Biomedical subjects

K Tokunaga

Publications and source records attributed to K Tokunaga.

At least 73 records · Page 4Linked to original sources

PubMed2001

Case-control study with narcoleptic patients and healthy controls who, like the patients, possess both HLA-DRB11501 and -DQB10602.

In previous studies, we suggested that the tumor necrosis factor (TNF-alpha and its receptor 2 (TNFR2) genes could be associated with the susceptibility to human narcolepsy, and that haplotype carrying DRB1*1502 had a negative association with the disorder. To further evaluate these associations, we herein compared narcoleptic patients with healthy individuals who, like the patients, possessed both DRB1*1501 and DQB1*0602. Results agreed with the negative association of DRB1*1502 and positive association of the TNF-alpha(-857T) and TNFR2-196R combination with the disorder. In addition, a significant association of the TNF-alpha(-857T) homozygote with the disorder and an increase in a rare haplotype carrying DRB1*1501 and TNF-alpha(-857T) in the patients were also observed in the present study.

Alleles↗

PubMed2001

Diversity of HLA among Taiwan's indigenous tribes and the Ivatans in the Philippines.

Taiwan's indigenous tribes, especially the east coast tribes are not only closely related to Oceania but also with the Australian aborigines. The Ivatans of the Batan Islands in the Philippines are closely related to the Yami tribe of Taiwan as cultural and anthropological studies have shown. Many DRB1 alleles (*15021, *16021, *0404, *04051, *11011, *12021, *1401, *08032) have high allele frequencies (>20%) in certain tribes, suggesting Taiwan's indigenous tribes are homogeneous populations. These high frequency DRB1 alleles and also some HLA-A-B-DR haplotypes found in Taiwan's indigenous tribes are also found in Oceania, Australian aborigines, south and north east Asians and American Indians, lending further support to our previous findings that Taiwan's indigenous tribes are more or less genetically related to both northern and southern Asians, possibly as well as Amerindians. HLA-A*2402 with a remarkably high frequency among Taiwan's indigenous tribes (52.1% approximately 86.3%), especially the central mountain tribes, possibly represents not only founder effects and population bottlenecks, but also positive selection of the allele. Although the Ami tribe has the highest ever reported frequencies of the DRB1*0404 and DRB1*0405, these alleles have not been found to be associated with rheumatoid arthritis as previously described for Caucasians. In addition, DRB1*1401 has a high frequency in most tribes but is not associated with psoriasis as previously indicated in some studies, suggesting the involvement of some additional genetic and/or environmental factors mechanism in the development of these diseases.

Alleles↗

PubMed2001

Identification of novel single nucleotide substitutions in the NKp30 gene expressed in human natural killer cells.

Cytotoxicity of natural killer (NK) cells is regulated by a balance of signals from two kinds of NK receptors, activating receptors and inhibitory receptors. Natural cytotoxicity receptors (NCR) family, which consists of NKp30, NKp44 and NKp46, is a major human activating NK receptor. NKp30 has been mapped to the HLA class III region near tumor necrosis factor (TNF) family loci. We have analyzed the NKp30 gene of healthy Japanese and found two synonymous substitutions in the coding region, c.111G>A and c.156C>T, and also identified two single-nucleotide polymorphisms (SNPs) in the promotor region, -201G>A and -163G>C. Furthermore, it was confirmed that these polymorphisms of the NKp30 gene show strong linkage disequilibria with each other and with HLA-DRB1 or TNFA polymorphisms. Since susceptibilities to certain diseases were mapped near this region, the NKp30 polymorphisms could be useful genetic markers.

Alleles↗

PubMed2001

Allele-specific binding of the ubiquitous transcription factor OCT-1 to the functional single nucleotide polymorphism (SNP) sites in the tumor necrosis factor-alpha gene (TNFA) promoter.

