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Objective. Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes, leading to disability and decreased quality of life. In past research and clinical studies, the lower limb function of DPN patients was often the principal subject of research, with little attention given to the upper limb and hand. Our goal was to assess and compare hand function between elderly diabetic patients with DPN and without DPN. Methods. A total of 52 diabetic patients were registered and underwent hand function assessments and electrodiagnostic tests. Dynamometer, pinch meter, Semmes Weinstein monofilaments, and the Purdue Pegboard Test (PPT) were used to assess the patients’ grip strength, pinch strength, tactile sensory threshold, and hand dexterity. Results. Compared with the non-DPN group, the elderly DPN group showed worse thumb-middle fingertip pinch strength and thumb-little fingertip pinch strength in the dominant hand (3.50 (2.50, 4.25) vs. 4.50 (3.00, 5.00), p = 0.019 ; 1.50 (1.00, 2.00) vs. 2.50 (2.00, 3.00), p < 0.001 ); the elderly DPN group displayed worse thumb-middle fingertip pinch strength, thumb-ring fingertip pinch strength, and thumb-little fingertip pinch strength in the nondominant hand (3.50 (2.00, 4.50) vs. 4.00 (3.00, 5.00), p = 0.013 ; 2.50 (1.25, 3.00) vs. 3.00 (2.50, 3.50), p = 0.033 ; 1.00 (0.75, 2.25) vs. 2.50 (2.00, 2.50), p < 0.001 ). The elderly DPN group scored lower than the non-DPN group on the PPT test of assembly ( 13.96 ± 5.18 vs. 16.96 ± 4.61 , t = 2.212 , p = 0.032 ). Conclusion. Motor function limitation is the principal hand dysfunction in elderly patients with DPN, which is mainly manifested as a decline in fingertip pinch strength and a decrease in hand dexterity. This trial is registered with Clinical Trial Registry no. ChiCTR1900025358.

Objective: Smyd3 (SET and MYND domain-containing protein 3) is an H3K4 (histone H3 lysine 4) dimethyltransferase and trimethyltransferase that activates the transcription of oncogenes and cell cycle genes in human cancer cells. We discovered its overexpression in proliferative vascular smooth muscle cells (VSMCs). However, whether Smyd3 plays a role in vascular remodeling remains unanswered. The objective of this study is to investigate the role and underlying mechanism of Smyd3 in phenotypic transition of VSMCs (such as proliferation and migration) and vascular remodeling (such as neointima formation). Approach and Results: We discovered upregulation of Smyd3 in both PDGF (platelet-derived growth factor) BB–induced vascular cell proliferation model and balloon injury–induced neointima formation model. Knockdown of Smyd3 or blockade of its enzymatic activity suppressed VSMCs proliferation and migration ability, whereas Smyd3 overexpression promoted VSMC migration and proliferation. Mechanistically, RNA-seq and ChIP-seq analysis revealed Smyd3 promoted neointimal formation by directly binding and increasing H3K4me3 to the promoter regions of target genes that are associated with cell proliferation and migration, cell cycle control. Furthermore, Smyd3 knockout mice profoundly ameliorated carotid artery ligation–induced neointimal hyperplasia, consistently, local knocking down Smyd3 in rats relieved balloon injury–induced neointimal formation, while restored VSMC contractile protein expression, suggesting that Smyd3 plays a critical role in vivo. Conclusions: Our results demonstrate that Smyd3 promotes VSMC proliferation and migration during injury-induced vascular remodeling, which provide a potential therapeutic target for preventing neointimal hyperplasia in proliferative vascular diseases.

Myocardial fibrosis is the pathological consequence of injury-induced fibroblastto-myofibroblast transition, resulting in increased stiffness and diminished cardiac function. Histone modification has been shown to play an important role in the pathogenesis of cardiac fibrosis. Here, we identified H3K27me3 demethylase JMJD3/KDM6B promotes cardiac fibrosis via regulation of fibrogenic pathways. Using neonatal rat cardiac fibroblasts (NRCF), we show that the expression of endogenous JMJD3 is induced by angiotensin II (Ang II), while the principle extracellular matrix (ECM) such as fibronectin, CTGF, collagen I and III are increased. We find that JMJD3 inhibition markedly enhances the suppressive mark (H3K27me3) at the beta (β)-catenin promoter in activated cardiac fibroblasts, and then substantially decreases expression of fibrogenic gene. Both inhibition of β-catenin-mediated transcription with ICG-001 and genetic loss of β-catenin can prevent Ang II-induced ECM deposition. Most importantly, in vivo inhibition of JMJD3 rescues myocardial ischemia-induced cardiac fibrosis and cardiac dysfunction. Collectively, our findings are the first to report a novel role of histone demethylase JMJD3 in the pro-fibrotic cardiac fibroblast phenotype, pharmacological targeting of JMJD3 might represent a promising therapeutic approach for the treatment of human cardiac fibrosis and other fibrotic diseases.

Background: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12–21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12–21 locus. Methods: We first did a genetic association study and meta-analysis using 17q12–21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12–21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12–21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). Findings: 17q12–21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p

Purpose: To evaluate and compare the corneal curvature and astigmatism in patients with persistent pupillary membrane (PPM) and healthy controls by partial coherence interferometry. Methods: This study included 14 eyes (9 patients) with PPM and 16 eyes (16 subjects) without PPM or other ocular disease, which were age and gender matched. The horizontal corneal radius of curvature (hCRC), vertical CRC (vCRC), average CRC (aveCRC), corneal astigmatic vectors (CAV), and axis were recorded using partial coherence interferometry. Uncorrected visual acuity and best corrected visual acuity (BCVA) were also recorded using a logMAR chart. Results: In the PPM group, the vCRC (45.46 ± 0.52 D) was significantly larger than that in the control group (44.05 ± 0.24 D) (p = 0.009). The aveCRC in the PPM group (43.90 ± 0.46 D) was also significantly larger than that in the control group (43.34 ± 0.23 D) (p = 0.018). In the PPM group, the hCRC (42.35 ± 0.41 D) was significantly smaller than that in the control group (42.63 ± 0.24 D) (p = 0.049). The astigmatisms were with-the-rule in both groups. The absolute value of CAV in PPM group (3.17 ± 0.23 D) was significantly higher than that of control (1.36 ± 0.09 D) (p = 0.001). BCVA (0.42 ± 0.08) in PPM group was significantly worse than that in control (0.90 ± 0.03) (p = 0.009). Conclusions: The larger vertical and smaller horizontal corneal curvature resulted in higher corneal astigmatism with the rule, which is a characteristic feature in patients with PPM. More attention should be paid to astigmatism status and correction treatment for these patients.

Background Prior ecologic studies suggest that UV exposure through sunlight to the retina might contribute to increased retinoblastoma incidence. Aims Our study objectives were (1) to examine the relationship between exposure to sunlight during postnatal retinal development (prior to diagnosis of sporadic disease) and the risk of retinoblastoma, and (2) to examine the relationship between sun exposure during postnatal retinal development, and the extent of disease among children with unilateral and bilateral retinoblastoma. Methods and results We interviewed 511 mothers in the EpiRbMx case‐control study about their child's exposure to sunlight during postnatal retinal cell division by examining three time periods prior to Rtb diagnosis coinciding with developmental stages in which outdoor activities vary. Weekly sun exposure was compared by age period, between unilateral (n = 259), bilateral (n = 120), and control (n = 132) children, accounting for two factors affecting UV exposure: residential elevation and reported use of coverings to shield eyes. For cases, association between sunlight exposure and clinical stage was examined by laterality at each age period. After adjusting for maternal education and elevation, sun exposure was lower in cases than controls in all three age periods especially during the first 6 months, and in children 12–23 months whose mothers did not cover their eyes when outdoors. In children diagnosed after 12 months of age, sun exposure during the second year of life (age 12–23 months) appeared inversely correlated (r = −0.25) with more advanced intraocular disease in bilateral Rtb children after adjusting for maternal education, residential elevation, and age of diagnosis (p

Cathepsin C (Cat C) participates in inflammation and immune regulation by affecting the activation of neutrophil serine proteases (NSPs). Therefore, cathepsin C is an attractive target for treatment of NSP-related inflammatory diseases. Here, the complete discovery process of the first potent "non-peptidyl non-covalent cathepsin C inhibitor" was described with hit finding, structure optimization, and lead discovery. Starting with hit

BACKGROUND: Studies of body mass index and semen quality have reported mixed results, but almost all were cross-sectional and many were conducted in selected populations. Longitudinal studies in population-based cohorts are necessary to identify how timing and duration of excess adiposity may affect semen quality. METHODS: In 193 members of the Child Health and Development Studies birth cohort, we examined associations of birth weight and adiposity at six time points spanning early childhood and adulthood with sperm concentration, motility, and morphology at mean age 44 years, as well as with corresponding 2010 World Health Organization (WHO) subfertility reference levels. RESULTS: Birth weight for gestational age percentile was positively associated with square-root sperm concentration (regression coefficient B [95% confidence interval] = 0.02 × 10(3) sperm/ml [0.004, 0.04]). Overweight/obesity in men’s 20s was associated with lower percent progressive motility (B =−5.2 [−9.9, −0.63]), higher odds of low motility (odds ratio (OR) = 2.4 [1.3, 4.4]), and higher odds of poor morphology (OR = 1.9 [0.94, 3.8]). Those who were overweight/obese in their 20s were also more likely to meet two or three WHO subfertility criteria (OR = 3.9 [1.6, 9.4]) compared with normal-weight men. Each additional adult decade in which a participant was overweight/obese was associated with higher odds of low motility (OR = 1.3 [0.96, 1.6]) and higher odds of meeting two or three WHO subfertility criteria (OR = 1.5 [1.0, 2.2]). CONCLUSIONS: In our data, associations among adiposity and sperm concentration, motility, and morphology varied according to timing and duration of exposure, potentially reflecting different biological mechanisms that influence these semen parameters.

