Nonlinear low dose hematotoxicity of benzene; a pooled analyses of two studies among Chinese exposed workers.

BACKGROUND: Impairment of the hematopoietic system is one of the primary adverse health effects from exposure to benzene. We previously have shown that exposure to benzene at low levels (<1 ppm) affects the blood forming system and that these effects were proportionally stronger at lower versus higher levels of benzene exposure. This observation is potentially explained by saturation of enzymatic systems. METHODS: Here we extend these analyses by detailed modeling of the exposure response association of benzene and its major metabolites (i.e. catechol, muconic acid, phenol, and hydroquinone) on peripheral white blood cell (WBC) counts and its major cell-subtypes (i.e. granulocytes, lymphocytes, and monocytes) using two previously published cross-sectional studies among occupationally exposed Chinese workers. RESULTS: Supra-linear exposure response associations were observed between air benzene concentrations (range âˆ¼ 0.1 - 100 ppm) and WBC counts and its cell-subtypes, with a larger than proportional decrease in cell counts at lower than at higher levels of benzene exposure. The hematotoxicity associations were largely similar in shape when the analyses were repeated with benzene urinary metabolites suggesting that enzymatic saturation is not a full explanation of the observed non-linearity with WBC endpoints. DISCUSSION: We hypothesize that the flattening of the exposure response curve especially at higher benzene exposure levels may reflect a response by the bone marrow to maintain hematopoietic homeostasis. Toxicity to the bone marrow and an induced hyper-proliferative response could both contribute to risk of subsequently developing a hematopoietic malignancy. Additional work is needed to explore this hypothesis.

A prediction model of delayed graft function in deceased donor for renal transplant: a multi-center study from China.

BACKGROUND: Kidneys obtained from deceased donors increase the incidence of delayed graft function (DGF) after renal transplantation. Here we investigated the influence of the risk factors of donors with DGF, and developed a donor risk scoring system for DGF prediction. METHODS: This retrospective study was conducted in 1807 deceased kidney donors and 3599 recipients who received donor kidneys via transplants in 29 centers in China. We quantified DGF associations with donor clinical characteristics. A donor risk scoring system was developed and validated using an independent sample set. RESULTS: The incidence of DGF from donors was 19.0%. Six of the donor characteristics analyzed, i.e., age, cause of death, history of hypertension, terminal serum creatinine, persistence of hypotension, and cardiopulmonary resuscitation (CPR) time were risk factors for DGF. A 49-point scoring system of donor risk was established for DGF prediction and exhibited a superior degree of discrimination. External validation of DGF prediction revealed area under the receiver-operating characteristic (AUC) curves of 0.7552. CONCLUSIONS: Our study determined the deceased donor risk factors related to DGF after renal transplantation pertinent to the Chinese cohort. The scoring system developed here had superior diagnostic significance and consistency and can be used by clinicians to make evidence-based decisions on the quality of kidneys from deceased donors and guide renal transplantation therapy.

Positively increased visceral adiposity index in hyperuricemia free of metabolic syndrome.

BACKGROUND: Visceral adiposity index (VAI) was closely associated with metabolic syndrome, however almost no research focused on VAI and hyperuricemia, therefore, this study was conducted to determine the relationship of VAI and hyperuricemia free of metabolic syndrome and estimate the power of VAI as predictor for hyperuricemia. METHODS: A cross-sectional research coming from a health check-up program was conducted. All participants were divided into four groups according to VAI quartiles. A multivariate logistic analysis was used to analyze the relationship between the quartiles and hyperuricemia. A receiver operating characteristic (ROC) curve analysis was used to evaluate the accuracy of predictions for hyperuricemia. RESULTS: VAI was independent risk factor of hyperuricemia. The ORs of which in the upper quartile were 3.077 (95%CI 1.78-5.293), P = 0.000, in model 1, after adjusting for age, systolic blood pressure, diastolic blood pressure, heart rate, fast plasma glucose, serum creatinine, triglyceride, total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol; and 3.041 (95CI 1.767-5.233), P = 0.000, in model 2, after adjusting for the above plus physical activity, diet, smoking habits, alcohol consumption, hypertension and diabetes history. The area under the ROC curve (AUC) value of VAI was 0.618 (95%CI 0.572-0.665), P = 0.000; it was higher than WC, which was 0.556 (95%CI 0.508-0.604), P = 0.024, for hyperuricemia. CONCLUSIONS: VAI was associated with hyperuricemia among individuals free of metabolic syndrome, and also a powerful indicator.

