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Biomedical subjects

K Tokunaga

Publications and source records attributed to K Tokunaga.

At least 109 records · Page 6Linked to original sources

Heterogeneity of Taiwan's indigenous population: possible relation to prehistoric Mongoloid dispersals.

Taiwan's 9 indigenous tribes (Tsou, Bunun, Paiwan, Rukai, Atayal, Saisiat, Ami, Puyuma, Yami) are highly homogeneous within each tribe, but diversified among the different tribes due to long-term isolation, most probably since Taiwan became an island about 12,000 years ago. Homogeneity of each tribe is evidenced by many HLA-A,B,C alleles having the world's highest ever reported frequencies, e.g. A24 (86.3%), A26 (18.8%), Cw10 (36.8%), Cw7 (66%), Cw8 (32.1%), B13 (27.9%), B62 (37.4%), B75 (18%), B39 (53.5%), B60 (33.3%), and B48 (24%). Also, all of these tribes have HLA class I haplotype frequencies greater than 10%, with A24-Cw7-B39 in Saisiat (44.5%) being the highest, suggesting Taiwan's indigenous tribes are probably the most homogeneous ( the "purest") population in the world. A24-Cw8-B48, A24-Cw10-B60 and A24-Cw9-B61 found common to many Taiwan indigenous tribes, have also been observed in Maori, Papua New Guinea Highlanders, Orochons, Mongolians, Inuit, Japanese, Man, Buryat, Yakut, Tlingit, Tibetans and Thais. These findings suggest Taiwan's indigenous groups are more or less genetically related to both northern and southern Asians. Principal component analysis and the phylogenetic tree (using the neighbor-joining method) showed close relationship between the indigenous groups and Oceanians. This relationship supports the hypothesis that Taiwan was probably on the route of prehistoric Mongoloid dispersals that most likely took place along the coastal lowland of the Asian continent (which is under the sea today). Cultural anthropology also suggests a relationship between Taiwan's indigenous tribes and southern Asians and to a lesser extent, northern Asians. However, the indigenous groups show little genetic relationship to current southern and northern Han Chinese.

Alleles↗

Analysis of HLA genes and haplotypes in Ainu (from Hokkaido, northern Japan) supports the premise that they descent from Upper Paleolithic populations of East Asia.

The Ainu people are assumed to be the descendants of pre-agricultural native populations of northern Japan, while the majority of population of present-day Japan (Hondo-Japanese) is considered to have descended mainly from post-neolithic migrants. Sequence-level polymorphisms of the HLA-class I (HLA-A and HLA-B) genes were investigated in DNA samples of 50 Ainu living in Hidaka district, Hokkaido. HLA-A*2402, A*0201, A*0206, A*2601, A*3101, B*1501, B*5101, B*3901, and B*3501 were observed at frequencies of more than 10% and most of these have previously been found in populations of not only Asians but also North and South American Indians. A*68012, which has not so far been detected in Hondo-Japanese, was found in the Ainu (3%). On the other hand, several alleles common in Hondo-Japanese, including HLA-A*3303, A*1101, B*4403, B*5201, B*5401, B*4601, and B*0702 were infrequent in Ainu (0-1%). Correspondence and neighbor-joining analyses of various populations based on HLA-A, -B and -DRB1 gene frequencies enabled distinction between Asian, Native South American, European, and African populations. The Ainu, as well as Tlingit (Na-Dene), were placed midway between other East Asians, including Hondo Japanese, and Native South Americans (Amerindians) in the correspondence analysis. Furthermore, several HLA-A-B and HLA-B-DR-DQ haplotypes common in the Ainu, are shared with some Native American populations. These observations strongly suggest a unique place for the Ainu as descendants of some Upper Paleolithic populations of East Asia, from whom some Native Americans may have descended.

Alleles↗

Significant association of the tumor necrosis factor receptor 2 (TNFR2) gene with human narcolepsy.

We report on the association study of the tumor necrosis factor receptor 2 (TNFR2) gene with human narcolepsy. A single-nucleotide polymorphism in TNFR2, which is involved in an amino acid substitution [methionine(M)/arginine(R)] at position 196, was investigated in 149 Japanese narcoleptic patients and 204 healthy individuals as controls. Results reveal that the frequency of the TNFR2-196R allele significantly increased in the patients as compared with that in the controls (P=0.029), suggesting that TNFR2 is likely associated with the susceptibility to narcolepsy. In addition, the analyses of the relationship of TNFR2 and TNF-alpha with the susceptibility to narcolepsy indicate the possibility that an additive effect on the susceptibility to the disorder lies between TNFR2-196R and TNF-alpha(-857T) alleles.

