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This project implemented the Stroke 1-2-0 stroke awareness programme across China and investigated its impact over a 2-year period. We initiated the Stroke 1-2-0 educational campaign and Stroke 1-2-0 special task forces (STF) across the nation. Massive media coverage, community-based educational sessions with videos and other related materials and induction of Stroke 1-2-0 STF were the major means of promotion. We delivered a survey at the end of 2016 and 2018 to evaluate the impact of our effort. A total of 3066 participants responded to the first survey in 2016, and 15 207 participants responded in 2018 across China. The acceptance rate for Stroke 1-2-0 versus FAST (an English-language stroke awareness tool) was 50.2% versus 19.1% in 2016, and changed significantly to 82.2% versus 8.0% in 2018 (p

We explored variables associated with patient-reported outcomes (PROs) including symptom burden, impact on daily life and work, obstacles during therapy, satisfaction level with therapy, and health-related quality of life in 1500 respondents with myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) in a multicenter, cross-sectional study across China, a representative of the developing countries. In multivariate analyses, urban household registration and higher education level were significantly-associated with no symptoms at diagnosis in respondents with ET or MF. CALR mutation was significantly-associated with lower MPN-10 scores in respondents with MF. Higher MPN-10 scores were significantly-associated with negative impact on daily life and work as well as lower satisfaction level in respondents with ET, PV and MF. Receiving ruxolitinib was significantly-associated with high satisfaction and satisfaction in respondents with MF. In addition, other demographics and clinical variables were also impacting PROs.

Background Epidemiological evidence of the association of long-term ambient fine particulate matter (aerodynamic diameter ≤2.5 μm; PM2.5) exposure with resting heart rate is limited. We explored the association of long-term (3-year average) ambient PM2.5 exposure with tachycardia and resting heart rate. Methods This cross-sectional study surveyed 10,427,948 reproductive-age (20–49 years) adults across China in 2015. Tachycardia was classified as a resting heart rate of >80 beats per minute (bpm). The annual average ambient PM2.5 concentrations were obtained from a hybrid satellite-based geophysical statistical model. Linear mixed models and mixed effects logistic regressions adjusted for potential confounding were performed to explore the associations of PM2.5 with resting heart rate and PM2.5 with tachycardia, respectively. The effect modifiers by sex, age, body mass index, urbanity, race, region, smoking status, and drinking status were also assessed. Attributable cases and population fraction were estimated according to the PM2.5- tachycardia relationship. Results The mean age was 28 years, and 16.3% of the participants had tachycardia. The odds ratio for tachycardia was 1.018 (95% confidence intervals [CI]: 1.017, 1.020) per 10 μg/m3 increase in the 3-year average PM2.5 exposure. A 10 μg/m3 increase in the 3-year average ambient PM2.5 level was associated with a 0.076 (95% CI: 0.073, 0.079) bpm elevation in the resting heart rate. Of the tachycardia burden, 4.0% (95% CI: 3.8%, 4.3%) could be attributed to ambient PM2.5 exposure in Chinese reproductive-age adults. Conclusions Exposures to ambient PM2.5 were associated with elevated resting heart rate. It might be possible to decrease China's avoidable tachycardia burden in reproductive-age adults through decreasing PM2.5 levels.

Background The relationship between PM2.5 exposure and preterm birth remains unclear. Objectives To explore the effect of exposure to PM2.5 on preterm birth in China. Methods The birth outcomes of 426,246 pregnant women enrolled between January 2014 and December 2014 in NFPCP (National Free Pre-pregnancy Checkups Project) were collected, and their individual PM2.5 exposure values were estimated from the China National Environmental Monitoring Centre. The time of gestational exposure to PM2.5 was divided into four periods (the first trimester, the second trimester, the third trimester and the entire pregnancy). The average concentration and the corresponding quartiles of PM2.5 were calculated in these periods by the daily average PM2.5 data. Cox proportional hazards regression was used and he effects of maternal age, education level, occupation, second-hand smoking, alcohol use, pre-pregnancy BMI, baby's sex, number of previous pregnancies, coastal areas and season of conception were adjusted for. Results A total of 426,246 singleton births were included, among which 35,261 (8.3%) were preterm birth. Effect of each 10 μg/m3 increase of PM2.5 on preterm birth was most significant during the third trimester (HR, 1.06; 95%CI, 1.06–1.07), and also significant during the first trimester (HR, 1.04; 95%CI, 1.03–1.04), the second trimester (HR, 1.02; 95%CI, 1.02–1.02) and the entire pregnancy (HR, 1.06; 95%CI, 1.05–1.06). Compared with the lowest quartile of PM2.5, other quartiles increased the risk of preterm birth, and were most significant during the third trimester (HR, 1.87; 95%CI, 1.69–2.06). Subgroup analysis showed that compared with other subgroups, women who were older than 30 years, had low education level, worked as farmers, had male baby, had previous pregnancies, not live in coastal areas and pregnant in winter were more sensitive to PM2.5 exposure. Conclusions Ambient PM2.5 exposure during pregnancy played an important role in the pregnancy process and increased the risk of preterm birth.

Objective To investigate the effect of folic acid (FA) supplementation on the risks of preterm delivery (PTD) and small for gestational age births (SGA). Data sources Cohort studies were identified from MEDLINE, EMBASE, the Cochrane Library, CINAHL, and CBM from inception to January 2015. Participants and included studies Healthy women who want to get pregnancy or being pregnant. Main outcome measures PTD and SGA. Results The association of FA and PTD was significant when supplement initiated after pregnancy (RR = 0.68, 95%CI, 0.52–0.90), whereas no effect was founded if the initiation time was before conception (RR = 0.89, 95%CI, 0.80–1.01). The results for the association between FA supplementation and SGA showed significant protective effect: initiated before conception (RR = 0.70, 95%CI, 0.57–0.85) and initiated after conception (RR = 0.84, 95%CI, 0.81–0.89). Conclusion Folic acid supplementation is associated with a significant reduction on the risk of PTD when initiated after conception. It can also protect fetus from SGA.

