Hajime Orimo

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.

Effects of 1 alpha-hydroxyvitamin D3 on lumbar bone mineral density and vertebral fractures in patients with postmenopausal osteoporosis.

The effects of 1α-hydroxyvitamin D3 [1α(OH)D3] on bone mineral density, fracture incidence, and bone metabolism were evaluated by a double-blind, placebo-controlled study. Eighty postmenopausal osteoporotic Japanese women (71.9±7.3 years, mean±SD) were randomly assigned to 1 μg of 1α(OH)D3 daily or inactive placebo for 1 year. All patients were given supplemental calcium (300 mg of elemental calcium daily). Lumbar (L2–L4) bone mineral density (BMD) determined by dual energy X-ray absorptiometry increased 0.65% with 1α(OH)D3 treatment and decreased 1.14% with placebo (P=0.037). BMD in both the femoral neck and Wards triangle did not yield any significant differences between the two groups, whereas trochanter BMD in the 1α(OH)D3-treated group increased 4.20% and decreased 2.37% with placebo (P=0.055). X-ray analysis demonstrated that new vertebral fractures occurred in two patients with 1α(OH)D3 and in seven patients with placebo. The vertebral fracture rate in the treated group was significantly less (75/1000 patient years) than in the control group (277/1000 patient years; P=0.029). Hypercalcemia (12.1 mg/100 ml) occurred in one patient receiving 1α(OH)D3; however, the serum calcium level in this patient promptly decreased to the reference range after cessation of the treatment. There were no significant changes in serum creatinine level in either group. A significant increase in urinary excretion of calcium was found but there was no significant change in urinary excretion of hydroxyproline in the treated group. The serum level of bone-derived alkaline phosphatase activity significantly decreased by−26±26 (mU/ml) after the treatment (P=0.003). These results indicate that 1α(OH)D3 treatment is effective for maintaining trabecular bone mass and prevents further vertebral fractures without any serious adverse effects in postmenopausal osteoporosis.

Multi‐Detector Row CT Imaging of Vertebral Microstructure for Evaluation of Fracture Risk

We applied MDCT for in vivo evaluation of the microarchitecture of human vertebrae. Microstructure parameters, such as structure model index, Eulers number, and bone volume fraction, revealed higher relative risk for prevalent vertebral fracture than did BMD obtained by DXA. Thus, microstructure analysis by MDCT, together with simultaneously obtained volumetric BMD values, is useful for clinical assessment of fracture risk.

Diagnostic criteria of primary osteoporosis

New diagnostic criteria of primary osteoporosis (2000 version) was presented. The basic concepts are as follows. Firstly, estimation of low bone mass should be made by lumbar BMD by DXA. However, when measurement of lumbar BMD is not appropriate due to fracture or deformities of the spine, hip, radial, calcaneal, or metacarpal BMD should be used. X ray picture of the spine should be used when DXA is not available. Secondary, in cases with fragility fractures, or in cases with BMD below 70% of young adult mean, differential diagnosis should be made in order to rule out other diseases with low BMD than primary osteoporosis.

Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: possible implications for hip-fracture risk.

Increasing evidence indicates a significant role for vitamin K in bone metabolism and osteoporosis. In this study, we found a large geographic difference in serum vitamin K2 (menaquinone-7; MK-7) levels in postmenopausal women. Serum MK-7 concentrations were 5.26 +/- 6.13 ng/mL (mean +/- SD) in Japanese women in Tokyo, 1.22 +/- 1.85 in Japanese women in Hiroshima, and 0.37 +/- 0.20 in British women. We investigated the effect of Japanese fermented soybean food, natto, on serum vitamin K levels. Natto contains a large amount of MK-7 and is eaten frequently in eastern (Tokyo) but seldom in western (Hiroshima) Japan. Serum concentrations of MK-7 were significantly higher in frequent natto eaters, and natto intake resulted in a marked, sustained increase in serum MK-7 concentration. We analyzed the relation between the regional difference in natto intake and fracture incidence. A statistically significant inverse correlation was found between incidence of hip fractures in women and natto consumption in each prefecture throughout Japan. These findings indicate that the large geographic difference in MK-7 levels may be ascribed, at least in part, to natto intake and suggest the possibility that higher MK-7 level resulting from natto consumption may contribute to the relatively lower fracture risk in Japanese women.

