M. Yasunami - Academia.edu (original) (raw)
Papers by M. Yasunami
Tropical Medicine and Health, 2020
Background The nutritional status of children may deteriorate after natural disasters such as ear... more Background The nutritional status of children may deteriorate after natural disasters such as earthquakes. A 7.8 Richter scale earthquake struck Nepal in 2015 that affected 1.1 million children. Children whose homes were destroyed and had to live in temporary shelters were at risk of malnutrition. With the support of Nagasaki University School of Tropical Medicine and Global Health (TMGH) and Siddhi Memorial Hospital (SMH), we conducted a nutritional survey of under-5 children living in temporary shelters in Bhaktapur Municipality in 2015 immediately after the earthquake and a follow-up survey in 2017. Results We found 591 under-5 children living in 22 temporary shelters in 2015. A total of 285 children were followed up and re-assessed in 2017. In a paired analysis (n = 285), the prevalence of underweight children increased from 10.9% in 2015 to 14.0% in 2017 (P < 0.001), stunting increased from 26.7 to 31.9% (P = 0.07), and wasting decreased from 4.2 to 2.5% (P = 0.19). Conclusi...
PLOS Neglected Tropical Diseases, 2019
Background Scrub typhus (ST) is a leading cause of non-malarial febrile illness in Southeast Asia... more Background Scrub typhus (ST) is a leading cause of non-malarial febrile illness in Southeast Asia, but evidence of its true disease burden is limited because of difficulties of making the clinical diagnosis and lack of adequate diagnostic tests. To describe the epidemiology and clinical characteristics of ST, we conducted an observational study using multiple diagnostic assays at a national tertiary hospital in Hanoi, Vietnam. Methodology/Principal findings We enrolled 1,127 patients hospitalized with documented fever between June 2012 and May 2013. Overall, 33 (2.9%) patients were diagnosed with ST by PCR and/or screening of ELISA for immunoglobulin M (IgM) with confirmatory tests: 14 (42.4%) were confirmed by indirect immunoperoxidase assay (IIP), and 19 (57.6%) were by IIP and PCR. Living by farming, conjunctival injection, eschar, aspartate aminotransferase elevation, and alanine aminotransferase elevation were significantly associated with ST cases (adjusted odds ratios (aORs): 2.8, 3.07, 48.8, 3.51, and 4.13, respectively), and having a comorbidity and neutrophilia were significantly less common in ST cases (aORs: 0.29 and 0.27, respectively). The majority of the ST cases were not clinically diagnosed with rickettsiosis (72.7%).
Malaria Journal, 2009
Background Severe malaria anaemia in the semi-immune individuals in the holo-endemic area has bee... more Background Severe malaria anaemia in the semi-immune individuals in the holo-endemic area has been observed to occur at low parasite density with individual variation in the responses. Thus the following has been thought to be involved: auto-immune-mediated mechanisms of uninfected red blood cell destruction, and host genetic factors to explain the differences in individual responses under the same malaria transmission. In this study, the extent of red blood cell (RBC) destruction in different strains of semi-immune mice model at relatively low parasitaemia was studied. Methodology To generate semi-immunity, four strains of mice were taken through several cycles of infection and treatment. By means of immunofluorescent assay and ELISA, sera were screened for anti-erythrocyte auto-antibodies, and their relationship with haematological parameters and parasitaemia in the strains of semi-immune mice was investigated. Results Upon challenge with Plasmodium berghei ANKA after generating s...
Human Immunology, 2006
We previously revealed that one of the human leukocyte antigen-linked susceptibility genes for Ta... more We previously revealed that one of the human leukocyte antigen-linked susceptibility genes for Takayasu's arteritis (TA) was mapped between TNFA and MICB loci and that Ϫ63T allele of NFKBIL1, which is between TNFA and MICB loci, was associated with rheumatoid arthritis (RA) in the Japanese population. We have developed a novel typing method based on reference strand-mediated conformation analysis for the upstream sequence of the NFKBIL1 gene, where Ϫ422 (T) 8 /(T) 9 , Ϫ325 C/G, Ϫ263 A/G, and Ϫ63 T/A polymorphisms were found. Upon the analysis of the patients with TA (n ϭ 84), those with RA (n ϭ 120), and healthy control subjects (n ϭ 217), five common haplotypes named IKBLp*01 through IKBLp*05 were found in the Japanese population. The frequency of IKBLp*03 was significantly increased in the patient with TA (57.1% vs 35.0%, giving an odds ratio of 2.47). In addition, the frequency of IKBLp*01, but not that of other Ϫ63T-bearing alleles, was increased in the patients with RA (73.3% vs 58.1%, giving an odds ratio of 1.99), suggesting that the susceptibility to RA was conferred not by Ϫ63T alone but by combination of single nucleotide polymorphisms in the NFKBIL1 promoter. A higher promoter activity associated with IKBLp*03 and a lower activity associated with IKBLp*01 may contribute to the susceptibility to TA and RA, respectively. Human Immunology 67, 363-373 (2006).
