Periconceptional folic acid intake and disturbing factors: A single-center study in Japan.

We investigated folic acid (FA) intake and disturbing factors in pregnant women who visited our center in 2017. Among 1531 pregnant women, 45.1% of women initiated FA supplementation before pregnancy. The risk of failure of supplementation was significantly lower among women of ≥35 (adjusted odds ratio [aOR] 0.43) and 30-34 years of age (aOR: 0.59) in comparison to women of <30 years of age, and among those conceived with timing/artificial insemination of husband (aOR 0.47) and in vitro fertilization/intracytoplasmic sperm injection (aOR 0.32) in comparison to those conceived naturally. The risk among those with 1 (aOR 1.44) or ≥2 previous deliveries (aOR 2.75) was significantly higher in comparison to nulliparous women. Young, multiparous women, and those with natural conception should be targeted to promote preconceptional FA intake.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Investigate the Effects of Kamishoyosan, a Traditional Japanese Medicine, on Menopausal Symptoms: The KOSMOS Study.

OBJECTIVE: The KOSMOS study, a multicenter, randomized, double-blind, placebo-controlled trial, investigated the effects and safety of kamishoyosan (TJ-24), a traditional Japanese medicine, in the treatment of climacteric disorder. METHODS: Japanese women with climacteric disorder were administered a placebo during a 4-week run-in period, after which they were classified as placebo responders (R group) if their score on the modified Questionnaire for the Assessment of Climacteric Symptoms in Japanese Women (m-QACS) with excitability and irritability as the primary outcome improved by ≥ 3 points and as placebo nonresponders (NR group) otherwise. Members of the NR group were randomly allocated to receive either TJ-24 or placebo. After 12 weeks, their m-QACS scores, anxiety and depression, sleep, and overall quality of life (QOL) were compared. RESULTS: The TJ-24 and placebo arms in the NR group included 20 patients each. The change in the m-QACS scores of members of the NR group for excitability and irritability at 12 weeks versus baseline was -3.1 ± 1.7 in the TJ-24 arm, a significant decrease, but compared with -2.7 ± 2.2 in the placebo arm, no significant difference was between two arms. However, the proportion of participants whose score improved by ≥3 points was significantly higher in the TJ-24 arm. In the subgroup analysis of premenopausal women, the changes in the score for excitability and irritability were significantly larger in the TJ-24 arm. The incidence of adverse drug reactions or adverse events did not differ between the two arms, and no serious events were reported. CONCLUSION: Although no significant difference was identified for the primary outcome, a significantly higher proportion of patients who received TJ-24 displayed improvement. Its high level of safety and effects on excitability and irritability in premenopausal women suggest that TJ-24 may be a useful treatment.

Depressive Symptoms in Middle-Aged and Elderly Women Are Associated with a Low Intake of Vitamin B6: A Cross-Sectional Study.

This study investigated the nutritional factors that are associated with anxiety and depressive symptoms in Japanese middle-aged and elderly women. We conducted a cross-sectional study with 289 study participants aged ≥40 years (mean age = 52.0 ± 6.9 years). Their dietary habits, menopausal status and symptoms, and varied background factors, such as body composition, lifestyle factors, and cardiovascular parameters, were assessed. Their anxiety and depressive symptoms were evaluated using the Hospital Anxiety and Depression Scale (HADS), where scores of 0-7 points, 8-10 points, and 11-21 points on either the anxiety or depression subscales were categorized as mild, moderate, and severe, respectively. The dietary consumption of nutrients was assessed using a brief self-administered diet history questionnaire. The relationships between the moderate-to-severe anxiety/depressive symptoms and the dietary intake of 43 major nutrients were investigated using multivariate logistic regression analyses. After adjusting for age, menopausal status, and the background factors that were significantly related to depressive symptoms, moderate and severe depression was significantly inversely associated with only vitamin B6 (adjusted odds ratio per 10 µg/MJ in vitamin B6 intake = 0.89, 95% confidence interval = 0.80-0.99). A higher intake of vitamin B6 could help relieve depressive symptoms for this population.

