Distribution of 2,2',5,5'-Tetrachlorobiphenyl (PCB52) Metabolites in Adolescent Rats after Acute Nose-Only Inhalation Exposure.

Inhalation of PCB-contaminated air is increasingly recognized as a route for PCB exposure. Because limited information about the disposition of PCBs following inhalation exposure is available, this study investigated the disposition of 2,2',5,5'-tetrachlorobiphenyl (PCB52) and its metabolites in rats following acute, nose-only inhalation of PCB52. Male and female Sprague-Dawley rats (50-58 days of age, 210 ± 27 g; n = 6) were exposed for 4 h by inhalation to approximately 14 or 23 µg/kg body weight of PCB52 using a nose-only exposure system. Sham animals (n = 6) were exposed to filtered lab air. Based on gas chromatography-tandem mass spectrometry (GC-MS/MS), PCB52 was present in adipose, brain, intestinal content, lung, liver, and serum. 2,2',5,5'-Tetrachlorobiphenyl-4-ol (4-OH-PCB52) and one unknown monohydroxylated metabolite were detected in these compartments except for the brain. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis identified several metabolites, including sulfated, methoxylated, and dechlorinated PCB52 metabolites. These metabolites were primarily found in the liver (7 metabolites), lung (9 metabolites), and serum (9 metabolites) due to the short exposure time. These results demonstrate for the first time that complex mixtures of sulfated, methoxylated, and dechlorinated PCB52 metabolites are formed in adolescent rats following PCB52 inhalation, laying the groundwork for future animal studies of the adverse effects of inhaled PCB52.

Twelve-month kidney and liver outcomes of kidney transplantation from Hepatitis C Viremic deceased donors to aviremic recipients.

INTRODUCTION: Utilization of hepatitis C viremic (HCV+) deceased donor kidneys (DDKT) for aviremic recipients increases opportunities for transplantation with excellent short-term outcomes. Our primary aim was to understand longer-term outcomes, specifically assessing kidney and liver function in the first year posttransplant. METHODS: This was a retrospective single-center study of adult DDKT recipients of HCV+ kidneys (cases) matched 1:1 to recipients of HCV- kidneys (comparators). Between-group outcomes were analyzed using comparisons of means and proportions, survival analysis methods, and multivariable mixed effects models. RESULTS: Sixty-five cases and 65 comparators had statistically comparable demographic and clinical characteristics. There were no between-group differences in serum creatinine or estimated glomerular filtration rate at month 12 (p = .662) or in their trajectories over months 1-12 (p > .292). Within the first 60 days, rates of liver function values >3 times upper limit of normal among cases were comparable to comparators for aspartate aminotransferase (AST) (14% vs. 6%, p = .242) and higher for alanine transaminase (ALT) (23% vs. 6%, p = .011). AST declined during the first 8 weeks (p = .005) and stabilized for both groups (p = .406) during the following 10 months. ALT declined during the first 8 weeks (p < .001), continued to decline over months 3-12 (p = .016), and the trajectory was unrelated to antiviral therapy initiation among cases. CONCLUSIONS: Aviremic recipients of HCV+ kidneys had comparable kidney outcomes to matched recipients of HCV- kidneys. Despite more HCV+ recipients having an elevation in ALT within the first 60 days, ALT values normalized with no identified liver complications attributed to HCV.

Trajectories of Hearing From Childhood to Adulthood.

OBJECTIVES: The Dunedin Multidisciplinary Health and Development Study provides a unique opportunity to document the progression of ear health and hearing ability within the same cohort of individuals from birth. This investigation draws on hearing data from 5 to 13 years and again at 45 years of age, to explore the associations between childhood hearing variables and hearing and listening ability at age 45. DESIGN: Multiple linear regression analyses were used to assess associations between childhood hearing (otological status and mid-frequency pure-tone average) and (a) age 45 peripheral hearing ability (mid-frequency pure-tone average and high-frequency pure-tone average), and (b) age 45 listening ability (listening in spatialized noise and subjective questionnaire on listening experiences). Sex, childhood socioeconomic status, and adult IQ were included in the model as covariates. RESULTS: Peripheral hearing and listening abilities at age 45 were consistently associated with childhood hearing acuity at mid-frequencies. Otological status was a moderate predicting factor for high-frequency hearing and utilization of spatial listening cues in adulthood. CONCLUSIONS: We aim to use these findings to develop a foundational model of hearing trajectories. This will form the basis for identifying precursors, to be investigated in a subsequent series of analyses, that may protect against or exacerbate hearing-associated cognitive decline in the Dunedin Study cohort as they progress from mid-life to older age.