Human Genetics, 2009
Coronary artery disease (CAD) is based on the atherosclerosis of coronary artery and may manifest... more Coronary artery disease (CAD) is based on the atherosclerosis of coronary artery and may manifest with myocardial infarction or angina pectoris. Although it is widely accepted that genetic factors are linked to CAD and several disease-related genes have been reported, only a few could be replicated suggesting that there might be some other CAD-related genes. To identify novel susceptibility loci for CAD, we used microsatellite markers in the screening and found six diVerent candidate CAD loci. Subsequent single nucleotide polymorphism (SNP) association studies revealed an association between CAD and megakaryoblastic leukemia factor-1 gene (MKL1). The association with a promoter SNP of MKL1, ¡184C > T, was found in a Japanese population and the association was replicated in another Japanese population and a Korean population. Functional analysis of the MKL1 promoter SNP suggested that the higher MKL1 expression was associated with CAD. These Wndings suggest that MKL1 is involved in the pathogenesis of CAD.
Molecular Brain Research, 2000
We have isolated and characterized the mouse gene for NDRF (neuroD-related factor), a basic helix... more We have isolated and characterized the mouse gene for NDRF (neuroD-related factor), a basic helix-loop-helix transcription factor implicated in neural development and function. The gene consists of two exons and the entire protein-coding sequence is encoded by a single downstream exon. RNA blot hybridization analysis revealed that NDRF mRNA was detectable at day 4 and increased to a maximal level at day 6 during neuronal differentiation of P19 cells. To elucidate the regulatory mechanisms of the NDRF gene expression during this process, a construct containing the genomic DNA fragment of about 3 kbp upstream of the NDRF coding region fused to a luciferase reporter gene was transfected into P19 cells, and stable transformants were pooled for assay of luciferase activities. When the stable transformants were treated with RA and aggregated to induce neuronal differentiation, the luciferase activities were induced in a temporal expression pattern similar to that of the endogenous NDRF mRNA. Further experiments using a series of deletion and mutation constructs indicated that the 376-bp sequence in the 59-flanking region of the NDRF gene is important, and that one of the E boxes in the sequence plays a critical role in the regulated expression. Transient transfection experiments also showed that the same E box is required for the transactivation of the NDRF promoter activity by neurogenin 1. These results suggest that the NDRF gene expression is regulated by an E box-binding factor during neuronal differentiation of P19 cells.
International Immunology, 2010
Background: Osteoclasts activated by inflammatory cytokines are responsible for bone erosion in r... more Background: Osteoclasts activated by inflammatory cytokines are responsible for bone erosion in rheumatoid arthritis (RA) patients. IL-6 levels in blood and synovial fluids of RA patients are higher than healthy people. IL-6 induces the expression of RANKL which is essential cytokine for osteoclastgenesis in synovial cells. These facts strongly suggest that IL-6 contributes to the differentiation of osteoclasts in RA synovia. Objectives: We examined the effect of IL-6 on the osteoclast formation. Methods: Osteoclast precursor cell line, RAW264.7 cells were cultured with soluble RANKL (sRANKL) in the presence of IL-6 for 3 days and the expression of osteoclastogenesis marker, TRAP was measured. Moreover, synovial cell line, SW982 cells and RAW264.7 cells were co-cultured in the presence of IL-6 for 3 days and the expression of TRAP was measured. Results: IL-6 dramatically decreased the induction of TRAP expression in RAW264.7 cells by sRANKL. In co-culture of SW982 cell and RAW264.7 cells, as the number of SW982 cells increased, IL-6 increased the expression of TRAP in RAW264.7 cells. When SW982 cells were cultured with IL-6 for 24 h, we found that IL-6 increased the expression of RANKL and ICAM-1 in SW982 cells. Either anti-RANKL or anti-ICAM-1 antibody inhibited increase of expression of TRAP by IL-6 in co-culture of SW982 cells and RAW264.7 cells. Moreover, the addition of soluble ICAM-1 reversed reduction of TRAP expression by IL-6 in RAW267.4 cells. Conclusions: IL-6-induced RANKL and ICAM-1 in synovial cells positively drives osteoclast differentiation in co-culture of RAW264.7 and SW982 cells.
Journal of Immunology, Jul 1, 1990
In an attempt to obtain direct evidence for the critical role of HLA class II molecules in regula... more In an attempt to obtain direct evidence for the critical role of HLA class II molecules in regulating the immune response, genomic genes for alpha- and beta-chains of HLA-DQw6 from HLA-Dw12 haplotype were introduced into the C57BL/6 (B6) strain of mouse and a line of HLA-DQw6 transgenic mouse was obtained. Tissue specificity of the expression of the transgenes was much the same as that of murine I-Ab genes. DQw6 molecules were expressed on B cells and macrophages in spleen cells and about 30 to 40% of the I-Ab+ spleen cells were positive for DQw6. The HLA-DQw6 transgenic B6 mouse became tolerant to the DQw6 molecules, as evidenced by the MLR and antibody production specific to the DQw6 molecules. The HLA-DQw6 transgenic B6 mouse showed a strong immune response to streptococcal cell wall antigen (SCW), whereas the B6 mouse was a low responder to SCW. The SCW-specific T cell line was established from the transgenic mouse and this T cell line recognized SCW in the context of HLA-DQw6 m...
