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Methicillin-resistant Staphylococcus aureus (MRSA) has become the most important pathogen of hospital-acquired (HA) or community-acquired (CA) infections. However, it is unclear of the cytokines responsible for pathological hyper-inflammation in sepsis related cytokine storm for MRSA infection. In this study, we selected typical HA-MRSA strain (YNSA163: ST239-t030-SCCmecⅢ) and two CA-MRSA isolates (YNSA7: ST59-t439-SCCmecⅣa and YNSA53: ST59-t437-SCCmecⅤb) from our previous research, infected on BALB/c mice, and analyzed the cytokine storm patterns during infection process. The animal experiments revealed the most serious lethal effect on BALB/c mice caused by YNSA7 strain infection, followed by YNSA53, and no BALB/c mice died for YNSA163 infection. Histopathological analyses revealed that lung was the most seriously damaged organs, followed by spleen and kidney, especially for CA-MRSA infection. The severe inflammatory reactions, tissue destruction, and massive exudation of inflammatory mediators and cells could be identified in CA-MRSA strains infected mice. Interleukin-6 (IL-6) and IL-10 were both highly expressed in spleen and lung of YNSA7 and YNSA53 dead cases compared with YNSA53 survived and YNSA163 cases, which demonstrated cytokine storm pattern for CA-MRSA strains infection. The results of IL-6 intervention experiment verified that the enhanced IL-6 secretion was responsible for the host lethality of YNSA7 infection. RNA-sequencing results among three MRSA isolates indicated most of the differentially expressed genes referred to cellular process, metabolism and genetic information processing of bacteria. Specifically, clpP, chp chemotaxis inhibit, fnbB, pathogencity island protein and virulence associated protein E were highly expressed in YNSA7 strain. In general, CA-MRSA strains provoked cytokine storm on BALB/c mice led to severe infection and lethality, the up-regulated of some virulence genes might play important role in pathogenesis.

Background Pulmonary fibrosis (PF) is a devastating disease characterized by remodeling of lung architecture and abnormal deposition of fibroblasts in parenchymal tissue and ultimately results in respiratory failure and death. Preclinical studies suggest that mesenchymal stem cell (MSC) administration may be a safe and promising option in treating PF. The objective of our meta-analysis is to assess the efficacy of MSC therapy in preclinical models of PF. Methods We performed a comprehensive literature search in PubMed, EMBASE, Web of Science, and Cochrane Library databases from inception to March 17, 2021. Studies that assessed the efficacy of MSC therapy to animals with PF were included. The SYRCLE bias risk tool was employed to evaluate the bias of included studies. The primary outcomes included survival rate and pulmonary fibrosis scores. Meta-analysis was conducted via Cochrane Collaboration Review Manager (version 5.4) and Stata 14.0 statistical software. Results A total of 1120 articles were reviewed, of which 24 articles met inclusion criteria. Of these, 12 studies evaluated the survival rate and 20 studies evaluated pulmonary fibrosis scores. Compared to the control group, MSC therapy was associated with an improvement in survival rate (odds ratios (OR) 3.10, 95% confidence interval (CI) 2.06 to 4.67, P < 0.001, I2 = 0%) and a significant reduction in pulmonary fibrosis scores (weighted mean difference (WMD) 2.05, 95% CI −2.58 to −1.51, P < 0.001, I2 = 90%). Conclusions MSC therapy is a safe and effective method that can significantly improve the survival and pulmonary fibrosis of PF animals. These results provide an important basis for future translational clinical studies.

Background Maternal stress and nutrition during pregnancy are two of the most commonly studied factors in the context of fetal development. However, few investigators have considered the combined effects of stress and diet in pregnant women and their offspring. Aims To determine the impact of maternal stress on offspring birth weight, and the potential mediating role of maternal dietary patterns. Methods A total of 3542 pregnant women and their singleton live births were recruited from Shanghai Maternal-Child Pairs Cohort (Shanghai MCPC). Maternal stress was assessed using the Life Event Scale for Pregnant Women (LESPW) in early and late pregnancy. Food frequency questionnaire (FFQ) was performed to evaluate maternal diet in late pregnancy. Multiple linear regression was conducted to estimate the associations between maternal stress and child birth weight. Logistic regression was performed to calculate the association between maternal stress and small for gestational age (SGA)/large for gestational age (LGA). The bootstrap method was used to investigate the mediating effects of maternal dietary patterns. Results Maternal subjective events stress (β = 0.367) and total stress (β = 0.079) in early pregnancy, and positive objective life events stress (β = 0.275) in late pregnancy, were positively associated with birth weight. Maternal dietary pattern of “high-fat and sugar” mediated the associations between subjective events stress and total stress during early pregnancy and birth weight. An increased risk for LGA was observed among women exposed to relatively higher stress during early pregnancy (OR, 1.416; 95% CI, 1.035-1.937). No statistically significant associations were found between maternal stress during late pregnancy and child birth weight or SGA/LGA. Conclusions Maternal life events stress during early pregnancy significantly increases neonatal birth weight and risk for LGA, which may mediate by a “high-fat and sugar” dietary pattern. Limitations The lack of biological markers limits the explanation of the mechanism. The assessment of diet used food intake frequency to evaluate dietary characteristics, which may miss information of energy intake.

Purpose To explore the association between maternal physical activity (PA) and sleep quality during pregnancy, and the necessary PA level at different gestational stages to attain improved sleep quality. Methods A total of 2443 participants were recruited from the Shanghai Maternal-Child Pairs Cohort (Shanghai MCPC) study, who had completed questionnaires including the Pittsburgh Sleep Quality Index (PSQI) and the International Physical Activity Questionnaire (IPAQ) at gestational weeks (GW) of 12-16 and 32-36. PSQI scores and their seven components at the two GW were compared, as were PSQI scores at 12-16 and 32-36 GW and the increment in PSQI relative to PA. Regression analysis was conducted to assess the effect of PA and its change on the total PSQI score at different GW. Results The mean PSQI scores increased significantly during pregnancy, from 6.30 ± 3.01 at 12-16 GW to 7.23 ± 3.47 at 32-36 GW. Compared with women in low PA level, moderate levels of PA at both 12-16 GW and 32-36 GW were significantly reduced PSQI scores of 0.42 (95% CI:-0.68,-0.16) and 0.32 (95% CI:-0.63,-0.01), respectively. At 32-36 GW, high PA level also significantly decreased PSQI score, with a greater decline than moderate PA level. (AOR=-0.87,95% CI:-1.57,-0.18). PA increment from 12-16 to 32-36 weeks of pregnancy created a significant decline of 0.54 in PSQI scores. Conclusion The study revealed sleep quality was worse at the third trimester and moderate PA level had the potential for improvement of sleep quality both in the first and the third trimester. High PA level was also beneficial to improve sleep quality of pregnant women in the third trimester.

Background Recent research suggested that oxytocin might be associated with prenatal anxiety or depression. Also, our previous study indicated that resilience could buffer the effect of stress on prenatal anxiety and depression, which is a kind of psychological adjustment ability to stress in life. The effects of oxytocin and resilience are supposed to be similar but no study was carried out to find the association between them. Current evidence on the effect of oxytocin on prenatal mental health were with small sample size and equivocal results, especially with a lack of studies in Chinese pregnant women. Aims To investigate the relationship between oxytocin and resilience, and its role in regulating prenatal anxiety and depression among Chinese women. Methods The study was based on a sub-sample of the Shanghai Maternal-Child Pairs Cohort (Shanghai MCPC) by stratified random sampling. A total of 632 participants completed blood collection for serum oxytocin measurement and questionnaires pertaining to early pregnancy stress and resilience in the second trimester, which were assessed by the Life Event Scale for Pregnancy Women (LESPW) and the revised Resilience Scale for Adults (RSA), respectively. Prenatal anxiety and depression were assessed by Self-Rating Anxiety Scale (SAS) and the Center for Epidemiological Survey, Depression Scale (CES-D), respectively, at the third trimester. Correlation analysis and stratified linear regression analyses were conducted to understand the role of oxytocin in regulating prenatal anxiety and depression. Results The concentration of serum oxytocin in the second trimester ranged from 98.14 pg⋅ml−1 to 197.28 pg⋅ml−1, and there was no significant difference between different gestational age (r = 0.024, P = 0.579). The association between stress and prenatal anxiety was stronger in high oxytocin group than that in low oxytocin group, with B value of 3.338 and 2.638, respectively, after adjusting for residence, educational level, family income and parity. The same effect was found in the association between stress and prenatal depression, with B value of 2.360 and 2.060, respectively. However, it was not significantly associated with early pregnancy stress (Z = 1.933, P = 0.630), prenatal anxiety (Z = 1.387, P = 0.165), prenatal depression (Z = −0.027, P = 0.978), nor resilience (F = 1.282, P = 0.280). Limitations The existence of recall bias and restricted residential areas of the participants may limit the extrapolation of the study. Also, unsynchronized sampling timing of the oxytocin and psychological resilience measures is another limitation. Conclusions Serum oxytocin levels in the second trimester had an effect of modification between early pregnancy stress and prenatal anxiety and depression. Pregnant women with high oxytocin in the second trimester should receive more attention and further study is needed on the mechanism of oxytocin for the mental health of pregnant women.