Hypokalemia is a common feature in patients with Cushing's syndrome (CS). Whether the occurrence of hypokalemia is associated with cortisol and adrenocorticotropic hormone (ACTH) levels is still unclear. Approximately 80% of cases of endogenous CS are due to Cushing's disease (CD). The purpose of this study was to determine the association of hypokalemia with cortisol and ACTH levels in patients with CD. The retrospective study included 195 patients with CD referred to our medical center from January 2011 to December 2017. The results show that 25.64% (50/195) of the patients had hypokalemia. The 24-h urinary free cortisol (UFC) and plasma cortisol levels were significantly higher in patients with hypokalemia than those with normokalemia (P0.05). Plasma ACTH levels were similar between the patients with hypokalemia and normokalemia (P0.05). Cortisol levels were negatively correlated with plasma potassium levels (08:00: r = -0.344 (P0.01), 00:00: r = -0.435 (P0.01); 24-h UFC: r = -0.281 (P0.05)). There was no significant correlation between the plasma ACTH and potassium (08:00: r = -0.093 (P0.05), 00:00: r = -0.184 (P0.050)). Our current data suggest that cortisol level, instead of ACTH level, is correlated with plasma potassium level. A high cortisol level may be the principal cause of hypokalemia.

Background Previous reports suggest that prenatal phthalate exposure is associated with lower scores on measures of motor skills in infants and toddlers. Whether these associations persist into later childhood or preadolescence has not been studied. Methods In a follow up study of 209 inner-city mothers and their children the concentrations of mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP), monomethyl phthalate (MEP), mono-carboxy-isooctyl phthalate (MCOP), and four di-2-ethylhexyl phthalate metabolites (ΣDEHP) were measured in spot urine sample collected from the women in late pregnancy and from their children at ages 3, 5, and 7 years. The Bruininks-Oseretsky Test of Motor Proficiency short form (BOT-2) was administered at child age 11 to assess gross and fine motor skills. Results The total number of children included in the study was 209. Of the 209 children, 116(55.5%) were girls and 93 were (45%) boys. Among girls, prenatal MnBP(b=−2.09; 95%CI: [−3.43, −0.75]), MBzP (b=−1.14; [95%CI: −2.13, −0.14]), and MiBP(b=−1.36; 95%CI: [−2.51, −0.21] and MEP(b=−1.23 [95%CI: −2.36, −0.11]) were associated with lower total BOT-2 composite score. MnBP (b= –1.43; 95% CI: [–2.44, –0.42]) was associated with lower fine motor scores and MiBP(b = –0.56; 95% CI: [–1.12, –0.01]) and MEP (b = –0.60; 95% CI: [–1.14, −0.06])was associated with lower gross motor scores. Among boys, prenatal MBzP (b = –0.79; 95% CI: [–1.40, −0.19]) was associated with lower fine motor composite score. The associations between MEP measured at age 3 and the BOT-2 gross motor, fine motor and total motor score differed by sex. In boys, there was an inverse association between ΣDEHP metabolites measured in childhood at ages 3 (b = –1.30; 95% CI: [–2.34, −0.26]) and 7 years (b = –0.96; 95% CI: [–1.79, −0.13]), and BOT-2 fine motor composite scores. Conclusions Higher prenatal exposure to specific phthalates was associated with lower motor function among 11- year old girls while higher postnatal exposure to ΣDEHP metabolites was associated with lower scores among boys. As lower scores on measures of motor development have been associated with more problems in cognitive, socioemotional functioning and behavior, the findings of this study have implications related to overall child development.

BACKGROUND: Arsenic exposure through drinking water persists in many regions. Inorganic As (InAs) is methylated to monomethyl-arsenical species (MMAs) and dimethyl-arsenical species (DMAs), facilitating urinary excretion. Arsenic methylation is dependent on one-carbon metabolism, which is influenced by nutritional factors such as folate and creatine. OBJECTIVE: This study investigated the effects of folic acid (FA) and/or creatine supplementation on the proportion of As metabolites in urine. DESIGN: In a 24-wk randomized, double-blinded, placebo-controlled trial, 622 participants were assigned to receive FA (400 or 800 μg per day), 3 g creatine per day, 400 μg FA + 3 g creatine per day, or placebo. The majority of participants were folate sufficient; all received As-removal water filters. From wk 12–24, half of the participants receiving FA received placebo. RESULTS: Among groups receiving FA, the mean decrease in ln(%InAs) and %MMAs and increase in %DMAs exceeded those of the placebo group at wk 6 and 12 (P

Aims/Introduction Carpal tunnel syndrome (CTS) and diabetic polyneuropathy (DPN) can occur together, and this concomitance is thought to be higher in diabetes patients. We aimed to examine and compare hand function in type 2 diabetes mellitus patients without CTS and DPN (CTS−DPN−), patients with CTS without DPN (CTS+DPN−), patients with DPN without CTS (CTS−DPN+), and patients with CTS and DPN (CTS+DPN+). Materials and Methods A total of 161 type 2 diabetes mellitus patients underwent physical examination and electrodiagnostic tests. Grip and pinch strengths, tactile sensory thresholds were measured for each participant. Purdue pegboard test was used in evaluating the hand dexterity of the participants. Results Of the 161 type 2 diabetes mellitus participants, 36 (22.4%) had both CTS and DPN. CTS participants had lower grip (26.6 ± 10.6 vs 35.2 ± 14.3, P, Carpal tunnel syndrome and diabetic polyneuropathy can occur together, and this concomitance is thought to be high in diabetes patients. We found in this study that type 2 diabetes mellitus patients with both carpal tunnel syndrome and diabetic polyneuropathy had lower grip and pinch strengths and decreased tactile sensation. Carpal tunnel syndrome and diabetic polyneuropathy together contribute to poor hand dexterity in diabetes patients.

To investigate the efficacy of an herbal formula of Bushen Jianpi ( BSJP) combined with sorafenib on hepatocellular carcinoma (HCC) in vitro and in vivo, and to study the underlying mechanisms of action.BSJP, a mixture of 12 raw herbs, was extracted in 70% alcohol/30% water and freeze-dried into a powder. The in vitro effects of BSJP alone, sorafenib alone, and their combination on cell survival, apoptosis, and cell cycle distribution were evaluated in HCC cell lines HCCLM3, HepG2, and SMMC-7721. The expression of B-cell lymphoma-2 (Bcl-2), caspase-3, and caspase-9 in HCCLM3 cells was measured using Western blots after drug administration. The in vivo effects of BSJP and sorafenib were evaluated in a tumor surgical resection model using 4-week old male athymic BALB/c nude mice injected with HCCLM3 cells. Immunohistochemical analysis of tumor tissues was performed to evaluate the effects of BSJP alone, sorafenib alone, and their combination on the expression of caspase-3, caspase-9, and Bcl-2.BSJP decreased the survival rate of HCC cell lines, and the combination of BSJP and sorafenib further decreased the survival rate. BSJP significantly promoted cell apoptosis and blocked cell-cycle progression in HCCLM3, HepG2, and SMMC-7721 cells in a dose-dependent manner. Furthermore, the administration of BSJP and sorafenib inhibited the growth of HCCLM3 cell xenografts in nude mice, with no reduction in body weight. In vivo and in vitro experiments showed that BSJP combined with sorafenib could significantly decrease the expression of Bcl-2.Our findings suggest that the herbal formula of BSJP is a potential HCC antitumor agent.

Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) are well-known key immune checkpoints that play a crucial dampening effect on regulating T-cell homeostasis and self-tolerance. In this study, we aimed to evaluate the association between immune checkpoints (CTLA-4 and PD-1) and Posner-Schlossman syndrome (PSS) in a southern Chinese population. A total of 137 patients with PSS and 139 healthy controls from a southern Chinese population were recruited. Five single nucleotide polymorphisms (SNPs) of CTLA-4 (rs733618, rs4553808, rs5742909, rs231775, and rs3087243) and five SNPs of PD-1 (rs10204525, rs2227981, rs2227982, rs41386349, and rs36084323) were genotyped by SNaPshot technique. Soluble CTLA-4 (sCTLA-4) and soluble PD-1 (sPD-1) were determined by ELISA and antibody array assay, respectively. The frequencies of T allele at rs733618 and A allele at rs231775 of CTLA-4 were significantly higher in PSS patients than in healthy controls (corrected p (Pc) = 0.037; Pc = 0.044, respectively). The haplotype frequencies of CACGG haplotype (rs733618-rs4553808-rs5742909-rs231775-rs3087243) of CTLA-4 and TGAGC haplotype (rs10204525-rs2227981-rs2227982-rs41386349-rs36084323) of PD-1 in the PSS group was significantly lower than those in the control group (Pc = 0.015, p = 0.034, respectively). Circulating plasma levels of sCTLA-4 and sPD-1 in PSS patients were significantly higher than those in controls (all p < 0.001). The present study suggests that CTLA-4 and PD-1 genetic polymorphisms are associated with the susceptibility to PSS in a southern Chinese population. The upregulated circulating plasma protein levels of sCTLA-4 and sPD-1 might provide some hints regarding the dysfunction of immune checkpoints in PSS during the active status.

