Erinacine A Prevents Lipopolysaccharide-Mediated Glial Cell Activation to Protect Dopaminergic Neurons against Inflammatory Factor-Induced Cell Death In Vitro and In Vivo.

Hericium erinaceus (HE) is a common edible mushroom consumed in several Asian countries and considered to be a medicinal mushroom with neuroprotective effects. Erinacine A (EA) is a bioactive compound in Hericium erinaceus mycelium (HEM) that has been shown to have a neuroprotective effect against neurodegenerative diseases, e.g., Parkinson's disease (PD). Although the etiology of PD is still unclear, neuroinflammation may play an important role in causing dopaminergic neuron loss, which is a pathological hallmark of PD. However, glial cell activation has a close relationship with neuroinflammation. Thus, this study aimed to investigate the anti-neuroinflammatory and neuroprotective effects of EA on lipopolysaccharide (LPS)-induced glial cell activation and neural damage in vitro and in vivo. For the in vitro experiments, glial cells, BV-2 microglial cells and CTX TNA2 astrocytes were pretreated with EA and then stimulated with LPS and/or IFN-γ. The expression of proinflammatory factors in the cells and culture medium was analyzed. In addition, differentiated neuro-2a (N2a) cells were pretreated with EA or HEM and then stimulated with LPS-treated BV-2 conditioned medium (CM). The cell viability and the amount of tyrosine hydroxylase (TH) and mitogen-activated protein kinases (MAPKs) were analyzed. In vivo, rats were given EA or HEM by oral gavage prior to injection of LPS into the substantia nigra (SN). Motor coordination of the rats and the expression of proinflammatory mediators in the midbrain were analyzed. EA pretreatment prevented LPS-induced iNOS expression and NO production in BV-2 cells and TNF-α expression in CTX TNA2 cells. In addition, both EA and HEM pretreatment significantly increased cell viability and TH expression and suppressed the phosphorylation of JNK and NF- κB in differentiated N2a cells treated with CM. In vivo, both EA and HEM significantly improved motor dysfunction in the rotarod test and the amphetamine-induced rotation test and reduced the expression of TNF-α, IL-1ß and iNOS in the midbrain of rats intranigrally injected with LPS. The results demonstrate that EA ameliorates LPS-induced neuroinflammation and has neuroprotective properties.

4-Acetylantroquinonol B induced DNA damage response signaling and apoptosis via suppressing CDK2/CDK4 expression in triple negative breast cancer cells.

BACKGROUND: Triple-negative breast cancer (TNBC) has a more aggressive phenotype and poorer prognosis than hormone receptor (HR+) and human epidermal growth factor receptor (HER2 -) subtypes. Inhibition of cyclin-dependent kinase (CDK)4 and CDK6 was successful in patients with advanced metastatic HR+/HER2- breast cancer, but those with TNBC exhibited low or no response to this therapeutic approach. This study investigated the dual therapeutic targeting of CDK2 and CDK4 by using 4-acetyl-antroquinonol B (4-AAQB) against TNBC cells. METHODS: We examined the effects of CDK2, CDK4, and CDK6 inhibition through 4-AAQB treatment on TNBC cell lines and established an orthotropic xenograft mouse model to confirm the in vitro results of inhibiting CDK2, CDK4, and CDK6 by 4-AAQB treatment. RESULTS: High expression and alteration of CDK2 and CDK4 but not CDK6 significantly correlated with poor overall survival of patients with breast cancer. CDK2 and CDK4 were positively correlated with damage in DNA replication and repair pathways. Docking results indicated that 4-AAQB was bound to CDK2 and CDK4 with high affinity. Treatment of TNBC cells with 4-AAQB suppressed the expression of CDK2 and CDK4 in vitro. Additionally, 4-AAQB induced cell cycle arrest, DNA damage, and apoptosis in TNBC cells. In vivo study results confirmed that the anticancer activity of 4-AAQB suppressed tumor growth through the inhibition of CDK2 and CDK4. CONCLUSION: The expression level of CDK2 and CDK4 and DNA damage response (DDR) signaling are prominent in TNBC cell cycle regulation. Thus, 4-AAQB is a potential agent for targeting CDK2/4 and DDR in TNBC cells.

4-Acetyl-Antroquinonol B Improves the Sensitization of Cetuximab on Both Kras Mutant and Wild Type Colorectal Cancer by Modulating the Expression of Ras/Raf/miR-193a-3p Signaling Axis.

