The crucial role of CTCF in mitotic progression during early development of sea urchin.

CCCTC-binding factor (CTCF), an insulator protein with 11 zinc fingers, is enriched at the boundaries of topologically associated domains (TADs) in eukaryotic genomes. In this study, we isolated and analyzed the cDNAs encoding HpCTCF, the CTCF homolog in the sea urchin Hemicentrotus pulcherrimus, to investigate its expression patterns and functions during the early development of sea urchin. HpCTCF contains nine zinc fingers corresponding to fingers 2-10 of the vertebrate CTCF. Expression pattern analysis revealed that HpCTCF mRNA was detected at all developmental stages and in the entire embryo. Upon expressing the HpCTCF-GFP fusion protein in early embryos, we observed its uniform distribution within interphase nuclei. However, during mitosis, it disappeared from the chromosomes and subsequently reassembled on the chromosome during telophase. Moreover, the morpholino-mediated knockdown of HpCTCF resulted in mitotic arrest during the morula to blastula stage. Most of the arrested chromosomes were not phospholylated at serine 10 of histone H3, indicating that mitosis was arrested at the telophase by HpCTCF depletion. Furthermore, impaired sister chromatid segregation was observed using time-lapse imaging of HpCTCF-knockdown embryos. Thus, HpCTCF is essential for mitotic progression during the early development of sea urchins, especially during the telophase-to-interphase transition. However, the normal development of pluteus larvae in CRISPR-mediated HpCTCF-knockout embryos suggests that disruption of zygotic HpCTCF expression has little effect on embryonic and larval development.

Maternal lifestyle and nutrient intakes during pregnancy and exclusive breastfeeding in relation to risk factors for breast cancer: The Japan Environment and Children's Study.

Breastfeeding has many benefits for infant growth and maternal health, such as reducing breast cancer risk. However, data on maternal factors influencing breastfeeding are insufficient. To clarify the associations between maternal lifestyle and diet during pregnancy and exclusive breastfeeding (EBF), we conducted a prospective study of pregnant women within the framework of the Japan Environment and Children's Study (a nationwide birth cohort study). Of 97,413 pregnant women recruited between January 2011 and March 2014, 27,775 with a singleton first live birth whose dietary data during pregnancy and lactation data were complete were eligible. Using logistic regression, we evaluated the associations between lifestyle factors including smoking and prepregnancy body mass index and intake of nutrients (macronutrients, isoflavones, and dietary fiber), some of which are known risk factors of breast cancer, and EBF for one month postpartum (initiation of EBF). To investigate the associations of these factors with EBF for 6 months (continuation of EBF), 9582 women who had successfully completed one-month EBF were further followed up. Smoking and prepregnancy obesity were inversely associated with the initiation and continuation of EBF. Intakes of protein, fat, isoflavone, and dietary fiber were positively associated (p trend = 0.0001 for dietary fiber), and carbohydrate intake was inversely associated with the initiation of EBF. Dietary fiber intake was also associated with the continuation of EBF (p trend = 0.048). These findings indicate that maternal lifestyles during pregnancy affect lactation performance. Lifestyle adjustments during pregnancy may have favorable effects on maternal and children's health through successful breastfeeding.

Recurrent bilateral adrenal infarction with myelodysplastic/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U): a case report.

BACKGROUND: Bilateral adrenal infarction is rare and only a small number of cases have been reported so far. Adrenal infarction is usually caused by thrombophilia or a hypercoagulable state, such as antiphospholipid antibody syndrome, pregnancy, and coronavirus disease 2019. However, adrenal infarction with myelodysplastic/myeloproliferative neoplasm (MDS/MPN) has not been reported. CASE PRESENTATION: An 81-year-old man with a sudden severe bilateral backache presented to our hospital. Contrast-enhanced computed tomography (CT) led to the diagnosis of bilateral adrenal infarction. Previously reported causes of adrenal infarction were all excluded and a diagnosis of MDS/MPN-unclassifiable (MDS/MPN-U) was reached, which was considered to be attributed to adrenal infarction. He developed a relapse of bilateral adrenal infarction, and aspirin administration was initiated. Partial primary adrenal insufficiency was suspected as the serum adrenocorticotropic hormone level was persistently high after the second bilateral adrenal infarction. CONCLUSION: This is the first case of bilateral adrenal infarction with MDS/MPN-U encountered. MDS/MPN has the clinical characteristics of MPN. It is reasonable to assume that MDS/MPN-U may have influenced bilateral adrenal infarction development, considering the absence of thrombosis history and a current comorbid hypercoagulable disease. This is also the first case of recurrent bilateral adrenal infarction. It is important to carefully investigate the underlying cause of adrenal infarction once adrenal infarction is diagnosed, as well as to assess adrenocortical function.