The tumor necrosis factor-alpha (TNFA) is characterized by several single nucleotide polymorphisms (SNPs) in its promoter region. Interestingly some of these SNPs appear to influence TNFA expression and susceptibility to various human diseases, but the molecular mechanisms by which such possibly functional SNPs modulate TNFA expression are poorly understood. In this study we show allele-specific binding of the ubiquitous transcription factor OCT-1 to the SNP sites at positions -863 and -857 in the promoter, which appear to affect TNFA expression: the protein was associated with variant allele possessing either -863A or -857T, but rarely with the common allele (-863C and -857C). The evidence presented here, therefore, suggests the possibility that OCT-1 could contribute to the modulation of TNFA expression by means of its allele-specific binding manner.

Alleles↗

PubMed2001

Presence of four major haplotypes in human BCMA gene: lack of association with systemic lupus erythematosus and rheumatoid arthritis.

BCMA (TNFRSF17), along with TACI, has recently been demonstrated to be a receptor for BLyS (TNFSF13B). Recent studies indicated substantial role of BLyS signaling pathway for systemic lupus erythematosus (SLE). In the present study, we made an attempt to screen for polymorphisms of human BCMA, and to test their possible association with SLE and rheumatoid arthritis (RA). Two single nucleotide polymorphisms (SNPs) were detected within the coding sequence, both of which were synonymous substitutions. In addition, two SNPs within the promoter, two SNPs in the 5'-untranslated region (UTR), one SNP and one single nucleotide deletion in the 3'UTR and four rare variations were detected. From the combination of the polymorphisms, it was elucidated that four major haplotypes account for most of the genotypes in the Japanese population. Association with SLE and RA was not detected, although a slight tendency for the increase of BCMA.03 in SLE was observed (P = 0.089). These results indicated that human BCMA is conserved with respect to the amino acid sequence, and evidence for association with SLE and RA was not observed.

Adult↗

PubMed2001

Analysis of the association of HLA-DRB1, TNFalpha promoter and TNFR2 (TNFRSF1B) polymorphisms with SLE using transmission disequilibrium test.

A number of studies reported associations of HLA-DRB1, TNFalpha (TNF) promoter and TNF receptor II (TNFR2, TNFRSF1B) polymorphisms with systemic lupus erythematosus (SLE), however, the results have often been inconsistent. Such lack of consistency could partly derive from the population admixture involved in the case-control study. To avoid such a problem, polymorphisms in these genes were analyzed using transmission disequilibrium test (TDT) in Caucasian SLE families. Ninety-one Caucasian SLE family samples recruited in southern California were analyzed for the association with HLA-DRB1, TNF promoter positions at -1031, -863, -857 and -308, and TNFR2-196M/R polymorphisms. Significant transmission was observed for HLA-DRB1*1501, but not for HLA-DRB1*0301, nor for TNF haplotype that codes for -308A. Interestingly, TNF haplotype coding for -1031C, -863A, -857C showed a tendency of preferential nontransmission in the patients without lupus nephritis and in those with malar rash. No transmission distortion was observed for TNFR2-196R allele. These findings confirmed the association of HLA-DRB1*1501, but did not replicate that of the HLA-DRB1*0301, TNFA-308A and TNFR2-196R with SLE in this population. In addition, a possible disease-protective role for TNF haplotype coding for -1031C, -863A, -857C was suggested.

Alleles↗

PubMed2001

Variations in the human CC chemokine eotaxin gene.

The CC chemokine eotaxin (CCL11) plays a major role in the recruitment and activation of eosinophils in allergic disorders. In the present study, we performed polymorphism screening of the coding and promoter regions of the eotaxin gene (SCYA11). A G to A single nucleotide substitution was detected at position 67, which resulted in a non-conservative amino acid change of Ala at position 23 to Thr (A23T) within the signal peptide. Two single nucleotide substitutions, ie, C to T at position -426 (-426C>T), and A to G at position -384 (-384A>G), were detected in the 5'-flanking regions. Significant linkage disequilibrium was observed between positions -426 and -384, and also between -384 and +67. No significant association was observed between these variations and susceptibility to asthma.