Objectives. To provide prevalence and trends of underweight, overweight, and obesity among reproductive-age women and adolescent girls in rural China. Methods. We measured weight and height in 16 742 344 women aged 20 to 49 years and 178 556 girls aged 15 to 19 years from the National Free Preconception Health Examination Project between 2010 and 2014. Results. Among women, the prevalence of underweight was 7.8% (95% confidence interval [CI] = 7.7%, 7.9%), and overweight or obesity was 16.5% (95% CI = 16.4%, 16.6%; World Health Organization criteria). Among adolescents, prevalence of underweight was 6.0% (95% CI = 5.7%, 6.2%; Centers for Disease Control and Prevention criteria) and overweight or obesity was 8.3% (95% CI = 7.9% to 8.8%; International Obesity Task Force criteria). According to Chinese criteria, overweight and obesity prevalence was 24.8% (95% CI = 24.7%, 24.9%) for women and 17.2% (95% CI = 16.6%, 17.8%) for adolescents, and underweight prevalence was 2.9% (95% CI = 2.8%, 3.1%) for adolescents. Considerable disparities existed in prevalence and trends within subpopulations (age groups, parity, region, education levels, and socioeconomic status). Conclusions. Our results reveal coexisting underweight and overweight or obesity among rural women and adolescents of reproductive age, which requires public health attention.

Background A mountain of evidence has shown that people’s physical and mental health can be affected by various air pollutions. Poor pregnancy outcomes are associated with exposure to air pollution. Therefore, this study aims to investigate the association between air pollutions (PM2.5, PM10, SO2, NO2, CO, and O3) and preterm birth/low birth weight in Guangdong province, China. Method All maternal data and birth data from January 1, 2014 to December 31, 2015 were selected from a National Free Pre-pregnancy Check-ups system, and the daily air quality data of Guangdong Province was collected from China National Environmental Monitoring Center. 1784 women with either preterm birth information (n = 687) or low birth weight information (n = 1097) were used as experimental group. Control group included 1766 women with healthy birth information. Logistic regression models were employed to evaluate the effects of air pollutants on the risk of preterm birth and low birth weight. Results The pollution levels of PM2.5, PM10, SO2, NO2, CO, and O3 in Guangdong province were all lower than the national air pollution concentrations. The concentrations of PM2.5, PM10, SO2, NO2 and CO had obvious seasonal trends with the highest in winter and the lowest in summer. O3 concentrations in September (65.72 μg/m3) and October (84.18 μg/m3) were relatively higher. After controlling for the impact of confounding factors, the increases in the risk of preterm birth were associated with each 10 μg/m3 increase in PM2.5 (OR 1.043, 95% CI 1.01–1.09) and PM10 (OR 1.039, 95% CI 1.01~1.14) during the first trimester and in PM2.5 (OR 1.038, 95% CI 1.01~1.12), PM10 (OR 1.024, 95% CI 1.02~1.09), SO2 (OR 1.081, 95% CI 1.01~1.29), and O3 (OR 1.016, 95% CI 1.004~1.35) during the third trimester. The increase in the risk of low birth weight was associated with PM2.5, PM10, NO2, and O3 in the first month and the last month. Conclusion This study provides further evidence for the relationships between air pollutions and preterm birth/low birth weight. Pregnant women are recommended to reduce or avoid exposure to air pollutions during pregnancy, especially in the early and late stages of pregnancy.

Background Adequate sedation is important in the post-anesthesia care unit (PACU) following uvulopalatopharyngoplasty (UPPP) to ensure patient comfort and decrease the duration of mechanical ventilation (MV), PACU stay, and bleeding. This study aimed to compare dexmedetomidine and propofol as sedatives after UPPP in the PACU. Material/Methods We randomized 124 mechanically ventilated adults following UPPP who were managed in the PACU of the General Hospital of the Shenyang Military Region between January 2014 and June 2014, to receive either dexmedetomidine or propofol. The patients in the propofol group received an infusion of propofol (3 mg/kg/h) titrated up to 6 mg/kg/h to attain a Ramsay sedation score ≥4. The dexmedetomidine group patients received 1.0 μg/kg of dexmedetomidine over a period of 10 minutes and then 0.5 to 1.0 μg/kg/h infusion to maintain a Ramsay sedation score ≥4. Results Bispectral index (BIS) values were significantly lower in the dexmedetomidine group than in the propofol group at Ramsay sedation scores of 4 and 5. The mean times to spontaneous breathing, waking, and extubation were shorter in the dexmedetomidine group. Tramadol requirement was significantly reduced in the dexmedetomidine group (P

