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Biomedical subjects

Akira Shimada

Publications and source records attributed to Akira Shimada.

At least 37 records · Page 2Linked to original sources
PubMed2004

CXC chemokine ligand 10 neutralization suppresses the occurrence of diabetes in nonobese diabetic mice through enhanced beta cell proliferation without affecting insulitis.

We have shown that neutralization of IFN-inducible protein 10/CXCL10, a chemokine for Th1 cells, breaks Th1 retention in the draining lymph nodes, resulting in exacerbation in Th1-dominant autoimmune disease models induced by immunization with external Ags. However, there have been no studies on the role of CXCL10 neutralization in Th1-dominant disease models induced by constitutive intrinsic self Ags. So, we have examined the effect of CXCL10 neutralization using a type 1 diabetes model initiated by developmentally regulated presentation of beta cell Ags. CXCL10 neutralization suppressed the occurrence of diabetes after administration with cyclophosphamide in NOD mice, although CXCL10 neutralization did not significantly inhibit insulitis and gave no influence on the trafficking of effector T cells into the islets. Because both CXCL10 and CXCR3 were, unexpectedly, coexpressed on insulin-producing cells, CXCL10 was considered to affect mature and premature beta cells in an autocrine and/or paracrine fashion. In fact, CXCL10 neutralization enhanced proliferative response of beta cells and resultantly increased beta cell mass without inhibiting insulitis. Thus, CXCL10 neutralization can be a new therapeutic target for beta cell survival, not only during the early stage of type 1 diabetes, but also after islet transplantation.

Animals↗
PubMed2004

Hypertensive disorders in Japanese women with gestational glucose intolerance.

We investigated the relationship between gestational glucose intolerance and the development of pregnancy-induced hypertension including gestational hypertension (GH) and preeclampsia. Consecutive Japanese women with singleton pregnancies underwent a standard 1h, 50g oral glucose challenge test (GCT) at 24-27 weeks of gestation, followed by a 75g, 2h oral glucose tolerance test (OGTT) if the GCT result exceeded 130mg/dl. Using criteria of the Japan Society of Obstetrics and Gynecology, gestational diabetes mellitus (GDM) was defined by two or more abnormal OGTT values and mild glucose intolerance by one abnormal value. The normal glucose tolerance group included women with GCT results below 130mg/dl or normal OGTT values. GH was defined as blood pressure of at least 140/90mmHg occurring for the first time after mid-pregnancy, without proteinuria. Preeclampsia was determined as GH with proteinuria. Of 2651 consecutive patients, 49 women were found to have GDM, and 139 showed mild glucose intolerance. Sixty patients showed GH, and 58 developed preeclampsia. The frequency of GH in mild glucose intolerance or GDM was 5.8% or 8.2%, respectively, significantly greater than in normal glucose tolerance (P<0.01). Incidence of preeclampsia was not significantly increased in women with mild glucose intolerance or GDM (2.2% or 4.1%, respectively, compared to those with normal glucose tolerance). Japanese women with gestational glucose intolerance therefore have an increased risk of developing GH.

Adult↗
PubMed2004

Incidence and underlying etiologies of bronchial secretion in terminally ill cancer patients: a multicenter, prospective, observational study.

Although bronchial secretion is frequently observed in terminally ill cancer patients and can cause significant distress for both patients and family members, the pathophysiology is unclear. The primary aim of this study was to investigate the incidence and underlying etiologies of bronchial secretion. A multicenter, prospective, observational study was conducted on consecutive terminally ill patients with lung or abdominal malignancies. Primary physicians and nurses prospectively evaluated patients' symptoms. Of 310 patients enrolled, bronchial secretions were observed in 41% in the final 3 weeks, and oral/bronchial suctioning, with considerable distress, was required in 9%; bronchial secretions were severe in 4.5% of all patients. Multiple logistic regression analyses revealed that the determinants of the development of bronchial secretion were primary lung cancer, pneumonia, and dysphagia. There were no statistically significant effects of severity of peripheral edema and pleural effusion on development of bronchial secretions and requirement for oral/bronchial suctioning. Etiology-based classification of bronchial secretion is useful to identify the most suitable palliative treatments and to clarify treatment efficacy in each specific pathophysiology.

Abdominal Neoplasms↗
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↗
PubMed2003

Proinflammatory cytokinemia associated with transient myeloproliferative disorder in down syndrome.