Amino Acid Substitution↗

Single nucleotide polymorphisms in the coding regions of human CXC-chemokine receptors CXCR1, CXCR2 and CXCR3.

Chemokines and their receptors have critical roles in inflammatory and immunological responses, and thus their genetic contribution to various human disorders needs investigation. In this study, systematic variation screening of the entire coding regions of CXCR1 (IL8RA), CXCR2 (IL8RB) and CXCR3 was carried out, using genomic DNA from a large number of Japanese healthy individuals and patients with rheumatic diseases. In addition to the previously reported variations in CXCR1 and in CXCR2, two non-synonymous, two synonymous substitutions and one nonsense mutation of CXCR1, one non-synonymous and two synonymous substitutions of CXCR2, two non-synonymous substitutions of CXCR3 were newly identified. The common single nucleotide polymorphisms (SNPs) at CXCR1 codon 827 and CXCR2 codon 786 were in strong linkage disequilibrium. In addition, familial analysis indicated that human CXCR3 is located on chromosome X. No significant association was observed between the variations and the tested rheumatic diseases. However, CXCR variations identified in this study will provide valuable information for the future studies in medical sciences as well as in human genetics.

Alleles↗

Independent contribution of HLA-DRB1 and TNF alpha promoter polymorphisms to the susceptibility to Crohn's disease.

Although a number of studies reported the association of HLA-DRB1 and Crohn's disease (CD), the actual alleles associated with CD are considerably variable among populations. On the other hand, the relevance of tumor necrosis factor alpha (TNF alpha) in the pathogenesis of CD is established through experimental as well as clinical studies, raising the possibility that TNFA polymorphism is primarily or independently contribute to the association of HLA region genes with CD. New polymorphisms which may affect the transcriptional activity were recently reported within the upstream promoter region of TNFA gene. In the present study, we compared HLA-DRB1, TNFA promoter and TNF receptor 2 (TNFR2) genotypes in 154 Japanese patients with CD and 265 unrelated healthy controls to evaluate the individual contribution of these genes to the genetic predisposition to CD. Significant positive association was observed in HLA-DRB1*0405 (P = 0.001, odds ratio (OR) = 2.02) and 0410 (P = 0.002, OR = 4.79). Among the TNFA promoter haplotypes, TNFA-U03 (-1031C, -863A, -857C) was significantly increased (P = 0.008, OR = 1.64), while TNFA-U04 (-1031C, -863C, -857C) was significantly decreased (P = 0.014, OR = 0.12), in CD. The association with TNFA-U03 was independent of that with DRB1*0405 and 0410, and apparent additive or multiplicative effect was not observed between these susceptibility alleles. No association was observed between TNFR2-196M/R polymorphism and CD. These results indicated that both of HLA-DRB1 and TNFA promoter polymorphisms contribute to the susceptibility to CD in an independent manner.

Adult↗

New single nucleotide polymorphisms in the coding region of human TNFR2: association with systemic lupus erythematosus.

We recently reported the association of the allele coding for Arg at the position 196 (196R: nucleotide [nt] 587G) of tumor necrosis factor receptor 2 (TNFR2, TNF-R75) with systemic lupus erythematosus (SLE) in Japanese. In the present study, we completed the variation screening of the entire coding region of TNFR2. Three new single nucleotide polymorphisms within the coding sequence (cSNPs), as well as several variations within the promoter, introns and 3'-untranslated region (3' UTR), were identified. Among the new SNPs, nt168G, a synonymous substitution (K56K), was in tight linkage disequilibrium with nt587G. Two other cSNPs, nt543 (C-->T) (P181P) and nt694 (G-->A) (E232K), were not significantly associated with SLE. Thus, among the non-synonymous cSNPs, only nt587 (T-->G) (M196R) was found to be significantly associated with SLE in Japanese.

Alleles↗

New polymorphisms of human CD80 and CD86: lack of association with rheumatoid arthritis and systemic lupus erythematosus.

