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Background The transcription factor NFIL3 exerts comprehensive effects on the immune system. Previous studies revealed that NFIL3 is related to the function and development of different immune cell subsets. Experimental autoimmune encephalomyelitis (EAE) is mediated by immune cells which results in inflammatory demyelination in the central nervous system (CNS). However, how NFIL3 affects EAE has not been thoroughly studied. Objectives The current study aimed to investigate how NFIL3 affects EAE, especially the changes of T cells and dendritic cells as well as the crosstalk between them. Methods We used NFIL3-/- mice and C57BL/6J mice (wildtype) to establish MOG35-55-induced EAE. The clinical scores were recorded daily. The immune cells within and outside the CNS of EAE mice were analyzed by flow cytometry. Histology was used to evaluated the neuroinflammation and demyelination in the CNS. Besides, CD11c+ dendritic cells (DCs) were cocultured with T cells and the interplay was measured. Results At the peak of EAE, Th17 cells decreased within the CNS accompanying with lower clinical scores and milder neuroinflammation and demyelination in NFIL3 knockout EAE mice. Outside the CNS, PD-1 and ICOS on CD4+T cells increased, whereas Th2, Th9, CD8+CD103+T cells and GM-CSF+CD4+T cells decreased. Besides, the pro-inflammatory capacity of NFIL3-/- CD11c+ dendritic cells was impaired while the anti-inflammatory capacity was promoted. Conclusions This study suggests that NFIL3 deficiency could alleviate MOG35-55-induced EAE through regulating different immune cell subsets, which is not only related with adaptive immunity and innate immunity, but also related with the cross-talk between them, especially CD4+ T cells and CD11c+ dendritic cells.

Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target for heart failure. However, BCAA catabolic enzymes are ubiquitously expressed in all cell types and a systemic BCAA catabolic defect is also manifested in metabolic disorder associated with obesity and diabetes. Therefore, it remains to be determined the cell-autonomous impact of BCAA catabolic defect in cardiomyocytes in intact hearts independent from its potential global effects. In this study, we developed two mouse models. One is cardiomyocyte and temporal-specific inactivation of the E1α subunit (BCKDHA-cKO) of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which blocks BCAA catabolism. Another model is cardiomyocyte specific inactivation of the BCKDH kinase (BCKDK-cKO), which promotes BCAA catabolism by constitutively activating BCKDH activity in adult cardiomyocytes. Functional and molecular characterizations showed E1α inactivation in cardiomyocytes was sufficient to induce loss of cardiac function, systolic chamber dilation and pathological transcriptome reprogramming. On the other hand, inactivation of BCKDK in intact heart does not have an impact on baseline cardiac function or cardiac dysfunction under pressure overload. Our results for the first time established the cardiomyocyte cell autonomous role of BCAA catabolism in cardiac physiology. These mouse lines will serve as valuable model systems to investigate the underlying mechanisms of BCAA catabolic defect induced heart failure and to provide potential insights for BCAA targeted therapy.

Myocardial hypertrophy leads to heart failure (HF), and emerging researchers have illustrated that long noncoding RNAs (lncRNAs) modulate myocardial hypertrophy. Here, we explored the role and mechanism of a novel lncRNA, NBR2, in modulating angiotensin II (Ang II)-induced myocardial hypertrophy. First, we examined plasma NBR2 levels in 25 patients with HF and myocardial hypertrophy and ten healthy donors and analyzed the correlation between NBR2 profiles and patients' clinical indicators. In addition, the overexpression experiment of NBR2 was carried out to probe the influence of NBR2 on myocardial hypertrophy. lncRNA NBR2 was down-regulated in plasma of patients with HF and myocardial hypertrophy (vs. healthy controls), and its level was negatively correlated with cardiac function (represented by left ventricular end-diastolic diameter and left ventricular ejection fraction) and degree of myocardial hypertrophy. Besides, Ang II treatment intensified the hypertrophy of human myocardial cell lines (HCM and AC16) and curbed the NBR2 expression. Overexpressing lncRNA NBR2 alleviated Angiotension II-induced myocardial hypertrophy and declined the profiles of hypertrophic markers. Moreover, up-regulating lncRNA NBR2 weakened Ang II-mediated endoplasmic reticulum (ER) stress and activated the LKB1/AMPK/Sirt1 pathway. Interfering with the LKB1/AMPK/Sirt1 axis abated the lncRNA NBR2-mediated inhibitory effect on myocardial hypertrophy and ER stress. This study confirmed that lncRNA NBR2 dampened myocardial hypertrophy and ER stress by modulating the LKB1/AMPK/Sirt1 pathway. Our study provides the first evidence that lncRNA NBR2 is positively associated with myocardial hypertrophy.