A transient myeloproliferative disorder (TMD) occurs in 10% of the infants with Down syndrome. While most cases resolve within a few months, in 20% of them TMDs are life-threatening or fatal. We encountered 4 patients with TMD, including 1 patient who died of liver failure and disseminated intravascular coagulation. Suspecting involvement of proinflammatory cytokines, we serially assayed them in patients' sera. Cytokines were significantly more abundant in patients than in controls. Interleukins 1 and 2, tumor necrosis factor alpha, interferon gamma, and granulocyte-macrophage colony-stimulating factor were greatly increased, especially in the infant who died. Sustained cytokinemia is likely to participate in TMD pathophysiology, and very high serum concentrations might predict a poor outcome.

Cytokines↗
PubMed2003

Systemic administration of IL-18 promotes diabetes development in young nonobese diabetic mice.

IL-18 is now identified as a pleiotropic cytokine that acts as a cofactor for both Th1 and Th2 cell development. Type 1 diabetes is considered a Th1-type autoimmune disease, and to date, the suppressive effect of exogenous IL-18 on the development of diabetes has been reported in 10-wk-old nonobese diabetic (NOD) mice. In the present study we administered exogenous IL-18 systemically in 4-wk-old NOD mice using i.m. injection of the IL-18 expression plasmid DNA (pCAGGS-IL-18) with electroporation. Contrary to previous reports, the incidence of diabetes development was significantly increased in NOD mice injected with pCAGGS-IL-18 compared with that in control mice. Systemic and pancreatic cytokine profiles deviated to a Th1-dominant state, and the the frequency of glutamic acid decarboxylase-reactive IFN-gamma-producing CD4(+) cells was also high in the IL-18 group. Moreover, it was suggested that the promoting effect of IL-18 might be associated with increased peripheral IL-12, CD86, and pancreatic IFN-inducible protein-10 mRNA expression levels. In conclusion, we demonstrate here that IL-18 plays a promoting role as an enhancer of Th1-type immune responses in diabetes development early in the spontaneous disease process, which may contribute to elucidating the pathogenesis of type 1 diabetes.

Age Factors↗
PubMed2003

Evaluation of the diagnostic accuracy of the stop codon (SC) assay for identifying protein-truncating mutations in the BRCA1and BRCA2genes in familial breast cancer.

Screening for protein-truncating mutations of the BRCA1 and BRCA2 genes is useful in genetic testing for familial breast cancer because, first, the methods are usually simple and not expensive, and second, the detected mutations indicate pathogenic mutations in general. We evaluated the diagnostic accuracy of the stop codon (SC) assay for detecting protein-truncating mutations in the BRCA1 and BRCA2 genes by comparing the results with DNA sequencing in samples from 29 patients with breast cancer from 24 Japanese families with a history of breast cancer. Protein-truncating mutations were detected in 5 of the 24 families (20.8%; two in the BRCA1 gene and three in the BRCA2 gene). Among the 176 DNA fragments examined using the SC assay, the existence of three protein-truncating mutations (one in the BRCA1 gene and two in the BRCA2gene) was predicted correctly by the assay. Only one reverse transcriptase-polymerase chain reaction fragment was positive for the SC assay but was negative using DNA sequencing. Our study showed clearly that the SC assay is sensitive (3 of 3, 100%) and specific (172 of 173, 99%) for detecting pathogenic protein-truncating mutations in the BRCA1 and BRCA2 genes, and that it could be useful for screening larger populations.

Biological Assay↗
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

Correlation between serum resistin level and adiposity in obese individuals.

OBJECTIVE: Resistin is associated with insulin resistance in mice and may play a similar role in humans. The aim of our study was to examine the relationship of serum resistin level to body composition, insulin resistance, and related obesity phenotypes in humans. RESEARCH METHODS AND PROCEDURES: Sixty-four young (age 32 +/- 10 years), obese (BMI 32.9 +/- 5.6), nondiabetic subjects taking no medication, and 15 lean (BMI 21.1 +/- 1.3) volunteers were studied cross-sectionally. Thirty-five of the subjects were also reevaluated after 1.5 years on a weight reduction program entailing dieting and exercise; changes of serum resistin were compared with changes of BMI, body composition, fat distribution, and several indices of insulin sensitivity derived from plasma glucose and serum insulin levels measured during 75-g oral glucose tolerance test. RESULTS: In a cross-sectional analysis, serum resistin was significantly higher in obese subjects than in lean volunteers (24.58 +/- 12.93 ng/mL; n = 64 vs. 12.83 +/- 8.30 ng/mL; n = 15; p < 0.01), and there was a correlation between resistin level and BMI, when the two groups were combined (rho = 0.35, p < 0.01). Although cross-sectional analysis in obese subjects revealed no correlation between serum resistin and parameters related to adiposity or insulin resistance, longitudinal analysis revealed change in serum resistin to be positively correlated with changes in BMI, body fat, fat mass, visceral fat area, and mean glucose and insulin (rho = 0.39, 0.40, 0.44, 0.50, 0.40, and 0.50; p = 0.02, 0.03, 0.02, <0.01, 0.02, and <0.01, respectively). DISCUSSION: Resistin appears to be related to human adiposity and to be a possible candidate factor in human insulin resistance.

