Search

The innovative pharmacological combination of low-dose rivaroxaban plus aspirin provides clinicians with an ideal opportunity to intensify the medical treatment of patients with coronary artery disease (CAD) and comorbid peripheral artery disease (PAD). We aimed to determine the cost-effectiveness of PAD screening using the ankle-brachial index (ABI) test in patients with CAD (with rivaroxaban administered if the PAD screening was positive) compared with no-screening strategy in China.A Markov decision model using a 1-month cycle was developed to simulate the 25-year effectiveness and cost of PAD screening on 75-year-old patients with CAD in China, evaluating the quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER). One-way, two-way, and probabilistic sensitivity analyses were conducted to assess the impact of variations in the key parameters for ICERs.Our model found an incremental cost of RMB4,959 (US$740) and an incremental QALY of 0.054 after one-time ABI screening, leading to an ICER of RMB91,936 (US$13,717) per QALY gained over a 25-year period. The reduction in all-cause mortality related to rivaroxaban and its cost were the factors most affecting the ICER. The screening would become cost-effective by decreasing the monthly cost of rivaroxaban to RMB184.5 (US$27.5) or by using domestic-brand rivaroxaban according to the threshold of a willingness to pay RMB72,447 (US$10,809) per QALY gained.Our study demonstrated that ABI screening for PAD to decide on low-dose rivaroxaban administration was not cost-effective for patients with CAD in China. Nevertheless, policy-guided cost changes for domestic-brand rivaroxaban could easily resolve this issue.

Luting Yang, Chuhui Wang, Yijing Zhang, Quanfang Wang, Yulan Qiu, Sihan Li, Bo Yang, Qian Du, Jiaojiao Chen, Mengmeng Teng, Taotao Wang, Yalin Dong Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of ChinaCorrespondence: Yalin Dong; Taotao Wang, Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China, Tel +86-29-85323241 ; Tel/Fax +86-29-85323243, Fax +86-29-85323240, Email dongyalin@mail.xjtu.edu.cn; wangtaotao1989@mail.xjtu.edu.cnPurpose: Voriconazole (VRC) is an antifungal agent which is used for treatment and prophylaxis of invasive fungal infections. The common clinical adverse reactions mainly include central nervous system (CNS) toxicity and abnormal liver function. These adverse reactions limit the clinical use of voriconazole to a certain extent. Therefore, the aim of this study was to analyze the risk factors of voriconazole neurotoxic side effects and to determine the plasma trough concentration (Cmin) threshold of voriconazole-induced CNS toxicity, so as to improve the safety of voriconazole treatment.Patients and Methods: This study retrospectively collected the clinical data of 165 patients who received voriconazole and underwent therapeutic drug monitoring (TDM). CNS toxicity was defined using the National Cancer Institute (NCI) criteria, logistic regression was used to analyze the risk factors of CNS toxicity, classification and Regression tree (CART) model was used to determine the Cmin threshold for CNS toxicity.Results: Voriconazole-related CNS toxicity occurred during treatment in 34 of 165 patients (20.6%) and the median time from administration to onset of CNS toxicity was 6 days (range, 2– 19 days). The overall incidence of CNS toxicity was 20.6% (34/165), including visual disturbances in 4.8% (8/165) and nervous system disorders in 15.8% (26/165). Cmin significantly affects the occurrence of CNS toxicity and the threshold of Cmin for voriconazole CNS toxicity was determined to be 4.85 mg/L, when Cmin > 4.85 mg/L and ≤ 4.85 mg/L, the incidence of CNS was 32.9% and 11.6%, respectively.Conclusion: Voriconazole trough concentration of Cmin is an independent risk factor for CNS toxicity, and the threshold of Cmin for CNS toxicity is 4.85mg/L. TDM should be routinely performed in patients with clinical use of voriconazole to reduce the occurrence of CNS toxicity of voriconazole.Keywords: voriconazole, TDM, Cmin, CNS toxicity, cohort study

Epidemiological studies have shown that ambient fine particulate matter (PM) can cause various neurodegenerative diseases, including Alzheimer's disease. Reactive astrocytes are strongly induced by ambient fine PM, although their role is poorly understood. Herein, we show that A1 reactive astrocytes (A1s) were induced by neuroinflammatory microglia activated by PM with an aerodynamic diameter ≤ 0.2 μm (PM

Background Results of studies on the association between periodontal disease (PD) and Alzheimer's disease (AD) or mild cognitive impairment (MCI) are inconsistent, and a previous meta-analysis published in 2017 included inadequate studies and is thus outmoded. This study aims to systematically evaluate the correlation between PD and the risk of AD or MCI. Methods The following electronic databases were screened by two investigators independently, without restriction of language: CENTRAL (Cochrane library), PubMed (MEDLINE), EMBASE, China National Knowledge Interne, China Science and Technology Journal Database, Wanfang Data, www.ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform. Meta-analysis was conducted using random-effects model or fixed-effects model according to the heterogeneity of included studies. Results Thirteen eligible studies, of which eight reported AD (291 114 participants) and eight reported MCI (4805 participants), were included in this meta-analysis. The pooled results showed that compared with the non-PD population, the risk of AD and MCI in PD patients was significantly higher (for AD: odds ratio (OR) = 1.78, 95% CI 1.15-2.76; for MCI: OR = 1.60, 95% CI 1.24-2.06), and especially in those with severe PD (for AD: OR = 4.89, 95% CI 1.60-14.97; for MCI, OR = 2.32, 95% CI 1.24-4.36). Conclusions This meta-analysis indicated that PD was related to an elevated risk of AD and cognitive impairment, and that it should receive early intervention.

