Effects of multiple metals exposure on abnormal liver function: The mediating role of low-density lipoprotein cholesterol.

Equilibration of metal metabolism is critical for normal liver function. Most epidemiological studies have only concentrated on the influence of limited metals. However, the single and synergistic impact of multiple-metal exposures on abnormal liver function (ALF) are still unknown. A cross-sectional study involving 1493 Chinese adults residing in Shenzhen was conducted. Plasma concentrations of 13 metals, including essential metals (calcium, copper, cobalt, iron, magnesium, manganese, molybdenum, zinc, and selenium) and toxic metals (aluminum, cadmium, arsenic, and thallium) were detected by the inductively coupled plasma spectrometry (ICP-MS). ALF was ascertained as any observed abnormality from albumin, alanine transaminase, aspartate transaminase, γ-glutamyl transpeptidase, and direct bilirubin. Diverse statistical methods were used to evaluate the single and mixture effect of metals, as well as the dose-response relationships with ALF risk, respectively. Mediation analysis was conducted to evaluate the role of blood lipids in the relation of metal exposure with ALF. The average age of subjects was 59.7 years, and 56.7 % were females. Logistic regression and the least absolute shrinkage and selection operator (LASSO) penalized regression model consistently suggested that increased levels of arsenic, aluminum, manganese, and cadmium were related to elevated risk of ALF; while magnesium and zinc showed protective effects on ALF (all p-trend < 0.05). The grouped weighted quantile sum (GWQS) regression revealed that the WQS index of essential metals and toxic metals showed significantly negative or positive relationship with ALF, respectively. Aluminum, arsenic, cadmium, and manganese showed linear whilst magnesium and zinc showed non-linear dose-response relationships with ALF risk. Mediation analysis showed that LDL-c mediated 4.41 % and 14.74 % of the relationship of plasma cadmium and manganese with ALF, respectively. In summary, plasma aluminum, arsenic, manganese, cadmium, magnesium, and zinc related with ALF, and LDL-c might underlie the pathogenesis of ALF associated with cadmium and manganese exposure. This study may provide critical public health significances in liver injury prevention and scientific evidence for the establishment of environmental standard.

[Improving effect of selenium on spermatogenesis in mice with cyclophosphamide-induced spermatogenic impairment and its underlying mechanism].

OBJECTIVE: To investigate the effect of selenium on cyclophosphamide (CTX)-induced spermatogenic impairment (SI) in mice and its underlying mechanism. METHODS: We equally randomized 36 male KM mice into 3 SI model and 3 control groups, the first 3 treated by intraperitoneal injection of CTX at 100 mg/kg (the SI model control group), CTX plus SI model control group, selenium deficient model group (－Se SI), selenium supplemented model group (+Se SI), while latter 3 by intraperitoneal injection of normal saline (the normal control), selenium deficiency control group (－Se control), selenium addition control group (+Se control), respectively, all once a week for 6 successive weeks. Then we observed the histopathological changes in the testes of all the mice by HE staining, obtained the sperm count in the epididymides, determined the expressions of glutathione peroxidase 4 (GPx4) and SLC7A11 proteins by Western blot and ferroptosis-related genes by RT-qPCR, and examined the changes in the expressions of ferroptosis-related proteins and genes in the GC2-spd cells treated with ferroptosis inhibitors and inducers in combination with different concentrations of inorganic sodium selenite (SeS) and organic selenomethionine (SeM). RESULTS: Compared with the normal controls, the SI model mice showed significantly decreased testicular and prostatic organ coefficients, reduced spermatogenic layers, increased voids, decreased serum ferritin concentration (P<0.05), and elevated transferrin concentration (P<0.05). The organ coefficients were significantly higher in the +Se SI and +Se control than in the －Se SI and －Se control groups (P<0.05, P<0.01), with evident pathological improvement of the testis tissue in the +Se controls. The expressions of the GPx4 and solute carrier family 7 members 11（SLC7A11） genes in the testis were dramatically down-regulated in the SI model controls (P<0.01), but up-regulated in the +Se SI and +Se control compared with those in the －Se SI and －Se control group (P<0.01 and P<0.05), but there were no statistically significant differences between their protein expressions. The results of in vitro GC2 spd cell experiments indicated that the GPx4 gene and GPx4 protein levels in the - Se group were significantly lower than those in the normal control group (P<0.05), while the SLC7A11 gene level decreased (P<0.01). Different doses of SeS and SeM significantly increased the GPx4 protein expression compared to the average Se group. Low doses of SeM promoted a significant increase in GPx4 gene levels, while high doses of SeS increased the expression levels of SLC7A11 gene and SLC7A11 protein (P<0.05, P<0.01). The Se group showed a significant decrease in the levels of acsl4 and ptgs2 genes compared to the normal control group. SeM promoted the expression of acsl4, while SeS promoted the expression of ptgs2 and fth1 (P<0.01, P<0.05). The intervention results of GC2 spd showed that the Erastin group had a decrease in ptgs2 compared to the normal control group, while the SeS+Erastin and SeM+Erastin groups had an increase in ptgs2 gene expression compared to the Erastin group. However, the ptgs2 expression of Fer-1 was lower than that of the normal control group, and the ptgs2 gene level of SeS+Fer-1 and SeM+Fer-1 groups was lower than that of Fer-1 group (P<0.05); The gene quantity of GPx4 in the SeM+Erastin and SeM+Fer-1 groups increased compared to the Erastin and Fer-1 groups (P<0.01, P<0.05); SeM+Erastin and SeS+Erastin showed a decrease in SLC7A11 compared to the Erastin group, as well as SeM+Fer-1 and SeS+Fer-1 groups compared to the Fer-1 group, accompanied by an increase in acsl4 and fth1 (P<0.01). CONCLUSION: Selenium deficiency causes the reduction of the SLC7A11 and GPx4 gene levels, disorder of ferroptosis-related genes and down-regulation of the GPx4 protein expression in the mouse testis and spermatocytes. Selenium can promote the expression of GPx4, up-regulate the level of SLC7A11, and improve spermatogenesis in the testis of the mouse with SI. There are differences between organic SeM and inorganic SeS in regulating the ferroptosis pathway-related genes.