The KRAS mutation is one of the leading driver mutations in colorectal cancer (CRC), and it is usually associated with poor prognosis and drug resistance. Therapies targeting the epidermal growth factor receptor (EFGR) are widely used for end-stage CRC. However, patients with KRAS mutant genes cannot benefit from this therapy because of Ras signaling activation by KRAS mutant genes. Our previous study revealed the anti-proliferative effect of 4-acetyl-antroquinonol B (4-AAQB) on CRC cells, but whether the drug is effective in KRAS-mutant CRC remains unknown. We screened CRC cell lines harboring the KRAS mutation, namely G12A, G12C, G12V and G13D, with one wild type cell line as the control; SW1463 and Caco-2 cell lines were used for further experiments. Sulforhodamine B assays, together with the clonogenicity and invasion assay, revealed that KRAS-mutant SW1463 cells were resistant to cetuximab; however, 4-AAQB treatment effectively resensitized CRC cells to cetuximab through the reduction of colony formation, invasion, and tumorsphere generation and of oncogenic KRAS signaling cascade of CRC cells. Thus, inducing cells with 4-AAQB before cetuximab therapy could resensitize KRAS-mutant, but not wild-type, cells to cetuximab. Therefore, we hypothesized that 4-AAQB can inhibit KRAS. In silico analysis of the publicly available GEO (GSE66548) dataset of KRAS-mutated versus KRAS wild-type CRC patients confirmed that miR-193a-3p was significantly downregulated in the former compared with the latter patient population. Overexpression of miR-193a-3p considerably reduced the oncogenicity of both CRC cells. Furthermore, KRAS is a key target of miR-193a-3p. In vivo treatment with the combination of 4-AAQB and cetuximab significantly reduced the tumor burden of a xenograft mice model through the reduction of the expression of oncogenic markers (EGFR) and p-MEK, p-ERK, and c-RAF/p-c-RAF signaling, with the simultaneous induction of miR-193a-3p expression in the plasma. In summary, our findings provide strong evidence regarding the therapeutic effect of 4-AAQB on KRAS-mutant CRC cells. Furthermore, 4-AAQB effectively inhibits Ras singling in CRC cells, through which KRAS-mutant CRC can be resensitized to cetuximab.

Early preterm preeclampsia outcomes by intended mode of delivery.

BACKGROUND: The optimal route of delivery in early-onset preeclampsia before 34 weeks is debated because many clinicians are reluctant to proceed with induction for perceived high risk of failure. OBJECTIVE: Our objective was to investigate labor induction success rates and compare maternal and neonatal outcomes by intended mode of delivery in women with early preterm preeclampsia. STUDY DESIGN: We identified 914 singleton pregnancies with preeclampsia in the Consortium on Safe Labor study for analysis who delivered between 24 0/7 and 33 6/7 weeks. We excluded fetal anomalies, antepartum stillbirth, or spontaneous preterm labor. Maternal and neonatal outcomes were compared between women undergoing induction of labor (n = 460) and planned cesarean delivery (n = 454) and women with successful induction of labor (n = 214) and unsuccessful induction of labor (n = 246). We calculated relative risks and 95% confidence intervals to determine outcomes by Poisson regression model with propensity score adjustment. The calculation of propensity scores considered covariates such as maternal age, gestational age, parity, body mass index, tobacco use, diabetes mellitus, chronic hypertension, hospital type and site, birthweight, history of cesarean delivery, malpresentation/breech, simplified Bishop score, insurance, marital status, and steroid use. RESULTS: Among the 460 women with induction (50%), 47% of deliveries were vaginal. By gestational age, 24 to 27 6/7, 28 to 31 6/7, and 32 to 33 6/7, the induction of labor success rates were 38% (12 of 32), 39% (70 of 180), and 54% (132 of 248), respectively. Induction of labor compared with planned cesarean delivery was less likely to be associated with placental abruption (adjusted relative risk, 0.33; 95% confidence interval, 0.16-0.67), wound infection or separation (adjusted relative risk, 0.23; 95% confidence interval, 0.06-0.85), and neonatal asphyxia (0.12; 95% confidence interval, 0.02-0.78). Women with vaginal delivery compared with those with failed induction of labor had decreased maternal morbidity (adjusted relative risk, 0.27; 95% confidence interval, 0.09-0.82) and no difference in neonatal outcomes. CONCLUSION: About half of women with preterm preeclampsia who attempted an induction had a successful vaginal delivery. The rate of successful vaginal delivery increases with gestational age. Successful induction has the benefit of preventing maternal and fetal comorbidities associated with previous cesarean deliveries in subsequent pregnancies. While overall rates of a composite of serious maternal and neonatal morbidity/mortality did not differ between induction of labor and planned cesarean delivery groups, women with failed induction of labor had increased maternal morbidity highlighting the complex route of delivery counseling required in this high-risk population of women.

Multispecies probiotics combination prevents ovalbumin-induced airway hyperreactivity in mice.

