)-deficiency: detection of three novel mutations and characterization of two paradoxical carriers].

Genetic basis of two patients (AT, MT) with ADA deficiency was studied. We identified three novel mutations (119 Q-->Stop, 235 R-->Q, one base deletion in Exon 4) from the patients. 119 Q-->Stop was detected in AT and her father. Deletion of one base in Exon 4 which would change the reading frame after codon 105 H, was detected in MT, her father and brother. There was no relation between the two families, however, 235 R-->Q was also detected in both the patients and their mothers. Extremely low ADA activity of PBMCs was revealed in healthy MT's mother and brother just as MT, although their dAXP levels of RBCs showed significantly lower than that of MT. We defined that they shared an additional mutation (310 M-->T) together with the mutation described above, respectively. EBV-transformed B-cell line (EBV-B) were established from the carriers. To our surprise, ADA activity of their lines was 1/10-1/5 of normal. The result of heat treatment studies using the EBV-B showed that the mutant ADA rapidly lose its enzyme activity without degradation of the protein. It suggests that 310 M-->T mutant ADA rapidly lost its enzyme activity due to conformational change of the catalytic site of ADA.

Adenosine Deaminase↗
PubMed1999

In vivo kinetics of transduced cells in peripheral T cell-directed gene therapy: role of CD8+ cells in improved immunological function in an adenosine deaminase (ADA)-SCID patient.

We previously reported successful peripheral T cell-directed gene therapy in a boy with adenosine deaminase (ADA)-SCID. In the present study, to better understand the reconstitutive effect of this gene therapy on his immunological system, we investigated the in vivo kinetics and functional subsets of T cells in PBL. Apparent immunological improvements were obtained after infusion of transduced cells at more than 4 x 108 cells/kg/therapy/3 mo. Frequency of ADAcDNA-integrated cells in PBL, ADA activity in PBL and clinical improvement showed good correlation, even though CD8+ cells gradually became predominant in PBL. On the basis that polyethylene glycol (PEG)-ADA was maintained at the same dosage as before gene therapy, we consider that his immunological improvement resulted from the gene therapy itself. Most CD3+ cells in PBL after gene therapy expressed TCRalphabeta. Analysis of TCR repertoire based on TCR V region usage revealed no expansion of limited clones in his PBL. The T cell subset cells CD8+CDw60+ and CD8+CD27+CD45RA-, which are reported to provide substantial help to B cells, were maintained throughout the gene therapy. Furthermore, his reconstituted peripheral T cells helped normal B cells to produce substantial IgG in vitro. Expression of both Th1- and Th2-type cytokine genes was induced in his reconstituted T cells at the same comparably high level as in normal subjects. Collectively, these results provide evidence of persistent and distinct functions of transduced cells in this patient's PBL after gene therapy.

Adenosine Deaminase↗
PubMed1999

Identification of an autoimmune enteropathy-related 75-kilodalton antigen.

BACKGROUND & AIMS: We have previously reported a 75-kilodalton autoantigen specific to X-linked autoimmune enteropathy (AIE) associated with tubulonephropathy. The aim of this study was to identify the autoantigen. METHODS: Complementary DNA (cDNA) clones were isolated by immunoscreening a human duodenal cDNA-expression library with serum from a patient with AIE. RESULTS: cDNA encoding the 75-kilodalton antigen (AIE-75) was identified. The composite nucleotide sequence of the cDNA for AIE-75 was 2214 base pairs long and encoded 552 amino acids. The genomic sequence of AIE-75 was found in Sequence DataBank, which consisted of 21 exons and was located on the chromosome 11p14.3. Recombinant AIE-75 specifically reacted with sera from 3 of 4 unrelated patients with AIE but not with 58 control sera. AIE-75 was predominantly distributed in the epithelial cells of the luminal surface and the upper half of the crypts of the intestine and in the proximal renal tubulus. Similarity searches revealed that the AIE-75 cDNA sequence was an authentic form of several colon cancer-related cDNAs of unknown function. The deduced amino acid sequence contained 3 conserved PSD-95/Dlg/ZO-1 (PDZ) domains. CONCLUSIONS: AIE-75 is a PDZ domain-containing protein expressed in the differentiated epithelial cells of the intestine and kidney and may be involved in protein-protein interaction. The identification of the autoantigen may prove useful in the approach to the pathogenesis of this poorly understood disease.