Daily Coffee and Green Tea Consumption Is Inversely Associated with Body Mass Index, Body Fat Percentage, and Cardio-Ankle Vascular Index in Middle-Aged Japanese Women: A Cross-Sectional Study.

This study aimed to investigate the links between coffee (CF)/green tea (GT) consumption and body composition/cardiovascular parameters in middle-aged Japanese women. We conducted a cross-sectional study of 232 Japanese women aged 40-65 years who had been referred to the menopause clinic of Tokyo Medical and Dental University Hospital between November 2007 and August 2017. Body composition, cardiovascular parameters, and CF/GT consumption frequency were evaluated on their initial visits, using a body composition analyzer, vascular screening system, and brief-type self-administered diet history questionnaire, respectively. We investigated the associations between variables using multivariate logistic regression. After adjustment for age, menopausal status, and other factors, daily CF consumption was inversely associated with high body mass index (BMI) (adjusted odds ratio, 0.14; 95% confidence interval, 0.14-0.96) and body fat percentage (BF%) (0.33; 0.14-0.82), and daily GT consumption with high BF% (0.36; 0.14-0.96). Daily CF + GT consumption was also inversely associated with high BMI (0.15; 0.05-0.50) and BF% (0.30; 0.12-0.74). In pre- and perimenopausal women, daily CF + GT consumption was inversely associated with high cardio-ankle vascular index (CAVI) (0.05; 0.003-0.743). In conclusion, daily CF/GT consumption was inversely associated with high BMI, BF%, and CAVI in middle-aged Japanese women.

Effects of Grape Seed Proanthocyanidin Extract on Vascular Endothelial Function in Participants with Prehypertension: A Randomized, Double-Blind, Placebo-Controlled Study.

This study aimed to investigate the effects of grape seed proanthocyanidin extract (GSPE) on blood pressure and vascular endothelial function in middle-aged Japanese adults with prehypertension. We conducted a randomized, double-blind, placebo-controlled study on 6 men and 24 women aged 40-64 years old. The participants were randomized to receive tablets containing either low-dose (200 mg/day) or high-dose (400 mg/day) GSPE, or placebo, for 12 weeks. Systolic and diastolic blood pressures (SBP and DBP, respectively), brachial flow-mediated dilation (FMD), and other cardiovascular parameters were measured before and after 4, 8, and 12 weeks of treatment. The mean SBP in the high-dose group significantly decreased by 13 mmHg after 12 weeks (P = 0.028), although FMD did not change. In an ad hoc analysis of non-smoking participants (n = 21), the mean SBP, DBP, stiffness parameter ß, distensibility, incremental elastic modulus (Einc), and pulse wave velocity (PWV) also significantly improved in the high-dose group after 12 weeks. Changes in Einc and PWV from baseline to 12 weeks were significantly greater in the high-dose group than in the placebo group (Einc, P = 0.023; PWV, P = 0.03). GSPE consumption could help maintain vascular elasticity and normal blood pressure in this population.

Normal/high-fat milk consumption is associated with higher lean body and muscle mass in Japanese women aged between 40 and 60 years: a cross-sectional study.

