Biomedical subjects

Taro Maruyama

Publications and source records attributed to Taro Maruyama.

At least 19 recordsLinked to original sources

PubMed2007

De novo CD5+ diffuse large B cell lymphoma with basophilia in the peripheral blood: successful treatment with autologous peripheral blood stem cell transplantation.

Basophils play an important role in allergic inflammation and are pathologically related to hematological disturbances, such as iron deficiency anemia and myeloproliferative disorders; however, they are only rarely encountered in lymphoid malignancies. Here, we report the case of a 33-year-old man with a bulky mass of the small intestine, multiple paraaortic lymphoadenopathy, pleural effusion, and ascites, who was diagnosed as a case of de novo CD5+ diffuse large B cell lymphoma (DLBCL). This patient showed a marked elevation of the basophil count in the peripheral blood, which appeared to run in parallel with the tumor burden. High dose chemotherapy followed by autologous peripheral blood cell transplantation yielded complete remission, and the patient has remained disease free for 5 years. To the best of our knowledge, this is the first report of a case of de novo CD5+ DLBCL showing marked elevation of the PB basophil count.

Adult↗

PubMed2006

Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter polymorphism and type 1 diabetes in Asian populations.

The protein tyrosine phosphatase, nonreceptor 22 gene (PTPN22) maps to human chromosome 1p13.3-p13.1 and encodes an important negative regulator of T-cell activation, lymphoid-specific phosphatase (Lyp). Recently, the minor allele of a single-nucleotide polymorphism (SNP) at nucleotide position 1858 (rs2476601, +1858C > T) was found to be associated with type 1 diabetes. However, the degree of the association is variable among ethnic populations, suggesting the presence of other disease-associated variants in PTPN22. To examine this possibility, we carried out a systemic search for PTPN22 using direct sequencing of PCR-amplified products in the Japanese population. Association and linkage studies were also conducted in 1,690 Japanese samples, 180 Korean samples, and 472 Caucasian samples from 95 nuclear families. We identified five novel SNPs, but not the +1858C > T SNP. Of these two frequent SNPs, -1123G > C, and +2740C > T were in strong linkage disequilibrium (LD), and the -1123G > C promoter SNP was associated with acute-onset but not slow-onset type 1 diabetes in the Japanese population (odds ratio [OR] = 1.42, 95% CI = 1.07-1.89, P = 0.015). This association was observed also in Korean patients with type 1 diabetes (Mantel-Haenszel chi2= 6.543, P = 0.0105, combined OR = 1.41 95% CI = 1.09-1.82). Furthermore, the affected family-based control (AFBAC) association test and the transmission disequilibrium analysis of multiplex families of European descent from the British Diabetes Association (BDA) Warren Repository indicated that the association was stronger in -1123G > C compared to +1858C > T. In conclusion, the type 1 diabetes association with PTPN22 is confirmed, but it cannot be attributed solely to the +1858C > T variant. The promoter -1123G > C SNP is a more likely causative variant in PTPN22.

Alleles↗

PubMed2006

A sensitive radioimmunoassay of insulin autoantibody: reduction of non-specific binding of [125I]insulin.

There has been a lack of consensus among results of assays for insulin autoantibody (IAA) carried out by different laboratories, despite a reduction in the non-specific effect using a cold insulin competitor in radioimmunoassays (RIAs) for IAA in type I diabetes. We speculated that the discrepancies are partly a result of the non-specific binding (NSB) of [125I]insulin to unidentified molecules in serum on polyethylene glycol separation, and tried to improve IAA RIAs. The molecular weight of a candidate for the factor causing NSB was estimated to be about 700 kDa by gel filtration analysis, resembling that of alpha 2-macroglobulin (a2M). Further, the addition of purified a2M to the assay resulted in an increase in NSB. Screening revealed that heterocyclic compounds, such as isothiazolinone derivatives (ProClin300), were greatly effective at reducing NSB in control subjects from 2.904+/-0.909% to 1.347+/-0.254% (n=283, mean+/-SD, p<0.0001). Using our newly developed IAA RIA with ProClin300, the sensitivity for newly diagnosed type I diabetes patients (n=55) was 32.7% and 30.9% with or without insulin competition, respectively, whereas that of the former assay without ProClin300 was only 20.0%.