Adult↗

PubMed2001

Profiling of genes expressed in human monocytes and monocyte-derived dendritic cells using cDNA expression array.

Using a human cDNA expression array, we obtained expression profiles of 588 genes in CD14+ monocytes and monocyte-derived dendritic cells (DCs). Overall, 22 genes were upregulated, and nine genes were downregulated in DCs of both samples from two different individuals. Many of the genes that were upregulated in DCs encode proteins that are related to differentiation, cell structure, migration, termination of cell cycle as well as proliferation, e.g. tumour necrosis factor-alpha (TNF-alpha), tumour necrosis factor receptor II (TNFRII), thymosin beta-10, epithelial discoidin domain receptor 1, replication factor C, putative transcription factor DB1, alpha catenin, transforming growth factor-beta 1, prohibitin, p53-regulating protein and neu differentiation factor. Among the downregulated genes in DCs were genes that encode proteins of cell cycle regulation: mitotic growth and transcription activator, platelet-derived growth factor receptor-beta subunit, interleukin 2 receptor (IL-2R)-gamma subunit, IL-7R-alpha subunit, leucocyte interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR). Semi-quantitative reverse transcription-polymerase chain reaction method confirmed the upregulated expression levels in DCs for TNFRII, TNF-alpha, alpha catenin and downregulation of IFN-gamma, GM-CSFR on four different donor samples of DCs and monocytes. Moreover, our data show the presence of a 'switch-on' step for the TNF-alpha and TNFRII gene expression in immature DCs for further differentiation into mature DCs.

Cell Cycle↗

PubMed2001

Dendritic cells rapidly undergo apoptosis in vitro following culture with activated CD4+ Valpha24 natural killer T cells expressing CD40L.

Human Valpha24 natural killer T (Valpha24NKT) cells are activated by alpha-glycosylceramide-pulsed dendritic cells (DCs) in a CD1d-dependent and T-cell receptor-mediated manner. There are two major subpopulations of Valpha24NKT cells, CD4- CD8- Valpha24NKT and CD4+ Valpha24NKT cells. We have recently shown that activated CD4- CD8- Valpha24NKT cells have cytotoxic activity against DCs, but knowledge of the molecules responsible for cytotoxicity of Valpha24NKT cells is currently limited. We aimed to investigate whether CD4+ Valpha24NKT cells also have cytotoxic activity against DCs and to determine the mechanisms underlying any observed cytotoxic activity. We demonstrated that activated CD4+ Valpha24NKT cells [CD40 ligand (CD40L) -positive] have cytotoxic activity against DCs (strongly CD40-positive), but not against monocytes (weakly CD40-positive) or phytohaemagglutinin blast T cells (CD40-negative), and that apoptosis of DCs significantly contributes to the observed cytotoxicity. The apoptosis of DCs following culture with activated CD4+ Valpha24NKT cells, but not with resting CD4+ Valpha24NKT cells (CD40L-negative), was partially inhibited by anti-CD40L mAb. Direct ligation of CD40 on the DCs by the anti-CD40 antibody also induced apoptosis of DCs. Our results suggest that CD40-CD40L interaction plays an important role in the induction of apoptosis of DCs following culture with activated CD4+ Valpha24NKT cells. The apoptosis of DCs from normal donors, triggered by the CD40-CD40L interaction, may contribute to the homeostatic regulation of the normal human immune system, preventing the interminable activation of activated CD4+ Valpha24NKT cells by virtue of apoptosis of DCs.

Antibodies, Monoclonal↗

PubMed2001

Haplotype analyses with the human leucocyte antigen and tumour necrosis factor-alpha genes in narcolepsy families.