Visceral Adiposity Index was a useful Predictor of Prediabetes.

AIM: To study the relationship of visceral adiposity index (VAI) and prediabetes and the power of which in predicting of prediabetes. METHODS: A cross-sectional epidemiological survey was conducted. All participants were divided into four groups: VAI and WC (both are normal), VAI↑ and WC (postcritical VAI and normal WC), VAI and WC↑ (Normal VAI and postcritical WC), and VAI↑ and WC↑ (postcritical VAI and postcritical WC). A multivariate logistic analysis was used to analyze the relationship between the four groups and prediabetes, and diabetes. A receiver operating characteristic (ROC) curve analysis was used to evaluate the accuracy of predictions for prediabetes and diabetes. RESULTS: Both VAI and WC were independent risk factors of Prediabetes. The ORs for Prediabetes in the VAI↑&WC group were 1.641 (95%CI 1.146-2.349), P=0.007, in males, in Model 2. The ORs for Prediabetes in the VAI&WC↑ group were 1.454 (95%CI 1.055-2.005), P=0.022, in males, in Model 2. The ORs for Prediabetes in the VAI↑&WC group were 2.305 (95%CI 1.623-3.273), P=0.000, in females, in Model 2. The ORs for Prediabetes in the VAI&WC↑ group were 1.997 (95%CI 1.529-2.608), P=0.000, in females, in Model 2. The AUC value of VAI were 0.601 (95%CI 0.568-0.634), P=0.000, in prediabetes of men; which were 0.645 (95%CI 0.618-0.672), P=0.000, in prediabetes women. WC had the highest AUC value of 0.605 (95%CI 0.571-0.638), P=0.000, in prediabetes of men, also had the highest of AUC value of 0.673 (95%CI 0.648-0.697), P=0.000, in prediabetes of women. CONCLUSION: VAI was positively associated with prediabetes, and also a usefulindicator of prediabetes.

Discussion on the risk factors of developing cardiovascular diseases (CVD) after the kidney transplantation.

To discuss the risk factors of developing cardiovascular disease (CVD) after the kidney transplantation. Retrospective analysis on the data of 1106 patients who had been underwent kidney allotransplantation in People's Hospital of Zhengzhou from July, 2010 to Dec, 2014 and conformed to the inclusion criteria was taken. Cox proportional hazard model was used to analyze the risk factors of developing CVD after the kidney transplantation. 7 days, 1 month, 3 months, 6 months and 12 months before and after the operation, the data collection and following-up visits were respectively arranged. 12 months after the operation, the following-up visits were arranged once a half year until the end of March, 2014. 216 (19.5%) patients developed CVD after the kidney transplantation. Among them, 47 (4.2%) patients developed CVD within the first three months after the operation, which accounted for 26.8% in the CVD patients; 125 (11.3%) patients developed CVD within the first one year after the operation, which accounted for 47.9% in the CVD patients. 51 (4.6%) patients died after the operation. Among them, 19 (2.7%) patients died of CVD, which accounted for 37.3% in the whole died patients. Multiple factors analysis revealed that the following were the risk factors to develop CVD after the kidney transplantation: The age of receptors was greater than 50 (OR=2.39, 95%CI 1.15-3.60); The receptors had diabetes before the surgery (OR=3.18, 95%CI 1.56-6.42); The receptors had CVD medical history before the surgery (OR=3.85, 95%CI 2.15-7.54); The primary diseases of receptors were diabetic nephropathy (DN) (OR=2.12, 95%CI 1.14-3.98); The preoperative dialysis time was greater than 12 months(OR=1.27, 95%CI 0.98-1.38); The postoperative serum creatinine of the receptors was greater than 200 µmol/L (OR=2.78, 95%CI 1.35~4.53); The delayed graft failure (DGF) occurred (OR=1.24, 95%CI 1.02~1.42); Acute rejection appeared(AR)(OR=2.98, 95%CI 1.56~5.72); Renal allograft dysfunction appeared (OR=4.86, 95%CI 3.15~7.78). The morbidity of CVD is high after the kidney transplantation and the risk factors are diversified. That revising or excluding relevant risk factors may lower the morbidity of developing CVD and is in favor of the long-term survival for the transplanted kidney.

