閉塞型睡眠時無呼吸症候群患者における早朝の高分子量フォンウィルブランド因子減少は無呼吸の重症度を反映する

Plasma von Willebrand factor (VWF), produced in and released from vascular endothelial cells by various stimuli including hypoxia, induces platelet aggregation under high shear stress and plays dual pivotal roles in haemostasis and thrombosis within arterioles, which are regulated by the size of vWF multimers (VWFMs). Patients with obstructive sleep apnoea (OSA) have increased risk of thrombotic cardiovascular events, but the pathogenesis is unclear. We examined the relationship between VWF and OSA by measuring VWF antigen (VWF:Ag), VWFMs, VWF collagen binding activity (VWF:CB) and a disintegrin-like, metalloproteinase, and thrombospiondin type 1 motifs 13. A total of 58 OSA patients were enrolled. Blood samples were collected before sleep, after sleep, and after one night of nasal continuous positive airway pressure therapy. Based on VWFM analysis, OSA patients were classified into three groups; consistently normal VWFMs (group 1, n=29), increased high molecular weight (HMW)-VWFMs at 06:00 h (group 2, n=18), and decreased or absent HMW-VWFMs at 06:00 h (group 3, n=11). Patients in group 3 had significantly worse apnoea/hypopnoea index; VWF:CB followed a similar pattern. We observed a significant decrease in platelet count between 21:00 h and 06:00 h in OSA patients, potentially associated with reduced larger VWFMs together with decreased VWF:Ag levels. Severe OSA may contribute to an arterial pro-thrombotic state.博士（医学）・乙第1294号・平成24年5月28日Copyright © 2012 by the European Respiratory Societ

Signal transduction of reactive oxygen species and mitogen-activated protein kinases in cardiovascular disease

Reactive oxygen species (ROS), generated by reduction-oxidation (redox) reactions, have been recognized as important chemical mediators that regulate signal transduction. It has been reported that increase in ROS generation may relate to a risk for cardiovascular diseases such as atherosclerosis, angina pectoris, and myocardial infarction. Therefore, understanding the ROS-generating biological processes and ROS-induced intracellular signaling will be informative to gain insights into the pathogenesis of these diseases. In this review, we focus on the sources and reactions of ROS in the cardiovascular system and the role of mitogen-activated protein (MAP) kinase pathway in redox-mediated signal transduction. Clinical implications of ROS and MAP kinase are then described to provide insight into the pathogenesis of various redox-sensitive cardiovascular diseases. The pathways responsible for ROS generation in the cardiovascular system may provide novel therapeutic targets

EDA-BASED ESTIMATION OF VISUAL ATTENTION BY OBSERVATION OF EYE BLINK FREQUENCY

This paper describes the relationship between visual attention and eye blink frequency. In an experiment, we prompted the activation of a subject's visual attention and examined the influence of visual attention (as measured using electrodermal activity (EDA), which is meaningfully correlated with visual attention) on the subject's eye blink frequency. Experimental results show that engagement of visual attention decreased eye blink frequency and that when visual attention was not activated, eye blink frequency increased. Knowledge of this relationship provides a technique using EDA to objectively determining a subject's visual attention status

Nocturnal hypoxic stress activates invasive ability of monocytes in patients with obstructive sleep apnea syndrome