Our previous study suggested that the tumour necrosis factor-alpha gene with thymine residue at position -857 in its promoter region [TNF-alpha(-857T)] could be associated with human narcolepsy independently of a strong association of the human leucocyte antigen (HLA)-DRB1*1501 with the disorder. To understand the relationship of DRB1*1501 with TNF-alpha(-857T) in narcoleptic patients, we investigated 28 members of four Japanese narcolepsy families and determined the haplotypes with the HLA-B, TNF-alpha(-857C/T) and HLA-DRB1 in the members. The resultant haplotypes indicated that not only the DRB1*1501-TNF-alpha(-857C) haplotype but also the DRB1*1501-TNF-alpha(-857T) haplotype, which is rare in healthy individuals and may have a strong predisposition to the disorder, were present in the affected members. From the chromosomal recombination observed in a few members, it is possible that chromosomal recombination could play a role in the generation of the rare DRB1*1501-TNF-alpha(-857T) haplotype.

Adult↗

PubMed2001

Long-term ingestion of dietary diacylglycerol lowers serum triacylglycerol in type II diabetic patients with hypertriglyceridemia.

We examined the effect of daily consumption of dietary diacylglycerol (DG) oil on serum lipid concentrations in patients with diabetes whose serum triacylglycerol (TG) levels were persistently increased despite continuous nutritional counseling at the outpatient clinic. Patients (n = 16) were divided into DG and control groups (n = 8 each). DG was incorporated (target dose 10 g/d) by substituting DG oil (80 g DG/100 g oil) for the ordinary TG cooking oil used at home for 12 wk. The control group continued consuming ordinary TG cooking oil. Dietary records indicated that there were no differences between groups in total energy intake or percentage of energy from fat. In the DG group, TG intake decreased from 26.8 +/- 9.3 to 15.7 +/- 8.9 g/d, whereas DG intake increased from 0.3 +/- 0.1 to 10.6 +/- 3.9 g/d. No differences between groups were observed in body weight, total fat intake or total oil consumption throughout the study period. In the DG group, serum TG levels decreased 39.4% from 2.51 +/- 0.75 mmol/L to 1.52 +/- 0.28 mmol/L. Serum glycohemoglobin A(1c) (HbA(1c)) concentration also decreased 9.7%. In contrast, there were no changes in these variables in the control group. Serum total and HDL cholesterol were not affected in either group. These results indicate that DG oil may be useful as an adjunct to the standard diet therapy of fat restriction in the management of diabetics with hypertriglyceridemia.

Blood Glucose↗

PubMed2001

Sequence analysis of fibroblast growth factor receptor 2 ( FGFR2 ) in Japanese patients with craniosynostosis.

Recently, mutations of the fibroblast growth factor receptor ( FGFR ) genes have been detected in syndromic craniosynostosis. We examined nucleotide sequences of FGFR2 in Japanese craniosynostosis patients (Crouzon syndrome: 9 cases; Apert syndrome: 6 cases; scaphocephaly: 3 cases as non-syndromic patients) by polymerase chain reaction (PCR) followed by direct sequencing methods. The results demonstrated FGFR2 heterozygous mutations at codons 252, 290 of exon 7, and at codon 342, 354 of exon 9 in Crouzon syndromes. In Apert syndrome patients, Ser252Trp and Pro253Arg were detected in five and one patients, respectively. No mutation was detected in one case of Crouzon, all cases of scaphocephaly and healthy individuals. Thus far sequence analysis of FGFR2 in syndromic craniosynostosis has been reported in many white patients, whereas in Japanese only several cases have been studied. The current study with 18 patients confirmed that a similar series of mutations occur in Japanese patients as in white patients regardless of ethnicity and environment. The frequency of the mutation was 82% (9/11 cases) in Japanese Crouzon patients. The ratio of S252W:P253R was 5 : 1 in Japanese Apert patients. Moreover, in Japanese Apert patients, complication rate of cleft palate was 60% for mutation of Ser252Trp and 0 of 2 patients for Pro253Arg, with their syndactyly score being 4.90 and 5.50, respectively.

Acrocephalosyndactylia↗

PubMed2001

Polymorphism of human leukocyte antigen-E gene in the Japanese population with or without recurrent abortion.