To examine the relationship between preconception blood pressure (BP) and the risk of preterm birth (PTB) using a historical cohort of reproductive-aged women and girls from a Chinese rural population.A historical cohort study established between 2010 and 2013 in People's Republic of China.Local family-planning service agencies and maternal-child care service centers.A total of 367,425 reproductive-aged women and girls who participated in the National Free Pre-pregnancy Checkups in 2010-2012 and subsequently had a live birth before October 2013.None.Incidence rates of PTB in reproductive-aged women and girls across preconception BP levels.Preterm births were defined as babies born alive at 28 to 37 weeks of pregnancy. Compared with the participants with a systolic BP of120 mm Hg, the multivariable-adjusted odds ratio (OR) for PTB was 0.99 (95% confidence interval [CI]: 0.95-1.03]), 1.21 (95% CI: 1.11-1.32), 1.47 (95% CI: 1.22-1.77), 1.80 (95% CI: 1.25-2.59), and 1.81 (95% CI: 1.20-2.73) for the participants with systolic BP of 120-129, 130-139, 140-149, 150-159, and ≥160 mm Hg, respectively. When the participants with normal BP were used as the reference, the adjusted OR for PTB was 1.04 (95% CI: 1.01-1.08), 1.38 (95% CI: 1.25-1.53), and 1.54 (95% CI: 1.21-1.97) for the participants with prehypertension, stage-1 hypertension, and stage-2 hypertension, respectively. In addition, isolated systolic and diastolic hypertension increased the risk of PTB by 55% and 30%, respectively.Our results indicated a strong linear and independent relationship between BP levels and the risk of PTB in Chinese reproductive-aged women and girls. Maternal hypertension before pregnancy can significantly increase the risk of PTB.

Background: Pre-gestational diabetes mellitus (pGDM) and elevated fasting blood glucose level are associated with increased risk of maternal, perinatal and neonatal morbidity and mortality. Only 30.1% of those with diabetes had been previously diagnosed in China. It was reported that nearly 50.0% of Chinese population is the rural population in the population census data in 2014. It has been verified the effects of glucose level during pregnancy on adverse pregnancy outcomes. However, data of the relationship between glucose level before pregnancy and its pregnancy outcomes is scarce. We investigated the epidemiology of reproductive-aged women in China, aiming to provide the data for the prevalence of pGDM and its association with pregnancy outcomes. Methods: Data are from a nationwide sample of women of reproductive age who participated in National Free Preconception Health Examination service in 31 provinces of rural China during 2010-16. Study population characteristics were presented as mean (SD) for continuous variables and number (percentages) for categorical variable, and analysis of variance and chi square test were used to test association between each level of blood glucose concentration, risk factors and adverse outcome. Findings: Of 7,094,807 registered women (age 20-49 years), 6,447,339 were included in analyses. The incidence of pGDM and IFG was 76,297 (1.18%) and 847,737 (13.15%), respectively. Only 917 (1.20%) women were aware that they had pGDM in rural China. Among women without previously diagnosed DM, there is a positive linear association between FPG levels and incidence of combined (counted when occurrence of any of the adverse outcome) and multiple adverse pregnancy outcome(counted when having ≥2 adverse outcomes at the same time) when FPG level was divided into 7 groups ( 10mmol/L). Interpretation: The awareness rate of pGDM prevalence in rural China is extremely low. The management of pGDM is unsatisfactory in women diagnosed with pGDM. PGDM is associated with an increased risk of adverse maternal, perinatal and neonatal outcomes across all levels of FPG. Further analysis is need to support decision on the cut-off point for increased risk of adverse outcome and target blood glucose level before pregnancy to achieve satisfactory outcome. Policy decision on adoption of an extensive screening of pGDM in prepregancy examination and strategies for pGDM and adverse pregnancy outcome control from a broader perspective require more evidence on cost-effectiveness of such approaches. Funding: The National Key Research and Development Program of Reproductive Health & Major Birth Defects Control and Prevention (Grant no. 2016YFC1000402); World Diabetes Foundation (Grant no. WDF14-908). National Natural Science Foundation (Grant no. 81402757) Declaration of Interest: We declare that we have no conflicts of interest. Ethical Approval: This study was approved by the Institutional Research Review Boards at NHFPC and Peking University First Hospital, and all participants provided written informed consent.

With the gradual increase of global warming, the impact of extreme temperatures on health has become a focus of attention, however, its relationship with preterm birth remains unclear.To investigate the association between exposure to extreme temperatures and preterm birth.Temperature exposures and birth outcomes of 1,020,471 pregnant women from 132 cities in China were investigated. The pregnancy process was divided into different pregnancy periods. Study areas were divided into three categories (cold, medium, and hot areas) according to the local average temperature by cluster analysis. Average temperature data for each province used in the cluster analysis came from the China Statistical Yearbook 2013. Logistic regression was used to compare the effects of exposure to hot and cold conditions on the outcomes of pregnancy in different periods and regions.A total of 1,020,471 singleton births were included, of which 73,240(7.2%) were preterm births. Compared with moderate temperatures (5th to 95th percentile), heat exposure (95th percentile) in different periods of pregnancy increased the risk of preterm birth in hot areas. The most obvious increase was during the 3 months before pregnancy (odds ratio (OR)=1.229, 95% confidence interval (CI): 1.166-1.295). In contrast to heat exposure, cold exposure (5th percentile) in hot areas reduced the risk of preterm birth; the protective effect was most pronounced in the 3 months before pregnancy (OR=0.784, 95% CI: 0.734-0.832). In medium and cold areas cold exposure also reduced the risk of preterm birth. The effect of exposure to extreme ambient temperatures throughout the entire pregnancy on preterm birth was similar to those of the periods above.Acute and chronic exposure to extreme temperatures may affect the risk of preterm birth. Extreme heat is a risk factor for preterm birth and extreme cold is a protective factor.