Background and Objective: Limited studies are available for male patients with anti-aquaporin-4 antibody (AQP4-Ab)-positive late-onset neuromyelitis optica spectrum disease (LONMOSD). The aim of this study was to investigate the clinical characteristics of Chinese male patients with AQP4-Ab-positive LONMOSD. Methods: We retrospectively reviewed the medical records of 12 male patients with LONMOSD, 16 male patients with early-onset NMOSD (EONMOSD), and 64 female patients with LONMOSD. These enrolled patients were classified according to the age of onset: LONMOSD (≥50 years of age at onset) versus EONMOSD (Results: Compared with female LONMOSD patients, male LONMOSD patients had less frequent transverse myelitis (TM) at onset (8.33 vs. 53.13%, p = 0.004) and lower Expanded Disability Status Scale (EDSS) scores (median 1 vs. 4, p = 0.036). Compared with male EONMOSD patients, male LONMOSD patients had a shorter time from onset to diagnosis (0.85 months vs. 6.00 months, p = 0.04). Conclusion: Less common TM at onset, less disease severity, and shorter time from onset to diagnosis probably occur in male LONMOSD patients.

Gonorrhea is one of the most common sexually transmitted diseases worldwide. To cure infection and prevent transmission, timely and appropriate antimicrobial therapy is necessary. Unfortunately, Neisseria gonorrhoeae, the etiological agent of gonorrhea, has acquired nearly all known mechanisms of antimicrobial resistance (AMR), thereby compromising the efficacy of antimicrobial therapy. Treatment failure resulting from AMR has become a global public health concern. Whole-genome sequencing is an effective method to determine the AMR characteristics of N. gonorrhoeae. Compared with next-generation sequencing, the MinION sequencer (Oxford Nanopore Technologies (ONT)) has the advantages of long read length and portability. Based on a pilot study using MinION to sequence the genome of N. gonorrhoeae, we optimized the workflow of sequencing and data analysis in the current study. Here we sequenced nine isolates within one flow cell using a multiplexed sequencing strategy. After hybrid assembly with Illumina reads, nine integral circular chromosomes were obtained. By using the online tool Pathogenwatch and a BLAST-based workflow, we acquired complete AMR profiles related to seven classes of antibiotics. We also evaluated the performance of ONT-only assemblies. Most AMR determinants identified by ONT-only assemblies were the same as those identified by hybrid assemblies. Moreover, one of the nine assemblies indicated a potentially novel antimicrobial-related mutation located in mtrR which results in a frame-shift, premature stop codon, and truncated peptide. In addition, this is the first study using the MinION sequencer to obtain complete genome sequences of N. gonorrhoeae strains which are epidemic in China. This study shows that complete genome sequences and antimicrobial characteristics of N. gonorrhoeae can be obtained using the MinION sequencer in a simple and cost-effective manner, with hardly any knowledge of bioinformatics required. More importantly, this strategy provides us with a potential approach to discover new AMR determinants.

Disruptions of the circadian rhythm and reduced circulating levels of the circadian hormone melatonin predispose to ischemic stroke. Although the nuclear receptor RORα is considered as a circadian rhythm regulator and a mediator of certain melatonin effects, its potential role in cerebral ischemia-reperfusion (CI/R) injury and in the neuroprotective effects of melatonin remain undefined. Here, we observed that CI/R injury in RORα-deficient mice was associated with greater cerebral infarct size, brain edema, and cerebral apoptosis compared with wild-type model. In contrast, transgenic mice with brain-specific overexpression of RORα versus non-transgenic controls exerted significantly reduced infarct volume, brain edema and apoptotic response induced by CI/R. Mechanistically, RORα deficiency was found to exacerbate apoptosis pathways mediated by endoplasmic-reticulum stress and mitochondria and aggravate oxidative/nitrative stress after CI/R. Further studies revealed that RORα deficiency intensified the activation of nuclear factor-κB signaling induced by CI/R. Given the emerging evidence of RORα as an essential melatonin activity mediator, we further investigated the RORα roles in melatonin-exerted neuroprotection against acute ischemic stroke. Melatonin treatment significantly decreased infarct volume and cerebral apoptosis; mitigated endoplasmic reticulum stress and mitochondrial dysfunction; and inhibited CI/R injury-induced oxidative/nitrative stress and nuclear factor-κB activation, which was eradicated in RORα-deficient mice. Collectively, current findings suggest that RORα is a novel endogenous neuroprotective receptor, and a pivotal mediator of melatonin's suppressive effects against CI/R injury.

ObjectivesTo characterise the prevalence and distribution of human papillomavirus (HPV) types in genital warts in Xi’an, China.MethodsThis prospective study was conducted in Shaanxi Provincial Institute for Skin Disease and STD Control (SPISSC) between September 2014 and April 2017. Genital wart samples were obtained from 879 patients, including 512 men and 367 women. HPV genotyping was performed by using an automatic nucleic acid hybridisation system.ResultsOf the 879 patients with genital warts, the detectable rates of low-risk, high-risk and total HPV types were 45.4%, 34.5% and 57.8%, respectively. The detectable rate of low-risk HPV types (45.4%) was significantly higher than that of high-risk HPV types (34.5%) (χ2=21.85, p2=23.90, pConclusionsThe results of this study suggest that low-risk HPV types are major pathogens of genital warts, but high-risk HPV type infections and multiple HPV type coinfections are also common in genital warts. HPV6, 11, 52 and 16 are the four most common HPV types in genital wart in Xi’an, China.