Journal of Human Genetics, 1985
Fukuoka igaku zasshi = Hukuoka acta medica, 1988
Clinical and experimental rheumatology, 2007
Familial Mediterranean Fever (FMF) is an autoinfl ammatory disease caused by mutations in the MEF... more Familial Mediterranean Fever (FMF) is an autoinfl ammatory disease caused by mutations in the MEFV gene and characterized by recurrent fever, polyserositis and arthritis. It is transmitted in an autosomal recessive pattern. FMF has been predominantly found in ethnic groups living around the Mediterranean basin (Jews, Arabs, Turks, and Armenians). Although accompanying infl ammatory diseases have been reported in FMF, the coexistance of fi bromyalgia syndrome (FMS) is very rare. MEFV gene analysis that the fi rst patient had compound heterozygous mutation (M680I+V726A) and the other patient had heterozygous mutation (M694V). This association will be discussed in this case report.
Clinical and experimental immunology, 2014
Inflammatory myopathy with abundant macrophages (IMAM) has recently been proposed as a new clinic... more Inflammatory myopathy with abundant macrophages (IMAM) has recently been proposed as a new clinical condition. Although IMAM shares certain similarities with other inflammatory myopathies, the mechanisms responsible for this condition remain unknown. Patients with familial Mediterranean fever (FMF) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS) also often develop myalgia. We therefore investigated the polymorphisms or mutations of MEFV and TNFRSF1A genes in patients with IMAM to identify their potential role in this condition. We analysed the clinical features of nine patients with IMAM and sequenced exons of the MEFV and TNFRSF1A genes. The patients with IMAM had clinical symptoms such as myalgia, muscle weakness, erythema, fever and arthralgia. Although none of the patients were diagnosed with FMF or TRAPS, seven demonstrated MEFV polymorphisms (G304R, R202R, E148Q, E148Q-L110P and P369S-R408Q), and one demonstrated a TNFRSF1A mutation (C43R). These resul...
Clinical & Experimental Immunology, 2015
Summary Autoinflammatory diseases include a large spectrum of monogenic diseases, e.g. familial M... more Summary Autoinflammatory diseases include a large spectrum of monogenic diseases, e.g. familial Mediterranean fever (FMF), as well as complex genetic trait diseases, e.g. adult-onset Still's disease (AOSD). In populations where FMF is common, an increased MEFV mutation rate is found in patients with rheumatic diseases. The aim of this study was to examine MEFV mutations in Japanese patients with AOSD. Genomic DNA was isolated from 49 AOSD patients and 105 healthy controls, and exons 1, 2, 3 and 10 of the MEFV gene genotyped by direct sequencing. MEFV mutation frequencies in AOSD patients were compared with controls. We found no significant difference in overall allele frequencies of MEFV variants between AOSD patients and controls. However, MEFV exon 10 variants (M694I and G632S) were significantly higher in AOSD patients than controls (6·1 versus 0%). In addition, there was no significant difference between MEFV variant carriers and non-carriers with clinical manifestations, bu...
Rheumatology, 2014
Objective. The aim of this study was to analyse the role of circulating cleaved IL-1b in patients... more Objective. The aim of this study was to analyse the role of circulating cleaved IL-1b in patients with FMF. Methods. We enrolled 20 patients with FMF (5 males and 15 females), 22 patients with RA (4 males and 18 females) and 22 healthy controls (6 males and 16 females). Serum levels of serum amyloid A (SAA) were measured by ELISA. We also determined whether IL-1b was present as the cleaved form (p17) in the sera of FMF patients by immunoblotting using anti-cleaved IL-1b antibody. Results. Although SAA concentrations were elevated in the sera, there was no significant difference in these concentrations between FMF patients and RA patients. Immunoblot analysis demonstrated that the cleaved form of IL-1b (p17) was present in sera from FMF patients during febrile attack periods, but not in healthy controls. Bands representing the cleaved form of IL-1b were not detected in serum from FMF patients at non-febrile attack periods or remission periods under colchicine treatment. The amounts of cleaved IL-1b (p17) were significantly higher in patients with FMF compared with those in patients with RA in the inflammatory phase. Conclusion. The cleaved form of IL-1b is a valuable biomarker for monitoring disease activity and response to colchicine treatment in patients with FMF. It might be useful to discriminate FMF from other non-IL-1b-mediated inflammatory disorders.
