Lead exposure, glucocorticoids, and physiological stress across the life course: A systematic review.

The biological pathways linking lead exposure to adverse outcomes are beginning to be understood. Rodent models suggest lead exposure induces dysfunction within the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid regulation, a primary physiological stress response system. Over time, HPA axis and glucocorticoid dysfunction has been associated with adverse neurocognitive and cardiometabolic health, much like lead exposure. This systematic review utilized PRISMA guidelines to synthesize the literature regarding associations between lead exposure and downstream effector hormones of the HPA axis, including cortisol, a glucocorticoid, and dehydroepiandrosterone (DHEA), a glucocorticoid antagonist. We additionally determined the state of the evidence regarding lead exposure and allostatic load, a measure of cumulative body burden resultant of HPA axis and glucocorticoid dysfunction. A total of 18 articles were included in the review: 16 assessed cortisol or DHEA and 3 assessed allostatic load. Generally, the few available child studies suggest a significant association between early life lead exposure and altered cortisol, potentially suggesting the impact of developmental exposure. In adulthood, only cross sectional studies were available. These reported significant associations between lead and reduced cortisol awakening response and increased cortisol reactivity, but few associations with fasting serum cortisol. Two studies reported significant associations between increasing lead exposure and allostatic load in adults and another between early life lead exposure and adolescent allostatic load. The paucity of studies examining associations between lead exposure and allostatic load or DHEA and overall heterogeneity of allostatic load measurements limit conclusions. However, these findings cautiously suggest associations between lead and dysregulation of physiological stress pathways (i.e., glucocorticoids) as seen through cortisol measurement in children and adults. Future research would help to elucidate these associations and could further examine the physiological stress pathway as a mediator between lead exposure and detrimental health outcomes.

Associations of prenatal and childhood Pb exposure with allostatic load in adolescence: Findings from the ELEMENT cohort study.

The biological pathways which link lead (Pb) and long-term outcomes are unclear, though rodent models and a few human studies suggest Pb may alter the body's stress response systems, which over time, can elicit dysregulated stress responses with cumulative impacts. This study examined associations between prenatal and early childhood Pb exposure and adolescent allostatic load, an index of an individual's body burden of stress in multiple biological systems, and further examined sex-based associations. Among 391 (51% male) participants in the ELEMENT birth cohort, we related trimester-specific maternal blood Pb, 1-month postpartum maternal tibia and patella Pb, and child blood Pb at 12-24 months to an allostatic load index in adolescence comprised of biomarkers of cardiovascular, metabolic, neuroendocrine, and immune function. The results were overall mixed, with prenatal exposure, particularly maternal bone Pb, being positively associated with allostatic load, and early childhood Pb showing mixed results for males and females. In adjusted Poisson regression models, 1 mcg/g increase in tibia Pb was associated with a 1% change in expected allostatic load (IRR = 1.01; 95%CI 0.99, 1.02). We found a significant Pb × sex interaction (IRR = 1.05; 95%CI 1.01, 1.10); where males saw an increasing percent change in allostatic load as 12 month Pb levels increased compared to females who saw a decreasing allostatic load. Further examination of allostatic load will facilitate the determination of potential mechanistic pathways between developmental toxicant exposures and later-in-life cardiometabolic outcomes.

A proof-of-principle study of the short-term effects of 3,4-methylenedioxymethamphetamine (MDMA) on tinnitus and neural connectivity.

Background: This study was conducted to investigate the short-term behavioural and neurophysiological effects of 3,4-methylenedioxymethamphetamine (MDMA) on tinnitus perception.Methods: A double-blind randomized controlled cross-over design. Part 1. Behavioural measures of tinnitus following 30 mg MDMA or placebo administration (N = 5 participants) and Part 2. Behavioural measures of tinnitus and correlations between pairs of apriori regions of interest (ROI) using resting-state functional magnetic resonance imaging (rs-fMRI) before and after 70 mg of MDMA or placebo (N = 8 participants).Results: The results to MDMA were similar to placebo. For the 70 mg dose, there was a significant reduction after 4 h in annoyance and ignore ratings. RsMRI showed decreased connectivity compared with placebo administration between the left hippocampal, right hippocampal, left amygdala and right amygdala regions, and between the right posterior parahippocampal cortex and the left amygdala after two hours of 70 mg MDMA administration. Increased connectivity compared to placebo administration was found post MDMA between the right post-central gyrus and right posterior and superior temporal gyrus, and between the thalamus and frontoparietal network.Conclusions: Following 70 mg of MDMA two tinnitus rating scales significantly improved. There was, however, a placebo effect. Compared with placebo the rsMRI following the MDMA showed reductions in connectivity between the amygdala, hippocampus and parahippocampal gyrus. There is sufficient proof of concept to support future investigation of MDMA as a treatment for tinnitus.

Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinson's disease cohort.

INTRODUCTION: Bi-allelic mutations in the gene for glucocerebrosidase (GBA) cause Gaucher disease, an autosomal recessive lysosomal storage disorder. Gaucher disease causing GBA mutations in the heterozygous state are also high risk factors for Parkinson's disease (PD). GBA analysis is challenging due to a related pseudogene and structural variations (SVs) that can occur at this locus. We have applied and refined a recently developed nanopore DNA sequencing method to analyze GBA variants in a clinically assessed New Zealand longitudinal cohort of PD. METHOD: We examined amplicons encompassing the coding region of GBA (8.9 kb) from 229 PD cases and 50 healthy controls using the GridION nanopore sequencing platform, and Sanger validation. RESULTS: We detected 23 variants in 21 PD cases (9.2% of patients). We detected modest PD risk variant p.N409S (rs76763715) in one case, p.E365K (rs2230288) in 12 cases, and p.T408 M (rs75548401) in seven cases, one of whom also had p.E365K. We additionally detected the possible risk variants p.R78C (rs146774384) in one case, p.D179H (rs147138516) in one case which occurred on the same haplotype as p.E365K, and one novel variant c.335C > T or p.(L335 = ), that potentially impacts splicing of GBA transcripts. Additionally, we found a higher prevalence of dementia among patients with GBA variants. CONCLUSION: This work confirmed the utility of nanopore sequencing as a high-throughput method to identify known and novel GBA variants, and to assign precise haplotypes. Our observations may contribute to improved understanding of the effects of variants on disease pathogenesis, and to the development of more targeted treatments.

Towards a Field-Portable Real-Time Organic and Elemental Carbon Monitor.

Diesel particulate matter (DPM) has been classified as a carcinogen to humans by the International Agency for Research on Cancer. As a result of its potential carcinogenic nature, DPM exposure is regulated by the Mine Safety and Health Administration. Currently, diesel emissions in the workplace are monitored by collecting the aerosol onto filters, which are then sent to a laboratory for thermal-optical analysis using the NIOSH method 5040. This process can take days or even weeks, and workers can potentially be exposed to excessive levels of DPM before the problem is identified. Moreover, the delay involved in getting the loaded filter to the lab inevitably means the loss of some of the more volatile organic carbon. To remedy this delay, researchers from the National Institute for Occupational Safety and Health are seeking to develop a field-portable, real-time method for measuring elemental and organic carbons in DPM aerosols. In the current study, the use of mid-infrared spectrometry was investigated. It is believed that mid-infrared spectroscopy is more suitable for use in a real-time field-portable device than thermo-optical analysis methods. This article presents a method for measuring organic carbon (OC) and elemental carbon (EC) in DPM for a broad range of OC/EC ratios. The method has been successfully applied to laboratory-generated and mine samples.

Direct Constraints on the Ultralight Boson Mass from Searches of Continuous Gravitational Waves.

Superradiance can trigger the formation of an ultralight boson cloud around a spinning black hole. Once formed, the boson cloud is expected to emit a nearly periodic, long-duration, gravitational-wave signal. For boson masses in the range (10^{-13}-10^{-11}) eV, and stellar mass black holes, such signals are potentially detectable by gravitational-wave detectors, like Advanced LIGO and Virgo. In this Letter, we present full band upper limits for a generic all-sky search for periodic gravitational waves in LIGO O2 data, and use them to derive-for the first time-direct constraints on the ultralight scalar boson field mass.

A mixed methods analysis of maternal response to children's consumption of a palatable food: differences by child weight status.