Background Alcohol use occurs across the life span beginning in adolescence and continuing through adulthood. Ethanol (EtOH)-induced pathology varies with age and includes changes in neurogenesis, neurodegeneration, and glial cell activation. EtOH-induced changes in glial activation and immune activity are believed to contribute to EtOH-induced neuropathology. Recent studies indicate an emerging role of glial-derived neuroimmune molecules in alcohol abuse and addiction. Methods Adolescent and adult C57BL/6 mice were treated via gavage with 6 g/kg EtOH for 10 days, and tissue was harvested 1 day post treatment. We compared the effects of EtOH on chemokine and cytokine expression and astrocyte glial fibrillary acidic protein (GFAP) immunostaining and morphology in the hippocampus, cerebellum, and cerebral cortex. Results EtOH increased mRNA levels of the chemokine CCL2/MCP-1 in all 3 regions of adult mice relative to controls. The cytokine interleukin-6 (IL-6) was selectively increased only in the adult cerebellum. EtOH did not affect mRNA levels of the cytokine tumor necrosis factor-alpha (TNF-α) in any of these brain regions in adult animals. Interestingly, CCL2, IL-6, and TNF-α mRNA levels were not increased in the hippocampus, cerebellum, or cortex of adolescent mice. EtOH treatment of adult and adolescent mice resulted in increased GFAP immunostaining. Conclusions Collectively, these data indicate an age- and region-specific susceptibility to EtOH regulation of neuroinflammatory and addiction-related molecules as well as astrocyte phenotype. These studies may have important implications concerning differential alcohol-induced neuropathology and alcohol addiction across the life span.

T-helper cells that produce interleukin-17 (T(H)17 cells) are a recently identified CD4(+) T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors α and γt (RORα and RORγt, respectively) have indispensible roles in the development of this cell type. Here we present SR1001, a high-affinity synthetic ligand-the first in a new class of compound-that is specific to both RORα and RORγt and which inhibits T(H)17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORα and RORγt, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors' transcriptional activity. SR1001 inhibited the development of murine T(H)17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human T(H)17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORα and RORγt to inhibit specifically T(H)17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases.

BACKGROUND: Bevacizumab improves outcome and reduces symptoms in patients with recurrent glioblastoma (GBM). However, GBMs develop adaptive resistance to bevacizumab- mediated angiogenesis inhibition resulting in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor, with pleotropic antiangiogenic effects, would delay emergence of resistance to bevacizumab therapy and improve clinical outcome. METHODS: In this multicenter phase II trial utilizing a novel Bayesian design, patients with recurrent glioblastoma were adaptively randomized to bevacizumab alone or bevacizumab+vorinostat based on a primary endpoint of progression-free survival (PFS) such that patients had a higher likelihood of receiving the more efficacious treatment. Secondary end points were overall survival (OS) and quality of life assessment (MDASI-BT). Eligible patients were adults (≥ 18 yrs) with histologically confirmed GBMs recurrent after prior radiation and temozolomide therapy, adequate organ function, KPS≥ 60, and no prior bevacizumab/HDAC inhibitors. RESULTS: Ninety patients (bevacizumab+vorinostat:49, bevacizumab:41) were enrolled and 74 were evaluable for PFS (bevacizumab+vorinostat:44, bevacizumab:30). Grade 3 or greater toxicities in 85 evaluable patients included hypertension (n=37), neurological changes (n=2), anorexia (n=2), infections (n=9), wound dehiscence (n=2), DVT/PE (n=2), and colonic perforation (n=1). There was one treatment-related death due to pulmonary embolism. Upon multivariate analysis for bevacizumab+vorinostat vs bevacizumab, median PFS (3.7 vs. 3.9 months, p=0.94, HR 0.63 [95% CI 0.38, 1.06, p=0.08]) or median OS (7.8 vs. 9.3 months, p=0.64, HR 0.93 [95% CI 0.5, 1.6, p=0.79]) were not significantly different between the two arms. Ongoing analyses of patient reported outcomes (MDASI-BT) and plasma biomarkers will be reported. CONCLUSIONS: Combining bevacizumab with vorinostat did not result in improved PFS or OS compared with bevacizumab alone in patients with recurrent GBM. This trial is the first to test a Bayesian PFS-based adaptive randomized design in patients with primary brain tumors and demonstrates the feasibility of using adaptive randomization in a multicenter setting.

The interleukin-12 (IL-12) family of cytokines which includes IL-12, IL-23, and IL-27 play critical roles in T cell differentiation and are important modulators of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Previously, we demonstrated that peroxisome proliferator-activated receptor (PPAR) -alpha agonists suppress the development of EAE. The present studies demonstrated that the PPAR-alpha agonist fenofibrate inhibited the secretion of IL-12p40, IL-12p70 (p35/p40), IL-23 (p19/p40), and IL-27p28 by lipopolysaccharide-stimulated microglia. The cytokines interferon-gamma and tumor necrosis factor-alpha also stimulated IL-12 p40 and IL-27 p28 expression by microglia, which was suppressed by fenofibrate. Furthermore, fenofibrate inhibited microglial expression of CD14 which plays a critical role in TLR signaling, suggesting a mechanism by which this PPAR-alpha agonist regulates the production of these pro-inflammatory molecules. In addition, fenofibrate suppressed the secretion of IL-12p40, IL-23, and IL-27p28 by lipopolysaccharide-stimulated astrocytes. Importantly, fenofibrate suppression of EAE was associated with decreased expression of IL-12 family cytokine mRNAs as well as mRNAs encoding TLR4, CD14, and MyD88 known to play critical roles in MyD88-dependent TLR signaling. These novel observations suggest that PPAR-alpha agonists including fenofibrate may modulate the development of EAE, at least in part, by suppressing the production of IL-12 family cytokines and MyD88-dependent signaling.