Research in Immunology, 1991
The particular alleles of the HLA-DQ locus may control the low immune response to natural antigen... more The particular alleles of the HLA-DQ locus may control the low immune response to natural antigens by a dominant genetic trait through the immune suppression mediated by CD8+ suppressor T cells. The suppressor T cells may be activated by DQ-restricted and antigen-specific CD4+ suppressor/inducer T cells, because (1) a statistically significant association and linkage between low immune responsiveness to the natural antigens and the HLA-DQ gene were observed; (2) antigen-specific CD4+ T cells restricted by the DQ molecules encoded for by the HLA-DQ allele associated with low responsiveness were evidenced in many low responders; and (3) anti-HLA-DQ mAb restored the immune response to natural antigens, in some low responders. This HLA-DQ-controlled polymorphism of immune response to the natural antigens may account for the association between HLA-DQ alleles and organ-specific autoimmune diseases.
Tissue Antigens, 2007
To investigate the recently reported associations of polymorphisms in lymphotoxin-alpha (LTA) and... more To investigate the recently reported associations of polymorphisms in lymphotoxin-alpha (LTA) and galectin-2 (LGALS2) with myocardial infarction (MI), we analyzed a single nucleotide polymorphism of LTA (LTA 252A>G in LTA intron 1) and that of LGALS2 (LGALS2 3279C>T in LGALS2 intron 1) in Japanese and Korean populations. Although significant associations with MI were not observed in either population, we found that LTA 252GG was significantly associated with the severity of the disease for both the Japanese and Korean populations (P=0.017 and P=0.001, respectively). On the other hand, the polymorphism of LGALS2 was not associated with the severity of coronary atherosclerosis. These observations showed that, while the LTA 252GG genotype might modify the development of coronary atherosclerosis, the relation of LTA and LGALS2 to MI itself remained much less certain.
Scandinavian Journal of Immunology, 2012
Fc gamma receptor (FccR) provides an important link between humoral and cellular immune responses... more Fc gamma receptor (FccR) provides an important link between humoral and cellular immune responses. FccRIIa-H131R polymorphism has been associated with differential binding to IgG subclasses and susceptibility to severe malaria phenotypes among different populations in the malaria endemic world. In this study, the effect of FCGR2A gene polymorphisms on susceptibility to symptomatic malaria among Ghanaian cohort children was investigated. Blood samples from four hundred and 29 (429) healthy Ghanaian children were genotyped for FCGR2A polymorphisms by direct DNA sequencing. Attributable and relative risks to symptomatic malaria were calculated for the polymorphic variants. Two major FCGR2A polymorphisms, rs1801274A ⁄ G (FccRIIa-H131R) and rs150311303 (FccRIIa-ins170L), were identified in the study population, and assessment of their risks did not show significant association with susceptibility to symptomatic malaria. The functional significance of these polymorphisms was also examined by evaluating their binding abilities to IgG subclasses using flow cytometric analysis of HEK cells transfected with the FccRIIa haplotype variants. The binding assay revealed the rs150311303, which was observed only among carriers of the FccRIIa-131RR genotype for the rs1801274 to consistently enhance binding capacities to all IgG subclasses. Thus, of the three FccRIIa haplotype variants observed in this study population, the FccRIIa RL haplotype variant was observed to have the highest binding ability to IgG1, IgG3 and IgG4.
Proceedings of the National Academy of Sciences, 1991
PLoS ONE, 2011
Background: Apoptosis is thought to play a role in the pathogenesis of severe dengue and the rele... more Background: Apoptosis is thought to play a role in the pathogenesis of severe dengue and the release of cell-free DNA into the circulatory system in several medical conditions. Therefore, we investigated circulating DNA as a potential biomarker for severe dengue. Methods and Findings: A direct fluorometric degradation assay using PicoGreen was performed to quantify cell-free DNA from patient plasma. Circulating DNA levels were significantly higher in patients with dengue virus infection than with other febrile illnesses and healthy controls. Remarkably, the increase of DNA levels correlated with the severity of dengue. Additionally, multivariate logistic regression analysis showed that circulating DNA levels independently correlated with dengue shock syndrome. Conclusions: Circulating DNA levels were increased in dengue patients and correlated with dengue severity. Additional studies are required to show the benefits of this biomarker in early dengue diagnosis and for the prognosis of shock complication.
Tissue Antigens, 2007
To investigate the recently reported associations of polymorphisms in lymphotoxin-alpha (LTA) and... more To investigate the recently reported associations of polymorphisms in lymphotoxin-alpha (LTA) and galectin-2 (LGALS2) with myocardial infarction (MI), we analyzed a single nucleotide polymorphism of LTA (LTA 252A>G in LTA intron 1) and that of LGALS2 (LGALS2 3279C>T in LGALS2 intron 1) in Japanese and Korean populations. Although significant associations with MI were not observed in either population, we found that LTA 252GG was significantly associated with the severity of the disease for both the Japanese and Korean populations (P=0.017 and P=0.001, respectively). On the other hand, the polymorphism of LGALS2 was not associated with the severity of coronary atherosclerosis. These observations showed that, while the LTA 252GG genotype might modify the development of coronary atherosclerosis, the relation of LTA and LGALS2 to MI itself remained much less certain.