Adolescent↗

PubMed2006

Association of ceramides in human plasma with risk factors of atherosclerosis.

Atherosclerosis is a multifactorial disorder. Recent studies indicate that the plasma level of sphingomyelin, which yields ceramide, correlates with the risk of coronary heart disease. Therefore, ceramide, a well-known lipid causing apoptosis in various cell types, may contribute to atherogenesis. We examined the relationship between ceramide concentration and risk factors of atherosclerosis in normal human plasma using electrospray tandem mass spectrometry (LC-MS/MS). Major ceramides in human plasma were C24:0 and C24:1. The ceramide concentration showed a significant positive correlation with total cholesterol (TC) and triglycerides (TG). In addition, plasma ceramide level increased drastically at a high level of LDL cholesterol (more than 170 mg/dL). Our previous studies demonstrated that the sum of fragmented and conjugated apolipoprotein B-100 proteins (B-ox), which were products of a radical reaction of LDL as well as plasma, was a reliable index of atherosclerosis. B-ox showed a significant positive correlation with the plasma ceramide level. Based on these results, we propose that the ceramide level in human plasma is a risk factor at the early stages of atherosclerosis.

Apolipoprotein B-100↗

PubMed2006

Immunopathological and genetic features in slowly progressive insulin-dependent diabetes mellitus and latent autoimmune diabetes in adults.

In 1982 we proposed the presence of a subtype of type 1 diabetes [slowly progressive insulin-dependent diabetes mellitus (SPIDDM)], which was characterized by persistently positive islet cell antibody, late age of onset, noninsulin-dependent diabetes, and slowly progressive beta cell failure. Since then many studies demonstrated that this subtype of type 1 diabetes is prevalent in many ethnic groups and was later called the latent autoimmune diabetes in adults (LADA). Recent epidemiological studies reported that about 10% of patients with apparent type 2 diabetes have at least one autoantibodies against islet-specific antigen with high potential to progress to insulin-dependent state. Between SPIDDM and LADA some differences are reported in terms of some genetic predispositions including HLA class II and class I genes, vitamin D receptor gene, and CTLA4 genes. Common features in SPIDDM and LADA including preserved beta cells at the onset of diabetes and weak T cell response to residual beta cells suggest that these subtypes of type 1 diabetes are suitable candidates for prevention treatment for further progression of beta cell failure.

Adult↗

PubMed2006

Expression levels of CXC chemokine receptors 3 are associated with clinical phenotype of type 1 diabetes.

Type 1 diabetes is recognized as one of T helper 1 cell (Th1)-mediated diseases. The purpose of this article was to investigate the expression levels of CXC chemokine receptor 3 (CXCR3) and CC chemokine receptor 5 (CCR5) on CD4 T cells as Th1 markers in Japanese patients with type 1 diabetes and control subjects. A total of 72 patients with type 1 diabetes and 24 healthy subjects were enrolled. Their peripheral mononuclear cells were obtained and stained with anti-CXCR3, anti-CCR5, and anti-CD4 monoclonal antibodies. Flow-cytometric analysis was performed and patients were classified according to their onset pattern as fulminant, typical, or slow onset. Statistical analysis was performed using ANOVA. CXCR3 expression on CD4 T cells in patients with a fulminant pattern of onset was significantly lower than that in the other groups, and that in patients with a typical pattern of onset was significantly higher than that in the other groups. CCR5 expression on CD4 T cells was not different among the three clinical phenotypes. CXCR3 expression level is associated with the onset pattern of type 1 diabetes. Further studies are needed to clarify the role of chemokines in type 1 diabetes.

Adult↗

PubMed2006

Frequency of CTLA-4 gene CT60 polymorphism may not be affected by vitamin D receptor gene Bsm I polymorphism or HLA DR9 in autoimmune-related type 1 diabetes in the Japanese.