The IL-12 family of cytokines, which include IL-12, IL-23, and IL-27, play critical roles in the differentiation of Th1 cells and are believed to contribute to the development of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Relatively little is known concerning the expression of IL-12 family cytokines by cells of the CNS, the affected tissue in MS. Previously, we and others demonstrated that peroxisome proliferator-activated receptor (PPAR)-γ agonists suppress the development of EAE, alter T cell proliferation and phenotype, and suppress the activation of APCs. The present studies demonstrated that PPAR-γ agonists, including the naturally occurring 15-deoxy-Δ12,14-PGJ2 and the synthetic thiazoladinedione rosiglitazone, inhibited the induction of IL-12p40, IL-12p70 (p35/p40), IL-23 (p19/p40), and IL-27p28 proteins by LPS-stimulated primary microglia. In primary astrocytes, LPS induced the production of IL-12p40, IL-23, and IL-27p28 proteins. However, IL-12p70 production was not detected in these cells. The 15-deoxy-Δ12,14-PGJ2 potently suppressed IL-12p40, IL-23, and IL-27p28 production by primary astrocytes, whereas rosiglitazone suppressed IL-23 and IL-27p28, but not IL-12p40 in these cells. These novel observations suggest that PPAR-γ agonists modulate the development of EAE, at least in part, by inhibiting the production of IL-12 family cytokines by CNS glia. In addition, we demonstrate that PPAR-γ agonists inhibit TLR2, MyD88, and CD14 expression in glia, suggesting a possible mechanism by which these agonists modulate IL-12 family cytokine expression. Collectively, these studies suggest that PPAR-γ agonists may be beneficial in the treatment of MS.

Background Folic acid (FA) supplementation before and during the first trimester can reduce the risk of occurrence of preterm delivery (PTD). Preconception body mass index (BMI) is also associated with PTD. This study aimed to investigate the combined effect of FA supplements and preconception BMI on the risk of PTD. Methods The data of a cohort from 2010–2011 that was obtained through a preconception care service in China was used (including 172,206 women). A multivariable regression model was used to investigate the association between maternal preconception conditions and the risk of PTD. The interaction of preconception BMI and FA supplementation was measured by a logistic regression model. Results Taking FA supplements in the preconception period or in the first trimester reduced the risk of PTD (odds ratio [OR] = 0.58 and OR = 0.61, respectively). Women with an abnormal BMI had an increased risk of PTD (OR = 1.09, OR = 1.10, and OR = 1.17 for underweight, overweight, and obese, respectively). Preconception BMI showed an interaction with the protective effect of FA supplementation for PTD. With regard to the interaction of FA supplementation, the adjusted odds ratio (aOR) was 0.57 (95 % CI: 0.51, 0.64) in underweight women, 0.85 (95 % CI: 0.73, 0.98) in overweight women, and 0.77 (95 % CI, 0.65, 0.91) in obese women. Preconception BMI also showed an interaction with the time of FA supplementation. Women with a normal BMI who began to take FA supplements in the preconception period had the lowest risk of PTD (aORs: 0.58 vs. 0.65 beginning in the first trimester). The aORs at preconception and the first trimester in the underweight group were 0.56 vs. 0.60. The aORs at preconception and the first trimester were 0.94 vs. 0.65 and 1.15 vs. 0.60 in the overweight and obesity groups, respectively. Conclusions In our study, FA supplements reduced the risk of PTD, while abnormal BMI raised the risk of PTD, although higher BMI categories did not have this higher risk once adjusted analysis was conducted. The protective effect of FA supplementation for PTD was reduced in women with overweight or obesity. To get better protection of FA supplementation, women with normal BMI or underweight should begin to use in preconception, while women with overweight or obesity should begin to use after conception.

The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) plays a key role in lipid metabolism and inflammation. Recently, we demonstrated that administration of the PPAR-alpha agonists gemfibrozil and fenofibrate, inhibit the clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In the present study, we investigated the effects of PPAR-alpha agonists on primary mouse astrocytes, a cell type implicated in the pathology of MS and EAE. Our studies demonstrated that the PPAR-alpha agonists fenofibrate, and WY 14643 inhibited NO production by LPS-stimulated astrocytes in a dose-dependent manner. Additionally, PPAR-alpha agonists inhibited the secretion of the pro-inflammatory cytokines TNF-alpha, IL-1beta, and IL-6 by LPS-stimulated astrocytes. Fenofibrate inhibited NF-kappaB DNA binding activity, suggesting a mechanism by which PPAR-alpha agonists may regulate the expression of genes encoding these pro-inflammatory molecules. Retinoid X receptors (RXRs) physically interact with PPAR-alpha receptors, and the resulting heterodimers regulate the expression of PPAR-responsive genes. Interestingly, a combination of 9-cis RA and the PPAR-alpha agonists fenofibrate or gemfibrozil cooperatively inhibited NO, TNF-alpha, IL-1beta, IL-6, and MCP-1 production by these cells. Collectively, these results raise the possibility that PPAR-alpha and RXR agonists might be effective in the treatment of MS, where activated astrocytes are believed to contribute to disease pathology.