Association between thermal stress and cardiovascular mortality in the subtropics.

Hazardous thermal conditions resulting from climate change may play a role in cardiovascular disease development. We chose the Universal Thermal Climate Index (UTCI) as the exposure metric to evaluate the relationship between thermal conditions and cardiovascular mortality in Shenzhen, China. We applied quasi-Poisson regression non-linear distributed lag models to evaluate the exposure-response associations. The findings suggest that cardiovascular mortality risks were significantly increased under heat and cold stress, and the adverse effects of cold stress were stronger than heat stress. Referencing the 50th percentile of UTCI (25.4°C), the cumulative risk of cardiovascular mortality was 75% (RRlag0-21 =1.75, 95%CI: 1.32, 2.32) higher in the 1st percentile (3.5°C), and 40% (RRlag0-21=1.40, 95%CI: 1.09, 1.80) higher in the 99th percentile (34.1°C). We observed that individuals older than 65 years were more vulnerable to both cold and heat stress, and females were identified as more susceptible to heat stress than males. Moreover, increased mortality risks of hypertensive disease and cerebrovascular disease were observed under cold stress, while heat stress was related to higher risks of mortality for hypertensive disease and ischemic heart disease. We also observed a stronger relationship between cold stress and ischemic heart disease mortality during the cold season, as well as a significant impact of heat stress on cerebrovascular disease mortality in the warm season when compared to the analysis of the entire year. These results confirm the significant relationship between thermal stress and cardiovascular mortality, with age and sex as potential effect modifiers of this association. Providing affordable air conditioning equipment, increasing the amount of vegetation, and establishing comprehensive early warning systems that take human thermoregulation into account could all help to safeguard the well-being of the public, particularly vulnerable populations, in the event of future extreme weather.

Obesity-related genetic polymorphisms are associated with the risk of early puberty in Han Chinese girls.

OBJECTIVE: To explore the association between obesity and precocious puberty from the perspective of genetic polymorphism. DESIGN: Two hundred and ninety-eight pairs of girls in early puberty and age-matched controls (±3 months) were recruited. The genotypes of four obesity-related single-nucleotide polymorphism (SNP) loci (rs10968576, rs12935153, rs4674340 and rs7635103) were determined and the effect of variation on early puberty in Chinese Han girls was evaluated. The unstimulated luteinizing hormone (LH), follicle-stimulating hormone and estradiol levels were also measured to determine the relationship with SNP polymorphisms. RESULTS: The effect allele A of rs12935153 was associated with early puberty (odds ratio [OR] = 1.256, 95% confidence interval [CI]: 1.010-1.585), but the significance disappeared after multiple comparisons. After adjusting for body mass index, rs12935153 variation increased the risk of early puberty in additive (OR = 1.589, 95% CI: 1.222-2.066), dominant (OR = 1.788, 95% CI: 1.210-2.642) and recessive (OR = 1.915, 95% CI: 1.207-3.038) models of inheritance. Individuals harbouring AA genotype in rs12935153 had a risk of higher LH levels than that of wild type (OR = 1.668, 95% CI: 1.093-2.546). CONCLUSIONS: The association between obesity and precocity can be explained from a genetic perspective. Our study suggests that variations in rs12935153 increase the risk of early puberty in Chinese girls. Further studies are needed to verify our findings.

The effects of selenium on GPX4-mediated lipid peroxidation and apoptosis in germ cells.