Functional topography of the neocortex predicts covariation in complex cognitive and basic motor abilities.

Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g. hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year-old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.

Long-term cancer and overall mortality associated with drinking water nitrate in the United States.

OBJECTIVES: Nitrate is a probable carcinogen regulated in drinking water by the US Environmental Protection Agency (EPA) to a maximum contaminant level (MCL) of 10 mg/L nitrate-nitrogen (NO3-N; equivalent to 44.3 mg/L NO3). We aimed to determine the association of US drinking water nitrate levels with overall as well as cardiovascular, cancer, and other cause mortality. STUDY DESIGN: This study used a population-based retrospective cohort design. METHODS: We analyzed data from 2029 participants of the 2005-2006 National Health and Nutrition Examination Survey followed for mortality until 2019 for a median of 13.9 years. We used Cox proportional hazards regression to estimate the hazard ratio (HR) and 95% confidence interval (CI) for mortality associated with drinking water nitrate, adjusting for covariates that included socio-economic factors and pack-years of cigarette smoking. RESULTS: Drinking water nitrate was detected in 50.8 % of the samples, had a median concentration of 0.77 mg/L NO3, and was above US EPA MCL in 0.4 % of participants. In adjusted analysis, drinking water nitrate detection was associated with 73 % higher cancer mortality (HR: 1.73, 95% CI: 1.19-2.51), whereas a 10-fold increase in drinking water nitrate levels was associated with 69 % higher cancer mortality (HR: 1.69, 95% CI: 1.24-2.31) and 21 % higher overall mortality (HR: 1.21, 95% CI: 1.00-1.46). Drinking water nitrate below EPA MCL was still associated with higher cancer mortality (HR: 1.61, 95% CI: 1.07-2.43 per 10-fold increase and HR: 1.61, 95% CI: 1.08-2.42 for detection). CONCLUSIONS: Levels of drinking water nitrate may be an overlooked contributor to cancer mortality in the United States.

An examination of point-particle Lagrangian simulations for assessing time-resolved hydroacoustic particle flux measurements in sediment-laden flows.

Accurate modelling and prediction of sediment transport in aquatic environments is essential for sustainable coastal and riverine management. Current capabilities rely on physical process-based numerical models and fine-scale sediment flux measurements. High-resolution hydroacoustic instrumentation has emerged as a promising tool for such measurements. However, challenges arise due to the inherent complexity of ultrasound scattering processes. This study introduces a numerical modelling using a point-particle approach to simulate the echoes backscattered by such instrumentation in sediment-laden flow conditions. The model considers geometric, statistical, particle cloud, and flow-induced effects on sediment velocity, concentration, and flux estimates using an acoustic concentration and velocity profiler as a reference. The model performance is assessed here under unidirectional constant flow conditions in terms of velocity, concentration, and time-resolved sediment flux estimates for a large range of the particles' advection speed and sampled volume sizes. Application to the estimation of the measurement accuracy of sediment flux in these flows is also considered, with a final error on the flux seen to be partially controlled by the residence time of particles within the sampled volumes. The proposed model provides insights into scattering processes and offers a tool for investigating robust sediment flux estimation techniques in various flow conditions.

An algorithm for quantitatively estimating occupational endotoxin exposure in the biomarkers of exposure and effect in agriculture study: II. Application to the study population.