BACKGROUND: Little is known about how mothers respond to their child eating palatable foods. OBJECTIVES: The objectives of the study are to examine maternal behaviours when children are presented with a large portion of energy-dense palatable food in an experimental setting and to examine differences by child weight status. METHODS: Mother-child dyads (N = 37) (mean child age 70.8 months) participated in a videotaped eating protocol with cupcakes. Anthropometrics were measured. Videos were analysed using discourse analysis and were reliably coded for the presence or absence of the most salient theme. Analysis of variance examined theme presence by child and mother weight status. RESULTS: Mothers disavowed responsibility for their child's eating. Mothers were observed to roll their eyes at the child, throw their hands up in exasperation and distance themselves both physically and emotionally when the child ate the cupcakes voraciously or with high enjoyment. Mothers of children with obesity (vs recommended weight) engaged in more counts of disavowal (p = 0.01). CONCLUSIONS: Mothers of children with obesity distanced themselves from their child, seeming to disavow responsibility for the child's eating of 'junk food'. Mothers may respond to their child's seemingly gluttonous eating by disavowing responsibility due to the stigma of being a parent of a child with obesity.

Seasonal variation of Mastophorus muris (Nematoda: Spirurida) in the water vole Arvicola amphibius from southern Sweden.

This study focused on the spirurid nematode Mastophorus muris in water voles (Arvicola amphibius) trapped in three regions in southern Sweden during spring and fall 2013. The collection of water voles formed part of a larger project (EMIRO) on the cestode Echinococcus multilocularis in rodents. The voles' stomach contents were examined for the presence of M. muris. Prevalence, mean abundance and mean intensity of infection were calculated. A generalized linear model model was used to examine the effects of sex, functional group, season and region on the number of M. muris individuals in each vole. Forty-seven of 181 (26%) voles were infected with M. muris, with up to 74 worms each. The overall mean intensity (worms per infected vole) was 15 (95% CI 10-21), and abundance (mean number of worms in all voles) was 4 (95% CI 2-6). Model output indicated a significant effect of season and region with respect to abundance of nematode infection, which was independent of sex and functional group of the investigated host.

Sequential gene regulatory events leading to glucocorticoid-evoked apoptosis of CEM human leukemic cells:interactions of MAPK, MYC and glucocorticoid pathways.

Gene expression responses to glucocorticoid (GC) in the hours preceding onset of apoptosis were compared in three clones of human acute lymphoblastic leukemia CEM cells. Between 2 and 20h, all three clones showed increasing numbers of responding genes. Each clone had many unique responses, but the two responsive clones showed a group of responding genes in common, different from the resistant clone. MYC levels and the balance of activities between the three major groups of MAPKs are known important regulators of glucocorticoid-driven apoptosis in several lymphoid cell systems. Common to the two sensitive clones were changed transcript levels from genes that decrease amounts or activity of anti-apoptotic ERK/MAPK1 and JNK2/MAPK9, or of genes that increase activity of pro-apoptotic p38/MAPK14. Down-regulation of MYC and several MYC-regulated genes relevant to MAPKs also occurred in both sensitive clones. Transcriptomine comparisons revealed probable NOTCH-GC crosstalk in these cells.

Development and preliminary validation of the Parenting around SNAcking Questionnaire (P-SNAQ).

Snacking makes significant contributions to children's dietary intake but is poorly understood from a parenting perspective. This research was designed to develop and evaluate the psychometrics of a theoretically grounded, empirically-informed measure of snack parenting. The Parenting around SNAcking Questionnaire (P-SNAQ) was developed using a conceptual model derived from current theory and mixed-methods research to include 20 hypothesized snack parenting practices along 4 parenting dimensions (autonomy support, structure, coercive control and permissiveness). Expert panel evaluation and cognitive interviews were used to refine items and construct definitions. The initial instrument of 105 items was administered to an ethnically diverse, low-income sample of 305 parents (92% mothers) of children aged 1-6 y participating in three existing cohort studies. The sample was randomly split into two equal samples. Exploratory factor analysis was conducted with the first sample to identify snack parenting practices within each parenting dimension, followed by confirmatory factor analysis with the second sample to test the hypothesized factor structure. Internal consistency of sub-scales and associations with existing measures of food parenting practices and styles and child weight status were evaluated. The final P-SNAQ scale included 51 items reflecting 14 snack parenting practices across four parenting dimensions. The factor structure of the P-SNAQ was consistent with prior theoretical frameworks. Internal consistency coefficients were good to very good for 12 out of 14 scales and subscale scores were moderately correlated with previously validated measures. In conclusion, initial evidence suggests that P-SNAQ is a psychometrically sound measure for evaluating a wide range of snack parenting practices in young children.

shapecoder: a new method for visual quantification of body mass index in young children.

