Risk Evaluation for Coronary Artery Disease in Patients With Impaired Glucose Tolerance After a Successful Coronary Intervention

信州大学博士（医学）・学位論文・平成23年3月31日授与（甲第880号）・堀込充章This is a non-final version of an article published in final form in CLINICAL NUCLEAR MEDICINE. 36(7):546-552 (2011)Purpose: Patients with coronary artery disease (CAD) often have risk factors that may influence endothelial function. The purpose of this study was to evaluate the endothelial function and its association with coronary risk factors after percutaneous coronary intervention (PCI). Materials and Methods: A total of 14 patients with impaired glucose tolerance and CAD underwent positron emission tomography with N-13 ammonia to measure myocardial blood flow (MBF) at rest and during a cold pressor test (CPT), to estimate endothelial function as a percent increase (%increase) of MBF. The results were compared among normal segments (normal), reperfused segments with PCI (PCI), and nonculprit CAD segments without PCI (non-PCI). Correlations between the %increase and major risk factors were also investigated. Results: CPT induced significant increase in MBF in all groups. The %increase of normal, non-PCI, and PCI groups were 33% +/- 22%, 21% +/- 23%, and 26% +/- 23%, respectively. Comparison with risk factors demonstrated significant correlations only in the non-PCI group. Specifically, there were negative correlations between %increase and fasting blood sugar (r = -0.64, P < 0.05), hemoglobin A1c (r = -0.74, P < 0.05), total cholesterol (r = -0.87, P < 0.05), triglyceride (r = -0.71, P < 0.05), and low-density lipoprotein cholesterol (r = -0.92, P < 0.005), respectively. Conclusions: Although impaired glucose tolerance patients with a PCI-treated coronary stenosis showed preserved response to CPT, the %increase negatively correlated with risk factors in the non-PCI segments. Therefore, coronary risk factors may affect CAD lesions in PCI-treated patients.ArticleCLINICAL NUCLEAR MEDICINE. 36(7):546-552 (2011)journal articl

Studies of Multiple Endocrine Neoplasia Type 2A Syndrome: Linkage Analyses and Comparison of Constitutional and Tumor Genotypes

Linkage analyses were carried out in nine Japanese kindreds with multiple endocrine neoplasia type 2A (MEN-2A) using polymorphic classical markers and DNA markers. We excluded close linkage of the MEN-2A gene (MEN2A) locus with Gm, JK, PGMl, and a DNA segment, D20S5, which is assigned to band 12 of the short arm of chromosome 20 (20p12.2). Assuming that MEN2A is recessive at the cellular level as in retinoblastoma (RB) and Wilms\u27 tumor (WT). comparison of constitutional and tumor genotypes may be useful in the search for the MEN2A locus. When DNA samples from 12 patients with medullary thyroid carcinoma (MTC) were compared with 15 polymorphic DNA markers including two assigned to chromosome 20, the results were negative. Both the negative linkage data and the failure to find loss of heterozygosity in MTC with chromosome 20 probes suggest that MEN2A may not be at 20p12.2, which was previously suggested as the site of an inherited chromosomal deletion in MEN-2A

Phytochrome-regulated EBL1 contributes to ACO1 upregulation in rice

The 1-aminocyclopropane-1-carboxylate oxidase gene (ACO1) was upregulated in rice (Oryza sativa L.) phyAphyBphyC mutants lacking any phytochrome and containing the GCC box element, a binding site for rice ethylene-responsive element binding protein 1 (OsEREBP1), in its promoter region. Since the OsEREBP1-like gene EBL1 (OsEREBP1-LIKE 1) was significantly downregulated in phyAphyBphyC mutants, EBL1 was suspected to repress ACO1 expression in wild-type plants. However, ACO1 was downregulated in EBL1 RNA interference plants, and the total length of these plants was slightly shorter than that of wild-type plants. This study shows that EBL1 is positively regulated by phytochrome B and associated with ACO1 upregulation

Dietary intake, mental status, physical activity, and lifestyle affecting bowel movement frequency and stool texture in young Japanese women