Backgrounds: Obstructive sleep apnea syndrome (OSAS) is known to be a risk factor of cardiovascular events. However, the precise mechanism has not been fully elucidated. OSAS-induced hypoxic stress may promote the production of inflammatory cytokines and chemokines by monocytes, which has a crucial role in the development of atherosclerosis. In addition, adhesion to the vascular endothelium and transendothelial migration of monocytes are considered to induce atherosclerosis. The aim of this study was to investigate the effects of hypoxic stress on the invasive ability of monocytes in OSAS. Methods; Twenty-one male OSAS patients and 17 male healthy control subjects, age- and body mass index-matched, were enrolled. Venous blood samples were collected not only before and after sleep but also after CPAP titration for the purpose of monocyte isolation. The invasive ability of monocytes was evaluated by counting the number of invasive cells using a BD BioCoat Matrigel Invasion Chamber. Results; The number of cells which represents invasive ability was significantly higher in OSAS patients as compared to control subjects in the early morning (p<0.001). Invasive ability in the early morning was significantly elevated as compared to that before sleep in OSAS patients (p<0.001), and it was positively correlated with oxygen desaturation index (p<0.05). CPAP titration led to alleviation of the invasive ability (p<0.001). Conclusions; The results indicate that OSAS-induced hypoxic stress activates the invasive ability of monocytes, and that this phenomenon observed during sleep may contribute to the development of atherosclerosis in OSAS.The definitive version is available at " http://dx.doi.org/10.1111/j.1440-1843.2009.01540.x "アジア太平洋呼吸器学会（APSR：Asia Pacific Society of Respirology）第1回最優秀論文賞「Fukuchi Award」受賞論

Possible role of bradykinin on stimulus-secretion coupling in adrenal chromaffin cells

Nonapeptide bradykinin is known to be a central nervous system neurotrans-mitter and to play a role in regulation of neuronal function. However, few details are known of the function of its peptide on stimulus-secretion coupling in neuronal cells. In this article, the role of bradykinin on catecholamine biosynthesis, secretion and Ca2+movement in adrenal chromaffin cells as a model for catecholamine-containing neurons are examined. Bradykinin receptors are classified as B1 and B2 receptor subtypes. These receptors are present on the adrenal chromaffin cell membrane. Bradykinin increases the influx of Ca2+ and the turnover of phosphoinositide through the stimulation of bradykinin B2 receptor. The secretion of catecholamine from the cells is initiated by the raise of [Ca2+]i. An increase in [Ca2+]i and production of diacylglycerol stimulate the activation of calcium-dependent protein kinases. These kinases stimulate the activation of tyrosine hydroxylase, a rate-limiting enzyme in the biosynthesis of catecholamine. Otherwise, bradykinin increases Ca2+ efflux from the cells through the stimulation of the bradykinin-B2 receptor. This action may be explained by an extracellular Na+-dependent mechanism, probably through acceleration of Na+/Ca2+ exchange. It is interesting that bradykinin, which stimulates the biosynthesis and secretion of catecholamine in adrenal chromaffin cells, plays a role in the termination of calcium-signal transduction through the stimu-lation of Ca2+ efflux from the cells

ヒト サイタイ ジョウミャク ナイヒ サイボウ HUVEC ニオケル Lysophosphatidylcholine LPC シゲキ ニヨル VEGF レセプター ノ トランス アクチベーション

One of the major lipid components of oxidized low density lipoprotein, lysophosphatidylcholine （LPC） is involved in numerous biological processes as a bioactive lipid molecule and has been shown to be involved in the progression of atherosclerosis. As counter-ligands, G２A and GPR４ were identified with high binding affinity for LPC that are belonging to orphan G-protein-coupled receptors （GPCRs） at plasma membranes. Although several GPCR ligands transactivate receptor tyrosine kinases （RTKs）, such as epidermal growth factor receptor, transactivation of RTK by LPC has not yet been reported. Here we observed for the first time that LPC treatment induces tyrosyl phosphorylation of vascular endothelial growth factor （VEGF） receptor２ （fetal liver kinase-１／kinase-insert domain-containing receptor, Flk-１／KDR） in human umbilical vein endothelial cells （HUVEC）. VEGF receptor tyrosine kinase inhibitors, SU１４９８ and VTKi inhibited Flk-１／KDR transactivation by LPC. Furthermore, we examined the effect of the Src family kinases inhibitors, Herbimycin A and PP２ on LPC-induced Flk-１／KDR transactivation. Herbimycin A and PP２ inhibited Flk-１／KDR transactivation in HUVEC, suggesting that c-Src is involved in LPC-induced Flk-１／KDR transactivation. Kinase-inactive （KI） Src transfection also inhibited LPC-induced Flk-１／KDR transactivation. In addition, LPC activated extracellular signal-regulated kinase１／２ and Akt, which are downstream effectors of Flk-１／KDR, and these were inhibited by SU１４９８，VTKi, Herbimycin A, PP２ and KI Src transfection in HUVEC. LPC-mediated HUVEC proliferation was shown to be secondary to transactivation because it was suppressed by SU１４９８，VTKi, Herbimycin A, PP２and KI Src transfection. It is concluded that c-Src-mediated Flk-１／KDR transactivation by LPC may have important implications for the progression of atherosclerosis

