Kenji Toba

Modulation of Endothelium-Dependent Flow-Mediated Dilatation of the Brachial Artery by Sex and Menstrual Cycle

BACKGROUND Estrogen has been reported to augment endothelium-dependent vasodilatation. The role of endogenous ovarian hormones in modulating endothelium-dependent vasodilatation, however, remains to be determined. The purpose of the present study was to investigate the effects of sex and menstrual cycle on endothelium-dependent flow-mediated vasodilatation. METHODS AND RESULTS Seventeen female volunteers 25.1 +/- 0.8 years old and 17 age-matched male volunteers were examined. We measured brachial artery diameters noninvasively using a 7.5-MHz ultrasound machine at rest, during reactive hyperemia, and after sublingual nitroglycerin administration. All female subjects were studied three times each, in three different phases of one menstrual cycle (M, menstrual phase; F, follicular phase; and L, luteal phase). Flow-mediated diameter (D) increase (%FMD; delta D/D x 100) in M, when serum estradiol level was low (121.9 +/- 12.5 pmol/L), was 11.22 +/- 0.58%, and the value was comparable to that in male subjects (10.60 +/- 0.75%). %FMD increased in F (18.20 +/- 0.81%, P < .01 versus M) and L (17.53 +/- 0.74%, P < .01 versus M), when serum estradiol level was high (F, 632.0 +/- 74.5 and L, 533.8 +/- 33.4 pmol/L, P < .01 versus M). Endothelium-independent vasodilatation by nitroglycerin increased in both F and L. However, the increment was smaller than that of %FMD. CONCLUSIONS Endothelium-dependent vasodilatation varies during the menstrual cycle. The endogenous estradiol may be involved in this menstrual cycle-related vasodilatation.

The impairment of flow-mediated vasodilatation in obese men with visceral fat accumulation.

BACKGROUND: Obesity has been reported to be associated with coronary artery disease and other atherosclerotic diseases. Recently, evidence has accumulated indicating that intra-abdominal visceral fat accumulation contributes to atherogenesis; however, the mechanism underlying this remains to be determined. This study was undertaken to elucidate whether intra-abdominal visceral fat accumulation impairs vascular endothelial function in obese men.METHODS AND RESULTS: Thirty-eight obese men (body mass index (BMI)≥26.0), aged 19–64 y (mean age 37.6±1.8 y) and 23 age-matched non-obese subjects were examined. According to the ratio of the maximum thickness of preperitoneal fat to the minimum thickness of subcutaneous fat (Pmax/Smin) obtained by longitudinal ultrasound scanning in the subxiphoid region in obese men, we divided obese subjects into two categories; visceral (Pmax/Smin≥1; n=23) and subcutaneous type (Pmax/Smin<1; n=15). To investigate endothelial function, we performed ultrasound measurement of the brachial artery diameter non-invasively both at rest and during reactive hyperaemia in the muscle distal to the brachial artery which causes endothelium-dependent vasodilatation. The brachial diameter change was also measured after sublingual administration of nitroglycerin, which causes endothelium-independent vasodilatation. Flow-mediated diameter (D) increase (%FMD; ΔD/D×100), in the subjects with visceral type obesity (3.09±0.43%) was significantly lower than those of the subjects with subcutaneous type obesity and non-obese subjects (7.90±0.51%, 8.91±0.44%, respectively, P<0.01). The magnitude of endothelium-independent vasodilatation by nitroglycerin was similar in all groups. On multiple regression analysis, the Pmax/Smin showed a significant inverse correlation with %FMD.CONCLUSIONS: The subjects with visceral type obesity, rather than those with the subcutaneous type, are associated with impaired flow-mediated endothelium-dependent vasodilatation of the brachial artery.

Correlation Between Flow-Mediated Vasodilatation of the Brachial Artery and Intima-Media Thickness in the Carotid Artery in Men