Vinyl chloride (VC) is a confirmed human carcinogen associated with hepatocellular carcinoma and angiosarcoma. However, the role of microRNAs (miRNAs) in liver cell cycle changes under VC exposure remains unclear, which prevents research on the mechanism of VC-induced carcinogenesis. In this study, male rats were injected intraperitoneally with VC (0, 5, 25, and 125 mg/kg body weight) for 6, 8, and 12 weeks. Cell cycle analysis of liver cells, miRNA-222, miRNA-199a, miRNA-195, and miRNA-125b expression in the liver and serum, and target protein expression were performed at different time points. The results showed a higher percentage of hepatocytes in the G1/G0 and S phases at the end of 6 and 12 weeks of VC exposure, respectively. MiRNA-222 expression decreased initially and then increased, whereas miRNA-199a, miRNA-195, and miRNA-125b expression increased initially and then decreased, which corresponded with changes in cell cycle distribution and related target proteins expression (p27, cyclinA, cyclinD1, and CDK6). The corresponding expression levels of miRNAs in serum did not change. Dynamic changes in miR-222, miR-199a, miR-195, and miR-125b induced by VC can lead to cell cycle deregulation by affecting cell cycle-related proteins, and these miRNAs can serve as early biomarkers for malignant transformation caused by VC.

To explore the epigenetic mechanism of deoxyribonucleic acid (DNA) damage induced by vinyl chloride (VC), we studied the micronuclei of peripheral blood lymphocytes in 193 subjects (92 in a VC exposure group employed in a chlorine-alkali plant; 101 in a control group employed in a power plant) and selected three pairs from the subjects (exposed and control) for whole-genome bisulfite sequencing (WGBS). The results showed that the rate of micronucleus formation in the VC exposure group was higher than that of control group (6.05 ± 3.28‰ vs. 2.01 ± 1.79‰). A total of 9534 differentially methylated regions (DMRs) were identified by WGBS, of which 4816 were hypomethylated and 4718 were hypermethylated. The Kyoto encyclopedia of genes and genomes (KEGG) pathway and gene ontology (GO) analyses showed the top three KEGG pathways were cancer , neuroactive ligand-receptor interaction, and axon guidance, and the top three GO-BP pathways enriched were multicellular organismal process, developmental process, and anatomical structure development. In the most enriched DMR pathway (pathways in cancer), we found that BCL2, TJP2, TAOK1, PFKFB3, LIPI, and LIPH were hypermethylated, and the methylation levels of BNIP1 and GRPEL2 were decreased. The methylation of differentially methylated genes (DMGs) mentioned above were verified by methylation-specific PCR (MSP) and agarose gel electrophoresis (AGE) in 50 pairs of subjects, where the coincidence rate was 60–100%. In conclusion, the epigenetic perturbations of specific DMGs ( BCL2, TJP2, TAOK1, PFKFB3, LIPI, LIPH, BNIP1, and GRPEL2) may be associated with DNA damage from vinyl chloride exposure.

Arsenic is a toxic metal, which ultimately leads to cell apoptosis. TLR4 signaling pathway played a key role in immunomodulatory. Therefore, alterations in related proteins on the TLR4 signaling pathway induced by arsenic exposure was systematically reviewed and analyzed by meta-analysis. Some databases were searched including PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and WANFANG MED ONLINE. The results of NF-κB, IKK, NF-κBp65, phospho-NF-κBp65, and TLR4 expressions were analyzed by Review Manage 5.3. In the arsenic intervention group, NF-κB, phospho-NF-κBp65, and TLR4 expression levels were higher than the control group, respectively. SMD and 95%CI were 11.29 (6.34, 16.24), 4.71(1.73, 7.68), and 5.79 (-4.22, 15.80). Compared to controls, in the exposed group, IKK levels were found to be 38.11-fold higher (Z = 0.97; P = 0.33); NF-κBp65 levels were found to be 0.92-fold higher (Z = 3.33; P = 0.0009) for normal cells and tissue, while IKK levels were found to be 5.18-fold lower (Z = 5.34; P 0.0001); NF-κBp65 levels were found to be 2.01-fold lower (Z = 3.87; P = 0.0001) for abnormal cells. With comparing of low dose, high dose of arsenic exposure was found to reduce the expression of NF-κB, but increase the expression of NF-κBp65. This review supports the alterations in related proteins on the TLR4 signaling pathway induced by arsenic exposure, which is helpful to provide theoretical basis for the mechanism of toxicity of arsenic-induced immune system damage.

There are numerous studies showing that exposure to arsenic (As) or fluoride (F) damages the nervous system, but there is no literature investigating the effects of combined As and F exposure to induce autophagy on neurotoxicity in the offspring. In this study, we developed a rat model of As and/or F exposure through drinking water from before pregnancy to 90 days postnatal. The offspring rats were randomly divided into nine groups. Sodium arsenite (NaAsO

Fluoride exposure may cause changes in blood pressure, but this conclusion is controversial. Therefore, this meta-analysis aims to investigate the potential relationship between fluoride exposure and blood pressure or hypertension. PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), WANFANG MED ONLINE, and Chinese Scientific Journals Full-Text Databases (VIP) were searched; in addition, two related studies were added manually. In total, 7 observational studies were identified, the pooled odds ratios (ORs) for hypertension between high and reference fluoride exposure groups were calculated, and the pooled standardized weighted mean difference (SMD) of systolic blood pressure (SBP) and diastolic blood pressure (DBP) was estimated using an inverse-variance weighted random-effects model; next, sensitivity analysis and subgroup analysis were used to assess potential sources of heterogeneity; furthermore, publication bias was assessed using the Begg and Egger test. In brief, there were no statistical differences between exposure groups and control groups in terms of blood pressure or hypertension when all included studies considered. However, subgroup analysis indicated that blood pressure will rise with the increase of fluoride exposure concentrations in endemic fluorosis areas. The corresponding pooled SMD estimates were 0.31 (95% CI 0.11, 0.51) and 0.27 (95% CI 0.11, 0.43) for SBP and DBP. Funnel plots suggested no asymmetry. Our findings support the possibility of a positive correlation between fluoride exposure and blood pressure in endemic fluorosis areas. Additional evidence is needed to assess the dose-response relationship between fluoride exposure and blood pressure.