BACKGROUND: We developed an algorithm to quantitatively estimate endotoxin exposure for farmers in the Biomarkers of Exposure and Effect in Agriculture (BEEA) Study. METHODS: The algorithm combined task intensity estimates derived from published data with questionnaire responses on activity duration to estimate task-specific cumulative endotoxin exposures for 13 tasks during four time windows, ranging from "past 12 months" to "yesterday/today." We applied the algorithm to 1681 participants in Iowa and North Carolina. We examined correlations in endotoxin metrics within- and between-task. We also compared these metrics to prior day full-shift inhalable endotoxin concentrations from 32 farmers. RESULTS: The highest median task-specific cumulative exposures were observed for swine confinement, poultry confinement, and grind feed. Inter-quartile ranges showed substantial between-subject variability for most tasks. Time window-specific metrics of the same task were moderately-highly correlated. Between-task correlation was variable, with moderately-high correlations observed for similar tasks (e.g., between animal-related tasks). Prior day endotoxin concentration increased with the total metric and with task metrics for swine confinement, clean other animal facilities, and clean grain bins. SIGNIFICANCE: This study provides insight into the variability and sources of endotoxin exposure among farmers in the BEEA study and summarizes exposure estimates for future investigations in this population.

An algorithm for quantitatively estimating occupational endotoxin exposure in the Biomarkers of Exposure and Effect in Agriculture (BEEA) study: I. Development of task-specific exposure levels from published data.

BACKGROUND/OBJECTIVE: Farmers conduct numerous tasks with potential for endotoxin exposure. As a first step to characterize endotoxin exposure for farmers in the Biomarkers of Exposure and Effect in Agriculture (BEEA) Study, we used published data to estimate task-specific endotoxin concentrations. METHODS: We extracted published data on task-specific, personal, inhalable endotoxin concentrations for agricultural tasks queried in the study questionnaire. The data, usually abstracted as summary measures, were evaluated using meta-regression models that weighted each geometric mean (GM, natural-log transformed) by the inverse of its within-study variance to obtain task-specific predicted GMs. RESULTS: We extracted 90 endotoxin summary statistics from 26 studies for 9 animal-related tasks, 30 summary statistics from 6 studies for 3 crop-related tasks, and 10 summary statistics from 5 studies for 4 stored grain-related tasks. Work in poultry and swine confinement facilities, grinding feed, veterinarian services, and cleaning grain bins had predicted GMs > 1000 EU/m3 . In contrast, harvesting or hauling grain and other crop-related tasks had predicted GMs below 100 EU/m3 . SIGNIFICANCE: These task-specific endotoxin GMs demonstrated exposure variability across common agricultural tasks. These estimates will be used in conjunction with questionnaire responses on task duration to quantitatively estimate endotoxin exposure for study participants, described in a companion paper.

Serum antioxidant vitamins and respiratory morbidity and mortality: a pooled analysis.

BACKGROUND: Oxidative stress plays a key role in the pathogenesis of respiratory diseases; however, studies on antioxidant vitamins and respiratory outcomes have been conflicting. We evaluated whether lower serum levels of vitamins A, C, D, and E are associated with respiratory morbidity and mortality in the U.S. adult population. METHODS: We conducted a pooled analysis of data from the 1988-1994 and 1999-2006 National Health and Nutrition Examination Survey (participants aged ≥ 20 years). We estimated covariate-adjusted odds ratios (aOR) per interquartile decrease in each serum vitamin level to quantify associations with respiratory morbidity, and covariate-adjusted hazard ratios (aHR) to quantify associations with respiratory mortality assessed prospectively through 2015. Vitamin supplementation and smoking were evaluated as potential effect modifiers. RESULTS: Lower serum vitamin C increased the odds of wheeze among all participants (overall aOR: 1.08, 95% CI: 1.01-1.16). Among smokers, lower serum α-tocopherol vitamin E increased the odds of wheeze (aOR: 1.11, 95% CI: 1.04-1.19) and chronic bronchitis/emphysema (aOR: 1.13, 95% CI: 1.03-1.24). Conversely, lower serum γ-tocopherol vitamin E was associated with lower odds of wheeze and chronic bronchitis/emphysema (overall aORs: 0.85, 95% CI: 0.79-0.92 and 0.85, 95% CI: 0.76-0.95, respectively). Lower serum vitamin C was associated with increased chronic lower respiratory disease (CLRD) mortality in all participants (overall aHR: 1.27, 95% CI: 1.07-1.51), whereas lower serum 25-hydroxyvitamin D (25-OHD) tended to increase mortality from CLRD and influenza/pneumonia among smokers (aHR range: 1.33-1.75). Mortality from influenza/ pneumonia increased with decreasing serum vitamin A levels in all participants (overall aHR: 1.21, 95% CI: 0.99-1.48). In pooled analysis, vitamin C deficiency and 25-OHD insufficiency were associated with mortality from influenza/pneumonia, increasing mortality risk up to twofold. CONCLUSIONS: Our analysis of nationally representative data on over 34,000 participants showed that lower serum levels of vitamins A, C, D, and α-tocopherol vitamin E are associated with increased respiratory morbidity and/or mortality in U.S. adults. The results underscore the importance of antioxidant vitamins in respiratory health.