Tropical Medicine and Health, 2020
Background The nutritional status of children may deteriorate after natural disasters such as ear... more Background The nutritional status of children may deteriorate after natural disasters such as earthquakes. A 7.8 Richter scale earthquake struck Nepal in 2015 that affected 1.1 million children. Children whose homes were destroyed and had to live in temporary shelters were at risk of malnutrition. With the support of Nagasaki University School of Tropical Medicine and Global Health (TMGH) and Siddhi Memorial Hospital (SMH), we conducted a nutritional survey of under-5 children living in temporary shelters in Bhaktapur Municipality in 2015 immediately after the earthquake and a follow-up survey in 2017. Results We found 591 under-5 children living in 22 temporary shelters in 2015. A total of 285 children were followed up and re-assessed in 2017. In a paired analysis (n = 285), the prevalence of underweight children increased from 10.9% in 2015 to 14.0% in 2017 (P < 0.001), stunting increased from 26.7 to 31.9% (P = 0.07), and wasting decreased from 4.2 to 2.5% (P = 0.19). Conclusi...
PLOS Neglected Tropical Diseases, 2019
Background Scrub typhus (ST) is a leading cause of non-malarial febrile illness in Southeast Asia... more Background Scrub typhus (ST) is a leading cause of non-malarial febrile illness in Southeast Asia, but evidence of its true disease burden is limited because of difficulties of making the clinical diagnosis and lack of adequate diagnostic tests. To describe the epidemiology and clinical characteristics of ST, we conducted an observational study using multiple diagnostic assays at a national tertiary hospital in Hanoi, Vietnam. Methodology/Principal findings We enrolled 1,127 patients hospitalized with documented fever between June 2012 and May 2013. Overall, 33 (2.9%) patients were diagnosed with ST by PCR and/or screening of ELISA for immunoglobulin M (IgM) with confirmatory tests: 14 (42.4%) were confirmed by indirect immunoperoxidase assay (IIP), and 19 (57.6%) were by IIP and PCR. Living by farming, conjunctival injection, eschar, aspartate aminotransferase elevation, and alanine aminotransferase elevation were significantly associated with ST cases (adjusted odds ratios (aORs): 2.8, 3.07, 48.8, 3.51, and 4.13, respectively), and having a comorbidity and neutrophilia were significantly less common in ST cases (aORs: 0.29 and 0.27, respectively). The majority of the ST cases were not clinically diagnosed with rickettsiosis (72.7%).
Malaria Journal, 2009
Background Severe malaria anaemia in the semi-immune individuals in the holo-endemic area has bee... more Background Severe malaria anaemia in the semi-immune individuals in the holo-endemic area has been observed to occur at low parasite density with individual variation in the responses. Thus the following has been thought to be involved: auto-immune-mediated mechanisms of uninfected red blood cell destruction, and host genetic factors to explain the differences in individual responses under the same malaria transmission. In this study, the extent of red blood cell (RBC) destruction in different strains of semi-immune mice model at relatively low parasitaemia was studied. Methodology To generate semi-immunity, four strains of mice were taken through several cycles of infection and treatment. By means of immunofluorescent assay and ELISA, sera were screened for anti-erythrocyte auto-antibodies, and their relationship with haematological parameters and parasitaemia in the strains of semi-immune mice was investigated. Results Upon challenge with Plasmodium berghei ANKA after generating s...
Human Immunology, 2006
We previously revealed that one of the human leukocyte antigen-linked susceptibility genes for Ta... more We previously revealed that one of the human leukocyte antigen-linked susceptibility genes for Takayasu's arteritis (TA) was mapped between TNFA and MICB loci and that Ϫ63T allele of NFKBIL1, which is between TNFA and MICB loci, was associated with rheumatoid arthritis (RA) in the Japanese population. We have developed a novel typing method based on reference strand-mediated conformation analysis for the upstream sequence of the NFKBIL1 gene, where Ϫ422 (T) 8 /(T) 9 , Ϫ325 C/G, Ϫ263 A/G, and Ϫ63 T/A polymorphisms were found. Upon the analysis of the patients with TA (n ϭ 84), those with RA (n ϭ 120), and healthy control subjects (n ϭ 217), five common haplotypes named IKBLp*01 through IKBLp*05 were found in the Japanese population. The frequency of IKBLp*03 was significantly increased in the patient with TA (57.1% vs 35.0%, giving an odds ratio of 2.47). In addition, the frequency of IKBLp*01, but not that of other Ϫ63T-bearing alleles, was increased in the patients with RA (73.3% vs 58.1%, giving an odds ratio of 1.99), suggesting that the susceptibility to RA was conferred not by Ϫ63T alone but by combination of single nucleotide polymorphisms in the NFKBIL1 promoter. A higher promoter activity associated with IKBLp*03 and a lower activity associated with IKBLp*01 may contribute to the susceptibility to TA and RA, respectively. Human Immunology 67, 363-373 (2006).