BACKGROUND: Probiotics could be beneficial to health and some of them have shown to modulate immune responses. AIM: The aim of this study is to investigate if the probiotic strains including Lactobacillus and Pediococcus strains are able to alleviate allergic reactions in an ovalbumin-induced airway allergy model. METHODS: Lactobacillus multi-species preparation (LMP) was gavaged to BALB/c for total six weeks and BALB/c was challenged with ovalbumin in the last two weeks. A barometric whole-body plethysmography was used to assess enhanced pause (Penh) of airway hyperreactivity (AHR). Immunoglobulins (Ig) such as IgE, IgG1, IgG2a and cytokines such as IL-12, IFN-γ, IL-4, IL-5, TNF-α and IL-13 in bronchoalveolar lavage fluid were assayed using ELISA kits. RESULTS: The results showed this LMP significantly reduced Th2 cytokines and enhanced Th1 cytokines production. OVA-specific IgE and IgG1 was lower in the probiotics-treated mice whereas IgG2a was increased. Most importantly, this murine model showed LMP supplementation significantly reduced AHR. CONCLUSIONS: Overall, this Lactobacillus multi-species preparation seemed to suppress OVA-sensitized airway hyperreactivity, thus serving as a possible candidate for therapeutic uses for allergic airway symptoms.

Racial/Ethnic Differences in Labor Induction in a Contemporary US Cohort: A Retrospective Cohort Study.

OBJECTIVE: To examine labor induction by race/ethnicity and factors associated with disparity in induction. STUDY DESIGN: This is a retrospective cohort study of 143,634 women eligible for induction ≥24 weeks' gestation from 12 clinical centers (2002-2008). Rates of labor induction for each racial/ethnic group were calculated and stratified by gestational age intervals: early preterm (240/7-336/7), late preterm (340/7-366/7), and term (370/7-416/7 weeks). Multivariable logistic regression examined the association between maternal race/ethnicity and induction controlling for maternal characteristics and pregnancy complications. The primary outcome was rate of induction by race/ethnicity. Inductions that were indicated, non-medically indicated, or without recorded indication were also compared. RESULTS: Non-Hispanic black (NHB) women had the highest percentage rate of induction, 44.6% (p < 0.001). After adjustment, all racial/ethnic groups had lower odds of induction compared with non-Hispanic white (NHW) women. At term, NHW women had the highest percentage rate (45.4%) of non-medically indicated or induction with no indication (p < 0.001). CONCLUSION: Compared with other racial/ethnic groups, NHW women were more likely to undergo non-medically indicated induction at term. As labor induction may avoid the occurrence of stillbirth, whether this finding explains part of the increased risk of stillbirth for NHB women at term merits further research.

Universal Rapid Human Immunodeficiency Virus Screening at Delivery: A Cost-Effectiveness Analysis.

Objective: To determine the cost-effectiveness of universal maternal HIV screening at time of delivery to decrease mother-to-child transmission (MTCT), by comparing the cost and quality-adjusted life years (QALYs) of universal rapid HIV screening at time of delivery to two current standards of care for prenatal HIV screening in the United States. Study Design: We conducted a cost-effectiveness analysis to compare the cost and QALY of universal intrapartum rapid HIV screening with two current standards of care: (I) opt-out rapid HIV testing limited to patients without previous third-trimester screening and (II) opt-out rapid HIV testing limited to patients without any prenatal screening. We developed a decision-tree model and performed sensitivity analyses to estimate the impact of variances in QALY, estimated lifetime medical costs, HIV prevalence, and cumulative incidence. Results: The incremental cost-effectiveness ratio for universal screening was $7,973.45/QALY. The results remained robust to sensitivity analysis, except for annual cumulative incidence. In areas with an annual cumulative incidence rate of <0.02% for reproductive-age women, the incremental cost-effectiveness ratio for the expanded program would exceed $89,926.94/QALY, approaching the commonly applied cost-effectiveness thresholds ($100,000/QALY). Conclusions: Intrapartum universal rapid HIV screening to decrease MTCT appears cost-effective in populations with high HIV incidence in the United States.

4-Acetylantroquinonol B suppresses autophagic flux and improves cisplatin sensitivity in highly aggressive epithelial cancer through the PI3K/Akt/mTOR/p70S6K signaling pathway.