Objective. The primary aim of this investigation was to analyze the microbiome in patients with combined periodontal-endodontic lesions. Method. Patients with loose and/or painful teeth referred for treatment from March 2020 to December 2020 in the First People’s Hospital of Jinzhong were recruited. Samples were collected from teeth diagnosed as chronic periodontics (PE), ulcerative pulpitis (PU), and retrograde pulpitis (RE). Genomic DNA was extracted. The quantitative polymerase chain reaction, targeting the 16S ribosomal RNA (rRNA), was adopted for the quantification of bacteria. Then, the V3-V4 hypervariable regions of the 16S rRNA gene were amplified and subjected to next-generation sequencing. The statistical analysis was performed by R software (V3.5.1). Results. A total of 57 qualified samples were collected from 48 patients and analyzed (7 PE, 21 PU, and 19 RE). By linear discriminant analysis effect size, Kingella and Barnesiella were significantly increased in the periodontal pocket of retrograde pulpitis (RE-PE), compared with PE. The relative abundance of Clostridiales Incertae Sedis XI, Fusobacteriaceae, Fusobacterium, Parvimonas, Micrococcaceae, and Rothia was significantly increased in the pulp of retrograde pulpitis (RE-PU) than PU and RE-PE. Prevotella, Leptotrichia, Porphyromonas, Streptococcus, and Fusobacterium are consistently at a high abundance, across PU, RE-PE, and RE-PU. Conclusion. The current study highlighted the evidence that a specific microbial community is associated with the occurrence of retrograde pulpitis. The microenvironment of the root canal and pulp chamber will select microbiota. This study offered insights into the pathogenesis of retrograde pulpitis.

Flaccid paralysis in the upper extremity is a severe motor impairment after stroke, which exists for weeks, months, or even years. Electroacupuncture treatment is one of the most widely used TCM therapeutic interventions for poststroke flaccid paralysis. However, the response to electroacupuncture in different durations of flaccid stage poststroke as well as in the topological configuration of the cortical network remains unclear. The objectives of this study are to explore the disruption of the cortical network in patients in different durations of flaccid stage and observe dynamic network reorganization during and after electroacupuncture. Resting-state networks were constructed from 18 subjects with flaccid upper extremity by partial directed coherence (PDC) analysis of multichannel EEG. They were allocated to three groups according to time after flaccid paralysis: the short-duration group (those with flaccidity for less than two months), the medium-duration group (those with flaccidity between two months and six months), and the long-duration group (those with flaccidity over six months). Compared with short-duration flaccid subjects, weakened effective connectivity was presented in medium-duration and long-duration groups before electroacupuncture. The long-duration group has no response in the cortical network during electroacupuncture. The global network measures of EEG data (sPDC, mPDC, and N ) indicated that there was no significant difference among the three groups. These results suggested that the network connectivity reduced and weakly responded to electroacupuncture in patients with flaccid paralysis for over six months. These findings may help us to modulate the formulation of electroacupuncture treatment according to different durations of the flaccid upper extremity.

Background Over 57 million people in Bangladesh are chronically exposed to arsenic-contaminated drinking water. Ingested inorganic arsenic (InAs) undergoes hepatic methylation generating monomethyl- (MMAs) and dimethyl- (DMAs) arsenic species in a process that facilitates urinary As (uAs) elimination. One-carbon metabolism (OCM), a biochemical pathway that is influenced by folate and vitamin B12, facilitates the methylation of As. OCM also supports nucleotide and amino acid synthesis, particularly during periods of rapid growth such as adolescence. While folate supplementation increases As methylation and lowers blood As (bAs) in adults, little data is available for adolescents. Objectives To examine the associations between OCM-related micronutrients and As methylation in Bangladeshi adolescents chronically exposed to As-contaminated drinking water. Methods We conducted a cross-sectional study of 679 Bangladeshi adolescents, including 320 boys and 359 girls aged 14–16 years. Nutritional status was assessed by red blood cell (RBC) folate, plasma folate, plasma B12 and homocysteine (Hcys). Arsenic-related outcomes included blood arsenic (bAs), urinary arsenic (uAs), and urinary arsenic metabolites expressed as a percentage of total urinary As: %InAs, %MMAs, %DMAs. Results Boys had significantly lower B12, higher Hcys, higher bAs, higher uAs, higher %MMAs, and a trend toward lower RBC folate compared to girls. Therefore, regression analyses controlling for water As and BMI were sex stratified. Among girls, RBC folate was inversely associated with bAs, plasma B12 was inversely associated with uAs, and plasma Hcys was inversely associated with %MMA. Among boys, plasma folate was inversely associated with %InAs and positively associated with %DMA, RBC folate was inversely associated with %InAs and positively associated with %MMA, while Hcys was positively associated with %InAs. Conclusions These findings suggest that associations between OCM nutritional status, bAs, and distribution of As metabolites in adolescents are similar to previously reported observations in adults and in children. The As methylation findings are statistically significant among boys but not among girls; this may be related to estrogen which more strongly influences OCM in females. The inverse association between Hcys and %MMA in girls is somewhat unexpected given that Hcys is known to be an indicator of impaired OCM and low folate/B12 in adults. Overall, these results indicate that the associations between OCM-related micronutrients and arsenic methylation in adolescents are generally similar to prior findings in adults, though these associations may differ by sex. Additionally, these findings suggest that more investigation into the role of Hcys in adolescent physiology is needed, perhaps particularly for girls. Additional studies are needed to evaluate the impact of OCM and As methylation on As-related adverse health outcomes (such as cancer and cardiovascular disease) in people exposed to As during adolescence.

IMPORTANCE: Cognitive deficits constitute core features of schizophrenia, but the trajectories of cognitive difficulties in chronic untreated schizophrenia remain unclear. OBJECTIVE: To assess the association of neuropsychological deficits with duration of untreated psychosis in individuals with chronic untreated schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Community-dwelling individuals with chronic untreated schizophrenia (untreated patient group) and individuals without mental illness (control group) were recruited from predominantly rural communities in Ningxia, China between June 20, 2016, and August 6, 2019, and administered the Structured Clinical Interview for DSM-IV, the Mini-Mental State Examination, an 8-test version of the MATRICS Consensus Cognition Battery adapted for use in individuals with low levels of education, and a measure of social cognition. MAIN OUTCOMES AND MEASURES: Comparison of cognitive test scores between the two groups and association of cognitive test scores with duration of untreated schizophrenia. RESULTS: The patient group included 197 individuals with chronic untreated schizophrenia (101 men [51.3%]; mean [SD] age, 52.1 [11.8] years; median [interquartile range] years of schooling, 3 [0-6] years; median [interquartile range] years of untreated psychosis, 22.9 [14.9-32.8] years). The control group included 220 individuals (118 men [53.6%]; mean [SD] age, 52.1 [11.2] years; median [interquartile range] years of schooling, 4 [0-6] years). The untreated patient group performed significantly worse than the control group on all cognitive measures (adjusted partial Spearman correlation coefficient [Spearman ρ] ranged from −0.35 for the revised Chinese version of the Reading the Mind in the Eyes Test to −0.60 for the Brief Visuospatial Memory Test-Revised; P < .001 for all comparisons). Longer durations of untreated psychosis were associated with lower performance in 3 MATRICS Consensus Cognition Battery measures assessing different aspects of executive functioning (Brief Visuospatial Memory Test–Revised [ρ = −0.20; P = .04]; Brief Assessment of Cognition in Schizophrenia, Symbol Coding subtest [ρ = −0.35; P < .001]; and Neuropsychological Assessment Battery, Mazes subtest [ρ = −0.24; P = .01]). The median duration of untreated psychosis (22.9 years) was associated with estimated score reductions in the 3 measures of 34% (95% CI, 10%-52%), 43% (95% CI, 28%-55%), and 57% (95% CI, 31%-73%), respectively. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that long-term untreated schizophrenia was associated with decreases in selective cognitive abilities; both neurodegenerative pathology and neurodevelopmental dysfunction may be factors in cognition in persistent psychosis. Expanding research to include cohorts of patients from underserved rural communities in low- and middle-income countries may provide new insights about the etiological factors, disease course, and management of schizophrenia.

Background Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease (AD) pathology, and short-term change in odor identification impairment with cholinesterase inhibitor (CheI) treatment may predict longer term cognitive outcomes. Objective In patients with mild cognitive impairment (MCI) treated prospectively with donepezil, a CheI, for 52 weeks, to determine if 1) acute decline in odor identification ability with anticholinergic challenge can predict cognitive improvement, and 2) change in odor identification over 8 weeks can predict cognitive improvement. Methods MCI was diagnosed clinically without AD biomarkers. At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and this dose was maintained for 52 weeks. Main outcomes were ADAS-Cog total score and Selective Reminding Test (SRT) total immediate recall score measured at baseline, 26 and 52 weeks. Results In 100 study participants, mean age 70.14 (SD 9.35) years, atropine-induced decrease in UPSIT score at baseline was not associated with change in ADAS-Cog or SRT scores over 52 weeks. Change in UPSIT score from 0 to 8 weeks did not show a significant association with change in the ADAS-Cog or SRT measures over 52 weeks. Conclusion These negative findings in a relatively large sample of patients with MCI did not replicate results in much smaller samples. Change in odor identification with anticholinergic challenge, and over 8 weeks, may not be useful predictors of cognitive improvement with CheI in patients with MCI.