The developmental journey of therapies targeting purine receptors: from basic science to clinical trials.

Since the discovery of ATP as an extracellular signalling molecule in 1972, purinergic signalling, mediated by extracellular purines and pyrimidines has been identified in virtually all mammalian tissues and is implicated in regulating fundamental cellular processes. In recent years, there has been an increasing focus on the pathophysiology and potential therapeutic interventions based on purinergic signalling. A vast range of compounds targeting purine receptors are in clinical development, and many more are in preclinical studies, which highlights the fast growth in this research field. As a tribute to Professor Geoffrey Burnstock's legacy in purinergic signalling, we present here a brief review of compounds targeting purine receptors that are in different stages of clinical trials. The review highlights the 50-year journey from basic research on purinergic receptors to clinical applications of therapies targeting purine receptors.

Toxicity Assessment of 91-Day Repeated Inhalation Exposure to an Indoor School Air Mixture of PCBs.

School indoor air contaminated with polychlorinated biphenyls (PCBs) released from older building materials and paint pigments may pose health risks to children, as well as teachers and staff, by inhalation of PCBs. The health effects of long-term inhalation exposure to PCBs are poorly understood. We conducted a comprehensive toxicity assessment of 91-day repeated inhalation exposure to a lab-generated mixture of PCBs designed to emulate indoor school air, combining transcriptomics, metabolomics, and neurobehavioral outcomes. Female Sprague-Dawley rats were exposed to school air mixture (SAM+) at a concentration of 45.5 ± 5.9 µg/m3 ∑209PCB or filtered air 4 h/day, 6 days/week for 13 weeks using nose-only exposure systems. The congener-specific PCB body burden was quantified in major tissues using GC-MS/MS. The generated SAM+ vapor recapitulated the target school air profile with a similarity coefficient, cos θ of 0.91. PCB inhalation yielded 875-9930 ng/g ∑209PCBlipid weight levels in tissues in the following ascending order: brain < liver < lung < serum < adipose tissue. We observed that PCB exposure impaired memory, induced anxiety-like behavior, significantly reduced white blood cell counts, mildly disrupted metabolomics in plasma, and influenced transcription processes in the brain with 274 upregulated and 58 downregulated genes. With relatively high exposure and tissue loading, evidence of toxicity from half the end points tested was seen in the rats.

PCB Sulfates in Serum from Mothers and Children in Urban and Rural U.S. Communities.

Serum samples from 24 subjects (6 mother-daughter and 6 mother-son dyads) in a rural community (Columbus Junction, Iowa) and 24 subjects (6 mother-daughter and 6 mother-son dyads) in an urban community (East Chicago, Indiana) were analyzed for 74 sulfated metabolites of polychlorinated biphenyls (PCBs). We detected significantly higher mean concentrations of total assessed PCB sulfates in the urban group (110-8900 ng/g fresh weight of serum, mean = 3400 ng/g, standard error = 300) than in the rural cohort (530-6700 ng/g fresh weight of serum, mean = 1800 ng/g, standard error = 500). Eight PCB sulfate congeners (4-PCB 2 sulfate, 4'-PCB 2 sulfate, 2'-PCB 3 sulfate, 4'-PCB 3 sulfate, 4-PCB 11 sulfate, 4'-PCB 18 sulfate, 4'-PCB 25 sulfate, and 4-PCB 52 sulfate) contributed over 90% of the total assessed PCB sulfates in most individuals. The serum samples were enriched in PCB sulfates with fewer than 5 chlorine atoms, and this congener distribution differed from those of PCBs and hydroxylated PCBs in previous studies in the same communities. Regression analysis indicated several significant congener-specific correlations in mother-child dyads, and these relationships differed by location and by mother-daughter or mother-son dyads. This is the first study reporting a broad range of PCB sulfates in populations from urban and rural areas.