Objectives Amphotericin B plus flucytosine is the most widely used induction therapy regimen for non-HIV-infected and non-transplant patients; however, the therapeutic outcomes are unsatisfactory, especially when two antifungal drugs are at sub-therapeutic doses. Methods In this study of induction therapy, all non-HIV-infected, non-transplant patients with a first episode of cryptococcal meningitis were divided into two groups. In group I, the patients received amphotericin B plus 5-flucytosine. In group II, in addition to amphotericin B and 5-flucytosine, the patients also received fluconazole. Results In this study, 32 patients were included in group I, and the other 30 were in group II. Although patients from group II had higher fungal burdens with approximately 2100 Cryptococci/ml CSF before treatment, they had a significantly higher frequency of satisfactory outcomes (80% vs. 50%, respectively, P = 0.014). Less time for more patients in group II to have CSF sterilization (P = 0.021; P = 0.046). And more patients in group II had improved neurological function circumstances evaluated by comparing the BMRC staging between patients at discharge and follow-up 10 weeks (P = 0.032). No significant difference was observed in the incidence of adverse events between the two groups. Conclusion Triple therapy a superior alternative induction regimen for patients with non-HIV- and non-transplant-associated cryptococcal meningitis.

Synaptic neurodegeneration is thought to be an early event initiated by soluble β-amyloid (Aβ) aggregates that closely correlates with cognitive decline in Alzheimer disease (AD). Apolipoprotein e4 (APOE4) is the most common genetic risk factor for both familial AD (FAD) and sporadic AD; it accelerates Aβ aggregation and selectively impairs glutamate receptor function and synaptic plasticity. However, its molecular mechanisms remain elusive and these synaptic deficits are difficult to monitor. AD- and APOE4-dependent plasma biomarkers have been proposed, but synapse-related plasma biomarkers are lacking. We evaluated neuronal pentraxin 1 (NP1), a potential CNS-derived plasma biomarker of excitatory synaptic pathology. NP1 is preferentially expressed in brain and involved in glutamate receptor internalization. NP1 is secreted presynaptically induced by Aβ oligomers, and implicated in excitatory synaptic and mitochondrial deficits. Levels of NP1 and its fragments were increased in a correlated fashion in both brain and plasma of 7–8 month-old E4FAD mice relative to E3FAD mice. NP1 was also found in exosome preparations and reduced by dietary DHA supplementation. Plasma NP1 was higher in E4FAD+ (APOE4+/+/FAD+/−) relative to E4FAD- (non-carrier; APOE4+/+/FAD−/−) mice, suggesting NP1 is modulated by Aβ expression. Finally, relative to normal elderly, plasma NP1 was also elevated in patients with mild cognitive impairment (MCI) and elevated further in the subset who progressed to early-stage AD. In those patients, there was a trend towards increased NP1 levels in APOE4 carriers relative to non-carriers. These findings indicate that NP1 may represent a potential synapse-derived plasma biomarker relevant to early alterations in excitatory synapses in MCI and early-stage AD.

Objective: This study aims to assess the protective effect of berberine against neuronal damage in the brain parenchyma of mice with experimental autoimmune encephalomyelitis (EAE). Methods: EAE was induced in female C57 BL/6 mice with myelin oligodendrocyte glycoprotein 35–55 amino acid peptide. The berberine treatment was initiated on the day of disease onset and administered daily until the mice were sacrificed. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, gelatin gel, and gelatin in situ zymography were analysed in this study. Results: Berberine reduced the TUNEL-positive neuronal cells of EAE mice. Gelatin gel and gelatin in situ zymography showed up-regulation of gelatinase activity, which was mainly located in neurons and colocalized with remarkable laminin degradation in EAE mice. Berberine significantly inhibited gelatinase activity and reduced the laminin degradation in EAE mice. Discussion: Our data suggest that berberine could provide protection against neuronal damage in EAE by inhibiting gelatinase activity and reducing laminin degradation. These findings provide further support that berberine can be a potential therapeutic agent for multiple sclerosis.

Summary Background In addition to their original applications for lowering cholesterol, statins display multiple neuroprotective effects. Inflammatory reactions and the PI3K/AKT/caspase 3 pathway are strongly implicated in dopaminergic neuronal death in Parkinson's disease (PD). This study aims to investigate how simvastatin affects 6-hydroxydopamine-lesioned PC12 via regulating PI3K/AKT/caspase 3 and modulating inflammatory mediators. Methods 6-hydroxydopamine-treated PC12 cells were used to investigate the neuroprotection of simvastatin, its association with the PI3K/AKT/caspase 3 pathway, and antiinflammatory responses. Dopamine transporters (DAT) and tyrosine hydroxylase (TH) were examined in 6-hydroxydopamine-treated PC12 after simvastatin treatment. Results Simvastatin-mediated neuroprotection was associated with a robust reduction in the upregulation induced by 6-OHDA of inflammatory mediators including IL-6, COX2, and TNF-α. The downregulated DAT and TH levels in 6-OHDA-lesioned PC12 were restored after simvastatin treatment. Simvastatin reversed 6-OHDA-induced downregulation of PI3K/Akt phosphorylation and attenuated 6-OHDA-induced upregulation of caspase 3 in PC12. Furthermore, the PI3K inhibitor LY294002 pronouncedly abolished the simvastatin-mediated attenuation in caspase 3. Conclusions Our results demonstrate that simvastatin provides robust neuroprotection against dopaminergic neurodegeneration, partially via antiinflammatory mechanisms and the PI3K/Akt/caspase 3 pathway. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD and might elucidate the molecular mechanisms of simvastatin effects in PD.

