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Objective: Previous in vitro and in vivo World Trade Center particulate matter (WTC PM ) exposure studies have provided evidence of exposure-driven oxidative/nitrative stress and inflammation on respiratory tract and aortic tissues. What remains to be fully understood are secondary organ impacts due to WTC PM exposure. This study was designed to test if WTC particle-induced nasal and neurologic tissue injury may result in unforeseen functional and behavioral outcomes. Material and Methods: WTC PM was intranasally administered in mice, evaluating genotypic, histopathologic, and olfaction latency endpoints. Results: WTC PM exposure was found to incite neurologic injury and olfaction latency in intranasally (IN) exposed mice. Single high-dose and repeat low-dose nasal cavity insults from WTC PM dust resulted in significant olfaction delays and enduring olfaction deficits. Anxiety-dependent behaviors also occurred in mice experiencing olfaction loss including significant body weight loss, increased incidence and time spent in hind stretch postures, as well as increased stationary time and decreased exploratory time. Additionally, WTC PM exposure resulted in increased whole brain wet/dry ratios and wet whole brain to body mass ratios that were correlated with exposure and increased exposure dose ( p <0.05). Discussion: The potential molecular drivers of WTC PM -driven tissue injury and olfaction latency may be linked to oxidative/nitrative stress and inflammatory cascades in both upper respiratory nasal and brain tissues. Conclusion: Cumulatively, these data provide evidence of WTC PM exposure in relation to tissue damage related to oxidative stress-driven inflammation identified in the nasal cavity, propagated to olfactory bulb tissues and, potentially, over extended periods, to other CNS tissues.

Objective: Air pollution is associated with the prevalence of respiratory diseases. This study aimed to evaluate the impacts of outdoor air pollutants and indoor Dermatophagoides pteronyssinus 1 ( Der p 1) exposure on levels of fractional exhaled nitric oxide (FeNO), exhaled breath condensate (EBC) pH, and pulmonary function in atopic children., Methods: This study recruited 59 atopic mild-to-moderate asthmatic children and 23 atopic non-asthmatic children. Data on personal characteristics, FeNO, EBC pH, and pulmonary function were collected. Group 1 allergens of Der p 1 were measured on the tops of mattresses and on bedroom floors in the children's homes, and outdoor air pollutant concentrations were estimated from air quality monitoring stations, using the ordinary kriging method., Results: Exposure levels of outdoor air pollutants, except for particulate matter (PM) 2.5 , for the recruited children met outdoor air quality standards set by the Taiwan Environmental Protection Agency. The lag effect of outdoor PM 10 exposure was negatively associated with the forced expiratory volume in one second (FEV 1 ) [(Lag 1: β =-0.771, p  = 0.028), and O 3 (Lag 1-7: β =-2.02, p  = 0.04, Lag 1-28: β =-3.213, p  = 0.029)]. Median pulmonary function parameters differed significantly in forced vital capacity (FVC) ( p  = 0.004) and FEV 1 ( p  = 0.024) values between atopic asthmatic and non-asthmatic children. No association was found between the FeNO/EBC pH level and exposure to Der p 1 allergen and air pollutants in the recruited children., Conclusions: Outdoor PM 10 and O 3 exposure was associated with reduction in FEV 1 in atopic asthmatic and non-asthmatic children.

Objective: To evaluate the diagnostic value of fractional exhaled nitric oxide (FeNO) and maximum mid-expiratory flow (MMEF) for differentiating cough variant asthma (CVA) from chronic cough in patients with or without allergic rhinitis., Methods: In total, 328 patients with chronic cough who underwent spirometry and FeNO testing were consecutively included in the retrospective analysis. Patients were divided into the CVA ( n  = 125) or NCVA ( n  = 203) groups according to the diagnostic criteria of CVA. Receiver operating characteristic (ROC) curves were established to assess the diagnostic efficiency and optimal cutoff points of FeNO and MMEF for the prediction of CVA., Results: The optimal cutoff values of FeNO and MMEF to discriminate CVA from chronic cough were 24.5 ppb (AUC, 0.765; sensitivity, 69.60%; specificity 72.91%; PPV, 61.27%; NPV, 79.57%) and 66.2% (AUC, 0.771; sensitivity, 67.20%; specificity 78.33%; PPV, 65.63%; NPV, 79.50%). The optimal cutoff values of combining FeNO with MMEF to discriminate CVA from chronic cough were >22 ppb for FeNO and <62.6% for MMEF (AUC, 0.877). In patients with and without allergic rhinitis, the optimal cutoff point of FeNO to discriminate CVA from chronic cough was 24.5 ppb (AUC, 0.820) and 33.5 ppb (AUC, 0.707), respectively., Conclusions: FeNO and MMEF might have greater value as negative parameters for differentiating CVA from chronic cough. Combining FeNO and MMEF provided a significantly better prediction than either alone. The diagnostic accuracy of FeNO for predicting CVA in chronic cough patients with allergic rhinitis was higher than in chronic cough patients without allergic rhinitis.

Background: Studies have revealed the increased incidence of health disorders in First Responders (FR) who were at Ground Zero over the initial 72 hr after the World Trade Center (WTC) collapses. Previous studies in rats exposed to WTC dusts using exposure scenarios that mimicked FR mouthbreathing showed exposure led to altered expression of genes whose products could be involved in lung ailments. Nevertheless, it was uncertain if repeated exposures (as occurred in earliest days post-disaster) might have given rise to long-term changes in the lungs/other organs, in white blood cell (WBC) profiles, and/or systemic expression of select (mostly immune-related) proteins. Methods: To examine this, rats were exposed on 2 consecutive days (2 hr/d, intratracheal inhalation) to WTC dusts and then examined over a 1-yr period thereafter. At select times post-exposure, organ (lung, heart, liver, kidney, spleen) weights, WBC profiles, and blood levels of a variety of proteins were evaluated. Results: The study showed that over the 1-yr period, there were nominal effects on organ weights (absolute, index) as a result of the dust exposures. There were significant changes (relative to in naïve rats) in WBC profiles, with exposed rats having increased monocyte-macrophage and decreased lymphocyte percentages. The study also found that dust exposure led to significant systemic increases in many proteins, including MCP-1, RANTES, MMP-9, RAGE, and Galectin-3. Conclusions: These results provide further support for our longstanding hypothesis that the WTC dusts could potentially have acted as direct inducers of many of the health effects that have been seen in the exposed FR.

Exposure to nicotine among people living with HIV (PLWH) may impact physical health as indicated by experienced symptoms. Yet, the empirical evidence documenting the relations between tobacco use and symptom experiences among PLWH remains limited. This study aims to assess the relationships between tobacco use and HIV symptoms through a cross-sectional survey conducted in Beijing and Shanghai. The WHO ASSIST screening test was used for frequency of tobacco use. Sixty-four items from the revised signs and symptoms checklist for persons with HIV disease (SSC-HIVrev) were used. "Total number of symptoms" was created by summing all the binary coded and "Maximal symptom severity" was created by taking the maximal severity level across all symptoms for each participant. After controlling for confounding variables, tobacco use was not associated with the total number of symptom, yet was associated with the maximal symptom severity. This study documents the link between tobacco use and experienced symptoms among PLWH by demonstrating that higher frequency of tobacco use is associated with greater odds of reporting more severe symptoms. Smoking cessation strategies should be integrated into symptom management interventions for PLWH to optimize their effectiveness.

China is experiencing a rapid increase in the number of HIV-infected women. In this study, we describe the development and preliminary evaluation of an intervention tailored for Chinese HIV-infected women and caregivers to improve their self- and family management, with goals of enhancing their physical quality of life (QOL) and decreasing their depressive symptomatology. Forty-one HIV-infected women and their caregivers were recruited from two premier Chinese hospitals from July 2014 through March 2016. Participants were randomized to either the control or intervention arm for the Self- and Family Management Intervention (SAFMI). Each study dyad in the intervention arm received three counseling sessions with a nurse interventionist. At baseline, immediate post-intervention (month 1) and follow-up (month 3), the participants were assessed by a self-reported survey. Generalized Hierarchical Linear Modeling was used to evaluate the efficacy of the intervention. Chinese HIV-infected women in the intervention arm had significantly higher probability of higher physical QOL at month 1 and lower probability of clinically meaningful depressive symptomatology at month 3 compared with women in the control arm. In contrast, the effects of the intervention were less salient for caregivers. This study represents one of the first in China to include family caregivers in HIV management. Feasibility and acceptability were high, in that family members were willing to join the study, learn about HIV, and practice new skills to support the HIV-infected women in their lives. A larger trial is needed to fully evaluate this intervention which shows promising preliminary effects in promoting physical QOL and decreasing depressive symptomatology among Chinese HIV-infected women.