Amino Acid Sequence↗
PubMed1999

Production of IL-4 and expression of CD40 ligand by human CD8 T cells.

BACKGROUND: The role of CD8(+) T cells in IgE synthesis remains unclear. OBJECTIVE: The aim of this study was to investigate IL-4 production and CD40 ligand expression by human CD8(+) T cells. METHODS: We conducted functional and phenotypic analyses of human T cells in peritoneal washings from severe combined immunodeficiency mice reconstituted with PBMCs from normal and atopic human donors. We also examined the expression of IL-4 and CD40 ligand by CD8(+) T cells from a patient with adenosine deaminase deficiency who received autologous T cell-directed gene therapy. RESULTS: Transfer of atopic cells into the mice caused production of IgE and IgG with increased expression of IL-4 and CD40 ligand mRNA. In addition, both intracellular IL-4 and cell surface CD40 ligand were detected in CD8(+) and in CD4(+) T cells. CD8(+) T-cell lines generated from the patient's T cells carrying the adenosine deaminase gene expressed not only IL-4 mRNA and protein but also CD40 ligand mRNA and protein after being stimulated with an anti-CD3 mAb. After anti-CD3 stimulation and paraformaldehyde fixation, CD8(+) T cells induced IgE synthesis by normal human B cells in the presence of recombinant IL-4. CONCLUSION: Taken together, these results demonstrate that IL-4-producing and CD40 ligand-expressing CD8(+) cells are detectable among human T cells and suggest that such cells may promote IgE production by B cells under some conditions.

Adenosine Deaminase↗
PubMed1999

Detection of lymphocytes and granulocytes expressing the mutant WASP message in carriers of Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disease caused by mutations in the recently identified WAS protein gene (WASP). In some X-linked genetic disorders skewed X-inactivation has been observed in all cell populations or some specific cell lineages of female carriers. Recently, female carriers of WAS were also revealed to present skewed X-inactivation patterns at the haemopoietic stem cell level. However, it is not clear if all haematological cells expressing the mutant WASP allele are eliminated in WAS carriers. By reverse transcription PCR methods, we studied 14 WAS carriers from 10 different families to assess whether blood cells expressing the mutant WASP message were present in their peripheral blood. The mutations of each WAS patient were known and carrier diagnosis of their female family members was performed using specific mutation analysis. We detected circulating lymphocytes and granulocytes expressing the mutant WASP message in most of the WAS carriers, nevertheless they showed skewed X-chromosomal inactivation patterns. Interestingly, the presence of blood cells expressing the mutant WASP message seemed to correlate to the WASP genotype and the age of the carriers.

Adult↗
PubMed1999

Gene therapy for severe combined immunodeficiency caused by adenosine deaminase deficiency: improved retroviral vectors for clinical trials.

Severe combined immunodeficiency (SCID) caused by adenosine deaminase deficiency (ADA-) is the first genetic disorder to be treated with gene therapy. Since 1990 when the first trial started for 2 patients with ADA- SCID, five clinical trials enrolling 11 patients have been conducted with different clinical approaches and the results obtained from these trials have recently been reported. According to these reports, T cell-directed gene transfer was useful in the treatment of ADA- SCID whereas the retroviral-mediated gene transfer to hematopoietic stem cells was insufficient for achievement of clinical benefits. This chapter reviews several crucial problems inherent in the current retroviral technology based on the clinical data observed in these pioneering ADA gene therapy trials and presents our new retroviral vector system for the next stem cell gene therapy.

Adenosine Deaminase↗