Effects of short-term exposure to particulate matters on heart rate variability: A systematic review and meta-analysis based on controlled animal studies.

BACKGROUND: Exposure to particulate matters (PM) is recognized as an important risk factor for cardiovascular disease. A change in cardiac autonomic function is one postulated mechanism leading to PM related cardiovascular events. This study therefore evaluated the associations of short-term exposure to PM and heart rate variability (HRV) parameters, which can reflect the cardiac autonomic function. METHODS: Four electronic databases were searched for controlled studies of rodents published prior to December 2018. A systematic review and meta-analysis was conducted. Effect sizes were calculated for five main HRV parameters, including standard deviation of normal-to-normal intervals (SDNN), square root of mean squared differences between successive normal-to-normal intervals (rMSSD), low frequency (LF), high frequency (HF), and the ratio of LF and HF (LF/HF). RESULTS: The review included 23 studies with 401 animals. Short-term exposure to PM by instillation yielded statistically significant effects on SDNN (Standardized Mean Difference [SMD] = -1.11, 95% Confidence Intervals [CI] = -2.22 to -0.01, P = 0.05), LF (SMD = -1.19, 95% CI = -1.99 to -0.40, P = 0.003) and LF/HF (SMD = -1.05, 95% CI = -2.03 to -0.07, P = 0.04). Short-term exposure to PM by inhalation only yielded statistically significant effect on LF/HF (SMD = -0.83, 95% CI = -1.39 to -0.27, P = 0.004). There was no evidence that animal model and exposure frequency influenced the relationship of PM and HRV. CONCLUSIONS: Short-term exposure to PM can decrease HRV of rodents, affecting cardiac autonomic function. Exposure methods can influence the relationships of PM and HRV parameters. Further studies should focus on the effects of long-term PM exposure, on human beings, and potential influential factors of PM-HRV associations.

Association between Environmental Dioxin-Related Toxicants Exposure and Adverse Pregnancy Outcome: Systematic Review and Meta-Analysis.

Dioxin-related compounds are associated with teratogenic and mutagenic risks in laboratory animals, and result in adverse pregnancy outcomes. However, there were inconsistent results in epidemiology studies. In view of this difference, we conducted a systematic review and meta-analysis to examine this association and to assess the heterogeneity among studies. Comprehensive literature searches were performed to search for relevant articles published in English up to 15 May 2012. In total, we identified 15 studies which included 9 cohort and 6 case control studies. The Cochrane Q test and index of heterogeneity (I(2)) were used to evaluate heterogeneity. In either cohort studies (I(2)=0.89, p<0.0001) or case control studies (I(2)=0.69, p=0.02), significant heterogeneity of risk estimates were observed. Subgroup analyses found no significant increased risk of adverse pregnancy outcome with air dioxin-related compounds exposure (RR=0.99, 95% CI:0.85-1.16), no significant increased risk of spontaneous abortion (SAB) with exposure to food dioxin-related compounds (RR=1.05, 95% CI:0.80-1.37), higher significant risks of low birth weight (LBW) with exposure to food dioxin-related compounds (RR=1.55, 95% CI:1.24-1.94), and higher significant risks of birth defects with maternal solid contaminants dioxin exposure (OR=1.24, 95% CI:1.19-1.29). In conclusion, more evidences are needed to confirm the association between environmental dioxin-related compounds exposure and pregnancy outcome.

Association between Maternal MTHFR Polymorphisms and Nonsyndromic Cleft Lip with or without Cleft Palate in Offspring, A Meta-Analysis Based on 15 Case-Control Studies.

BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) is thought to be involved in the development of nonsyndromic cleft lip with or without cleft palate (NSCL/P). However, conflicting results have been obtained when evaluating the association between maternal MTHFR C677T and A1298C polymorphisms and the risk of NSCL/P. In light of this gap, a meta-analysis of all eligible case-control studies was conducted in the present study. MATERIALS AND METHODS: A total of 15 case-control studies were ultimately identified after a comprehensive literature search and Hardy-Weinberg equilibrium (HWE) examination. Cochrane's Q test and index of heterogeneity (I(2)) indicated no obvious heterogeneity among studies. RESULTS: Fixed or random-effects models were used to calculate the pooled odds ratios (ORs). The results showed that the TT genotype in mothers increased the likelihood of having NSCL/P offspring 1.25 times (95% CI: 1.047-1.494) more than the CC homozygotes. Meanwhile, maternal TT genotype increased the risk of producing NSCL/P offspring in recessive model (OR=1.325, 95% CI: 1.124-1.562). However, the CT heterozygote and the CT+TT dominant models had no association with NSCL/P offspring compared with the CC wild-type homozygote model. Subgroup analyses based on ethnicity indicated that maternal TT genotype increased the likelihood of having NSCL/P offspring in Whites (OR=1.308, 95% CI: 1.059-1.617) and Asians (OR=1.726, 95% CI: 1.090-2.733) in recessive model. Also, subgroup analyses based on source of control showed that mothers with the 677TT genotype had a significantly increased susceptibility of having NSCL/P children in hospital based population (HB) when compared with CC homozygotes (OR=1.248, 95% CI: 1.024-1.520) and un- der the recessive model (OR=1.324, 95% CI: 1.104-1.588). Furthermore, maternal A1298C polymorphism had no significant association with producing NSCL/P offspring (dominant model OR=0.952, 95% CI: 0.816-1.111, recessive model OR=0.766, 95% CI: 0.567-1.036). CONCLUSION: MTHFR C677T polymorphism is associated with the risk of generating NSCL/P offspring, and being a 677TT homozygote is a risk factor. MTHFR A1298C polymorphism was not associated with generating NSCL/P offspring. However, further work should be performed to confirm these findings.

Negative interplay of retinoic acid and TGF-ß signaling mediated by TG-interacting factor to modulate mouse embryonic palate mesenchymal-cell proliferation.

Mesenchymal-cell proliferation is the main process in shelf outgrowth. Both all-trans-retinoic acid (atRA) and transforming growth factor-ß3 (TGF-ß3) play an important role in mouse embryonic palate mesenchymal (MEPM) cell proliferation. In the present study, we investigated the crosstalk between RA and TGF-ß signaling in MEPM-cell proliferation. We found that atRA inhibited MEPM-cell proliferation by downregulating TGF-ß/Smad signaling and that TGF-ß3 treatment was able to antagonize RA signaling. Transforming growth-interacting factor (TGIF) is a transcriptional repressor that suppresses both TGF-ß- and retinoid-driven gene transcription. Furthermore, we investigated the role of TGIF in the interaction between both TGF-ß and RA signaling in MEPM-cell proliferation. The results showed that both atRA and TGF-ß3 significantly increased the expression level of TGIF, and TGIF mediated the negative interaction between TGF-ß and RA signaling pathways, which depended on TGIF binding to Smad2 or RARß (RA receptor beta). Moreover, after deletion of TGIF, both the effects of atRA on TGF-ß-dependent protein expression and the effects of TGF-ß on RA-dependent protein expression were lost. So we conclude that there is a negative functional interplay of RA and TGF-ß signaling mediated by TGIF to modulate MEPM-cell proliferation.

Excessive retinoic acid impaired proliferation and differentiation of human fetal palatal chondrocytes (hFPCs).