Context: In China, the social stigma of both substance use and HIV remains major barriers. HIV+ individuals have been demonstrated to have higher psychosocial distress in the literature. To ensure quality of life among HIV+ Chinese individuals, self-efficacy in HIV-related management including substance use and anxiety is the key to suppress viral load and maintain healthy lives., Objectives: We examine the mediation relationship among substance use, anxiety, and self-management efficacy., Method: A cross-sectional study design was used. 137 HIV+ individuals were recruited from two premier Chinese hospitals: Beijing's Ditan Hospital and Shanghai's Public Health Clinic Center (SPHCC)., Results: HIV+ substance users had significantly lower HIV-management efficacy and higher anxiety scores. About a third of the relations between substance use and anxiety was mediated by HIV-management self-efficacy. Those who used substances in the previous week had higher anxiety levels suggesting the presence of a recent effect. Their higher levels of anxiety could be largely explained by their lower HIV-management efficacy., Conclusion: It is useful for healthcare providers to assess substance use behaviors in HIV+ individuals as well as provide support in managing anxiety in this population. Meanwhile, enhancing self-management efficacy to ensure healthy lifestyles may support achieving optimal lives with HIV., Competing Interests: Conflict of Interest Statement No conflict of interest has been declared by the authors.

Purpose: The transforming growth factor-beta (TGF-β) pathway is an important in the initiation and progression of cancer. Due to a strong association between an elevated colorectal cancer risk and increase fecal excretion of cholest-4-en-3-one, we aim to determine the effects of cholest-4-en-3-one on TGF-β signaling in the mink lung epithelial cells (Mv1Lu) and colorectal cancer cells (HT29) in vitro., Methods: The inhibitory effects of cholest-4-en-3-one on TGF-β-induced Smad signaling, cell growth inhibition, and the subcellular localization of TGF-β receptors were investigated in epithelial cells using a Western blot analysis, luciferase reporter assays, DNA synthesis assay, confocal microscopy, and subcellular fractionation., Results: Cholest-4-en-3-one attenuated TGF-β signaling in Mv1Lu cells and HT29 cells, as judged by a TGF-β-specific reporter gene assay of plasminogen activator inhibitor-1 (PAI-1), Smad2/3 phosphorylation and nuclear translocation. We also discovered that cholest-4-en-3-one suppresses TGF-β responsiveness by increasing lipid raft and/or caveolae accumulation of TGF-β receptors and facilitating rapid degradation of TGF-β and thus suppressing TGF-β-induced signaling., Conclusions: Our results suggest that cholest-4-en-3-one inhibits TGF-β signaling may be due, in part to the translocation of TGF-β receptor from non-lipid raft to lipid raft microdomain in plasma membranes. Our findings also implicate that cholest-4-en-3-one may be further explored for its potential role in colorectal cancer correlate to TGF-β deficiency.

Recent studies have shown that circulating serotonin plays a potential role in bone metabolism. However, conflicting results have been reported for the relationship between serum serotonin concentrations and bone mineral density (BMD). We investigated whether the serum serotonin concentrations related to BMD in Chinese postmenopausal women. Serum serotonin and bone turnover concentrations of 117 premenopausal women and 262 asymptomatic postmenopausal women were analyzed by enzyme-linked immunosorbent assay. BMD at the lumbar spine and femoral neck was measured by dual energy X-ray absorptiometry. The relationship between serotonin and BMD was investigated. The postmenopausal women had lower mean serum serotonin concentrations compared to the premenopausal women. Serotonin concentrations were negatively associated with age, weight, BMI, fat mass, and β-CTX concentrations in postmenopausal women. No significant correlations were found between serotonin and these parameters in premenopausal women. In postmenopausal women, age- and BMI-adjusted serotonin concentrations were positively correlated with BMD of the lumbar spine and femoral neck. Multiple regression analyses showed serum serotonin and β-CTX were the predictors for lumbar spine BMD. Only serum serotonin was the determinant for femoral neck BMD. In conclusion, lower serum serotonin concentrations are linked to low lumbar spine and femoral neck BMD in postmenopausal women.

Objective: Prenatal genetic analysis in primary immunodeficiency diseases (PIDs) can decrease morbidity and mortality., Methods: We compared the postnatal prognoses of index cases and their subsequent sibling-fetuses using prenatal genetic analysis., Results: From 2007 to 2014, 14 sibling-fetuses receiving a prenatal diagnosis born to four mothers with WAS, three with X-CGD, and one each with IPEX, XLA and severe combined immunodeficiency [RAG2-SCID] were recruited. There were six affected, two carriers, and six wild types. Among the six affected, four [3X-CGD and 1RAG2-SCID] were terminated and two [1WAS and 1X-CGD] with early prophylactics underwent successful hematopoietic stem cell transplantation (HSCT) without infection. In the 12 index cases with a postnatal diagnosis, eight died (five due to infections and one each due to refractory bleeding, severe diarrhea, and post-transplant pneumothorax), two X-CGD underwent reconstituted HSCT after recurrent life-threatening infections, one WAS developed malignancy, and another WAS developed autoimmune disorders despite the administration of prophylactics and regular immunoglobulin infusion., Conclusion: Instead of recurrent life-threatening infections leading to mortality in the postnatal diagnosis group, the severe PIDs who received early prophylactics were cured by HSCT, and all of mortality were terminations in the prenatal diagnosis group. Further large-scale studies are needed to validate this beneficial effect. Key message Prenatal genetic analysis in fetuses born to PIDs carrier mothers allows for the affected fetuses to receive optimal management including prophylactics against infections and HSCT if indicated. Patients with PIDs diagnosed postnatally who are prone to severe infections have higher rates of morbidity and mortality than their subsequent siblings who have a prenatal genetic diagnosis.

The World Trade Center (WTC) twin towers in New York City collapsed on 9/11/2001, converting much of the buildings' huge masses into dense dust clouds of particles that settled on the streets and within buildings throughout Lower Manhattan. About 80-90% of the settled WTC Dust, ranging in particle size from ∼2.5 μm upward, was a highly alkaline mixture of crushed concrete, gypsum, and synthetic vitreous fibers (SVFs) that was readily resuspendable by physical disturbance and low-velocity air currents. High concentrations of coarse and supercoarse WTC Dust were inhaled and deposited in the conductive airways in the head and lungs, and subsequently swallowed, causing both physical and chemical irritation to the respiratory and gastroesophageal epithelia. There were both acute and chronic adverse health effects in rescue/recovery workers; cleanup workers; residents; and office workers, especially in those lacking effective personal respiratory protective equipment. The numerous health effects in these people were not those associated with the monitored PM2.5 toxicants, which were present at low concentrations, that is, asbestos fibers, transition and heavy metals, polyaromatic hydrocarbons or PAHs, and dioxins. Attention was never directed at the very high concentrations of the larger-sized and highly alkaline WTC Dust particles that, in retrospect, contained the more likely causal toxicants. Unfortunately, the initial focus of the air quality monitoring and guidance on exposure prevention programs on low-concentration components was never revised. Public agencies need to be better prepared to provide reliable guidance to the public on more appropriate means of exposure assessment, risk assessment, and preventive measures.

First responders (FR) present at Ground Zero in the first 72 h after the World Trade Center (WTC) collapsed have progressively exhibited significant respiratory injuries. The few toxicology studies performed to date evaluated effects from just fine (< 2.5 µm) WTC dusts; none examined health effects/toxicities from atmospheres bearing larger particle sizes, despite the fact the majority (> 96%) of dusts were > 10 µm and most FR likely entrained dusts by mouth breathing. Using a system that generated/delivered supercoarse (10-53 µm) WTC dusts to F344 rats (in a manner that mimicked FR exposures), this study sought to examine potential toxicities in the lungs. In this exploratory study, rats were exposed for 2 h to 100 mg WTC dust/m(3) (while under isoflurane [ISO] anesthesia) or an air/ISO mixture; this dose conservatively modeled likely exposures by mouth-breathing FR facing ≈750-1000 mg WTC dust/m(3). Lungs were harvested 2 h post-exposure and total RNA extracted for subsequent global gene expression analysis. Among the >  1000 genes affected by WTC dust (under ISO) or ISO alone, 166 were unique to the dust exposure. In many instances, genes maximally-induced by the WTC dust exposure (relative to in naïve rats) were unchanged/inhibited by ISO only; similarly, several genes maximally inhibited in WTC dust rats were largely induced/unchanged in rats that received ISO only. These outcomes reflect likely contrasting effects of ISO and the WTC dust on lung gene expression. Overall, the data show that lungs of rats exposed to WTC dust (under ISO) - after accounting for any impact from ISO alone - displayed increased expression of genes related to lung inflammation, oxidative stress, and cell cycle control, while several involved in anti-oxidant function were inhibited. These changes suggested acute inflammogenic effects and oxidative stress in the lungs of WTC dust-exposed rats. This study, thus, concludes that a single very high exposure to WTC dusts could potentially have adversely affected the respiratory system - in terms of early inflammatory and oxidative stress processes. As these changes were not compared with other types of dusts, the uniqueness of these WTC-mediated effects remains to be confirmed. It also still remains to be determined if these effects might have any relevance to chronic lung pathologies that became evident among FR who encountered the highest dust levels on September 11, 2001 and the 2 days thereafter. Ongoing studies using longer-range post-exposure analyses (up to 1-year or more) will help to determine if effects seen here on genes were acute, reversible, or persistent, and associated with corresponding histopathologic/biochemical changes in situ.