Obesity predicts persistence of resistant hypertension after surgery in patients with primary aldosteronism.

OBJECTIVE: Primary aldosteronism (PA) is considered a major cause of resistant hypertension (RHT). The prevalence of RHT has been recently reported to reach 18% in general hypertension. However, little is known about the prevalence and the outcomes after adrenalectomy of RHT in PA. Therefore, we aimed to clarify the prevalence and surgical outcomes in patients with both PA and RHT. PATIENTS AND DESIGN: Among 550 patients who underwent adrenalectomy for unilateral PA in the Japan PA Study, RHT was defined as an uncontrolled blood pressure (≥140/90 mm Hg) despite treatment with at least any three antihypertensives or hypertension controlled with at least four drugs. Surgical outcome was assessed by the biochemical and clinical outcome. RESULTS: Although 40 (7.3%) patients fulfilled the criteria for preoperative RHT, this should be underestimated because only 36% of patients with postoperative RHT were classified as having preoperative RHT. The prevalence of preoperative RHT was approximately 20% when estimated using the total number of patients with postoperative RHT and the ratio of postoperative RHT in patients with preoperative RHT. Although an improvement in hypertension was achieved in approximately 80% of patients with preoperative RHT, 20% of these exhibited persistent RHT. These patients were more obese than those for whom RHT improved after surgery. Notably, body mass index of ≥25 kg/m2 was an independent predictor of postoperative RHT. CONCLUSIONS: The prevalence of RHT in PA was lower than expected even with the adjustment for underestimation. Furthermore, obesity is an independent factor predicting the postoperative persistence of RHT.

Reducing the gender gap in academic activities: a 10-year progress report by the Japan Endocrine Society Women Endocrinologists Association (JES-We-Can).

The Japan Endocrine Society (JES) has the largest ratio of female membership among societies associated with Internal Medicine in Japan; half of female members are in their 20s or 30s at present. In 2009, JES organized the "JES-We-Can" committee to promote women's career development. To evaluate the effectiveness of JES-We-Can, we investigated the gender balance of various activities at JES in fiscal 2009 and 2017. Significant gender-differences were not observed in the acquisition rate of board-certified endocrinologists (BCEs) aged <40 y in 2009 and 2017. However, the acquisition rate of BCEs among women aged ≥40 y was significantly lower than men in 2009. In 2017, the gender-difference among BCEs in this group (currently aged ≥50 y) has considerably improved, but is not resolved. The acquisition rate of certificated endocrine educators (CEEs) among women was still significantly lower than men at all ages in 2017. Since the ratio of women oral speakers or poster presenters at annual academic meetings have grown to equal or surpass the membership ratio, female members make efficient contributions to JES. The numbers of women chairpersons, symposiasts, lecturers and invited speakers have increased, but remain limited. JES-We-Can was found to be effective in reducing the gender gap in academic activities at JES, but JES-We-Can should support women more intensely to raise the rate of CEEs among all ages and BCEs currently over 50 y, and to promote more women into higher positions in JES in the future. These actions are expected to introduce new and diverse perspectives into academia.

Effectiveness and safety of cinacalcet for primary hyperparathyroidism: a single center experience.

Primary hyperparathyroidism (PHPT) is a common endocrine disease. Although surgical treatment is curative in most cases, there are few alternative therapies for the hypercalcemia caused by PHPT. Cinacalcet is a positive allosteric modulator of the calcium sensing receptor and was conditionally approved in Japan in 2014 to treat PHPT cases. However, there have been few reports on the outcomes. In our present study, we investigated the efficacy and safety of cinacalcet in 61 PHPT patients who were treated with this agent at our hospital between January 2014 and March 2017. The corrected serum Ca and intact PTH levels were significantly reduced by this treatment, whereas the serum phosphorus levels significantly increased. There were no significant differences in the eGFR or urinary Ca to urinary creatinine ratio between baseline and the maintenance phase. In terms of bone mineral density, there were significant increases observed in the 16 cases for whom a baseline value was available, 11 of whom had been treated for osteoporosis. The most common adverse events from cinacalcet treatment were gastrointestinal symptom, such as nausea and appetite loss. Other adverse events included severe dehydration due to hypercalcemia, myalgia, hypocalcemia, and increased urinary calcium excretion. Seven patients were switched to surgical treatment, and the drug was discontinued in 9 other patients, due to adverse effects. Our present study findings demonstrate that cinacalcet is an effective therapeutic option for PHPT from the perspective of hypercalcemia improvement but that adverse gastrointestinal effects of this drug occur at a frequency of about 10%.