Minocycline has shown anti-inflammatory, anti-apoptotic, and antioxidative activities in many models of cerebral ischemia and human acute ischemic stroke. However, the cellular and molecular bases for its neuroprotective effects have not been fully elucidated. In this study, we investigated whether pre-treatment with minocycline could attenuate oxygen-glucose deprivation-induced PC12 cytotoxicity. The activity of matrix metalloproteinase-9 was detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis zymography. And the expressions of integrin β1, Akt and phosphorylated Akt were analyzed by Western blot. Our results showed that minocycline could ameliorate oxygen-glucose deprivation-induced PC12 cell cytotoxicity at concentrations of 20 nM-20 μM, down-regulate the production and activity of matrix metalloproteinase-9, inhibit the degradation of integrin β1, and up-regulate Akt phosphorylation at optimal concentration of 200 nM. The results may provide a new area for minocycline's therapeutic intervention for improving the outcomes of cerebral ischemia.

Objective:Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). The aim of this study is to examine oxidant biomarkers including homocysteine (Hcys), bilirubin, uric acid, lipids, and potential environmental risk factors and to ascertain whether these data correlate with MSA in a Chinese population.Methods:In this study, serum levels of Hcys, bilirubin, uric acid, and lipids were studied in 55 MSA patients and 76 healthy controls (HCs). Education, anti-parkinsonian agent usage, smoking, drinking, farming, and living area of the subjects also were analyzed. The Unified MSA Rating Scale (UMSARS), Hoehn & Yahr stage, International Cooperative Ataxia Rating Scale, and Mini-Mental State Examination were used to assess the disease severity, the parkinsonism, ataxia, and the cognitive ability of MSA, respectively.Results:The levels of Hcys were higher (prs=0.422, p=0.001) and UMSARS-I (rs=0.555, prs=−0.325, p=0.015). Farming was more frequent in MSA patients (1-20 years: odds ratio, 6.36; p20 years: odds ratio, 10.26; p=0.001), whereas current smoking was less frequent (odds ratio, 0.13, p=0.002).Conclusions:Elevated Hcys and decreased high-density lipoprotein cholesterol may be associated with the disease severity of MSA. Environmental exposures such as farming and smoking may contribute to the occurrence but not the progression of MSA.

Serum gamma-glutamyltransferase (GGT) has been reported to predict vascular risk. We enrolled 978 patients (507 men and 471 women) with established coronary artery disease (CAD). The GGT, brachial–ankle pulse wave velocity ([baPWV] to assess arterial stiffness), and conventional risk factors were evaluated. The means of baPWV tend to increase in both genders according to GGT tertiles. Body mass index, GGT, logarithmical (systolic blood pressure [LnSBP]), uric acid (UA), total bilirubin, Ln (cholinesterase), and Ln (total cholesterol) were correlated with baPWV in men in a multivariate model. However, only GGT, LnSBP, UA, and Ln (high-density lipoprotein cholesterol) were correlated with baPWV in women. The GGT was a significant determinant for increased baPWV both in men (β = 0.017; P < .001) and in women (β = 0.015; P < .001). In conclusion, GGT was independently associated with increased arterial stiffness both in men and in women with established CAD.

To estimate the prevalence of hyperuricemia and lifestyle risk factors for hyperuricemia in elderly women.Cross-sectional study.The suburban area of Guangzhou, Guangdong province, China.The study included 856 Chinese women aged 60 to 102 years who received their annual health examinations in the suburban area of Guangzhou, south China in 2002.Information on anthropometric measurements and lifestyle factors were obtained via a questionnaire processed by the attending physicians or nurses. Blood biochemistry was performed after subjects fasted for 8-14 h. Unconditional logistic regression analysis was used to investigate associations between hyperuricemia, meat intake quintiles, physical activity quintiles, and alcohol intake quintiles.The prevalence of hyperuricemia in the studied population was 12.01%. Alcohol, meat and seafood consumption; being overweight or obese; hypertension; and abnormal triglyceride levels were strongly associated with a higher prevalence of hyperuricemia. Physical activity was inversely related to the prevalence of hyperuricemia. The odds ratios for hyperuricemia for quintiles of physical activity were 1.00, 0.74, 0.72, 0.63, and 0.55 (P0.01).Our data suggest that the prevalence of hyperuricemia is high in elderly women in suburban Guangzhou in Guangdong province of South China. Obesity, meat and seafood intake and alcohol consumption are associated with a higher prevalence of hyperuricemia, whereas daily physical activity is inversely related to the prevalence of hyperuricemia.