Clinical effect of treating renal transplant recipients with percutaneous coronary intervention and its safety.

OBJECTIVE: To explore clinical effect of treating acute coronary syndrome (ACS) of renal transplant recipients with percutaneous coronary intervention and its safety. METHODS: Forty two renal transplant recipients who were diagnosed with acute coronary syndrome and received percutaneous coronary intervention (PCI) in our hospital were selected. Serum creatinine (Cr) and glomerular filtration rate (GFR) were compared before surgery, 48 ~ 72 hour after surgery and one year after surgery. All patients were followed up. RESULTS: All patients successfully completed PCI. Contrast-induced nephropathy was not found after surgery. Cr and GFR 48 ~ 72 hour after surgery and one year after surgery had no significant differences with that before surgery (P>0.05). The follow up lasted for (61.2±32.2) months averagely. Of 42 cases, 4 cases died, 6 cases were found with nonfatal myocardial infarction, 4 cases were observed with repeat revascularization and 12 cases had accumulative major adverse cardiovascular events (MACE). CONCLUSION: PCI is proved to be effective in treating renal transplant recipients; no severe complications are found and renal function recovers well after treatment.

Clinical significance of quantitative and qualitative detection of BK and JC virus in blood and urine of renal transplantation recipients.

OBJECTIVE: To evaluate value of quantitative and qualitative detection of BK virus (BKV) and JC virus (JCV) in timely diagnosing polyomavirus-associated nephropathy (PVAN) occurring inrenal transplantation recipients. METHODS: We collected 306 cases of urine specimen and 310 cases of blood specimen from 306 patients who underwent renal transplant. Levels of BKV and JCV in blood and urine were detected using real-time quantitative polymerase chain reaction (PCR). RESULTS: Detection rate of BKV DNA was 33.3% (102/306) in urine and 34.8% (108/310); while that of JCV DNA was 30.7% (94/306) and 33.5% (104/310) respectively. The lowest detectable limit of BCK and JCV detection for patients who underwent renal transplant was 2×10(3) copies/ml, suggesting high specificity and sensitivity. CONCLUSION: Real-time quantitative PCR is able to monitor BCV and JCV in renal transplant recipients in a convenient and rapid way, thus it is beneficial for early discovery, diagnosis and treatment of PVAN.

Improving Knowledge about Children's Environmental Health in Northwest China.

The main purpose of this study was to identify policy maker opinions and attitudes towards children's environmental health (CEH), potential barriers to child-specific protective legislation and implementation in northwest China, and evaluate knowledge and attitudes about CEH before and after an educational conference. We conducted seventy-two interviews with regional officials, researchers and non-governmental organization representatives from five provinces, and surveyed participants (forty-seven) before and after an educational conference in northwest China about CEH. Interviews identified general consensus among participants of the adverse effects of air pollution on children, yet few participants knew of policies to protect them. Barriers identified included limited funding and enforcement, weak regional governments and absence of child-specific policy-making. After the conference, substantially greater self-efficacy was identified for lead, mercury, air pollution and polychlorinated biphenyls (+0.57-0.72 on a 1-5 Likert scale, p = 0.002-0.013), and the scientific knowledge for the role of environment in children's health (+0.58, p = 0.015), and health care provider control (+0.52, p = 0.025) were rated more strongly. We conclude that policy makers in Northwest China appreciate that children are uniquely vulnerable, though additional regulations are needed to account for that vulnerability. Further research should examine effectiveness of the intervention on a larger scale and scope, and evaluate the usefulness of such interventions in translating research into improved care/reduced exposure to environmental hazards.

Investigation of the structure of anti-human seminal plasma protein single-chain antibody and its association with linker peptide length.