Comparing effects of inhaled particles across rodent test systems and between rodent test systems and humans is a key obstacle to the interpretation of common toxicological test systems for human risk assessment. These comparisons, correlation with effects and prediction of effects, are best conducted using measures of tissue dose in the respiratory tract. Differences in lung geometry, physiology and the characteristics of ventilation can give rise to differences in the regional deposition of particles in the lung in these species. Differences in regional lung tissue doses cannot currently be measured experimentally. Regional lung tissue dosimetry can however be predicted using models developed for rats, monkeys, and humans. A computational model of particle respiratory tract deposition and clearance was developed for BALB/c and B6C3F1 mice, creating a cross-species suite of available models for particle dosimetry in the lung. Airflow and particle transport equations were solved throughout the respiratory tract of these mice strains to obtain temporal and spatial concentration of inhaled particles from which deposition fractions were determined. Particle inhalability (Inhalable fraction, IF) and upper respiratory tract (URT) deposition were directly related to particle diffusive and inertial properties. Measurements of the retained mass at several post-exposure times following exposure to iron oxide nanoparticles, micro- and nanoscale C60 fullerene, and nanoscale silver particles were used to calibrate and verify model predictions of total lung dose. Interstrain (mice) and interspecies (mouse, rat and human) differences in particle inhalability, fractional deposition and tissue dosimetry are described for ultrafine, fine and coarse particles.

Background: Biomarkers of T-cell receptor excision circles (TRECs) and immunoglobulin κ-deleting recombination excision circles (KRECs) reflect naïve T and B cell emigrants. This study assessed the biomarkers in patients with primary immunodeficiency diseases (PIDs) to determine the lymphocyte output disturbance and the correlation to lymphocytes., Methods: A standard plasmid was constructed to calculate TRECs and KRECs in 250 ng genomic DNA from whole blood of PIDs patients. These were correlated to naïve and memory lymphocytes for further classification and adequate treatment., Results: In 69 studied patients, the low TRECs mainly included those with severe combined T and B immunodeficiency (SCID, 7/8), combined immunodeficiency (CID, 4/4), and common variable immunodeficiency (CVID, 6/7). The diminished KRECs was in SCID (4/8), CID (4/4), CVID (7/7), Bruton's tyrosine kinase mutation (Btk, 3/4), anti-B cell deletion (by anti-CD20 antibody in 1), and Behçet syndrome under steroid treatment (1). The TRECs and KRECs positively correlated to absolute naïve T (CD4 + CD45RA+) and naïve B (CD19 + CD27-), and to memory B (CD19 + CD27+) numbers, respectively., Conclusion: This study validates that low TRECs and KRECs values reflect low naïve T and B lymphocytes in 'combined immunodeficiencies' and in some CVID patients with the potential to develop the CID phenotype.

Objective: To identify the relationship between glycemic indices and β cell function in patients with newly diagnosed type 2 diabetes., Methods: The cross-sectional analysis included 61 patients with newly diagnosed type 2 diabetes who received continuous glucose monitoring (CGM) for 72 hours. The association between β cell function and glycemic indices including A1C and glycemic variability was investigated., Results: A1C (r = -0.405, p = 0.001) and standard deviation of blood glucose (SDBG, r = -0.274, p = 0.032) were significantly correlated to HOMA-β cell function (HBCI), whereas mean amplitude of glycemic excursions (MAGE, r = -0.210, p = 0.104) was not informative. After multiple confounders adjustments, A1C (β = -7.35, p < 0.001), MAGE (β = -4.64, p = 0.040), and SDBG (β = -12.3, p = 0.012) were associated with HBCI., Conclusion: A1C and glycemic variability were both associated with β cell function in patients with newly diagnosed type 2 diabetes. The main limitations of the present study are the cross-sectional design in nature and the limited sample size.

Introduction: The discovery of endothelial progenitor cells (EPCs) may help to explain observed cardiovascular effects associated with inhaled nickel nanoparticle exposures, such as increases in vascular inflammation, generation of reactive oxygen species, altered vasomotor tone and potentiated atherosclerosis in murine species., Methods: Following an acute whole body inhalation exposure to 500 µg/m(3) of nickel nanoparticles for 5 h, bone marrow EPCs from C57BL/6 mice were isolated. EPCs were harvested for their RNA or used in a variety of assays including chemotaxis, tube formation and proliferation. Gene expression was assessed for important receptors involved in EPC mobilization and homing using RT-PCR methods. EPCs, circulating endothelial progenitor cells (CEPCs), circulating endothelial cells (CECs) and endothelial microparticles (EMPs) were quantified on a BD FACSCalibur to examine endothelial damage and repair associated with the exposure., Results and Conclusions: Acute exposure to inhaled nickel nanoparticles significantly increased both bone marrow EPCs as well as their levels in circulation (CEPCs). CECs were significantly elevated indicating that endothelial damage occurred due to the exposure. There was no significant difference in EMPs between the two groups. Tube formation and chemotaxis, but not proliferation, of bone marrow EPCs was impaired in the nickel nanoparticle exposed group. These results coincided with a decrease in the mRNA of receptors involved in EPC mobilization and homing. These data provide new insight into how an acute nickel nanoparticle exposure to half of the current Occupational Safety & Health Administration (OSHA) permissible exposure limit may adversely affect EPCs and exacerbate cardiovascular disease states.

Objective: The aim of this study was to apply the International Classification of Functioning, Disability and Health - Child and Youth (ICF-CY) framework to identify the factors related to the participation of children with autism., Method: A convenience sample included 162 preschool children with autism ages 36 to 72 months. The raters collected data using the ICF-CY-based questionnaire as an instrument to construct the structural equation modeling of factors associated with participation., Results: The internal structure of the model was acceptable, indicating that the observed variables would suffice in accounting for latent variables. The structural model showed that the performance of participation in children with autism was influenced by body functions and personal factors. All the variables accounted for 77% of the explained variance for activities and for participation by 71% of the children with autism., Conclusion: These findings may provide critical information pertaining to predictive factors of participation for parents, educators, and professionals who work with children with autism.

Particulate matter (PM) varies in chemical composition and mass concentration based on a number of factors including location, season, source and particle size. The aim of this study was to evaluate the in vitro and in vivo toxicity of coarse and fine PM simultaneously collected at three rural and two urban sites within the metropolitan New York City (NYC) region during two seasons, and to assess how particle size and elemental composition affect toxicity. Human pulmonary microvascular endothelial (HPMEC-ST1.6R) and bronchial epithelial (BEAS-2B) cell lines were exposed to PM (50 μg/mL) and analyzed for reactive oxygen species (ROS). Mice (FVB/N) were exposed by oropharyngeal aspiration to 50 µg PM, and lavage fluid was analyzed for total protein and PMN influx. The ROS response was greater in the HPMEC-ST1.6R cell line compared to BEAS-2B cells, but the responses were significantly correlated (p < 0.01). The ROS response was affected by location, locale and the location:size interaction in both cell lines, and an additional association for size was observed from HPMEC-ST1.6R cells. Urban fine PM generated the highest ROS response. In the mouse model, inflammation was associated with particle size and by a season:size interaction, with coarse PM producing greater PMN inflammation. This study showed that the aerodynamic size, locale (i.e. urban versus rural), and site of PM samples affected the ROS response in pulmonary endothelial and epithelial cells and the inflammatory response in mice. Importantly, these responses were dependent upon the chemical composition of the PM samples.

Objective: Asthma is a chronic respiratory disorder characterized by airway hyperreactivity, eosinophilic infiltration, high titer of allergen-specific IgE, and overproduction of T helper 2 (Th2) cytokines. Antigen combined with an appropriate adjuvant and administrated through the proper route can elicit suitable immunological responses to protect humans and animals from diseases. Antigen formulated with monophosphoryl lipid A (MPLA) can produce priming of Th1-mediated immune responses. The purpose of this study was to examine the utility of MPLA as an adjuvant to prevent asthma., Methods: BALB/c mice were immunized with ovalbumin (OVA) formulated with or without MPLA by intraperitoneal, footpad, or subcutaneous injection. Vaccinated mice were challenged with OVA aerosol to estimate the protective efficacy of MPLA in comparison to Th2-adjuvant aluminum hydroxide (Alum). Airway hyperresponsiveness to methacholine, eosinophilia in bronchoalveolar lavage fluid (BALF), circulating titers of OVA-specific antibodies, and stimulating levels of IFN-γ and IL-4 cytokines from splenocytes were evaluated., Results: Mice immunized by all injection routes with OVA formulated with MPLA increased the ratio of Th1/Th2 responses compared to mice receiving antigen alone. For prophylactic vaccination purpose, MPLA reduced airway responsiveness and eosinophilic inflammation in the lung, decreased serum OVA-specific IgE level, and increased the serum ratio of OVA-specific IgG2a/IgG1 and the ratio of IFN-γ/IL4 from OVA-activated splenocytes compared with mice vaccinated with Alum., Conclusion: MPLA may be clinically useful in the vaccination of individuals predisposed to asthma.