Aim The SYNTAX score is a semi-quantitative angiographic tool used to determine the extent and severity of coronary artery disease (CAD). Automatic computer-assisted measurement of the brachial-ankle pulse wave velocity (baPWV) is a reproducible and valid method by which to assess arterial stiffness. Limited information is available for the association between the SYNTAX score and arterial stiffness in a CAD patient. We aim to assess the association between arterial stiffness determined by PWV and CAD severity assessed by angiography and the SYNTAX score. Methods 321 subjects underwent measurement of both baPWV and angiography from 2010 to 2011. BaPWV was divided into tertiles. Multiple logistic and linear regression analyses were used to evaluate the relationship between the SYNTAX score and baPWV. Results After adjusting for age, body mass index, smoking habits, family history of CAD, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), total cholesterol, triglycerides, LDL-cholesterol, fasting glucose, serum creatinine, uric acid and cysteine proteinase, analyses revealed that baPWV groups were significantly associated with the SYNTAX score. Compared with the lowest baPWV tertile, the adjusted odds ratios (ORs) of having a SYNTAXHIG for the MID and HIG baPWV tertiles were 4.76 (95% confidence interval: 1.71-6.33) and 4.13 (95% confidence interval: 1.12-5.27), respectively. We also used multiple linear regression analyses to assess the association between baPWV and the SYNTAX score, which showed that baPWV was associated with the SYNTAX score. Conclusion Arterial stiffness determined by PWV is related to CAD severity assessed by angiography and the SYNTAX score.

We aimed to investigate the regulation and contribution of vascular endothelial growth factor (VEGF) and sFlt-1(1-3) to human monocytic THP-1 migration.Ad-sFlt-1/FLAG, a recombinant adenovirus carrying the human sFlt-1(1-3) (the first three extracellular domains of FLT-1, the hVEGF receptor-1) gene, was constructed. L929 cells were infected with Ad-sFlt-1/FLAG and the expression of sFlt-1 was detected by immunofluorescent assay and ELISA. Corning(®) Transwell(®) Filter Inserts containing polyethylene terephthalate (PET) membranes with pore sizes of 3 μm were used as an experimental model to simulate THP-1 migration. Five VEGF concentrations (0, 0.1, 1, 10 and 100 ng/ml), four concentrations of sFlt-1(1-3)/FLAG expression supernatants (0.1, 1, 10 and 100 ng/ml), and monocyte chemoattractant protein-1 (MCP-1, 10 ng/ml) were used to test the ability of THP-1 cells to migrate through PET membranes.The sFlt-1(1-3) gene was successfully recombined into Ad-sFlt-1/FLAG. sFlt-1(1-3) was expressed in L929 cells transfected with Ad-sFlt-1/FLAG. THP-1 cell migration increased with increasing concentrations of VEGF, while cell migration decreased with increasing concentrations of sFlt1(1-3)/FLAG. sFlt1(1-3)/FLAG had no effect on MCP-1-induced cell migration.This study demonstrated that VEGF is able to elicit a migratory response in THP-1 cells, and that sFlt-1(1-3) is an effective inhibitor of THP-1 migration towards VEGF.

The nuclear factor (NF)-κB signaling pathway is an important intracellular mediator of cardiac hypertrophy. Recent studies have indicated that the anti-malarial agent artemisinin has the ability to inhibit NF-κB activation. We hypothesized that artemisinin would suppress cardiac hypertrophy by inhibiting NF-κB signal pathways. We tested this hypothesis using primary cultured rat cardiac myocytes and well-established rat models of cardiac hypertrophy. Artemisinin blocked angiotensin II-induced cardiac hypertrophy in vitro in a concentration-dependent manner. Furthermore, artemisinin protected against rat cardiac hypertrophy induced by transaortic constriction (TAC), as assessed by heart weight/body weight and lung weight/body weight ratios, echocardiographic parameters, and gene expression of hypertrophic markers. Electrophoretic mobility shift assays revealed increased NF-κB binding activity in cardiac nuclear extracts of banded rats that was prevented by artemisinin treatment. Banded rats treated with oral artemisinin, compared with untreated rats, showed significantly decreased the levels of IL-6, TNF-α and MCP-1 mRNA expression and increased protein levels of IκB-α, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. The effect of artemisinin on cardiac hypertrophy was blocked after IκB-α was silenced by transfection of cardiomyocytes with IκB-α siRNA. Our results indicate that artemisinin inhibits cardiomyocyte growth by interfering with NF-κB signaling.