BACKGROUND: Few tools exist to quantify body mass index visually. OBJECTIVE: To examine the inter-rater reliability and validity (sensitivity and specificity for overweight/obesity and obesity) of a three-dimensional visual rating system to quantify body mass index (BMI) in young children. METHODS: Children (n = 242, mean age 5.9 years, 50.0% male; 40.5% overweight/ obese) participated in a videotaped protocol and weight and height were measured. Research staff applied a novel three-dimensional computer-based figure rating system (shapecoder) to the child's videotaped image. Inter-rater reliability was calculated, as well as correlation with measured body mass index (BMI) and sensitivity, specificity, positive predictive value and negative predictive value for overweight/obesity and obesity. RESULTS: Inter-rater reliability was excellent (intraclass correlation coefficient = 0.98). The correlation of shapecoder-generated BMI with measured BMI was 0.89. For overweight/obesity, the sensitivity, specificity, positive predictive value and negative predictive value were 62%, 97%, 94% and 79% respectively. For obesity, these values were 65%, 99%, 97% and 92% respectively. CONCLUSION: shapecoder provides a method to quantify child BMI from video images with high inter-rater reliability, fair sensitivity and good specificity for overweight/obesity and obesity. The approach offers an improvement over existing two-dimensional rating scales for BMI.

p16 controls epithelial cell growth and suppresses carcinogenesis through mechanisms that do not require RB1 function.

The p16/RB1 tumor suppressor pathway is inactivated in the vast majority, if not all, human cancers. The current paradigm is that p16 and RB1 function in a linear pathway to suppress tumorigenesis; however p16 is preferentially lost in human cancers suggesting that p16 has critical tumor suppressive functions not mediated through RB1. Carcinomas arise from transformed epithelial cells and account for 80% of adult malignancies highlighting the need to understand p16/RB1 pathway function in organ epithelia. Lung cancer is the leading cause of cancer deaths and is associated with p16/RB1 pathway deregulation. We demonstrate that p16 is upregulated in the lung epithelium after Rb1 ablation in genetically engineered mouse models. In contrast to fibroblasts, loss of RB1 family proteins, p107 or p130, did not result in p16 induction, demonstrating that p16 suppression is a unique RB1 pocket protein function in the lung epithelium in vivo. p16 upregulation did not induce cellular senescence but rather promoted survival of RB1-deficient lung epithelial progenitor cells. Mechanistic studies show that p16 protects RB1-deficient cells from DNA damage. Consequently, additional loss of p16 led to genetic instability and increased susceptibility to cellular immortalization and transformation. Mice with combined RB1/p16-deficient lungs developed lung tumors including aggressive metastatic lung cancers. These studies identify p16 loss as a molecular event that causes genetic instability and directly demonstrate that p16 protects against DNA damage in the absence of RB1 function providing an explanation for why p16 is preferentially targeted in human cancers.

Low-income mothers' feeding goals predict observed home mealtime and child feeding practices.

BACKGROUND: Mothers' goals are important for health behavior change, and engagement in child obesity interventions. It is unknown if maternal feeding goals are associated with observed home mealtime or feeding practices. The objective of this study was to examine the association of four common feeding goals (restrict junk food, promote fruit or vegetable intake, promote autonomy in eating and prevent obesity) with mothers' observed home mealtime and feeding practices. METHODS: Low-income mothers (N = 265) of children (mean child age 70.8 months) participated in a semi-structured interview about child feeding. A coding scheme was developed and reliably applied to identify mothers' feeding goals from transcripts. Mothers' observed home mealtime and feeding practices were reliably coded from home mealtimes and a laboratory eating protocol. Mothers completed a questionnaire and reported demographics. Participant weights and heights were obtained. Regression models were used to test the association of each feeding goal with observed maternal practices, controlling for covariates. RESULTS: The goal of restricting junk food was associated with the child always eating at a table (OR 2.87, 95% CI (1.39-5.96) p = 0.005), but not with the mother restricting junk food. The goal of promoting fruit or vegetable intake was associated with observationally promoting vegetables (OR 1.41, 95% CI (1.09-1.84), p = 0.01). The goals of promoting autonomy and preventing obesity were not associated with any observed maternal home mealtime or feeding practices. CONCLUSIONS: While mothers' goals to restrict junk food and promote fruit or vegetable intake were associated with observed home mealtime and feeding practices, promoting autonomy and preventing obesity were not. Increased understanding of why low-income mothers may not translate certain feeding goals into practices may inform childhood obesity interventions.