BackgroundThe AtyPical Asthma in China (APAC) cohort is a multi-center prospective, observational cohort set-up to investigate the clinical, pathophysiological features, prognosis, and mechanisms of cough variant asthma (CVA).ObjectivesTo present the characteristics of newly physician-diagnosed adults with CVA (n = 328) compared to mild-moderate classic asthma (CA, n = 206).Methods and Main ResultsCVA subjects showed a higher proportion of female (67.1 vs. 55.3%, P = 0.0084), abnormal laryngopharyngeal sensations (71 vs. 51%, p < 0.0001) than CA, but presented with near normal spirometry and higher methacholine PD20-FEV1 values [4.2 (1, 8.6) vs. 0.8 (0.4, 4.7), P < 0.0001]. Lower fractional exhaled nitric oxide (FENO) levels [38.5 (19.8, 72.5) vs. 53. (28.5, 92.2), P = 0.0019], blood eosinophil counts [0.2 (0.1, 0.4) vs. 0.3 (0.2, 0.5), P = 0.0014], and sputum eosinophils [2.3 (0.3, 8.0) vs. 12.2 (2, 34.5), p < 0.0001] were found in CVA. Despite lower total serum IgE levels in CVA, there was similar proportion of atopy in both groups. The prevalence of cough in CA was 86.4%, while CVA reported more severe cough on Visual Analog Scale, Cough Evaluation Test, and Leicester Cough Questionnaire, similar anxiety and depression scores but better asthma control scores as reflected by Asthma Control Test compared to CA. No correlation was found between cough assessment outcomes and sputum eosinophil count, blood eosinophil count, FENO, spirometry variables, or PD20-FEV1.ConclusionCough variant asthma is distinctive from classic asthma in regard to clinical features, lung function, and airway inflammation. Quality of life is badly impaired as well in spite of better asthma control scores.

Soil pollution is one of the major threats to the environment and jeopardizes the provision of key soil ecosystem services. Vertical barriers, including slurry trench walls and walls constructed with soil mix technology, have been employed for decades to control groundwater flow and subsurface contaminant transport. This paper comprehensively reviewed and assessed the typical materials and mechanical and permeability properties of soil–bentonite, cement–bentonite and soil mix barriers, with the values of mix design and engineering properties summarized and compared. In addition, the damage and durability of barrier materials under mechanical, chemical, and environmental stresses were discussed. A number of landmark remediation projects were documented to demonstrate the effectiveness of the use of barrier systems. Recent research about crack-resistant and self-healing barrier materials incorporating polymers and minerals at Cambridge University and performance monitoring techniques were analyzed. Future work should focus on two main areas: the use of geophysical methods for non-destructive monitoring and the optimization of resilient barrier materials.

Background UV filters are emerging contaminants with endocrine disrupting effects, but little is known about their health effects, especially for children. Objective To assess the association between multiple organic UV filters exposure and adiposity measures and by gender in peripubertal children. Methods This prospective follow-up study included 327 children aged 7–15 years old. Urinary organic UV filters including benzophenone derivatives (BP-2, BP-3), octyl dimethyl para-aminobenzoic acid (OD-PABA), ethylhexyl methoxycinnamate (EHMC) and its metabolite (4-MCA and 4′-MAP) were quantified. Six adiposity biometrics including height, weight, waist and hip circumferences, and triceps and subscapular skinfold thickness were measured with 1.5-year duration. The Bayesian kernel machine regression method was used to estimate the associations of UV filters mixture with adiposity measurements, and longitudinal analyses were then considered to further evaluate the associations between individual UV filters and trajectories of growth development using linear mixed models or generalized linear mixed models. Results Exposure to mixture of UV filters was negatively associated with most adiposity measurements, with a reduction of 1.399 kg/m2 (95% CI: −2.246 to −0.551 kg/m2) in BMI, 0.674 (95% CI: −1.045 to −0.304) in BMI z-score, 0.033 BF% (95% CI: −0.053 to −0.013), and 2.301 mm (95% CI: −3.823 to −0.78) in subscapular skinfold thickness at baseline, comparing the 75th percentile to the 25th level of UV filters mixture exposure. Consistent associations were found at follow-up. Both baseline and follow-up results suggested that EHMC was identified as the most important contributor to lower adiposity measurements, which was also confirmed by linear mixed models in longitudinal analyses. No significant effects were found in girls. Conclusion This study found that childhood organic UV filters exposure was negatively associated with adiposity measures in peripubertal boys, but not girls.

Increasing evidence supports that maternal exposure to vanadium (V) is associated with adverse birth outcomes including preterm birth and low birth weight. However, the effect of V exposure on intrauterine fetal growth and the underlying biological mechanism are still unclear. The present study includes 227 mother-infant pairs from the Shanghai Maternal-Child Pairs Cohort to assess the gender-specific effect of intrauterine V exposure on fetal growth and related cytokines. Maternal blood samples were collected to measure V concentration and biomarkers of growth. We used multiple linear regression to evaluate the gender-specific effect of prenatal V exposure on birth parameter and growth-related cytokines. Mixed-effect models were applied to assess the non-linear association between gestational V exposure and intrauterine fetal growth. Covariates adjusted in the regression models as potential confounders including maternal age, pre-pregnancy body mass index, gestational weeks, parity, socio-demographic status, etc. Results showed that prenatal V exposure was negatively associated with birth weight (β = −64.73) in female newborns and body length (β = −0.10) in male. During the fetal period, maternal V exposure was associated with decreased biparietal diameter (β = −0.91), head circumference (β = −2.96), femur length (β = −0.72) and humerus length (β = −0.64) in male. Trimester-specific analyses showed that serum V concentration in the second trimester was associated with significant reductions in intrauterine growth parameters. Besides, prenatal V exposure could down-regulate the expression of growth hormone (GH) in both maternal blood (β = −0.23) and umbilical cord blood (β = −1.66) in male fetuses, and the expression of brain derived neurotrophic factor (BDNF) in cord blood in females (β = −0.52). Our results suggest that prenatal V exposure has a gender-specific effect on fetal growth and the second trimester may be a sensitive window. The disruption of grow-related cytokines may potentially be the biological mechanism of these effects.

Ambient fine particulate matter (PM2.5) pollution has been implicated in the development of hypertensive disorders of pregnancy. However, evidence on the effects of PM2.5-derived chemical constituents on gestational blood pressure (BP) is limited, and the potential mechanisms underlying the association remain unclear. In this study, we repeated three consecutive 72-h personal air sampling and BP measurements in 215 pregnant women for 590 visits during pregnancy. Individual PM2.5 exposure level was assessed by gravimetric method and 28 PM2.5 chemical constituents were analyzed by ED-XRF method. Plasma biomarkers of endothelial function and inflammation were measured using multiplexed immunoassays. Robust multiple linear regression models were used to estimate the associations among personal PM2.5 exposure and chemical constituents, BP changes (compared with pre-pregnancy BP) and plasma biomarkers. Mediation analyses were performed to evaluate underlying potential pathways. Result showed that exposure to PM2.5 was significantly associated with increases in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) in the early second trimester. Meanwhile, elevated concentration of lead (Pb) constituent in PM2.5 was significant associated with increases in DBP and MAP after adjusting for PM2.5 total mass. PM2.5 and Pb constituent also presented positive associations with plasma biomarkers of endothelial function (ET-1, E-selectin, ICAM-1) and inflammation (IL-1β, IL-6, TNFα) significantly. After multiple adjustment, elevated ET-1 and IL-6 were significantly correlated with increased gestational BP, and respectively mediated 1.24%-25.06% and 7.01%-10.69% of the increased BP due to PM2.5 and Pb constituent exposure. In conclusion, our results suggested that personal exposure to PM2.5 and Pb constituent were significantly associated with increased BP during pregnancy, and the early second trimester might be the sensitive window of PM2.5 exposure. The endothelial dysfunction and elevated inflammation partially mediated the effect of PM2.5 and Pb constituent on BP during pregnancy.