The objectives of this study were to screen high-fluoride and high-arsenic drinking waters, to evaluate the effectiveness of fluoride-reducing projects and to assess the present condition of endemic fluorosis and arsenism in Shaanxi province in western China. For screening high-fluoride drinking waters, five water samples were collected from each selected village where dental fluorosis patients were detected in 8-12 year-old children. For evaluating the effectiveness of fluoride-reducing projects, four water samples were collected from each project at end-user level. Fluoride concentrations in water samples were measured by fluoride-selective electrode method or spectrophotometry. Dental fluorosis in children aging 8-12 years was examined according to Horowitz's Tooth Surface Index of Fluorosis. Skeletal fluorosis in adults was detected clinically and radiologically according to Chinese Criteria of Clinical Diagnosis of Skeletal Fluorosis. For screening high-arsenic waters, 20 water samples were collected from each village which was selected from areas characterized by the geographic features to induce high-arsenic underground water, i.e., alluvial plains, ore mining or smelting areas, geothermal artesians, and thermal springs. Arsenic concentrations in water samples were determined by spectrophotometry or arsine generation atomic fluorospectrophotometry. Arsenism in adults aging 40-89 years was examined in villages with arsenic concentrations in drinking water above 0.05 mg/l according to Chinese Criteria for Classification of Endemic Arsenism Areas and Clinical Diagnoses of Endemic Arsenism. The results showed that the fluoride level of 7144 water samples was 1.17 +/- 0.93 mg/l. There were 3396 (47.6%) high-fluoride waters (fluoride level was above 1.0 mg/l) distributing in 786 (45.1%) villages, where about 0.8 million (50.0%) people inhabited. Additionally, the 1315 fluoride-reducing projects were studied. The fluoride level of the projects was 2.79 +/- 1.09 and 0.98 +/- 0.47 mg/l before and after building the projects, which remained at relatively lower level (1.03 +/- 0.47 mg/l). But there were still 58.0% of the projects providing drinking waters with fluoride concentrations beyond 1.0mg/l. The rates of dental fluorosis and skeletal fluorosis were 38.2% and 11.8%, respectively. The arsenic level of 1732 water samples was 0.010 +/- 0.082 mg/l. There were 174 (14.9%) high-arsenic waters (arsenic level was above 0.010 mg/l) being detected, distributing in 41 (38.7%) villages. The arsenic level in 53 (4.5%) water samples was beyond 0.025 mg/l. There were 3 villages with arsenic level in drinking water beyond Chinese National Permissible Limits (0.050 mg/l), and the prevalence rate of arsenism reached 37.0% in these three villages, 3.7%, 22.2%, and 11.1% of subjects suffering from mild, moderate, and severe arsenism, respectively. Conclusively, the wide distribution of high-fluoride drinking waters contributes to the prevalence of dental and skeletal fluorosis in Shaanxi province and the quality of fluoride-reducing projects should be further improved. Ore mining and smelting induces high-arsenic drinking waters, resulting in arsenism prevalence in Shang-luo city. Proper measures should be taken to deal with water pollution in the ore mining and smelting areas in order to solve the high-arsenic water problem in Shaanxi province.

This study explored the association between cerebral metabolic rates of glucose (CMRGlc) and the severity of Vascular Parkinsonism (VP) and Parkinson's disease (PD). A cross-sectional study was performed to compare CMRGlc in normal subjects vs. VP and PD patients. Twelve normal subjects, 22 VP, and 11 PD patients were evaluated with the H&Y and MMSE, and underwent 18F-FDG measurements. Pearson's correlations were used to identify potential associations between the severity of VP/PD and CMRGlc. A pronounced reduction of CMRGlc in the frontal lobe and caudate putamen was detected in patients with VP and PD when compared with normal subjects. The VP patients displayed a slight CMRGlc decrease in the caudate putamen and frontal lobe in comparison with PD patients. These decreases in CMRGlc in the frontal lobe and caudate putamen were significantly correlated with the VP patients' H&Y, UPDRS II, UPDRS III, MMSE, cardiovascular, and attention/memory scores. Similarly, significant correlations were observed in patients with PD. This is the first clinical study finding strong evidence for an association between low cerebral glucose metabolism and the severity of VP and PD. Our findings suggest that these changes in glucose metabolism in the frontal lobe and caudate putamen may underlie the pathophysiological mechanisms of VP and PD. As the scramble to find imaging biomarkers or predictors of the disease intensifies, a better understanding of the roles of cerebral glucose metabolism may give us insight into the pathogenesis of VP and PD.

Previous studies have suggested that minocycline can attenuate cognitive deficits in animal models of conditions such as Alzheimer's disease and cerebral ischemia through inhibiting microglia associated anti-inflammatory actions. However the pathway that minocycline targets to enhance cognitive performance is not fully defined. Here we examined the effects of minocycline on learning and memory in aged (22-month-old) C57 BL/6 mice. We treated one group of mice with minocycline (30 mg/kg/day), and another group of mice with donepezil (2 mg/kg/day) as a positive control. The Morris water maze and passive avoidance tests were used to evaluate the effects of minocycline on learning and memory deficits. We also used high-frequency stimulation-induced long-term potentiation and Golgi-Cox staining to assess the effect of minocycline on synaptic plasticity and synaptogenesis. The effects of minocycline on synapse-associated signaling proteins were determined by western blot. We found that minocycline ameliorates cognitive deficits, enhances neuroplasticity, activates brain-derived neurotrophic factor- extracellular signal-regulated kinases signaling and increases expression of Arc, EGR1 and PSD-95 in the CA1 and dentate gyrus regions of the hippocampus in aged mice. The effects of minocycline in aged mice were similar to those of donepezil. Our results suggest that minocycline could improve learning and memory through enhancing synaptic plasticity and synaptogenesis, modulating the expression of synapse-associated signaling proteins, which provide a rationale for exploring the viability of using minocycline treatment in cognitive deficits.