Vinyl chloride (VC) is a common industrial organic chlorine and environmental pollutant. In recent years, the dietary structure of residents especially Chinese has gradually shifted to western dietary patterns. VC aggravates dietary fatty acid-induced hepatic steatosis, but its mechanism is still unclear. And if the risk factors for steatosis persist, more severe diseases such as fibrosis and cirrhosis will occur. Therefore, we studied the effects and mechanisms of VC (160 and 800 mg/m3 ) and its metabolite (chloroacetaldehyde, 2.25, 4.5, and 9 μM) on hepatic steatosis of high-fat diet (HFD)-fed mice and palmitic acid (PA, 100 μM) treated HepG2 cells. Liver and serum biochemical indicators and pathological staining of the liver showed that the hepatic steatosis of VC combined with HFD groups was more severe than that of single-exposure groups (HFD group, low-dose VC group, and high-dose VC group). Moreover, VC enhanced HFD-induced oxidative stress (OS) and endoplasmic reticulum stress (ERS) and further upregulated the expression of sterol regulatory element-binding protein 1 (SREBP-1) and FAS. Besides, antioxidants and ERS inhibitors reduced the steatosis of HepG2 cells induced by VC metabolites and PA. These results suggest that VC exposure can enhance the degree of hepatic steatosis in HFD-fed mice. VC combined with HFD led to OS and ERS and upregulated the expression of de novo lipogenesis-related proteins, which may be related to the occurrence of hepatic steatosis. And the increased expression of CYP2E1 induced by VC combined with HFD may be the cause of OS.

Nationwide mass social unrest has emerged in the US since May 25 and raised broad concerns about its impacts on the local COVID-19 epidemics. We compared the COVID-19 transmissibility between May 19-May 25 and May 29-June 4 for each state of the US. We found that social unrest is likely associated with the rebound of the COVID-19 transmissibility, which might raise difficulties in the pandemic control.

Many studies have shown that fluorosis due to long-term fluoride intake has damaging effects on the heart. However, the mechanisms underlying cardiac fluorosis have not been illuminated in detail. We performed high-throughput transcriptome sequencing (RNA-Seq) on rat cardiac tissue to explore the molecular effects of NaF exposure. In total, 372 and 254 differentially expressed genes (DEGs) were identified between a group given 30 mg/L NaF and control and between a group given 90 mg/L NaF and control, respectively. The transcript levels of most of these genes were significantly down-regulated and many were distributed in the Toll-like receptor signaling pathway. Transcriptome analysis revealed that herpes simplex infection, ECM-receptor interaction, influenza A, cytokine-cytokine receptor interaction, apoptosis, and Toll-like receptor signaling pathway were significantly affected. IL-6 and IL-10 may play a crucial role in the cardiac damage caused by NaF as external stimuli according to protein-protein interaction (PPI) network analysis. The results of qRT-PCR and Western blotting showed a marked decreased mRNA and protein levels of IL-1, IL-6, and IL-10 in the low concentration fluoride (LF) and high concentration fluoride (HF) groups, which was in agreement with RNA-Seq results. This is the first study to investigate NaF-induced cardiotoxicity at a transcriptome level.

Asthma is a complex chronic disease and the pathogenesis is still not entirely clear. In this study, we aimed to clarify the role and mechanism of miR-29b in the development of asthma. We observed that miR-29b levels were decreased in the lung and spleen of OVA-induced asthmatic mice. Reverse transcription-quantitative polymerase chain reaction and flow cytometry demonstrated that the inducible co-stimulator (ICOS) expression at mRNA and protein levels was elevated in the lung of asthmatic mice, and miR-29b expression in the lung of asthmatic mice was negatively associated with ICOS mRNA levels by Pearson Correlation analysis. Additional, flow cytometry showed that the percentage of CD4+ICOS+ T cells in the lung and spleen was regulated by miR-29b, and dual luciferase reporter assay confirmed ICOS was a target gene of miR-29b. Furthermore, miR-29b overexpression in asthmatic mice was induced with miR-29b agomir by intranasal administration; miR-29b alleviated total inflammatory cell infiltration and CCL24 levels, decreased IL-5 levels in bronchoalveolar lavage fluid and serum, and upregulated IFN-γ expression in serum. This study demonstrates that miR-29b targets ICOS, thereby reverses the imbalance of T helper 1 cells (Th1)/Th2 responses and decreases eosinophils recruitment in the airway, which are key features of allergic airway inflammation. Therefore, miR-29b might be an attractive candidate target for asthma treatment.