Background Prenatal anxiety/depression has been a major public health problem globally with higher prevalence in developing countries, which leads to negative health outcomes for both mothers and children. Maternal stress varies over the course of pregnancy and the stress occurring in early pregnancy is the most critical. However, few studies have focused on the impact of resilience to stress on mental health of pregnant women. Aims To explore the effect of resilience to stress on prenatal anxiety/depression in pregnant women. Methods 2813 participants were recruited from Shanghai Maternal-Child Pairs Cohort (Shanghai MCPC) in this study. The Life Event Scale for Pregnancy Women (LESPW) was used to assess stress at 12–16 weeks of pregnancy and at 32–36 weeks of pregnancy, respectively. Resilience was assessed by the revised Resilience Scale for Adults (RSA) at 12–16 weeks of pregnancy. The prenatal anxiety and depression were assessed at 32–26 weeks of pregnancy by Self-Rating Anxiety Scale (SAS) and the Center for Epidemiological Survey, Depression Scale (CES-D), respectively. Hierarchical linear regression analyses were conducted to explore the direct effect of stress and resilience on prenatal anxiety and depression. The indirect effects of mediation were analyzed by structural equation models, and the indirect effect of modification was examined by stratification analysis. Results There were 11.1% and 10.3% of pregnant women in Shanghai MCPC indicating anxiety and depressive mood, respectively. The stress caused by both subjective and objective events at 32–36 weeks of pregnancy is less than that at 12–16weeks of pregnancy. We found that resilience was a protective factor for maternal mental health and meanwhile it was both an effect modifier and a mediator to the association between stress and prenatal anxiety/depression, with the mediating effect ratio of 15.1% and 23.8%, respectively. Limitations The existence of recall bias, missing data, and restricted residential areas of the participants may limit the generalizability of the study. The measurements of resilience, prenatal anxiety, and depression were not designed specifically for pregnant women, so that they might have missed some important indications of mental issues related to pregnant women only. Conclusions Resilience could be a direct and indirect protective factor for prenatal anxiety and depression caused by pregnancy stress.

Background: The association between antibiotic use during pregnancy and neonatal birth outcomes has received considerable attention. Most of the previous assessment of antibiotic exposure during pregnancy relied on questionnaires and clinical prescriptions, and very few studies examined pregnancy exposure to antibiotics using human biomonitoring data. Objective: To explore the association between the cumulative exposure of antibiotics during the whole pregnancy and neonatal birth measurements using biomonitoring data of antibiotics in meconium. Methods: Three hundred and sixty nine pregnant women within the Maternal Psychological and Environmental Assessments of Kids Cohort Study were randomly selected into this study. Eighteen common antibiotics of six categories (six β‑lactams, three tetracyclines, four sulfonamides, one phenicols, one lincosamides and three fluoroquinolones) were selected as the target antibiotics in meconium. The measurement was conducted by ultraperformance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry platform. Neonatal birth measurements were obtained from the medical records. Multiple linear regression models were used to examine the associations of antibiotic exposure with neonatal birth outcome (birth weight, birth length) and placental growth indicators (placental surface area, placental weight). Logistic regressions were used to evaluate associations with small for gestational age (SGA) and large for gestational age (LGA). Results: Twelve of the eighteen antibiotics were found in 62.1% of the meconium, with detection rates ranging from 0.3% to 43.9%. The three antibiotics with the highest detection rates were chlortetracycline (43.9%), penicillin (16.5%) and chloramphenicol (10.8%), respectively. The highest antibiotic concentration among detected antibiotics was penicillin (24,243.15 μg/kg). The concentration of penicillin was positively associated with the birth weight (β: 0.025; 95% CIs: 0.003–0.047). A significant positive association was also observed between the concentration of chlortetracycline and the placental surface area (β: 2.559; 95% CIs: 0.296–4.822). These associations were sex related and mainly observed in female newborns. Exposure to penicillin was also found to be associated with increased risk of LGA, which was consistent with changes in birth weight. Conclusions: Pregnancy exposure to certain antibiotics was associated with altered fetal growth and development, which may affect the normal growth trajectory of infants and children in later life. Keywords: Cumulative exposure of antibiotics, Meconium, Biomonitoring data, Birth outcomes, Placental growth indicators, LGA

Background: Microbiome residing in the respiratory tract has emerged as an important player in the etiology and progression of COPD, but results are conflicting regarding the features of respiratory tract microbiome in COPD and at exacerbations and it is unknown whether these features differ by ethnicity and geography. To address these questions, we enrolled healthy individuals and patients with COPD, including healthy-COPD pairs from same households, from four geographical regions of Yunan province, representative of different ethnicities and/or environmental exposures. Sputum and oropharyngeal swabs were collected from these healthy individuals and from COPD patients at stable state (COPD) or exacerbations (AECOPD) and subjected to 16S amplicon sequencing. Results: We found that both COPD disease status and region had an impact on alpha-diversity of sputum and oropharyngeal microbiomes, with AECOPD having the lowest microbiome diversity. Shifts in the relative abundance (≥ 1.5 fold, adj.p < 0.05) of microbes at healthy, exacerbation and stable COPD. Microbes enriched at exacerbation COPD were primarily Proteobacteria and Firmicutes phylum in upper respiratory tract. In the lower respiratory tract, population-based study did not find any statistical differential abundance of microbe, however, paired-based study showed phylum of Proteobacteria, Chloroflexi, Bacteroidota, Acidobacteriota, Desulfobacterota, Firmicutes and Verrucomicrobiota enriched in exacerbation COPD. Conclusions: This study was the first attempt to combine the population-based and core-family-based to investigate the microbiome profiling in the upper and lower respiratory tract in COPD patients, and specific microbial flora characteristics may inform future study on the pathogenesis or management of COPD patients.

Objectives: This article is based on deep learning algorithms and uses MRI to study the development of congenital heart septal defects in neonatal brain tissue. Methods: From January 2018 to December 2019, 150 cases of congenital cardiac paper septal defect were retrospectively analyzed on 50 cases of normal newborns and neonates. The four index parametersbrain MR imaging, lateral ventricle pre-angle measurement index (F/F’), body index (D/ D’), caudal nucleus index (C/C’) were analyzed. The independent sample t test is performed to compare the difference parameters between groups. Results: F congenital heart disease group and control group/F ‘values were 0.301 ± 0.035 and 0.296 ± 0.031; Evans index was 0.239 ± 0.052 and 0.233 ± 0.025; 2 sets of D/D’ values were 0.261 ± 0.039 and 0.234 ± 0.032; C/C ‘value was 0.138 ± 0.018 and 0.124 ± 0.015 respectively. The congenital heart disease group D/D ‘, and the value of C/C’ obtained under the ROC curve area value, respectively 0.698 and 0.750, Youden index corresponding to the maximum D/D ‘, and the value of C/C’ values were 0.28 and 0.12. Conclusion: Lateral ventricle D/D ‘and C/C’ is more sensitive indicator which can be evaluated with the difference between the volume of congenital heart septal defects in newborn normal neonatal brain; when the D/D ‘value> 0.28, C/C’ value> 0.12. For the diagnosis and evaluation of congenital heart septal defect neonatal brain volume abnormalities have a certain reference value. List of acronyms: MRI: Magnetic Resonance Imaging. POX: Pulse oximetry. CHD: Congenital Heart Disease.DWI: Diffusion-weighted Imaging. T1WI: T1-weighted imaging T2WITSE: T2-weighted imaging, Turbo Spin Echo. FOV: Field of View. FLAIR: Fluid Attenuated Inversion Recovery. TE: Echo Time. TR: Repetition Time. ICC: Intra-group Correlation Coefficient. doi: https://doi.org/10.12669/pjms.37.6-WIT.4863 How to cite this:Zhu J, Chen J, Zhang Y, Ji J. Brain tissue development of neonates with Congenital Septal Defect: Study on MRI Image Evaluation of Deep Learning Algorithm. Pak J Med Sci. 2021;37(6):1652-1656. doi: https://doi.org/10.12669/pjms.37.6-WIT.4863 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen for human infection. Hospital-acquired (HA) and community-acquired (CA) MRSA infections are serious clinical problems worldwide. In this study, we selected typical HA-MRSA strain and CA-MRSA isolates from our previous research and compared their phenotypic and pathogenic abilities both in vitro and in vivo. Results ST59-t437-SCCmecIVa (YNSA7) and ST59-t437-SCCmecVb (YNSA53) belonged to two prevalent subclones of CA-MRSA, while ST239-t030-SCCmecIII (YNSA163) was an HA-MRSA epidemic clone in Southwest China. ST59-t437 strains demonstrated faster growth ability, higher survival rate resistance to human blood, and more toxin secretion levels and cytotoxicity than ST239-t030. The virulence and regulatory genes of hld, psm-α, RNAIII, agrA, and crtN were highly expressed on CA-MRSA isolates, especially the ST59-t437-SCCmecIVa subclone. However, the ST239-t030 strain had the strongest adhesion and biofilm ability among these MRSA bacteria. Animal experiments revealed the most serious lethal effect on BALB/c mice caused by the YNSA7 strain infection. The survival rates of BALB/c mice infected with the three MRSA strains were 16.7, 50.0 and 100.0% for YNSA7, YNSA53 and YNSA163, respectively. Histopathological analyses of infected animals indicated that the lungs were the most seriously damaged organs, especially for ST59-t437 MRSA. Severe inflammatory reactions, tissue destruction, and massive exudation of inflammatory mediators and cells could be identified in ST59-t437 strain-infected animals. Conclusions In general, ST59-t437 strains showed higher pathogenic ability than the ST239-t030 isolate, while ST239-t030 MRSA revealed the features prevalent in hospital settings, specifically for adhesion and biofilm ability.