Time course of pulmonary inflammation and trace element biodistribution during and after sub-acute inhalation exposure to copper oxide nanoparticles in a murine model.

BACKGROUND: It has been shown that copper oxide nanoparticles (CuO NPs) induce pulmonary toxicity after acute or sub-acute inhalation exposures. However, little is known about the biodistribution and elimination kinetics of inhaled CuO NPs from the respiratory tract. The purposes of this study were to observe the kinetics of pulmonary inflammation during and after CuO NP sub-acute inhalation exposure and to investigate copper (Cu) biodistribution and clearance rate from the exposure site and homeostasis of selected trace elements in secondary organs of BALB/c mice. RESULTS: Sub-acute inhalation exposure to CuO NPs led to pulmonary inflammation represented by increases in lactate dehydrogenase, total cell counts, neutrophils, macrophages, inflammatory cytokines, iron levels in bronchoalveolar lavage (BAL) fluid, and lung weight changes. Dosimetry analysis in lung tissues and BAL fluid showed Cu concentration increased steadily during exposure and gradually declined after exposure. Cu elimination from the lung showed first-order kinetics with a half-life of 6.5 days. Total Cu levels were significantly increased in whole blood and heart indicating that inhaled Cu could be translocated into the bloodstream and heart tissue, and potentially have adverse effects on the kidneys and spleen as there were significant changes in the weights of these organs; increase in the kidneys and decrease in the spleen. Furthermore, concentrations of selenium in kidneys and iron in spleen were decreased, pointing to disruption of trace element homeostasis. CONCLUSIONS: Sub-acute inhalation exposure of CuO NPs induced pulmonary inflammation, which was correlated to Cu concentrations in the lungs and started to resolve once exposure ended. Dosimetry analysis showed that Cu in the lungs was translocated into the bloodstream and heart tissue. Secondary organs affected by CuO NPs exposure were kidneys and spleen as they showed the disruption of trace element homeostasis and organ weight changes.

Diagnostic and management plan concordance across advanced audiologists, paediatric audiologists and non-specialist ENT doctors.

OBJECTIVE: To compare the concordance of advanced audiologists (AA), junior doctors (JD) and paediatric audiologists (PA) with an Ear, Nose and Throat (ENT) specialist on the diagnosis and management of children with middle ear or hearing concerns. DESIGN: A clinical equivalence (concordance) study. STUDY SAMPLE: Three AAs, five JDs, three PAs and one ENT specialist asynchronously reported diagnoses and management plans for ten, online paediatric cases consisting of video-otoscopic images and clinical findings. RESULTS: For medical diagnosis, significant agreement with the ENT specialist was observed at moderate and near-perfect levels for two AAs (k = 0.561 and 0.815), moderate levels for four JDs (k = 0.5 to 0.603) and near-perfect level for one PA (k = 0.815). For management decisions, significant agreement with the ENT specialist was observed at substantial (k = 0.636) and near-perfect (k = 0.818) levels for two AAs, and at a moderate level (k = 0.538) for one PA. Within group inter-rater agreement for management plans was substantial for AAs and JDs, and moderate for PAs. CONCLUSIONS: For children with middle ear disease or hearing concerns, AAs, JDs and PAs showed similar levels of agreement with an ENT specialist on diagnosis, but AAs were more likely than JDs or PAs to agree with an ENT specialist on management.

Parental satisfaction with an advanced audiology-led triage service in paediatric ENT outpatient clinics.