Targeting residual self-renewing, chemoresistant cancerous cells may represent the key to overcoming therapy resistance. The entry of these quiescent cells into an activated state is associated with high metabolic demand and autophagic flux. Therefore, modulating the autophagy pathway in aggressive carcinomas may be beneficial as a therapeutic modality. In this study, we evaluated the anti-tumor activities of 4-acetylantroquinonol B (4-AAQB) in chemoresistant ovarian cancer cells, particularly its ability to modulate autophagy through autophagy-related genes (Atg). Atg-5 was overexpressed in invasive ovarian cancer cell lines and tissue (OR: 5.133; P=0.027) and depleting Atg-5 in ES-2 cell lines significantly induced apoptosis. 4-AAQB effectively suppressed viability of various subtypes of ovarian cancer. Cells with higher cisplatin-resistance were more responsive to 4-AAQB. For the first time, we demonstrate that 4-AAQB significantly suppress Atg-5 and Atg-7 expression with decreased autophagic flux in ovarian cancer cells via inhibition of the PI3K/Akt/mTOR/p70S6K signaling pathway. Similar to Atg-5 silencing, 4-AAQB-induced autophagy inhibition significantly enhanced cell death in vitro. These results are comparable to those of hydroxychloroquine (HCQ). In addition, 4-AAQB/cisplatin synergistically induced apoptosis in ovarian cancer cells. In vivo, 4-AAQB/cisplatin also significantly induced apoptosis and autophagy in an ES-2 mouse xenografts model. This is the first report demonstrating the efficacy of 4-AAQB alone or in combination with cisplatin on the suppression of ovarian cancer via Atg-5-dependent autophagy. We believe these findings will be beneficial in the development of a novel anti-ovarian cancer therapeutic strategy.

Nonmedically indicated induction in morbidly obese women is not associated with an increased risk of cesarean delivery.

BACKGROUND: The prevalence of morbid obesity (body mass index ≥40 kg/m2) in women aged 20-39 years was 7.5% in 2009 through 2010. Morbid obesity is associated with an increased risk of stillbirth compared with normal body mass index, especially >39 weeks' gestation. The data regarding increased risk of cesarean delivery associated with nonmedically indicated induction of labor compared to expectant management in morbidly obese women are limited. OBJECTIVE: We sought to compare the cesarean delivery rate of nonmedically indicated induction of labor with expectant management in morbidly obese women without other comorbidity. STUDY DESIGN: This was a retrospective cohort study from the Consortium on Safe Labor of morbidly obese women with singleton, cephalic gestations without previous cesarean, chronic hypertension, or gestational or pregestational diabetes between 37 0/7 and 41 6/7 weeks' gestation. We examined maternal outcomes including cesarean delivery, operative delivery, third- or fourth-degree laceration, postpartum hemorrhage, and composite maternal outcome (any of: transfusion, intensive care unit admission, venous thromboembolism). We also examined neonatal outcomes including shoulder dystocia, macrosomia (>4000 g), neonatal intensive care unit admission, and composite neonatal outcome (5-min Apgar score <5, stillbirth, neonatal death, or asphyxia or hypoxic-ischemic encephalopathy). Adjusted odds ratios with 95% confidence intervals were calculated, controlling for maternal characteristics, hospital type, and simplified Bishop score. Analyses were conducted at early and full term (37 0/7 to 38 6/7 and 39 0/7 to 40 6/7 weeks' gestation, respectively). Women who delivered between 41 0/7 and 41 6/7 weeks' gestation were included as expectant management group. RESULTS: Of 1894 nulliparous and 2455 multiparous morbidly obese women, 429 (22.7%) and 791 (32.2%) had nonmedically indicated induction, respectively. In nulliparas, nonmedically indicated induction was not associated with increased risks of cesarean delivery and was associated with decreased risks of macrosomia (2.2% vs 11.0%; adjusted odds ratio, 0.24; 95% confidence interval, 0.05-0.70) at early term and decreased neonatal intensive care unit admission (5.1% vs 8.9%; adjusted odds ratio, 0.59; 95% confidence interval, 0.33-0.98) at full term compared with expectant management. In multiparas, nonmedically indicated induction compared with expectant management was associated with a decreased risk of macrosomia at early term (4.2% vs 14.3%; adjusted odds ratio, 0.30; 95% confidence interval, 0.13-0.60), cesarean delivery at full term (5.4% vs 7.9%; adjusted odds ratio, 0.64; 95% confidence interval, 0.41-0.98), and composite neonatal outcome (0% vs 0.6%; adjusted odds ratio, 0.10; 95% confidence interval, <.01-0.89) at full term. CONCLUSION: In morbidly obese women without other comorbidity, nonmedically indicated induction was not associated with an increased risk of cesarean delivery.

Neonatal outcomes in fetuses with cardiac anomalies and the impact of delivery route.