Emerging evidence suggests that selenium plays an essential role in sperm maturation. However, the specific signaling pathway by which selenium exerts effect has not been elucidated. To evaluate the effect of selenium on GPX4-mediated lipid peroxidation and apoptosis in germ cells, selenium deficiency was modeled by culturing GC2-spd cells in serum-free medium. Treatment with 0.5-µM sodium selenite (NaSe) or 5.0-µM selenomethionine (SeMet) significantly improved the proliferation rate and GPX4 protein expression after selenium deficiency. Moreover, NaSe and SeMet decreased the MDA content and lipid peroxidation. When adenovirus was used to knockdown the expression of the GPX4 gene (shRNA-GPX4), the early apoptosis rate of the shRNA-GPX4 cells was significantly higher than that of the EGFP cells. Increased expression of Caspase3 and Bax, as well as MDA content were observed in the shRNA-GPX4 cells compared with EGFP cells. In further, overexpression of the GPX4 gene (ORF-GPX4) cells exhibited increased cell proliferation and decreased MDA content. However, there was no significant difference in 12/15-lox expression both in ORF-GPX4 cells and shRNA-GPX4 cells. Conclusively, GPX4 was involved in the regulation of lipid peroxidation and apoptosis in GC2-spd cells. Selenium played a role in promoting cell proliferation by mediating GPX4. The regulation of GPX4 may occur independently of 12/15-Lox. These findings confirmed the effect of selenium on spermatogenesis and offered a potential target for treating abnormal semen quality in men.

Associations of multiple plasma metals with the risk of metabolic syndrome: A cross-sectional study in the mid-aged and older population of China.

BACKGROUND: Metal exposures have been reported to be related to the progress of metabolic syndrome (MetS), however, the currents results were still controversial, and the evidence about the effect of multi-metal exposure on MetS were limited. In this study, we intended to evaluate the relationships between metal mixture exposure and the prevalence of MetS in a mid-aged and older population of China. METHODS: The plasma levels of 13 metals (aluminum, magnesium, calcium, iron, manganese, cobalt, copper, arsenic, zinc, selenium, cadmium, molybdenum and thallium) were detected by inductively coupled plasma mass spectrometry (ICP-MS) in 1277 adults recruited from the Eighth Affiliated Hospital of Sun Yat-Sen University (Shenzhen, China). Logistic regression, the adaptive least absolute shrinkage and selectionator operator (LASSO) penalized regression analysis and restricted cubic spline (RCS) analysis were used to explore the associations and dose-response relationships of plasma metals with MetS. To evaluate the cumulative effect of metals, the Bayesian Kernel Machine Regression (BKMR) model was applied. RESULTS: The concentrations of magnesium and molybdenum were lower in the MetS group (p < 0.05). In the single-metal model, the adjusted ORs (95%CI) in the highest quartiles were 0.44 (0.35, 0.76) for magnesium and 0.30 (0.17, 0.51) for molybdenum compared with the lowest quartile. The negative associations and dose-dependent relationships of magnesium and molybdenum with MetS were further validated by the stepwise model, adaptive LASSO penalized regression and RCS analysis. The BKMR models showed that the metal mixture were associated with decreased MetS when the chemical mixtures were≥ 25th percentile compared to their medians, and Mg, Mo were the major contributors to the combined effect. Moreover, concentrations of magnesium were significantly related to blood glucose, and molybdenum was related with BMI, blood glucose and blood pressure. CONCLUSIONS: Elevated levels of plasma magnesium and molybdenum were associated with decreased prevalence of MetS. Further investigations in larger perspective cohorts are needed to confirm our findings.

Modification effects of seasonal and temperature variation on the association between exposure to nitrogen dioxide and ischemic stroke onset in Shenzhen, China.

The independent associations of extreme temperature and ambient air pollutant with the admission to hospital and mortality of ischemic stroke have been widely investigated. However, knowledge about the modification effects of variation in season and temperature on the association between exposure to nitrogen dioxide (NO2) and ischemic stroke onset is still limited. This study purposed to explore the effect of NO2 on daily ischemic stroke onset modified by season and ambient temperature, and identify the potential population that susceptible to ischemic stroke onset connected with NO2 and ambient temperature. Data on daily ischemic stroke counts, weather conditions, and ambient air pollutant concentrations in Shenzhen were collected between January 1, 2008, and December 31, 2014. The seasonal effect on the NO2-associated onset was measured by a distributed-lag linear model. Furthermore, a generalized additive model that incorporated with stratification analyses was used to calculate the interactive effects between NO2 and ambient temperature. During the winter, the average percentage increase in daily ischemic stroke onset for each 10 µg/m3 increment in NO2 concentration on lagged 2 days was 3.05% (95% CI: 1.31-4.82%), while there was no statistically significant effect of NO2 during summer. And the low-temperature days ([Formula: see text] mean temperature), with a 2.23% increase in incidence (95% CI: 1.18-3.29%) for the same concentration increase in NO2, were significant higher than high temperature days ([Formula: see text] mean temperature). The modification effects of temperature on the study association were more pronounced in individuals aged 65 years or more and in males. The adverse health effects of NO2 on ischemic stroke are more pronounced during winter or low temperature periods. Elderly adults or males presented higher risks with these exposures.

