Placenta accrete after a frozen-thawed embryo transfer in a systemic lupus erythematosus patient treated with hydroxychloroquine.

Placenta accreta (PA) is a life-threatening disorder associated with decidual maldevelopment and a thin endometrium. Few cases of systemic lupus erythematosus (SLE) pregnancy complicated by PA have been reported, and the background pathophysiology remains elusive. Here, we report a case of PA in SLE pregnancy treated with hydroxychloroquine. A nulligravida woman with SLE, aged 41 years, visited our hospital because of infertility problems. Her SLE was treated with prednisolone and tacrolimus. We conducted assisted reproductive technology and gained several embryos. An artificial cycle successfully prepared the endometrium for embryo transfer with sufficient thickness. Over time, her SLE exacerbated, and we started hydroxychloroquine administration. Consequently, the endometrium did not respond to hormonal supplementation and remained thin, but we transferred the embryo and managed to achieve pregnancy. On the 38th week of gestation, we conducted labor induction because of elevated blood pressure. Induction was not effective, so we performed cesarean section; PA was observed. We performed compression suturing and were able to stop the hemorrhage. Postoperative uterine infarction and pelvic infection were successfully managed with conservative treatment. The present case highlights the use of hydroxychloroquine during endometrial development and contributes evidence regarding the pathogenesis of PA in pregnancy complicated by SLE.

27-Hydroxycholesterol Promotes Adiposity and Mimics Adipogenic Diet-Induced Inflammatory Signaling.

27-Hydroxycholesterol (27HC) is an abundant cholesterol metabolite and has detrimental effects on the cardiovascular system, whereas its impact on adiposity is not well known. In this study, we found that elevations in 27HC cause increased body weight gain in mice fed a high-fat/high-cholesterol diet in an estrogen receptor α-dependent manner. Regardless of diet type, body fat mass was increased by 27HC without changes in food intake or fat absorption. 27HC did not alter energy expenditure in mice fed a normal chow diet and increased visceral white adipose mass by inducing hyperplasia but not hypertrophy. Although 27HC did not augment adipocyte terminal differentiation, it increased the adipose cell population that differentiates to mature adipocytes. RNA sequencing analysis revealed that 27HC treatment of mice fed a normal chow diet induces inflammatory gene sets similar to those seen after high-fat/high-cholesterol diet feeding, whereas there was no overlap in inflammatory gene expression among any other 27HC administration/diet change combination. Histological analysis showed that 27HC treatment increased the number of total and M1-type macrophages in white adipose tissues. Thus, 27HC promotes adiposity by directly affecting white adipose tissues and by increasing adipose inflammatory responses. Lowering serum 27HC levels may lead to an approach targeting cholesterol to prevent diet-induced obesity.

Estrogen Receptor Beta-Mediated Modulation of Lung Cancer Cell Proliferation by 27-Hydroxycholesterol.

27-hydroxycholesterol (27HC) is an abundant cholesterol metabolite in human circulation and promotes breast cancer cell proliferation. Although lung is one of the organs that contain high levels of 27HC, the role of 27HC in lung is unknown. In this study, we found that 27HC promotes lung cancer cell proliferation in an estrogen receptor ß (ERß)-dependent manner. The expression of 27HC-generating enzyme CYP27A1 is higher in lung cancer cells than in normal lung cells. Treatment with 27HC increased cell proliferation in ERß-positive lung cancer cells, but not in ERα-positive or ER-negative cells. The effect on cell proliferation is specific to 27HC and another oxysterol, 25-hydroxycholesterol that has a similar oxysterol structure with 27HC. Moreover, among ligands for nuclear receptors tested, only estrogen had the proliferative effect, and the effect by 27HC and estrogen was inhibited by ERß-specific, but not ERα-specific, inhibitors. In addition, the effect by 27HC was not affected by membrane-bound estrogen receptor GPR30. Interestingly, despite the high expression of CYP27A1, endogenously produced 27HC was not the major contributor of the 27HC-induced cell proliferation. Using kinase inhibitors, we found that the effect by 27HC was mediated by the PI3K-Akt signaling pathway. These results suggest that 27HC promotes lung cancer cell proliferation via ERß and PI3K-Akt signaling. Thus, lowering 27HC levels may lead to a novel approach for the treatment of lung cancer.

Dkk-3 induces apoptosis through mitochondrial and Fas death receptor pathways in human mucinous ovarian cancer cells.

OBJECTIVE: Dkk-3 is a Wnt signaling inhibitor that is frequently inactivated in human cancers. Dkk-3 possesses an antiproliferative activity and induces apoptosis in tumor cells, suggesting that it functions as a tumor suppressor. In this study, we investigated the molecular function of Dkk-3 in human ovarian cancer cells. METHODS: We assessed the levels of Dkk-3 protein expression in human mucinous and clear cell ovarian cancer cells, and compared cell viabilities between cell lines that expressed Dkk-3 and those that did not, as well as between cells that expressed Dkk-3 and those whose expression of Dkk-3 was reduced by small interfering RNA. We also evaluated the characteristic fragmentation of DNA to detect apoptosis in Dkk-3-deficient cells. To further investigate the molecular mechanisms of apoptosis, we assessed the expression of molecules involved in apoptosis signaling pathways in Dkk-3-deficient cells. RESULTS: The expression of the Dkk-3 protein was observed in most of the ovarian cancer cell lines tested. Dkk-3-deficient cells showed faster growth than Dkk-3-replete cells. The characteristic fragmentation of DNA was not observed in Dkk-3-deficient cells, which showed decreased levels of expression in caspase-3, activated caspase-9, Bax, p53, activated caspase-8, and Fas/CD95, as well as an increase in Bcl-2 expression. CONCLUSIONS: Although Dkk-3 expression was observed in most of human ovarian cancer cell lines, Dkk-3 has a tumor-suppressive function and a proapoptotic effect, inducing apoptosis through mitochondrial and Fas death receptor pathways in human mucinous ovarian cancer MCAS cells.