Reviewing the definition of “elderly”

Conventionally, “elderly” has been defined as a chronological age of 65 years old or older, while those from 65 through 74 years old are referred to as “early elderly” and those over 75 years old as “late elderly.” However, the evidence on which this definition is based is unknown. We have attempted to review the definition of elderly by analyzing data from long‐term longitudinal epidemiological studies, and clinical and pathological studies that have been accumulated at the Tokyo Metropolitan Geriatric Hospital and the Tokyo Metropolitan Institute of Gerontology. Our recommendation might be a starting point in developing a strategy for a successful society by reviewing the definition of elderly based on comprehensive evidence in all aspects of social, cultural and medical sciences.

Klotho gene polymorphisms associated with bone density of aged postmenopausal women

Because mice deficient in klotho gene expression exhibit multiple aging phenotypes including osteopenia, we explored the possibility that the klotho gene may contribute to age‐related bone loss in humans by examining the association between klotho gene polymorphisms and bone density in two genetically distinct racial populations: the white and the Japanese. Screening of single‐nucleotide polymorphisms (SNPs) in the human klotho gene identified 11 polymorphisms, and three of them were common in both populations. Associations of the common SNPs with bone density were investigated in populations of 1187 white women and of 215 Japanese postmenopausal women. In the white population, one in the promoter region (G‐395A, p = 0.001) and one in exon 4 (C1818T, p = 0.010) and their haplotypes (p < 0.0001) were significantly associated with bone density in aged postmenopausal women (≥65 years), but not in premenopausal or younger postmenopausal women. These associations were also seen in Japanese postmenopausal women. An electrophoretic mobility shift analysis revealed that the G‐A substitution in the promoter region affected DNA‐protein interaction in cultured human kidney 293 cells. These results indicate that the klotho gene may be involved in the pathophysiology of bone loss with aging in humans.

Effect of soy protein on bone metabolism in postmenopausal Japanese women.

Abstract: We conducted a cross-sectional study of the effects of soybean protein intake on bone mineral density and biochemical markers in 85 postmenopausal Japanese women. Nutrients in the diet of postmenopausal Japanese women visiting the osteoporosis unit, including subjects with normal lumbar spine bone mineral density (L2–4 BMD), were investigated by questionnaire, and the calculated daily energy, protein, soy protein and calcium intake were obtained. L2–4 BMD was measured with dual-energy X-ray absorptiometry, and assays done of serum alkaline phosphatase (ALP) and serum intact osteocalcin (IOC) as bone formation markers and urinary pyridinoline (UPYR) and urinary deoxypyridinoline (UDPYR) as bone resorption markers. Soy protein intake was significantly associated with the Z-score for L2–4 BMD (r= 0.23, p = 0.038) and UDPYR (r =−0.23, p = 0.034). Stepwise multiple regression analyses showed that soy protein intake is significantly associated with the Z-score for L2–4 BMD (β= 0.225, p = 0.04) and UDPYR (β=−0.08, p = 0.03) among four nutritional factors. These results suggest that high soy protein intake is associated with a higher bone mineral density and a lower level of bone resorption, but further studies are needed to confirm the causal dynamic mechanisms.

17β-Estradiol Inhibits Ca2+ Influx and Ca2+ Release Induced by Thromboxane A2 in Porcine Coronary Artery

Background We wished to investigate the possible mechanism of the protective effect of estrogen replacement on coronary atherosclerosis observed in postmenopausal women. Methods and Results Cytosolic Ca2+ concentration ([Ca2+]i) and contraction were measured simultaneously in fura 2–loaded porcine coronary arterial strips stimulated by the thromboxane A2 analogue U46619 and high-K+ depolarization in the presence and absence of 17β-estradiol. Pretreatment with 17β-estradiol (30 nmol/L to 30 μmol/L) inhibited the sustained elevation of [Ca2+]i and the sustained contraction induced by 300 nmol/L U46619. Higher concentrations of 17β-estradiol (1 to 100 μmol/L) also inhibited the U46619-induced transient increase in [Ca2+]i and contraction in the absence of extracellular Ca2+. In the strips precontracted by 90 mmol/L K+, 17β-estradiol (30 μmol/L) inhibited the increases in [Ca2+]i and contraction to resting levels. In contrast, 30 μmol/L 17β-estradiol only partially inhibited the U46619-induced sustained contr...

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.