Adipose Tissue↗
PubMed2003

Assessment of beta cell mass and oxidative peritoneal exudate cells in murine type 1 diabetes using adoptive transfer system.

Because it is controversial how the beta cell mass is reduced during the disease process in type 1 diabetes, we transferred splenocytes from Non-obese diabetic (NOD) to NOD-scid mice and evaluated the relation between the status of the pancreas in donors and the time taken to transfer diabetes to the recipients. We also evaluated the usefulness of assessment of the proportion of oxidative peritoneal exudate cells (PEC) as a novel marker of disease activity in this system. We examined the proportion of oxidative PEC, pancreatic insulin content and pancreatic histology in 16-18-week-old female NOD mice (donors), and transferred their splenocytes into 5-week-old female NOD-scid mice (recipients). After the onset of diabetes in NOD-scid recipients, we assessed the relation between insulin content (or severity of insulitis) of NOD donors and the time taken to transfer diabetes to NOD-scid recipients. The insulin content of "diabetes-prone" donors whose disease status was considered to be just before the onset of diabetes ("malignant" donors) was the same as that of diabetic mice, whereas the insulin content of "diabetes-prone" donors excluding "malignant" donors ("benign" donors) was the same as that of "non-diabetes-prone" donors. Because its proportion of oxidative PEC was inversely correlated with the severity of insulitis, we then evaluated the relation between the proportion of oxidative PEC and the time taken to transfer diabetes. "Malignant" donors had less proportion of oxidative PEC (< 10%), as compared to "benign" and "non-diabetes-prone" donors. These results suggest that a marked reduction of beta cell mass occurs at the very late prediabetic stage, and assessment of the proportion of oxidative PEC is useful to evaluate disease activity in type 1 diabetes.

Adoptive Transfer↗
PubMed2003

The oral-to-intravenous equianalgesic ratio of morphine based on plasma concentrations of morphine and metabolites in advanced cancer patients receiving chronic morphine treatment.

To provide additional pharmacokinetic evidence for the oral-to-parenteral relative potency ratio of 1:2 to 1:3 for chronic morphine use in a palliative care setting, we determined the plasma concentrations of morphine and its major metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), in hospitalized advanced cancer patients maintained on long-term oral or intravenous morphine. There were significant linear correlations between daily doses of morphine and plasma concentrations (molar base) of morphine, M3G and M6G for both routes of administration. The oral-to-intravenous relative ratios of the regression coefficients were 2.9 for morphine and 1.8 for morphine + M6G. The morphine kinetic variables were not significantly influenced by any hepato-renal biochemical markers. These results support the commonly used oral-to-intravenous relative potency ratio of 1:2 to 1:3 in patients with cancer pain receiving chronic morphine treatment.

Administration, Oral↗
PubMed2003

Relationship between beta cell mass of NOD donors and diabetes development of NOD-scid recipients in adoptive transfer system.

BACKGROUND: There is controversy about the way the beta cell mass is reduced in type 1 diabetes. One view is that a gradual fall in beta cell mass begins soon after the onset of insulitis. Another view is that a sudden wave of beta cell destruction occurs just before the onset of diabetes. To clarify how the beta cell mass is reduced, we performed adoptive transfer experiments and examined the relationship between the pancreatic status of NOD donors and the time taken to transfer diabetes into NOD-scid recipients. METHODS: We killed 18-week-old female NOD mice (n = 20), removed their spleen, and transferred splenocytes into 5-week-old female NOD-scid mice (n = 60). The relationship between the pancreatic status of donors and the time taken to transfer diabetes into recipients was assessed. As pancreatic status, we measured insulin content and severity of insulitis. RESULTS: There was no linear correlation between the pancreatic status of donors and the time taken to transfer diabetes into recipients. NOD donors who needed 7 or more weeks to transfer diabetes in NOD-scid recipients had similar levels of insulin content or severity of insulitis as those of NOD donors who could not transfer diabetes. On the other hand, NOD donors who needed 6 or less weeks to transfer diabetes in recipients had similar levels of insulin content or severity of insulitis as those of diabetic NOD mice. CONCLUSIONS: According to our observations, beta cell mass seems to be preserved until just before the onset of diabetes and decreased dramatically within a few weeks.

Adoptive Transfer↗
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↗