OBJECTIVE A number of potential interactions between angiotensin-converting enzyme inhibitors and lithium have been described in the literature. In the present study, we investigated the effects of a low-dose combination treatment with lithium and captopril on survival and stroke prevention in salt-loaded, stroke-prone spontaneously hypertensive rats (SHRSP). METHODS Eight-week-old saline-drinking SHRSP (n = 21 per group) were treated with vehicle, LiCl (1 mmol/kg per day), captopril (25 mg/kg per day) and captopril plus LiCl for up to 37 weeks. Body weight, salt water intake blood pressure and mortality were recorded throughout the experimental period. Plasma renin activity, plasma lithium concentration and urinary excretion of albumin, sodium and potassium were measured at different time points. RESULTS Captopril treatment doubled the life expectancy when compared with vehicle-treated rats. Lithium alone had minor effects on survival but led to a dramatic increase in survival when added to captopril (mean survival time > 237 versus 147 days, P < 0.001). Systolic blood pressure increased with age in all treatment groups but was comparable in the captopril-treated and the captopril-plus-lithium-treated groups. Plasma renin activity as well as urinary sodium and potassium excretion did not differ between both groups. In the captopril group a striking fivefold increase of albuminuria occurred between 14 and 26 weeks of age, while this progression was completely abolished by the addition of lithium. CONCLUSIONS Our results demonstrate that the addition of lithium to captopril dramatically prolong the effects of the angiotensin-converting enzyme inhibitor on survival in salt-loaded SHRSP. This effect was independent of a reduction in blood pressure.

The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) plays a key role in lipid metabolism and inflammation. Recently, we demonstrated that administration of the PPAR-alpha agonists gemfibrozil and fenofibrate, inhibit the clinical signs of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). In the present study we investigated the effects of PPAR-alpha agonists on primary mouse microglia, a cell type implicated in the pathology of MS and EAE. Our studies demonstrated that the PPAR-alpha agonists ciprofibrate, fenofibrate, gemfibrozil, and WY 14,643 each inhibited NO production by cytokine-stimulated microglia in a dose-dependent manner. However, fenofibrate and WY 14,643 were more potent inhibitors than gemfibrozil and ciprofibrate. In LPS-stimulated microglia, only fenofibrate and WY 14,643 significantly suppressed NO production. Additionally, PPAR-alpha agonists inhibited the secretion of the proinflammatory cytokines IL-1beta, TNF-alpha, IL-6, and IL-12 p40 and the chemokine MCP-1 by LPS-stimulated microglia. Retinoid X receptors (RXRs) physically interact with PPAR-alpha receptors, and the resulting heterodimers regulate the expression of PPAR-responsive genes. Interestingly, the RXR agonist 9-cis retinoic acid (9-cis RA) inhibited NO production by LPS-stimulated microglia. Furthermore, a combination of 9-cis RA and the PPAR-alpha agonist fenofibrate cooperatively inhibited NO production by these cells. A combination of these agonists also selectively inhibited the expression of proinflammatory cytokines including IL-1beta, TNF-alpha, and IL-6 by LPS-stimulated microglia. Collectively, these results raise the possibility that PPAR-alpha and RXR agonists might have benefit as a therapy in MS, where activated microglia are believed to contribute to disease pathology.

Background and Purpose— In vitro and in vivo studies have demonstrated neuroprotective actions of lithium. The present study investigated the effect of a low dose of lithium on infarct volume and neurological outcome as well as on apoptotic and inflammatory processes in rats exposed to focal ischemia. Methods— Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 90 minutes followed by reperfusion. Lithium (1 mmol/kg) was given subcutaneously daily for 14 days before the onset of MCAO and 2 days thereafter. Blood parameters and cerebral blood flow were assessed before, during, and after MCAO. Rats were examined for neurological deficits 24 and 48 hours after MCAO. Two days after MCAO, the brains were removed for immunohistochemical evaluation of caspase-3, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL), activated microglia, and the expression of AP-1 proteins (c-Fos and c-Jun). Infarct volume was assessed by cresyl violet staining. Results— Pretreatment with lithium did not alter cerebral blood flow or blood parameters. Neurological deficits were significantly decreased in rats treated with lithium at 24 and 48 hours after ischemia. Infarct volume was reduced in rats treated with lithium at 48 hours after ischemia. Lithium significantly decreased the ischemia-induced caspase-3 immunoreactivity and TUNEL staining as well as the AP-1 protein expression in the penumbra of the ischemic cortex. No changes in activated microglia were observed. Conclusions— The present study demonstrates that chronic treatment with lithium at a low dose exhibits neuroprotection in transient focal cerebral ischemia. Antiapoptotic mechanisms are involved in the lithium-induced neuroprotective effects.

Glioblastomas are the most common and aggressive form of adult primary brain tumors and are associated with a dismal prognosis. Accumulating evidences suggest that a subset of therapy-resistant cancer stem cells are responsible for recurrence in tumors targeting which may help in gliomas. We identified a significant overexpression of Brachyury (T-box transcription factor) in correlation with glioma histological grade when compared to non-tumor brain controls, with the highest expression being in grade IV gliomas. We also observed increased expression of Brachyury in several glioma cell lines and stem cells (GSCs) when compared to normal human astrocytes. Serum-induced differentiation of GSCs resulted in loss of Brachyury expression along with decreased stem-cell marker levels in these cells, which prompted us to study the potential role of Brachyury in glioma stemness and to delineate the underlying signaling mechanisms. Specific shRNA-mediated knockdown of Brachyury significantly decreased proliferation, migration and invasion in glioma cell lines. Brachyury suppression led to inhibition of sphere formation of GSCs and decreased stem cells marker expression including CD133, nestin and Nanog. Brachyury knockdown also inhibited the activation of sonic hedgehog (Shh) signaling and decreased Gli1 levels in these cells. On the other hand, stable overexpression of Brachyury resulted in the activation of Shh pathway and elevated stem cell marker expression in GSCs. Based on these in vitro findings, our future studies will be focused on determining the role of Brachyury in orthotopic tumor growth in vivo. In summary, our data reveals a novel role for Brachyury in the regulation of tumor invasiveness and stemness, and indicates a potential for therapeutic targeting of Brachyury in patients with gliomas. Citation Format: Divya Kesanakurti, Alessandro Canella, Jihong Xu, Vinay K. Puduvalli. A novel role for brachyury as a key regulator of sonic hedgehog signaling (Shh) and maintenance of stemness in gliomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2519.

