PubMed Health⌕ Search

Biomedical subjects

Taizo Wada

Publications and source records attributed to Taizo Wada.

17 recordsLinked to original sources
PubMed2005

Analysis of T-cell repertoire diversity in Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia, eczema, and variable degrees of impaired cellular and humoral immunity. Age-dependent T-cell lymphopenia has been described in WAS, however, the diversity of the T-cell compartment over time in these patients has not been characterized. We have used complementarity-determining region 3 (CDR3) size distribution analysis to assess T-cell receptor (TCR) Vbeta repertoire in 13 patients with WAS. Diverse CDR3 size pattern was demonstrated in patients under 15 years of age regardless of the levels of WAS protein (WASP) expression. In contrast, older patients showed significantly higher skewing of TCRVbeta repertoire as compared with healthy adults. We did not find correlation between clinical score and complexity of TCRVbeta repertoire. These findings suggest that WASP deficiency does not limit thymic generation of a normal TCR and indicate that T-cell oligoclonality may contribute to the immunodeficiency in older patients with WAS.

Adolescent↗
PubMed2005

Depression, activities of daily living, and quality of life of community-dwelling elderly in three Asian countries: Indonesia, Vietnam, and Japan.

The purpose of this study was to examine the prevalence of screening-based depression and the association of depression with activities of daily living (ADL) and quality of life (QOL) of community-dwelling elderly in the developing and developed countries. A total of 2,695 community-dwelling elderly subjects aged 60 years or older living in five rural Asian towns (Indonesia: 411, Vietnam: 379, Japan: 1,905) participated in this cross-sectional study. Depressive symptoms were assessed using a 15-item geriatric depression scale (GDS-15). ADL, higher daily activities, and medical and social history were assessed by interviews or self-report questionnaires. For the assessment of subjective QOL, a 100mm visual analogue scale was used. Using a cut-point of 5/6 for the GDS-15, 782 participants (29.0%) appeared to have depression (Indonesia: 33.8%, Vietnam: 17.2%, Japan: 30.3%). Subjects with depression had significantly lower scores for both ADL and QOL than those without depression in all the three countries. In all the three countries, 17.2-33.8% of community-dwelling elderly subjects had screening-based depression, which was commonly associated with both lower quantitative ADL and lower QOL.

Activities of Daily Living↗
PubMed2005

Oligoclonal expansion of T lymphocytes with multiple second-site mutations leads to Omenn syndrome in a patient with RAG1-deficient severe combined immunodeficiency.

Omenn syndrome (OS) is a rare primary immunodeficiency characterized by the presence of activated/oligoclonal T cells, eosinophilia, and the absence of circulating B cells. OS patients carry leaky mutations of recombination activating genes (RAG1 or RAG2) resulting in partial V(D)J recombination activity, whereas null mutations cause severe combined immunodeficiency with absence of mature T and B cells (T-B- SCID). Here we describe somatic mosaicism due to multiple second-site mutations in a patient with RAG1 deficiency. We found that he is homozygous for a single base deletion in the RAG1 gene, which results in frameshift and likely abrogates the protein function. However, the patient showed typical OS features. Molecular analysis revealed that several second-site mutations, all of which restored the RAG1 reading frame and resulted in missense mutations, were demonstrated in his T cells. These findings suggest that his revertant T-cell mosaicism is responsible for OS phenotype switched from T-B- SCID.

Cell Proliferation↗
PubMed2004

Paradoxical enhancement of oxidative cell injury by overexpression of heme oxygenase-1 in an anchorage-dependent cell ECV304.