Human Genetics, 2009
Coronary artery disease (CAD) is based on the atherosclerosis of coronary artery and may manifest... more Coronary artery disease (CAD) is based on the atherosclerosis of coronary artery and may manifest with myocardial infarction or angina pectoris. Although it is widely accepted that genetic factors are linked to CAD and several disease-related genes have been reported, only a few could be replicated suggesting that there might be some other CAD-related genes. To identify novel susceptibility loci for CAD, we used microsatellite markers in the screening and found six diVerent candidate CAD loci. Subsequent single nucleotide polymorphism (SNP) association studies revealed an association between CAD and megakaryoblastic leukemia factor-1 gene (MKL1). The association with a promoter SNP of MKL1, ¡184C > T, was found in a Japanese population and the association was replicated in another Japanese population and a Korean population. Functional analysis of the MKL1 promoter SNP suggested that the higher MKL1 expression was associated with CAD. These Wndings suggest that MKL1 is involved in the pathogenesis of CAD.
Molecular Brain Research, 2000
We have isolated and characterized the mouse gene for NDRF (neuroD-related factor), a basic helix... more We have isolated and characterized the mouse gene for NDRF (neuroD-related factor), a basic helix-loop-helix transcription factor implicated in neural development and function. The gene consists of two exons and the entire protein-coding sequence is encoded by a single downstream exon. RNA blot hybridization analysis revealed that NDRF mRNA was detectable at day 4 and increased to a maximal level at day 6 during neuronal differentiation of P19 cells. To elucidate the regulatory mechanisms of the NDRF gene expression during this process, a construct containing the genomic DNA fragment of about 3 kbp upstream of the NDRF coding region fused to a luciferase reporter gene was transfected into P19 cells, and stable transformants were pooled for assay of luciferase activities. When the stable transformants were treated with RA and aggregated to induce neuronal differentiation, the luciferase activities were induced in a temporal expression pattern similar to that of the endogenous NDRF mRNA. Further experiments using a series of deletion and mutation constructs indicated that the 376-bp sequence in the 59-flanking region of the NDRF gene is important, and that one of the E boxes in the sequence plays a critical role in the regulated expression. Transient transfection experiments also showed that the same E box is required for the transactivation of the NDRF promoter activity by neurogenin 1. These results suggest that the NDRF gene expression is regulated by an E box-binding factor during neuronal differentiation of P19 cells.
International Immunology, 2010
Background: Osteoclasts activated by inflammatory cytokines are responsible for bone erosion in r... more Background: Osteoclasts activated by inflammatory cytokines are responsible for bone erosion in rheumatoid arthritis (RA) patients. IL-6 levels in blood and synovial fluids of RA patients are higher than healthy people. IL-6 induces the expression of RANKL which is essential cytokine for osteoclastgenesis in synovial cells. These facts strongly suggest that IL-6 contributes to the differentiation of osteoclasts in RA synovia. Objectives: We examined the effect of IL-6 on the osteoclast formation. Methods: Osteoclast precursor cell line, RAW264.7 cells were cultured with soluble RANKL (sRANKL) in the presence of IL-6 for 3 days and the expression of osteoclastogenesis marker, TRAP was measured. Moreover, synovial cell line, SW982 cells and RAW264.7 cells were co-cultured in the presence of IL-6 for 3 days and the expression of TRAP was measured. Results: IL-6 dramatically decreased the induction of TRAP expression in RAW264.7 cells by sRANKL. In co-culture of SW982 cell and RAW264.7 cells, as the number of SW982 cells increased, IL-6 increased the expression of TRAP in RAW264.7 cells. When SW982 cells were cultured with IL-6 for 24 h, we found that IL-6 increased the expression of RANKL and ICAM-1 in SW982 cells. Either anti-RANKL or anti-ICAM-1 antibody inhibited increase of expression of TRAP by IL-6 in co-culture of SW982 cells and RAW264.7 cells. Moreover, the addition of soluble ICAM-1 reversed reduction of TRAP expression by IL-6 in RAW267.4 cells. Conclusions: IL-6-induced RANKL and ICAM-1 in synovial cells positively drives osteoclast differentiation in co-culture of RAW264.7 and SW982 cells.
Journal of Immunology, Jul 1, 1990
In an attempt to obtain direct evidence for the critical role of HLA class II molecules in regula... more In an attempt to obtain direct evidence for the critical role of HLA class II molecules in regulating the immune response, genomic genes for alpha- and beta-chains of HLA-DQw6 from HLA-Dw12 haplotype were introduced into the C57BL/6 (B6) strain of mouse and a line of HLA-DQw6 transgenic mouse was obtained. Tissue specificity of the expression of the transgenes was much the same as that of murine I-Ab genes. DQw6 molecules were expressed on B cells and macrophages in spleen cells and about 30 to 40% of the I-Ab+ spleen cells were positive for DQw6. The HLA-DQw6 transgenic B6 mouse became tolerant to the DQw6 molecules, as evidenced by the MLR and antibody production specific to the DQw6 molecules. The HLA-DQw6 transgenic B6 mouse showed a strong immune response to streptococcal cell wall antigen (SCW), whereas the B6 mouse was a low responder to SCW. The SCW-specific T cell line was established from the transgenic mouse and this T cell line recognized SCW in the context of HLA-DQw6 m...