Impact of HIV-1 CRF55_01B infection on the evolution of CD4 count and plasma HIV RNA load in men who have sex with men prior to antiretroviral therapy.

BACKGROUND: CRF55_01B is a newly identified HIV-1 circulating recombinant form originated from MSM in China. However, its impact on the disease progression and transmission risk has not been investigated. This study aimed to determine the impact of CRF55_01B infection on viral dynamics and immunological status so as to provide scientific evidence for further control and prevention effort on CRF55_01B. Linear mixed effect models were applied to evaluate CD4 cell count decline and viral load increase by subtype. RESULTS: Of the 3418 blood samples, 1446 (42.3%) were CRF07_BC, 1169 (34.2%) CRF01_AE, 467 (13.7%) CRF55_01B, 249 (7.3%) type B, and 87 (2.5%) other subtypes (CRF_08BC, CRF_01B, C). CRF55_01B had become the third predominant strain since 2012 in Shenzhen, China. CRF55_01B-infected MSM showed lower median of CD4 count than CRF07_BC-infected MSM (349.5 [IQR, 250.2-474.8] vs. 370.0 [IQR, 278.0-501.0], P < 0.05). CRF55_01B infection was associated with slower loss of CD4 count than CRF01_AE (13.6 vs. 23.3 [cells/µl]¹/²/year, P < 0.05)among MSM with initial CD4 count of 200-350 cells/µl. On the other hand, those infected with CRF55_01B showed higher median plasma HIV RNA load (5.4 [IQR, 5.0-5.9]) than both CRF01_AE (5.3 [IQR, 4.8-5.7], P < 0.05) and CRF07_BC (5.0 log10 [IQR, 4.5-5.5], P < 0.001) at the initiation of antiretroviral therapy. Furthermore, the annual increasing rate of viral load for CRF55_01B infection was significantly higher than that of CRF07_BC (2.0 vs. 0.7 log10 copies/ml/year, P < 0.01). CONCLUSIONS: The relatively lower CD4 count and faster increase of plasma HIV RNA load of CRF55_01B-infected MSM without antiretroviral therapy suggest that CRF55_01B may lead to longer asymptomatic phase and higher risk of HIV transmission. Strengthened surveillance, tailored prevention strategies and interventions, and in-depth research focusing on CRF55_01B are urgently needed to forestall potential epidemic.

Effect of ambient temperature on stroke onset: a time-series analysis between 2003 and 2014 in Shenzhen, China.

OBJECTIVE: Evidence on the relationship between ambient temperature and morbidity of different stroke subtypes in China is limited. This study aimed to assess the influence of ambient temperature on stroke risk in Shenzhen, China. METHODS: From 1 January 2003 to 31 December 2014, 114 552 stroke cases in Shenzhen were collected. A generalised additive model with quasi-Poisson regression combined with a distributed lag non-linear model was applied to evaluate the temperature effects on stroke subtypes. Furthermore, this study explored the variability of the effects across sex, age and education. RESULTS: The immediate heat effects on ischaemic stroke (IS) and the persistent effects of ambient temperature on intracerebral haemorrhage (ICH) were significant. Overall, the cold-related relative risks (RRs) of IS, ICH and subarachnoid haemorrhage (SAH) were 1.02 (0.97-1.07), 1.16 (1.04-1.30) and 1.12 (0.61-2.04), whereas the heat-related RRs were 1.00 (0.97-1.04), 0.80 (0.73-0.88) and 1.05 (0.63-1.78), respectively. For IS, a weakly beneficial cold effect was found among men while a detrimental heat effect among both men and women, the elderly and higher-educated population at lag0. However, regarding ICH, the temperature effects in men, the young and higher-educated population are stronger at lag0-4, lag0-7 as cold reveals threat and heat reveals protection. CONCLUSION: Responses of diverse stroke subtypes to ambient temperature varied. Effective measures should be taken to increase public awareness about the effects of ambient temperature on stroke attack and to educate the public about self-protection.

Inhibition of S-Adenosylhomocysteine Hydrolase Induces Endothelial Dysfunction via Epigenetic Regulation of p66shc-Mediated Oxidative Stress Pathway.