Co-exposure to inorganic arsenic (iAs) and fluoride (F−) and their collective actions on cardiovascular systems have been recognized as a global public health concern. Emerging studies suggest an association between the perturbation of gut bacterial microbiota and adverse cardiovascular effects (CVEs), both of which are the consequence of iAs and F− exposure in human and experimental animals. The aim of this study was to fill the gap of understanding the relationship among co-exposure to iAs and F−, gut microbiota perturbation, and adverse CVEs. We systematically assessed cardiac morphology and functions (blood pressure, echocardiogram, and electrocardiogram), and generated gut microbiota profiles using 16S rRNA gene sequencing on rats exposed to iAs (50 mg/L NaAsO2), F− (100 mg/L NaF) or combined iAs and F− (50 mg/L NaAsO2 + 100 mg/L NaF), in utero and during early postnatal periods (postnatal day 90). Correlation analysis was then performed to examine relationship between significantly altered microbiota and cardiac performance indices. Our results showed that co-exposure to iAs and F− resulted in more prominent effects in CVEs and perturbation of gut microbiota profiles, compared to iAs or F− treatment alone. Furthermore, nine bacterial genera (Adlercreutzia, Clostridium sensu stricto 1, Coprococcus 3, Romboutsia, [Bacteroides] Pectinophilus group, Lachnospiraceae NC2004 group, Desulfovibrio, and two unidentified genera in Muribaculaceae and Ruminococcaceae family), which differed significantly in relative abundance between control and iAs and F− co-exposure group, were strongly correlated with the higher risk of CVEs (correlation coefficient = 0.70–0.88, p

Exposure to arsenic (As) or fluoride (F) has been shown to cause cardiovascular disease (CVDs). However, evidence about the effects of co-exposure to As and F on myocardium and their mechanisms remain scarce. Our aim was to fill the gap by establishing rat and H9c2 cell exposure models. We determined the effects of As and/or F exposure on the survival rate, apoptosis rate, morphology and ultrastructure of H9c2 cells; in addition, we tested the related genes and proteins of endoplasmic reticulum stress (ERS) and apoptosis in H9c2 cells and rat heart tissues. The results showed that As and/or F exposure induced early apoptosis of H9c2 cells and caused endoplasmic reticulum expansion. Additionally, the mRNA and protein expression levels of GRP78, PERK and CHOP in H9c2 cells were higher in the exposure groups than in the control group, and could be inhibited by 4-PBA. Furthermore, we found that As and/or F exposure increased the expression level of GRP78 in rat heart tissues, but interestingly, the expression level of CHOP protein was increased in the F and As groups, while significantly decreased in the co-exposure group. Overall, our results suggested that ERS-induced apoptosis was involved in the damage of myocardium by As and/or F exposure. In addition, factorial analysis results showed that As and F mainly play antagonistic roles in inducing myocardial injury, initiating ERS and apoptosis after exposure.

Fluoride exposure may cause changes in blood pressure, but this conclusion is controversial. Therefore, this meta-analysis aims to investigate the potential relationship between fluoride exposure and blood pressure or hypertension. PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), WANFANG MED ONLINE, and Chinese Scientific Journals Full-Text Databases (VIP) were searched; in addition, two related studies were added manually. In total, 7 observational studies were identified, the pooled odds ratios (ORs) for hypertension between high and reference fluoride exposure groups were calculated, and the pooled standardized weighted mean difference (SMD) of systolic blood pressure (SBP) and diastolic blood pressure (DBP) was estimated using an inverse-variance weighted random-effects model; next, sensitivity analysis and subgroup analysis were used to assess potential sources of heterogeneity; furthermore, publication bias was assessed using the Begg and Egger test. In brief, there were no statistical differences between exposure groups and control groups in terms of blood pressure or hypertension when all included studies considered. However, subgroup analysis indicated that blood pressure will rise with the increase of fluoride exposure concentrations in endemic fluorosis areas. The corresponding pooled SMD estimates were 0.31 (95% CI 0.11, 0.51) and 0.27 (95% CI 0.11, 0.43) for SBP and DBP. Funnel plots suggested no asymmetry. Our findings support the possibility of a positive correlation between fluoride exposure and blood pressure in endemic fluorosis areas. Additional evidence is needed to assess the dose-response relationship between fluoride exposure and blood pressure.

Hypertension is a common chronic disease in middle-aged and elderly people and is an important risk factor for many cardiovascular diseases. Its pathogenesis remains unclear. Epidemiological studies have found that the loss of telomere length in peripheral blood cells can increase the risk of coronary heart disease, myocardial infarction, and other diseases. However, a correlation between loss of telomere length and hypertension has not been established. In this study, we aimed to explore the association between telomere length and the risk of essential hypertension (EH) in Chinese coal miners. A case-control study was performed with 215 EH patients and 222 healthy controls in a large coal mining group located in North China. Face-to-face interviews were conducted by trained staff with the necessary medical knowledge. Relative telomere length (RTL) was measured by a quantitative real-time PCR assay using DNA extracted from peripheral blood. In the control group, the age-adjusted RTL was statistically significantly lower in miners performing hard physical labour compared with nonphysical labour ( P = 0.043 ). A significantly shorter age-adjusted RTL was found in the control group of participants who consumed alcohol regularly compared with those who do not consume alcohol ( P = 0.024 ). Age-adjusted RTL was negatively correlated with body mass index (BMI) and alcohol consumption. Hypertension was also found to be significantly correlated with factors such as age, BMI, alcohol consumption, smoking, and tea consumption. Our results suggest that RTL is associated with hypertension in coal miners.