One of the CTLA-4 SNPs, +6230G>A (CT60), has recently been reported to be related to susceptibility to type 1 diabetes and autoimmune thyroid disease. We have previously reported an association between acute-onset type 1 diabetes in Japanese and the Vitamin D receptor (VDR) gene Bsm I large B polymorphism, which is related to the Th1-type response. Moreover, we found a significant correlation between autoimmune-related type 1 diabetes with HLA DR9 and detection of GAD-reactive Th1 (T helper 1)-type cells. In the present article, we tried to clarify whether the frequency of one of the CTLA-4 SNPs, +6230G>A (CT60), is affected by the VDR gene Bsm I polymorphism or by HLA DR9 in Japanese type 1 diabetics. The frequency of the CT60 GG genotype did not appear to be affected by either the VDR gene Bsm I large B polymorphism or HLA DR9.

Adult↗

PubMed2006

Immunochemical quantification of free immunoglobulin light chains from an analytical perspective.

Immunoglobulin light chains are components of antibodies, but some exist in a free form in serum and urine as a result of their excess production over heavy chains. Free light chain (FLC) levels are of the order of milligram per liter in normal serum and urine, but marked increases have been observed in various disease conditions. It has now been established that the measurement of FLC levels contributes to diagnosis and clinical management in monoclonal gammopathies. Recent developments in FLC assays have been adapted to several automated platforms and they have now become available in laboratories. There have, however, been some concerns regarding the analytical aspects. The current assay specificity appears to be insufficient to prevent the influence of intact light chains of several orders of magnitude greater than FLCs in serum. Moreover, the heterogeneous nature of light chains makes accurate quantification unreliable. FLC assays have never been standardized because of the lack of an international reference calibrator. In this review, we summarize the reports on FLC measurements and examine the specificity of anti-FLC antibodies and the reliability of FLC assays. We also discuss difficulties in the standardization and setting of normal reference intervals for FLC assays.

Antibodies, Monoclonal↗

PubMed2006

Serum apolipoprotein j in health, coronary heart disease and type 2 diabetes mellitus.

Apolipoprotein (apo) J, clusterin, is ubiquitously expressed in many tissues, and is a component of high-density lipoproteins (HDLs). There is experimental evidence that it may be anti-atherogenic through its effects on cholesterol transport, smooth muscle cell proliferation and lipid peroxidation. HDLs containing apo J and apo A-I carry paraoxonase (PON1), which protects low-density lipoproteins from oxidative modification; however, the extent to which apo J affects coronary heart disease (CHD) is not known. We have developed a sandwich ELISA that enables apo J to be assayed in the range of 13-200 microg/mL. Serum apo J was 52.8+/-0.8 microg/mL (mean+/-SEM; range, 36.0-84.3 microg/mL; n=92) in healthy Japanese men, and 49.3+/-0.5 microg/mL (34.5-72.8; n=241) in healthy Japanese women. Multiple regression of these data and results from 67 men with CHD showed that apo J concentration was unrelated to age, sex or body mass index, but was positively related to serum PON1 (p<0.001) and apo B (p<0.02) concentrations. In women, it was also positively related to blood glucose (p<0.02). After adjusting for its associations with covariates, serum apo J averaged 5.4 microg/mL, lower in CHD men than in controls (p<0.003). Type 2 diabetics had higher apo J concentrations (men, 83.1+/-3.4 microg/mL, n=64; women, 64.0+/-2.3 microg/mL, n=46) than healthy men and women (p<0.001). In these Type 2 diabetics, apo J concentration was unrelated to PON1 concentration, but was positively related to blood glucose (p<0.01). After adjustment for its relation to blood glucose, the mean apo J concentration was similar in diabetics and healthy subjects. These findings suggest that apo J may be anti-atherogenic in humans, and that its concentration is raised by Type 2 diabetes.

Antibodies, Monoclonal↗

PubMed2005

The association of CTLA4 polymorphism with type 1 diabetes is concentrated in patients complicated with autoimmune thyroid disease: a multicenter collaborative study in Japan.