IntroductionCurcumin (CUR) was reported to stimulate the expression of methyltransferase‐like 3 (METTL3), a potential new target for the replacement therapy of osteoporosis. Besides, marrow stem cells (MSC)-derived exosomes (EXO) were proven to improve osteoporosis by promoting the proliferation of osteoblasts. In this study, we aimed to study the effect of CUR and BMSC-derived exosomes in the treatment of osteoporosis.Material and methodsMicroscopy was used to characterize exosomes derived from bone marrow stem cells (BMSCs). MicroCT was carried out to analyze the parameters of bone formation. Western blot was carried out to analyze the expression of surface markers on BMSC-derived exosomes and METTL3/Runt-related transcription factor 2 (RUNX2) proteins under different conditions. Real-time PCR was used to assess the gene expression under different circumstances.ResultsThe exosomes derived from CUR-treated BMSCs showed an enhanced therapeutic effect on osteoporosis mice compared with exosomes derived from untreated BMSCs. Mechanistically, the effect of BMSC-derived exosomes on restoring the de-regulated expression of METTL3, miR-320 and RUNX2 was significantly enhanced by CUR treatment upon BMSCs. Besides, CUR treatment upon BMSCs showed an obvious effect on enhancing the stimulatory role of BMSC-derived exosomes in the expression of METTL3, miR-320, RUNX2, BGLAP and LAP in BMSCs. Furthermore, luciferase assay demonstrated that miR-320 was capable of suppressing the expression of RUNX2 through binding to the 3’ UTR of RUNX2.ConclusionsOur study demonstrated that BMSC-derived exosomes could modulate the METTL3/miRNA-320/RUNX2 axis to attenuate osteoporosis by promoting osteogenic differentiation of BMSCs. Moreover, the CUR treatment upon BMSCs promoted the therapeutic effect of BMSC-derived exosomes.

The contamination of soil by lead (Pb) is a serious and widespread problem in China, especially in mining areas. This paper summarized the available data regarding Pb-contaminated soils around various metal mines in China. Based on these data, the Pb concentration in the soil and its temporal and spatial changes were analyzed. Potential ecological hazards and adult lead models were also used to estimate ecological and health risks. The results indicated that the concentration of Pb was closely related with the type of mine. Compared with other types of mine, soil around lead-zinc (Pb-Zn) and tin (Sn) mines with high Pb contents in the metallic ores and high pollutant emission coefficient were more strongly polluted by Pb. The characteristic spatial and temporal variations of Pb pollution status in China were clarified, and the results showed that the concentration was high in the southern, southwestern, and central regions of China where many mining areas were located, and the mean value passed a turning point in 2012. Ecological risk assessments indicated that some areas around mines were at considerable to high risk, and the risk was relatively severe in Pb-Zn mining areas. According to the adult lead model, Pb-Zn mines had a greater impact on blood Pb concentration than the other types of mine.

Qianyu Yue,* Yanyan Xu,* Xiaoli Deng, Shenglan Wang, Jingman Qiu, Baojiang Qian, Yunhui Zhang Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, 650032, Yunnan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunhui Zhang; Xiaoli DengDepartment of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), No. 157, Jinbi Road, Kunming, 650032, Yunnan, People’s Republic of ChinaTel +86 871-63638515Email Yueqianyu2020@163.com; xeygyc@163.comBackground: Circular RNA (circRNA) is a key regulator of cancer, and it has been proved to be involved in the regulation of cancer progression including non-small cell lung cancer (NSCLC). Circ-PITX1 was found to be a significantly upregulated circRNA in NSCLC, and its role and potential mechanism in NSCLC progression deserve further investigation.Methods: The expression levels of circ-PITX1, microRNA (miR)-1248 and cyclin D2 (CCND2) were examined by quantitative real-time PCR (qRT-PCR). Cell proliferation, apoptosis, cell cycle process, migration and invasion were determined using cell counting kit 8 (CCK8) assay, colony formation assay, flow cytometry, wound healing assay and transwell assay. Xenograft models were built to explore the role of circ-PITX1 in NSCLC tumor growth in vivo. The glycolysis and glutamine metabolism of cells were assessed by detecting the consumptions of glucose and glutamine, cell extracellular acidification rate (ECAR), and the productions of lactate, α-ketoglutaric acid (α-KG) and ATP. The protein levels of hexokinase 2 (HK-2), glutaminase 1 (GLS1) and CCND2 were tested by Western blot (WB) analysis. Dual-luciferase reporter assay and RIP assay were employed to verify the interaction between miR-1248 and circ-PITX1 or CCND2.Results: Circ-PITX1 was upregulated in NSCLC and its silencing could inhibit the proliferation, migration, invasion, cell cycle process, glycolysis, glutamine metabolism, and promote the apoptosis of NSCLC cells in vitro, as well as reduced tumor growth in vivo. In the terms of mechanism, we found that circ-PITX1 could act as a sponge of miR-1248, and miR-1248 could target CCND2. In addition, miR-1248 inhibitor reversed the inhibitory effect of circ-PITX1 knockdown on NSCLC progression. Similarly, CCND2 overexpression also reversed the suppressive effect of miR-1248 on NSCLC progression. Moreover, circ-PITX1 positively regulated CCND2 expression by sponging miR-1248.Conclusion: Circ-PITX1 served as a sponge of miR-1248 to promote NSCLC progression by upregulating CCND2.Keywords: non-small cell lung cancer, circ-PITX1, miR-1248, CCND2

Background Chronic obstructive pulmonary disease (COPD) is mainly induced by the increased content of particulate matter 2.5 (PM2.5) in the atmosphere. This study aimed to evaluate the effects of betulinic acid derivative on lung inflammation in a mouse model of chronic obstructive pulmonary disease induced by particulate matter 2.5. Material/Methods The mice were given a PM2.5 (25 μl) suspension for 7 days by the intranasal route to establish a COPD model. The content of TNF-α and IL-6 in the BALF samples was measured by commercially available ELISA kits. Results The PM2.5-induced higher LDH and ACP levels were significantly alleviated in mouse lung tissues by treatment with betulinic acid derivative. Treatment with betulinic acid derivative also suppressed PM2.5-induced increase in AKP and ALB levels in mouse lung tissues. Betulinic acid derivative reversed PM2.5-mediated suppression of SOD activity and elevation of NOS level in mouse BALF. Moreover, the PM2.5-induced excessive NO and MDA levels in mouse BALF were significantly reduced (P

Background: Microbiome residing in the respiratory tract has emerged as an important player in the etiology and progression of COPD, but results are conflicting regarding the features of respiratory tract microbiome in COPD and at exacerbations and it is unknown whether these features differ by ethnicity and geography. Method: To address these questions, we enrolled healthy individuals and patients with COPD, including healthy-COPD pairs from same households, from four geographical regions of Yunan province, representative of different ethnicities and/or environmental exposures. Sputum and oropharyngeal swabs were collected from these healthy individuals and from COPD patients at stable state (COPD) or exacerbations (AECOPD) and subjected to 16S microbiome profiling. Results: Both COPD disease status and region had an impact on alpha-diversity of sputum and oropharyngeal microbiomes, with AECOPD having the lowest microbiome diversity. Shifts in the relative abundance (≥ 1.5 fold, adj. p < 0.05) of microbes at healthy, exacerbation and stable COPD. Microbes enriched at exacerbation COPD were primarily Proteobacteria and Firmicutes phylum in upper respiratory tract. In the lower respiratory tract, population-based study did not find any statistical differential abundance of microbe, however, paired-based study showed phylum of Proteobacteria, Chloroflexi, Bacteroidota, Acidobacteriota, Desulfobacterota, Firmicutes and Verrucomicrobiota enriched in exacerbation COPD. Conclusions: COPD is associated with specific changes in upper and lower respiratory tract microbiomes, whereas exacerbation events confer additional alterations in respiratory tract microbiome compositions. These specific microbiome changes may inform future study on the pathogenesis or management of COPD.