The crucial role of costimulatory molecules, CD28, CTLA-4, CD80 and CD86, for T cell activation and inhibition has been established. In the previous study, we reported the results of a polymorphism screening of human CTLA-4 gene. In this study, we screened for polymorphisms of human CD28, CD80 and CD86 genes, and detected that polymorphisms were tested for the association with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Variations were identified in the coding regions of CD80 (452G/A, 614C/G and 864A/G) and CD86 (1057A/G), while no variation was observed in the coding region of CD28. The variations at CD80 position 452 and CD86 position 1057 were present in a substantial proportion of the Japanese population, and were considered to be single nucleotide polymorphisms within the coding sequence (cSNPs). CD80 864 (G-->A) leads to the amino acid substitution N186D, and CD86 1057 (A-->G) results in A304T substitution. Furthermore, in the analysis of CD80 5'-flanking region, six SNPs, -454C/A, -387T/C, -232G/A, -79G/C, -7T/C and /A, and one insertion, -558ins (CATGA), were identified. The combination of these variations was found to constitute four promoter alleles of CD80. None of the observed variations was significantly associated with RA or SLE. Further studies will be of particular interest to examine the functional difference of the promoter alleles for the transcriptional activity of CD80, as well as the evolutionary pathway of the four alleles.

Alleles↗

New variations in human OX40 ligand (CD134L) gene.

We found three new variations in the OX40 ligand (OX40L, CD134L) gene and its 5' upstream region. -921 (G-->A) at 5' upstream region, -19 (C-->G) at 5' untranslated region, and 202 + 25 (G-->T) at intron 2 were identified. -921 (G-->A) and 202 + 25 (G-->T) were detected in a substantial proportion of healthy Japanese individuals and were considered to be single nucleotide polymorphisms (SNPs). -19 (C-->G) was detected in only one healthy individual. There was no association between these variations and the presence of rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).

Arthritis, Rheumatoid↗

Superparamagnetic iron oxide-enhanced magnetic resonance images of hepatocellular carcinoma: correlation with histological grading.

Superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance (MR) imaging has been used for the detection of hepatic tumors. However, little is known about this technique in relation to hepatocellular carcinoma (HCC). The aim of this study was to investigate whether SPIO-enhanced MR imaging can be useful in assessing histological grades of HCC. The authors studied histologically proven tumors including 31 HCCs and 6 dysplastic nodules. The ratio of the Kupffer-cell count in the tumorous tissue relative to that in the nontumorous tissue (Kupffer-cell-count ratio) decreased as HCCs became less well differentiated. The ratio of the intensity of the tumorous lesion to that of the nontumorous area on SPIO-enhanced MR images (SPIO intensity ratio) correlated inversely with Kupffer-cell-count ratio in HCCs and dysplastic nodules (r = -.826, P <.001) and increased as the degree of differentiation of HCCs decreased, indicating that the uptake of SPIO in HCCs decreased as the degree of differentiation of HCCs declined. All of the dysplastic nodules and some well-differentiated HCCs showed hypointense or isointense enhancement, relative to the surrounding liver parenchyma, indicating greater or similar uptake of SPIO in the tumor when compared with nontumorous areas. These results suggest that SPIO-enhanced MR imaging reflects Kupffer-cell numbers in HCCs and dysplastic nodules, and is useful for estimation of histological grading in HCCs, although uncertainties persist in differentiating dysplastic nodules from well-differentiated HCCs.

Aged↗

Curative treatment of cerebral arteriovenous malformations by embolisation using cellulose acetate polymer followed by surgical resection.

AIM: To investigate the usefulness of embolising cerebral arteriovenous malformations (AVMs) with a cellulose acetate polymer solution before surgical resection. METHODS: The cases of 12 patients with AVMs treated by embolisation before surgical resection were renewed. Two types of cellulose acetate polymer solutions were used to occlude 40 feeding vessels. All patients underwent surgical resection 1-51 days after embolisation. RESULTS: Reduction of the nidus volume after embolisation ranged from 20% to nearly 100%. Transient neurological deficits occurred in three patients, persistent deficits occurred in one and there were no haemorrhagic complications. All but one arteriovenous malformation were completely resected. Embolisation helped to identify feeding vessels and ease dissection. Histopathological examination of resected specimens disclosed mild inflammatory reactions in the acute stage and no unfavourable granulomatous changes in the chronic stage. CONCLUSION: Embolisation with cellulose acetate polymer solutions followed by surgical resection is safe and efficacious for treating cerebral AVMs.

Adult↗

Fine localization of a major disease-susceptibility locus for diffuse panbronchiolitis.