Purpose: A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG). Experimental Design: This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m2/day for 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m2/day for 5 days of the first cycle and 200 mg/m2/day for 5 days of the subsequent 28-day cycles. Results: In part 1, the MTD of vorinostat administered on days 1 to 7 and 15 to 21 of every 28-day cycle, in combination with TMZ, was 500 mg daily. Dose-limiting toxicities (DLT) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In part 2, the MTD of vorinostat on days 1 to 7 and 15 to 21 of every 28-day cycle, combined with TMZ, was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells. Conclusion: Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway. Clin Cancer Res; 18(21); 6032–9. ©2012 AACR.

LXR agonists alter Th17 cell function and suppress EAE. CD4+ Th17 cells are believed to play an important role in the development of a variety of autoimmune diseases including EAE, an animal model of MS. Previously, we and others demonstrated that LXR agonists suppressed the activation of primary glial cells and blocked the development of EAE. The present studies demonstrated that the LXR agonist T0901317 suppressed IL-17A expression from splenocytes derived from Vα2.3/Vβ8.2 TCR transgenic mice and from MOG35–55-immunized C57BL/6 mice. Furthermore, in vitro treatment with IL-23 alone or in combination with MOG35–55 induced IL-17A expression from splenocytes derived from MOG35–55-immunized mice, and T0901317 blocked this induction. In vitro treatment with the LXR agonist suppressed IL-23R expression by splenocytes. In addition, in vivo treatment with the LXR agonist suppressed IL-17A and IL-23R mRNA and protein expression in EAE mice. These studies suggest that LXR agonists suppress EAE, at least in part by suppressing IL-23 signaling. Recent studies indicate that the cytokines IL-21 and IL-22 are produced by Th17 cells and modulate immune responses. Our studies demonstrate that the LXR agonist T0901317 suppressed MOG35–55-induced expression of IL-21 and IL-22 mRNA in splenocytes derived from MOG35–55-immunized mice. Finally, we demonstrate that the LXR agonist T0901317 suppressed the development of EAE in an experimental paradigm involving treatment of established EAE. Collectively, these studies suggest that LXR agonists may be effective in the treatment of MS.

Glioblastomas (GB) are the most aggressive of primary brain tumors with high rates of tumor recurrence and poor prognosis. Epithelial-mesenchymal transition (EMT) is the dynamic transdifferentiation process which leads to acquisition of invasiveness, stem-like characteristics and drug resistance in tumor cells. A small fraction of radio- and chemo-resistant cancer stem cells (CSC) with a capacity of self-renewal is considered to be crucial for tumor recurrence. Our previous studies indicated high levels of expression of p21-activated kinase 4 (PAK4) in GBs and confirmed its role in the regulation of proliferation, migration and invasion. Here, we aimed to determine whether PAK4-regulated invasiveness was associated with mesenchymal transition of glioma cells and to delineate the essential signaling events that governed EMT and maintenance of stemness in GBs. PAK4 overexpression in glioma cells resulted in loss of E-cadherin and Zo-1 and a significant increase in N-cadherin and vimentin levels. Conversely, shRNA-mediated PAK4 downregulation led to loss of mesenchymal phenotype and markers in glioma cell lines. Further, irradiation (IR, 8 Gy) treatments significantly elevated PAK4 expression and nuclear localization in correlation with increased EMT in glioma cells. FACS analysis and western blotting indicated an enrichment of CD133+ CSCs with high expression of CD133 and Nestin in IR-treated cells. In order to study the significance IR-induced EMT and stemness with PAK4 nuclear translocation, we performed a transcription factor (TF) interaction array with immunoprecipitated PAK4 as bait, which revealed nuclear-PAK4 association with PPARγ and other TFs. Moreover, immunoprecipitation, ChIP and re-ChIP experiments showed IR-induced PAK4 binding with PPARγ nuclear receptor complex and recruitment on the PPREs of NADPH oxidase-1 promoter and elevated Nox1 expression in IR-treated cells. PAK4-knockdown suppressed the IR-induced EMT and stemness in the glioma cells lines. In line with these in vitro results, mouse orthotopic intracranial xenograft experiments showed decreased tumor growth and N-cadherin expression in tumors from PAK4-shRNA expressing cells when compared with controls. These results strongly support a role for PAK4 in the regulation of IR-induced EMT and stemness via PPARγ/Nox1 signaling and provide a rationale for PAK4 as a new therapeutic target against glioblastoma and suggest a potential for overcoming radioresistance in these tumors. Citation Format: Divya Kesanakurti, Jihong Xu, Rao S. Jasti, Vinay K. Puduvalli. A novel role for PAK4 in the regulation of EMT and stemness in glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3324. doi:10.1158/1538-7445.AM2015-3324