There has been increasing evidence suggesting the potent anti-inflammatory roles of heme oxygenase-1 (HO-1) in protecting renal tubular epithelial cells, vascular endothelial cells, and circulating monocytes. Based on these findings, novel therapeutic interventions have been proposed to control the expression of endothelial HO-1 levels to ameliorate various vascular diseases. We evaluated the effect of HO-1 gene transfer into an anchorage-dependent cell, ECV304. Effect of HO-1 production on the cell injury induced by hydrogen peroxide was evaluated after hemin stimulation and after HO-1 gene transfection. Morphological changes and the induction of various anti-apoptotic proteins were examined at the same time. Levels of HO-1 expression were variable in different clones of HO-1-transfected ECV304 cells. Among these, the clones with moderate levels of HO-1 expression were significantly more resistant to oxidative stress. In contrast, those with the highest levels of HO-1 exhibited paradoxically enhanced susceptibility to oxidative injury. Interestingly, the cell survival after oxidative stress was in parallel with the levels of Bcl-2 expression and of fibronectin receptor, alpha5 integrin. It is suggested from these results, that excessive HO-1 not only leads to enhanced cell injury, but also prolongs the repair process of the injured endothelial tissue. However, HO-1 reduces the oxidative cell injury and protects the endothelial cells, if its expression is appropriately controlled.

Actins↗
PubMed2004

Multiple patients with revertant mosaicism in a single Wiskott-Aldrich syndrome family.

We previously reported on a 43-year-old patient with Wiskott-Aldrich syndrome (WAS) who experienced progressive clinical improvement and revertant T-cell mosaicism. Deletion of the disease-causing 6-bp insertion was hypothesized to have occurred by DNA polymerase slippage. We now describe 2 additional patients from the same family who also had revertant T lymphocytes that showed selective in vivo advantage. Somatic mosaicism was demonstrated on leukocytes cryopreserved in the first patient when he was 22 years old, 11 years before his death from kidney failure. The second patient is now 16 years old, has a moderate clinical phenotype, and developed revertant cells after the age of 14 years. These results support DNA polymerase slippage as a common underlying mechanism, and they indicate that T-cell mosaicism may have different clinical effects in WAS.

Adolescent↗
PubMed2003

Differential contribution of Wiskott-Aldrich syndrome protein to selective advantage in T- and B-cell lineages.

Somatic mosaicism because of in vivo reversion has been recently reported in a small number of patients affected with Wiskott-Aldrich syndrome (WAS). Flow cytometry analysis of WAS protein (WASP) expression has shown that these patients carried revertant cells only among T lymphocytes. Here, we have used high-resolution capillary electrophoresis to analyze genomic DNA from highly purified cells of one of these patients and detected revertant sequences also within the B-cell fraction. The demonstration of revertant cells among both T and B lymphocytes in this patient is consistent with the reversion event having occurred in a common lymphoid progenitor. However, although WASP-expressing T cells showed selective advantage and were readily detectable in the periphery of the mosaic patient, revertant B lymphocytes remained below the detection threshold of flow cytometry. These findings suggest that, contrary to T cells, differentiation and survival of B lymphocytes is minimally dependent on WASP.

B-Lymphocytes↗
PubMed2003

Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings.

Revertant mosaicism due to true back mutations or second-site mutations has been identified in several inherited disorders. The occurrence of revertants is considered rare, and the underlying genetic mechanisms remain mostly unknown. Here we describe somatic mosaicism in two brothers affected with Wiskott-Aldrich syndrome (WAS). The original mutation causing disease in this family is a single base insertion (1305insG) in the WAS protein (WASP) gene, which results in frameshift and abrogates protein expression. Both patients, however, showed expression of WASP in a fraction of their T cells that were demonstrated to carry a second-site mutation causing the deletion of 19 nucleotides from nucleotide 1299 to 1316. This deletion abrogated the effects of the original mutation and restored the WASP reading frame. In vitro expression studies indicated that mutant protein encoded by the second-site mutation was expressed and functional, since it was able to bind to cellular partners and mediate T cell receptor/CD3 downregulation. These observations were consistent with evidence of in vivo selective advantage of WASP-expressing lymphocytes. Molecular analysis revealed that the sequence surrounding the deletion contained two 4-bp direct repeats and that a hairpin structure could be formed by five GC pairs within the deleted fragment. These findings strongly suggest that slipped mispairing was the cause of this second-site mutation and that selective accumulation of WASP-expressing T lymphocytes led to revertant mosaicism in these patients.