To enhance the activity of seminoprotein single­chain variable fragment (γ­Sm­ScFv) antibodies, modulation of the length of the linker peptide, which connects the variable region of the heavy chain (VH) and the light chain (VL) of single­chain antibodies, was performed in the present study. Homologous modeling of single VH and VL were performed, respectively. Subsequently, modeling of the whole ScFv sequence, which was previously modified with added linkers of different lengths was also performed, and the (Gly4Ser)n peptide chain structure was used as the linker. The similarities between VH and VL prior to and following the addition of the linker were compared by applying the algorithm of protein similarity, based on spherical coordinates layering. In addition, changes in the fore and aft distance, and diffusion radius were calculated using a MATLAB tool, based on which changes in structural stability were analyzed. Finally, the single­chain antibody was assessed in a nude mouse model. When n=3 or n=6, the similarity between the original distance and VH and VL were the highest, and the fore and aft distance and diffusion radius were relatively close. In addition, the nude mouse model indicated that, when n=3 or n=6, the inhibitory rate of the single­chain antibody against tumor cells was significantly higher, compared with the other linker peptides of different lengths. The effect of structural changes of the linker peptides in the single­chain antibodies on the whole antibody molecule was examined at different levels using a combination of mathematical modeling, bioinformatics methods and biological experiments. The findings of the present study may provide a foundation for further investigation into the preparation of single­chain antibodies.

Metal rich particulate matter impairs acetylcholine-mediated vasorelaxation of microvessels in mice.

BACKGROUND: Exposure to PM2.5 (particulate matter<2.5 µm) has been associated with changes in endothelial function. PM2.5 was collected from two Chinese cities, Jinchang (JC) and Zhangye (ZH), both with similar PM2.5 concentrations. However, JC had levels of nickel (Ni), selenium (Se), copper (Cu), and arsenic (As) that were 76, 25, 17, and 7 fold higher than that measured in ZH, respectively. We used this unique PM sample to delineate the chemical components that drive pulmonary and systemic effects and explore the mechanism(s) by which vascular dysfunction is caused. METHODS: Male FVB/N mice received oropharyngeal aspiration of water or PM2.5 from JC, ZH or ZH spiked with one of the following elements at the same concentrations found in the JC PM (Ni=4.76; As=2.36; Se=0.24; Cu=2.43 µg/mg) followed by evaluation of markers of pulmonary and systemic inflammation. Mesenteric arteries were isolated for gene expression or functional response to various agonists (Phenylephrine, Acetylcholine, and Sodium Nitroprusside) and inhibitors (L-NAME, Apocynin, and VAS2870) ex vivo. RESULTS: Protein and total cell counts from lung lavage revealed significant pulmonary inflammation from ZH (p<0.01) and JC and ZH+NiSO4 (p<0.001) as compared to control and a significant decrease in mesenteric artery relaxation (p<0.001) and this decrease is blunted in the presence of NADPH oxidase inhibitors. Significant increases in gene expression (TNF-α, IL-6, Nos3; p<0.01; NOX4; p<0.05) were observed in JC and ZH+NiSO4, as well as significantly higher concentrations of VEGF and IL-10 (p<0.01, p<0.001; respectively). CONCLUSIONS: Our results indicate that the specific toxicity observed in PM from JC is likely due to the nickel component in the PM. Further, since VAS2870 was the most successful inhibitor to return vessels to baseline relaxation values, NADPH Oxidase is implicated as the primary source of PM-induced O2•-.

Significantly increased visceral adiposity index in prehypertension.