BACKGROUND: Elevated levels of S-adenosylhomocysteine (SAH), the precursor of homocysteine, are positively associated with the risk of cardiovascular disease and with the development and progression of atherosclerosis. However, the role of SAH in endothelial dysfunction is unclear. METHODS: Apolipoprotein E-deficient ( apoE-/-) mice received dietary supplementation with the SAH hydrolase (SAHH) inhibitor adenosine dialdehyde or were intravenously injected with a retrovirus expressing SAHH shRNA. These 2 approaches, along with the heterozygous SAHH gene knockout ( SAHH+/-) mouse model, were used to elevate plasma SAH levels and to examine the role of SAH in aortic endothelial dysfunction. The relationship between plasma SAH levels and endothelial dysfunction was also investigated in human patients with coronary artery disease and healthy control subjects. RESULTS: Plasma SAH levels were increased in SAHH+/- mice and in apoE-/- mice after dietary administration of adenosine dialdehyde or intravenous injection with SAHH shRNA. SAHH+/- mice or apoE-/- mice with SAHH inhibition showed impaired endothelium-dependent vascular relaxation and decreased nitric oxide bioavailability after treatment with acetylcholine; this was completely abolished by the administration of the endothelial nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester. Furthermore, SAHH inhibition induced production of reactive oxygen species and p66shc expression in the mouse aorta and human aortic endothelial cells. Antioxidants and p66shc siRNA prevented SAHH inhibition-induced generation of reactive oxygen species and attenuated the impaired endothelial vasomotor responses in high-SAH mice. Moreover, inhibition of SAHH induced hypomethylation in the p66shc gene promoter and inhibited expression of DNA methyltransferase 1. Overexpression of DNA methyltransferase 1, induced by transduction of an adenovirus, was sufficient to abrogate SAHH inhibition-induced upregulation of p66shc expression. Finally, plasma SAH levels were inversely associated with flow-mediated dilation and hypomethylation of the p66shc gene promoter and positively associated with oxidative stress levels in patients with coronary artery disease and healthy control subjects. CONCLUSIONS: Our findings indicate that inhibition of SAHH results in elevated plasma SAH levels and induces endothelial dysfunction via epigenetic upregulation of the p66shc-mediated oxidative stress pathway. Our study provides novel molecular insight into mechanisms of SAH-associated endothelial injury that may contribute to the development of atherosclerosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03345927.

Association between short-term exposure to air pollution and ischemic stroke onset: a time-stratified case-crossover analysis using a distributed lag nonlinear model in Shenzhen, China.

BACKGROUND: Stroke, especially ischemic stroke (IS), has been a severe public health problem around the world. However, the association between air pollution and ischemic stroke remains ambiguous. METHODS: A total of 63, 997 IS cases aged 18 years or above in Shenzhen were collected from 2008 to 2014. We used the time-stratified case-crossover design combining with distributed lag nonlinear model (DLNM) to estimate the association between air pollution and IS onset. Furthermore, this study explored the variability across gender and age groups. RESULTS: The cumulative exposure-response curves were J-shaped for SO2, NO2 and PM10, and V-shaped for O3, and crossed over the relative risk (RR) of one. The 99th, 50th (median) and 1st percentiles of concentration (µg/m3) respectively were 37.86, 10.06, 3.71 for SO2, 116.26, 41.29, 18.51 for NO2, 145.94, 48.29, 16.14 for PM10, and 111.57, 49.82, 16.00 for O3. Extreme high-SO2, high-NO2, high-PM10, high-O3, and low-O3 concentration increased the risk of IS, with the maximum RR values and 95% CIs: 1.50(1.22, 1.84) (99th vs median) at 0-12 lag days, 1.37(1.13, 1.67) (99th vs median) at 0-10 lag days, 1.26(1.04, 1.53) (99th vs median) at 0-12 lag days, 1.25(1.04, 1.49) (99th vs median) at 0-14 lag days, and 1.29(1.03, 1.61) (1st vs median) at 0-14 lag days, respectively. The statistically significant minimal RR value and 95% CI was 0.79(0.66,0.94) at 0-10 lag days for extreme low-PM10. The elderly aged over 65 years were susceptible to extreme pollution conditions. Difference from the vulnerability of males to extreme high-SO2, high-NO2 and low-O3, females were vulnerable to extreme high-PM10 and high-O3. Comparing with the elderly, adults aged 18-64 year were immune to extreme low-NO2 and low-PM10. However, no association between CO and IS onset was found. CONCLUSIONS: SO2, NO2, PM10 and O3 exerted non-linear and delayed influence on IS, and such influence varied with gender and age. These findings may have significant public health implications for the prevention of IS.

miR-129-2-3p directly targets SYK gene and associates with the risk of ischaemic stroke in a Chinese population.

Spleen tyrosine kinase (SYK) gene has been identified as novel susceptibility locus for ischaemic stroke (IS) previously. However, regulation of SYK gene remains unknown in IS. In this study, we aimed to identify miRNAs that might be involved in the development of IS by targeting SYK gene. miRNAs were firstly screened by bioinformatics predicting tool. The expression levels of SYK gene were detected by qRT-PCR and western blotting, respectively, after miRNA transfection. Luciferase reporter assay was applied to investigate the direct binding between miRNAs and target gene. miRNA levels were detected by miRNA TaqMan assays in the blood cells of 270 IS patients and 270 control volunteers. Results suggest that SYK gene might be a direct target of miR-129-2-3p. The blood level of miR-129-2-3p was significantly lower in IS patients (P < 0.05), and negatively associated with the risk of IS (adjusted OR: 0.88; 95% CI: 0.80-0.98; P = 0.021) by multivariable logistic regression analysis. The blood levels of SYK gene were significantly higher in IS patients, and miR-129-2-3p expression was negatively correlated with mean platelet volume. In summary, our study suggests that miR-129-2-3p might be involved in the pathogenesis of IS through interrupting SYK expression and the platelet function, and further investigation is needed to explore the underlying mechanism.