Although previous studies have reported the adverse effect of air pollution exposure during pregnancy on neurodevelopment in children, epidemiological evidence is limited, and the results are inconsistent. This study aimed to explore the association between prenatal ambient fine particulate matter (PM2.5) exposure and early childhood neurodevelopment in a large birth cohort study of 4009 maternal-child pairs. Prenatal daily PM2.5 exposure concentrations at 1 km spatial revolution were estimated using high-performance machine-learning models. Neurodevelopmental outcomes of children at ages 2, 6, 12, and 24 months were assessed using the Ages and Stages Questionnaire (ASQ). Distributed lag nonlinear models were used to identify critical windows of prenatal PM2.5 exposure. General linear mixed models with binomially distributed errors were used to estimate the effect of prenatal PM2.5 exposure on suspected developmental delay (SDD) in five developmental domains based on the longitudinal design. Prenatal PM2.5 exposure was significantly associated with decreased scores for all neurodevelopmental domains of children at ages 2, 6, and 24 months. Each 10-μg/m3 increase in PM2.5 exposure was significantly associated with increased risk of SDD for all subjects (RR: 1.52 95% CI: 1.19, 2.03), specifically, in problem-solving domain for girls (RR: 2.23, 95% CI: 1.22, 4.35). Prenatal PM2.5 exposure in weeks 18 to 34 was significantly associated with both ASQ scores and SDDs. Our study proposed that prenatal PM2.5 exposure affected early childhood neurodevelopment evaluated with the ASQ scale. PM2.5 exposure might increase the risk of SDD for boys and girls, specifically in the problem-solving domain for girls.

Although abundant evidence has suggested that early-life antibiotic exposure was associated with adipogenesis later in life, limited data were available on the effect of intrauterine antibiotic exposure on infant growth and growth speed. Additionally, few studies have investigated the role of the neonatal gut microbiota in the above association. In this study, we examined the association between intrauterine cumulative antibiotic exposure and infant growth and explored the potential role of the neonatal gut microbiota in the association. 295 mother-child pairs from the Shanghai Maternal-Child Pairs Cohort (MCPC) study were included, and meconium samples and infant growth measurements were assessed. Z-scores of length-for-age, weight-for-age (weight-for-age), and body mass index (BMI)-for-age (BMI-for-age) were calculated. Eighteen common antibiotics were measured in meconium. Multivariable linear regression models were applied to test the interrelationships between antibiotic exposure, diversity indicators, and the relative abundance of selected bacterial taxa from phylum to genus levels from least absolute shrinkage and selection operator (LASSO) and infant growth indicators. The detection rates of the 18 antibiotics, except for chlortetracycline, penicillin, and chloramphenicol, were below 10 %. Penicillin was found to be positively associated with infant growth at birth and with growth speed from 2 to 6 months. The Pielou and Simpson indexes were negatively associated with meconium penicillin. Nominally significant associations between penicillin and the relative abundances of several bacterial taxa from the phyla Proteobacteria, Bacteroidetes, and Firmicutes were found. The Pielou and Simpson indexes were also found to be negatively associated with infant growth. Among taxa selected from LASSO regression, the relative abundances of the phyla Actinobacteria and Firmicutes and order Bifidobacteriales were found to be significantly associated with weight and BMI growth speeds from 2 to 6 months. In conclusion, intrauterine antibiotic exposure can affect infant growth. The neonatal gut microbiota might play a role in the abovementioned association.

Background Lung nodules are a diagnostic challenge. Current clinical management of lung nodule patients is inefficient and therefore causes patient misclassification, which increases healthcare expenses. However, a precise and robust lung nodule classifier to minimize discomfort for patients and healthcare costs is still lacking. The aim of the present protocol is to evaluate the effectiveness of using a liquid biopsy classifier to diagnose nodules compared to physician estimates and whether the classifier can reduce the number of unnecessary biopsies in benign cases. Methods A prospective cohort of 10,560 patients enrolled at 23 clinical centers in China with non-calcified pulmonary nodules, ranging from 0.5 to 3 cm in diameter, indicated by LDCT or CT will be included. After signed consent forms, the participants' pulmonary nodules will be assessed using three evaluation tools: (I) physician cancer probability estimates (II) validated lung nodule risk models, including Mayo Clinic and Veteran's Affairs models (III) ctDNA methylation classifier previously established. Each patient will undergo LDCT/CT follow-ups for 2 to 3 years and their information and one blood sample will be collected at baseline, 3, 6, 12, 24 and 36 months. The primary study outcomes will be the diagnostic accuracy of the methylation classifier in the cohort. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) will be used to compare the diagnostic value of each testing tool in differentiating benign and malignant pulmonary nodules. Discussion We are conducting an observational study to explore the accuracy of using a ctDNA methylation classifier for incidental lung nodules diagnosis. Trial registration Clinicaltrials.gov NCT03651986.

Bing Yuan,1,* Feng Liao,1,* Zhi-Zhou Shi,2 Yuan Ren,1 Xiao-Li Deng,1 Ting-Ting Yang,1 Deng-Yuan Li,1 Ru-Fang Li,1 Dan-Dan Pu,1 Yu-Jue Wang,1 Yan Tan,1 Zhen Yang,1 Yun-Hui Zhang1 1Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of China; 2Medical School, Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of China*These authors contributed equally to this work.Correspondence: Zhen YangDepartment of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of ChinaEmail 49387127@qq.comYun-Hui ZhangDepartment of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of ChinaEmail yunhuizhang3188@126.comObjective: Lung cancer is the first leading cause of cancer-related deaths both worldwide and in China and threatens human health and quality of life. New drugs and therapeutic methods are urgently needed. Our study evaluated the roles of dihydroartemisinin (DHA) in lung cancer and further explored its underlying mechanisms.Methods: CCK-8, colony formation and trypan blue exclusion assays were used to detect the cell viability, colony formation ability and cell death. qRT-PCR and Western blotting assays were applied to analyze the expressions of key molecules.Results: DHA inhibited the proliferation and colony formation abilities and enhanced the cell death and induced ferroptosis of lung NCI-H23 and XWLC-05 cancer cells. DHA reduced PRIM2 expression and silencing PRIM2 mimicked the inhibitory roles on proliferation and colony formation and promotive roles on cell death and ferroptosis of DHA in lung NCI-H23 and XWLC-05 cancer cells. We further found that DHA treatment and loss of PRIM2 reduced the GSH level and increased the cellular lipid ROS and mitochondrial MDA levels, and further downregulated the expressions of SLC7A11 and β-catenin in lung cancer cells, respectively. Exogenetic overexpression of PRIM2 recovered the inhibitory effects of DHA on proliferation and colony formation in lung NCI-H23 cancer cells, meanwhile loss of PRIM2 sensitizes NCI-H23 cells to DHA therapy. In vivo experiment further showed that DHA treatment significantly suppressed the tumor growth and downregulated PRIM2 and SLC7A11.Conclusion: Our study suggested that DHA inhibited the proliferation, colony formation and enhanced cell death and induced ferroptosis of lung cancer cells by inactivating PRIM2/SLC7A11 axis. Loss of PRIM2 induced ferroptosis might developed to be a novel therapeutic method in lung cancer therapy.Keywords: dihydroartemisinin, lung cancer, proliferation, ferroptosis, PRIM2, SLC7A11

Background: Allergic diseases in offspring are suggested to originate from fetal life. The role of in-utero stress exposures in early childhood allergic diseases development has not been completely elucidated. We aimed to determine the effect of exposures to different kinds of maternal stressed-affective factors during pregnancy on the risk of childhood allergy during first 2 years of life. Methods: A sample of 4178 children born in 2016-2018 from the Shanghai Maternal-Child Pairs Cohort were included in this study. Indicators for maternal stressed-affective factors included life events stress at early and late pregnancy, respectively, and prenatal depression and anxiety at late pregnancy, which were measured by the Life Events Scale for Pregnant Women (LESPW), Self-Rating Anxiety Scale (SAS) and Center for Epidemiologic Studies, Depression Scale (CES-D). The children’s allergic diseases or manifestations were assessed through the questionnaires at 2,6,12,24 months after birth, respectively, including eczema, atopic dermatitis, food allergy, wheezing, asthma, and allergic rhinitis. The impacts of maternal stressed-affective factors on child allergic diseases were analyzed using multivariable binary logistic regression adjusting for potential covariates. Results: During the first 2 years of life, all forms of allergic disease were continuously reported, with allergic diseases of skin preceded the development of other atopic diseases. Children whose mothers had high life events stress during the early pregnancy or the late pregnancy would have an increased risk of eczema at 2 months respectively (AdjOR:1.30, 95%CI:1.01-1.67; AdjOR:1.64, 95%CI:1.14-2.36). Children whose mothers with high life events stress in late pregnancy were also more likely to have food allergy at 6 months (AdjOR:3.22, 95%CI:1.27-8.12). Maternal prenatal anxiety may lead to offspring’s childhood wheeze at 24 months (AdjOR:2.15, 95%CI:1.09-4.27). Conclusions: Maternal stressed-affective factors could have effects on offspring’s allergic diseases, especially eczema at 2 months. Understanding the temporal-specific effects of maternal stressed-affective factors may better inform prevention strategies.