CONTEXT: Transracial studies are a powerful tool for genetic association studies of multifactorial diseases, such as type 1 diabetes. The low incidence of type 1 diabetes in Asian countries, however, makes it difficult to perform large-scale studies in Asia. OBJECTIVE: To overcome this, we have assembled a multicenter study group in Japan and studied the association of CTLA4 polymorphisms with type 1 diabetes relative to autoimmune thyroid disease (AITD) phenotypes. SUBJECTS: Subjects included a total of 1837 samples, including 1114 cases (769 with type 1 diabetes and 345 with AITD) and 723 control subjects. METHODS: The +6230G>A and +49G>A polymorphisms of CTLA4 as well as HLA-DRB1 and -DQB1 were genotyped. RESULTS: The +6230G>A polymorphism was significantly associated with type 1 diabetes complicated with AITD (odds ratio, 1.54; P = 0.027) and with AITD alone (odds ratio, 1.31; P = 0.045) but not with type 1 diabetes without AITD. The association with type 1 diabetes positive for autoantibodies to both pancreatic islets and thyroid was particularly strong (odds ratio, 1.87; P = 0.001). Type 1 diabetic patients with the disease-associated GG genotype were characterized by a significantly higher frequency of AITD (P = 0.013), of positivity for both AITD and antiislet autoantibody (P = 0.00086), and of high-risk HLA genotypes (P = 0.034). CONCLUSIONS: Given the high frequency of AITD in patients with type 1 diabetes, these data suggest the possibility that the association of CTLA4 with type 1 diabetes in previous studies may have been secondary to AITD, suggesting the importance of subclassification of type 1 diabetes relative to AITD in genetic studies.

Adult↗

PubMed2004

GAD-reactive T cells were mainly detected in autoimmune-related type 1 diabetic patients with HLA DR9.

Type 1 diabetes mellitus (T1DM) is considered to be a T cell-mediated disease, and many reports suggest that some HLA types, especially HLA DR4 and DR9, convey susceptibility to T1DM in Japanese. We investigated the association between T cell reactivity against GAD and HLA types in "islet-associated autoantibody-positive" T1DM in Japanese. Blood samples were obtained from 36 "autoantibody-positive" type 1 diabetic patients with HLA DR4 or DR9 and 23 type 2 diabetic patients with HLA DR4 or DR9 as controls. They were divided into three groups, DR4/9, DR4/X, and DR9/X groups. In each HLA type group, GAD-reactive IFN-gamma-producing CD4(+) cells were assessed by means of intracellular cytokine staining for flow cytometry. Type 1 diabetic patients with HLA DR9/X had significantly higher numbers of GAD-reactive IFN-gamma-producing CD4(+) cells as compared to type 1 diabetic patients with DR4/X or DR4/9 (P < 0.05) and all type 2 diabetic patients. There was no significant difference in the number of GAD-reactive IFN-gamma-producing CD4(+) cells between type 1 diabetic and type 2 diabetic patients belonging to the DR4/X and DR4/9 groups. There was an association between T cell reactivity against GAD and HLA DR9 in Japanese type 1 diabetes.

Adult↗

PubMed2004

Relation between development of nephropathy and the p22phox C242T and receptor for advanced glycation end product G1704T gene polymorphisms in type 2 diabetic patients.

OBJECTIVE: The development of diabetic nephropathy is considered to be associated with oxidative stress. NADPH oxidase and the receptor for advanced glycation end products (RAGE) have attracted attention as mechanisms of generating oxidative stress. We studied the relation between the genotypes of the NADPH p22phox C242T and RAGE G1704T polymorphisms and the development of diabetic nephropathy in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Using a retrospective review of clinical data, we allocated 181 Japanese type 2 diabetic patients to one of two groups: patients without diabetic nephropathy (group N; n = 108) and patients developing diabetic nephropathy (group D; n = 73) for 10 years or more. The p22phox C242T and RAGE G1704T polymorphisms were examined by Taqman PCR methods. RESULTS: The frequency of the p22phox CC genotype was significantly higher in group D than in group N (90 vs. 79%; P = 0.0427). The frequency of the RAGE GT + TT genotype was significantly higher in group D than in group N (26 vs. 13%; P = 0.0313). The frequency of the combination of p22phox CC and RAGE GT + TT genotypes was significantly higher in group D than in group N (22 vs. 8%; P = 0.0057). In multiple logistic regression analysis, systolic blood pressure, HbA(1c), triglycerides, and the combination of polymorphisms were shown to be independent variables. CONCLUSIONS: These results suggest that assessment of the combination of NADPH p22phox C242T and RAGE G1704T polymorphisms may be useful in identifying the risk for developing diabetic nephropathy in type 2 diabetic patients.