PROBLEM: The aim of this study was to investigate the gene frequencies and shared alleles of human leukocyte antigen (HLA)-E gene in Japanese couples with or without recurrent abortion. METHOD OF STUDY: Polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis was carried out to detect polymorphism in exon 3 of the HLA-E gene in 30 Japanese couples with recurrent abortion and 38 normal Japanese couples with proven fertility. RESULTS: No point mutation was detected in exon 3 of HLA-E in both recurrent aborters and normal controls. HLA-EG and HLA-ER alleles were detected with frequencies of 66.7% and 33.3% in couples with recurrent abortion and 69.2% and 30.8 in normal couples, respectively. The gene frequency of HLA-EG was higher than that of HLA-ER, which is contrary to that found in Caucasian, African-American and Hispanic people but similar to Chinese people. The frequency of each allele was not significantly different between recurrent aborters and normal controls. The number of shared alleles between each couple with recurrent abortion is not significantly different from that with normal controls. CONCLUSION: Allele frequencies of HLA-E were suggested to be different in Asian people from those in other ethnic people. In light of no specific distribution pattern in recurrent aborters, HLA-E polymorphism does not seem to play a role in the pathogenesis of recurrent abortion.

Abortion, Habitual↗

PubMed2001

Molecular basis for cell tropism of CXCR4-dependent human immunodeficiency virus type 1 isolates.

Laboratory isolates of human immunodeficiency virus type 1 (HIV-1) that utilize CXCR4 as a coreceptor infect primary human macrophages inefficiently even though these express a low but detectable level of cell surface CXCR4. In contrast, infection of primary macrophages by primary CXCR4-tropic HIV-1 isolates is readily detectable. Here, we provide evidence suggesting that this difference in cell tropism results from a higher requirement for cell surface CXCR4 for infection by laboratory HIV-1 isolates. Transfected COS7 cells that express a high level of CD4 but a low level of CXCR4 were infected significantly more efficiently by two primary CXCR4-tropic HIV-1 isolates compared to the prototypic laboratory HIV-1 isolate IIIB. More importantly, overexpression of either wild-type or signaling-defective CXCR4 on primary macrophages dramatically enhanced the efficiency of infection by the laboratory HIV-1 isolate yet only modestly enhanced infection by either primary CXCR4-tropic virus. Overexpression of CD4 had, in contrast, only a limited effect on macrophage infection by the laboratory HIV-1, although infection by the primary isolates was markedly enhanced. We therefore conclude that the laboratory CXCR4-tropic HIV-1 isolate exhibits a significantly higher CXCR4 requirement for efficient infection than do the primary CXCR4-tropic isolates and that this difference can explain the poor ability of the laboratory HIV-1 isolate to replicate in primary macrophages. More generally, we propose that the cell tropisms displayed by different strains of HIV-1 in culture can largely be explained on the basis of differential requirements for cell surface CD4 and/or coreceptor expression levels.

Animals↗

PubMed2001

Variation in malaria endemicity in relation to microenvironmental conditions in the Admiralty Islands, Papua New Guinea.

For 197 adults and adolescents in four villages of three small islands in the Admiralty Islands, Papua New Guinea, antimalarial antibody titers were examined using the indirect fluorescent antibody test (IFAT) and malaria parasites were detected by the microtiter plate hybridisation (MPH) method using polymerase chain reaction (PCR) technique. The parasite rate (either Plasmodium falciparum or P. vivax, or both) averaged 39.2%, varying from 31.1% to 44.8% among the four villages due to natural and artificial microenvironmental conditions related to breeding sites of mosquitoes (Anopheles farauti). The lack of flat zones owing to geomorphological formation contributed to the lowest parasite rate in the extremely small island. However, human-modified environments such as a wet-land (naturally formed but artificially reformed) and an open well played significant roles in other inter-village differences. The present findings imply significant roles of microenvironment in diversified malaria prevalence and suggest some ways of mitigation of malarial hazards.

Adolescent↗

PubMed2001

Cloning and functional analysis of a family of nuclear matrix transcription factors (NP/NMP4) that regulate type I collagen expression in osteoblasts.