BACKGROUND: The prevalence of prehypertension has increased in China, and prehypertension frequently progress to hypertension over a short time period; both have become public health problems. Therefore, this study was conducted to determine the relationship between the Visceral Adiposity Index (VAI) and blood pressure (BP) in China. METHODS: A cross-sectional epidemiological survey was conducted in China using a stratified random cluster sampling method. Sex-specific VAI quartile cut-off points were used as follows: 0.88, 1.41, 2.45 in males and 0.85, 1.33, 2.22 in females. Prehypertension and hypertension were each defined according to The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines. A multivariate logistic analysis was conducted to analyze the relationship among VAI, prehypertension and hypertension. RESULTS: The ORs for prehypertension and hypertension in the upper quartiles of the VAI were 1.514 (1.074-2.133), P=0.018 and 1.660 (1.084-2.542), P=0.020, in males, after adjusting for age, education, smoking habits, alcohol consumption, physical activity, serum creatinine, fasting glucose, and plasma insulin. Following further adjustments for the above confounders, chronic kidney disease, and diabetes, the ORs for prehypertension and hypertension in the upper quartile of the VAI were 1.660 1.533 (1.086-2.165), P=0.015, and 1.743 (1.133-2.680), P=0.011, in males. The ORs for prehypertension and hypertension in the upper quartile of the VAI were 1.691 (1.223-2.338), P=0.001, and 1.682 (1.162-2.435), P=0.006, in females, after adjusting for age, education, smoking habits, alcohol consumption, physical activity, serum creatinine, fasting glucose, and plasma insulin. Following further adjustments for the above confounders, chronic kidney disease, and diabetes, the ORs for prehypertension and hypertension in the upper quartile of the VAI were 1.688 (1.220-2.334), P=0.002, and 1.657 (1.141-2.406), P=0.008, in females. CONCLUSIONS: A higher VAI was positively associated with both prehypertension and hypertension in both males and females. It is both essential and urgent that clinicians take steps to control and prevent visceral adiposity.

Horsetail mixture on rheumatoid arthritis and its regulation on TNF-α and IL-10.

Taking autoimmune inflammation of rheumatoid arthritis as entry point, this paper discussed the clinical effect of horsetail mixture on rheumatoid arthritis (RA) and its mechanism. A total of 60 cases of patients with RA were randomly divided into experimental group and control group using randomized controlled trial. We observed its biochemistry, TNF-α and IL-10 before and after treatment, and then systematically assessed the clinical effect of horsetail on RA. Results showed that the total effective rate of experimental group was 80%, while that of control group was 16.67%. After statistical treatment, the differences between two groups were significant (p<0.01). Comparison of the difference value of TNF-α (p<0.05) and IL-0.05 in serum between groups before and after treatment, there were significant differences. Comparison of CRP within group before and after treatment was significantly different (p<0.05), while comparison of CRP between groups was not significantly different (p>0.05). Comparison of ESR and RF within group before and after treatment was significantly different (p<0.01), and comparison of them between groups was also significantly different (p<0.05). Comparison of difference values within group before and after treatment were also significantly different (p<0.01). It was concluded that horsetail mixture has remarkable curative effect on rheumatoid arthritis, and its clinical application is safe and reliable. It has obvious down regulatory effect on cell factor TNF-α related to RA, that is, it can down regulate the level of pre-inflammatory factor TNF-α as well as the level of anti-inflammatory factor IL-10. Therefore, it is considered that the regulating effect of horsetail mixture on TNF-α and IL-10 is one of the mechanisms of its treatment on RA.

The acute exposure effects of inhaled nickel nanoparticles on murine endothelial progenitor cells.

INTRODUCTION: The discovery of endothelial progenitor cells (EPCs) may help to explain observed cardiovascular effects associated with inhaled nickel nanoparticle exposures, such as increases in vascular inflammation, generation of reactive oxygen species, altered vasomotor tone and potentiated atherosclerosis in murine species. METHODS: Following an acute whole body inhalation exposure to 500 µg/m(3) of nickel nanoparticles for 5 h, bone marrow EPCs from C57BL/6 mice were isolated. EPCs were harvested for their RNA or used in a variety of assays including chemotaxis, tube formation and proliferation. Gene expression was assessed for important receptors involved in EPC mobilization and homing using RT-PCR methods. EPCs, circulating endothelial progenitor cells (CEPCs), circulating endothelial cells (CECs) and endothelial microparticles (EMPs) were quantified on a BD FACSCalibur to examine endothelial damage and repair associated with the exposure. RESULTS AND CONCLUSIONS: Acute exposure to inhaled nickel nanoparticles significantly increased both bone marrow EPCs as well as their levels in circulation (CEPCs). CECs were significantly elevated indicating that endothelial damage occurred due to the exposure. There was no significant difference in EMPs between the two groups. Tube formation and chemotaxis, but not proliferation, of bone marrow EPCs was impaired in the nickel nanoparticle exposed group. These results coincided with a decrease in the mRNA of receptors involved in EPC mobilization and homing. These data provide new insight into how an acute nickel nanoparticle exposure to half of the current Occupational Safety & Health Administration (OSHA) permissible exposure limit may adversely affect EPCs and exacerbate cardiovascular disease states.