Adult↗

PubMed2004

Relationships of nutrient intake and lifestyle-related factors to serum folate and plasma homocysteine concentrations in 30-69 year-old Japanese.

We studied non-hospitalized 30-69 y-old Japanese subjects to ascertain the influences of a 677C-T methylene-tetrahydrofolate reductase (MTHFR) genotype, nutritional intake and lifestyle-related factors on plasma homocysteine (Hcys) and serum folate concentrations. Hcys was higher and serum folate was lower in males than in females (p < .01). The Hcys concentration was higher in the VV group than in the AA and AV groups for both males and females. However, a relatively low serum folate concentration of 18 +/- 7 nmol/L was found in the entire male group as compared with 22 +/- 10 nmol/L in all females. In the female subjects, serum folate concentrations differed among MTHFR genotypes, being lowest in the VV group. In all male subjects, log folate intake per 1,000 kcal was a significant positive predictor of log serum folate concentration (p < 0.01), while in females the log vitamin C intake per standard body weight was a significant positive variable (p < 0.001) predicting the log serum folate concentration. Smokers had significantly lower serum folate concentrations, regardless of dietary folate intake. High folate and vitamin C consumptions, appears to be beneficial to normal and heterozygous MTHFR genotype subjects for maintaining serum folate concentrations. Even a 400 microg daily intake of folate might be less than what is needed, especially for homozygous MTHFR subjects and smokers, to maintain an adequate serum folate concentration.

Adult↗

PubMed2003

NAD(P)H oxidase p22phox Gene C242T polymorphism and lipoprotein oxidation.

BACKGROUND: Vascular NAD(P)H oxidase is a key enzyme of superoxide anion production in human vessel walls. The C242T mutation in the CYBA gene coding for p22phox, a component of the enzyme, may change the redox state. The aim of this study was to evaluate the influence of the polymorphism on serum concentrations of oxidative stress markers. METHODS: Serum samples were collected from 134 Type 2 diabetic patients and analyzed for oxidized high-density lipoprotein (HDL) by in-house ELISA, and oxidized low-density lipoprotein (LDL) and thiobarbituric acid reactive substance (TBARS) by commercial kits. For genotyping, the Taqman PCR method was adapted to detect the polymorphism. RESULTS: Circulating concentrations of oxidized HDL were about 1.5-fold lower in those of the CT/TT genotypes than the CC genotype [3.3 +/- 0.3 and 5.0 +/- 0.3 U/dl (mean +/- S.E.M.), respectively; multiple regression analysis, p=0.006], whereas concentrations of oxidized LDL were slightly greater (1.1-fold, p=0.01) in those with the CT/TT genotypes. However, no significant difference was observed in TBARS between the genotypes. CONCLUSIONS: The effect was inconsistent among the markers, but these results suggest that the CYBA C242T polymorphism is involved in NAD(P)H oxidase activity and affects oxidation of lipoproteins by altering the redox state in the vasculature.

Adult↗

PubMed2003

T-cell function in anti-GAD65(+)diabetes with residual beta-cell function.

We have recently reported that in patients with anti-glutamic acid decarboxylase (GAD) 65(+)diabetes with residual beta-cell function, most with a 'high-titer' (>10U/ml) required insulin within 5 years, whereas most with a 'low-titer' (1.3-9.9U/ml) did not need insulin for over 15-20 years after the onset. We therefore examined T-cell function to evaluate the difference between the high-titer and low-titer groups. Interleukin (IL)-10 production upon polyclonal activation was significantly lower in the high-titer group than in the low-titer group. The serum level of interferon-inducible protein-10 (IP-10) was higher in the high-titer than the low-titer group. Although GAD65-reactive CD4(+)cells in the periphery were detected in both groups, a significant positive correlation between serum IP-10 level and the number of GAD65-reactive CD4(+)cells was observed only in the high-titer group. Therefore, it has been speculated that the co-existence of GAD65-reactive IFN-gamma-producing CD4(+)cells and a high serum IP-10 level may be important for rapid disease progression as seen in the high-titer group. Based upon these results, T-cell function is considered to be different between the high-titer and low-titer groups in anti-GAD65(+)diabetes with residual beta-cell function, supporting our previous findings regarding the clinical outcome of insulin-dependence in the two groups.