This study was designed to examine the impact of prenatal fine particulate matter (PM2.5) exposure on fetal growth and the underlying placental epigenetic mechanism in a cohort of Chinese women. Within the prospective Shanghai Mother-Child Pairs cohort (Shanghai MCPC), 329 women carrying singleton pregnancy with a due date in 2018 were recruited between 2017 and 2018. Maternal PM2.5 exposure levels were estimated using gestational exposure prediction model combining satellite-driven ambient concentrations and personal air sampling. Fetal growth characteristics were evaluated by prenatal ultrasound examinations and anthropometric measurements at birth. In a discovery phase, whole-genome DNA methylation analysis was performed using the Infinium 850 K array. In a validation phase, placental DNA methylation was measured using bisulfite pyrosequencing for five candidate genes that showed the most significant alterations and function relevance in our methylation array screen, including BID (BH3 interacting domain death agonist), FOXN3 (Forkhead box N3), FOXP1 (Forkhead box P1), IGF2 (Insulin-like growth factor 2) and HSD11B2 (Hydroxysteroid 11-beta dehydrogenase 2). Multivariate linear regression models were applied to examine the associations among PM2.5 exposure, fetal growth characteristics and DNA methylation on placental candidate genes. Sobel tests were used to evaluate the mediating role of DNA methylation in multivariable models. After excluding women who withdrew or failed to provide placenta, a total of 287 pregnant women with an average age of 30 entered the final analysis. Increased PM2.5 exposure was significantly associated with reduced biparietal diameter (BPD) (β: −0.136 mm, 95% CI: −0.228 to −0.043), head circumference (HC) (β: −0.462 mm, 95% CI: −0.782 to −0.142), femur length (FL) (β: −0.113 mm, 95% CI: −0.185 to −0.041) and abdominal circumference (AC) (β: −0.371 mm, 95% CI: −0.672 to −0.071) in the second trimester and birth length (β: −0.013 cm, 95% CI: −0.025 to −0.001). Prenatal PM2.5 exposure could lead to aberrant changes in DNA methylation profile of placenta genome, which were mainly enriched in reproductive development, energy metabolism and immune response. DNA methylation of IGF2 and BID showed significant associations with PM2.5 exposures during all exposure windows. In addition, BID methylation was negatively correlated with HC (β: −1.396 mm, 95% CI: −2.582 to −0.209) and BPD (β: −0.330 mm, 95% CI: −0.635 to −0.026) in the second trimester. Further mediation analysis indicated that BID methylation mediated about 30% of the effects of PM2.5 exposure on HC. These findings collectively suggested that prenatal PM2.5 exposure may cause adverse effects on fetal growth by modifying placental DNA methylation.

Vilaprisan is a novel selective progesterone receptor modulator for the long‐term treatment of uterine fibroids and endometriosis. This study investigated the pharmacokinetics, safety, and tolerability of vilaprisan in healthy Chinese postmenopausal women. Twelve participants received multiple doses of vilaprisan once daily over 14 days as a 2‐mg tablet. Plasma vilaprisan concentrations were determined using liquid chromatography–tandem mass spectrometry. The main pharmacokinetic parameters of vilaprisan were assessed with noncompartmental analysis, including maximum observed concentration (Cmax), systemic exposure (area under the plasma concentration–time curve), time to reach Cmax and terminal half‐life. Safety assessments include the documentation of adverse events, measurement of clinical/anthropometric parameters and vital signs, electrocardiogram, and physical and gynecologic examination. The participants had a mean age of 53.3 (± 4.2) years and a body mass index of 23.8 ± 2.8 kg/m2. Median time to reach Cmax was 1.5 hours after both single and multiple vilaprisan administration. Mean Cmax values obtained after multiple dosing (23.3 μg/L [standard deviation (SD) = 6.73]) were 1.92‐fold (SD = 0.554) higher compared to single dosing (12.5 μg/L [SD = 3.04]). Mean area under the plasma concentration–time curve in the dosing interval increased with an accumulation factor of 2.98 (SD = 0.767) between single (91.3 μg · h/L [SD = 20.4]) and multiple dosing (276 μg · h/L [SD = 109]). The mean terminal half‐life of vilaprisan was 44.5 hours (SD = 10.3) after multiple dosing. Mild to moderate adverse events were observed similar to previous studies. Overall, daily oral administration of the therapeutic dose of 2 mg of vilaprisan over 14 days was safe and well tolerated by all participants.

Background: UV filters, widely used in personal care and industrial products, are being found in the environment and, in humans where with limited understanding on their potential health effects, especially during puberty. Objectives: To examine the association between UV filter exposure and pubertal development in a prospective follow-up study. Methods: This study included 521 elementary and high school students from a suburban area of Shanghai. The initial study was done in October to November 2011; the follow-up study in April to May 2013. Twelve urinary organic UV filters were quantified, and the pubertal development was assessed at each study period by trained physicians using Tanner staging. We used (ordered) logistic regression model and multilevel mixed-effect (ordered) logistic regression model to assess cross-sectional and longitudinal effects between urinary concentration of five major UV filters and pubertal development of stages, onset and pace. Results: Ethylhexyl methoxycinnamate (EHMC) and its metabolite 4′-methoxyacetophenone (4′-MAP), two benzophenone derivatives (BP-2, BP-3) and Ethylhexyl dimethyl PABA (OD-PABA) were the most extensively detected UV filters in urine with geometric means (95% CI) in 2010 and 2012 as 1.77 (1.599, 1.956) and 2.28 (1.985, 2.622) ng/mL for EHMC; 4.55 (4.219, 4.907) and 5.26 (4.783, 5.775) ng/mL for 4′-MAP; 4.38 (4.011, 4.774) and 5.74 (5.023, 6.562) ng/mL for BP-2; 0.83 (0.760, 0.903) and 1.09 (0.967, 1.220) ng/mL for BP-3; 5.37 (4.949, 5.820) and 5.80 (5.193, 6.486) pg/mL for OD-PABA. Significant trend P-values (P

Recently, several miRNAs have been revealed to play critical roles in oncogenesis and tumor progression of many cancers. Thioredoxin-1 (Trx-1) binding protein-2 (TBP-2) is an internal inhibitor of Trx-1, which plays the role in regulating oxidative stress, inhibiting cell growth, and promoting apoptosis. The expression of TBP-2 is usually decreased in cancer tissues. However, whether the miRNAs regulate the TBP-2 expression in lung cancer is still unclear. In this study, we examined the levels of TBP-2, miR-93, miR-373, and miR-17-5p in lung cancer tissues and their adjacent normal lung tissues of 36 patients. We found that the expressions of miR-93, miR-373, and miR-17-5p were higher, whereas the expression of TBP-2 mRNA and protein was significantly lower in lung cancer tissues compared with adjacent normal lung tissues. After the three miRNA mimics were transfected in the lung cancer cells, NCI-H460, the level of TBP-2 mRNA and TBP-2 protein was decreased. Then, the anti-cancer drug 5-fluorouracil was used to stimulate the NCI-H460 cells; the mRNA levels of miR-93, miR-373, and miR-17-5p were decreased, and the level of TBP-2 mRNA and protein was increased. Collectively, the above results suggest that miR-93, miR-373, and miR-17-5p negatively regulate the TBP-2 expression in lung cancer. This study may provide therapeutic targets with lung cancer.

Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor family, attract wide attention as promising therapeutic targets for the treatment of multiple diseases, and their target selective ligands were also intensively developed for pharmacological agents such as the approved drugs fibrates and thiazolidinediones (TZDs). Despite their potent pharmacological activities, PPARs are reported to be involved in agent- and pollutant-induced multiple organ toxicity or protective effects against toxicity. A better understanding of the protective and the detrimental role of PPARs will help to preserve efficacy of the PPAR modulators but diminish adverse effects. The present review summarizes and critiques current findings related to PPAR-mediated types of toxicity and protective effects against toxicity for a systematic understanding of PPARs in toxicology and applied pharmacology.

In China, data relating to the historic prevalence of childhood lead poisoning suggest its pervasiveness. This review analysed published epidemiological data on blood lead levels (BLLs) of 735,271 Chinese children aged 0–6 between 1987 and 2017. Among these children, the geometric mean (GM) BLL was 95.1 μg/L (geometric SD = 1.62), and 24.1% suffered lead poisoning (BLL ≥ 100 μg/L). Importantly, there was a temporal decrease in the GM BLL value, from 182.9 μg/L in 1987–1991 to 42.4 μg/L in 2012–2017. However, a rebound was seen in the most recent two years (2016 and 2017). Moreover, the GM BLL among Chinese children has not fallen as low as U.S. children. This indicates that either (1) leaded petrol or lead based-paint exposure sources have not been adequately controlled in China, or (2) other pollution sources, such as industry, traffic, and e-waste, are impacting Chinese children. Drivers behind spatio-temporal variations were explored to provide scientific evidence regarding the prevention of childhood lead poisoning. We found that BLLs among children in the central and eastern areas of China have dropped lower than those in the western area, and that the GM BLL of children living in rural areas now exceeds children in urban areas. These reversals may be associated with the industrial decentralization policy of the late 1980s, when many heavily polluting industries and manufacturers moved away from cities on the east coast. It was discovered that the BLLs of children living in areas associated with mining have remained high (GM BLL = 155.0 μg/L for 2007–2017), and that the lead poisoning rate (LPR) has become exceptionally high in areas associated with e–waste. Finally, the review offers a data comparison with other countries, an overview of potentially influencing factors and sources, as well as some suggested prevention strategies to reduce childhood lead exposure. Keywords: Blood lead levels, Childhood lead exposure, Lead poisoning, Pb, E-waste

Humans are exposed to polybrominated diphenyl ethers (PBDEs) via ingestion of food, dust inhalation, and dermal absorption. Exposure to PBDEs via the placenta and breast milk is a special and important pathway in infants. This nested case-control study aimed to investigate the levels of PBDEs in maternal serum and colostrum, and to assess the association between the occurrence of fetal growth restriction (FGR) and prenatal exposure to PBDEs. We recruited 293 mother-newborn pairs, including 98 FGR cases and 195 healthy controls in Wenzhou, China. Maternal serum and colostrum samples were collected during pregnancy and after delivery, respectively, and the levels of PBDEs were measured by gas chromatography-tandem mass spectrometry. The total levels of PBDEs in maternal serum and colostrum were found to be in equilibrium, but congener profiles of PBDEs in these matrices were different. Increased BDE-207, BDE-209, ∑BDE196-209 and ∑PBDEs levels in maternal serum and BDE-99, ∑BDE17-154 and ∑PBDEs levels in colostrum were correlated with decreased birth weight Z score. Increased concentrations of higher brominated BDEs in maternal serum (odds ratio (OR) = 1.010, 95%CI = 1.003–1.018) and low-to moderately brominated BDEs in colostrum (OR = 1.004, 95%CI = 1.000–1.009) were associated with increased risk of FGR, which showed an exposure–response relationship. In addition, infants with FGR were more exposed to PBDEs in colostrum after birth than healthy infants. Longitudinal birth cohort studies are needed to determine the prolonged effect of PBDEs exposure on the growth of FGR infants in the future.

The high-density polyethylene (HDPE) double-wall corrugated pipe, which is a kind of flexible pipe, is widely used in municipal drainage networks. The characteristics of the surrounding soil and pipe bed, pipe cover depth, backfill compaction, type of pavement and pavement design, and traffic loads are some of the major factors that affect the stress and deformation of pipes. In this study, the ABAQUS 3D finite element model was used to analyze the influence of backfill compactness, traffic loads, diameter, and hoop stiffness on the mechanical characteristic of an HDPE pipe under traffic loads. A series of full-scale tests were carried out to verify the validity of the simulation results. For the conditions tested, the results showed the following: (1) the Von-Mises stress of the pipe was mainly determined by the earth pressure at the crown, and the stress caused by backfill compaction increased significantly but had a short duration and limited impact on the pipe, (2) traffic load alone had little influence on the mechanical behavior of the pipe: while under the action of the loose backfill in contact with the pipe, the pipes were more sensitive to the traffic load response, (3) the fluctuations in the Von-Mises stress of the pipe mainly depended on the magnitude and speed of the traffic load, (4) for pipes with a small diameter, non-compacted backfill easily caused stress concentration in the pipe, while the degree of backfill compaction had almost the same effect on the distribution of stress for pipes with different hoop stiffness.

Human exposure to lead (Pb) is a growing global public health concern. Elevated blood lead is thought to cause the mental retardation of >0.6 million children globally each year, and has recently been attributed to ~18% of all-cause mortality in the US. Due to the severe health risk, the international community, led by the United Nations Environment Programme (UNEP) and the World Health Organization (WHO), is actively supporting the global phase-out of lead-based paint by 2020. However, there are many significant hurdles on the way to achieving this goal. In light of the importance of the lead-based paint issue, and the urgency of achieving the 2020 phase-out goal, this review provides critical insights from the existing scientific literature on lead-based paint, and offers a comprehensive perspective on the overall issue. The global production and international trade of lead-based paints across Asia, Africa, Latin America, and Europe are critically discussed – revealing that lead-based paints are still widely used in many low and middle-income developing countries, and that the production and trade of lead-based paint is still wide-spread globally. In India, as well as many south-east Asian, African, Latin American and European countries, lead concentrations in paints often exceed 10,000 mg/kg. This will certainly pose a serious global threat to public health from surfaces painted with these products for many decades to come. The sources and pathways of exposure are further described to shed light on the associated health risk and socioeconomic costs. Finally, the review offers an overview of the potential intervention and abatement strategies for lead-based paints. In particular, it was found that there is a general lack of consensus on the definition of lead based paint; and, strengthening regulatory oversight, public awareness, and industry acceptance are vital in combating the global issue of lead based paint. Keywords: Lead-based paint, Lead exposure, Blood lead level, Soil contamination

Objective: Metabolomics may unravel global metabolic changes in response to environmental exposures and identify important biological pathways involved in the pathophysiology of childhood obesity. Phthalate has been considered an obesogen and contributing to overweight and obesity in children. The purpose of this study is to evaluate changes in urine metabolites in response to the environmental phthalate exposure among overweight or obese children, and to investigate the metabolic mechanisms involved in the obesogenic effect of phthalate on children at puberty. Methods: Within the national Puberty Timing and Health Effects in Chinese Children (PTHEC) study, 69 overweight/obese children and 80 normal weight children were selected into the current study according to their puberty timing and WGOC (The Working Group for obesity in China) references. Urinary concentrations of six phthalate monoesters (MMP, MEP, MnBP, MEHP, MEOHP and MEHHP) were measured using API 2000 electrospray triple quadrupole mass spectrometer (ESIMS/MS). Metabolomic profiling of spot urine was performed using gas chromatography-mass spectrometry. Differentially expressed urinary metabolites associated with phthalate monoesters exposure were examined using orthogonal partial least square-discriminant analysis and multiple linear regression models. In addition, the candidate metabolites were regressed to obesity indices with multiple linear regression models and logistic regression models in all subjects. Results: Compared with normal weight children, higher levels of MnBP were detected in urinary samples of children with overweight and obesity. After adjusting for confounders including chronological age, gender, puberty onset, daily energy intake and physical activity and socio-economic level, positive association remained between urinary MnBP concentration and childhood overweight/obesity [OR = 1.586, 95% CI:1.043,2.412]. We observed elevated MnBP concentration was significantly correlated with increased levels of monostearin, 1-monopalmitin, stearic acid, itaconic acid, glycerol 3-phosphate, 5-methoxytryptamine, kyotorphin, 1-methylhydantoin, d-alanyl-d-alanine, pyrrole-2-carboxylic acid, 3,4-Dihydroxyphenylglycol, and butyraldehyde. Meanwhile, increased MnBP concentration was also significantly correlated with decreased levels of lactate, glucose 6-phosphate, d-fructose 6-phosphate, palmitic acid, 4-acetamidobutyric acid, l-glutamic acid, n-acetyl-l-phenylalanine, iminodiacetic acid, hydroxyproline, pipecolinic acid, l-ornithine, n-acetyl-l-glutamic acid, guanosine, cytosin, and (s)-mandelic acid in the normal weight subjects. The observations indicated that MnBP exposure was related to global urine metabolic abnormalities characterized by disrupting arginine and proline metabolism and increasing oxidative stress and fatty acid reesterification. Among the metabolic markers related to MnBP exposure, 1-methylhydantoin, pyrrole-2-carboxylic acid and monostearin were found to be positively correlated with obesity indices, while hydroxyproline, l-ornithine, and lactate were negatively associated with overweight/obesity in children. Conclusions: Our results suggested that the disrupted arginine and proline metabolism associated with phthalate exposure might contribute to the development of overweight and obesity in school-age children, providing insights into the pathophysiological changes and molecular mechanisms involved in childhood obesity. Keywords: Phthalate, Childhood overweight/obesity, Metabolic profiles, Arginine and proline metabolism