Journal of Human Genetics, 1985
Fukuoka igaku zasshi = Hukuoka acta medica, 1988
Clinical and experimental rheumatology, 2007
Familial Mediterranean Fever (FMF) is an autoinfl ammatory disease caused by mutations in the MEF... more Familial Mediterranean Fever (FMF) is an autoinfl ammatory disease caused by mutations in the MEFV gene and characterized by recurrent fever, polyserositis and arthritis. It is transmitted in an autosomal recessive pattern. FMF has been predominantly found in ethnic groups living around the Mediterranean basin (Jews, Arabs, Turks, and Armenians). Although accompanying infl ammatory diseases have been reported in FMF, the coexistance of fi bromyalgia syndrome (FMS) is very rare. MEFV gene analysis that the fi rst patient had compound heterozygous mutation (M680I+V726A) and the other patient had heterozygous mutation (M694V). This association will be discussed in this case report.
Clinical and experimental immunology, 2014
Inflammatory myopathy with abundant macrophages (IMAM) has recently been proposed as a new clinic... more Inflammatory myopathy with abundant macrophages (IMAM) has recently been proposed as a new clinical condition. Although IMAM shares certain similarities with other inflammatory myopathies, the mechanisms responsible for this condition remain unknown. Patients with familial Mediterranean fever (FMF) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS) also often develop myalgia. We therefore investigated the polymorphisms or mutations of MEFV and TNFRSF1A genes in patients with IMAM to identify their potential role in this condition. We analysed the clinical features of nine patients with IMAM and sequenced exons of the MEFV and TNFRSF1A genes. The patients with IMAM had clinical symptoms such as myalgia, muscle weakness, erythema, fever and arthralgia. Although none of the patients were diagnosed with FMF or TRAPS, seven demonstrated MEFV polymorphisms (G304R, R202R, E148Q, E148Q-L110P and P369S-R408Q), and one demonstrated a TNFRSF1A mutation (C43R). These resul...
Clinical & Experimental Immunology, 2015
Summary Autoinflammatory diseases include a large spectrum of monogenic diseases, e.g. familial M... more Summary Autoinflammatory diseases include a large spectrum of monogenic diseases, e.g. familial Mediterranean fever (FMF), as well as complex genetic trait diseases, e.g. adult-onset Still's disease (AOSD). In populations where FMF is common, an increased MEFV mutation rate is found in patients with rheumatic diseases. The aim of this study was to examine MEFV mutations in Japanese patients with AOSD. Genomic DNA was isolated from 49 AOSD patients and 105 healthy controls, and exons 1, 2, 3 and 10 of the MEFV gene genotyped by direct sequencing. MEFV mutation frequencies in AOSD patients were compared with controls. We found no significant difference in overall allele frequencies of MEFV variants between AOSD patients and controls. However, MEFV exon 10 variants (M694I and G632S) were significantly higher in AOSD patients than controls (6·1 versus 0%). In addition, there was no significant difference between MEFV variant carriers and non-carriers with clinical manifestations, bu...
Rheumatology, 2014
Objective. The aim of this study was to analyse the role of circulating cleaved IL-1b in patients... more Objective. The aim of this study was to analyse the role of circulating cleaved IL-1b in patients with FMF. Methods. We enrolled 20 patients with FMF (5 males and 15 females), 22 patients with RA (4 males and 18 females) and 22 healthy controls (6 males and 16 females). Serum levels of serum amyloid A (SAA) were measured by ELISA. We also determined whether IL-1b was present as the cleaved form (p17) in the sera of FMF patients by immunoblotting using anti-cleaved IL-1b antibody. Results. Although SAA concentrations were elevated in the sera, there was no significant difference in these concentrations between FMF patients and RA patients. Immunoblot analysis demonstrated that the cleaved form of IL-1b (p17) was present in sera from FMF patients during febrile attack periods, but not in healthy controls. Bands representing the cleaved form of IL-1b were not detected in serum from FMF patients at non-febrile attack periods or remission periods under colchicine treatment. The amounts of cleaved IL-1b (p17) were significantly higher in patients with FMF compared with those in patients with RA in the inflammatory phase. Conclusion. The cleaved form of IL-1b is a valuable biomarker for monitoring disease activity and response to colchicine treatment in patients with FMF. It might be useful to discriminate FMF from other non-IL-1b-mediated inflammatory disorders.