Chondrocyte proliferation and differentiation is a fundamental process during hard palatogenesis. Excessive retinoic acid (RA), the biologically most active metabolite of vitamin A, has been reported to adversely affect chondrogenesis. The aim of this study was to investigate the mechanisms underlying RA-induced chondrocyte differentiation by using human fetal palatal chondrocytes (hFPCs) aging about 9 weeks of amenorrhea. RA treatment inhibited proliferation and induced apoptosis in hFPCs. Alkaline phosphatase activity assay, quantitative alcian blue staining, and real-time PCR analysis revealed that RA treatment stimulated hFPCs to undergo maturation and terminal differentiation, as demonstrated by decreased chondrogenic markers and increased osteogenic markers. Further studies demonstrated that RA treatment increased Wnt/ß-catenin signaling, as demonstrated by Wnt/ß-catenin target gene expression analysis and a luciferase-based ß-catenin-activated reporter assay. To address the role of Wnt/ß-catenin signaling, we treated hFPCs with Dickkopf-related protein 1, an extracellular inhibitor of Wnt/ß-catenin signaling, and the observed all-trans retinoic acid-mediated increases in nuclear accumulation of ß-catenin, alkaline phosphatase activity, and type I collagen mRNA were attenuated, suggesting that RA modulated Wnt signaling at ligand-receptor level. In summary, excessive all-trans retinoic acid inhibited proliferation and promoted ossification of hFPCs by upregulation of Wnt/ß-catenin signaling.

Grape seed extract attenuates arsenic-induced nephrotoxicity in rats.

Oxidative stress is a recognized factor in nephrotoxicity induced by chronic exposure to inorganic arsenic (As). Grape seed extract (GSE) possesses antioxidant properties. The present study was designed to evaluate the beneficial effects of GSE against arsenic-induced renal injury. Healthy, male Sprague-Dawley rats were exposed to As in drinking water (30 ppm) with or without GSE (100 mg/kg) for 12 months. The serum proinflammatory cytokine levels and mRNA expression levels of fibrogenic markers in the renal tissues were evaluated using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. The protein expression levels of nicotinamide adenine dinucleotide phosphate (NADPH) subunits, transforming growth factor-ß1 (TGF-ß1) and phosphorylated Smad2/3 (pSmad2/3) were assessed using western blot analysis. The results demonstrated that cotreatment with GSE significantly improved renal function, as demonstrated by the reductions in relative kidney weight (% of body weight) and blood urea nitrogen, and the increase in the creatinine clearance capacity. GSE attenuated the As-induced changes in the serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1ß and the mRNA levels of TGF-ß1, α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF) and fibronectin (FN) in renal tissue. Furthermore, administration of GSE markedly reduced As-stimulated reactive oxygen species (ROS) production and Nox activity, as well as the protein expression levels of the NADPH subunits (Nox2, p47phox and Nox4). In addition, GSE cotreatment was correlated with a significant reduction in TGF-ß/Smad signaling, as demonstrated by the decreased protein levels of TGF-ß1 and pSmad2/3 in renal tissue. This study indicated that GSE may be a useful agent for the prevention of nephrotoxicity induced by chronic exposure to As. GSE may exert its effects through the suppression of Nox and inhibition of TGF-ß/Smad signaling activation.

Retinoic acid remodels extracellular matrix (ECM) of cultured human fetal palate mesenchymal cells (hFPMCs) through down-regulation of TGF-ß/Smad signaling.

The regulation of extracellular matrix (ECM) by retinoic acid (RA) is interesting in light of the fact that the ECM plays an essential role in morphogenesis and palatal shelf elevation. In the current study, we explored the effect of RA overexposure on ECM and the probable mechanisms in cultured human fetal palate mesenchymal cells (hFPMCs). RA dose-dependently inhibited cell proliferation and mRNA and protein levels of ECM components fibronectin, tenascin C and fibrillin-2. Zymography revealed that MMP-2 activity was suppressed by RA. Further analysis revealed that mRNA levels of MMP2 and TIMP2 were decreased, while the MMP2/TIMP2 mRNA ratio was increased, which might facilitate the ECM degradation. Because of the pivotal role of TGF-ß/Smad pathway in palatogenesis we therefore checked the effect of RA on TGF-ß/Smad signaling. The results indicated RA treatment increased Smad7 expression and decreased the levels of TGF-ß1, TGF-ß3, TGF-ß type II receptor (TßRII) and phosphorylated Smad2 and Smad3. Activation of the Smad pathways by either exogenous TGF-ß3 or recombinant adenoviruses for Smad3 attenuated RA-induced inhibition of cell proliferation and ECM components and rescued the RA-altered MMP2/TIMP2 mRNA ratio. In conclusion, these findings suggested that RA overexposure inhibited cell proliferation and disrupted the ECM network through down-regulation of TGF-ß/Smad pathway.