The Environment and Children's Health Care in Northwest China.

BACKGROUND: Industrialization in the northwest provinces of the People's Republic of China is accelerating rapid increases in early life environmental exposures, yet no publications have assessed health care provider capacity to manage common hazards. METHODS: To assess provider attitudes and beliefs regarding the environment in children's health, determine self-efficacy in managing concerns, and identify common approaches to managing patients with significant exposures or environmentally-mediated conditions, a two-page survey was administered to pediatricians, child care specialists, and nurses in five provinces (Gansu, Shaanxi, Xinjiang, Qinghai, and Ningxia). Descriptive and multivariable analyses assessed predictors of strong self-efficacy, beliefs or attitudes. RESULTS: 960 surveys were completed with <5% refusal; 695 (72.3%) were valid for statistical analyses. The role of environment in health was rated highly (mean 4.35 on a 1-5 scale). Self-efficacy reported with managing lead, pesticide, air pollution, mercury, mold and polychlorinated biphenyl exposures were generally modest (2.22-2.52 mean). 95.4% reported patients affected with 11.9% reporting seeing >20 affected patients. Only 12.0% reported specific training in environmental history taking, and 12.0% reported owning a text on children's environmental health. Geographic disparities were most prominent in multivariable analyses, with stronger beliefs in environmental causation yet lower self-efficacy in managing exposures in the northwestern-most province. CONCLUSIONS: Health care providers in Northwest China have strong beliefs regarding the role of environment in children's health, and frequently identify affected children. Few are trained in environmental history taking or rate self-efficacy highly in managing common hazards. Enhancing provider capacity has promise for improving children's health in the region.

Gene expression profiles in peripheral blood mononuclear cells of Chinese nickel refinery workers with high exposures to nickel and control subjects.

BACKGROUND: Occupational exposure to nickel (Ni) is associated with an increased risk of lung and nasal cancers. Ni compounds exhibit weak mutagenic activity, alter the cell's epigenetic homeostasis, and activate signaling pathways. However, changes in gene expression associated with Ni exposure have only been investigated in vitro. This study was conducted in a Chinese population to determine whether occupational exposure to Ni was associated with differential gene expression profiles in the peripheral blood mononuclear cells (PBMC) of Ni-refinery workers when compared with referents. METHODS: Eight Ni-refinery workers and ten referents were selected. PBMC RNA was extracted and gene expression profiling was conducted using Affymetrix exon arrays. Differentially expressed genes (DEG) between both groups were identified in a global analysis. RESULTS: There were a total of 2,756 DEGs in the Ni-refinery workers relative to the referents [false discovery rate (FDR) adjusted P < 0.05] with 770 upregulated genes and 1,986 downregulated genes. DNA repair and epigenetic genes were significantly overrepresented (P < 0.0002) among the DEGs. Of 31 DNA repair genes, 29 were repressed in the Ni-refinery workers and 2 were overexpressed. Of the 16 epigenetic genes, 12 were repressed in the Ni-refinery workers and 4 were overexpressed. CONCLUSIONS: The results of this study indicate that occupational exposure to Ni is associated with alterations in gene expression profiles in PBMCs of subjects. IMPACT: Gene expression may be useful in identifying patterns of deregulation that precede clinical identification of Ni-induced cancers.

The role of metal components in the cardiovascular effects of PM2.5.