Note: A portable laser induced breakdown spectroscopy instrument for rapid sampling and analysis of silicon-containing aerosols.

A portable instrument has been developed for measuring silicon-containing aerosols in near real-time using laser-induced breakdown spectroscopy (LIBS). The instrument uses a vacuum system to collect and deposit airborne particulate matter onto a translatable reel of filter tape. LIBS is used to analyze the deposited material, determining the amount of silicon-containing compounds present. In laboratory testing with pure silica (SiO2), the correlation between LIBS intensity for a characteristic silicon emission and the concentration of silica in a model aerosol was determined for a range of concentrations, demonstrating the instrument's plausibility for identifying hazardous levels of silicon-containing compounds.

The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models.

The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT-PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (P<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (P<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.

Low-income pre-schoolers with higher temperamental surgency enjoy and respond more to food, mediating the path to higher body mass index.

BACKGROUND: Temperament is associated with obesity risk. However, the mechanisms linking temperament and eating behaviour to childhood adiposity are unclear. OBJECTIVES: To examine whether three temperament dimensions (surgency, effortful control and negative lability) are uniquely associated with an increased BMI z score (BMIz) concurrently and an excessive rate of change in BMIz longitudinally through four eating behaviours (food responsiveness, enjoyment of food, emotional overeating and satiety responsiveness) among low-income pre-schoolers, independent of home environment quality. METHODS: 379 pre-schoolers were recruited from Head Start in the Midwest region of the United States. Primary caregivers reported child temperament, eating behaviours and the level of chaos at home. Child BMIz was derived from weight and height measurements at ages 4, 5 and 6 years on average. RESULTS: Path analyses revealed that higher levels of surgency predicted more food responsiveness and enjoyment of food, which was in turn associated with higher concurrent BMIz, independent of effortful control, negative lability and home chaos. CONCLUSION: Low-income surgent pre-schoolers were more likely to have elevated BMIz as they were more inclined to eat in response to external cues and have a high appetitive drive. Obesity prevention programmes might target low-income children with surgent temperaments, and the identified eating behaviours.

Birth order and sibship composition as predictors of overweight or obesity among low-income 4- to 8-year-old children.

OBJECTIVE: This study aimed to examine the association of birth order and number and sex of siblings with overweight or obesity among 4- to 8-year-olds. METHODS: This is a cross-sectional study involving 273 low-income mother-child dyads. Questionnaires and anthropometry were completed. Multiple logistic regression was used to examine the association of birth order, having younger siblings, having older siblings, having at least one brother and having at least one sister with odds of overweight or obesity. Analyses were repeated to additionally include non-biological siblings. Models were adjusted for potential confounders and intermediate variables. RESULTS: Prevalence of child overweight or obesity was 42.5%. Adjusting for covariates, only children and youngest siblings had higher odds of overweight or obesity compared with oldest siblings (odds ratio [OR]: 4.18, 95% confidence interval [CI]: 1.67, 10.46 and OR: 3.21, 95% CI: 1.41, 7.33, respectively). Having one or more younger siblings and having at least one brother were associated with lower odds (OR: 0.38, 95% CI: 0.21, 0.69 and OR: 0.47, 95% CI: 0.28, 0.81, respectively). Including non-biological siblings did not meaningfully change the associations. CONCLUSION: Birth order and sibship composition are associated with overweight or obesity among 4- to 8-year-olds. Future studies identifying the underlying behavioural mechanism can help inform family-based intervention programmes.