BACKGROUND: Milk is known to contain various nutrients that may have health benefits for postmenopausal women who are at an increased risk of cardiovascular and musculoskeletal diseases. We investigated the association between normal/high- and low-fat milk consumption and body composition in Japanese women aged 40 to 60 years. METHODS: This cross-sectional study used the baseline data collected in a previous study that examined the effects of a dietary supplement on a variety of health parameters in 85 Japanese women aged 40 to 60 years. Participants had been assessed for age, menopausal status, lifestyle factors, and body composition. We estimated the consumption of normal/high- and low-fat milk using a brief-type self-administered diet history questionnaire (BDHQ). Normal/high- and low-fat milk intake were classified as consumer (drank milk at least twice a week) or non-consumer (drank milk at most once a week), in order to identify the parameters that were independently associated with the consumption of normal/high- and low-fat milk. RESULTS: Of the 85 participants who completed the BDHQ, 27 were categorized as non-consumers, 18 as exclusive low-fat milk consumers, and 29 as exclusive normal/high-fat milk consumers. 11 women who consumed both low-fat and normal/high-fat milk were excluded from the analysis. Compared with non-consumers and exclusive low-fat milk consumers, exclusive high-fat milk consumers had significantly higher lean body mass (mean ± standard deviation [SD], 39.4 ± 2.7 kg vs. 37.9 ± 2.2 kg and 37.6 ± 2.9 kg, P < 0.05) and muscle mass (mean ± SD, 37.2 ± 2.5 kg vs. 35.8 ± 2.0 kg and 35.5 ± 2.7 kg, P < 0.05). Both lean body and muscle masses were significantly correlated with vitamin D intake from milk (Pearson r = 0.29, P = 0.008, and Pearson r = 0.29, P = 0.008, respectively). CONCLUSION: Normal/high-fat milk consumption was associated with higher lean body and muscle mass in middle-aged Japanese women presumably through high vitamin D intake.

Effect of soy lecithin on fatigue and menopausal symptoms in middle-aged women: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Lecithin is a complex mixture of phospholipids which compose lipid bilayer cell membranes. Lipid replacement therapy, or administration of phospholipids for the purpose of repairing the dmaged cell membranes, had been shown to alleviate fatigue. The present study aimed to investigate the effect of soy lecithin on fatigue in middle-aged women, as well as other menopausal symptoms and various health parameters. METHODS: This randomized, double-blind, placebo-controlled study included 96 women aged 40 to 60 years who complained of fatigue. The participants were randomized to receive active tablets containing high-dose (1200 mg/day; n = 32) or low-dose (600 mg/day; n = 32) soy lecithin, or placebo (n = 32), for 8 weeks. The following parameters were evaluated: age, menopausal status, lifestyle factors, physical and psychological symptoms of menopause, subjective symptoms of insomnia and fatigue, body composition, cardiovascular parameters, and physical activities and objective sleep states obtained from actigraphy before and 4 and 8 weeks after treatment. Fatigue was evaluated using the Profile of Mood States (POMS)-brief, Menopausal Health-Related Quality of Life questionnaire, Chalder Fatigue Scale, and Brief Fatigue Inventory. RESULTS: Eighty-nine women completed the study. There were no significant differences in the changes in Chalder Fatigue Scale score (placebo vs low-dose vs high-dose groups: -2.9 ± 1.1, -3.2 ± 1.1, and -3.5 ± 1.0; P = 0.79). On the other hand, the improvements were greater in the high-dose group compared with the placebo group concerning vigor scores in the POMS-brief (1.9 ± 0.7 vs 0.2 ± 0.6; P = 0.02), diastolic blood pressure (-4.1 ± 1.8 vs 1.2 ± 1.9; P = 0.05), and cardio-ankle vascular index (-0.4 ± 0.2 vs 0.07 ± 0.1; P = 0.03) after 8 weeks of treatment. CONCLUSIONS: High-dose (1200 mg/day) soy lecithin not only increases vigor, but also lowers the diastolic blood pressure and cardio-ankle vascular index in middle-aged women who present with fatigue. TRIAL REGISTRATION: UMIN-CTR UMIN000017127 .

An Elevation of Serum Ferritin Level Might Increase Clinical Risk for the Persistence of Patent Ductus Arteriosus, Sepsis and Bronchopulmonary Dysplasia in Erythropoietin-Treated Very-Low-Birth-Weight Infants.