Endothelial dysfunction has been reported to be the initial step in atherosclerosis. A noninvasive technique that uses ultrasound to measure the intima-media thickness of the carotid artery has been applied to evaluate localized atherosclerosis. This study was undertaken to elucidate whether endothelial dysfunction in the brachial artery is related to the intima-media thickness of the carotid artery. Thirty-four men with atherosclerosis (mean+/-SE age 61+/-2 years) and 33 age-matched men without clinical atherosclerosis were examined. The intima-media thickness and plaque formation of the common carotid artery were assessed by B-mode ultrasonography. We also noninvasively measured brachial artery diameter by the same ultrasound machine when the subjects were at rest, during reactive hyperemia, which causes endothelium-dependent vasodilatation, and after sublingual administration of nitroglycerin, which causes endothelium-independent vasodilatation. The atherosclerosis group had a significantly greater intima-media thickness of the common carotid artery than did the control group (1. 02+/-0.04 versus 0.91+/-0.03 mm, P<0.05). The flow-mediated diameter (FMD) increase (percent FMD=DeltaD/D x 100) in the atherosclerosis group was significantly smaller than that in the control group (2. 8+/-0.4% versus 5.1+/-0.6%, P<0.01). A significant negative correlation between the intima-media thickness of the carotid artery and percent FMD was found in all of the subjects. On multiple regression analysis, percent FMD showed a significant negative correlation with the intima-media thickness of the common carotid artery. These findings support the concept that endothelial dysfunction is significantly related to atherogenesis.

A randomized cross-over study of a traditional Japanese medicine (kampo), yokukansan, in the treatment of the behavioural and psychological symptoms of dementia

The effectiveness and safety of yokukansan (TJ-54), a traditional Japanese medicine (kampo) for the treatment of the behavioural and psychological symptoms of dementia (BPSD), were evaluated in 106 patients diagnosed as having Alzheimers disease (AD) (including mixed-type dementia) or dementia with Lewy bodies. Patients were randomly assigned to group A (TJ-54 treatment in period I and no treatment in period II; each period lasting 4 wk) or group B (no treatment in period I and TJ-54 treatment in period II). BPSD and cognitive functions were evaluated using the Neuropsychiatric Inventory (NPI) and the Mini-Mental State Examination (MMSE), respectively. Activities of daily living (ADL) were evaluated using Instrumental Activities of Daily Living (IADL) in outpatients and the Barthel Index in in-patients. For the safety evaluation, adverse events were investigated. Significant improvements in mean total NPI score associated with TJ-54 treatment were observed in both periods (Wilcoxon test, p=0.040 in period I and p=0.048 in period II). The mean NPI scores significantly improved during TJ-54 treatment in groups A and B (p=0.002 and p=0.007, respectively) but not during periods of no treatment. Among the NPI subscales, significant improvements were observed in delusions, hallucinations, agitation/aggression, depression, anxiety, and irritability/lability. The effects of TJ-54 persisted for 1 month without any psychological withdrawal symptoms in group A. TJ-54 did not show any effect on either cognitive function or ADL. No serious adverse reactions were observed. The present study suggests that TJ-54 is an effective and well-tolerated treatment for patients with BPSD.

Estrogen receptor ß is involved in the anorectic action of estrogen

OBJECTIVE: Estrogen has been implicated in feeding behavior and adiposity. This study was undertaken to elucidate the mechanism underlying the anti-obesity and anorectic action of estrogen and the role of estrogen receptor (ER) in the central nervous system.METHODS AND RESULTS: Ovariectomy in 8-week-old female Wistar rats induced hyperphagia along with an increase in body weight and abdominal fat accumulation compared to control sham-operated rats. These changes were fully reversed by subcutaneous replacement of estradiol and were abrogated by pair-feeding. Then, the effects of intracerebroventricular infusion of estradiol, alone or in combination with antisense oligodeoxynucleotides (ODN), for ER in ovariectomized rats were examined. The estradiol group showed 10–20% lower daily food intake, and after the 2-week infusion period a 14% reduction in body weight with a similar reduction in abdominal fat compared to the vehicle group. The inhibitory effect of estradiol on food intake and body weight was blocked by co-administration of ER-ß antisense ODN, whereas ER-α antisense ODN did not show any influence.CONCLUSION: These results indicate that ER-ß in the central nervous system is involved in the anorectic action of estrogen.

Estrogen inhibits cuff-induced intimal thickening of rat femoral artery: effects on migration and proliferation of vascular smooth muscle cells

The present study was performed to elucidate the mechanism underlying the anti-atherogenic action of estrogen. We investigated the effect of estrogen on intimal thickening of the rat femoral artery induced by cuff placement and further examined the effect of estrogen on migration and proliferation of vascular smooth muscle cells (VSMCs) in culture. Intimal thickening was significantly greater in males than in control females. Intimal thickening in females was increased to the level in males by ovariectomy. Estrogen replacement to ovariectomized rats reversed this effect. Proliferating cell nuclear antigen immunohistochemistry showed that in vivo proliferation of VSMCs contributed to the difference in intimal thickening. There was no difference in blood pressure and serum lipids, suggesting that estrogen directly acted on artery and inhibited intimal thickening. 17 beta-Estradiol (E2, 1-100 nmol/l) inhibited migration of cultured rat VSMCs, assayed using a microchemotaxis chamber, in a concentration-dependent manner. E2 (0.01-100 nmol/l), but not progesterone or testosterone, also inhibited [3H]thymidine incorporation in rat VSMCs in a concentration-dependent manner. Indomethacin, NG-monomethyl-L-arginine and methylene blue did not influence the inhibitory action of E2 on [3H]thymidine incorporation, suggesting that prostanoids and nitric oxide are not involved in the action of E2. E2 did not provoke VSMC injury, as measured by the release of incorporated [3H]2-deoxy-D-glucose. These results suggest that the inhibition of migration and proliferation of VSMCs contributes to the inhibitory effect of estrogen on intimal thickening.