OBJECTIVE: Elevated serum bilirubin concentrations protect from atherosclerotic diseases, however it is not clear whether or not higher serum bilirubin concentrations have the same effect in coronary artery disease (CAD). The brachial-ankle pulse wave velocity (baPWV) is a reproducible method to assess arterial stiffness. This study was aimed to investigate the relationship between serum total bilirubin (TB) and baPWV in patients with established CAD. METHODS: We enrolled 638 patients (390 men, 248 women) with established CAD. TB was divided into tertiles. Simple and multiple linear regression analyses were used to assess the correlation between baPWV and TB. RESULTS: The mean baPWV tended to decrease in men according to TB tertiles: Tertile 1=2,126.0, Tertile 2=1,832.5, and Tertile 3=1,692.5 cm/s. Likewise, the mean baPWV tended to decrease in women according to TB tertiles: Tertile 1=1,920.8, Tertile 2=1,829.0, and Tertile 3=1,701.3 cm/s. Univariate analysis showed that age, BMI, TB, ALT, GGT, Cho, SBP, DBP, UA, and TC were significantly associated with baPWV in men. In women, age, BMI, current smoker, Cho, SBP, DBP, UA, TC, TG, HDL-C, and LDL-C were significantly associated with baPWV. BMI, LnSBP, UA, TB, LnCho, and LnTC were correlated with baPWV in men in the multivariate model. However, only LnSBP, UA, and LnHDL-C were correlated with baPWV in women. TB was found to be a significant determinant for decreased baPWV only in men (β=-0.136; p

Donepezil is a potent and selective acetylcholinesterase inhibitor. It has been reported to restore cognitive performance in multiple sclerosis (MS) patients and experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. However, there are no reports about the anti-inflammatory effects of donepezil on EAE. In this study, the donepezil treatments on EAE mice were initiated at day 7 post immunization (7 p.i., subclinical periods, early donepezil treatment) and day 13 p.i. (clinical periods, late donepezil treatment) with the dosage of 1, 2 and 4 mg/kg/d respectively and the treatments persisted throughout the experiments. Blood-brain barrier (BBB) permeability was detected by Evan's blue content, the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, Akt and phosphorylated Akt (p-Akt) as well as nerve growth factor (NGF) and its precursor form (proNGF) in the brains of EAE mice were detected by Western blot, and the levels of interferon-γ and interleukin-4 in the splenocytes culture supernatants and brains of EAE mice were evaluated by ELISA. The results showed that the 2 mg/kg/d late donepezil treatment was the optimal dosage and could ameliorate clinical and pathological parameters, improve magnetic resonance imaging outcomes, reduce the permeability of BBB, inhibit the production of MMP-2 and MMP-9, modulate the expression of NGF and proNGF, increase Th2 bias and the phosphorylation of Akt in the brains of EAE mice. Our data suggested that the anti-inflammatory effects of donepezil may be a novel mechanism on treating EAE and provided further insights to understand the donepezil's neuroprotective activities in MS.

BACKGROUND: Melanosomes are specialized membrane-surrounded organelles, which are involved in the synthesis, storage and transport of melanin. Glycoprotein (transmembrane) non-metastatic melanoma protein b (GPNMB), a melanosome-specific structural protein, shares significant amino acid sequence homology with Pmel-17. Proteomic analysis demonstrated that GPNMB is present in all stages (I-IV) of melanosomes. However, little is known about the role of GPNMB in melanosomes. METHODOLOGY/PRINCIPAL FINDINGS: Using real-time quantitative PCR, Western blotting and immunofluorescence analysis, we demonstrated that the expression of GPNMB in PIG1 melanocytes was up-regulated by ultraviolet B (UVB) radiation. Transmission electron microscopy analysis showed that the total number of melanosomes in PIG1 melanocytes was sharply reduced by GPNMB-siRNA transfection. Simultaneously, the expression levels of tyrosinase (Tyr), tyrosinase related protein 1 (Trp1), Pmel17/gp100 and ocular albinism type 1 protein (OA1) were all significantly attenuated. But the expression of microphthalmia-associated transcription factor (MITF) was up-regulated. Intriguingly, in GPNMB silenced PIG1 melanocytes, UVB radiation sharply reduced MITF expression. CONCLUSION: Our present work revealed that the GPNMB was critical for the formation of melanosomes. And GPNMB expression down-regulation attenuated melanosome formation in a MITF-independent fashion.

High serum uric acid (SUA) has been well demonstrated to be associated with morbidity and mortality in the general population as well as in patients with coronary artery disease (CAD). Recent studies show that the clinical SYNTAX score (CSS) is a new tool for the risk stratification of patients with complex CAD. In this study, we aimed to evaluate whether SUA was associated with the complexity of CAD as evaluated by the CSS.The study population consisted of 451 patients (69% male) who underwent coronary angiography for the assessment of CAD. A lesion was defined as significant if it caused a 50% reduction of the luminal diameter by visual estimation in vessels ≥1.5 mm. CSS was calculated by multiplying the SYNTAX score by a modified value of age, creatinine, and ejection fraction (ACEF) score (age/ejection fraction +1 for each 10 mL the creatinine clearance60 mL/min per 1.73 m²).All subjects were divided into three groups according to CSS tertiles: CSSLOW (CSS 2-11; n = 147), CSSMID (CSS 12-21; n = 152), and CSSHIGH (CSS 22-68; n = 152). The SUA level was prominently related with CSS (5.29 ± 1.23 mg/dL, 6.92 ± 1.23 mg/dL, and 8.31 ± 1.46 mg/dL; P.001). SUA was a significant predictor of CSS after adjustment for other risk factors (OR, 2.68; P.001).SUA level was significantly associated with the severity and complexity of CAD evaluated by CSS. Further prospective clinical studies are needed to clarify the exact physiopathologic role of SUA in CAD.