OBJECTIVE: The advanced audiology-led service is designed to triage and manage children who are referred to Ear Nose and Throat (ENT) outpatient services with middle ear or hearing concerns. This service has resulted in shorter waiting times for children to receive ENT treatment, and improved ENT capacity. The aim of this study was to explore parental satisfaction with the advanced audiology-led ENT service and to determine if there were cultural or process factors affecting satisfaction. DESIGN: Prospective cross-sectional study using a modified Visit-Specific Satisfaction Questionnaire (VSQ-9) survey. STUDY SAMPLE: One hundred and thirteen parents of children consecutively attending a first appointment in the advanced audiology-led service recruited between October 2016 and October 2017. RESULTS: There were a total of 100 valid responses (rate of 88.5%). The survey showed high levels of satisfaction. Satisfaction scores were significantly higher for items related to interactions with the audiologist compared to items related to waiting times. There were no differences in satisfaction across cultural groups. Parents were equally satisfied with the service whether their child was managed independently by the audiologist or required another appointment for medical input. CONCLUSIONS: The advanced audiology-led service had high levels of satisfaction from parents attending with their children.

House dust microbiota in relation to adult asthma and atopy in a US farming population.

BACKGROUND: Bacterial exposure from house dust has been associated with asthma and atopy in children but whether these relationships are present in adults remains unclear. OBJECTIVE: We sought to examine associations of house dust microbiota with adult asthma, atopy, and hay fever. METHODS: Vacuumed bedroom dust samples from the homes of 879 participants (average age, 62 years) in the Agricultural Lung Health Study, a case-control study of asthma nested within a farming cohort, were subjected to 16S rRNA amplicon sequencing to characterize bacterial communities. We defined current asthma and hay fever using questionnaires and current atopy by blood specific IgE level > 0.70 IU/mL to 1 or more of 10 common allergens. We used linear regression to examine whether overall within-sample bacterial diversity differed by outcome, microbiome regression-based kernel association test to evaluate whether between-sample bacterial community compositions differed by outcome, and analysis of composition of microbiomes to identify differentially abundant bacterial taxa. RESULTS: Overall diversity of bacterial communities in house dust was similar by asthma status but was lower (P < .05) with atopy or hay fever. Many individual bacterial taxa were differentially abundant (false-discovery rate, <0.05) by asthma, atopy, or hay fever. Several taxa from Cyanobacteria, Bacteroidetes, and Fusobacteria were more abundant with asthma, atopy, or hay fever. In contrast, several taxa from Firmicutes were more abundant in homes of individuals with adequately controlled asthma (vs inadequately controlled asthma), individuals without atopy, or individuals without hay fever. CONCLUSIONS: Microbial composition of house dust may influence allergic outcomes in adults.

Purinergic Signalling in the Cochlea.

The mammalian cochlea is the sensory organ of hearing with a delicate, highly organised structure that supports unique operating mechanisms. ATP release from the secretory tissues of the cochlear lateral wall (stria vascularis) triggers numerous physiological responses by activating P2 receptors in sensory, supporting and neural tissues. Two families of P2 receptors, ATP-gated ion channels (P2X receptors) and G protein-coupled P2Y receptors, activate intracellular signalling pathways that regulate cochlear development, homeostasis, sensory transduction, auditory neurotransmission and response to stress. Of particular interest is a purinergic hearing adaptation, which reflects the critical role of the P2X2 receptor in adaptive cochlear response to elevated sound levels. Other P2 receptors are involved in the maturation of neural processes and frequency selectivity refinement in the developing cochlea. Extracellular ATP signalling is regulated by a family of surface-located enzymes collectively known as "ectonucleotidases" that hydrolyse ATP to adenosine. Adenosine is a constitutive cell metabolite with an established role in tissue protection and regeneration. The differential activation of A1 and A2A adenosine receptors defines the cochlear response to injury caused by oxidative stress, inflammation, and activation of apoptotic pathways. A1 receptor agonism, A2A receptor antagonism, and increasing adenosine levels in cochlear fluids all represent promising therapeutic tools for cochlear rescue from injury and prevention of hearing loss.

A High-Fat Diet Induces Low-Grade Cochlear Inflammation in CD-1 Mice.