Exposure to ambient fine particulate matter (PM2.5) increases risks for cardiovascular disorders (CVD). However, the mechanisms and components responsible for the effects are poorly understood. Based on our previous murine exposure studies, a translational pilot study was conducted in female residents of Jinchang and Zhangye, China, to test the hypothesis that specific chemical component of PM2.5 is responsible for PM2.5 associated CVD. Daily ambient and personal exposures to PM2.5 and 35 elements were measured in the two cities. A total of 60 healthy nonsmoking adult women residents were recruited for measurements of inflammation biomarkers. In addition, circulating endothelial progenitor cells (CEPCs) were also measured in 20 subjects. The ambient levels of PM2.5 were comparable between Jinchang and Zhangye (47.4 and 54.5 µg/m(3), respectively). However, the levels of nickel, copper, arsenic, and selenium in Jinchang were 82, 26, 12, and 6 fold higher than Zhangye, respectively. The levels of C-reactive protein (3.44 ± 3.46 vs. 1.55 ± 1.13), interleukin-6 (1.65 ± 1.17 vs. 1.09 ± 0.60), and vascular endothelial growth factor (117.6 ± 217.0 vs. 22.7 ± 21.3) were significantly higher in Jinchang. Furthermore, all phenotypes of CEPCs were significantly lower in subjects recruited from Jinchang than those from Zhangye. These results suggest that specific metals may be important components responsible for PM2.5-induced cardiovascular effects and that the reduced capacity of endothelial repair may play a critical role.

Plasma Anti-Glycan Antibody Profiles Associated with Nickel level in Urine.

Nickel (Ni) compounds are widely used in industrial and commercial products including household and cooking utensils, jewelry, dental appliances and implants. Occupational exposure to nickel is associated with an increased risk for lung and nasal cancers, is the most common cause of contact dermatitis and has an extensive effect on the immune system. The purpose of this study was two-fold: (i) to evaluate immune response to the occupational exposure to nickel measured by the presence of anti-glycan antibodies (AGA) using a new biomarker-discovery platform based on printed glycan arrays (PGA), and (ii) to evaluate and compile a sequence of bioinformatics and statistical methods which are specifically relevant to PGA-derived information and to identification of putative "Ni toxicity signature". The PGAs are similar to DNA microarrays, but contain deposits of various carbohydrates (glycans) instead of spotted DNAs. The study uses data derived from a set of 89 plasma specimens and their corresponding demographic information. The study population includes three subgroups: subjects directly exposed to Nickel that work in a refinery, subjects environmentally exposed to Nickel that live in a city where the refinery is located and subjects that live in a remote location. The paper describes the following sequence of nine data processing and analysis steps: (1) Analysis of inter-array reproducibility based on benchmark sera; (2) Analysis of intra-array reproducibility; (3) Screening of data - rejecting glycans which result in low intra-class correlation coefficient (ICC), high coefficient of variation and low fluorescent intensity; (4) Analysis of inter-slide bias and choice of data normalization technique; (5) Determination of discriminatory subsamples based on multiple bootstrap tests; (6) Determination of the optimal signature size (cardinality of selected feature set) based on multiple cross-validation tests; (7) Identification of the top discriminatory glycans and their individual performance based on nonparametric univariate feature selection; (8) Determination of multivariate performance of combined glycans; (9) Establishing the statistical significance of multivariate performance of combined glycan signature. The above analysis steps have delivered the following results: inter-array reproducibility ρ=0.920 ± 0.030; intra-array reproducibility ρ=0.929 ± 0.025; 249 out of 380 glycans passed the screening at ICC>80%, glycans in selected signature have ICC ≥ 88.7%; optimal signature size (after quantile normalization)=3; individual significance for the signature glycans p=0.00015 to 0.00164, individual AUC values 0.870 to 0.815; observed combined performance for three glycans AUC=0.966, p=0.005, CI=[0.757, 0947]; specifity=94.4%, sensitivity=88.9%; predictive (cross-validated) AUC value 0.836.

Association of systemic inflammation with marked changes in particulate air pollution in Beijing in 2008.