Estrogen Prevents Oxidative Stress–Induced Endothelial Cell Apoptosis in Rats

Background —Estrogen replacement attenuates the increased risk of cardiovascular disease in postmenopausal women. Recent studies using an in vitro culture system have shown that estrogen inhibits endothelial cell (EC) apoptosis. The in vivo relevance of this finding, however, is not defined. To do so, we have developed a rat vascular injury model in which EC apoptosis induced by hydrogen peroxide plays a role. Methods and Results —Intracarotid arterial administration of 0.01 mmol/L hydrogen peroxide for 5 minutes evoked EC apoptosis after 6 to 24 hours, determined by nuclear staining with Hoechst 33342, terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling, and electron microscopy. Apoptosis was associated with EC loss and was followed by EC regeneration at 72 hours and neointima formation at 1 to 2 weeks. Estradiol replacement in ovariectomized female Wistar rats decreased the rate of apoptotic ECs by ≈50%, assayed by nuclear morphology of en face specimens, resulting in increased remaining ECs and decreased neointima formation. Progesterone did not influence the effects of estradiol on EC apoptosis. Conclusions —These results provide new insight into the cardioprotective action of estrogen as well as a paradigm of the response-to-injury hypothesis.

Toward the realization of a better aged society: Messages from gerontology and geriatrics

1. Background:  Recent medical advancements, and improvements in hygiene and food supply have led to Japan having the longest life expectancy in the world. Over the past 50 years, the percentage of the elderly population has increased fourfold from 5.7% in 1960 to 23.1% in 2010. This change has occurred at the fastest rate in the world. Compared with France, where the percentage of the elderly population has increased just twofold in the past 100 years, Japanese society is aging at an unprecedented rate. In addition, the percentage of the very elderly (aged 75 years and over), comprising more frail people, exceeded 10% of the nations population in 2008. In such a situation, many elderly Japanese wish to spend their later years healthy, and wish to achieve great accomplishments in their lives. To achieve that, rather than considering an aging population as a negative social phenomenon, we should create a society where elderly people can enjoy a healthy, prosperous life through social participation and contribution.

Impact of Blood Pressure Variability on Cardiovascular Events in Elderly Patients with Hypertension

Blood pressure variability is one of the characteristic features of hypertension in the elderly. However, its clinical significance remains to be determined. We therefore examined the impact of blood pressure variability on the development of cardiovascular events in elderly hypertensive patients. A total of 106 consecutive hypertensive patients aged more than 60 years old (mean age, 73.9±8.1 years old; male, 54%), all of whom underwent 24-h ambulatory blood pressure monitoring, were followed up (median, 34 months; range, 3−60 months). During the follow-up period, 39 cardiovascular events were observed, including 14 cases of cerebral infarction and 7 cases of acute myocardial infarction. The coefficient of variation (CV) of 24-h systolic blood pressure (SBP) values was used as an index of blood pressure variability. The patients showed a mean CV value of 10.6%, and were divided into two groups according to this mean value as a cut-off point: a high CV group (n=46) and a low CV group (n=60). Although baseline clinical characteristics were similar in the two groups, Kaplan-Meier plots for event-free survival revealed that the rate of cardiovascular events was significantly higher in high CV group than in low CV group (p<0.05). Coxs proportional hazards analysis showed that increased blood pressure variability (a high CV value of 24-h SBP) was an independent predictive variable for cardiovascular events. The CV value of daytime SBP and the SD value of both 24-h SBP and daytime SBP also had positive correlations with the onset of cardiovascular events. These results suggest that increased blood pressure variability may be an independent risk factor for cardiovascular events in elderly hypertensive patients.

Vitality Index as a useful tool to assess elderly with dementia

Background: The aim of the present paper was to establish a new objective scale to measure vitality related to activities of daily living in elderly patients with dementia.