永井 良三

Purpose The aim of this study was to assess the prevalence of carotid atherosclerosis in people of both genders who underwent general health screening.<br>Results Of 8144 enrolled subjects (5473 men,2671 women),29.4% of the men and 16.5% of women, and 14.9% of the men and 9.2% of the women had carotid plaque and intima-media thickening, respectively, and the prevalence of both increased with age in both genders. The male-to-female rations for the prevalence of carotid plaque and intima-media thickening peaked at 41-45 years (8.62) and 46-50 years (5.72), respectively. The gender gap for these values declined thereafter, and the male-to-female ratios for the prevalence of carotid plaque and intima-media thickening was 1.29 and 0.93 at age ≥76 years. Conclusion A gender gap in terms of the prevalence of carotid plaque and intima-media thickening is present in mid-life, and thereafter the deference declines in the Japanese population.

Purpose The aim of the present study was to analyze the presence of metabolic syndrome in the Japanese population.<br>Methods Data from 49375 subjects (16886 women,32489 men) with a mean age of 52.2±10.2 years who underwent general health screening between 1994 and 2003 at our institute were analyzed. Metabolic syndrome was diagnosed using modified criteria of the National Cholesterol Education Program Adult Treatment Panel III including five components; increased body mass index, hypertension, increased serum triglycerides, decreased serum HDL cholesterol, and increased fasting glucose.<br>Results The mean overall rate of metabolic syndrome was 10.0% (women,4.1%; men,13.1%), seeming to reach a plateau after 50 years of age in men, but with a continual age-associated increase in women. HOMA-IR rose as the number of metabolic syndrome risk factors increased in both genders. After adjusting for age, serum total cholesterol levels, and smoking status, the frequency of metabolic syndrome was greatest in men (odds ratio,3.17,95% CI 2.89-3.48, p<0.0001).<br>Conclusion In this large Japanese study population undergoing general health screening, metabolic syndrome was found to be over three times more frequent in men than women.

To study the mechanisms of vascular dysfunction in diabetes mellitus, we examined the responses of the aorta to adrenomedullin (AM) and ANG II in obese Zucker (OZ), lean Zucker (LZ), and OZ rats administered fluvastatin (OZ + Flu). AM-induced endothelium-dependent vasorelaxation was impaired in OZ rats compared with LZ rats, and fluvastatin restored AM-induced, endothelium-dependent vasorelaxation (%Deltatension at 10(-7) mol/l AM; LZ, -85.1 +/- 3.1%; OZ, -50.7 +/- 2.5%; OZ + Flu, -75.6 +/- 2.7%). Expression of endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in response to AM (10(-7) mol/l) were also diminished in OZ rats. Fluvastatin restored the eNOS expression and Akt phosphorylation [eNOS expression (relative intensity): LZ, 2.3 +/- 0.4; OZ, 1.0 +/- 0.2; OZ + Flu, 1.8 +/- 0.3; Akt phosphorylation (relative intensity): LZ, 2.3 +/- 0.2; OZ, 1.0 +/- 0.3; OZ + Flu, 1.9 +/- 0.2]. ANG II-induced vasoconstriction was enhanced in the aortic rings of OZ rats compared with LZ rats, and this enhanced vasoconstriction was partially normalized by fluvastatin and was abolished when the aorta of OZ rats was preincubated with the Rho kinase inhibitor Y-27632. GTPgammaS-induced contraction of permeabilized aortic smooth muscle cells, which is an indicator of the Rho-dependent Ca(2+) sensitization of contraction, was enhanced in OZ rats compared with LZ rats, and this enhanced contraction was suppressed in OZ + Flu rats. These results suggested that endothelium-dependent vasorelaxation was impaired, Ca(2+) sensitization of contraction was augmented in blood vessels of OZ rats and that fluvastatin restored vascular function by activating the Akt-dependent pathway and inhibiting the Rho-dependent pathway.

BACKGROUND: It is well known that diabetes mellitus is a major risk factor for vascular diseases such as atherosclerosis and restenosis after angioplasty. It has become clear that advanced glycation end products (AGE) and their receptor (RAGE) are implicated in vascular diseases, especially in diabetes mellitus. Nevertheless, the mechanisms by which diabetes mellitus is often associated with vascular diseases remain unclear. METHODS AND RESULTS: To study the role of endogenous cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 in the development of vascular diseases and in the expression of RAGE, we used semapimod, a pharmacological inhibitor of cytokine production, and examined its effect on neointimal formation in the femoral artery of obese Zucker (OZ) rats. We also used an adenovirus construct expressing a dominant negative mutant of the receptor for TNF-alpha (AdTNFRDeltaC) to block the action of endogenous TNF-alpha. Semapimod significantly suppressed neointimal formation and RAGE expression in OZ rats compared with untreated OZ rats. This inhibitory effect of semapimod on neointimal formation was overcome by infection of an adenovirus expressing RAGE into the femoral artery of OZ rats. Furthermore, AdTNFRDeltaC infection significantly suppressed neointimal formation and RAGE expression in the femoral artery of OZ rats. CONCLUSIONS: These results suggest that endogenous cytokines, especially TNF-alpha, were implicated in neointimal formation in OZ rats and that RAGE was a mediator of the effect of these cytokines on neointimal formation.

社会技術研究ミッションプログラムI医療安全研究グループにおいては，大学医学部附属病院における理論構築環境（研究）と，技術実装環境（大学医学部附属病院）を活用して，他の研究グループと連携を図りつつ，医療安全向上を目的とした包括的，かつ多層的なアプローチで研究を行った．その中でも，社会技術としては，医師-患者間，医師間，医療機関間において，臨床判断に資する情報共有，コミュニケーションを促進するツールとしての診療ナビゲーションシステムを開発し，東京大学医学部附属病院循環器内科において実装した．

Disruption of histamine H2 receptor and gastrin receptor had different effects growth of gastric mucosa: hypertrophy and atrophy, respectively. To clarify the roles of gastrin and histamine H2 receptors in gastric mucosa, mice deficient in both (double-null mice) were generated and analyzed. Double-null mice exhibited atrophy of gastric mucosae, marked hypergastrinemia and higher gastric pH than gastrin receptor-null mice, which were unresponsive even to carbachol. Comparison of gastric mucosae from 10-week-old wild-type, histamine H2 receptor-null, gastrin receptor-null and double-null mice revealed unique roles of these receptors in gastric mucosal homeostasis. While small parietal cells and increases in the number and mucin contents of mucous neck cells were secondary to impaired acid production, the histamine H2 receptor was responsible for chief cell maturation in terms of pepsinogen expression and type III mucin. In double-null and gastrin receptor-null mice, despite gastric mucosal atrophy, surface mucous cells were significantly increased, in contrast to gastrin-null mice. Thus, it is conceivable that gastrin-gene product(s) other than gastrin-17, in the stimulated state, may exert proliferative actions on surface mucous cells independently of the histamine H2 receptor. These findings provide evidence that different G-protein coupled-receptors affect differentiation into different cell lineages derived from common stem cells in gastric mucosa.