While numerous studies have shown that fluoride or arsenic exposure may damage the reproductive system, there are few reports of co-exposure to fluoride and arsenic. In addition, the literature on autophagy and intestinal flora composition in reproductive toxicity studies of co-exposure to fluoride and arsenic is insufficient. In this study, we developed a rat model of fluoride and arsenic exposure via drinking water from pre-pregnancy to 90 days postnatal. Sprague-Dawley rats were randomly divided into sterile water control group, fluoride group (100 mg/L NaF), arsenic group (50 mg/L NaAsO2) and combined exposure group (100 mg/L NaF+50 mg/L NaAsO2). Our results showed that fluoride and arsenic exposure caused a reduction in testicular weight and significant pathological damage to tissue. We found that the levels of follicle-stimulating hormone, luteinizing hormone, and testosterone were reduced to varying degrees. Meanwhile experiments showed that fluoride and arsenic exposure can modulate autophagic flux, causing increased levels of Beclin1 and LC3 expression and decreased p62 expression. Analogously, by performing 16S sequencing of rat feces, we found 24 enterobacterial genera that differed significantly among the groups. Furthermore, the flora associated with testicular injury were identified by correlation analysis of hormonal indices and autophagy alterations with intestinal flora composition at the genus level, respectively. In summary, our study shows that fluoride and arsenic co-exposure alters autophagic flux in the testis, causes testicular injury, and reveals an association between altered intestinal flora composition and testicular injury.

Streptococcus pneumoniae is a leading cause of infectious diseases in children under 5-year-old. Vaccine has been used as an indispensable strategy to prevent S. pneumoniae infection for more than 30 years. Our previous studies confirmed that mucosal immunization with live attenuated strain SPY1 can protect mice against nasopharyngeal colonization of S. pneumoniae and lethal pneumococcal infection, and the protective effects are comparable with those induced by commercially available 23-valent polysaccharide vaccine. However, live attenuated vaccine SPY1 needs four inoculations to get satisfactory protective effect, which may increase the risk of virulence recovery. It is reported that heterologous primeboost approach is more effective than homologous primeboost approach. In the present study, to decrease the doses of live SPY1 and improve the safety of SPY1 vaccine, we immunized mice with SPY1 and DnaJ protein alternately. Our results showed that heterologous prime-boost immunization with SPY1 and DnaJ protein could significantly reduce the colonization of S. pneumoniae in the respiratory tract of mice, and induce stronger Th1 and Th17 cellular immune responses than SPY1 alone. These results indicate heterologous prime-boost immunization method not only elicits better protective effect than SPY1 alone, but also reduces the doses of live SPY1 and decreases the risk of SPY1 vaccine. This work is the first time to study the protective efficiency with two different forms of S. pneumoniae candidate vaccine, and provides a new strategy for the development of S. pneumoniae vaccine.

Numerous studies have shown that chronic excessive fluoride intake can adversely affect different organ systems. In particular, the cardiovascular system is susceptible to disruption by a high concentration of fluoride. The objectives of this study were to explore the mechanism of apoptosis by detecting the toxic effects of different concentrations of sodium fluoride (NaF) in H9c2 cells exposed for up to 96 h. NaF not only inhibited H9c2 cell proliferation but also induced apoptosis and morphological damage. With increasing NaF concentrations, early apoptosis of H9c2 cells was increased while the mitochondrial membrane potential was decreased. Compared with the control group, the mRNA levels of caspase-3, caspase-9, and cytochrome c all increased with increasing concentrations of NaF. In summary, these data suggest that apoptosis is involved in NaF-induced H9c2 cell toxicity and that activation of the mitochondrial pathway may occur.

Tuberculosis (TB) remains a significant challenge to public health, especially in developing countries. Failure in early diagnosis and lack of rapid and accurate diagnostic methods lead to ongoing prevalence and transmission of TB. Recently, the recombinase polymerase amplification (RPA) technique has made it possible to rapidly amplify and detect nucleic acids without specialized devices. We developed a RPA-based method for identifying Mycobacterium tuberculosis (MTB) by detecting mts90, a more specific target identified in our previous research. Different screening methods were employed for selecting a preferred primer pair of amplification, and probes were confirmed as very fast and reliable tools in the screening of potential primer candidates. The results showed that the mts90 RPA assay was very sensitive and capable of detecting 6 copies of recombinant plasmid containing mts90 sequence per reaction. The assay was specific for detecting MTB, as it did not identify the genomic DNA from other mycobacteria and pathogens. When applied to analyze clinical samples, including sputum, bronchoalveolar lavage fluid (BALF) and tissues, the mts90 RPA assay had a coincidence rate of 96.43% (27/28) compared to the Biochip test, which has been used in clinics for diagnosing TB. The mts90 RPA assay can be completed within 20 minutes at 39 °C without thermal cycling; its simple operation and rapid detection suggest RPA-based MTB assays could be further developed for TB diagnosis in resource-poor settings.

Background Course quality assessment contributes to evaluate teaching effectiveness and to improve student learning. Several course quality assessment questionnaires have been carried out associated with teaching quality evaluation of medical education. However, little is known about views of medical students regarding the quality of preclinical courses. To fill this gap, we aimed to develop a novel multi-dimension instrument for assessing teaching quality with the perception of medical students in preclinical courses.Methods The original Teaching Quality Evaluation Questionnaire (TQEQ) containing seven dimensions: course contents, teaching abilities, teaching methods, teaching attitudes, learning outcomes, teacher characteristics, student subjection, consisting of 47 items was formed according to literature reviews and group design. We sent the original questionnaires with items in a random order to medical students of Shanghai Jiao Tong University School of Medicine. After collecting the valid questionnaires, the exploratory factor analysis was conducted to assess construct validity and Cronbach’s alpha coefficient was used for evaluating internal consistency reliability of the questionnaires.Results In total, 590/646 (91.3%) of participants completed the questionnaire regarding preclinical course evaluation. The exploratory factor analysis yielded seven common factors, learning outcomes, teaching attitudes, student subjection, teaching abilities, teaching methods, teacher characteristics, teaching interactions, consisting of 39 items explained 58.449% of total variance and the factor loading value was above 0.4. In addition, Cronbach’s alpha coefficients ranged from 0.669 to 0.914.Conclusion This study provides a new, validated and useful instrument for measuring teaching effectiveness of preclinical courses based on the views of medical students. It is feasible for use in medical schools.