There is growing evidence for a relationship between gut dysbiosis and hearing loss. Inflammatory bowel disease, diet-induced obesity (DIO), and type 2 diabetes have all been linked to hearing loss. Here, we investigated the effect of a chronic high-fat diet (HFD) on the development of inner ear inflammation using a rodent model. Three-week-old CD-1 (Swiss) mice were fed an HFD or a control diet for ten weeks. After ten weeks, mouse cochleae were harvested, and markers of cochlear inflammation were assessed at the protein level using immunohistochemistry and at the gene expression level using quantitative real-time RT-PCR. We identified increased immunoexpression of pro-inflammatory biomarkers in animals on an HFD, including intracellular adhesion molecule 1 (ICAM1), interleukin 6 receptor α (IL6Rα), and toll-like-receptor 2 (TLR2). In addition, increased numbers of ionized calcium-binding adapter molecule 1 (Iba1) positive macrophages were found in the cochlear lateral wall in mice on an HFD. In contrast, gene expression levels of inflammatory markers were not affected by an HFD. The recruitment of macrophages to the cochlea and increased immunoexpression of inflammatory markers in mice fed an HFD provide direct evidence for the association between HFD and cochlear inflammation.

Interaction between Genetic Risk Scores for reduced pulmonary function and smoking, asthma and endotoxin.

RATIONALE: Genome-wide association studies (GWASs) have identified numerous loci associated with lower pulmonary function. Pulmonary function is strongly related to smoking and has also been associated with asthma and dust endotoxin. At the individual SNP level, genome-wide analyses of pulmonary function have not identified appreciable evidence for gene by environment interactions. Genetic Risk Scores (GRSs) may enhance power to identify gene-environment interactions, but studies are few. METHODS: We analysed 2844 individuals of European ancestry with 1000 Genomes imputed GWAS data from a case-control study of adult asthma nested within a US agricultural cohort. Pulmonary function traits were FEV1, FVC and FEV1/FVC. Using data from a recent large meta-analysis of GWAS, we constructed a weighted GRS for each trait by combining the top (p value<5×10-9) genetic variants, after clumping based on distance (±250 kb) and linkage disequilibrium (r2=0.5). We used linear regression, adjusting for relevant covariates, to estimate associations of each trait with its GRS and to assess interactions. RESULTS: Each trait was highly significantly associated with its GRS (all three p values<8.9×10-8). The inverse association of the GRS with FEV1/FVC was stronger for current smokers (pinteraction=0.017) or former smokers (pinteraction=0.064) when compared with never smokers and among asthmatics compared with non-asthmatics (pinteraction=0.053). No significant interactions were observed between any GRS and house dust endotoxin. CONCLUSIONS: Evaluation of interactions using GRSs supports a greater impact of increased genetic susceptibility on reduced pulmonary function in the presence of smoking or asthma.

Effectiveness of portable HEPA air cleaners on reducing indoor endotoxin, PM10, and coarse particulate matter in an agricultural cohort of children with asthma: A randomized intervention trial.

We conducted a randomized trial of portable HEPA air cleaners in the homes of children age 6-12 years with asthma in the Yakima Valley, Washington. All families received asthma education while intervention families also received two HEPA cleaners (child's bedroom, living room). We collected 14-day integrated samples of endotoxin in settled dust and PM10 and PM10-2.5 in the air of the children's bedrooms at baseline and one-year follow-up, and used linear regression to compare follow-up levels, adjusting for baseline. Seventy-one families (36 HEPA, 35 control) completed the study. Baseline geometric mean (GSD) endotoxin loadings were 1565 (6.3) EU/m2 and 2110 (4.9) EU/m2 , respectively, in HEPA vs. control homes while PM10 and PM10-2.5 were 22.5 (1.9) µg/m3 and 9.5 (2.9) µg/m3 , respectively, in HEPA homes, and 19.8 (1.8) µg/m3 and 7.7 (2.0) µg/m3 , respectively, in control homes. At follow-up, HEPA families had 46% lower (95% CI, 31%-57%) PM10 on average than control families, consistent with prior studies. In the best-fit heterogeneous slopes model, HEPA families had 49% (95% CI, 6%-110%) and 89% lower (95% CI, 28%-177%) PM10-2.5 at follow-up, respectively, at 50th and 75th percentile baseline concentrations. Endotoxin loadings did not differ significantly at follow-up (4% lower, HEPA homes; 95% CI, -87% to 50%).