Circulating Multiple Metals and Incident Stroke in Chinese Adults.

Background and Purpose- Circulating metals synchronously reflect multiple metal exposures from both natural and anthropogenic sources, which may be linked with the risk of stroke. However, there is a lack of prospective studies investigating the associations of multiple metal exposures with incident stroke. Methods- We performed a nested case-control study within the ongoing Dongfeng-Tongji cohort launched in 2008. A total of 1304 incident stroke cases (1035 ischemic strokes and 269 hemorrhagic strokes) were prospectively identified by December 31, 2016, and matched to incident identity sampled controls according to age (within 1 year), sex, and blood sampling date (within 1 month). We determined the concentrations of 24 plasma metals and assessed the associations of plasma multiple metal concentrations with incident stroke using conditional logistic regression and elastic net model. Results- The average follow-up was 6.1 years. After adjusting for established risk confounders, copper, molybdenum, and titanium were significantly associated with higher risk of ischemic stroke (odds ratios according to per interquartile range increase, 1.29 [95% CI, 1.13-1.46], 1.19 [95% CI, 1.05-1.35], and 1.30 [95% CI, 1.07-1.59]), whereas rubidium and selenium were associated with lower risk of hemorrhagic stroke (odds ratios according to per interquartile range increase, 0.66 [95% CI, 0.50-0.87] and 0.68 [95% CI, 0.51-0.91]). The predictive plasma metal scores based on multiple metal exposures were significantly associated with higher risk of ischemic and hemorrhagic stroke (adjusted odds ratios according to per interquartile range increase, 1.37 [95% CI, 1.20-1.56] and 1.53 [95% CI, 1.16-2.01]). Conclusions- Plasma copper, molybdenum, and titanium were associated with higher risk of ischemic stroke, whereas plasma rubidium and selenium were associated with lower risk of hemorrhagic stroke. These findings may have important public health implications given the ever-increasing burden of stroke worldwide.

Associations between dietary patterns and the risk of breast cancer: a systematic review and meta-analysis of observational studies.

BACKGROUND: Epidemiologic evidence suggests that certain dietary patterns were associated with breast cancer risk, but the results have been inconclusive. We assessed the associations between different dietary patterns and the risk of breast cancer by conducting a meta-analysis of observational studies. METHODS: Relevant articles were searched in PubMed, Embase, and Cochrane library databases through September 2017. Multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs) comparing the highest and lowest categories of Western and prudent dietary patterns were combined by using the random-effects meta-analyses. RESULTS: We identified 32 eligible articles including 14 cohort and 18 case-control studies (34 Western and 35 prudent studies). The pooled analyses found that a Western dietary pattern was associated with a 14% increased risk (RR 1.14, 95% CI 1.02, 1.28), whereas a prudent dietary pattern was associated with an 18% reduced risk of breast cancer (RR 0.82, 95% CI 0.75, 0.89). In addition, sub-group analyses showed that the positive association between a Western dietary pattern and breast cancer risk was significant among postmenopausal (RR 1.20, 95% CI 1.06, 1.35), but not premenopausal women (RR 1.18, 95% CI 0.99, 1.40), and significant for hormone receptor-positive tumors (RR 1.18, 95% CI 1.04, 1.33), but not receptor-negative tumors (RR 0.97, 95% CI 0.83, 1.12). In contrast, the inverse association between a prudent dietary pattern and breast cancer was significant in premenopausal (RR 0.77, 95% CI 0.61, 0.98), but not postmenopausal women (RR 0.88, 95% CI 0.74, 1.03), and significant for both hormone receptor-positive and receptor-negative tumors. CONCLUSIONS: The results of the current meta-analysis suggest a possible increased risk of breast cancer associated with a Western dietary pattern and a reduced risk with a prudent dietary pattern. Large-scale cohort studies with a high quality need to be conducted to further confirm the findings of the current meta-analysis. As dietary patterns are modifiable, these findings may provide viable strategies for breast cancer prevention through changes in dietary intake.

Global cytokine/chemokine profile identifies potential progression prediction indicators in hand-foot-and-mouth disease patients with Enterovirus A71 infections.