Bear bile is a valuable medicinal material used in traditional Chinese medicine for over 2000 years. However, developing a substitute has become necessary because of protection measures for this endangered species. The ingredients of in vitro cultured bear bile powder (CBBP) include tauroursodeoxycholic acid (TUDCA), taurochenodeoxycholic acid (TCDCA), ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA, and it has pharmacological properties that are similar to those of natural bear bile powder (NBBP). In this study, the pharmacokinetic parameters of both CBBP and NBBP were measured in rats with a new surrogate analyte LC-MS method using stable isotopes as surrogate analytes (D4-TUDCA, D4-TCDCA, D4-UDCA and D4-CDCA) with response factors validated in authentic matrix (plasma) for simultaneously monitoring the authentic analytes (TUDCA, TCDCA, UDCA and CDCA). The method validation was satisfactory for the linear regression (r, 0.9975-0.9994), precision (RSD intra-day, 0.72-9.35%; inter-day, 3.82-9.02%), accuracy (RE, -12.42-5.67%) and matrix effect (95.53-99.80%), along with analyte recovery (95.90-98.82%) and stability (89.48-101.81%) of surrogate analytes, and precision (RSD intra-day, 1.06- 11.51%; inter-day, 2.23- 11.38%), accuracy (RE, -7.40-10.76%) and stability (87.37-111.70%) of authentic analytes. We successfully applied this method to evaluate the pharmacokinetics of CBBP and NBBP in rats, which revealed the critical in vivo properties of both bear bile preparations.

Cyclin-dependent kinases (CDKs) are promising therapeutic targets for cancer therapy. Herein, we describe our efforts toward the discovery of a series of 5-chloro

Introduction: Phthalates are a group of high production chemicals, generally used as plasticizers and odor enhancers. Phthalates cross the blood-placenta barrier and are associated with deficits in cognitive functions and behavior problems in offspring. We previously reported sex-specific associations with motor function when phthalates are considered singly. Because exposure to phthalates usually occurs as mixtures, here we assess these associations between a mixture of phthalates and motor function at age 11 years. Methods: Data come from the prospective cohort study of mothers and offspring who participated in the Columbia Center for Children’s Environmental Health birth cohort (CCCEH). Seven phthalate metabolites were measured in maternal spot urine obtained during the third trimester and motor function was evaluated using the short form of the Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition (BOT-2) at the age of 11 years. We used Weighted Quartile Sum (WQS) regression models to examine the effect of phthalate metabolites in males and females separately. The models were adjusted for child age in months, child BMI, maternal race (African-American vs. Dominican), prenatal alcohol consumption, maternal demoralization score, HOME score, and urine specific gravity. In a secondary analysis we used linear regression models to examine the association between the sum of molar concentrations of both DEHP and non-DEHP metabolites, and outcomes of gross and fine motor functions. Results: 209 mother-child pairs were eligible for this analysis. A significant decrease in fine-motor functions was observed among females, but not among males, following exposure to high levels of weighted quartile sum of seven phthalate metabolites (Covariates-adjusted coefficient estimate B = −2.7, 95% Confidence Interval [CI] −4.64 to −0.75, p = 0.01 for females [n = 116] and B = −1.63, 95%CI −3.94 to 0.69, p = 0.16 for males [n = 93]). The most highly weighted phthalate metabolites, associated with fine-motor functions among females, were MBP, MBZP, and MIBP, all non-DEHP phthalates.No significant associations were found between the weighted quartile sum of seven phthalate metabolites and gross-motor functions at the age of 11 years for males (B = −0.81, 95%CI −1.17 to 1.96, p = 0.23).With the molar sum of four non-DEHP phthalates as main predictor of linear regression models, we found significant decrease in gross and fine motor functions among females prenatally exposed to non-DEHP phthalates B = −0.98, 95%CI −1.98 to 0.03, p = 0.05 and B = −0.85, 95%CI −1.49 to −0.20, p = 0.01, respectively). Conclusions: Phthalate exposure during pregnancy was associated with decreased motor functions among 11-year-old girls. Keywords: Phthalates, Motor functions

Vascular endothelial cell senescence and endoplasmic reticulum (ER) stress induced unfolded protein response (UPR) are two critical contributors to individual aging. However, whether these two biological events have crosstalk and are controlled by shared upstream regulators are largely unknown. Here, we found PARP16, a member of the Poly (ADP-ribose) polymerases family that tail-anchored ER transmembrane, was upregulated in angiotensin II (Ang II)-induced vascular aging and promoted UPR. Further, PARP16 was epigenetically upregulated by Smyd3, a histone H3 lysine 4 methyltransferase that bound to the promotor region of Parp16 gene and increased H3K4me3 level to activate its host gene's transcription. Intervention of either Smyd3 or PARP16 ameliorated vascular aging associated phenotypes in both cell and mice models. This study identified Smyd3-PARP16 as a novel signal axis in regulating UPR and endothelial senescence, and targeting this axis has implications in preventing vascular aging and related diseases.

There are limited data examining the consequences of environmental exposure to arsenic on the immune system in adults, particularly among smokers. Smoking has been shown to exacerbate or contribute to impaired immune function in men chronically exposed to arsenic. In contrast, vitamin D (VitD) is known to have a positive influence on innate and adaptive immune responses. The effect of circulating VitD on arsenic-associated immune dysfunction is not known. Here we examine the relationship of arsenic exposure and T cell proliferation (TCP), a measure of immune responsiveness, and circulating VitD among adult men and women in Bangladesh. Arsenic exposure was assessed using total urinary arsenic as well as urinary arsenic metabolites all adjusted for urinary creatinine. TCP was measured ex vivo in cryopreserved peripheral blood mononuclear cells from 614 adult participants enrolled in the Bangladesh Health Effects of Arsenic Longitudinal Study; serum VitD was also evaluated. The influence of cigarette smoking on arsenic-induced TCP modulation was assessed only in males as there was an inadequate number of female smokers. These studies show that arsenic suppressed TCP in males. The association was significantly strong in male smokers and to a lesser extent in male non-smokers. Interestingly, we found a strong protective effect of high/sufficient serum VitD levels on TCP among non-smoking males. Furthermore, among male smokers with low serum VitD (⊔20 ng/ml), we found a strong suppression of TCP by arsenic. On the other hand, high VitD (>20 ng/ml) was found to attenuate effects of arsenic on TCP among male-smokers. Overall, we found a strong protective effect of VitD, when serum levels were >20 ng/ml, on arsenic-induced inhibition of TCP in men, irrespective of smoking status. To our knowledge this is the first large study of immune function in healthy adult males and females with a history of chronic arsenic exposure.

Objectives:Essential tremor (ET) confers an increased risk for developing both amnestic and non-amnestic mild cognitive impairment (MCI). Yet, the optimal measures for detecting mild cognitive changes in individuals with this movement disorder have not been established. We sought to identify the cognitive domains and specific motor-free neuropsychological tests that are most sensitive to mild deficits in cognition as defined by a Clinical Dementia Rating (CDR) of 0.5, which is generally associated with a clinical diagnosis of MCI.Methods:A total of 196 ET subjects enrolled in a prospective, longitudinal, clinical-pathological study underwent an extensive motor-free neuropsychological test battery and were assigned a CDR score. Logistic regression analyses were performed to identify the neuropsychological tests which best identified individuals with CDR of 0.5 (mild deficits in cognition)versus0 (normal cognition).Results:In regression models, we identified five tests in the domains of Memory and Executive Function which best discriminated subjects with CDR of 0.5versus0 (86.9% model classification accuracy). These tests were the California Verbal Learning Test II Total Recall, Logical Memory II, Verbal-Paired Associates I, Category Switching Fluency, and Color-Word Inhibition.Conclusions:Mild cognitive difficulty among ET subjects is best predicted by combined performance on five measures of memory and executive function. These results inform the nature of cognitive dysfunction in ET and the creation of a brief cognitive battery to assess patients with ET for cognitively driven dysfunction in life that could indicate the presence of MCI. (JINS, 2018,24, 1084–1098)

Aims Jumonji domain-containing protein 3 (JMJD3), also called lysine specific demethylase 6B (KDM6b), is an inducible histone demethylase which plays an important role in many biological processes, however, its function in vascular remodelling remains unknown. We aim to demonstrate that JMJD3 mediates vascular neointimal hyperplasia following carotid injury, and proliferation and migration in platelet-derived growth factor BB (PDGF-BB)-induced vascular smooth muscle cells (VSMCs). Methods and results By using both genetic and pharmacological approaches, our study provides the first evidence that JMJD3 controls PDGF-BB-induced VSMCs proliferation and migration. Furthermore, our in vivo mouse and rat intimal thickening models demonstrate that JMJD3 is a novel mediator of neointima formation based on its mediatory effects on VSMCs proliferation, migration, and phenotypic switching. We further show that JMJD3 ablation by small interfering RNA or inhibitor GSK J4 can suppress the expression of NADPH oxidase 4 (Nox4), which is correlated with H3K27me3 enrichment around the gene promoters. Besides, deficiency of JMJD3 and Nox4 prohibits autophagic activation, and subsequently attenuates neointima and vascular remodelling following carotid injury. Above all, the increased expression of JMJD3 and Nox4 is further confirmed in human atherosclerotic arteries plaque specimens. Conclusions JMJD3 is a novel factor involved in vascular remodelling. Deficiency of JMJD3 reduces neointima formation after vascular injury by a mechanism that inhibits Nox4-autophagy signalling activation, and suggesting JMJD3 may serve as a perspective target for the prevention and treatment of vascular diseases.