Previous evidence demonstrated that minocycline could ameliorate clinical severity of experimental autoimmune encephalomyelitis and exhibit several anti-inflammatory and neuroprotective activities. However, few studies have been carried out to assess its effects on the expression of neurotrophins in experimental autoimmune encephalomyelitis or multiple sclerosis. Here we investigated the alteration of brain-derived neurotrophic factor and nerve growth factor in the sera, cerebral cortex, and lumbar spinal cord of experimental autoimmune encephalomyelitis C57 BL/6 mice in vivo as well as the splenocytes culture supernatants in vitro after minocycline administration. Our results demonstrated that minocycline could up-regulate the expression of brain-derived neurotrophic factor and nerve growth factor both in peripheral (sera and splenocytes culture supernatants) and target organs (cerebral cortex and lumber spinal cord) of mice with experimental autoimmune encephalomyelitis. These data suggest that up-regulation of neurotrophins in experimental autoimmune encephalomyelitis may be a novel neuroprotective mechanism of minocycline.

BackgroundIn addition to their original applications to lowering cholesterol, statins display multiple neuroprotective effects. N-methyl-D-aspartate (NMDA) receptors interact closely with the dopaminergic system and are strongly implicated in therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate how simvastatin impacts on experimental parkinsonian models via regulating NMDA receptors.Methodology/principal findingsRegional changes in NMDA receptors in the rat brain and anxiolytic-like activity were examined after unilateral medial forebrain bundle lesion by 6-hydroxydopamine via a 3-week administration of simvastatin. NMDA receptor alterations in the post-mortem rat brain were detected by [³H]MK-801(Dizocilpine) binding autoradiography. 6-hydroxydopamine treated PC12 was applied to investigate the neuroprotection of simvastatin, the association with NMDA receptors, and the anti-inflammation. 6-hydroxydopamine induced anxiety and the downregulation of NMDA receptors in the hippocampus, CA1(Cornu Ammonis 1 Area), amygdala and caudate putamen was observed in 6-OHDA(6-hydroxydopamine) lesioned rats whereas simvastatin significantly ameliorated the anxiety-like activity and restored the expression of NMDA receptors in examined brain regions. Significant positive correlations were identified between anxiolytic-like activity and the restoration of expression of NMDA receptors in the hippocampus, amygdala and CA1 following simvastatin administration. Simvastatin exerted neuroprotection in 6-hydroxydopamine-lesioned rat brain and 6-hydroxydopamine treated PC12, partially by regulating NMDA receptors, MMP9 (matrix metalloproteinase-9), and TNF-a (tumour necrosis factor-alpha).Conclusions/significanceOur results provide strong evidence that NMDA receptor modulation after simvastatin treatment could partially explain its anxiolytic-like activity and anti-inflammatory mechanisms in experimental parkinsonian models. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD via NMDA receptors.

BACKGROUND: The elevation of plasma homocysteine (Hcy) and C-reactive protein (CRP) has been correlated to an increased risk of Parkinson's disease (PD) or vascular diseases. The association and clinical relevance of a combined assessment of Hcy and CRP levels in patients with PD and vascular parkinsonism (VP) are unknown. METHODOLOGY/PRINCIPAL FINDINGS: We performed a cross-sectional study of 88 Chinese patients with PD and VP using a clinical interview and the measurement of plasma Hcy and CRP to determine if Hcy and CRP levels in patients may predict the outcomes of the motor status, non-motor symptoms (NMS), disease severity, and cognitive declines. Each patient's NMS, cognitive deficit, disease severity, and motor status were assessed by the Nonmotor Symptoms Scale (NMSS), Mini-Mental State Examination (MMSE), the modified Hoehn and Yahr staging scale (H&Y), and the unified Parkinson's disease rating scale part III (UPDRS III), respectively. We found that 100% of patients with PD and VP presented with NMS. The UPDRS III significantly correlated with CRP (P = 0.011) and NMSS (P = 0.042) in PD patients. The H&Y was also correlated with Hcy (P = 0.002), CRP (P = 0.000), and NMSS (P = 0.023) in PD patients. In VP patients, the UPDRS III and H&Y were not significantly associated with NMSS, Hcy, CRP, or MMSE. Strong correlations were observed between Hcy and NMSS as well as between CRP and NMSS in PD and VP. CONCLUSIONS/SIGNIFICANCE: Our findings support the hypothesis that Hcy and CRP play important roles in the pathogenesis of PD. The combination of Hcy and CRP may be used to assess the progression of PD and VP. Whether or not anti-inflammatory medication could be used in the management of PD and VP will produce an interesting topic for further research.

Statins have been widely used for the treatment of a variety of medical conditions including psychoneurological disorders beyond their original use in lowering cholesterol. Histamine receptors play an important role in the regulation of neural activity, however, it is unknown whether statins act on histamine receptors, particularly for their neural regulatory effects. This study examined the effects of simvastatin and 6-hydroxydopamine (6-OHDA) lesions on histamine H1 receptors using [(3)H] pyrilamine binding autoradiography. Compared to the saline group, simvastatin (1 mg/kg/day) significantly decreased H1 receptor bindings in the primary motor cortex (M1), ventromedial hypothalamic nucleus (VMH), caudate putamen (CPu), accumbens core (AcbC) and prefrontal cortex (PfC) (all p