Objective: Gerstmann's syndrome is a rare neurological disorder characterized by right-left disorientation, finger agnosia, agraphia and acalculia. Several causes for the manifestation of this rare syndrome have been reported in previous publications; however, thus far, an association between secondary diagnostic cerebral angiography and Gerstmann's syndrome has not been reported., Case Report: A 48-year-old woman diagnosed with subarachnoid haemorrhage underwent a secondary diagnostic cerebral angiography 7 months after the episode. The patient showed memory impairment, agraphia, acalculia, right-left disorientation, occasional errors in speech and finger agnosia accompanied by an acute infarction in the left middle cerebral artery territory. However, she showed excellent recovery after intensive rehabilitation and conservative treatment., Conclusion: The previously reported rate of permanent neurological complications associated with diagnostic cerebral angiography was very low (0-0.5%). To the best of the authors' knowledge, this is the first case report of Gerstmann's syndrome as a complication of cerebral angiography. This report discusses the complications associated with the neurological condition and emphasizes the need for early rehabilitation in cases of Gerstmann's syndrome.

Objective: The gene (SCGB1A1) encoding Clara cell 10-kDa protein (CC10), a steroid-inducible immune modulator, is a candidate gene for asthma, but the evidence is equivocal. The potential influence of a common variant on asthma severity and serum CC10 levels during acute exacerbation and after corticosteroid treatment in Chinese case-control children and its functional relevance was investigated., Methods: Genotyping of a non-coding variant G+38A was performed in 489 children, of whom 277 had asthma with varying severity, and 212 healthy controls. Associations were tested for asthma, asthma severity, and responsiveness to steroid treatment. The transcriptional activity of this variant was examined in a Clara-like cell line (H358) using transient transfection assays., Results: Significant association was observed for the combined GA and AA genotypes of the CC10 G+38A variant and an increased risk of asthma [odds ratio (OR), 2.62, p < .001]. This association was correlated with asthma severity (moderate: OR, 2.85, p < .001; near-fatal: OR, 4.81, p < .001). Also, patients with the GA and AA genotypes showed significantly lower serum CC10 (p < .01) and provocation concentration causing a 20% fall (PC(20)) in forced expiratory volume in 1 s (FEV(1)) (p < .0001) when compared with those with the GG. After glucocorticoid treatment, the CC10 levels were significantly increased in asthmatic patients with GG (p < .0001), but not those with the GA and AA genotypes. Moreover, a lower dexamethasone-induced reporter (luciferase) activity was observed for H358 cells transiently transfected with the G38A risk allele (A) compared with wild-type allele (G)., Conclusions: These findings suggest that the CC10 G+38A variant may contribute to the severity of asthma and lower level of steroid responsiveness.

The total surface area is known to be an effective exposure metric for predicting the lung toxicity of low solubility nanoparticles (NPs). However, if NPs are dissolved quickly enough in the lungs, the mass may be correlated with the toxicity. Recent studies have found that the toxicity of zinc oxide (ZnO) NPs was caused by the release of zinc ions. Thus, we hypothesized that mass could be used as an exposure metric for the toxicity of ZnO NPs. Healthy Sprague-Dawley rats were exposed to a low, moderate, or high dose of 35 and 250 nm ZnO particles or filtered air. Bronchoalveolar lavage fluid was collected to determine lung inflammation, injury and oxidative stress. The lung inflammation induced by ZnO particles according to different concentration metrics, including number, mass and surface area, was compared. The mass concentration was significantly correlated with the percentage of neutrophils (R(2) = 0.84), number of neutrophils (R(2) = 0.84) and total cells (R(2) = 0.73). Similarly, surface area concentration was significantly correlated with the percentage of neutrophils (R(2) = 0.94), number of neutrophils (R(2) = 0.81) and total cells (R(2) = 0.76). There was no correlation between the number and lung inflammation. We found that both mass and surface area were effective as metrics for the toxicity of ZnO NPs, although only surface area was previously indicated to be an effective metric. Our results are also consistent with recent study results that ZnO NPs and released zinc ions may play a role mediating the toxicity of NPs.

Background: Little is known about the prevalence of allergic diseases in children of different ages. This study aimed to investigate the prevalence of allergic diseases and allergic sensitization in children over a wide age range, with emphasis on the influence of age, gender, and body mass index (BMI)., Methods: In a cross-sectional study, we assessed 5351 Taiwanese children aged 4-18 years using an International Study of Asthma and Allergies in Childhood questionnaire, BMI, and total and specific serum immunoglobulin E., Results: Forty-eight percent were currently symptomatic for at least one of three allergic diseases. Prevalence of wheeze ever, current wheeze, and diagnosed asthma were 17.0%, 7.5%, and 9.8%, respectively; analogous features for rhinitis were 47.8%, 44.2%, and 39.8%. Allergic sensitization was very common (57.3%). Half of the children (50.6%) with current wheeze had not been diagnosed with asthma by physicians, whereas undiagnosed rates were 32.3% for rhinitis and 25.3% for eczema. The male-to-female prevalence ratios of current wheeze increased with age from <1 at 4-5 years, peaked at 10-11 years (2.24), then reversed to 0.57 at 16-18 years. Childhood wheezing tended to remit with age, but rhinitis and eczema were more persistent. Total immunoglobulin E levels increased with age until 14-15 years, and declined thereafter. Elevated BMI was associated with greater prevalence of wheezing and eczema, with no evidence of significant effect modification by either gender or age. Multivariate analyses revealed that younger age, boys, and obesity were significantly and independently associated with current wheezing in children (all p < .01)., Conclusions: The burden and co-morbidity of childhood allergies are substantial. There are striking age-dependent gender differences in asthma prevalence, exhibiting an inverted U-shaped curve for male-to-female prevalence ratios by age. Obesity is associated with a greater prevalence of asthma in children with no evidence of a significant modulation by either gender or age.

In this pilot study, we investigated which physicochemical properties of nickel hydroxide nanoparticles (nano-NH) were mainly responsible in inducing pulmonary toxicity. First, we studied the role of nickel ions solubilized from nano-NH by comparing the toxic effects of nano-NH to those of readily soluble nickel sulfate nanoparticles (nano-NS). Additionally, to test whether there was a non-specific stress response due to particle morphology, we compared the toxicity of nano-NH with that of carbon nanoparticles (nano-C) and titanium dioxide nanoparticles (nano-Ti), both of which had similar physical properties such as particle size and shape, to nano-NH. We exposed mice to each type of nanoparticles for 4?h via a whole-body inhalation system and examined oxidative stress and inflammatory responses in the lung. We also determined the lung burden and clearance of Ni following nano-NH and nano-NS exposures. The results showed that lung deposition of nano-NH was significantly greater than that of nano-NS and nano-NH appeared to have stronger inflammogenic potential than nano-NS even when lung Ni burden taken into consideration. This suggests that the toxicity of nano-NH is not driven solely by released Ni ions from deposited nano-NH particles. However, it is unlikely that the greater toxic potential of nano-NH is attributable to a generic stress response from any nanoparticle exposure, since nano-C and nano-Ti did not elicit toxic responses similar to those of nano-NH. These results indicate that the observed pulmonary toxicity by inhaled nano-NH were chemical-specific and deposited dose and solubility are key factors to understand toxicity induced by nano-NH.

While many studies found associations between ambient particulate matter (PM) and morbidity or mortality outcomes, it is unclear whether these associations were dependent on the composition of PM, which varies with the source of that PM. We address this knowledge gap by conducting a time-series PM-health effects assessment that specifically investigates the role of source-apportioned fine PM (PM2.5) on the oxidant generation capacity that might be responsible for respiratory and cardiovascular health outcomes. Daily PM2.5 composition speciation and black carbon (BC) measurements, conducted in rural New York for 303 days between March 2003 and January 2005, were analyzed using factor analysis source-apportionment model, and five source categories (transported aerosol/secondary sulfate, resuspended soil, metals, residual oil combustion, and industrial/incineration) were identified. After the exposure of human epithelial cells (BEAS-2B) to these PM2.5 samples, cellular nuclear factor-κB (NF-κB) activation showed a relatively significant association Ni (concentration averaging 38 ng/m(3)), and weaker but still significant correlations with Ba (13 ng/m(3)), Mn (9 ng/m(3)), and Fe (500 ng/m(3)). The single-source regression analysis of NF-κB signal showed significant association with metal source only. Our results showed that metals in PM2.5 were the important source for cellular oxidant generation and may be responsible for subsequent health effects associate with particle air pollution.

Introduction: Particulate matter (PM), specifically nickel (Ni) found on or in PM, has been associated with an increased risk of mortality in human population studies and significant increases in vascular inflammation, generation of reactive oxygen species, altered vasomotor tone, and potentiated atherosclerosis in murine exposures. Recently, murine inhalation of Ni nanoparticles have been shown to cause pulmonary inflammation that affects cardiovascular tissue and potentiates atherosclerosis. These adverse cardiovascular outcomes may be due to the effects of Ni on endothelial progenitor cells (EPCs), endogenous semi-pluripotent stem cells that aid in endothelial repair. Thus, we hypothesize that Ni nanoparticle exposures decrease cell count and cause impairments in function that may ultimately have significant effects on various cardiovascular diseases, such as, atherosclerosis., Methods: Experiments involving inhaled Ni nanoparticle exposures (2 days/5 h/day at ∼1200 µg/m(3), 3 days/5 h/day at ∼700 µg/m(3), and 5 days/5 h/day at ∼100 µg/m(3)), were performed in order to quantify bone marrow resident EPCs using flow cytometry in C57BL/6 mice. Plasma levels of human stromal cell-derived factor 1α (SDF-1α) and vascular endothelial growth factor (VEGF) were assessed by enzyme-linked immunosorbent assay and in vitro functional assessments of cultured EPCs were conducted., Results and Conclusions: Significant EPC count differences between exposure and control groups for Ni nanoparticle exposures were observed. Differences in EPC tube formation and chemotaxis were also observed for the Ni nanoparticle exposed group. Plasma VEGF and SDF-1α differences were not statistically significant. In conclusion, this study shows that inhalation of Ni nanoparticles results in functionally impaired EPCs and reduced number in the bone marrow, which may lead to enhanced progression of atherosclerosis.