BACKGROUND: The substantial risk of iron overload is not routinely monitored in most of the neonatal intensive care units (NICUs) in Japan; however, blood transfusion is an essential strategy for successfully treating preterm low-birth-weight infants. OBJECTIVE: The aim of this study was to investigate the iron status and clinical features of infants with a birth weight of <1,500 g, i.e. very-low-birth-weight infants (VLBWIs). METHODS: This prospective observational study enrolled 176 (82.6%) patients from a total of 213 VLBWIs admitted to our NICU from 2009 to 2014. Clinical information was collected including maternal records and infant morbidity and treatment. Management strategies including enteral iron supplementation, erythropoietin administration and blood transfusion were allowed according to the consensus in Japan. The hematological status was surveyed from birth to 12 postnatal weeks of age. The iron status was determined according to serum iron, unbound iron-binding capacity and serum ferritin. The definition of hyperferritinemia was set as a value of ≥500 ng/ml. RESULTS: Twenty-four (13.6%) infants displayed hyperferritinemia. A multiple logistic analysis selected 3 associated factors of hyperferritinemia: surgical ligation for patent ductus arteriosus, sepsis and moderate or severe states of bronchopulmonary dysplasia. We also verified that the value of ferritin was significantly correlated with those of aspartate transaminase, creatine kinase and C-reactive protein according to a multilinear regression analysis. After excluding the ferritin data of these outliers, we did not observe any factors associated with hyperferritinemia. CONCLUSIONS: Hyperferritinemia might be associated with oxygen radical diseases and susceptibility to infection.

Effects of the kampo formula tokishakuyakusan on headaches and concomitant depression in middle-aged women.

Objectives. To identify the correlates of headaches in middle-aged women and investigate the effects of Tokishakuyakusan (TJ-23), a formula of traditional Japanese herbal therapy Kampo, on headache and concomitant depression. Methods. We examined cross-sectionally the baseline records of 345 women aged 40-59 years who visited our menopause clinic. Among them, 37 women with headaches were treated with either hormone therapy (HT) or TJ-23; the data of these women were retrospectively analyzed to compare the effects of the treatment. Results. The women were classified into 4 groups on the basis of their headache frequency, and no significant intergroup differences were noted in the physical or lifestyle factors, except age. Multiple logistic regression analysis revealed that the significant contributors to the women's headaches were their age (adjusted OR 0.92 (95% CI 0.88-0.97)) and their depressive symptoms (adjusted OR 1.73 (95% CI 1.39-2.16)). Compared to women treated with HT, women treated with TJ-23 reported relief from headaches (65% versus 29%) and concomitant depression (60% versus 24%) more frequently. Improvement in the scores of headaches and depression correlated significantly with TJ-23 treatment. Conclusions. Headache in middle-aged women is significantly associated with depression; TJ-23 could be effective for treating both of these symptoms.