Atherosclerosis of the carotid bulb is associated with the severity of orthostatic hypotension in non-diabetic adult patients: a cross-sectional study.

BACKGROUND: The carotid bulb has a high density of baroreceptors that play an important role in maintaining blood pressure. We hypothesized that atherosclerosis of the carotid bulb would reflect the severity of orthostatic hypotension more accurately than would atherosclerosis of other carotid artery segments. METHODS: This cross-sectional study included 198 non-diabetic adults. We measured the cardio-vascular ankle index as an index of arterial stiffness, intima-media thickness in each carotid artery segment (internal carotid artery, carotid bulb, distal and proximal portions, respectively, of the common carotid artery) as a measure of atherosclerosis, and heart rate variability as a measure of cardiac autonomic function. The sit-to-stand test was used to assess severity of orthostatic hypotension. RESULTS: Intima-media thickness of the carotid bulb was correlated with orthostatic systolic blood pressure change (r = -0.218, p = 0.002), cardio-ankle vascular index (r = 0.365, p < 0.001) and heart rate variability parameters. Multivariate regression analysis revealed that among all of the segments, only intima-media thickness of the carotid bulb was an independent predictor of orthostatic systolic blood pressure change (p = 0.022). CONCLUSION: Atherosclerosis of the carotid bulb was associated with severity of orthostatic hypotension, arterial stiffening and cardiac autonomic dysfunction than that of other carotid artery segments.

Effects of tolvaptan in patients with chronic kidney disease and chronic heart failure.

BACKGROUND: Tolvaptan, a vasopressin V2 receptor blocker, has a diuretic effect for patients with heart failure. However, there were a few data concerning the effects of tolvaptan in patients with chronic kidney disease (CKD). METHODS: We retrospectively analyzed 21 patients with chronic heart failure and CKD. Tolvaptan was co-administered with other diuretics in-use, every day. We compared clinical parameters before and after the treatments with tolvaptan. Furthermore, we examined the correlations between baseline data and the change of body weight. RESULTS: Tolvaptan decreased the body weight and increased the urine volume (p = 0.001). The urine osmolality significantly decreased throughout the study period. Urinary Na/Cr ratio and FENa changed significantly after 4 h, and more remarkable after 8 h (p = 0.003, both). Serum creatinine increased slightly after 1 week of treatment (p = 0.012). The alteration of body weight within the study period correlated negatively with the baseline urine osmolality (r = -0.479, p = 0.038), the baseline urine volume (r = -0.48, p = 0.028), and the baseline inferior vena cava diameter (IVCD) (r = -0.622, p = 0.017). Hyponatremia was improved to the normal value, and the augmentations of the sodium concentration were negatively associated with the basal sodium levels (p = 0.01, r = -0.546). CONCLUSIONS: Tolvaptan is effective in increasing diuresis and improved hyponatremia, even in patients with CKD. The baseline urine osmolality, urine volume, and IVCD may be useful predictors for diuretic effects of tolvaptan.

The Role of CNS in the Effects of Salt on Blood Pressure.

Sympathetic nerve activity is involved in the pathogenesis of salt-sensitive hypertension. The central nervous system, which regulates sympathetic nerve activity and blood pressure, plays a pivotal role. Central sympathoexcitation is deeply involved in the pathogenesis of salt-sensitive hypertension, although the precise mechanisms have not been fully elucidated because of their complexity. The role of brain oxidative stress in sympathoexcitation has been suggested in some types of hypertensive animal models. We have shown that increased brain oxidative stress may elevate arterial pressure through central sympathoexcitation in salt-sensitive hypertension. Several other factors such as mineralocorticoid receptors, aldosterone, corticosterone, epithelial sodium channels, and angiotensin II also play important roles in central sympathetic activation, some of which can be associated with brain oxidative stress. Furthermore, brain paraventricular nucleus Gαi2-protein-mediated transduction has been recently reported as a candidate for the molecular mechanism countering the development of salt-sensitive hypertension.