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.

The effects of Dickkopf-4 on the proliferation, differentiation, and apoptosis of osteoblasts.

The Dickkopf family of proteins is comprised of four members (Dkk1, Dkk2, Dkk3, Dkk4) that are known to modulate Wnt/ß-catenin signaling, which is activated during bone formation. Although the effects of Dkk1 on Wnt/ß-catenin signaling have been well studied, little is known about the effects of Dkk4. Therefore, to evaluate the role of Dkk4 in osteoblastogenesis, we used the mouse osteoblastic cell line MC3T3-E1, in which Dkk4 expression was suppressed by small interfering RNA knockdown. Our results showed that the suppression of Dkk4 expression promoted osteoblast proliferation and differentiation and suppressed apoptosis. In colony-forming unit alkaline phosphatase assay, Dkk4 knockdown cells possessed markedly higher alkaline phosphatase activity compared with Dkk1 knockdown cells. Reduced Dkk4 expression also led to the up-regulation of ß-catenin levels, ß-catenin/T cell factor activity, and Wnt-target genes. In contrast, overexpression of Dkk4 in MC3T3-E1 cells led to inhibition of osteoblast differentiation. Our findings reveal that Dkk4 functions as an inhibitor of osteoblastogenesis through Wnt/ß-catenin signaling, providing new insights into the relationship between Wnt/ß-catenin signaling and Dkk4 in bone formation.

Associations among depression, anxiety and somatic symptoms in peri- and postmenopausal women.

AIM: The aim of this study was to investigate the associations among depression, anxiety and physical symptoms in peri- and postmenopausal women in a clinical setting. MATERIAL AND METHODS: Two hundred and thirty-seven peri- and postmenopausal women enrolled in the Systematic Health and Nutrition Education Program at the Menopause Clinic of the Tokyo Medical and Dental University Hospital. Their responses to the Menopausal Health-Related Quality of Life (MHR-QOL) and Hospital Anxiety and Depression Scale (HADS) questionnaires were subjected to a cross-sectional analysis. The study focused on the relationship between the scores for HADS depression (HADS-D) and anxiety (HADS-A) subscales and those for somatic (nausea, dizziness, numbness, muscle and joint pains, tiredness, headaches), urinary (frequent urination), and vasomotor symptoms (hot flashes, night sweats) in the MHR-QOL questionnaire. RESULTS: The correlations among the scores for the six somatic symptoms and HADS-D and HADS-A were stronger than those for urinary or vasomotor symptoms. Multiple logistic regression analysis revealed that the score for headaches and that for HADS-A were significantly associated with severe depression after adjustment (odds ratio (OR) [95% confidence interval (CI)]: 1.49 [1.06-2.10] and 1.58 [1.37-1.83], respectively), whereas the scores for nausea and numbness, as well as HADS-D, were significantly associated with severe anxiety (OR [95% CI]: 1.65 [1.15-2.39], 1.39 [1.05-1.84], and 1.36 [1.23-1.50], respectively). CONCLUSION: Headaches were associated with depression, whereas nausea and numbness were associated with anxiety in peri- and postmenopausal women. The assessment of underlying mood disorders is required for the management of middle-aged women presenting with these somatic symptoms.

Associations between anxiety, depression and insomnia in peri- and post-menopausal women.

OBJECTIVES: To determine the correlation between somatic and psychological symptoms and insomnia and the contribution of depression and anxiety to insomnia in a sample of peri- and post-menopausal women in a clinical setting. STUDY DESIGN: The responses of 237 peri- and post-menopausal women enrolled in the Systematic Health and Nutrition Education Program (SHNEP) at the Menopause Clinic of the Tokyo Medical and Dental University Hospital between November 2007 and December 2010 to the Menopausal Health-Related Quality of Life (MHR-QOL) and Hospital Anxiety and Depression Scale (HADS) questionnaires were subjected to Spearman's rank correlation and logistic regression analyses. RESULTS: The analysis revealed that (1) insomnia is highly prevalent, (2) the symptoms of difficulty in initiating sleep (DIS) and experiencing non-restorative sleep (NRS) are more strongly correlated with psychological than somatic symptoms, and (3) DIS is strongly associated with anxiety while NRS is strongly associated with depression in the population studied. CONCLUSIONS: Insomnia is highly prevalent among peri- and post-menopausal female patients in a clinical setting and more closely associated with psychological than somatic symptoms. DIS is strongly correlated with anxiety while NRS is strongly correlated with depression.

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.