This study investigated patterns of probable posttraumatic stress disorder (PTSD) and their predictors among 2,431 Asian American and 31,455 non-Hispanic White World Trade Center (WTC) Registry participants 2-3 years and 5-6 years after the WTC attack. Participants were divided into four PTSD pattern groups: resilient, remitted, delayed onset, and chronic. Asians had a lower proportion in the resilient group (76.5% vs. 79.8%), a higher proportion in the chronic (8.6% vs. 7.4%) and remitted (5.9% vs. 3.4%) groups, and a similar proportion in the delayed onset group (about 9%) compared to Whites. In multinomial logistic regression analyses, disaster exposure, immigrant status, lower income, pre-attack depression/anxiety, and lower respiratory symptoms were associated with increased odds of chronic and delayed onset PTSD (vs. resilience) among both races. Education and employment were protective against chronic and delayed onset PTSD among Whites only. These results can inform targeted outreach efforts to enhance prevention and treatment for Asians affected by future events.

Cystathionine-γ-lyase (CSE), an enzyme associated with hydrogen sulfide (H(2)S) production, is an important endogenous regulator of inflammation. Jumonji domain-containing protein 3 (JMJD3) is implicated in the immune response and inflammation. Here, we investigated the potential contribution of JMJD3 to endogenous CSE-mediated inflammation in rheumatoid arthritis (RA). Upregulated CSE and JMJD3 were identified in synovial fibroblasts (SFs) from RA patients as well as in the joints of arthritic mice. Knocking down CSE augmented inflammation in IL-1β-induced SFs by increasing JMJD3 expression. In addition, CSE(−/−) mice with collagen-induced arthritis (CIA) developed severe joint inflammation and bone erosion. Conversely, overexpressing CSE inhibited JMJD3 expression by the transcription factor Sp-1 and was accompanied by reduced inflammation in IL-1β-treated SFs. Furthermore, JMJD3 silencing or the administration of the JMJD3 inhibitor GSK-J4 significantly decreased the inflammatory response in IL-1β-treated SFs, mainly by controlling the methylation status of H3K27me3 at the promoter of its target genes. GSK-J4 markedly attenuated the severity of arthritis in CIA mice. In conclusion, suppressing JMJD3 expression by the transcription factor Sp-1 is likely responsible for the ability of CSE to negatively modulate the inflammatory response and reduce the progression of RA.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by abnormal inflammation, angiogenesis, and cartilage destruction. In RA, neoangiogenesis is an early and crucial event to promote the formation of pannus, causing further inflammatory cell infiltration. The transcription factor GATA4 is a critical regulator of cardiac differentiation-specific gene expression. We find that a higher level of GATA4 exists in synovium of rheumatoid arthritis (RA) patients, but the function of GATA4 in RA remains unclear. In the present study, IL-1β induces inflammation in fibroblast-like synoviocytes (FLS) MH7A, which is accompanied with the increased expression of GATA4 and VEGF production. Through application of GATA4 loss-of-function assays, we confirm the requirement of GATA4 expression for inflammation induced by IL-1β in FLS. In addition, we demonstrate for the first time that GATA4 plays key roles in regulating VEGF secretion from RA FLS to promote cellular proliferation, induce cell migration, and angiogenic tube formation of endothelial cells. GATA4 induces the angiogenic factors VEGFA and VEGFC, by directly binding to the promoter and enhancing transcription. The knockdown of GATA4 attenuates the development of collagen-induced arthritis (CIA) and prevents RA-augmented angiogenesis in vivo, which are accompanied with decreased VEGF level. These results reveal a previously unrecognized function for GATA4 as a regulator of RA angiogenesis and we provide experimental data validating the therapeutic target of GATA4 in RA mice.

Overproduction of inflammatory mediators contributes to uncontrolled inflammation during endotoxin shock. Cystathionine-γ-lyase (CSE), an enzyme involved in hydrogen sulfide (H2S) biosynthesis, has potential anti-inflammatory activity in a variety of inflammatory diseases. Jumonji domain-containing protein 3 (JMJD3), a histone 3 Lys27 (H3K27) demethylase, has been implicated in macrophage activation, but its function in CSE-mediated anti-inflammatory activities remains unknown. In the present study CSE was found to be upregulated in macrophages and mouse lipopolysaccharide (LPS) challenge models. LPS stimulation also enhanced the activation of JMJD3 and decreased H3K27me3 levels. JMJD3 knockdown upregulated H3K27me3 levels and attenuated the LPS-mediated inflammatory response. CSE knockout amplified the inflammatory cascade by increasing JMJD3 expression in septic mice. Similarly, enhanced production of inflammatory mediators by macrophages was mitigated by CSE overexpression via inhibition of JMJD3 expression. This is the first report indicating that inflammation enhanced CSE/H2S system biosynthesis, that in turn attenuated the LPS-triggered inflammatory response by regulating JMJD3 expression. Thus, the CSE/H2S system represents an epigenetic-based modification mechanism to prevent uncontrolled inflammation.

Background/Aims: Sepsis is a severe and complicated syndrome that is characterized by dysregulation of host inflammatory responses and organ failure. Cystathionine-γ-lyase (CSE)/ hydrogen sulfide (H2S) has potential anti-inflammatory activities in a variety of inflammatory diseases. NADPH oxidase 4 (Nox4), a member of the NADPH oxidases, is the major source of reactive oxygen species (ROS) and its expression is increased in sepsis, but its function in CSE-mediated anti-inflammatory activities remains unknown. Methods: Macrophages were either transfected with CSE, Nox4 siRNA or transduced with lentiviral vector encoding CSE or Nox4, and then stimulated with lipopolysaccharide (LPS). The expression of inflammatory mediators and signaling pathway activation were measured by quantitative PCR (qPCR), ELISA, and immunoblotting. LPS-induced shock severity in WT, Nox4 knockdown and CSE knockout (CSE-/-) mice was assessed. Results: Here we showed that CSE and Nox4 were upregulated in macrophage and mouse in response to LPS. After LPS stimulation, the inflammatory responses were significantly ameliorated by lentiviral Nox4 shRNA knockdown, but were exacerbated by lentiviral overexpressing Nox4. Furthermore, Nox4 mediated inflammation through PI3K/Akt and p-p38 mitogen-activated protein kinase signal pathway. Notably, CSE knockout served to amplify the inflammatory cascade by increasing Nox4-ROS signaling activation in septic mice and macrophage. Similarly, the enhanced production of inflammatory mediators by macrophages was reduced by CSE overexpression. Conclusion: Thus, we demonstrated that CSE/H2S attenuated LPS-induced sepsis against oxidative stress and inflammation damage probably largely through mediated Nox4 pathway.

Background Organophosphate insecticides and the herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D) are used to protect crops or control weeds. Pyrethroids are used to manage pests both in agriculture and in residences, and to reduce the transmission of insect-borne diseases. Several studies have reported inverse associations between exposure to organophosphates (as a larger class) and birth outcomes but these associations have not been conclusive for pyrethroids or 2,4-D, specifically. We aimed to investigate the association between birth outcomes and urinary biomarkers of pyrethroids, organophosphates and 2,4-D among healthy pregnant women living in New York City. Methods We quantified urinary biomarkers of 2,4-D and of organophosphate and pyrethroid insecticides from 269 women from two cohorts: a) Thyroid Disruption And Infant Development (TDID) and b) Sibling/Hermanos cohort (S/H). We used weighted quantile sum regression and multivariable linear regression models to evaluate the associations between a mixture of urinary creatinine-adjusted biomarker concentrations and birth outcomes of length, birthweight and head circumference, controlling for covariates. We also used linear regression models and further classified biomarkers concentrations into three categories (i: non-detectable; ii: between the limit of detection and median; and iii: above the median) to investigate single pesticides’ association with these birth outcomes. Covariates considered were delivery mode, ethnicity, marital status, education, income, employment status, gestational age, maternal age and pre-pregnancy BMI. Analyses were conducted separately for each cohort and stratified by child sex within each cohort. Results In TDID cohort, we found a significant inverse association between weighted quantile sum of mixture of pesticides and head circumference among boys. We found that the urinary biomarkers of organophosphate chlorpyrifos, TCPy, and 2,4-D had the largest contribution to the overall mixture effect in the TDID cohort among boys (b = −0.57, 95%CI: −0.92, −0.22) (weights = 0.81 and 0.16 respectively) but not among girls. In the multivariable linear regression models, we found that among boys, for each log unit increase in 3,5,6-trichloro-2-pyridinol (TCPy, metabolite of organophosphate chlorpyrifos) in maternal urine, there was a −0.56 cm decrease in head circumference (95%CI: −0.92, −0.19). Among boys in the TDID cohort, 2,4-D was associated with smaller head circumference in the second (b = −1.57; 95%CI: −2.74, −0.39) and third (b = −1.74, 95%CI: −2.98, −0.49) concentration categories compared to the first. No associations between pyrethroid and organophosphate biomarkers and birth outcomes were observed in girls analyzed in WQS regression or individually in linear regression models in TDID cohort. In the S/H cohort, head circumference increased with higher concentrations of 3-phenoxybenzoic acid (3-PBA, a biomarker of several pyrethroids) (b = 0.53, 95%CI: 0.03, 1.04) among boys and head circumference was lower among girls in the high compared to low category of 2,4-D (b = −2.27, 95%CI: − 3.98, −0.56). Birth length was also positively associated with the highest concentration of 2,4-D compared to the lowest among boys (b = 4.01, 95%CI: 0.02,8.00). Conclusions Weighted quantile sum of pesticides was negatively associated with head circumference among boys in one cohort. Nonetheless, due to directional homogeneity assumption in WQS no positive associations were detected. In linear regression models with individual pesticides, concentrations of TCPy were inversely associated with head circumference in boys and higher concentrations of 2,4-D was inversely associated with head circumference among girls; 2,4-D concentrations were also associated with higher birth length among boys. Concentrations of 3-PBA was positively associated with head circumference among boys.