Collagen expression is coupled to cell structure in connective tissue. We propose that nuclear matrix architectural transcription factors link cell shape with collagen promoter geometry and activity. We previously indicated that nuclear matrix proteins (NP/NMP4) interact with the rat type I collagen alpha1(I) polypeptide chain (COL1A1) promoter at two poly(dT) sequences (sites A and B) and bend the DNA. Here, our objective was to determine whether NP/NMP4-COL1A1 binding influences promoter activity and to clone NP/NMP4. Promoter-reporter constructs containing 3.5 kilobases (kb) of COL1A1 5' flanking sequence were fused to a reporter gene. Mutation of site A or site B increased promoter activity in rat UMR-106 osteoblast-like cells. Several full-length complementary DNAs (cDNAs) were isolated from an expression library using site B as a probe. These clones expressed proteins with molecular weights and COLIA1 binding activity similar to NP/NMP4. Antibodies to these proteins disrupted native NP/NMP4-COL1A1 binding activity. Overexpression of specific clones in UMR-106 cells repressed COL1A1 promoter activity. The isolated cDNAs encode isoforms of Cys2His2 zinc finger proteins that contain an AT-hook, a motif found in architectural transcription factors. Some of these isoforms recently have been identified as Cas-interacting zinc finger proteins (CIZ) that localize to fibroblast focal adhesions and enhance metalloproteinase gene expression. We observed NP/NMP4/CIZ expression in osteocytes, osteoblasts, and chondrocytes in rat bone. We conclude that NP/NMP4/CIZ is a novel family of nuclear matrix transcription factors that may be part of a general mechanical pathway that couples cell structure and function during extracellular matrix remodeling.

Alternative Splicing↗

PubMed2001

Visceral fat is a major contributor for multiple risk factor clustering in Japanese men with impaired glucose tolerance.

OBJECTIVE: The significance of abdominal visceral fat accumulation was evaluated in Japanese men with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: The IGT subjects (n = 123) were aged 55 +/- 9 years with a BMI of 24 +/- 3 kg/m(2). The 148 control subjects with normal glucose tolerance (NGT) were matched for age and BMI. IGT and NGT were classified according to the 1985 World Health Organization criteria. Abdominal fat distribution was analyzed by computed tomography at umbilical level. Plasma lipid, glucose, and insulin concentrations and blood pressure (BP) were measured. RESULTS: In subjects with IGT, the average visceral fat area (VFA) was significantly greater than in subjects with NGT. Fasting insulin, the sum of insulin concentrations during an oral glucose tolerance test, insulin resistance according to a homeostasis model assessment for insulin resistance (HOMA-IR), systolic BP, and serum triglyceride were significantly higher, whereas the DeltaI(30-0)/DeltaG(30-0) was significantly lower, in subjects with IGT. Subjects with IGT and NGT were then divided into three subgroups according to the number of risk factors they possessed (dyslipidemia, hypertension, neither, or both). In both IGT and NGT subjects, BMI, VFA, subcutaneous fat area, fasting insulin, HOMA-IR, and insulin secretion of the homeostasis model assessment were significantly higher in the double-risk factor subgroup than in the no-risk factor subgroup, and VFA was a potent and independent variable in association with the presence of a double risk factor. CONCLUSIONS: Visceral fat accumulation is a major contributor for multiple risk factor clustering in Japanese men with IGT and NGT.

Adipose Tissue↗

PubMed2001

Coil embolization of intradural pseudoaneurysms caused by arterial injury during surgery: report of two cases.

Intradural pseudoaneurysms arose in two patients as a result of arterial injury incurred during surgery. In the first patient, the pseudoaneurysm developed in the middle cerebral artery, at the site of vessel perforation during aneurysmal surgery. In the second patient, the pseudoaneurysm developed in the anterior communicating artery after removal of a tuberculum sellae meningioma. These aneurysms had small ostia and were successfully embolized with electrolytically detachable coils. The clinical features and the treatment of intracranial pseudoaneurysms are discussed.

Adult↗