[Cost-utility analysis on universal childhood hepatitis A vaccination in regions with different anti-HAV prevalence rates of China].

OBJECTIVE: To explore the inputs and outputs of areas with different anti-HAV prevalence rates on universal childhood vaccination, and to provide a scientific basis for the formulation of the immunization strategy. METHODS: Since hepatitis A vaccination was scheduled at 12 and 18 months of age for all the healthy children, a single cohort including 1 000 000 individuals was formed in 2009, using the Chinese inactivated vaccine. Decision analysis was used to build Markov-decision tree model. The universal childhood hepatitis A vaccination was compared with non-vaccination group to evaluate the number of symptomatic infection, hospitalization, death, quality-adjusted life years (QALYs) lost, and the incremental cost-utility from the health system and the societal perspectives. Outcomes of the vaccination for the next 70 years were also predicted. The process of analysis was run separately in five regions defined by the anti-HAV prevalence rates (around 50%, 50% - 69%, 70% - 79%, 80% - 89% and > 90%). Sensitivity analysis was performed to test the stability or reliability of the results, and to identify sensitive variables. RESULTS: The study projected that, in the lowest, lower, and intermediate infection regions, the cost and output indicators of universal childhood hepatitis A vaccination were all lower than non-vaccinated group. Universal vaccination could gain QALYs and save both costs from the health system or the society. In the regions with higher infection rate, the output indicators of universal childhood hepatitis A vaccination were lower than in those non-vaccinated groups, except for the number of death due to hepatitis A, which had a 20 cases of increase. The model also predicted that in the highest infected region, universal vaccination would increase 4 560 814 and 5 840 430 RMB Yuan in the total costs from both the health system and the societies, respectively, when compared to the non-vaccination groups. Universal vaccination would also decrease the numbers of symptomatic infection, hospitalization, and QALYs lost, but would increase 51 deaths due to hepatitis A, and 1507, 1929 more RMB Yuan for each QALY gained from the health system and societal respectively, in the regions with highest infection rate. Sensitivity analyses discovered that the infection rate among those susceptible population and the proportion of those who initially under protection but subsequently lost their immunity every year, were the two main sensitive variables in the model. CONCLUSION: Our research discovered that the universal vaccination strategy should be based on the protective period of the vaccine and the anti-HAV prevalence in different endemic areas.

Inhibition of arsenic-induced rat liver injury by grape seed exact through suppression of NADPH oxidase and TGF-ß/Smad activation.

Chronic arsenic exposure induces oxidative damage to liver leading to liver fibrosis. We aimed to define the effect of grape seed extract (GSE), an antioxidant dietary supplement, on arsenic-induced liver injury. First, Male Sprague-Dawley rats were exposed to a low level of arsenic in drinking water (30ppm) with or without GSE (100mg/kg, every other day by oral gavage) for 12months and the effect of GSE on arsenic-induced hepatotoxicity was examined. The results from this study revealed that GSE co-treatment significantly attenuated arsenic-induced low antioxidant defense, oxidative damage, proinflammatory cytokines and fibrogenic genes. Moreover, GSE reduced arsenic-stimulated Smad2/3 phosphorylation and protein levels of NADPH oxidase subunits (Nox2, Nox4 and p47phox). Next, we explored the molecular mechanisms underlying GSE inhibition of arsenic toxicity using cultured rat hepatic stellate cells (HSCs). From the in vitro study, we found that GSE dose-dependently reduced arsenic-stimulated ROS production and NADPH oxidase activities. Both NADPH oxidases flavoprotein inhibitor DPI and Nox4 siRNA blocked arsenic-induced ROS production, whereas Nox4 overexpression suppressed the inhibitory effects of GSE on arsenic-induced ROS production and NADPH oxidase activities, as well as expression of TGF-ß1, type I procollagen (Coll-I) and α-smooth muscle actin (α-SMA) mRNA. We also observed that GSE dose-dependently inhibited TGF-ß1-induced transactivation of the TGF-ß-induced smad response element p3TP-Lux, and that forced expression of Smad3 attenuated the inhibitory effects of GSE on TGF-ß1-induced mRNA expression of Coll-I and α-SMA. Collectively, GSE could be a potential dietary therapeutic agent for arsenic-induced liver injury through suppression of NADPH oxidase and TGF-ß/Smad activation.