Efficacy of additional radiofrequency ablation after transcatheter arterial chemoembolization for intermediate hepatocellular carcinoma.

AIM: For intermediate hepatocellular carcinoma (HCC), transcatheter arterial chemoembolization (TACE) therapy is recommended in the guidelines as a monotherapy, although TACE is a non-curative therapy. The aims of the present study were to evaluate the efficacy of adding radiofrequency ablation (RFA) to TACE in patients with intermediate HCC, and to identify the factors that were associated with favorable survival in these patients. METHODS: Fifty-nine patients with intermediate HCC were enrolled in this retrospective study. Thirty-nine patients were treated with TACE alone and 20 patients were treated with additional RFA after TACE. RESULTS: The recurrence-free survival rates at 0.5, 1 and 2 years for the additional RFA group were 32%, 19% and 13%, respectively, and these were significantly higher than those of the TACE group (8%, 3% and 0%, respectively; log-rank test, P = 0.001). The cumulative survival rates of the additional RFA group were significantly higher than those of the TACE group (log-rank test, P = 0.002), although this significant difference was not found in the subgroup of treatment naive patients because of small sample size. Multivariate analysis indicated male sex, lower total bilirubin, lower α-fetoprotein, lower des-γ-carboxyprothrombin, newly recurrent HCC nodules within the last 12 months and additional RFA as independent factors that were significantly associated with favorable overall survival. CONCLUSION: Additional RFA of nodules insufficiently treated by TACE is effective therapy for obtaining favorable disease-free survival in patients with intermediate HCC, and leads to better overall survival particularly in recurrent patients.

Efficacy of cyclosporine combination therapy for new-onset minimal change nephrotic syndrome in adults.

BACKGROUND: Cyclosporine and prednisolone combination therapy has been used in the treatment of minimal change nephrotic syndrome (MCNS). However, few studies have evaluated the efficacy of cyclosporine combined with intravenous methylprednisolone pulse therapy (MPT) as a first-line treatment for new-onset MCNS. We conducted a retrospective clinical study to evaluate the efficacy and safety of cyclosporine combined with MPT and oral prednisolone for new-onset MCNS in adults. METHODS: Forty-six adult patients with biopsy-proven MCNS were analyzed retrospectively. This study included three groups. Group 1 (n = 17) was treated with intravenous MPT (0.5 or 1.0 g/day for 3 days) followed by oral cyclosporine (2-3 mg/kg/day) and prednisolone (30 mg/day). Group 2 (n = 15) was treated with intravenous MPT followed by oral prednisolone (0.4-0.8 mg/kg/day). Group 3 (n = 14) was treated with oral prednisolone (0.6-1.0 mg/kg/day) alone. RESULTS: The length of hospital stay was the shortest in Group 1 (P < 0.001). The mean duration to achieve <20 mg/day of prednisolone was also the shortest in Group 1 (P < 0.05). Complete remission rates were 100 % in Group 1, 85.7 % in Group 2, and 69.2 % in Group 3 during the 9-month follow-up (P = 0.073). The rate of adverse effects caused by prednisolone was less in Group 1 (P < 0.05). Multivariate analysis revealed that the independent determinants of durations of remission were the selectivity index (P = 0.004), eGFR (P = 0.001) and the use of cyclosporine (P = 0.045). CONCLUSIONS: Combination therapy with cyclosporine may be a beneficial treatment option for new-onset MCNS in adults because of its clinical efficacy and safety.

Hepatitis C virus NS4B protein targets STING and abrogates RIG-I-mediated type I interferon-dependent innate immunity.