Background: The use of nanoparticles (NPs) in technological applications is rapidly expanding, but the potential health effects associated with NP exposure are still largely unknown. Given epidemiological evidence indicating an association between inhaled ambient ultrafine particles and increased risk of cardiovascular disease morbidity and mortality, it has been suggested that exposure to NPs via inhalation may induce similar cardiovascular responses., Methods: Male C57BL/6 mice were exposed via whole-body inhalation to either filtered air (FA) or nickel hydroxide (NH) NPs (100, 150, or 900 µg/m(3)) for 1, 3, or 5 consecutive days (5 h/day). At 24-h post-exposure, vascular function in response to a vasoconstrictor, phenylephrine (PE), and a vasodilator, acetylcholine (ACh), was measured in the carotid artery., Results: Carotid arteries from mice exposed to all concentrations of NH-NPs showed statistically significant differences in graded doses of PE-induced contractile responses compared with those from FA mice. Similarly, vessels from NH-NP-exposed mice also demonstrated impaired vasorelaxation following graded doses of ACh as compared with FA mice., Conclusions: These results suggest that short-term exposure to NH-NPs can induce acute endothelial disruption and alter vasoconstriction and vasorelaxation. These findings are consistent with other studies assessing vascular tone and function in the aorta, coronary, and mesenteric vessels from mice exposed to motor vehicular exhaust and concentrated ambient particles.

The World Trade Center (WTC) collapse on September 11, 2001 released copious amounts of particulate matter (PM) into the atmosphere of New York City. Follow-up studies on persons exposed to the dusts have revealed a severely increased rate for asthma and other respiratory illnesses. There have only been a few studies that have sought to discern the possible mechanisms underlying these untoward pathologies. In one study, an increased cytokine release was detected in cells exposed to WTC fine dusts (PM₂.₅ fraction or WTC₂.₅). However, the mechanism(s) for these increases has yet to be fully defined. Because activation of the mitogen-activated protein kinase (MAPK) signaling pathways is known to cause cytokine induction, the current study was undertaken to analyze the possible involvement of these pathways in any increased cytokine formation by lung epithelial cells (as BEAS-2B cells) exposed to WTC₂.₅. Our results showed that exposure to WTC₂.₅ for 5 hr increased interleukin-6 (IL-6) mRNA expression in BEAS-2B cells, as well as its protein levels in the culture media, in a dose-dependent manner. Besides IL-6, cytokine multiplex analyses revealed that formation of IL-8 and -10 was also elevated by the exposure. Both extracellular signal-regulated kinase (ERK) and p38, but not c-Jun N-terminal protein kinase, signaling pathways were found to be activated in cells exposed to WTC₂.₅. Inactivation of ERK signaling pathways by PD98059 effectively blocked IL-6, -8, and -10 induction by WTC₂.₅; the p38 kinase inhibitor SB203580 significantly decreased induction of IL-8 and -10. Together, our data demonstrated activation of MAPK signaling pathway(s) likely played an important role in the WTC₂.₅-induced formation of several inflammatory (and, subsequently, anti-inflammatory) cytokines. The results are important in that they help to define one mechanism via which the WTC dusts may have acted to cause the documented increases in asthma and other inflammation-associated respiratory dysfunctions in the individuals exposed to the dusts released from the WTC collapse.

Ambient air PM(2.5) (particulate matter less than 2.5 mum in diameter) has been associated with cardiovascular diseases (CVDs), but the underlying mechanisms affecting CVDs are unknown. The authors investigated whether subchronic inhalation of concentrated ambient PM(2.5) (CAPs), whole diesel exhaust (WDE), or diesel exhaust gases (DEGs) led to exacerbation of atherosclerosis, pulmonary and systemic inflammation, and vascular dysfunction; and whether DEG interactions with CAPs alter cardiovascular effects. ApoE(-/-) mice were simultaneously exposed via inhalation for 5 hours/day, 4 days/week, for up to 5 months to one of five different exposure atmospheres: (1) filtered air (FA); (2) CAPs (105 microg/m(3)); (3) WDE (DEP = 436 microg/m(3)); (4) DEG (equivalent to gas levels in WDE group); and (5) CAPs+DEG (PM(2.5): 113 microg/m(3); with DEG equivalent to WDE group). After 3 and 5 months, lung lavage fluid and blood sera were analyzed, and atherosclerotic plaques were quantified by ultrasound imaging, hematoxylin and eosin (H&E stain), and en face Sudan IV stain. Vascular functions were assessed after 5 months of exposure. The authors showed that (1) subchronic CAPs, WDE, and DEG inhalations increased serum vascular cell adhesion molecule (VCAM)-1 levels and enhanced phenylephrine (PE)-induced vasoconstriction; (2) for plaque exacerbation, CAPs > WDE > DEG = FA, thus PM components (not present in WDE) were responsible for plaque development; (3) atherosclerosis can exacerbated through mechanistic pathways other than inflammation and vascular dysfunction; and (4) although there were no significant interactions between CAPs and DEG on plaque exacerbation, it is less clear whether the effects of CAPs on vasomotor dysfunction and pulmonary/systemic inflammation were enhanced by the DEG coexposure.

Purpose: To investigate the penetration of topical 1% voriconazole through the cornea into the aqueous humor in New Zealand white rabbits and to determine the effect of mechanical scraping of the corneal epithelium., Materials and Methods: The right eyes of 29 New Zealand white rabbits were maintained with the epithelium intact, and the left eyes underwent mechanical epithelium debridement of the central 7.5 mm of the cornea. A loading dose consisted of a drop of 1% voriconazole applied every 5 min for the initial half hour and followed by a maintenance dose consisting of a drop every 20 min, which was applied for about 2 hr. Then, the first sample was obtained 5 min after the first seven doses (loading dose) were given, and then four more samples were taken 5 min after four more subsequent drops (maintenance dose). The samples were analyzed by high performance liquid chromatography., Results: The mean aqueous concentration of voriconazole was 33.44 +/- 5.77 microg/mL 5 min after the loading dose in the non-scraped group and 57.67 +/- 6.77 microg/mL in the scraped group, respectively. The mean aqueous concentration of voriconazole was maintained in a range from 19.97 to 23.70 microg/mL 5 min after the maintenance doses in the non-scraped group and from 44.44 to 49.02 microg/ mL in the scraped group. The mean vitreous concentration of voriconazole ranged from 0.38 to 0.49 microg/mL in the non-scraped group and ranged from 0.72 to 0.94 microg/mL in the scraped group. These levels were statistically significant (P < 0.05) between the scraped and non-scraped groups., Conclusions: Topically administered voriconazole achieved minimum inhibitory concentrations in the aqueous for all the organisms most commonly involved in fungal endophthalmitis and achieved minimum inhibitory concentrations in the vitreous for some pathogenic fungi. The concentrations of voriconazole were higher in the scraped group than in the non-scraped group.

Ambient PM(2.5) (particulate matter with an aerodynamic diameters of less than 2.5 mum) is associated with alterations in the autonomic nervous system and cardiac function, but there are significant response variations. The authors simultaneously studied the effects of concentrated PM(2.5) (CAPs) in Sterling Forest (SF; dominated by long-range transported PM) and at the Mount Sinai School of Medicine (MS; rich in Ni and elemental/organic carbon [EC/OC]) in Manhattan, NY. ApoE(-/-) mice (n = 8/group) were exposed to filtered air or CAPs (average 133 and 123 microg/m(3) in SF and MS, respectively) for 6 h/day, 5 days/week for 6 months. Electrocardiogram (ECG) tracings were monitored using telemetry. At MS, current day CAPs mass was negatively associated with short-term changes in heart rate (HR), and positively with HR variability (HRV). At SF, CAPs mass was positively associated with HR, and negatively with HRV. At MS, HR and HRV changes were associated with PM(2.5) components associated with residual oil combustion > long-range transport > traffic > FeMn > incineration > soil, and fireworks had no associations. At SF, HR and HRV were associated with long-range transport > Ni refinery > soil > residual oil combustion/traffic. At both sites, there were cardiac function associations with PM(2.5), but not EC. At MS, there were associations with Ni and P, whereas at SF, they were with a mixture of long-range transported PM, crustal material, and combustion products. Thus subchronic CAPs exposures at locations with different particle compositions produced different effects on cardiac function in ApoE(-/-) mice.