OBJECTIVE: New clinical indicators are urgently needed for predicting the progression and complications of hand-foot-and-mouth disease (HFMD) caused by EV-A71 infections. MATERIALS AND METHODS: Serum specimens from 132 EV-A71 HFMD patients and 73 health children were collected during 2012-2014 in Shenzhen, China. The specific cytokines/chemokines were detected with a 274-human cytokine antibody array, followed by a 38-inflammation cytokine array, and further validated by ELISA. RESULTS: Cytokines varied in different severity of EV-A71 HFMD patients. The ROC curve analysis revealed 5 serum cytokines with high sensitivity and specificity in predicting the disease progression. Eotaxin, IL-8 and IP-10 have showed high AUC values (0.90-0.95) for discrimination between the health controls and the patient group. The three cytokines showed high sensitivity (80-91%) and specificity (88-95%). MMP-8 had a high sensitivity and specificity to predict mild HFMD (100%, 100%). IL-1b and leptin discriminated the severe/critical group from the mild group (79% and 69% in sensitivity, 73% and 63% in specificity). CONCLUSIONS: Eotaxin, IP-10 and IL-8 could be potential indicators for predicting HFMD progression with EV-A71 infection. MMP-8 is a specific indicator for mild infection, while IL-1b and leptin display potential for predicting the severity and criticality.

Use of gay app and the associated HIV/syphilis risk among non-commercial men who have sex with men in Shenzhen, China: a serial cross-sectional study.

OBJECTIVES: Geosocial networking application specific to men who have sex with men (MSM) (gay app) has revolutionised the social networking of MSM globally, much concern was raised over its linkage to HIV/syphilis risk. This study sought to examine the association between use of gay app and sexual behaviours and HIV/syphilis risk among Chinese MSM. METHODS: Eligible MSM were recruited through combined offline methods from 2015 to 2017 in Shenzhen, China, with data collected including demographics, sexual behaviours, app use, recreational drug use and HIV testing. All participants are required to sign a written informed consent and take a confidential HIV and syphilis testing. RESULTS: The prevalence of app use among non-commercial MSM (NcMSM) has rapidly increased from 12.5% in 2015 to 52.6% in 2017. The primary four apps used were Blued (97.2%), Aloha (18.4%), Jack'd (14.1) and Zank (14.1%). After controlling for confounders, HIV prevalence was still significantly lower among app users than non-app users (adjusted odds ratios [AOR]: 0.77, 95% CI 0.61 to 0.97), yet the lower prevalence of syphilis was not significant (AOR: 0.97, 95% CI 0.76 to 1.23). App-using NcMSM were more likely to be younger, unmarried, self-identified as homosexuality and having higher education level and income than non-app-using NcMSM. App-using NcMSM had higher rate of consistent condom use and HIV testing, higher level of knowledge on HIV/AIDS prevention and condom use; however, they were more likely to have multiple sexual partners, practice receptive role in anal sex and use recreational drug. CONCLUSIONS: App-using NcMSM are more likely to have sexual risk behaviours as well as risk-reduction behaviours such as consistent condom use and HIV testing. Scaled-up and innovative venue-based HIV interventions are warranted for these high-risk MSM frequent social venues with less condom use and fewer HIV tests. Meanwhile, gay app should alternatively serve as an intervention and education platform for the MSM hard-to-reach via venue-based approaches.

Predicting temporal propagation of seasonal influenza using improved gaussian process model.

Influenza rapidly spreads in seasonal epidemics and imposes a considerable economic burden on hospitals and other healthcare costs. Thus, predicting the propagation of influenza accurately is crucial in preventing influenza outbreaks and protecting public health. Most current studies focus on the spread simulation of influenza. However, few studies have investigated the dependencies between meteorological variables and influenza activity. This study develops a non-parametric model based on Gaussian process regression for influenza prediction considering meteorological effect to capture temporal dependencies hidden in influenza time series. To identify the most explanatory external variables, L1-regularization is applied to identify meteorology factor subsets, and three types of covariance functions are designed to characterize non-stationary and periodic behavior in influenza activity. The dependencies of diseases and meteorology are modeled through the designed cross-covariance function. A real case in Shenzhen, China was studied to validate our proposed model along with comparisons to recently developed multivariate statistical models for influenza prediction. Results show that our proposed influenza prediction approach achieves superior performance in terms of one-week-ahead prediction of influenza-like illness.

Urinary phthalate metabolites in primary school starters in Pearl River Delta, China: Occurrences, risks and possible sources.