Many studies have linked ambient fine particulate matter (aerodynamic diameters less than 2.5 µm, PM2.5) air pollution to increased morbidity and mortality of cardiovascular diseases in the general population, but the biologic mechanisms of these associations are yet to be elucidated. In this study, we aimed to evaluate the relationship between daily variations in exposure to PM2.5 and inflammatory responses in mice during and for 2 months after the Beijing Olympic Games. Male C57BL/6 mice were exposed to Beijing PM2.5 or filtered air (FA) in 2008 during the 2 months of Beijing Olympic and Paralympic Games, and for 2 months after the end of the Games. During the Games, circulating monocyte chemoattractant protein 1 and interleukin 6 were increased significantly in the PM2.5 exposure group, when compared with the FA control group, although there were no significant inter-group differences in tumor necrosis factor-α or interferon-γ, or in macrophages, neutrophils or lymphocytes in the spleen or thymus between these 2 groups. However, macrophages were significantly increased in the lung and visceral fat with increasing PM2.5. After the Olympic Games, there were no significant PM2.5-associated differences for macrophages, neutrophils or lymphocytes in the thymus, but macrophages were significantly elevated in the lung, spleen, subcutaneous and visceral fat with increasing PM2.5, and the numbers of macrophages were even higher after than those during the Games. Moreover, the number of neutrophils was markedly higher in the spleen for the PM2.5-exposed- than the FA-group. These data suggest that short-term increases in exposure to ambient PM2.5 leads to increased systemic inflammatory responses, primarily macrophages and neutrophils in the lung, spleen, and visceral adipose tissue. Short-term air quality improvements were significantly associated with reduced overall inflammatory responses.

The effect of exposure to carcinogenic metals on histone tail modifications and gene expression in human subjects.

The precise mechanisms by which nickel and arsenic compounds exert their carcinogenic properties are not completely understood. In recent years, alterations of epigenetic mechanisms have been implicated in the carcinogenesis of compounds of these two metals. In vitro exposure to certain nickel or arsenic compounds induces changes in both DNA methylation patterns, as well as, in the levels of posttranslational modifications of histone tails. Changes in DNA methylation patterns have been reported in human subjects exposed to arsenic. Here we review our recent reports on the alterations in global levels of posttranslational histone modifications in peripheral blood mononuclear cells (PBMCs) of subjects with occupational exposure to nickel and subjects exposed to arsenic in their drinking water. Occupational exposure to nickel was associated with an increase in H3K4me3 and decrease in H3K9me2. A global increase in H3K9me2 and decrease in H3K9ac was found in subjects exposed to arsenic. Additionally, exposure to arsenic resulted in opposite changes in a number of histone modifications in males when compared with females in the arsenic population. The results of these two studies suggest that exposure to nickel or arsenic compounds, and possibly other carcinogenic metal compounds, can induce changes in global levels of posttranslational histone modifications in peripheral blood mononuclear cells.

Global levels of histone modifications in peripheral blood mononuclear cells of subjects with exposure to nickel.

BACKGROUND: Occupational exposure to nickel (Ni) is associated with an increased risk for lung and nasal cancers. Ni compounds exhibit weak mutagenic activity, cause gene amplification, and disrupt cellular epigenetic homeostasis. However, the Ni-induced changes in global histone modification levels have only been tested in vitro. OBJECTIVE: This study was conducted in a Chinese population to determine whether occupational exposure to Ni is associated with alterations of global histone modification levels and to evaluate the inter- and intraindividual variance of global histone modification levels. METHOD: Forty-five subjects with occupational exposure to Ni and 75 referents were recruited. Urinary Ni and global H3K4 trimethylation, H3K9 acetylation, and H3K9 dimethylation levels were measured in peripheral blood mononuclear cells (PBMCs) of subjects. RESULTS: H3K4me3 was elevated in Ni-exposed subjects (0.25% ± 0.11%) compared with referents (0.15% ± 0.04%; p = 0.0004), and H3K9me2 was decreased (Ni-exposed subjects, 0.11% ± 0.05%; referents, 0.15% ± 0.04%; p = 0.003). H3K4me3 was positively (r = 0.4, p = 0.0008) and H3K9ac was negatively (r = 0.1, p = 0.01) associated with urinary Ni. Interindividual variances of H3K4me3, H3K9ac, and H3K9me2 were larger compared with intraindividual variance in both exposure test groups, resulting in reliability coefficients (an estimate of consistency of a set of measurements) of 0.60, 0.67, and 0.79 for H3K4me3, H3K9ac, and H3K9me2, respectively, for Ni-exposed subjects and of 0.75, 0.74, and 0.97, respectively, for referent subjects. CONCLUSION: The results of this study indicate that occupational exposure to Ni is associated with alterations of global histone modification levels and that measurements of global levels of histone modifications are relatively stable over time in human PBMCs.