Constipation is a symptom-based disorder, and its definition is mainly subjective. Patients are more concerned with ease ofpassage and consistency rather than frequency of bowel movement. Studies on bowel movement frequency and stool texture inthe general population are sparse, especially in young women. In this cross-sectional study, data obtained from self-administered questionnaires, including age, height, body weight, lifestyle, food habits, anxiety, depressive status, frequency of bowel movements,stool texture, and defecation-related symptoms were analyzed in 245 female Japanese university students. An establishedsemiquantitative questionnaire available for clinical investigation (FFQg) was used to obtain a detailed assessment of food intake and physical activity levels. Of the participants, 21.4% had bowel movements ?3 times per week and 33.3% had hard or lumpy stools ?25% and loose (mushy) or watery stools <25% of bowel movements. There was a positive association between infrequent bowel movements and hard or lumpy stools. These two situations both caused similar symptoms such as a sensation of incomplete evacuation and straining. There was no association of bowel movement frequency and stool texture with any specificnutrients and foods, dietary intake, mental status, or physical activity. Several lifestyle factors such as regular bowel movements and hesitation with evacuation were associated with bowel movement frequency and stool texture. Several lifestyle factors, but not mental, physical, or dietary intake factors, were associated with bowel movement frequency and stool texture in young Japanese women

Increased Systemic Glucose Tolerance with Increased Muscle Glucose Uptake in Transgenic Mice Overexpressing RXRγ in Skeletal Muscle

BACKGROUND: Retinoid X receptor (RXR) γ is a nuclear receptor-type transcription factor expressed mostly in skeletal muscle, and regulated by nutritional conditions. Previously, we established transgenic mice overexpressing RXRγ in skeletal muscle (RXRγ mice), which showed lower blood glucose than the control mice. Here we investigated their glucose metabolism. METHODOLOGY/PRINCIPAL FINDINGS: RXRγ mice were subjected to glucose and insulin tolerance tests, and glucose transporter expression levels, hyperinsulinemic-euglycemic clamp and glucose uptake were analyzed. Microarray and bioinformatics analyses were done. The glucose tolerance test revealed higher glucose disposal in RXRγ mice than in control mice, but insulin tolerance test revealed no difference in the insulin-induced hypoglycemic response. In the hyperinsulinemic-euglycemic clamp study, the basal glucose disposal rate was higher in RXRγ mice than in control mice, indicating an insulin-independent increase in glucose uptake. There was no difference in the rate of glucose infusion needed to maintain euglycemia (glucose infusion rate) between the RXRγ and control mice, which is consistent with the result of the insulin tolerance test. Skeletal muscle from RXRγ mice showed increased Glut1 expression, with increased glucose uptake, in an insulin-independent manner. Moreover, we performed in vivo luciferase reporter analysis using Glut1 promoter (Glut1-Luc). Combination of RXRγ and PPARδ resulted in an increase in Glut1-Luc activity in skeletal muscle in vivo. Microarray data showed that RXRγ overexpression increased a diverse set of genes, including glucose metabolism genes, whose promoter contained putative PPAR-binding motifs. CONCLUSIONS/SIGNIFICANCE: Systemic glucose metabolism was increased in transgenic mice overexpressing RXRγ. The enhanced glucose tolerance in RXRγ mice may be mediated at least in part by increased Glut1 in skeletal muscle. These results show the importance of skeletal muscle gene regulation in systemic glucose metabolism. Increasing RXRγ expression may be a novel therapeutic strategy against type 2 diabetes

Parkinson’s disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling

Mutations in the iPLA2-VIA/PLA2G6 gene are responsible for PARK14-linked Parkinson’s disease (PD) with α-synucleinopathy. However, it is unclear how iPLA2-VIA mutations lead to α-synuclein (α-Syn) aggregation and dopaminergic (DA) neurodegeneration. Here, we report that iPLA2-VIA–deficient Drosophila exhibits defects in neurotransmission during early developmental stages and progressive cell loss throughout the brain, including degeneration of the DA neurons. Lipid analysis of brain tissues reveals that the acyl-chain length of phospholipids is shortened by iPLA2-VIA loss, which causes endoplasmic reticulum (ER) stress through membrane lipid disequilibrium. The introduction of wild-type human iPLA2-VIA or the mitochondria–ER contact site-resident protein C19orf12 in iPLA2-VIA–deficient flies rescues the phenotypes associated with altered lipid composition, ER stress, and DA neurodegeneration, whereas the introduction of a disease-associated missense mutant, iPLA2-VIA A80T, fails to suppress these phenotypes. The acceleration of α-Syn aggregation by iPLA2-VIA loss is suppressed by the administration of linoleic acid, correcting the brain lipid composition. Our findings suggest that membrane remodeling by iPLA2-VIA is required for the survival of DA neurons and α-Syn stability