慢性閉塞性肺疾患患者における骨塩量の分布と体重および運動能との関連

Background: Although low bone mineral density is highly prevalent in patients with chronic obstructive pulmonary disease (COPD), the distribution of the reduced bone mass has not been fully elucidated. Objectives: To determine regional bone mass loss in patients with COPD and investigate whether the change in distribution may be associated with body weight loss and functional capacity. Methods: Body mass index (BMI) was assessed, and height squared indices were derived for the bone mineral content index (BMCI) of the arms, legs and trunk by dual-energy X-ray absorptiometry in 45 male patients with COPD and 12 age- and sex-matched control subjects. Pulmonary function tests were performed, and maximal oxygen uptake (V·O2max) was measured. Results: The BMCI was lower in the total bone, legs and trunk of patients with COPD than in control subjects, although the BMCI in the arms was similar between the groups. BMI correlated significantly with the BMCI in all 3 segments. Bone mineral content (BMC) in the trunk, expressed as a percentage of total BMC (BMC trunk/total BMC), correlated significantly with BMI. The BMCI in the trunk was closely related with V·O2max but not with airflow limitation. Conclusions: There was a regional difference in BMC reduction, but a predominant reduction of bone mass in the trunk was not associated with the severity of airflow limitation but rather with body weight loss and exercise intolerance. These data suggest that body weight loss and exercise intolerance are important risk factors for vertebral fracture in patients with COPD.博士（医学）・乙第1341号・平成26年7月22日The definitive version is available at " http://dx.doi.org/10.1159/000355095

Effect of endothelin-1 (1-31) on the renal resistance vessels

Human chymase produces not only angiotensin II but also endothelin(ET)-1(1-31). We previously reported that ET-1(1-31) had several biological activities in vascular smooth muscle cells. In this study, we investigated the vasoconstrictor effect of ET-1(1-31) on the renal resistance vessels using in vitro micro perfused rabbit afferent and efferent arterioles.ET-1(1-31) decreased the lumen diameter of the afferent and efferent arterioles dose-dependently.ET-1(1-31)-induced afferent arteriolar vasoconstriction was not affected by phosphoramidon, an ET converting enzyme inhibitor. ET-1(1-31)-induced renal arteriolar vasoconstriction was inhibited by BQ123, an ETA receptor inhibitor, but not by BQ788, an ETB receptor inhibitor. These results suggest that ET-1(1-31)-induced renal arteriolar vasoconstriction may be mediated by ETA-like receptors

IVC diameter in patients undergoing HD

Background : IVC diameter on expiration (IVCdexp) is measured by echocardiography routinely. It is used to estimate volume status and designated as a definitive marker for determining dry weight (DW) in patients undergoing hemodialysis (HD). Methods : A cross-sectional study. Outpatients (n = 107), and inpatients (n = 35) undergoing HD were enrolled. IVCdexp was measured on non-dialysis days in outpatients and dialysis days before and after the dialysis session in inpatients. In outpatients, the relationship of IVCdexp with echocardiography findings and clinical characteristics was analyzed. IVCdexp was compared with the other DW markers as a predictive factor for intradialytic hypotension. In inpatients, IVCdexp was analyzed by dividing inpatients with or without fluid in extravascular space. Results : IVCdexp ranged from 5.4 to 16.9 mm in outpatients who had optimal DW. IVCdexp could reflect on volume status, but not predictive for intradialytic hypotension and not suggestive of fluid in extravascular space. Conclusions : IVCdexp was a rough marker to estimate volume status and only useful in suggesting apparent hypervolemia or hypovolemia. We should know that the IVCdexp value is affected by a lot of factors and not a definitive marker for estimating practical DW