Assessment of children's exposure risks of phthalates before puberty is important, as phthalates are ubiquitous and are associated with reproductive development. However, relevant data in Pearl River Delta, China are scarce. Nineteen phthalate metabolites were analyzed in urine samples from 1490 primary school starters (6-8 years old) recruited in 2016-2017 using ultra-performance liquid chromatography and tandem mass spectrometry (UHPLC-MS/MS). Nine phthalate metabolites were detected more than 80% of the urine samples. Monobutyl phthalate (MnBP) was the highest metabolite (median, 212 µg/g creatinine), followed by two short chained phthalate metabolites, four secondary metabolites of di(2-ethylhexyl) phthalate (DEHP), and the primary metabolites of DEHP. The MnBP level was the third highest of those reported worldwide while other metabolites were in the lower range compared with previous studies. Significantly positive associations were found between urinary metabolite levels and family income as well as parent education levels (p < 0.05). Duration since the latest interior decoration was inversely associated with phthalate metabolites (p < 0.05). Significantly positive associations had also been found between the frequency of eating takeaway food and four DEHP metabolites (p < 0.01). The geometric mean of estimated daily intake (EDI) of di-n-butyl phthalate (DnBP), DEHP, di-iso-butyl phthalate (DiBP), dimethyl phthalate, diethyl phthalate and butylbenzyl phthalate (BBzP) were 6.24, 2.67, 1.06, 0.64, 0.44, and 0.01 µg/kg bw/day, respectively. Hazard quotient (HQ) was defined as the ratio of EDI and the tolerable daily intake (TDI). Approximately 38% children had HQ DnBP >1 indicating potential reproductive risks caused by DnBP. To evaluate cumulative exposure risks, hazard index (HI) was calculated as the sum of the HQs of DnBP, DiBP, DEHP, and BBzP. Nearly 48% children had HI > 1 suggesting extremely high cumulative risks in children in Pearl River Delta, China. To our best knowledge, this was the largest study on evaluating phthalate exposure among children in China.

Cellular metabolomics reveals glutamate and pyrimidine metabolism pathway alterations induced by BDE-47 in human neuroblastoma SK-N-SH cells.

Polybrominated diphenyl ethers (PBDEs) as potential neurotoxicants in environment may possess hazards to human health. Previous studies have reported that PBDEs exposure could induce oxidative stress and disturb mitochondrial functions in mammalian cells. However, the toxicological mechanism remains to be clarified. In this work, the neurotoxic effect and underlying mechanism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) was investigated by using human neuroblastoma SK-N-SH cells as an effective model. A liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approach combined with cell viability assay was applied to elucidate the metabolic perturbations and relevant toxicological pathways upon BDE-47 exposure. Our results shown that the SK-N-SH cell viability decreased in a dose-dependent manner after exposure to BDE-47 at 24 h within the concentration range of 5-250 µM, and an IC50 value of 88.8 µM was obtained. Based on the dose-response curve and cell morphological observation, the 5 and 10 µM BDE-47 doses (equal to IC5 and IC10, respectively) were used for metabolomics study to capture the sensitive metabolic response following BDE-47 exposure. After BDE-47 treatment, nine metabolites were identified as potential biomarkers, and the most disturbed metabolic pathways were mainly involved in alanine, aspartate and glutamate metabolism, glutathione metabolism, tyrosine and phenylalanine metabolism, and pyrimidine metabolism, which imply that metabolic changes related to neurotransmitters, oxidative stress, and nucleotide-mediated signal transduction systems were the sensitive pathways mostly influenced. Our findings reported here may provide potential neurotoxic effect biomarkers and prompt deep understanding of the molecular and metabolic mechanisms triggered by BDE-47 exposure.

Differences in genome characters and cell tropisms between two chikungunya isolates of Asian lineage and Indian Ocean lineage.

BACKGROUND: Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus within the family Togaviridae, which has attracted global attention due to its recent re-emergence. In one of our previous studies, we successfully isolated two CHIKV virus strains, SZ1050 and SZ1239, from the serum samples of two imported patients in 2010 and 2012, respectively. However, the differences in their genome characters and cell tropisms remain undefined. METHODS: We extracted the RNA of two CHIKV isolates and performed PCR to determine the sequence of the whole viral genomes. The genotypes were classified by phylogenetic analysis using the Mega 6.0 software. Furthermore, the cell tropisms of the two CHIKV isolates were evaluated in 13 cell lines. RESULTS: The lengths of the whole genomes for SZ1050 and SZ1239 were 11,844 nt and 12,000 nt, respectively. Phylogenetic analysis indicated that SZ1050 belonged to the Indian Ocean lineage (IOL), while SZ1239 was of the Asian lineage. Comparing to the prototype strain S27, a gap of 7 aa in the nsP3 gene and missing of one repeated sequence element (RSE) in the 3' UTR were observed in SZ1239. The E1-A226V mutation was not detected in both strains. SZ1050 and SZ1239 could infect most of the evaluated mammalian epithelial cells. The K562 cells were permissive for both SZ1050 and SZ1239 while the U937 cells were refractory to both viruses. For Aedes cell lines C6/36 and Aag-2, both SZ1050 and SZ1239 were able to infect and replicate efficiently. CONCLUSIONS: Compared to the prototype S27 virus, some deletions and mutations were found in the genomes of SZ1050 and SZ1239. Both viruses were susceptible to most evaluated epithelia or fibroblast cells and Aedes cell lines including C6/36 and Aag-2 in spite of marginal difference.