Research in Immunology, 1991
The particular alleles of the HLA-DQ locus may control the low immune response to natural antigen... more The particular alleles of the HLA-DQ locus may control the low immune response to natural antigens by a dominant genetic trait through the immune suppression mediated by CD8+ suppressor T cells. The suppressor T cells may be activated by DQ-restricted and antigen-specific CD4+ suppressor/inducer T cells, because (1) a statistically significant association and linkage between low immune responsiveness to the natural antigens and the HLA-DQ gene were observed; (2) antigen-specific CD4+ T cells restricted by the DQ molecules encoded for by the HLA-DQ allele associated with low responsiveness were evidenced in many low responders; and (3) anti-HLA-DQ mAb restored the immune response to natural antigens, in some low responders. This HLA-DQ-controlled polymorphism of immune response to the natural antigens may account for the association between HLA-DQ alleles and organ-specific autoimmune diseases.
Tissue Antigens, 2007
To investigate the recently reported associations of polymorphisms in lymphotoxin-alpha (LTA) and... more To investigate the recently reported associations of polymorphisms in lymphotoxin-alpha (LTA) and galectin-2 (LGALS2) with myocardial infarction (MI), we analyzed a single nucleotide polymorphism of LTA (LTA 252A>G in LTA intron 1) and that of LGALS2 (LGALS2 3279C>T in LGALS2 intron 1) in Japanese and Korean populations. Although significant associations with MI were not observed in either population, we found that LTA 252GG was significantly associated with the severity of the disease for both the Japanese and Korean populations (P=0.017 and P=0.001, respectively). On the other hand, the polymorphism of LGALS2 was not associated with the severity of coronary atherosclerosis. These observations showed that, while the LTA 252GG genotype might modify the development of coronary atherosclerosis, the relation of LTA and LGALS2 to MI itself remained much less certain.
Scandinavian Journal of Immunology, 2012
Fc gamma receptor (FccR) provides an important link between humoral and cellular immune responses... more Fc gamma receptor (FccR) provides an important link between humoral and cellular immune responses. FccRIIa-H131R polymorphism has been associated with differential binding to IgG subclasses and susceptibility to severe malaria phenotypes among different populations in the malaria endemic world. In this study, the effect of FCGR2A gene polymorphisms on susceptibility to symptomatic malaria among Ghanaian cohort children was investigated. Blood samples from four hundred and 29 (429) healthy Ghanaian children were genotyped for FCGR2A polymorphisms by direct DNA sequencing. Attributable and relative risks to symptomatic malaria were calculated for the polymorphic variants. Two major FCGR2A polymorphisms, rs1801274A ⁄ G (FccRIIa-H131R) and rs150311303 (FccRIIa-ins170L), were identified in the study population, and assessment of their risks did not show significant association with susceptibility to symptomatic malaria. The functional significance of these polymorphisms was also examined by evaluating their binding abilities to IgG subclasses using flow cytometric analysis of HEK cells transfected with the FccRIIa haplotype variants. The binding assay revealed the rs150311303, which was observed only among carriers of the FccRIIa-131RR genotype for the rs1801274 to consistently enhance binding capacities to all IgG subclasses. Thus, of the three FccRIIa haplotype variants observed in this study population, the FccRIIa RL haplotype variant was observed to have the highest binding ability to IgG1, IgG3 and IgG4.
Proceedings of the National Academy of Sciences, 1991
PLoS ONE, 2011
Background: Apoptosis is thought to play a role in the pathogenesis of severe dengue and the rele... more Background: Apoptosis is thought to play a role in the pathogenesis of severe dengue and the release of cell-free DNA into the circulatory system in several medical conditions. Therefore, we investigated circulating DNA as a potential biomarker for severe dengue. Methods and Findings: A direct fluorometric degradation assay using PicoGreen was performed to quantify cell-free DNA from patient plasma. Circulating DNA levels were significantly higher in patients with dengue virus infection than with other febrile illnesses and healthy controls. Remarkably, the increase of DNA levels correlated with the severity of dengue. Additionally, multivariate logistic regression analysis showed that circulating DNA levels independently correlated with dengue shock syndrome. Conclusions: Circulating DNA levels were increased in dengue patients and correlated with dengue severity. Additional studies are required to show the benefits of this biomarker in early dengue diagnosis and for the prognosis of shock complication.
Tissue Antigens, 2007
To investigate the recently reported associations of polymorphisms in lymphotoxin-alpha (LTA) and... more To investigate the recently reported associations of polymorphisms in lymphotoxin-alpha (LTA) and galectin-2 (LGALS2) with myocardial infarction (MI), we analyzed a single nucleotide polymorphism of LTA (LTA 252A>G in LTA intron 1) and that of LGALS2 (LGALS2 3279C>T in LGALS2 intron 1) in Japanese and Korean populations. Although significant associations with MI were not observed in either population, we found that LTA 252GG was significantly associated with the severity of the disease for both the Japanese and Korean populations (P=0.017 and P=0.001, respectively). On the other hand, the polymorphism of LGALS2 was not associated with the severity of coronary atherosclerosis. These observations showed that, while the LTA 252GG genotype might modify the development of coronary atherosclerosis, the relation of LTA and LGALS2 to MI itself remained much less certain.