Adult↗

PubMed2003

NKT cell frequency in Japanese type 1 diabetes.

A numerical and functional deficit of natural killer T (NKT) cells has been reported to be associated with the pathogenesis of Caucasian patients with type 1 diabetes. However, a conflicting finding of a higher frequency of NKT cells (Valpha24+ Vbeta11+ T cells) was observed in islet-associated Ab+ and Ab- Japanese "classic" type 1 diabetes. Here, we combined the data of NKT cell frequency in Ab+ and Ab- "classic" type 1 diabetic patients and then analyzed the relationship between NKT cell frequency and disease activity.

Adolescent↗

PubMed2003

Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) P22 Phox C242T gene polymorphism in type 1 diabetes.

Type 1 diabetes is caused by the immune-mediated destruction of insulin-secreting pancreatic beta cells and is thought to be an autoimmune disease resulting from a complex interaction of genetic and environmental factors. In animal models of type 1 diabetes, macrophages and their products, superoxides, have central roles in the beta cell destruction, but in humans their roles remain unclear. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase produces superoxide in macrophages, and its essential component, p22 phox, is a critical enzyme for superoxide production. The C242T polymorphism in the p22 phox coding gene has been reported to be associated with reduced oxidase activity. We therefore investigated whether the p22 phox gene polymorphism affected the susceptibility to and clinical course of type 1 diabetes. We examined 287 Japanese type 1 diabetic patients and 425 unrelated nondiabetic subjects. In addition, we allocated the diabetic patients to the following three groups: (1) acute-onset type 1 diabetes with at least one autoantibody (GADA, IA-2, IAA); (2) acute-onset type 1 diabetes without autoantibodies; and (3) slow-onset type 1 diabetes with autoantibody. We could not find a significant difference in p22 phox genotype and T allele frequency between overall type 1 diabetic patients and control subjects. Regardless of the onset pattern and autoantibody positivity of type 1 diabetes, no difference in p22 phox genotype and T allele frequency was found among the groups. In conclusion, the p22 phox C242T gene polymorphism did not affect the susceptibility to and clinical course of Japanese type 1 diabetes.

Base Sequence↗

PubMed2003

Stromal cell-derived factor-1 chemokine gene polymorphism is not associated with onset age of Japanese type 1 diabetes.

Type 1 diabetes is characterized by cell-mediated autoimmune destruction of pancreatic beta cells. Although the disease shows a strong association with HLA class II alleles, other genes may influence the initiation or the rate of progression of the autoimmune process. Recently, it was reported that a polymorphism of the stromal cell-derived factor-1 (SDF-1) (a kind of chemokine) gene was associated with early onset of type 1 diabetes in Caucasians. Therefore, we examined SDF-1 gene polymorphism in Japanese type 1 diabetes in this study. We examined the SDF-1 gene polymorphism (801G-->A) in 298 unrelated Japanese type 1 diabetic patients and 270 healthy subjects by the TaqMan PCR method. Allelic and genotypic frequencies of the SDF-1 A variants were similar in overall type 1 diabetic patients and healthy subjects. We then stratified the patients by their onset pattern (acute vs. slow onset) and islet-associated autoantibody positivity. However, no significant difference was found among each group of type 1 diabetes. Furthermore, unlike the previous report in "Caucasian" type 1 diabetics, the SDF-1 A variant was not associated with early onset of the disease in Japanese type 1 diabetics. The SDF-1 gene polymorphism was not associated with onset age (or onset pattern) of type 1 diabetes in Japanese. Further study is necessary to conclude whether SDF-1 gene polymorphism affects the onset age in type 1 diabetes in general.

Adult↗