BACKGROUND: Congenital fetal cardiac anomalies compromise the most common group of fetal structural anomalies. Several previous reports analyzed all types of fetal cardiac anomalies together without individualized neonatal morbidity outcomes based on cardiac defect. Mode of delivery in cases of fetal cardiac anomalies varies greatly as optimal mode of delivery in these complex cases is unknown. OBJECTIVE: We sought to determine rates of neonatal outcomes for fetal cardiac anomalies and examine the role of attempted route of delivery on neonatal morbidity. STUDY DESIGN: Gravidas with fetal cardiac anomalies and delivery >34 weeks, excluding stillbirths and aneuploidies (n = 2166 neonates, n = 2701 cardiac anomalies), were analyzed from the Consortium on Safe Labor, a retrospective cohort study of electronic medical records. Cardiac anomalies were determined using International Classification of Diseases, Ninth Revision codes and organized based on morphology. Neonates were assigned to each cardiac anomaly classification based on the most severe cardiac defect present. Neonatal outcomes were determined for each fetal cardiac anomaly. Composite neonatal morbidity (serious respiratory morbidity, sepsis, birth trauma, hypoxic ischemic encephalopathy, and neonatal death) was compared between attempted vaginal delivery and planned cesarean delivery for prenatal and postnatal diagnosis. We used multivariate logistic regression to calculate adjusted odds ratio for composite neonatal morbidity controlling for race, parity, body mass index, insurance, gestational age, maternal disease, single or multiple anomalies, and maternal drug use. RESULTS: Most cardiac anomalies were diagnosed postnatally except hypoplastic left heart syndrome, which had a higher prenatal than postnatal detection rate. Neonatal death occurred in 8.4% of 107 neonates with conotruncal defects. Serious respiratory morbidity occurred in 54.2% of 83 neonates with left ventricular outflow tract defects. Overall, 76.3% of pregnancies with fetal cardiac anomalies underwent attempted vaginal delivery. Among patients who underwent attempted vaginal delivery, 66.1% had a successful vaginal delivery. Women with a fetal cardiac anomaly diagnosed prenatally were more likely to have a planned cesarean delivery than women with a postnatal diagnosis (31.7 vs 22.8%; P < .001). Planned cesarean delivery compared to attempted vaginal delivery was not associated with decreased composite neonatal morbidity for all prenatally diagnosed (adjusted odds ratio, 1.67; 95% confidence interval, 0.85-3.30) or postnatally diagnosed (adjusted odds ratio, 0.99; 95% confidence interval, 0.77-1.27) cardiac anomalies. CONCLUSION: Most fetal cardiac anomalies were diagnosed postnatally and associated with increased rates of neonatal morbidity. Planned cesarean delivery for prenatally diagnosed cardiac anomalies was not associated with less neonatal morbidity.

Induction of Labor in Women with Oligohydramnios: Misoprostol Compared with Prostaglandin E2.

Objective To compare perinatal outcomes in women with oligohydramnios and an unfavorable cervix undergoing labor induction with misoprostol to prostaglandin E2. Study Design We conducted a secondary analysis of women with oligohydramnios undergoing labor induction in the Consortium on Safe Labor study (2002-2008). Oligohydramnios was recorded in the medical chart. We evaluated perinatal outcomes. We limited the analysis to women with an unfavorable cervix defined by simplified Bishop score ≤ 4. Misoprostol was compared with prostaglandin E2. Women could have received oxytocin, underwent mechanical dilation, or had artificial rupture of membranes, but women who underwent induction with both misoprostol and prostaglandin E2 were excluded. We calculated adjusted odds ratios with 95% confidence intervals, controlling for maternal age, maternal body mass index (kg/m2), parity, and mechanical dilation. Results Among women with oligohydramnios and an unfavorable cervix who underwent induction of labor, 141 (39.4%) received misoprostol and 217 (60.6%) received prostaglandin E2. There were no significant differences in cesarean delivery, chorioamnionitis, postpartum hemorrhage, transfusion, neonatal intensive care unit (NICU) admission, NICU stay > 72 hours, mechanical ventilation, and neonatal sepsis. Conclusion In women with oligohydramnios and an unfavorable cervix, induction of labor with misoprostol was comparable to prostaglandin E2.

Stabilized Wide Bandgap Perovskite Solar Cells by Tin Substitution.

Wide bandgap MAPb(I1-yBry)3 perovskites show promising potential for application in tandem solar cells. However, unstable photovoltaic performance caused by phase segregation has been observed under illumination when y is above 0.2. Herein, we successfully demonstrate stabilization of the I/Br phase by partially replacing Pb2+ with Sn2+ and verify this stabilization with X-ray diffractometry and transient absorption spectroscopy. The resulting MAPb0.75Sn0.25(I1-yBry)3 perovskite solar cells show stable photovoltaic performance under continuous illumination. Among these cells, the one based on MAPb0.75Sn0.25(I0.4Br0.6)3 perovskite shows the highest efficiency of 12.59% with a bandgap of 1.73 eV, which make it a promising wide bandgap candidate for application in tandem solar cells. The engineering of internal bonding environment by partial Sn substitution is believed to be the main reason for making MAPb0.75Sn0.25(I1-yBry)3 perovskite less vulnerable to phase segregation during the photostriction under illumination. Therefore, this study establishes composition engineering of the metal site as a promising strategy to impart phase stability in hybrid perovskites under illumination.

Inhibitory Effects of Probiotic Lactobacillus on the Growth of Human Colonic Carcinoma Cell Line HT-29.