Adolescent↗
PubMed2002

Retrovirus-mediated WASP gene transfer corrects Wiskott-Aldrich syndrome T-cell dysfunction.

The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by thrombocytopenia, eczema, and immunodeficiency. At present, the only definitive therapy for the disease is allogeneic bone marrow transplantation (BMT). Because of the frequent lack of suitable donors and the potential severe complications associated with BMT, the development of gene-based therapeutic strategies for WAS is highly desirable. To study whether corrective gene transfer into WAS T cells can lead to restoration of the immunologic defects of WAS, a retroviral vector expressing the WAS protein (WASP) gene was used to transduce human T-lymphotropic virus type 1-transformed T-cell lines and primary T lymphocytes from patients with WAS. After transduction, WAS T cells showed levels of WASP expression similar to those found in cells from normal individuals. In addition, the reconstituted WASP interacted in vitro with proteins containing SH3 domain such as Grb2, PLC-gamma1, and Fyn, each of which are connected to signaling pathways linked to the actin cytoskeleton. Furthermore, after CD3 cross-linking, transduced WAS T lines showed improvement of actin polymerization and T-cell receptor/CD3 down-regulation. More importantly, primary WAS T lymphocytes transduced with WASP acquired the ability to proliferate in response to anti-CD3 stimulation. These findings suggest that biologic defects of WAS T cells can be corrected in vitro by retrovirus-mediated gene transfer and pose the basis for future investigation of gene therapy as treatment for WAS.

Actins↗
PubMed2002

[Heart rate variability analysis and neurobehavioral function in community-dwelling older people aged 75 or older].

BACKGROUND: Although heart rate variability (HRV) has been found to be associated with increased mortality in the elderly, the association of HRV and cognitive function and activity of daily living (ADL) capacity in the very elderly are not clear. METHODS: A sample of very elderly people (N = 138), aged 75 years and older, living in Urausu, Hokkaido, participated in this study. Participants were classified into three groups: normal, borderline, and dementia. Time and frequency domain measures of HRV were compared with behavioral and cognitive functions. RESULTS: HRV components, except for the LF/HF ratio, did not correlate with age in the very elderly. The LF component showed a statistically significant correlation with all the variables of behavioral functions. Most HRV components showed statistically significant and positive correlations with the flexibility of the back. The LF and LF/HF ratio were significantly lower in the dementia group than in the normal group. CONCLUSION: Although the meaning of the LF component is still controversial, we foundadefinite relationship between the LF component and behavioral functions. A positive relationship between most HRV components and the flexibility of the back may suggest that reduced flexibility leads to deteriorated cardiopulmonary function and reduced HRV. A further prospective study is needed to examine whether HRV and neurobehavioral functions are independent predictors of morbidity and mortality in very elderly people.

Activities of Daily Living↗
PubMedDate not supplied

Depression in Japanese community-dwelling elderly--prevalence and association with ADL and QOL.

This cross-sectional study examined the prevalence of screening-based depression and compared the scores of activities of daily living (ADL) and quality of life (QOL) between community-dwelling elderly subjects with and without depression in Japan. Elderly subjects aged 65 or older living in four rural towns participated in 2000 or 2001 (n = 5363, female 58.3%, mean (S.D.) age 74.6 (7.0) years). Depressive symptoms were assessed using a 15-item Geriatric Depression Scale (GDS-15) and ADL, higher functions, and medical and social histories were assessed by self-report questionnaires. For assessing subjective QOL, a 100 mm visual analogue scale was used. One thousand seven hundred ninety-eight participants (33.5%, range, 32.3-34.6%) had suggestive depression using cutoff 5/6 of GDS-15. Subjects with depression revealed significantly lower scores for ADL and QOL than those without depression. Prevalence of screening-based depression was similar in the four different rural Japanese towns. However, the reported prevalence of depression varies enormously in different country. Primary physicians and caregivers should pay more attention to depression in the community-dwelling elderly population, especially below the threshold of major depression as minor depression or dysthymia.

Activities of Daily Living↗