Diffuse panbronchiolitis affecting East Asians is strongly associated with the class I human leukocyte antigen (HLA) alleles. Recent observations suggest that a major disease-susceptibility gene may be located between the HLA-B and HLA-A loci in the class I region of the major histocompatibility complex on chromosome 6. To test this possibility, we analyzed 14 polymorphic markers in 92 Japanese patients and 93 healthy controls. Of these, seven marker alleles, including HLA-B54 and HLA-A11, were significantly associated with the disease. Maximum-likelihood haplotype analysis and subsequent direct determination of individual haplotypes identified a group of disease-associated haplotypes, one of which contained all seven disease-associated marker alleles. Another haplotype, containing HLA-B*5504, was also associated with the disease. All these haplotypes seem to have diverged from a common ancestral haplotype in East Asians and share a specific segment containing three consecutive markers between the S and TFIIH loci in the class I region. Furthermore, one of the markers within the candidate region showed the highest delta value, indicating the strongest association. Of 20 Korean patients with diffuse panbronchiolitis, 17 also shared the combination of the disease-associated marker alleles within the candidate region. These results indicate that an HLA-associated major susceptibility gene for diffuse panbronchiolitis is probably located within the 200 kb in the class I region 300 kb telomeric of the HLA-B locus on the chromosome 6p21.3.

Alleles↗

Sojourn times and substitution rate at overdominant and linked neutral loci.

The sojourn times until fixation of an overdominant allele were investigated based on the diffusion equation. Furthermore, the rate of accumulation of mutations, or the substitution rate, was predicted from the mean extinction time of a common overdominant allele. The substitution rate calculated theoretically agreed well with that determined by computer simulation. Overdominant selection enhances the polymorphism at linked loci, while its effect on the sojourn times and the substitution rate at linked loci has not been studied yet. To solve these problems, a model that assumed two linked loci, each with infinite alleles, was examined by computer simulation. A decrease in the recombination rate between two loci markedly changed the distribution of sojourn times of a neutral allele. Although overdominant selection obviously increased the sojourn times and the polymorphism at a linked locus, the rate of nucleotide substitution at the neutral locus was not influenced significantly even if complete linkage was assumed. These results suggest that, in regions containing overdominant genes, linked neutral loci will exhibit elevated levels of polymorphism, but their rate of molecular evolution remains that predicted by neutral theory.

Alleles↗

Effect of external stenting and systemic hypertension on intimal hyperplasia in rat vein grafts.

OBJECTIVE: Overdistention of vein grafts in arterial circulation and systemic hypertension are thought to be influential risk factors contributing to vein graft failures. This study tested the effects of external stenting in preventing systemic hypertension and overdistention of the rat vein graft in the long term. METHODS: Jugular vein grafts were interposed into the carotid artery of normotensive (n = 39) and two-kidney, one-clip hypertensive (n = 30) rats. Jugular vein grafts wrapped with 1.5-mm-diameter polyester stents were used in normotensive (n = 26) and hypertensive (n = 25) rats. The vein grafts were harvested at 1, 2, 4, 8, 12, and 24 weeks after the grafting procedure. The neointimal area and wall thickness were measured by computerized planimetry, and Ki-67 immunohistochemistry was used to detect replicative smooth muscle cells in the graft wall. RESULTS: In each group, intimal hyperplasia was apparent at 1 week and increased gradually to 24 weeks. The number of Ki-67-positive cells was most increased at 2 weeks after the grafting procedure and gradually decreased thereafter. The numbers of Ki-67-positive cells and the extent of intimal hyperplasia were not significantly different between normotensive and hypertensive rats. Both neointima formation and cell proliferation in the graft wall were significantly reduced by external stenting as compared with the results with unstented grafts. CONCLUSION: Systemic hypertension by itself is not a risk factor for intimal hyperplasia and experimental vein graft failure in the long term. External stenting is effective against intimal hyperplasia, and it is possible to reduce the subsequent atherosclerotic change of the vein graft wall and improve the long-term patency of the vein graft with external stenting.

Animals↗

Intermittent propofol sedation during embolization of cerebral arteriovenous malformations.

Embolization procedure was performed for a 12-year-old boy with a left parietal arteriovenous malformation. Although provocative tests for the feeders to be occluded were considered very informative, the patient had to be sedated during microcatheter insertion. We used intermittent sedation with propofol during the interventional procedure, and obtained successful embolization.