Increased endothelial cell proliferation and aberrant neovascularization are pathological hallmarks of glioblastoma that correlate with clinical outcome. Recent studies have also implicated ionizing radiation (IR)-induced angiogenesis as a potential cause for tumor recurrence and metastases in several malignancies. Its impact in gliomas has not been characterized. Factors that drive endothelial proliferation, angiogenesis and interaction of endothelial cells with tumor cells in the context of radiotherapy are potentially novel targets for glioma therapy. Our previous studies demonstrated high levels of expression of p21-activated kinase 4 (PAK4) in gliomas; analyses of tumor cell medium (CM) prepared from shRNA-mediated PAK4-knockdown cells using an angiogenesis antibody array showed a significant decrease in key angiogenic factors including CXCL1. Treatment of human brain microvascular endothelial cells (HBMECs) with CM from PAK4-knockdown cells (PAK4-kd CM) significantly inhibited proliferation, migration and microtubule formation compared with CM from control and scrambled vector-expressing glioma cells. PAK4-kd CM treatment also suppressed CXCR2 activation and decreased the expression levels of p-STAT3, VEGF, MMP-2 and cyclinD1 in HBMECs. Additionally, treatment with CM from ionizing radiation (IR, 8 Gy)-treated cells resulted in elevated CXCL1, MMP-2 and VEGF levels in HBMECs, and induced high levels of endothelial capillary network formation on matrigel, indicating an IR-induced angiogenesis in these cells. Conversely, PAK4-kd inhibited IR-induced angiogenesis and decreased p-STAT3, VEGF and MMP-2 levels in IR-treated HBMECS. Further, in vivo experiments with orthotopic intracranial tumors in nude mice showed growth suppression in PAK4-knockdown tumors compared to control tumors. Immunohistochemical analyses of brain tumor sections revealed a significant decrease in CXCL1, VEGF and MMP-2 in PAK4.sh tumors. In summary, our studies emphasize a novel regulation of angiogenic switch and endothelial CXCL1/CXCR2 signaling by PAK4 in tumor cells, thereby, suggests the role of PAK4 as a critical mediator of tumor-endothelial cell interactions in glioblastoma. Abrogation of key angiogenic signaling after IR treatment and inhibition of in vivo tumor growth by PAK4 suppression indicates its therapeutic potential in the treatment of glioma. Citation Format: Divya Kesanakurti, Jihong Xu, Alessandro Canella, Prabhakaran Nagarajan, Balveen Kaur, Vinay K. Puduvalli. Novel PAK4-mediated regulation of endothelial CXCL1/CXCR2 signaling and angiogenesis in glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4158. doi:10.1158/1538-7445.AM2015-4158

Peroxisome proliferator-activated receptor (PPAR)-gamma agonists, including thiazolidinediones (TZDs) and 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)), have been shown to be effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). This study aimed to compare the anti-inflammatory actions of three TZDs - rosiglitazone, pioglitazone, and ciglitazone - with those of 15d-PGJ(2) on stimulated mouse microglia and astrocytes. The results show that TZDs and 15d-PGJ(2) are effective in inhibiting production of nitric oxide, the pro-inflammatory cytokines TNF-alpha, IL-1beta, and IL-6, and the chemokine MCP-1 from microglia and astrocytes. However, 15d-PGJ(2) was a more potent suppressor of pro-inflammatory activity than the TZDs. These studies suggest that PPAR-gamma agonists modulate EAE, at least in part, by inhibiting the activation of microglia and astrocytes. The studies further suggest that PPAR-gamma agonists may be effective in the treatment of MS.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of proteins. The role of PPARs in regulating the transcription of genes involved in glucose and lipid metabolism has been extensively characterized. Interestingly, PPARs have also been demonstrated to mediate inflammatory responses. Microglia participate in pathology associated with multiple sclerosis (MS). Upon activation, microglia produce molecules including NO and TNF-alpha that can be toxic to CNS cells including myelin-producing oligodendrocytes and neurons, which are compromised in the course of MS. Previously, we and others demonstrated that PPAR-gamma agonists including 15d-PGJ(2) are effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. PPAR-gamma modulation of EAE may occur, at least in part, by inhibition of microglial cell activation. Here, we indicate that 15d-PGJ(2) is a more potent inhibitor of microglial activation than thiazolidinediones, which are currently used to treat diabetes. Furthermore, 15d-PGJ(2) acts cooperatively with 9-cis retinoic acid, the ligand for the retinoid X receptor (RXR), in inhibiting microglial cell activation. This suggests that 15d-PGJ(2) and 9-cis RA inhibit cell activation through the formation of PPAR-gamma/RXR heterodimers. Interestingly, PGA(2), which like 15d-PGJ(2) is a cyclopentenone prostaglandin, but which unlike 15d-PGJ(2) does not bind PPAR-gamma, is a potent inhibitor of microglial cell activation. Collectively, these studies suggest that 15d-PGJ(2) inhibits microglial cell activation by PPAR-gamma-dependent as well as PPAR-gamma-independent mechanisms. The studies further suggest that the PPAR-gamma agonist 15d-PGJ(2) in combination with retinoids may be effective in the treatment of MS.

Background Alcohol abuse has dramatic effects on the health of the elderly. Recent studies indicate that ethanol increases immune activity in younger animals and that some of these proinflammatory molecules alter alcohol consumption and addiction. However, the effects of alcohol on immune activation in aged animals have not been thoroughly investigated. Findings We compared the effects of ethanol on chemokine and cytokine expression in the hippocampus, cerebellum, and cerebral cortex of aged C57BL/6 mice. Mice were treated via gavage with 6 g/kg ethanol for 10 days and tissue was harvested 1 day post-treatment. Ethanol selectively increased mRNA levels of the chemokine (C-C motif) ligand 2/monocyte chemotactic protein-1 in the hippocampus and cerebellum, but not in the cortex of aged mice relative to control animals. In this paradigm, ethanol did not affect mRNA levels of the cytokines IL-6 or TNF-α in any of these brain regions in aged animals. Conclusions Collectively, these data indicate a region-specific susceptibility to ethanol regulation of neuroinflammatory and addiction-related molecules in aged mice. These studies could have important implications concerning alcohol-induced neuropathology and alcohol addiction in the elderly.