This study was conducted to investigate the inhibitory effect of Lactobacillus cells and supernatants on the growth of the human colon cancer cell line HT-29. Our study results indicated that the PM153 strain exhibits the best adhesion ability and the highest survival in the gastrointestinal tract simulation experiment. Furthermore, after an 8-h co-culture of PM153 and HT-29 cells, the PM153 strain can induce the secretion of nitric oxide from the HT-29 cells. In addition, after the co-culture of the BCRC17010 strain (108 cfu/mL) and HT-29 cells, the Bax/Bcl-2 ratio in the HT-29 cells was 1.19, which showed a significant difference from the other control and LAB groups (p < 0.05), which therefore led to the inference that the BCRC17010 strain exerts a pro-apoptotic effect on the HT-29 cells. Upon co-culture with HT-29 cells for 4, 8 and 12 h, the BCRC14625 strain (108 cfu/mL) demonstrated a significant increase in lactate dehydrogenase (LDH) activity (p < 0.05), causing harm to the HT-29 cell membrane; further, after an 8-h co-culture with the HT-29 cells, it induced the secretion of nitric oxide (NO) from the HT-29 cells. Some lactic acid bacteria (LAB) strains have ability to inhibit the growth of the colorectal cancer cell line HT-29 Bax/Bcl-2 pathway or NO production. In summary, we demonstrated that the BCRC17010 strain, good abilities of adhesion and increased LDH release, was the best probiotic potential for inhibition of HT-29 growth amongst the seven LAB strains tested in vitro.

Indications for primary cesarean delivery relative to body mass index.

BACKGROUND: Obesity is a known risk factor for cesarean delivery. Limited data are available regarding the reasons for the increased rate of primary cesarean in obese women. It is important to identify the factors leading to an increased risk of cesarean to identify opportunities to reduce the primary cesarean rate. OBJECTIVE: We evaluated indications for primary cesarean across body mass index (kg/m(2)) classes to identify the factors contributing to the increased rate of cesarean among obese women. STUDY DESIGN: In the Consortium of Safe Labor study from 2002 through 2008, we calculated indications for primary cesarean including failure to progress or cephalopelvic disproportion, nonreassuring fetal heart tracing, malpresentation, elective, hypertensive disease, multiple gestation, placenta previa or vasa previa, failed induction, HIV or active herpes simplex virus, history of uterine scar, fetal indication, placental abruption, chorioamnionitis, macrosomia, and failed operative delivery. For women with primary cesarean for failure to progress or cephalopelvic disproportion, dilation at the last recorded cervical examination was evaluated. Women were categorized according to body mass index on admission: normal weight (18.5-24.9), overweight (25.0-29.9), and obese classes I (30.0-34.9), II (35.0-39.9), and III (≥40). Cochran-Armitage trend test and χ(2) tests were performed. RESULTS: Of 66,502 nulliparous and 76,961 multiparous women in the study population, 19,431 nulliparous (29.2%) and 7329 multiparous (9.5%) women underwent primary cesarean. Regardless of parity, malpresentation, failure to progress or cephalopelvic disproportion, and nonreassuring fetal heart tracing were the common indications for primary cesarean. Regardless of parity, the rates of primary cesarean for failure to progress or cephalopelvic disproportion increased with increasing body mass index (normal weight, overweight, and classes I, II, and III obesity in nulliparous women: 33.2%, 41.6%, 46.4%, 47.4%, and 48.9% [P < .01] and multiparous women: 14.5%, 20.3%, 22.8%, 27.2%, and 25.3% [P < .01]), whereas the rates for malpresentation decreased (normal weight, overweight, and classes I, II, and III obesity in nulliparous women: 23.7%, 17.2%, 14.6%, 12.0%, and 9.1% [P < .01] and multiparous women: 35.6%, 30.6%, 26.5%, 24.3%, and 22.9% [P < .01]). Rates of primary cesarean for nonreassuring fetal heart tracing were not statistically different for nulliparous (P > .05) or multiparous (P > .05) women. Among nulliparous women who had a primary cesarean for failure to progress or cephalopelvic disproportion, rates of cesarean prior to active labor (6 cm) increased as body mass index increased, accounting for 39.3% of women with class I, 47.1% of women with class II, and 56.8% of women with class III obesity compared to 35.2% for normal-weight women (P < .01). CONCLUSION: Similar to normal-weight women, the indication of cesarean for failure to progress or cephalopelvic disproportion was the major factor contributing to the increase in primary cesarean in obese women, but was even more prevalent with increasing obesity class. The rates of intrapartum primary cesarean prior to achieving active labor increased with increasing obesity class in nulliparous women.

Multi-Strain Probiotics Inhibit Cardiac Myopathies and Autophagy to Prevent Heart Injury in High-Fat Diet-Fed Rats.