Arsenic and fluoride are two of the major groundwater pollutants. To better understand the liver damage induced during development, 24 male rats exposed to fluoride (F), arsenic (As), and their combination (As + F) from the prenatal stage to 90 days after birth were selected for analysis. Histopathological results showed vacuolar degeneration in the As and As + F groups. Compared to those in the control group, aspartate aminotransferase and alanine aminotransferase levels were significantly increased in the combined group. Catalase activity significantly decreased in the treatment groups compared to that in the controls, and the malondialdehyde content in the As and As + F groups was significantly higher than those in the control group. We further evaluated whether this damage is linked to endoplasmic reticulum stress and its related pathways. The mRNA expression levels of PERK, GRP78, EIF2α, ATF4, and CHOP as well as the protein levels of CHOP was significantly increased in the As + F group compared with the control group. These results demonstrate that As, F, and their combination could lead to liver function damage and reduce the antioxidant capacity of the liver to cause oxidative damage to tissues. Moreover, the combination of As and F triggers endoplasmic reticulum stress-induced apoptosis in liver cells by activating the PERK pathway in the unfolded protein response. As and F seem to have different independent effects, whereas their combination resulted in more severe effects overall.

Underground drinking water is commonly contaminated with arsenite (As) and fluoride (F) associated with chronic kidney diseases in humans; however, the combined renal toxicity of these pollutants and the underlying mechanisms are still unclear. The aim of the present study was to investigate the interaction between As and F regarding toxic effects on the kidney of rat offspring exposed to pollutants during prenatal and postnatal development. Pregnant rats were randomly divided into four groups that received NaAsO2 (50 mg/L), NaF (100 mg/L), NaAsO2 (50 mg/L) and NaF (100 mg/L) in drinking water, or clean water, respectively, during gestation and lactation. After weaning, six male pups were randomly selected from each group and continued on the same treatment as their mothers for up to three months. The results revealed that subchronic exposure to high-dose As and/or F decreased the organ coefficient of the kidneys and disrupted kidney ultrastructure, moreover inhibited the activity of antioxidant enzymes and increased the generation of malondialdehyde in the kidney. As exposure alone or combined with F led to an upregulation of nuclear factor erythroid 2-related factor-2 (Nrf2) and its regulatory targets (Ho-1, Gclc, and Nqo1), whereas the effect of F alone was not significant. These results suggest that the renal toxicity of As and F is associated with the induction of mitochondrial damage and oxidative stress, and alters the expression of Nrf2 and its regulatory targets. Furthermore, variance analysis results showed that an interaction between As and F in the toxicity process.

Background: Mast cells participate in immune responses by releasing potent immune system modifiers via degranulation. Due to currently reported controversial roles of mast cells in Streptococcus pneumoniae infections, this study aimed to determine the role and mechanism of mast cells in clearing S. pneumoniae in mice. Methods: In vivo mouse model of mast cell degranulation established by administration of C48/80 was evaluated for the influences of mast cell degranulation on bacterial colonization and inflammation. In vitro model was established to observe the influences of mast cell degranulation on phagocytic and bactericidal functions of neutrophils and macrophages. IL-6 null and TNF-α null mice on the C57BL/6 background were used to investigate the effects of inflammatory factors released by mast cell degranulation on bacterial clearance. Results: Mast cell degranulation increased IL-6 and TNF-α levels and immune cell numbers in nasal lavage fluid, and inhibited the bactericidal function of macrophages and neutrophils in vitro. It decreased the number of neutrophils and macrophages recruited to respiratory tract after S. pneumoniae challenge and inhibited the clearance of S. pneumoniae in mice. After pretreatment with C48/80, S. pneumoniae loads were significantly lower in IL-6 null mice than in wild type mice, while no differences were observed between TNF-α null and wild type mice. Conclusions: Mast cell degranulation can cause inflammation and impair immune cell recruitment to respiratory tract after S. pneumoniae challenge. Products of mast cell degranulation including IL-6 decreased the bactericidal function of neutrophils and macrophages. Through these mechanisms, mast cell degranulation inhibited clearance of S. pneumoniae in mice. Keywords: Degranulation, Inflammatory response, Mast cell, Streptococcus pneumoniae

Recent studies suggested that long-term exposure to fine particulate matter (PM2.5) was related to a higher risk of dementia incidence or hospitalizations in western populations, but the evidence is limited in Asian cities. Here we explored the link between long-term PM2.5 exposure and dementia incidence in the Hong Kong population and whether it varied by population sub-group. We utilized a Hong Kong Chinese cohort of 66,820 people aged ≥65 years who were voluntarily enrolled during 1998–2001 and were followed up to 2011. Prevalent dementia cases were excluded based on the face-to-face interview at baseline. We ascertained the first occurrence of hospitalization for all-cause dementia and major subtypes during the follow-up period. We assessed PM2.5 concentrations using a satellite data-based model with a 1 × 1 km2 resolution on the residential address. Cox proportional hazards models were adopted to estimate associations of annual mean PM2.5 exposure with dementia incidence, adjusting for potential confounders. We identified 1183 incident cases of all-cause dementia during the follow-up period, of which 655 (55.4%) were cases of Alzheimer’s disease, and 334 (28.2%) were those of vascular dementia. We found a positive association between annual mean PM2.5 exposure and all-cause dementia incidence in the fully adjusted model. The estimated hazard ratio was 1.06 (95% confidence interval (CI): 1.00, 1.13) per every 3.8 μg/m3 increase in annual mean PM2.5 exposure. And the estimated HRs for Alzheimer’s disease and vascular dementia were 1.03 (95% CI: 0.94, 1.12) and 1.09 (95% CI: 0.98, 1.22), respectively. We did not find effect modifications by age, sex, BMI, hypertension, diabetes, or heart disease on the associations. Results suggest that long-term exposure to PM2.5 is associated with a higher risk of dementia incidence in the Asian population.