A cost-effectiveness analysis of universal childhood hepatitis A vaccination in China.

The socioeconomic improvement has impacted hepatitis A virus (HAV) infection with a shift from high to intermediate endemicity in many parts of China. The first China-developed inactivated hepatitis A vaccine, with significantly low price, was licensed in 2002, prompting us to evaluate whether universal childhood vaccination is advisable now in China. We considered vaccination scheduled at ages 12 and 18 months for all healthy children, and assumed that a single cohort was enrolled in 2005. A Markov model was used to predict hepatitis A outcomes and costs. Vaccination was compared with no vaccination, and the cost-effectiveness of vaccination was evaluated from the health system and the societal perspectives. The analysis was run separately in five regions (covering all the 31 provinces of Mainland China) defined by anti-HAV prevalence (around 50%, 50-69%, 70-79%, 80-89% and 90%-). The study projects that with the Chinese low-cost vaccine, vaccination could gain quality adjusted life years (QALYs) through the whole country and save health system or societal costs in the lowest, lower, intermediate and higher infection regions. Vaccination should also be cost-effective in the highest infection region because of low additional costs per QALY gained. However, vaccination would increase the probability of death due to hepatitis A in the highest and higher infection regions by 38 and 37 per million enrolled, respectively, and as vaccine protection loss increases the risk would also occur in intermediate and lower infection regions. The trend that the lower infection level the region has, the more cost-effective vaccination would be is obvious. Sensitivity analyses prove that our conclusions are robust. Considering the potential risk of vaccination, as well as unbalanced socioeconomic developments and significant differences in HAV infection through the whole country, the study suggests that universal childhood hepatitis A vaccination should be first administrated in provinces with the lowest infection level. With knowledge accumulation and further evaluations, the zone of immunization would be considered to be expanded gradually from provinces with lower infection level to those with higher.

[A survey on reproductive health related sexual behavior among middle school students in Luoyang city].

OBJECTIVE: To explore the appropriate ways and contents of reproductive health education for middle school students and to understand reproductive health related sexual behavior and influencing factors among middle school students. METHODS: Reproductive health related sexual behavior was evaluated among junior and senior middle school students in Luoyang by cluster sampling. The statistical software of SAS 8.1 was adopted for data analyses. Sexual behavior and influencing factors were analyzed by logistic regression. RESULTS: Critical sexual behaviors were found significantly higher in senior students, including masturbation, sexual fantasy and sexual intercourse than that in junior students (P < 0.05), and boys had higher prevalence than girls (P < 0.05). Results from multivariate logistic regression model analyses indicated that incidence rate of sexual behavior among those who ever having had experiences was higher than those who were inexperienced (OR = 2.62, 95%CI: 1.21 - 5.66). Incidence rate of sexual behavior was related to access of reproductive health and STD/AIDS knowledge (OR = 3.09, 95%CI: 1.43 - 6.51). In addition, incidence rate of sexual behavior was related to attitude and relation of amour between boys and girls (OR = 2.24, 95%CI: 1.32 - 3.75). CONCLUSION: Awareness on reproductive health knowledge among middle school students was not enough. Marginal sexual behaviors as masturbation and sexual fantasy had not been correctly and openly discussed to avoid inappropriate sexual activities.