UNLABELLED: Hepatitis C virus (HCV) infection blocks cellular interferon (IFN)-mediated antiviral signaling through cleavage of Cardif by HCV-NS3/4A serine protease. Like NS3/4A, NS4B protein strongly blocks IFN-ß production signaling mediated by retinoic acid-inducible gene I (RIG-I); however, the underlying molecular mechanisms are not well understood. Recently, the stimulator of interferon genes (STING) was identified as an activator of RIG-I signaling. STING possesses a structural homology domain with flaviviral NS4B, which suggests a direct protein-protein interaction. In the present study, we investigated the molecular mechanisms by which NS4B targets RIG-I-induced and STING-mediated IFN-ß production signaling. IFN-ß promoter reporter assay showed that IFN-ß promoter activation induced by RIG-I or Cardif was significantly suppressed by both NS4B and NS3/4A, whereas STING-induced IFN-ß activation was suppressed by NS4B but not by NS3/4A, suggesting that NS4B had a distinct point of interaction. Immunostaining showed that STING colocalized with NS4B in the endoplasmic reticulum. Immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays demonstrated that NS4B specifically bound STING. Intriguingly, NS4B expression blocked the protein interaction between STING and Cardif, which is required for robust IFN-ß activation. NS4B truncation assays showed that its N terminus, containing the STING homology domain, was necessary for the suppression of IFN-ß promoter activation. NS4B suppressed residual IFN-ß activation by an NS3/4A-cleaved Cardif (Cardif1-508), suggesting that NS3/4A and NS4B may cooperate in the blockade of IFN-ß production. CONCLUSION: NS4B suppresses RIG-I-mediated IFN-ß production signaling through a direct protein interaction with STING. Disruption of that interaction may restore cellular antiviral responses and may constitute a novel therapeutic strategy for the eradication of HCV.

Factors Associated with Anemia and Iron Deficiency during Pregnancy: A Prospective Observational Study in Japan.

Gestational anemia (GA) is a global health concern with a remarkably high prevalence in Japan, which is associated with various maternal and neonatal outcomes. This study aimed to explore whether GA and non-anemic iron deficiency (NAID) during the third trimester is associated with maternal characteristics, nutrient intake, low birth weight (LBW), and preterm birth. Participants were categorized into GA, NAID, and normal groups, based on serum ferritin and hemoglobin levels. Nutrient intake was assessed using the Brief Diet History Questionnaire. Data from 317 pregnant women were analyzed, including 110 (34.7%), 151 (47.6%), and 56 (17.6%) women in the GA, NAID, and normal groups, respectively. Factors associated with GA included being multipara (p < 0.001) and not taking any type of iron supplements in the third trimester (p = 0.043). The normal group had a significantly higher proportion of preterm birth and LBW than the GA and NAID groups. The GA group had a significantly higher energy intake than the normal group (p = 0.044). Overall, energy and micronutrient intake were significantly below the estimated average requirement in the dietary reference intakes for Japanese. Health care professionals need to consider nutritional advice that can prevent GA by focusing on overall micronutrients, not just energy intake.

25-Hydroxyvitamin D3 suppresses hepatitis C virus production.

UNLABELLED: Because the current interferon (IFN)-based treatment for hepatitis C virus (HCV) infection has a therapeutic limitation and side effects, a more efficient therapeutic strategy is desired. Recent studies show that supplementation of vitamin D significantly improves sustained viral response via IFN-based therapy. However, mechanisms and an active molecular form of vitamin D for its anti-HCV effects have not been fully clarified. To address these questions, we infected HuH-7 cells with cell culture-generated HCV in the presence or absence of vitamin D(3) or its metabolites. To our surprise, 25-hydroxyvitamin D(3) [25(OH)D(3) ], but not vitamin D(3) or 1,25-dihydroxyvitamin D(3) , reduced the extra- and intracellular levels of HCV core antigen in a concentration-dependent manner. Single-cycle virus production assay with a CD81-negative cell line reveals that the inhibitory effect of 25(OH)D(3) is at the level of infectious virus assembly but not entry or replication. Long-term 25(OH)D(3) treatment generates a HCV mutant with acquired resistance to 25(OH)D(3) , and this mutation resulting in a N1279Y substitution in the nonstructural region 3 helicase domain is responsible for the resistance. CONCLUSION: 25(OH)D(3) is a novel anti-HCV agent that targets an infectious viral particle assembly step. This finding provides insight into the improved efficacy of anti-HCV treatment via the combination of vitamin D(3) and IFN. Our results also suggest that 25(OH)D(3) , not vitamin D(3) , is a better therapeutic option in patients with hepatic dysfunction and reduced enzymatic activity for generation of 25(OH)D(3) .

The role of CNS in salt-sensitive hypertension.