Mast Cell Infiltration is Associated with Myelofibrosis and Angiogenesis in Myelodysplastic Syndromes

Myelodysplastic syndromes are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by persistent peripheral cytopenia with morphological and functional abnormalities of hematopoietic cells. Mast cells infiltrate into or around tumor tissues and play a role in remodeling of the stromal microenvironment, contributing to tumor progression. Increased mast cell numbers are associated with fibrosis, angiogenesis and a poor prognosis in human carcinomas. The aim of this study was to determine whether mast cell infiltration contributes to myelofibrosis or angiogenesis in myelodysplastic syndromes. We evaluated the correlation between mast cell density and the extent of myelofibrosis and angiogenesis in myelodysplastic syndromes. Fifty bone marrow biopsies taken from patients with a diagnosis of myelodysplastic syndromes were examined. Grading of myelofibrosis was evaluated by silver impregnation staining. Mast cell density and microvessel density were evaluated by immunohistochemistry. Human mast cells have been divided into two phenotypes. We designated a tryptase-positive mast cell as MCT and a chymase-positive mast cell as MCTC. Microvessels were identified by CD34-positive endothelial cells. Microvessel density and the extent of myelofibrosis were significantly greater in patients with high MCT and MCTC density compared to those with low MC density. Based on this, we suggest that the presence of high mast cell numbers is associated with myelofibrosis and angiogenesis in myelodysplastic syndromes

Serological assessment of gastric mucosal atrophy in gastric cancer

<p>Abstract</p> <p>Background</p> <p>Non-invasive tools for gastric cancer screening and diagnosis are lacking. Serological testing with the detection of pepsinogen 1 (PG1), pepsinogen 2 (PG2) and gastrin 17 (G17) offers the possibility to detect preneoplastic gastric mucosal conditions. Aim of this study was to assess the performance of these serological tests in the presence of gastric neoplasia.</p> <p>Methods</p> <p>Histological and serological samples of 118 patients with gastric cancer have been assessed for tumor specific characteristics (Laurén type, localisation), degree of mucosal abnormalities (intestinal metaplasia, atrophy) and serological parameters (PG1, PG2, PG1/2-ratio, G17, <it>H. pylori </it>IgG, CagA status). Association of the general factors to the different serological values have been statistically analyzed.</p> <p>Results</p> <p>Patients with intestinal type gastric cancer had lower PG1 levels and a lower PG1/2-ratio compared to those with diffuse type cancer (<it>p </it>= 0.003). The serum levels of PG2 itself and G17 were not significantly altered. <it>H. pylori </it>infection in general had no influence on the levels of PG1, PG2 and G17 in the serum of gastric cancer patients. There was a trend towards lower PG1 levels in case of positive CagA-status (<it>p </it>= 0.058). The degree of both intestinal metaplasia and atrophy correlated inversely with serum levels for PG1 and the PG1/2-ratio (p < 0.01). Laurén-specific analysis revealed that this is only true for intestinal type tumors. Univariate ANOVA revealed atrophy and CagA-status as the only independent factors for low PG1 and a low PG1/2-ratio.</p> <p>Conclusions</p> <p>Glandular atrophy and a positive CagA status are determinant factors for decreased pepsinogen 1 levels in the serum of patients with gastric cancer. The serological assessment of gastric atrophy by analysis of serum pepsinogen is only adequate for patients with intestinal type cancer.</p

Cultivation of Research Literacy in the First Year of Graduate School: A Report on the Educational Practices of "Introduction to International Cultural Studies" in the Master's Course of the Graduate School of International Cultural Studies

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