Anesthetics, Intravenous↗

Computer simulation analysis suggests weak balancing selection operative at the MICA locus.

A high degree of polymorphism has been reported at the major histocompatibility class I chain-related gene A (MICA) locus, which is located 46 kb away from HLA-Bin the human major histocompatibility complex (MHC) class I region. Although it is known that the polymorphisms at the conventional MHC class I loci have been maintained by balancing selection, it is unclear whether positive natural selection is also operative in maintaining the polymorphism at the MICA locus. In order to explain the degree of polymorphism at the MICA locus, a computer simulation study was carried out. The high degree of polymorphism at the MICA locus (heterozygosity and number of polymorphic residues) could not be explained solely by balancing selection at the HLA-B locus even if no recombination was assumed between MICA and HLA-B. Although there is no definite evidence indicating that balancing selection is operative at the MICA locus, our results suggest that the MICA gene is subject to weak balancing selection.

Alleles↗

Human leukocyte antigen and season of birth in Japanese patients with schizophrenia.

OBJECTIVE: Five Japanese studies, to the authors' knowledge, without exception, have consistently shown an increased frequency of human leukocyte antigen (HLA)-DR1 in patients with schizophrenia. This suggests an association between HLA-DR1 and schizophrenia in the Japanese population. The mechanism of the association is unknown; however, prenatal infections may be involved. The present study explored factors, including winter birth, that might correlate with this mechanism. Age at onset and gender were also studied. METHOD: Factors were compared between Japanese patients with schizophrenia with and in those without HLA-DR1 (N=60 and N=307, respectively). RESULTS: A significantly higher incidence of births in February and March was observed in patients with (31.7%) than those without (15. 6%) HLA-DR1. No association was found between the presence of HLA-DR1 and other variables. CONCLUSIONS: Although this result is preliminary, it may suggest an interaction between HLA and winter birth in the development of schizophrenia in the Japanese population.

Adult↗

Combined use of cellulose acetate polymer and retrievable platinum coils for the thrombosis of cervical carotid aneurysms.

Cellulose acetate polymer (CAP) solution is a new liquid embolic material, and it has been used clinically for the thrombosis of cerebral aneurysms. The purpose of the study was to test a method of aneurysm treatment. In an experimental model, retrievable interlocking detachable coils (IDCs) were used to create an intraaneurysmal frame or prop and then CAP was injected into 20 experimentally induced canine cervical aneurysms. Intraaneurysmal thrombosis was induced 1 week after aneurysm creation. Complete thrombosis was attempted in 12 aneurysms, and partial thrombosis was attempted in 4. Four other aneurysms served as controls. Follow-up angiography was performed for up to 8 weeks, and with the exception of 4 aneurysms, which were kept for a 2-year long-term follow-up study, the aneurysms were then harvested for histological examination. Thrombosis was successfully achieved in all cases except for 2 enlarged aneurysms that were initially partially thrombosed. No thromboembolism to distal vessels was observed. No compaction or shift of the CAP-IDC complex occurred even after 2 years. Histologically, CAP and IDCs conformed to the massive thrombotic complex without any fragmentation. By creating a frame or prop with retrievable microcoils, we were able to inject the CAP implies a comparison safely and precisely than has been previously reported. Our findings suggest that this method will be useful for the treatment of cerebral aneurysms.

Aneurysm↗

Profiles of cytokine expression in radicular cyst-lining epithelium examined by RT-PCR.

Levels of messenger RNA (mRNA) extracted from five samples of radicular cyst-lining epithelium were analyzed for cytokines, growth factors and epithelial cell growth-related receptors by RT-PCR. All five samples expressed IL-1alpha, -1beta, IL-6, IL-8, IL-11, TGF-beta1, PDGF-A and aFGF, and receptors for EGF (c-erbB), KGF, HGF (c-met) and IL-6. Some of the specimens expressed MIP-1alpha, RANTES, GM-CSF, M-CSF, TNF-alpha, PDGF-B and bFGF, but no expression of IL-2, IL-4, IFN-gamma, IGF-I, EGF and KGF was detected. These results indicate that radicular cyst-lining epithelium, which is considered to be identical to the cell rests of Malassez, may play a role in periodontal pocket formation or apical cyst formation by interaction with surrounding connective tissue or hematopoietic cells through the expression of various cytokines.

Cytokines↗