The role of sympathetic nerve activity in hypertension is currently receiving increased attention, because catheter-based renal denervation was recently shown to reduce blood pressure safely in patients with treatment-resistant hypertension. The central nervous system, which regulates sympathetic nerve activity and blood pressure, is pivotal. Central sympathoexcitation has been shown to be deeply involved in the pathogenesis of salt-sensitive hypertension, although its precise mechanisms have not yet been fully elucidated due to their complexity. Recently, a role for brain oxidative stress in sympathoexcitation has been suggested in some hypertensive animal models. We have demonstrated that increased brain oxidative stress may elevate arterial pressure through central sympathoexcitation in salt-sensitive hypertension. Several factors other than oxidative stress have also been shown to play important roles in central sympathetic activation. In the future, strategies may be developed to elicit a sympathetic inhibition by modulating these factors to prevent and manage salt-sensitive hypertension.

TNF-α -857C>T genotype is predictive of clinical response after treatment with definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma.

BACKGROUND: Genotypes of tumor necrosis factor alpha (TNF-α) and its surface receptors, TNFRSF1A and TNFRSF1B, have been examined in terms of the progression, metastasis, clinical efficacy, and prognosis of various cancers; however, little is known about their effects on clinical outcome in patients with esophageal squamous cell carcinoma (ESCC). In this study, TNF-α and TNFRSF1A genotypes were retrospectively evaluated in terms of predicting clinical response, long-term survival, and severe acute toxicities in 46 male Japanese ESCC patients treated with definitive 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT). METHODS: A course consisted of the continuous infusion of 5-FU at 400 mg/m(2)/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1-5, 8-12, and 15-19, with a second course being repeated after a 2-week interval. The TNF-α -1031T>C (rs1799964), -863C>A (rs1800630), -857C>T (rs1799724), -308G>A (rs1800629), -238G>A (rs361525), TNFRSF1A -609G>T (rs4149570), and 36A>G (rs767455) genotypes were evaluated. RESULTS: The TNF-α -857C>T genotype was found to be predictive of clinical response, i.e., complete response or not (P = 0.010, Fisher's exact test), but had no effect on long-term survival (CC(-857) vs. CT(-857) + TT(-857), P = 0.072, Fisher's exact test, P = 0.070, Log-rank test). CONCLUSIONS: The TNF-α -857C>T genotype was found to be predictive of clinical response and was more likely to predict long-term survival in Japanese ESCC patients receiving definitive 5-FU/CDDP-based CRT. Further clinical investigations with a larger number of patients or experiments in vitro should be performed to assess the predictive value of this genotype following CRT.

Association of Eicosapentaenoic and Docosahexaenoic Acid Intake with Low Birth Weight in the Second Trimester: The Japan Pregnancy Eating and Activity Cohort Study.

This study examined the association of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake during the second trimester with low birth weight (LBW) in pregnant Japanese women and was conducted in conjunction with the Japan Pregnancy Eating and Activity Cohort (J-PEACH) study. The study included 504 pregnant women from four Japanese sites. During the second trimester (14-27 weeks), the participants filled out a self-administered questionnaire assessing the frequency of DHA and EPA supplement intake in the past month, as well as a brief-type self-administered diet history questionnaire (BDHQ). The analysis involved data from two time points: responses to the BDHQ and infant data at birth. In total, 471 and 33 participants were classified into the normal birth weight and LBW groups, respectively. The participants were divided into high-, medium-, and low-intake groups based on their total dietary and EPA and DHA supplementary intakes. The Cochran-Armitage trend test was used to analyze the data; the prevalence of LBW was higher in the low-intake group (p = 0.04). There was no significant sex-based trend (p = 0.27 and p = 0.35). In Japanese women, low dietary and supplementary EPA and DHA intake until the second trimester were risk factors for LBW.

Dietary Intake and Its Association with Birth Outcomes in Women with Nausea and Vomiting during the Second Trimester of Pregnancy: A Prospective Cohort Study in Japan.