In a sample of 442 births from the Child Health and Development Studies cohort, we examined associations between maternal prenatal exposure to hydroxylated polychlorinated biphenyl metabolites (OH-PCBs) and pregnancy outcomes, and whether associations were mediated by maternal thyroid hormone levels and/or modified by maternal smoking. Compared to nonsmokers, smokers had twice the mean concentration of 4-OH-CB107 (p

Background: Posttranslational histone modifications (PTHMs) are altered by arsenic, an environmental carcinogen. PTHMs are also influenced by nutritional methyl donors involved in one-carbon metabolism (OCM), which may protect against epigenetic dysregulation. Methods: We measured global levels of three PTHMs, which are dysregulated in cancers (H3K36me2, H3K36me3, H3K79me2), in peripheral blood mononuclear cells (PBMC) from 324 participants enrolled in the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults. Sex-specific associations between several blood OCM indices (folate, vitamin B12, choline, betaine, homocysteine) and PTHMs were examined at baseline using regression models, adjusted for multiple tests by controlling for the false discovery rate (PFDR). We also evaluated the effects of folic acid supplementation (400 μg/d for 12 weeks), compared with placebo, on PTHMs. Results: Associations between choline and H3K36me2 and between vitamin B12 and H3K79me2 differed significantly by sex (Pdiff < 0.01 and Conclusions: OCM indices may influence PTHMs in a sex-dependent manner, and folic acid supplementation, at this dose and duration, does not alter PTHMs in PBMCs. Impact: This is the first study to examine the influences of OCM indices on PTHMs in a population that may have increased susceptibility to cancer development due to widespread exposure to arsenic-contaminated drinking water and a high prevalence of hyperhomocysteinemia. Cancer Epidemiol Biomarkers Prev; 26(2); 261–9. ©2016 AACR.

There is limited data on disease progression and survival in adult diagnosis cystic fibrosis (CF). This study evaluates change of lung function over time and rates of death/lung transplant in adult diagnosis CF.The CF Foundation Patient Registry was reviewed for patients diagnosed 1993-2003. Rate of FEV1 decline was calculated up to 2010 for age groups 6-11, 12-17, and 18 and above. Kaplan Meier method was used for 10 and 15year survival rate calculations for patients diagnosed as adults. Cox Proportional hazards models using predictors affecting disease progression and survival without transplant were run.Between 1993 and 2003, 11,884 patients were diagnosed with CF, of which 2848 were ages 6 and older. Annual rate of change of FEV1% predicted over 5years differed by diagnosis age group: -1.42% per year for ages 6-11, -2.04% for ages 12-17 and -1.13% for ages 18-65 (p0.0001). Pseudomonas aeruginosa infection was associated with faster rates of lung function decline in all age groups. Survival without transplant for CF patients diagnosed at ≥18years were 76% and 65% by 10 and 15years, respectively. Of adults with FEV1 of70% predicted at diagnosis, 95% were alive without transplant at 10years, whereas of those with FEV140% predicted at diagnosis, 31% were alive without transplant at 10years.Lung function declines at a slower rate in adult diagnosis CF. However, particularly in those with low lung function at diagnosis, rates of death or transplant in adult diagnosis CF after 10 and 15years is not negligible.

In a cohort of approximately 200 Bangladeshi men, equally divided into smokers and nonsmokers and equally divided by exposure to high and low levels of drinking water arsenic, we examined ex vivo a series of immune markers and immune function tests in peripheral blood mononuclear cells (PBMC). These immune parameters included PBMC cell surface markers (CSM) for B, T, monocytes, and NK cells, activated T and B cell markers, cytokine production in vitro, and analysis of CD4 subsets (Th1, Th2, Treg, and Th17 cells). We found that the effects of cigarette smoke were quite different than those associated with arsenic or polycyclic aromatic hydrocarbon (PAH)-DNA adducts. Cigarette smoking was associated with a significant increase in the number of PAH-DNA adducts as well as an increase in urinary levels of 1-hydropxypyrene (1-OHP). After correcting for arsenic exposure and PAH-DNA adducts, we found that cigarette smoking was associated with an increase in the percentage of CD19+ B cells, as well as the percentage of activated B cells (CD19+, HLA-DR(bright) cells) found in PBMC. These findings demonstrate activation of the immune system during chronic exposure to cigarette smoke, which is a known risk factor for autoimmune diseases.

The intracellular NOD-like receptor nucleotide-binding domain-like receptors Family Pyrin Domain Containing 3 (NLRP3) is a pivotal regulator of intestinal homeostasis through regulating a variety of inflammatory and autoimmune diseases. The Jumonji domain-containing 3 (Jmjd3) plays important role in inflammatory responses and thus has been proposed as a novel attractive epigenetic target for the treatment of inflammatory diseases. We here investigated whether targeting Jmjd3 regulates NLRP3 inflammasome during experimental colitis. Jmjd3 specific inhibitor GSK J4 or knocking down Jmjd3 significantly inhibited NLRP3 inflammasome activation in lipopolysaccharide (LPS) and nigericin-stimulated bone marrow-derived macrophages. Chromatin immunoprecipitation-PCR analysis validated that GSK J4 rescued the decreased repressive H3K27me3 recruitment level on the promotors of nuclear factor-erythroid 2-related factor 2 (Nrf2) in LPS plus nigericin-induced macrophages. Nrf2 knockdown abolished NLRP3 inflammasome activation. Notably, oral administration of GSK J4 attenuated the disease progression in dextran sodium sulfate-induced colitis mouse model, including reduced disease activity index, improved body weight, rescued bowel shortening and NLRP3 inflammasome activation. Overall, our study reveals that Jmjd3 is a potential epigenetic regulator for the treatment of inflammatory bowel disease (IBD), suggesting that Nrf2 is a potential target gene of Jmjd3 by mediating methylation status of trimethylated H3 lysine 27 (H3K27me3) in the promotor and is required for NLRP3 inflammasome activation, thereby providing the platform for potential future therapeutic interventions in IBD.

Exposures to environmental arsenic (As) and polycyclic aromatic hydrocarbons (PAH) have been shown to independently cause dysregulation of immune function. Little data exists on the associations between combined exposures to As and PAH with immunotoxicity in humans. In this work we examined associations between As and PAH exposures with lymphoid cell populations in human peripheral blood mononuclear cells (PBMC), as well as alterations in differentiation and activation of B and T cells. Two hundred men, participating in the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh, were selected for the present study based on their exposure to As from drinking water and their cigarette smoking status. Blood and urine samples were collected from study participants. We utilized multiparameter flow cytometry in PBMC to identify immune cells (B, T, monocytes, NK) as well as the T-helper (Th) cell subsets (Th1, Th2, Th17, and Tregs) following ex vivo activation. We did not find evidence of interactions between As and PAH exposures. However, individual exposures (As or PAH) were associated with changes to immune cell populations, including Th cell subsets. Arsenic exposure was associated with an increase in the percentage of Th cells, and dose dependent changes in monocytes, NKT cells and a monocyte subset. Within the Th cell subset we found that Arsenic exposure was also associated with a significant increase in the percentage of circulating proinflammatory Th17 cells. PAH exposure was associated with changes in T cells, monocytes and T memory (Tmem) cells and with changes in Th, Th1, Th2 and Th17 subsets all of which were non-monotonic (dose dependent). Alterations of immune cell populations caused by environmental exposures to As and PAH may result in adverse health outcomes, such as changes in systemic inflammation, immune suppression, or autoimmunity.

The objective of this study was to determine the long-term test–retest reliability of the University of Pennsylvania Smell Identification Test (UPSIT), and its individual items, in cognitively intact older adults. A community sample of older adults received a neuropsychological test battery, including the 12-item, 6-trial Selective Reminding Test (SRT). The UPSIT was administered at baseline and follow-up that occurred between 1 and 4 years after baseline. UPSIT scores of participants who were cognitively intact and did not decline cognitively were examined for test–retest reliability. In 92 older adults with mean age 77.6 years followed for 2.79 (standard deviation [SD] 0.69) years, mean UPSIT score declined from 30.29 (SD 5.83) to 27.80 (SD 5.50). In linear mixed models that adjusted for time, age, sex, and education, intraclass correlation coefficients for UPSIT were 0.65, SRT delayed recall 0.59, and SRT total immediate recall 0.49. Among 4 possible response combinations, the largest proportion of participants had correct responses at both visits for 35 out of 40 items. Consistency of item responses ranged from 50% to 90% across the 2 time points. The long-term test–retest reliability of the UPSIT was moderately strong without practice effects over long periods of time in older adults. These results provide indirect support to prior findings on odor identification impairment predicting cognitive decline and dementia, and suggest potential use of olfactory testing as a biomarker in prevention and treatment trials of cognitive enhancers.