Many “hot spot” geographic areas across the world with drinking water co-contaminated with inorganic arsenic (iAs) and fluoride (F-), two of the most common natural contaminants in drinking water. Both iAs and F- are known neurotoxins and affect neurodevelopment of children. However, very few studies have investigated the neurodevelopmental effects of concurrent exposure to iAs and F-, which could potentially pose a greater risk than iAs or F- exposure alone. Further, perturbations of gut microbiota, which plays a regulatory role in neurodevelopment, resulting from iAs and F- exposure has been reported in numerous studies. There is lacking of information regarding to the relationship among concurrent iAs and F- exposure, microbiome disruption, and neurodevelopmental impacts. To fill these gaps, we treated offspring rats to iAs (50 mg/L NaAsO2) and F- (100 mg/L NaF), alone or combined from early life (in utero and childhood) to puberty. We applied Morris water maze test to assess spatial learning and memory of these rats and generated gut microbiome profiles using 16S rRNA gene sequencing. We showed that concurrent iAs and F- exposure caused more prominent neurodevelopmental effects in rats than either iAs or F- exposure alone. Moreover, Unsupervised Principal Coordinates Analysis (PCoA) and Linear Discriminant Analysis Effect Size (LEfSe) analysis of gut microbiome sequencing results separated concurrent exposure group from others, indicating a more sophisticated change of gut microbial communities occurred under the concurrent exposure condition. Further, a correlation analysis between indices of the water maze test and microbial composition at the genus level identified featured genera that were clearly associated with neurobehavioral performance of rats. 75% (9 out of 12) genera, which had a remarkable difference in relative abundance between the control and combined iAs and F- exposure groups, showed significantly strong correlations (r = 0.70–0.90) with the water maze performance indicators. Collectively, these results suggest that concurrent iAs and F- exposure led to more prominent effects on neurodevelopment and gut microbiome composition structures in rats, and the strong correlation between them indicates a high potential for the development of novel microbiome-based biomarkers of iAs and/or F- associated neurodevelopmental deficits.

Streptococcus pneumoniae is a major pathogen leading to substantial morbidity and mortality in children under 5 years of age. Vaccination is an effective strategy to prevent S. pneumoniae infection. SPY1 is a pneumococcal vaccine candicate strain obtained in our previous study. To improve its stability and immunogencity, in this study, we constructed the SPY1△lytA strain which lacks autolysin activity and was coated with an artificial exterior surface calcium phosphate shell by in situ mineralization. The resulting strain SPY1△lytACaPi displayed enhanced thermal stability enabling storage at 37oC for one week. Furthermore, mucosal and subcutaneous immunization with the SPY1△lytACaPi strain induced better protective effects than SPY1△lytA in anti-colonization after challenging with 19F and anti-invasion by D39 in mice. Subcutaneous immunization with SPY1△lytACaPi elicited higher IgG level while mucosal immunization primarily elicited an immune response which is supposed to be related to Th17 cells. Taken together, the mineralized strain may be a promising candidate for an attenuated S. pneumoniae vaccine.

In humans, arsenic is primarily metabolized by arsenic (+3 oxidation state) methyltransferase (As3MT) to yield both trivalent and pentavalent methylated metabolites. We recently reported that the putative N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) can biotransform monomethylarsonous acid (MMA(III)) to dimethylarsinic acid, conferring resistance of human cells to arsenic exposure. To further decipher the role of N6AMT1 and its interaction with As3MT in arsenic biomethylation, we examined the relative contribution of N6AMT1 and As3MT in metabolizing arsenic using several newly modified UROtsa human urothelial cells, ie, UROtsa cells with either a constant level of N6AMT1 or As3MT in combination with an inducible level of As3MT or N6AMT1, respectively. Our analysis confirmed the involvement of N6AMT1 in MMA(III) biomethylation but not for inorganic arsenic. In a comparable level of N6AMT1 and As3MT, the effect of N6AMT1 mediated MMA(III) biomethylation was obscured by the action of As3MT. Furthermore, we showed that the levels of N6AMT1 and As3MT proteins varied among and within human normal and cancerous tissues. Overall, the data showed that N6AMT1 has a role in MMA(III) biomethylation, but its effect is relatively minor and limited compared with As3MT. In addition, the varied levels and distributions of N6AMT1 and As3MT among human tissues may potentially contribute to the tissue specificity and susceptibility to arsenic toxicity and carcinogenicity.

Chronic excessive fluoride intake is known to be toxic, and effects of long-term fluorosis on different organ systems have been examined. However, there are few studies about the effects of fluorosis on cardiovascular systems. Here, we studied the fluoride-induced apoptosis in H9c2 cells and determined the underlying molecular mechanisms including the cell viability, intracellular reactive oxygen species (ROS) level, the changes of mitochondrial membrane potential (ΔΨm), and the cell apoptosis. Sodium fluoride (NaF) at concentrations of 0, 2, 4, 8, and 16 mg/L was administered to cultured H9c2 cells for up to 48 h. After the treatment, H9c2 cells were collected and the associated parameters were measured by flow cytometry. Our study found that fluoride not only inhibited H9c2 cell proliferation but also induced cell apoptosis. With the increment of NaF concentration, the apoptotic rates and ROS generation were increased, while the ΔΨm was decreased. In summary, these data suggested that NaF-induced H9c2 cell apoptosis is mediated by direct increased intracellular ROS and downregulated ΔΨm.