High-fat diets induce obesity, leading to cardiomyocyte fibrosis and autophagy imbalance. In addition, no previous studies have indicated that probiotics have potential health effects associated with cardiac fibrosis and autophagy in obese rats. This study investigates the effects of probiotics on high-fat (HF) diet-induced obesity and cardiac fibrosis and autophagy in rat hearts. Eight-week-old male Wistar rats were separated randomly into five equally sized experimental groups: Normal diet (control) and high-fat (HF) diet groups and groups fed a high-fat diet supplemented with low (HL), medium (HM) or high (HH) doses of multi-strain probiotic powders. These experiments were designed for an 8-week trial period. The myocardial architecture of the left ventricle was evaluated using Masson's trichrome staining and immunohistochemistry staining. Key probiotics-related pathway molecules were analyzed using western blotting. Abnormal myocardial architecture and enlarged interstitial spaces were observed in HF hearts. These interstitial spaces were significantly decreased in groups provided with multi-strain probiotics compared with HF hearts. Western blot analysis demonstrated that key components of the TGF/MMP2/MMP9 fibrosis pathways and ERK5/uPA/ANP cardiac hypertrophy pathways were significantly suppressed in probiotic groups compared to the HF group. Autophagy balance is very important in cardiomyocytes. In this study, we observed that the beclin-1/LC3B/Atg7 autophagy pathway in HF was increased after probiotic supplementation was significantly decreased. Together, these results suggest that oral administration of probiotics may attenuate cardiomyocyte fibrosis and cardiac hypertrophy and the autophagy-signaling pathway in obese rats.

Heat-Killed Lactobacillus salivarius and Lactobacillus johnsonii Reduce Liver Injury Induced by Alcohol In Vitro and In Vivo.

The aim of the present study was to determine whether Lactobacillus salivarius (LS) and Lactobacillus johnsonii (LJ) prevent alcoholic liver damage in HepG2 cells and rat models of acute alcohol exposure. In this study, heat-killed LS and LJ were screened from 50 Lactobacillus strains induced by 100 mM alcohol in HepG2 cells. The severity of alcoholic liver injury was determined by measuring the levels of aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (γ-GT), lipid peroxidation, triglyceride (TG) and total cholesterol. Our results indicated that heat-killed LS and LJ reduced AST, ALT, γ-GT and malondialdehyde (MDA) levels and outperformed other bacterial strains in cell line studies. We further evaluated these findings by administering these strains to rats. Only LS was able to reduce serum AST levels, which it did by 26.2%. In addition LS significantly inhibited serum TG levels by 39.2%. However, both strains were unable to inhibit ALT levels. In summary, we demonstrated that heat-killed LS and LJ possess hepatoprotective properties induced by alcohol both in vitro and in vivo.

4-Acetylantroquinonol B inhibits colorectal cancer tumorigenesis and suppresses cancer stem-like phenotype.

4-Acetylantroquinonol B (4-AAQB), closely related to the better known antroquinonol, is a bioactive isolate of the mycelia of Antrodia camphorata, a Taiwanese mushroom with documented anti-inflammatory, hypoglycemic, vasorelaxative, and recently demonstrated, antiproliferative activity. Based on its traditional use, we hypothesized that 4-AAQB may play an active role in the suppression of cellular transformation, tumor aggression and progression, as well as chemoresistance in colorectal carcinoma (CRC). In this study, we investigated the antiproliferative role of 4-AAQB and its underlying molecular mechanism. We also compared its anticancer therapeutic potential with that of antroquinonol and the CRC combination chemotherapy of choice - folinic acid, fluorouracil and oxaliplatin (FOLFOX). Our results showed that 4-AAQB was most effective in inhibiting tumor proliferation, suppressing tumor growth and attenuating stemness-related chemoresistance. 4-AAQB negatively regulates vital oncogenic and stem cell maintenance signal transduction pathways, including the Lgr5/Wnt/ß-catenin, JAK-STAT, and non-transmembrane receptor tyrosine kinase signaling pathways, as well as inducing a dose-dependent downregulation of ALDH and other stemness related factors. These results were validated in vivo, with animal studies showing 4-AAQB possessed comparable tumor-shrinking ability as FOLFOX and potentiates ability of the later to reduce tumor size. Thus, 4-AAQB, a novel small molecule, projects as a potent therapeutic agent for monotherapy or as a component of standard combination chemotherapy.

Risk factors for retained placenta.