Arsenic and polycyclic aromatic hydrocarbons (PAH) are environmental pollutants to which people around the world are exposed through water, food and air. In mouse and in vitro studies of human cells, both of these chemicals have been shown to modulate the immune system. In some experimental studies, a synergistic disruption of immune function was observed by a combined exposure to arsenic and PAH. However, a joint effect of arsenic and PAH on immune function has not been studied in humans. We have conducted an epidemiological investigation to examine effects of chronic arsenic and PAH exposures on immune function. We assessed T-cell proliferation (TCP) and cytokine production of anti-CD3/anti-CD28 stimulated lymphocytes in human peripheral blood mononuclear cells (HPBMC) among 197 healthy men enrolled to the Health Effects of Arsenic Longitudinal (HEALS) cohort in Bangladesh. By design, approximately half were active smokers and the rest were never smokers. Our analyses demonstrated that IL-1b, IL-2, IL-4 and IL-6 were significantly stimulated as a function of urinary arsenic levels in models adjusted for age, body mass index (BMI), smoking status and PAH-DNA adducts. After correcting for false detection rate (FDR), only IL-1b remained statistically significant. We found a U-shaped dose response relationship between urinary arsenic and IL-1b. On the other hand, PAH-DNA adducts were associated with an inhibition of TCP and appeared as an inverted U-shape curve. Dose response curves were non-monotonic for PAH-DNA adduct exposures and suggested that cytokine secretion of IFNg, IL-1b, IL-2, IL-10 and IL17A followed a complex pattern. In the majority of donors, there was a trend towards a decrease in cytokine associated with PAH-DNA adducts. We did not observe any interaction between urinary arsenic and PAH-DNA adducts on immune parameters. Our results indicate that long-term exposures to arsenic and PAH have independent, non-monotonic associations with TCP and cytokine production.

BACKGROUND Folic acid (FA) supplementation facilitates urinary excretion of arsenic, a human carcinogen. A better understanding of interactions between one-carbon metabolism intermediates may improve the ability to design nutrition interventions that further facilitate arsenic excretion. OBJECTIVE The objective was to determine if FA and/or creatine supplementation increase choline and betaine and decrease dimethylglycine (DMG). METHODS We conducted a secondary analysis of the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults (n = 605, aged 24-55 y, 50.3% male) who received arsenic-removal water filters. We examined treatment effects of FA and/or creatine supplementation on plasma choline, betaine, and DMG concentrations, measured by LC-tandem mass spectrometry at baseline and at week 12. Group comparisons were between 1) 400 and 800 μg FA/d (FA400 and FA800, respectively) compared with placebo, 2) creatine (3 g/d) compared with placebo, and 3) creatine plus FA400 compared with FA400. RESULTS Choline decreased in the placebo group (-6.6%; 95% CI: -10.2%, -2.9%) but did not change in the FA groups (FA400: 2.5%; 95% CI: -0.9%, 6.1%; FA800: 1.4%; 95% CI: -2.5%, 5.5%; P < 0.05). Betaine did not change in the placebo group (-3.5%; 95% CI: -9.3%, 2.6%) but increased in the FA groups (FA400: 14.1%; 95% CI: 9.4%, 19.0%; FA800: 13.0%; 95% CI: 7.2%, 19.1%; P < 0.01). The decrease in DMG was greater in the FA groups (FA400: -26.7%; 95% CI: -30.9%, -22.2%; FA800: -27.8%; 95% CI: -31.8%, -23.4%) than in the placebo group (-12.3%; 95% CI: -18.1%, -6.2%; P < 0.01). The percentage change in choline, betaine, and DMG did not differ between creatine treatment arms and their respective reference groups. CONCLUSION Supplementation for 12 wk with FA, but not creatine, increases plasma betaine, decreases plasma DMG, and prevents a decrease in plasma choline in arsenic-exposed Bangladeshi adults. This trial was registered at clinicaltrials.gov as NCT01050556.

Background Chronic exposure to well water arsenic (As) remains a major rural health challenge in Bangladesh and some other developing countries. Many mitigation programs have been implemented to reduce As exposure, although evaluation studies for these efforts are rare in the literature. Objectives In this study we estimated associations between a school-based intervention and various outcome measures of As mitigation. Methods We recruited 840 children from 14 elementary schools in Araihazar, Bangladesh. Teachers from 7 schools were trained on an As education curriculum, whereas the remaining 7 schools without any training formed the control group. Surveys, knowledge tests, and well-water testing were conducted on 773 children both at baseline and postintervention follow-up. Urine samples were collected from 210 children from 4 intervention schools and the same number of children from 4 control schools. One low-As (< 10 μg/L) community well in each study village was ensured during an 18-month intervention period. Results After adjustment for the availability of low-As wells and other sociodemographic confounders, children receiving the intervention were five times more likely to switch from high- to low-As wells (p < 0.001). We also observed a significant decline of urinary arsenic (UAs) (p = < 0.001) (estimated β = –214.9; 95% CI: –301.1, –128.7 μg/g creatinine) among the children who were initially drinking from high-As wells (> Bangladesh standard of 50 μg/L) and significantly improved As knowledge attributable to the intervention after controlling for potential confounders. Conclusions These findings offer strong evidence that school-based intervention can effectively reduce As exposure in Bangladesh by motivating teachers, children, and parents. Citation Khan K, Ahmed E, Factor-Litvak P, Liu X, Siddique AB, Wasserman GA, Slavkovich V, Levy D, Mey JL, van Geen A, Graziano JH. 2015. Evaluation of an elementary school–based educational intervention for reducing arsenic exposure in Bangladesh. Environ Health Perspect 123:1331–1336; http://dx.doi.org/10.1289/ehp.1409462

Background Emerging evidence suggests that phthalate exposure may be associated with behavior problems in children and that these associations may be sex specific. Methods In a follow up study of 411 inner-city minority mothers and their children, mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP), monethyl phthalate (MEP) and four di-2-ethylhexyl phthalate metabolites (DEHP) were quantified in maternal urine samples collected during the third trimester and in child urine samples at ages 3 and 5 years. The Conners’ Parent Rating Scale-Revised: Long Form (CPRS) and Child Behavior Checklist (CBCL) were administered to the mothers to assess children’s behavior problems at 7 years of age. The analysis included children with available measures of CBCL, CPRS and phthalates measured in maternal urine. We performed both Quasi-Poisson regression and a mixture analysis using Weighted Quantile Sum(WQS) regression to assess the risk for CPRS scores and for internalizing and externalizing behaviors (from the CBCL) following intra-uterine exposure to the phthalate metabolites for boys and girls separately. Results Among boys, increases in in anxious-shy behaviors were associated with prenatal exposure to MBzP (Mean Ratio [MR] = 1.20, 95%CI 1.05–1.36) and MiBP (Mean Ratio (MR) = 1.22, 95%CI 1.02–1.47). Among girls, increases in perfectionism were associated with MBzP (MR = 1.15, 95%CI 1.01–1.30). In both boys and girls, increases in psychosomatic problems were associated with MiBP (MR = 1.28, 95%CI 1.02–1.60), and MnBP (MR = 1.28, 95%CI 1.02–1.59), respectively. Among girls, decreased hyperactivity was associated with two DEHP metabolites, mono(2-ethyl-5-oxohexyl) phthalate (MR = 0.83, 95%CI 0.71–0.98) and mono(2-ethyl-5-hydroxyhexyl) phthalate (MR = 0.85, 95%CI 0.72–0.99). Using weighted Quantile Sum logistic regression, no associations were found between the Weighted Quantile Sum (WQS) of phthalate metabolites and CPRS scores or externalizing and internalizing behaviors. Nonetheless, when the analysis was performed separately for DEHP and non-DEHP metabolites significant associations were found between the WQS of DEHP metabolites and social problems in boys (OR = 2.15, 95%CI 1.13–4.06, p-value = 0.02) anxious-shy problems in girls (OR = 2.19, 95%CI 1.15–4.16, p = 0.02), and emotional lability problems in all children (OR = 0.61, 95%CI 0.38–0.97, p = 0.04). MEHP and MEOHP were the most highly weighted DEHP metabolites in WQS mixture. The analysis performed with CBCL scale corroborated these associations. Conclusion Concentration of non-DEHP metabolites was associated with anxious-shy behaviors among boys. DEHP phthalate metabolites were associated with decreased hyperactivity and impulsivity among girls on CPRS scores. These findings lend further support to the adverse associations between prenatal phthalate exposure and childhood outcomes, and clearly suggest that such associations are sex and mixture specific.

Acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure in clinic. Fisetin (FST) is a phenolic compound that has been isolated from many natural products.Our aim is to study the protection effect and mechanisms of FST on APAP-induced hepatotoxicity in endogenous metabolism and metabolomics in vitro and in vivo.FST was i.g. administered to mice at 10, 20 and 40 mg/kg for 7 days and a single dose of APAP (400 mg/kg) was given on the last day. Serum and tissue were collected for biochemical analysis. L-02 cells were used to assess cell viability. LC-MS was used to study the metabolic fingerprinting in vivo and vitro. PCA and OPLS-DA were used to search the potential biomarkers (VIP1, p 0.05). The pathway analysis was conducted on Metaboanalyst 4.0. Then liver oxidative stress indices and glutathione markers were examined using PCR and kits.ALT, AST, liver histological observation and cell viability results showed that FST could reverse APAP induced toxicology in mice and L-02 cells. In metabolomics study, 26 metabolites in vitro and 60 metabolites in vivo were identified by searching in the library and most of them decreased to normal level in FST treatment. It is observed in pathway analysis that the most significant pathway was glutathione metabolism. Furthermore, the results of mRNA and immunofluorescence showed that FST suppressed ROS formation in liver tissue and L-02 cells, as well as restored the expression of GPX1, GST and other antioxidative enzymes genes.Our results indicate that FST prevented APAP-induced hepatotoxicity by regulating glutathione metabolism and the expression of related antioxidative signals.