The 1/2ABC formula is the method most commonly used in clinical practice to rapidly estimate intracerebral hemorrhage (ICH) volume. We aimed to compare this method with the alternative '2/3Sh' formula for both regularly and irregularly-shaped hematomas.Computed tomography (CT) images from 344 ICH patients (median volume: 16·66 ml) were retrospectively reviewed. According to the maximum slice, the shape was classified into regular or irregular (multilobular, conical, and other). Volumes as determined by the 1/2ABC and 2/3Sh formulas were compared against the gold standard, computer-assisted planimetry, for various hematoma shapes.With the 1/2ABC method, errors were seen non-significantly more frequently for irregularly-shaped hematomas [OR: 2.85 (95% CI: 0.65-12.50)]. The 1/2ABC method misclassified a greater proportion of hematomas as greater or less than 30 ml in volume: 7.0% (95% CI: 6.0-9.9%). Both the 1/2ABC and 2/3Sh formulas correlated well with gold standard (correlation coefficients0.9 for each shape). While there was no statistically significant measurement error bias for either method, the 95% confidence intervals of the limit of agreement for 2/3Sh were tighter: -0.22 ml (-4.7-4.25 ml) versus 2·50 ml (-10.35-15.34 ml). Measurement errors were significantly greater with the 1/2ABC method, for both regular and irregular hematomas [1.17 ml (0.48-2.83 ml) versus 0.88 ml (0.42-1.68 ml) and 2.65 ml (1.07-5.88 ml) versus 0·99 ml (0.47-2.28 ml); P0.05, respectively], although the magnitude of error would only rarely be clinically relevant for regular hematomas. Errors were most evident in assessing multilobular-shaped hematomas [6.49 ml (3.35-13.98 ml) versus 1.86 ml (0.96-9.94 ml); P0·001].The 2/3Sh formula leads to fewer clinically-relevant hematoma volume misclassifications than the 1/2ABC formula, and is particularly superior in estimating volumes of irregularly-shaped hematomas.

DNA damage induced by benzene reactive metabolites is thought of as an important mechanism underlying benzene hematotoxicity and genotoxicity, and genetic variation in cell-cycle control genes may contribute to susceptibility to chronic benzene poisoning (CBP). Using a case-control study that included 307 benzene-poisoned patients and 299 workers occupationally exposed to benzene in south China, we aimed to investigate the association between genetic polymorphisms of p53 and p21 and the odds of CBP. To investigate whether benzene exposure may influence mRNA expression of p53 and p21 in benzene-exposed workers, we also chose 39 CBP workers, 38 occupationally benzene-exposure workers, and 37 nonexposure workers in the same region of China. PCR-restriction fragment length polymorphism technique was applied to detect polymorphisms of p53 (rs17878362, rs1042522, and rs1625895) and p21 (rs1801270 and rs1059234), and real-time PCR was applied to detect the quantity of gene mRNA expression. We found that p21 C98A variant genotypes (CA+AA) or C70T variant genotypes (CT+TT) were associated with decreased odds of CBP [odds ratio (OR), 0.51; 95% confidence interval (95% CI), 0.32-0.83, and OR, 0.53; 95% CI, 0.29-0.95, respectively. Further analysis showed the decreased odds of CBP in the subjects with p21 CC/AT diplotype (OR, 0.51; 95% CI, 0.30-0.85). In addition, p53 mRNA expression of CBP workers or benzene-exposure workers was significantly lower than that of nonexposure workers. Although these results require confirmation and extension, our results show that polymorphisms in p21 may be protective against the risk of CBP in the Chinese occupational population. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1821–8)

Vinyl chloride monomer (VCM) is genotoxic and cancerogen agent. Individual variations in response to the exposure have been noticed and the variations may be due to genetic differences in the removal of VCM-DNA adducts, such as polymorphism in genes NER pathway and BER pathway. This study explores the relationship between genetic polymorphism of seven genes within the NER pathway (XPA, XPD, XPC, XPG, XPF, and ERCC1) and BER pathway (APE1), and susceptibility to chromosomal damage after exposure to VCM. One hundred and eighty workers occupationally exposed to VCM and 43 unexposed controls were investigated. Chromosome damage in peripheral lymphocytes was measured by the cytokinesis-blocked micronucleus assay. PCR-RFLP technique was applied to detect polymorphisms of the seven genes. The influence of genotype, age, gender, cumulative exposure dose, alcohol consumption, and smoking status on the frequencies of MN was determined using univariate and multiple Poisson regression analyses. We found XPA A23G variant workers had significantly higher MN frequencies than those from the wild-type homozygous counterparts (P = 0.01). Those with the variant XPD Lys751Gln genotype had marginally higher MN frequencies (P = 0.07). On the other hand, XPC PAT and XPF 5'-UTR T2063A variant workers had significantly lower MN frequencies compared with those from their wild-type homozygous counterparts (P = 0.04 and P = 0.004, respectively). Our findings suggest that XPC PAT, XPD Lys751Gln, XPA A23G and XPF 5'-UTR T2063A contribute to the level of chromosome damage in occupational exposure to VCM in Chinese population.