OBJECTIVE: Retained placenta complicates 2-3% of vaginal deliveries and is a known cause of postpartum hemorrhage. Treatment includes manual or operative placental extraction, potentially increasing risks of hemorrhage, infections, and prolonged hospital stays. We sought to evaluate risk factors for retained placenta, defined as more than 30 minutes between the delivery of the fetus and placenta, in a large US obstetrical cohort. STUDY DESIGN: We included singleton, vaginal deliveries ≥24 weeks (n = 91,291) from the Consortium of Safe Labor from 12 US institutions (2002-2008). Multivariable logistic regression analyses estimated the adjusted odds ratios (OR) and 95% confidence intervals (CI) for potential risk factors for retained placenta stratified by parity, adjusting for relevant confounding factors. Characteristics such as stillbirth, maternal age, race, and admission body mass index were examined. RESULTS: Retained placenta complicated 1047 vaginal deliveries (1.12%). Regardless of parity, significant predictors of retained placenta included stillbirth (nulliparous adjusted OR, 5.67; 95% CI, 3.10-10.37; multiparous adjusted OR, 4.56; 95% CI, 2.08-9.94), maternal age ≥30 years, delivery at 24 0/7 to 27 6/7 compared with 34 weeks or later and delivery in a teaching hospital. In nulliparous women, additional risk factors were identified: longer first- or second-stage labor duration, whereas non-Hispanic black compared with non-Hispanic white race was found to be protective. Body mass index was not associated with an increased risk. CONCLUSION: Multiple risk factors for retained placenta were identified, particularly the strong association with stillbirth. It is plausible that there could be something intrinsic about stillbirth that causes a retained placenta, or perhaps there are shared pathways of certain etiologies of stillbirth and a risk of retained placenta.

Preterm induction of labor: predictors of vaginal delivery and labor curves.

OBJECTIVE: The purpose of this study was to evaluate the labor curves of patients who undergo preterm induction of labor (IOL) and to assess possible predictors of vaginal delivery (VD). STUDY DESIGN: Data from the National Institute of Child Health and Human Development Consortium on Safe Labor were analyzed. A total of 6555 women who underwent medically indicated IOL at <37 weeks of gestation were included in this analysis. Patients were divided into 4 groups based on gestational age (GA): group A, 24-27+6 weeks; B, 28-30+6 weeks; C, 31-33+6 weeks; and D, 34-36+6 weeks. Pregnant women with a contraindication to VD, IOL ≥37 weeks of gestation, and without data from cervical examination on admission were excluded. Analysis of variance was used to assess differences between GA groups. Multiple logistic regression was used to assess predictors of VD. A repeated measures analysis was used to determine average labor curves. RESULTS: Rates of vaginal live births increased with GA, from 35% (group A) to 76% (group D). Parous women (odds ratio, 6.78; 95% confidence interval, 6.38-7.21) and those with a favorable cervix at the start of IOL (odds ratio, 2.35; 95% confidence interval, 2.23-2.48) were more likely to deliver vaginally. Analysis of labor curves in nulliparous women showed shorter duration of labor with increasing GA; the active phase of labor was, however, similar across all GAs. CONCLUSION: Most women who undergo medically indicated preterm IOL between 24 and 36+6 weeks of gestation deliver vaginally. The strongest predictor of VD was parity. Preterm IOL had a limited influence on estimated labor curves across GAs.

Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy.

OBJECTIVE: We sought to determine predictors of adverse neonatal outcomes in women with intrahepatic cholestasis of pregnancy (ICP). STUDY DESIGN: This study was a multicenter retrospective cohort study of all women diagnosed with ICP across 5 hospital facilities from January 2009 through December 2014. Obstetric and neonatal complications were evaluated according to total bile acid (TBA) level. Multivariable logistic regression models were developed to evaluate predictors of composite neonatal outcome (neonatal intensive care unit admission, hypoglycemia, hyperbilirubinemia, respiratory distress syndrome, transient tachypnea of the newborn, mechanical ventilation use, oxygen by nasal cannula, pneumonia, and stillbirth). Predictors including TBA level, hepatic transaminase level, gestational age at diagnosis, underlying liver disease, and use of ursodeoxycholic acid were evaluated. RESULTS: Of 233 women with ICP, 152 women had TBA levels 10-39.9 µmol/L, 55 had TBA 40-99.9 µmol/L, and 26 had TBA ≥100 µmol/L. There was no difference in maternal age, ethnicity, or prepregnancy body mass index according to TBA level. Increasing TBA level was associated with higher hepatic transaminase and total bilirubin level (P < .05). TBA levels ≥100 µmol/L were associated with increased risk of stillbirth (P < .01). Increasing TBA level was also associated with earlier gestational age at diagnosis (P < .01) and ursodeoxycholic acid use (P = .02). After adjusting for confounders, no predictors were associated with composite neonatal morbidity. TBA 40-99.9 µmol/L and TBA ≥100 µmol/L were associated with increased risk of meconium-stained amniotic fluid (adjusted odds ratio, 3.55; 95% confidence interval, 1.45-8.68 and adjusted odds ratio, 4.55; 95% confidence interval, 1.47-14.08, respectively). CONCLUSION: In women with ICP, TBA level ≥100 µmol/L was associated with increased risk of stillbirth. TBA ≥40 µmol/L was associated with increased risk of meconium-stained amniotic fluid.