In vitro acetylcholinesterase inhibitory activity and the antioxidant properties of Aegle marmelos leaf extract: implications for the treatment of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder clinically characterized by loss of memory and cognition. The effective therapeutic options for AD are limited and thus there is a demand for new drugs. Aegle marmelos (Linn.) (A. marmelos) leaves have been used in traditional medicine to promote intellect and enhance memory. In this study, we evaluated A. marmelos for its acetylcholinesterase (AChE) inhibitory activity and antioxidant property in vitro in the treatment of AD. METHODS: A crude methanol extract and four fractions (petroleum ether, chloroform, ethyl acetate and aqueous) were prepared from the leaves of A. marmelos. The preparations were assessed for AChE inhibitory activity by the Ellman method, and their antioxidant properties were assessed by several assays: reducing power, scavenging of 1,1-diphenyl-2-picrylhydrazyl free radical and hydroxyl radical, and inhibition of lipid peroxidation. Qualitative and quantitative analyses of endogenous substances in A. marmelos were performed by the standard phytochemical methods. RESULTS: Among the different extracts tested, the ethyl acetate fraction exhibited the highest inhibition of AChE activity. In the same way, ethyl acetate fraction showed the highest reducing activity and radical scavenging ability towards the 1,1-diphenyl-2-picrylhydrazyl (half maximal inhibitory concentration = 3.84 µg/mL) and hydroxyl free radicals (half maximal inhibitory concentration = 5.68 µg/mL). The antiradical activity of the ethyl acetate fraction appeared to be similar to that of the reference standard butylated hydroxytoluene and catechin used in this study. In addition, the ethyl acetate fraction displayed higher inhibition of brain lipid peroxidation. Phytochemical screening of different extractives of A. marmelos showed the presence of phenols and flavonoids, alkaloid, saponin, glycoside, tannin and steroids. Quantitative analysis revealed higher contents of phenolics (58.79-mg gallic acid equivalent/g dried extract) and flavonoids (375.73-mg gallic acid equivalent/g dried extract) in the ethyl acetate fraction. CONCLUSION: The results suggest that the ethyl acetate fraction of A. marmelos is a significant source of polyphenolic compounds with potential AChE inhibitory property and antioxidant activity and, thus, may be useful in the treatment of AD.

Effects of grape seed proanthocyanidin extract on menopausal symptoms, body composition, and cardiovascular parameters in middle-aged women: a randomized, double-blind, placebo-controlled pilot study.

OBJECTIVE: This study aims to assess the effects of proanthocyanidin-a class of polyphenol antioxidants extracted from grape seeds-on menopausal symptoms, body composition, and cardiovascular parameters in middle-aged women. METHODS: We conducted a randomized, double-blind, placebo-controlled study in 96 women aged 40 to 60 years who had at least one menopausal symptom. The study participants were randomized to receive grape seed extract tablets containing either low-dose (100 mg/d) or high-dose (200 mg/d) proanthocyanidin, or placebo, for 8 weeks. Their menopausal symptoms were evaluated using the Menopausal Health-Related Quality of Life Questionnaire, Hospital Anxiety and Depression Scale, and Athens Insomnia Scale before and after 4 and 8 weeks of treatment. Body composition and cardiovascular parameters were also measured. RESULTS: A total of 91 women (95%) completed the study. Background characteristics, including age, menopause status, subjective symptom scores, body composition, and cardiovascular parameters, were similar among the groups. The following significant changes were observed during the course of the study: (1) physical symptom score, hot flash score, and (2) Athens Insomnia Scale score decreased in the high-dose group after 8 weeks of treatment; (3) Hospital Anxiety and Depression Scale Anxiety score and (4) systolic and diastolic blood pressure decreased in the low-dose and high-dose groups after 4 weeks; and, (5) lastly, muscle mass increased in the low-dose and high-dose groups after 8 weeks of treatment. CONCLUSIONS: Grape seed proanthocyanidin extract is effective in improving the physical and psychological symptoms of menopause while increasing muscle mass and reducing blood pressure in middle-aged women.

Effects of the Kampo medication keishibukuryogan on blood pressure in perimenopausal and postmenopausal women.

OBJECTIVE: To examine the effects of keishibukuryogan (TJ-25)-a medicine of the Kampo tradition (the Japanese adaptation of Chinese herbal medicine)-on middle-aged women with high blood pressure. METHODS: The records of 77 peri- and postmenopausal women with high-normal blood pressure or hypertension were analyzed retrospectively. The women had participated in the Systematic Health and Nutrition Education Program at the Tokyo Medical and Dental University in Tokyo, Japan, and had received education only (controls; n = 47) or education and treatment with TJ-25 (n = 30). RESULTS: The baseline characteristics of the 2 groups were comparable. After approximately 6 months, women in the TJ-25 group showed significant reductions in their systolic blood pressure (from 148.4mm Hg to 134.8mm Hg), diastolic blood pressure (from 89.7 mm Hg to 83.7 mm Hg), pulse rate (from 79.5 beats/min to 73.5 beats/min), and resting energy expenditure (from 1552 kcal/day to 1373 kcal/day). Several menopausal symptoms including perspiration, difficulty in initiating sleep, nonrestorative sleep, and headaches/dizziness were also improved. In addition, women in the TJ-25 group had increased health-related quality of life scores in the domains of physical health and life satisfaction. CONCLUSION: TJ-25 alleviates menopausal symptoms and concurrently lowers the blood pressure of middle-aged women with high blood pressure.