Nausea and vomiting in pregnancy (NVP) is a common symptom. Although the influence of NVP during the first trimester on dietary intake and birth outcomes has been revealed, no study has focused on NVP during the second trimester. This study aimed to reveal whether NVP severity during the second trimester is associated with dietary intake, gestational weight gain (GWG), birth weight, and delivery week. Participants completed a questionnaire at 18-27 gestational weeks. NVP severity was assessed using the modified Pregnancy-Unique Quantification of Emesis and Nausea scale in the questionnaire. Dietary habits were assessed using a brief-type diet history questionnaire. In total, 825 responses were analyzed: 202 (24.5%), 135 (16.4%), and 8 (1.0%) women reported mild, moderate, and severe NVP, respectively; 480 (58.2%) women did not have NVP during the second trimester. No significant association was observed between energy and nutrient intake and no/mild and moderate/severe NVP. Women with moderate/severe NVP had lower total GWG than those with no/mild NVP (p = 0.007). There was no significant difference in low birth weight and preterm birth rates (p = 0.246 and p = 0.604). This is the first study to investigate whether NVP severity during the second trimester is associated with dietary intake and birth outcomes.

A hyperaldosteronism subtypes predictive model using ensemble learning.

This study aimed to develop a machine-learning algorithm to diagnose aldosterone-producing adenoma (APA) for predicting APA probabilities. A retrospective cross-sectional analysis of the Japan Rare/Intractable Adrenal Diseases Study dataset was performed using the nationwide PA registry in Japan comprised of 41 centers. Patients treated between January 2006 and December 2019 were included. Forty-six features at screening and 13 features at confirmatory test were used for model development to calculate APA probability. Seven machine-learning programs were combined to develop the ensemble-learning model (ELM), which was externally validated. The strongest predictive factors for APA were serum potassium (s-K) at first visit, s-K after medication, plasma aldosterone concentration, aldosterone-to-renin ratio, and potassium supplementation dose. The average performance of the screening model had an AUC of 0.899; the confirmatory test model had an AUC of 0.913. In the external validation, the AUC was 0.964 in the screening model using an APA probability of 0.17. The clinical findings at screening predicted the diagnosis of APA with high accuracy. This novel algorithm can support the PA practice in primary care settings and prevent potentially curable APA patients from falling outside the PA diagnostic flowchart.

Cytotoxicity of 15-deoxy-Δ(12,14)-prostaglandin J(2) through PPARγ-independent pathway and the involvement of the JNK and Akt pathway in renal cell carcinoma.

INTRODUCTION: Agonists of peroxisome proliferator-activated receptor gamma (PPARγ) have been examined as chemopreventive and chemotherapeutic agents. The aim was to investigate the cytotoxicity and action mechanisms of 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), one of endogenous ligands for PPARγ, in terms of PPARγ-dependency and the mitogen-activated protein kinase (MAPK) and Akt pathway in three human renal cell carcinoma (RCC)-derived cell lines. METHODS: 786-O, Caki-2 and ACHN cells were used as human RCC-derived cell lines. Cell viability and caspase-3 activity was detected by fluorescent reagents, and chromatin-condensation was observed with a brightfield fluorescent microscope after staining cells with Hoechst33342. The expression levels of proteins were detected by Western blot analysis. RESULTS: 15d-PGJ(2) showed cytotoxicity in dose-dependent manner. 15d-PGJ(2) induced chromatin-condensation and elevated caspase-3 activity, and the cell viability was restored by co-treatment with a pan-caspase inhibitor, Z-VAD-FMK, indicating the involvement of caspase-dependent apoptosis. The cytotoxicity was not impaired by a PPARγ inhibitor, GW9662, suggesting that 15d-PGJ(2) exerted the cytotoxicity in a PPARγ-independent manner. Some antioxidants rescued cells from cell death induced by 15d-PGJ(2), but some did not, suggesting that reactive oxygen species (ROS) did not contribute to the apoptosis. 15d-PGJ(2) also increased the expression levels of phospho-c-Jun N terminal kinase (JNK) in Caki-2 cells, and decreased those of phospho-Akt in 786-O cells, indicating that the JNK MAPK and the Akt pathways participated in the anticancer effects of 15d-PGJ(2) in some cell lines. CONCLUSION: 15d-PGJ(2) exerted cytotoxic effects accompanying caspase-dependent apoptosis, and this effect was elicited in a PPARγ-independent manner in three cell lines. In addition, the JNK MAPK and Akt pathway was involved in the cytotoxicity of 15d-PGJ(2) to some extent in some cell line. Therefore, our study showed the 15d-PGJ(2) to potentially be an interesting approach for RCC treatment.