Outbreaks of avian influenza virus continue to pose threats to human health. Animal models such as the mouse, ferret, and macaque are used to understand the pathogenesis of avian influenza virus infection in humans. We previously reported that the tree shrew (Tupaia belangeri, family Tupaiidae), which is regarded as a “low-level primate”, has α2,3- and α2,6-linked sialic acid receptor distributions similar to those of humans and is potentially a useful mammalian model for studying mild human influenza (H1N1) virus infection. In this study, we used the tree shrew experimental model to investigate the pathogenesis of avian influenza A (H9N2) virus infection and the effect of the E627K mutation in the PB2 gene, an adaptation to mammalian hosts. Evidence of disease, virus titers in the upper and lower respiratory tract, histopathology and induction of proinflammatory cytokines are described. We also established ex vivo culture models of tree shrew respiratory tissues to study the tropism and replication of the H9N2 virus. Our results demonstrated that the tree shrew is a viable new in vivo experimental model for avian influenza research that provides results comparable to those observed in ferrets. The disease spectrum and pathogenesis in tree shrews correlate well with what is observed in humans.

Previous studies have linked prenatal polybrominated diphenyl ether (PBDE) exposure to adverse birth outcomes. Reductions in placental size might mediate those adverse effects. We examined whether umbilical cord blood PBDEs concentrations were associated with placental size at birth. A total of 121 mother-newborn pairs residing in Wenzhou were enrolled in this study. Concentrations of 19 PBDEs in umbilical cord blood were determined by gas chromatography tandem mass spectrometry (GC-MS). Placental length, breadth and surface area was measured by medical professionals after delivery. BDE-206, 207, 208, 209 and the total of 19 PBDE congeners concentrations were negatively associated with placental length, breadth and surface area. Our results suggest that prenatal PBDEs exposure may suppress placental growth, resulting in reduced placental size.

Intrauterine modifiable maternal metabolic factors are essential to the early growth of offspring. The study sought to evaluate the associations of pre-pregnancy BMI and third-trimester fasting plasma glucose (FPG) with offspring growth outcomes within 24 months among GDM-negative pregnant women. Four hundred eighty-three mother –offspring dyads were included from the Shanghai Maternal-Child Pairs Cohort. The pregnant women were categorized into four mutually exclusive groups according to pre-pregnancy BMI as normal or overweight/obesity and third-trimester FPG as controlled or not controlled. Offspring growth in early life was indicated by the BAZ (BMI Z-score), catch-up growth, and overweight/obesity. Among those with controlled third-trimester FPG, pre-pregnancy overweight/obesity significantly increased offspring birth weight, BAZ, and risks of overweight/obesity (RR 1.83, 95% CI 1.23 to 2.73) within 24 months. Those who had uncontrolled third-trimester FPG had a reduced risk of offspring overweight/obesity within 24 months by 47%. The combination of pre-pregnancy overweight/obesity and maternal uncontrolled third-trimester FPG increased 5.24-fold risk of offspring catch-up growth within 24 months (p &lt, 0.05). Maternal pre-pregnancy overweight/obesity and uncontrolled third-trimester glycemia among GDM-negative women both have adverse effects on offspring growth within 24 months. With the combination of increasing pre-pregnancy BMI and maternal third-trimester FPG, the possibility of offspring catch-up growth increases.

Gestational diabetes mellitus (GDM) has become a new global epidemic with a rapidly increasing prevalence. Previous studies have suggested that air pollution is associated with GDM risk, but the results are inconsistent, and mechanistic studies are limited. Based on a hospital-based cohort, a total of 6374 participants were included in this study. Individual daily PM2.5 exposure at a 1-km resolution was predicted using a full-spatiotemporal-coverage model. The results of multiple linear regression showed that glycated hemoglobin (HbA1c) was significantly associated with PM2.5 both in the 1-month preconception and in the first trimester of pregnancy. Additionally, HbA1c decreased 0.437% (95% CI: − 0.629, − 0.244) as the serum 25-hydroxyvitamin D (25(OH)D) increased by one interquartile range (IQR) (9.2 ng/ml). An IQR increase in PM2.5 exposure was also negatively associated with serum 25(OH)D (estimated change% and 95% CI: − 7.249 (− 9.054, − 5.408) in the 1-month preconception and − 13.069 (− 15.111, − 10.979) in the first trimester of pregnancy). Mediation analysis showed that serum 25(OH)D status mediated the association between HbA1c and PM2.5 exposure both in the preconception and in the first trimester (mediated percent: 2.00% and 4.05% (Sobel p ＜ 0.001), respectively). The result suggested a vicious cycle among PM2.5 exposure, lower serum VD status and a higher HbA1c. More studies are warranted since the protective effect of 25(OH)D against glucose disorders associated with air pollution in this study was limited.

Triptolide (TP), a primary bioactive ingredient isolated from the traditional Chinese herbal medicine Tripterygium wilfordii Hook. F. (TWHF), has attracted great interest for its therapeutic biological activities in inflammation and autoimmune disease. However, its clinical use is limited by severe testicular toxicity, and the underlying mechanism has not been elucidated. Our preliminary evidence demonstrated that TP disrupted glucose metabolism and caused testicular toxicity. During spermatogenesis, Sertoli cells (SCs) provide lactate as an energy source to germ cells by glycolysis. The transcription factors GATA-binding protein 4 (GATA4) and specificity protein 1 (Sp1) can regulate glycolysis. Based on this evidence, we speculate that TP causes abnormal glycolysis in SCs by influencing the expression of the transcription factors GATA4 and Sp1. The mechanism of TP-induced testicular toxicity was investigated in vitro and in vivo. The data indicated that TP decreased glucose consumption, lactate production, and the mRNA levels of glycolysis-related transporters and enzymes. TP also downregulated the protein expression of the transcription factors GATA4 and Sp1, as well as the glycolytic enzyme phosphofructokinase platelet (PFKP). Phosphorylated GATA4 and nuclear GATA4 protein levels were reduced in a dose- and time-dependent manner after TP incubation. Similar effects were observed in shGata4-treated TM4 cells and BALB/c mice administered 0.4 mg/kg TP for 28 days, and glycolysis was also inhibited. Gata4 knockdown downregulated Sp1 and PFKP expression. Furthermore, the Sp1 inhibitor plicamycin inhibited PFKP protein levels in TM4 cells. In conclusion, TP inhibited GATA4-mediated glycolysis by suppressing Sp1-dependent PFKP expression in SCs and caused testicular toxicity.

The aim of the study was to determine whether applying an assistance force to the pelvis and legs during treadmill training can improve walking function in children with cerebral palsy.Twenty-three children with cerebral palsy were randomly assigned to the robotic or treadmill only group. For participants who were assigned to the robotic group, a controlled force was applied to the pelvis and legs during treadmill walking. For participants who were assigned to the treadmill only group, manual assistance was provided as needed. Each participant trained 3 times/wk for 6 wks. Outcome measures included walking speed, 6-min walking distance, and clinical assessment of motor function, which were evaluated before, after training, and 8 wks after the end of training, and were compared between two groups.Significant increases in walking speed and 6-min walking distance were observed after robotic training (P = 0.03), but no significant change was observed after treadmill training only. A greater increase in 6-min walking distance was observed after robotic training than that after treadmill only training (P = 0.01).Applying a controlled force to the pelvis and legs, for facilitating weight-shift and leg swing, respectively, during treadmill training may improve walking speed and endurance in children with cerebral palsy.Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) discuss the importance of physical activity at the participation level (sports programs) for children with cerebral palsy; (2) contrast the changes in walking ability and endurance for children in GMFCS level I, II and III following sports programs; and (3) identify the impact of higher frequency of sports program attendance over time on walking ability.Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.