Effects of three Kampo formulae: Tokishakuyakusan (TJ-23), Kamishoyosan (TJ-24), and Keishibukuryogan (TJ-25) on Japanese peri- and postmenopausal women with sleep disturbances.

PURPOSE: To assess the effects of Kampo, a traditional Japanese adaptation of Chinese herbal medicine, on peri- and postmenopausal women with sleep disturbances. METHODS: Among the records of 1,523 peri- and postmenopausal women who are enrolled in the Health and Nutrition Education Program at the Tokyo Medical and Dental University, Menopause Clinic, during 1995-2009, about 151 women suffering from moderate to severe sleep disturbances were retrospectively analyzed. These women had received only health/nutrition education (control; n = 77) or received treatment with one of the three major Kampo formulae: Tokishakuyakusan (TJ-23; n = 42), Kamishoyosan (TJ-24; n = 16), or Keishibukuryogan (TJ-25; n = 16) according to their "Sho" or symptom patterns. Subjective sleep parameters, menopausal symptoms, health-related quality of life, body composition, blood pressure, and pulse rate were compared before and after the intervention. RESULTS: The TJ-25 group had significantly higher body weight, body mass index, body fat, lean body mass, resting energy expenditure, and relatively high blood pressure and heart rate at baseline than the other groups. After ~5-month follow up, TJ-23 reduced the sleep disruption frequency, increased lean body mass, and decreased diastolic pressure. TJ-24 alleviated subjective sleep disturbances; improved difficulties in initiating sleep, disrupted sleep, and non-restorative sleep; and relieved headache/dizziness. TJ-25 improved subjective sleep disturbances, alleviated perspiration, and reduced systolic/diastolic pressure and heart rate. CONCLUSIONS: Each of the Kampo formulae effectively alleviated sleep disturbances in Japanese peri- and postmenopausal women. Middle-aged female patients having sleeping disorder could successfully be treated using Kampo medicines.

Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer.

ZAC is a paternally expressed, imprinted gene located on chromosome 6q24, within a region known to harbor a tumor suppressor gene for several types of neoplasia, including human ovarian cancer (HOC). We have failed to identify genetic mutations in the ZAC gene in tumor material. Many imprinted genes contain differentially allele-specific-methylated regions (DMR) and harbor promoter activity that is regulated by the DNA methylation. Aberrant DNA methylation is a common feature of neoplasia and changes in DNA methylation at the ZAC locus have been reported in some cases of HOC. We investigated the DNA methylation and ZAC mRNA expression levels in a larger sample of primary HOC material, obtained by laser capture microdissection. ZAC mRNA expression was reduced in the majority of samples and this correlated with hypermethylation of the ZAC-DMR. Treatment of hypermethylated cells lines with a demethylating agent restored ZAC expression. Our studies indicate that transcriptional silencing of ZAC is likely to be caused by DNA methylation in HOC. Forced expression of ZAC resulted in a reduction in proliferation and marked induction of apoptotic cell death. The ZAC-mediated apoptosis signal is p53-independent and eliminated by inhibitors of caspase 3, 8 and 9. Reduced expression of ZAC would therefore favor tumor progression. As there were no significant differences in either DNA methylation or expression of ZAC mRNA between localized and advanced tumors, our data indicates that loss of ZAC is a relatively early event in HOC. (Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.)