Rheumatoid arthritis (RA) is an immune-mediated disease with the characteristics of progressive joint destruction, deformity, and disability. Epigenetic changes have been implicated in the development of some autoimmune disorders, resulting in an alteration of gene transcription. Here, we investigated how Jumonji C family of histone demethylases (JMJD3) regulated the proliferation and activation of fibroblast-like synoviocytes (FLSs), which are involved in RA joint destruction and pathologic process. The JMJD3 expression and proliferation markers in RA-FLS were higher than those in healthy-FLS and were upregulated in platelet-derived growth factor (PDGF)-induced FLS. Elevated JMJD3 promoted the proliferation and migration of FLS. Treatment with JMJD3 small interfering RNA or inhibitor glycogen synthase kinase (GSK) J4 led to decreased proliferation and migration of FLS. Interestingly, induction of proliferating cell nuclear antigen (PCNA), a major player of the cell-cycle regulation, was correlated with trimethylated lysine 27 in histone H3 loss around the gene promoters. The knockdown of JMJD3 abolished PCNA expression in PDGF-induced FLS and further inhibited cell proliferation and migration, suggesting that JMJD3/PCNA played a crucial role in aspects of FLS proliferation and migration. In vivo, the ability of GSK J4 to hinder collagen-induced arthritis (CIA) in DBA/1 mice was evaluated. We found that GSK J4 markedly attenuated the severity of arthritis in CIA mice. The therapeutic effects were associated with ameliorated joint swelling and reduced bone erosion and destruction. This study revealed how JMJD3 integrated with epigenetic processes to regulate RA-FLS proliferation and invasion. These data suggested that JMJD3 might contribute to rheumatoid synovial hyperplasia and have the potential as a novel therapeutic target for RA.-Jia, W., Wu, W., Yang, D., Xiao, C., Su, Z., Huang, Z., Li, Z., Qin, M., Huang, M., Liu, S., Long, F., Mao, J., Liu, X., Zhu, Y. Z. Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis.

BACKGROUND: Depressive symptoms are associated with essential tremor (ET). However, the relationship between cognitive, functional, and motor measures with depressive symptoms in ET is not yet understood. METHODS: The following measures were cross-sectionally assessed in a group of 223 subjects with ET: the Montreal Cognitive Assessment (MoCA) Scale, the Lawton Independent Activities of Daily Living (IADL) Scale, a neurologist assessment of tremor severity, and the Geriatric Depression Scale (GDS). RESULTS: 20% (44) of the subjects met GDS criteria for depression (GDS ≥ 10). 43% (94) of the subjects showed at least some cognitive impairment (≤ 24 on the MoCA), and 15.3% (34) reported significant functional impairment (IADL score < 7). There was no significant association between GDS score and tremor scale score. The total GDS was negatively associated with the total MoCA score (Spearman’s r=−0.15, p=0.03). The total GDS was also negatively associated with the IADL score (Spearman’s r=−0.19, p=0.02), (logistic model odds ratio, OR=4.91, p

Despite the fact that Asians constituted a sizeable proportion of those exposed to the World Trade Center attack on September 11, 2001 due to its proximity to Chinatown and many South Asians working in the nearby buildings, no study had focused on examining the mental health impact of the attack in this group. Based on data collected by the World Trade Center Health Registry from a sample of 4721 Asians 2–3 years after the disaster, this study provides a baseline investigation for the prevalence and the risk and protective factors for PTSD among Asian Americans directly exposed to the attack and compared this population against 42,862 non-Hispanic Whites. We found that Asians had a higher prevalence of PTSD compared to Whites (14.6 vs 11.7%). “Race-specific factors” significantly associated to PTSD in the multivariate analyses were noted among sociodemographics: higher education was protective for Whites but a risk factor for Asians; being employed was protective for Whites but had no effect for Asians; and being an immigrant was a risk factor for Whites but had no effect for Asians. However, income was a protective factor for both races. Other “universal factors” significantly increased the odds of PTSD symptoms but showed no racial differences, including exposure to the disaster and the presence of lower respiratory symptoms which intensified odds of PTSD by the greatest magnitude (3.6–3.9 times). Targeted effort to reach out to Asians is essential for prevention and follow up treatment given this group’s striking history of underutilization of mental health services.

Aims Angiotensin II (Ang II) causes vascular inflammation, leading to vascular endothelial cell dysfunction, and is associated with the development of cardiovascular diseases. Therefore, interventions in inflammation may contribute to the reduction of cardiovascular diseases. Here, we aim to demonstrate that HDAC4, one of class IIa family histone de-acetylases (HDACs) members, promotes autophagy-dependent vascular inflammation. Methods and results By loss-of-function approaches, our study provides the first evidence that HDAC4 mediates Ang II-induced vascular inflammation in vitro and in vivo. In response to the Ang II, HDAC4 expression is up-regulated rapidly, with increased autophagic flux and inflammatory mediators in vascular endothelial cells (VECs). In turn, HDAC4 deficiency suppresses activation of autophagy, leading to reduced inflammation in Ang II-induced VECs. Consistently, using autophagy inhibitor or silencing LC3-II also alleviates vascular inflammation. Furthermore, HDAC4 regulates autophagy via facilitating transcription factor forkhead box O3a (FoxO3a) de-acetylation, thereby to increase its transcriptional activity. Loss of HDAC4 in VECs results in inhibition of FoxO3a de-acetylation to block its transcriptional activity, leading to downregulation of the downstream FoxO3a target, and hence reduces autophagy and vascular inflammation. FoxO3a silencing using siRNA approach significantly inhibits activation of autophagy. Finally, knockdown of HDAC4 in Ang II-infused mouse models ameliorates vascular inflammation, suggesting that inhibitor of HDAC4 may be potential therapeutics for vascular diseases associated with inflammation. Conclusion These results suggest that HDAC4-mediated FoxO3a acetylation regulates Ang II-induced autophagy activation, which in turn plays an essential role in causing vascular inflammation.

Arsenic (As) methylation capacity in epidemiologic studies is typically indicated by the proportions of inorganic As (%InAs), monomethylarsonic acid (%MMA), and dimethylarsinic acid (%DMA) in urine as a fraction of total urinary As. The relationship between renal function and indicators of As methylation capacity has not been thoroughly investigated.Our two aims were to examine (1) associations between estimated glomerular filtration rate (eGFR) and %As metabolites in blood and urine, and (2) whether renal function modifies the relationship of blood %As metabolites with respective urinary %As metabolites.In a cross-sectional study of 375 As-exposed Bangladeshi adults, we measured blood and urinary As metabolites, and calculated eGFR from plasma cystatin C.In covariate-adjusted linear models, a 1 ml/min/1.73 m(2) increase in eGFR was associated with a 0.39% increase in urinary %InAs (p0.0001) and a mean decrease in urinary %DMA of 0.07 (p=0.0005). In the 292 participants with measurable blood As metabolites, the associations of eGFR with increased blood %InAs and decreased blood %DMA did not reach statistical significance. eGFR was not associated with urinary or blood %MMA in covariate-adjusted models. For a given increase in blood %InAs, the increase in urinary %InAs was smaller in those with reduced eGFR, compared to those with normal eGFR (p=0.06); this effect modification was not observed for %MMA or %DMA.Urinary excretion of InAs may be impaired in individuals with reduced renal function. Alternatively, increased As methylation capacity (as indicated by decreased urinary %InAs) may be detrimental to renal function.

Background: Creatine synthesis from guanidinoacetate consumes ;50% of s-adenosylmethionine (SAM)–derived methyl groups, accounting for an equivalent proportion of s-adenosylhomocysteine (SAH) and total homocysteine (tHcys) synthesis. Dietary creatine inhibits the synthesis of guanidinoacetate, thereby lowering plasma tHcys in rats. Objective: We tested the hypotheses that creatine supplementation lowers plasma guanidinoacetate, increases blood SAM, lowers blood SAH, and lowers plasma tHcys. Methods: Bangladeshi adults were randomly assigned to receive 1 of 4 treatments for 12 wk: placebo (n = 101), 3 g/d creatine (Cr; n = 101), 400 mg/d folic acid (FA; n = 153), or 3 g/d creatine plus 400 mg/d folic acid (Cr+FA; n = 103). The outcomes of plasma guanidinoacetate and tHcys, as well as whole blood SAM and SAH, were analyzed at baseline and week 12 by HPLC. Treatment effects of creatine supplementation were examined with the use of the group comparisons of Cr vs. placebo and Cr+FA vs. FA. Results: Plasma guanidinoacetate declined by 10.6% (95% CI: 4.9, 15.9) in the Cr group while increasing nonsignificantly in the placebo group (3.7%; 95% CI: 20.8, 8.5) (Pgroup difference = 0.0002). Similarly, plasma guanidinoacetate declined by 9.0% (95% CI: 3.4, 14.2) in the Cr+FA group while increasing in the FA group (7.0%; 95% CI: 2.0, 12.2) (Pgroup difference < 0.0001). Plasma tHcys declined by 23.4% (95% CI: 19.5, 27.1) and 21.0% (95% CI: 16.4, 25.2) in the FA and Cr+FA groups, respectively (Pgroup difference = 0.41), with no significant changes in the placebo or Cr groups (Pgroup difference = 0.35). A decrease in guanidinoacetate over time was associated with a decrease in tHcys over time in the Cr+FA group (b = 0.30; 95% CI: 0.17, 0.43; P < 0.0001). Conclusions: Our findings indicate that whereas creatine supplementation downregulates endogenous creatine synthesis, this may not on average lower plasma tHcys in humans. However, tHcys did decrease in those participants who experienced a decline in plasma guanidinoacetate while receiving creatine plus folic acid supplementation. This trial was registered at clinicaltrials.gov as NCT01050556. J Nutr doi: 10.3945/jn.115.216739.