Environmental tobacco smoke (ETS) and ambient air fine particulate matter (PM(2.5)) are both complex mixtures that have important adverse effects on the cardiovascular system. Although exposures to these complex mixtures have been studied individually, direct comparisons between the two has not been performed. In this study, the authors employed a novel, noninvasive ultrasound biomicroscopy method (UBM) to assess the effects of long-term, low-concentration inhalations of side-stream smoke (SS) and concentrated ambient PM(2.5) (CAPs) on plaque progression. ApoE(-/-) mice (n = 8/group) on high-fat chow (HFC), or normal chow (NC), were exposed to SS (PM = 450 microg/m(3)) or filtered air (FA) for 6 h/day, 5 days/week, for 6 months; CAPs exposure was at 134 microg/m(3) (NC only). Mortality during the SS exposure was greater in the HFC than in the NC, and SS significantly enhanced the effects of diet. No mortality was observed in CAPs-exposed mice. At 4 and 6 months, SS produced the greatest change in plaque area in the left common carotid artery (CCA) in HFC as compared to FA or NC, but not in the brachiocephalic artery. In contrast, CAPs exposure significantly enhanced plaque areas in brachiocephalic and left CCA at 3 and 6 months of exposure. The effect of SS was comparable in magnitude to that produced by CAPs at an average PM(2.5) mass concentration that was only 30% as high. In light of the employment of the same animal model, uniform inhalation exposure protocols, time schedules, a noninvasive monitoring protocol, and a parallel study design, these findings have broad applicability.

Short and long-term pulmonary response to inhaled nickel hydroxide nanoparticles (nano-Ni(OH)(2), CMD = 40 nm) in C57BL/6 mice was assessed using a whole body exposure system. For short-term studies mice were exposed for 4 h to nominal concentrations of 100, 500, and 1000 mg/m(3). For long-term studies mice were exposed for 5 h/d, 5 d/w, for up to 5 months (m) to a nominal concentration of 100 mg/m(3). Particle morphology, size distribution, chemical composition, solubility, and intrinsic oxidative capacity were determined. Markers of lung injury and inflammation in bronchoalveolar lavage fluid (BALF); histopathology; and lung tissue elemental nickel content and mRNA changes in macrophage inflammatory protein-2 (Mip-2), chemokine ligand 2 (Ccl2), interleukin 1-alpha (Il-1α), and tumor necrosis factor-alpha (Tnf-α) were assessed. Dose-related changes in BALF analyses were observed 24 h after short-term studies while significant changes were noted after 3 m and/or 5 m of exposure (24 h). Nickel content was detected in lung tissue, Ccl2 was most pronouncedly expressed, and histological changes were noted after 5 m of exposure. Collectively, data illustrates nano-Ni(OH)(2) can induce inflammatory responses in C57BL/6 mice.

In situ reactions of metal ions or their compounds are important mechanisms by which particles alter lung immune responses. The authors hypothesized that major determinants of the immunomodulatory effect of any metal include its redox behavior/properties, oxidation state, and/or solubility, and that the toxicities arising from differences in physicochemical parameters are manifest, in part, via differential shifts in lung iron (Fe) homeostasis. To test the hypotheses, immunomodulatory potentials for both pentavalent vanadium (VV; as soluble metavanadate or insoluble vanadium pentoxide) and hexavalent chromium (CrVI; as soluble sodium chromate or insoluble calcium chromate) were quantified in rats after inhalation (5h/day for 5 days) of each at 100 microg metal/m3. Differences in effects on local bacterial resistance between the two VV, and between each CrVI, agents suggested that solubility might be a determinant of in situ immunotoxicity. For the soluble forms, VV had a greater impact on resistance than CrVI, indicating that redox behavior/properties was likely also a determinant. The soluble VV agent was the strongest immunomodulant. Regarding Fe homeostasis, both VV agents had dramatic effects on airway Fe levels. Both also impacted local immune/airway epithelial cell Fe levels in that there were significant increases in production of select cytokines/chemokines whose genes are subject to regulation by HIF-1 (whose intracellular longevity is related to cell Fe status). Our findings contribute to a better understanding of the role that metal compound properties play in respiratory disease pathogenesis and provide a rationale for differing pulmonary immunotoxicities of commonly encountered ambient metal pollutants.

Owing to increased obesity, non-alcoholic fatty liver disease (NAFLD) is now the most prevalent liver disease in the United States. NAFLD is considered a component of metabolic syndrome, a cluster of disorders that also includes diabetes mellitus, dyslipidemia, arteriosclerosis, and hypertension. Exposure to ambient air particulate matter with aerodynamic diameters < 2.5 microm (PM(2.5)) is a risk factor for arteriosclerosis and lung disease, but its effect on NAFLD is unknown. PM(2.5) induces pulmonary dysfunction via Toll-like receptor (TLR) activation on alveolar macrophages. TLR activation of Kupffer cells, resident hepatic macrophages, and subsequent pro-inflammatory cytokine production have been shown to play a key role in NAFLD progression. We hypothesized that PM(2.5) exposure is a significant risk factor for the progression of NAFLD. Thus, following exposure of male C57BL/6 mice fed high fat chow (HFC) to concentrated air particulate matter (CAPs) or filtered air for 6 weeks, progression of NAFLD was evaluated by standardized histological assessment of hepatic inflammation and fibrosis. In mice fed HFC, the hepatic inflammatory grade (3.00 +/- 0.00 vs. 1.50 +/- 0.71, P < 0.001) and fibrosis stage (1.00 +/- 0.00 vs. 0.60 +/- 0.52, P = 0.023) were both significantly higher in mice exposed to CAPs versus filtered air, respectively. Increased numbers of Kupffer cells contained PM in CAPs-exposed mice scores of (2.00 +/- 0.94 vs. 0.20 +/- 0.42, respectively, P < 0.001). PM exposure increased IL-6 secretion up to seven-fold in a dose-dependent manner by isolated wild-type but not TLR4(-/-) Kupffer cells (P < 0.050). In conclusion, ambient PM(2.5) exposure may be a significant risk factor for NAFLD progression.

Background: Monocyte chemotactic protein 1 (MCP-1) plays an important role in various immune and allergic disorders since it is a potent chemo-attractant for inflammatory cells, such as eosinophils, memory T cells, and monocytes., Objective: To investigate serum MCP-1 during asymptomatic state and acute attacks of bronchial asthma., Methods: In this longitudinal cohort design study, sequential serum levels of MCP-1 were measured by a sandwich enzyme-linked immunosorbent assay (ELISA). Twenty-four asthma patients' MCP-1 levels were examined at 5 time points: during the asymptomatic phase, in an acute wheezing episode, and at 1 week, 1 month, and 2 months after acute asthma attack. Fifteen children without asthma were enrolled as control., Results: During the asymptomatic phase of asthma, serum MCP-1 levels were significantly higher than that of normal controls (329.57 +/- 99.20 pg/ml vs. 213.63 +/- 77.29 pg/ml, p = 0.001). In comparison with the asymptomatic phase, the serum MCP-1 levels during the acute asthma attack were significantly higher (682.88 +/- 88.45 pg/ml vs. 329.57 +/- 99.20 pg/ml, p < 0.001). After treatment of acute asthma exacerbation, all of the serum MCP-1 levels declined within 1 week, but were still higher than control 2 months later., Conclusion: In asthma patients, the consistently elevated serum levels of MCP-1 suggest its role in the pathogenesis of bronchial asthma - not only in the chronic inflammatory processes, but also in acute asthma attack exacerbation. These findings suggest a possible role for MCP-1 in the pathogenesis of asthma and a potential role for its use in anti-asthma treatment in the future.

Epidemiology studies have reported associations between increased mortality and morbidity with exposure to particulate air pollution, particularly within individuals with preexisting cardiovascular disease (CVD). Clinical and toxicological studies have provided evidence that exposure to ambient air particulate matter (PM) impacts CVD by increasing plaque size. It is unclear whether PM-induced increased plaque size is associated with molecular disease progression. This study examines molecular profiles within plaques recovered from ApoE(-/-) mice exposed to concentrated ambient air particles (CAPs) to determine whether pulmonary deposition of PM contributes to molecular alterations leading to vascular disease progression. Laser capture microdissection was used to recover atherosclerotic plaques from ApoE(-/-) male mice exposed daily for 5 mo to filtered air or CAPs. Alterations in mRNA expression was assessed in microdissected plaques of CAPs-exposed and air controls using the Affymetrix microarray platform. Bioinformatic analysis indicated alterations in 611 genes: 395 genes downregulated and 216 genes upregulated. Gene ontology revealed CAPs-induced changes to inflammation, proliferation, cell cycle, hematological system, and cardiovascular pathways. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) verified microarray data also revealing gene expression alterations undetected by the microarray analysis, i.e., decreased expression of alpha-actin for smooth muscle cells, and increased expression of the macrophage marker Cd68 and of beta-actin. Comparison of CAPs-induced gene expression profiles demonstrated consistency with previously published gene expression profiles in the ApoE(-/-) mouse model and humans associated with plaque progression. These results indicate that exposure to fine PM induces molecular alterations associated with vascular disease progression and provides insight into potential biological pathways responsible for this effect.

We review literature that provides insights on health-related effects observed in laboratory-based inhalation studies in humans and laboratory animals using concentrated ambient air particulate matter (CAPs) in the fine, thoracic coarse, and ultrafine size ranges. The CAPs studies are highly informative on the health effects of ambient air particulate matter (PM) because they represent realistic PM exposure mixtures. When PM components are also analyzed and regressed against the effects, they can sometimes be used to identify influential individual components or source-related mixtures responsible for the effects. Such CAPs inhalation studies are analogous to epidemiological studies of human populations for which both health-related effects were observed and PM composition data were available for multi-pollutant regression analyses or source apportionment. Various acute and chronic health-related effects have occurred in short- and long-term CAPs inhalation studies in the cardiovascular, nervous, hepatic, and pulmonary systems, as well as changes in markers of the metabolic syndrome, and many correspond to effects associated with ambient air PM exposures in epidemiological studies. In addition, many CAPs studies have been conducted in coordination with in vitro studies that have identified biomarkers indicative of the underlying biological mechanisms that account for the responses.

We review literature providing insights on health-related effects caused by inhalation of ambient air particulate matter (PM) containing metals, emphasizing effects associated with in vivo exposures at or near contemporary atmospheric concentrations. Inhalation of much higher concentrations, and high-level exposures via intratracheal (IT) instillation that inform mechanistic processes, are also reviewed. The most informative studies of effects at realistic exposure levels, in terms of identifying influential individual PM components or source-related mixtures, have been based on (1) human and laboratory animal exposures to concentrated ambient particles (CAPs), and (2) human population studies for which both health-related effects were observed and PM composition data were available for multipollutant regression analyses or source apportionment. Such studies have implicated residual oil fly ash (ROFA) as the most toxic source-related mixture, and Ni and V, which are characteristic tracers of ROFA, as particularly influential components in terms of acute cardiac function changes and excess short-term mortality. There is evidence that other metals within ambient air PM, such as Pb and Zn, also affect human health. Most evidence now available is based on the use of ambient air PM components concentration data, rather than actual exposures, to determine significant associations and/or effects coefficients. Therefore, considerable uncertainties about causality are associated with exposure misclassification and measurement errors. As more PM speciation data and more refined modeling techniques become available, and as more CAPs studies involving PM component analyses are performed, the roles of specific metals and other components within PM will become clearer.

Recent studies have suggested a link between inhaled particulate matter (PM) exposure and atherogenesis. We investigated tissue factor (TF) expression with ambient fine particulate matter (diameter < 2.5 microm, PM(2.5)) exposure and in response to in vitro exposure to fine and ultrafine PM in cultured human bronchial epithelial cells, vascular smooth muscle cells (hSMCs), and monocytes. ApoE-/- mice, fed with normal chow (NC) or high-fat chow (HFC), were exposed to concentrated PM(2.5) or filtered air (FA) for 6 mo (6 h/day, 5 day/wk, n = 28). Following in vivo ultrasound bio-microscopy (UBM) assessment of plaque area, macrophage infiltration (CD68) and TF expression in the aorta were quantified. Cultured cells were incubated with size-fractionated PM from cascade impactors, or with standard reference PM material (SRM, number 1649a) and assayed for TF protein, mRNA, and activity. UBM-derived plaque areas were 7 +/- 1% larger in the PM(2.5)-HFC than the FA-HFC group (p = .04), but not significantly different between the PM(2.5)-NC and FA-NC groups (p = .07). Immunohistochemistry revealed increased TF (15 +/- 3% vs. 8 +/- 2%, p < .01) and macrophage infiltration (19 +/- 2% vs. 14 +/- 3%, p < .01) in the plaques of PM(2.5)-HFC compared with FA-HFC groups. Impactor-collected PM(2.5) and ultrafine particles consistently increased TF protein in bronchial epithelial cells, monocytes, and hSMCs. TF mRNA expression increased rapidly (within 1 h) in response to SRM PM. We conclude that in vivo and in vitro exposure to ambient air PM(2.5) induces TF expression.

Objective: The condition intractable hiccup (IH) is generally an incapacitating disorder indicating neurologic or non-neurologic disorders. Linearly polarized, near-infrared irradiation (SL) is shown to be effective in the treatment of IH where it is applied on custom-set acupoints. The aim of this study was to investigate the treatment efficacy of IH by SL on the acupoints and to survey the relationship between IH and comorbid-related factors. MATERIAL AND METHODS. A total of 35 patients with IH were enrolled prospectively and divided into central and non-central groups. All patients received SL using an SG-type lens unit on the relevant acupoints and were followed-up for up to 6 months for efficacy of the novel therapy., Results: There was no significant difference between patients with IH produced by central or non-central origins (p=0.7105) regarding the therapeutic effect of SL; however, the effects of age, bed-shaking, gun-waving motion and nasogastric (NG)-tube placement were significant. The severity index of IH was analyzed and found to be associated with the seasons. For those patients with elevated levels of aspartate aminotransferase (ASAT) after therapy, it took a significantly shorter (p=0.0029) period of time to treat IH with this novel therapy (p=0.0029). Thirty-four patients had complete resolution of IH within a few days of beginning SL, with partial resolution in 1 patient only., Conclusions: Without potential side effects, SL on custom-set acupoints could be a complementary therapy for patients with IH regardless of central or non-central origins.

Ambient particulate matter (PM) damages pulmonary tissue through oxidative stress (OS) pathways. Several reports indicate that the brain is another affected target of PM exposure. Since microglia (brain macrophages) are critical to OS-mediated neurodegeneration, the cellular and genomic response of immortalized mouse microglia (BV2) was examined in response to fine (or= 250 microg/ml) and depolarized mitochondrial membranes (>or= 6 microg/ml) within 15 min of exposure. HP and LP CAPs (>or= 25 microg/ml) differentially affected the endogenous scavengers, glutathione and nonprotein sulfhydryl in BV2 microglia after 1.5 h of exposure. Both HP and LP CAPs stimulated the release of proinflammatory cytokines tumor necrosis factor (TNF) alpha and interleukin (IL)-6 after 6 h of exposures. Microarray analysis of BV2 microglia exposed to either HP or LP CAPs (75 microg/ml, 4 h) identified 3200 (HP CAPs) and 160 (LP CAPs) differentially expressed (up- and downregulated) genes relative to media controls. Of the 3200 genes significantly affected by HP CAPs, the most prominent upregulated gene probes related to inflammatory pathways associated with Toll-like receptor signaling, MAPK signaling, T- and B-cell receptor signaling, apoptosis, and various proinflammatory cytokines and their receptors. LP CAPs significantly affected 160 genes that related to pathways associated with cellular maintenance and division, cell cycling and nuclear events. These data suggest that HP CAPs, which contained higher levels of nickel and vanadium than LP CAPs, appear to be more inflammatory and selectively upregulated the expression of inflammatory and innate immunity pathways in BV2 microglia.

The in situ reactions of metal ions/complexes are important in understanding the mechanisms by which environmental and occupational metal particles alter lung immune responses. A better understanding of these reactions in situ will also allow for the improved specificity and controlled toxicity of novel metallocompounds to be used as inhaled diagnostics or therapeutics. Our previous work showed that inhalation of metals (e.g., chromium, vanadium, nickel) caused altered lung immune cell function and host resistance. The data also suggested that the degree of immunomodulation induced depended not only on the amount of metal deposited, but also the compound used. If specificity governs pulmonary immunomodulatory potential, it follows that physicochemical properties inherent to the metal have a role in the elicited effects. We hypothe-size that major determinants of any metal compound's potential are its redox behavior, valency (generally referred to as oxidation state and considered speciation in chemical literature), and/or solubility. In accord with the extensive work carried out with vanadium (chemical symbol V) compounds showing the importance of form used, differences in potential for a range of V agents (pentavalent [V(V)] insoluble vanadium pentoxide and soluble sodium metavanadate, tetravalent [V(IV)] vanadyl dipicolinate, and trivalent [V(III)] bis(dipicolinato)vanadium) were quantified based on induced changes in local bacterial resistance after host inhalation of each agent at 100 mu g V/m(3) (5 hr/d for 5 d). Differences in effect between V(V) forms indicated that solubility was a critical property in in situ pulmonary immunotoxicity. Among the soluble forms, oxidizing vanadate had the greatest impact on resistance; reducing V(III) altered resistance to a lesser extent. Both the V(IV) and insoluble V(V) had no effect. When data was analyzed in the context of pre-infection lung V burdens, soluble V agents with different oxidation states induced varying responses, supporting the hypothesis that differences in immunomodulatory potential might be attributed to redox behavior or valency. Our findings both provide a basis for understanding why some metals could be a greater health risk than others (when encountered in equal amounts) and will assist in the design of inhalable metallopharmaceuticals by allowing researchers to preempt selection of certain metal ions or complexes for use in such products.

Increasing the understanding of how metal ions/complexes react in situ will allow for the improved specificity and controlled toxicity of novel synthetic metallocompounds that will be used as inhaled diagnostics or therapeutics. Our previous work showed that inhalation of select metals (e.g., chromium, vanadium, nickel, iron) caused alterations in lung immune cell function and in local bacterial resistance. The data also suggested that variations in the degree of immuno-modulation induced were not solely dependent on the amount of metal deposited in the lung, but also on the specific compound. If specificity governs immunomodulatory potential, it follows that physicochemical properties inherent to the metal may have a role in the elicited effects. We hypothesize that major determinants of any metal compound's immunomodulatory potential in situ are its redox behavior, valency, and/or solubility. Using changes in local bacterial resistance as an endpoint, differences in immunotoxic potential in the lungs were quantified for a range of chromium agents (insoluble calcium chromate(VI), and soluble sodium chromate(VI), potassium bis(dipicolinato)chromate(III) and sodium bis(dipicolinato)chromate(II)). Results indicated that among the latter three forms of Cr, strongly oxidizing hexavalent Cr (Cr[VI]) had the greatest impact on resistance, while reducing divalent and fairly unreactive trivalent forms of Cr had no effect at an equal exposure level (i.e., 100 microg Cr/m(3), 5 hr/d, for 5 d). Insoluble Cr(VI) had a greater effect than its soluble form. When data was analyzed in the context of pre-infection lung Cr burdens, it was seen that immunomodulatory potentials for both Cr(VI) agents did not differ significantly; however, complexes with different oxidation states did induce varying responses, suggesting that differences in potential might be attributed to redox behavior. From this it was concluded that for Cr, certain physicochemical properties are likely more important to any in situ pulmonary immunotoxicity than others (i.e., redox behavior is more critical than solubility). Our findings, in part, will help provide a basis for understanding why certain metals could be a greater health risk than others, even when encountered in equal amounts. This, in turn, will help researchers in the design of inhalable diagnostic/therapeutic metallopharmaceuticals by pre-empting the selection of certain metal ions/complexes for potential use in these products.

This study was conducted to determine whether a particular Chinese medicinal preparation is effective in alleviating menopausal symptoms. Chinese women with menopausal symptoms were recruited to receive treatment for 3 months followed by 3 months without treatment. The severity of menopausal symptoms and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol levels were assessed at baseline, 3 and 6 months. Data from 97 women with a mean age of 52.3 years were analyzed. Sixty women (62%) were postmenopausal. The serum FSH level (interquartile range) was 58.0 (39.5-72.4) IU/l at baseline and rose significantly 3 months after treatment. The difference remained significant in the postmenopausal group while there was no significant difference in the perimenopausal women. The changes in serum LH and estradiol levels remained unchanged. The baseline menopausal symptom score was 8.9 +/- 6.0. The menopausal symptom score improved markedly after treatment and remained at the same level at 6 months. All individual menopausal symptoms improved significantly after 3 months of treatment except dry eye. Most of these symptoms remained significantly improved at 6 months compared with the pre-treatment assessment. We observed that the Chinese medicinal preparation used in this study is effective in improving menopausal symptoms in healthy Chinese women. Further randomized controlled trial will be needed to confirm this observation.

Recent epidemiological studies suggest that long-term exposure to particulate matter (PM) causes chronic effects on the cardiovascular system that result in cumulative increases cardiovascular morbidity and mortality. Since atherosclerosis is a progressive irreversible condition and an underlying cause of many cardiovascular diseases, we hypothesized that long-term exposure to PM causes adverse cardiovascular effects by exacerbating atherosclerosis. In this study, we exposed C57- and ApoE-deficient (ApoE-/-) and ApoE, LDLr (DK)-deficient mice to concentrated ambient PM2.5 for 6 h/5 days/wk, for up to 5 mo. The overall mean exposure concentration for these groups of animals was 110 microg/m3. The cross-sectional area of the aorta root of DK mice was examined morphologically using confocal microscopy for the severity of lesion, extent of cellularity, and lipid contents. Aortas from the arch to the iliac bifurcations were also sectioned longitudinally and lesion areas were stained with Sudan IV. All DK mice regardless of exposure had developed extensive lesions in the aortic sinus regions, with lesion areas that covered more than 79% of the total area. In male DK mice, the lesion areas in the aortic sinus regions appeared to be enhanced by concentrated ambient particles (CAPs), with changes approaching statistical significance (p = .06). In addition, plaque cellularity was increased by 28% (p = .014, combined), whereas there were no CAPs-associated changes in the lipid content in these mice. When examining the entire aorta opened longitudinally, both the ApoE-/- and DK mice had prominent areas of severe atherosclerosis covering 40% or more of the lumenal surface. Visual examination of all images suggested that plaques tend to form in clusters concentrating near the aortic arch and and the iliac bifurcations. Quantitative measurements showed that CAPs exposure increased the percentage of aortic intimal surface covered by grossly discernible atherosclerotic lesion by 57% in the ApoE-/- mice (p = .03). Changes produced by CAPs in male (10% increase) or female DK mice (8% increase) were not statistically significant. In this study, we have demonstrated that subchronic exposure to CAPs in mice prone to develop atherosclerotic lesions had a significant impact on the size, severity, and composition of aortic plaque.

In order to examine the biologic plausibility of adverse chronic cardiopulmonary effects in humans associated with ambient particulate matter (PM) exposure, we exposed groups of normal mice (C57) and knockout mice that develop atherosclerotic plaque (ApoE-/- and ApoE-/- LDLr-/-) for 6 h/day, 5 days/wk for 5 or 6 mo during the spring/summer of 2003 to either filtered air or 10-fold concentrated ambient particles (CAPs) in Tuxedo, NY (average PM2.5 concentration during exposure = 110 microg/m3). Some of the mice had implanted electrocardiographic monitors. We demonstrated that: (1) this complex interdisciplinary study was technically feasible in terms of daily exposure, collection of air quality monitoring data, the collection, analysis, and interpretation of continuous data on cardiac function, and the collection and analyses of tissues of the animals sacrificed at the end of the study; (2) the daily variations in CAPs were significantly associated, in ApoE-/- mice, with daily variations in cardiac functions; (3) there were significant differences between CAPs and sham-exposed ApoE-/- mice in terms of cardiac function after the end of exposure period, as well as small differences in atherosclerotic plaque density, coronary artery disease, and cell density in the substantia nigra in the brain in the ApoE-/- mice; (4) there are suggestive indications of gene expression changes for genes associated with the control of circadian rhythm in the ApoE-/- LDLr-/- double knockout (DK) mice. These various CAPs-related effects on cardiac function and the development of histological evidence of increased risk of clinically significant disease at the end of exposures in animal models of atherosclerosis provide biological plausibility for the premature mortality associated with PM2.5 exposure in human subjects and provide suggestive evidence for neurogenic disease as well.

This subchronic (6-mo) inhalation study of the effects of concentrated ambient air fine particulate matter (PM2.5) in normal mice (C57) and a murine model of humans with an advanced level of aortic plaque (ApoE-/- or ApoE-/- LDLr-/-) was designed to determine the presence and extent of a variety of health-related responses. The animals were exposed for 6 h/day, 5 day/wk during the spring and summer of 2003 to concentrations that were elevated 10-fold in Tuxedo, NY, a regional background site that is upwind and approximately 50 km west-northwest of New York City. The average PM2.5 concentration during exposure was 110 microgram/m3, and the long-term average was 19.7 microg/m3. There were substantial daily variations in concentration, and we sought evidence both for the influence of peak exposures on acute responses and for the cumulative effects of the prolonged series of exposures. Acute responses were characterized in terms of: (1) short-term electrocardiographic (EKG), core body temperature, and physical activity differences between PM and sham-exposed mice; and (2) in vitro toxicity of a simultaneously collected PM2.5 sample to lung epithelial cells. Cumulative responses to PM2.5 were characterized in terms of changes in heart rate, heart-rate variability, heart-rate variance, aortic plaque density, genetic marker expression, and brain cell distributions. There were no significant changes in the normal mice. The nature and extent of the exposure-related responses that were seen in the ApoE-/- as well as ApoE-/- LDLr-/- mice are described in the articles that follow in this special issue of Inhalation Toxicology.

Normal mice (C57) and mice prone to develop atherosclerosis (ApoE-/-) were implanted with electrocardiograph (EKG), core body temperature, and motion transmitters were exposed daily for 6 h to Tuxedo, NY, concentrated ambient particles (CAPs) for 5 day/wk during the spring and summer of 2003. The series of 5-min EKG monitoring and body-temperature measurements were obtained for each animal in the CAPs and filtered air sham exposure groups. Our hypothesis was that chronic exposure could cause cumulative health effects. We used our recently developed nonparametric method to estimate the daily time periods that mean heart rates (HR), body temperature, and physical activity differed significantly between the CAPs and sham exposed group. CAPs exposure most affected heart rate between 1:30 a.m. and 4:30 a.m. With the response variables being the average heart rate, body temperature, and physical activity, we adopted a two-stage modeling approach to obtain the estimates of chronic and acute effects on the changes of these three response variables. In the first stage, a time-varying model estimated daily crude effects. In the second stage, the true means of the estimated crude effects were modeled with a polynominal function of time for chronic effects, a linear term of daily CAPs exposure concentrations for acute effects, and a random component for unknown noise. A Bayesian framework combined these two stages. There were significant decreasing patterns of HR, body temperature, and physical activity for the ApoE-/- mice over the 5 mo of CAPs exposure, with smaller and nonsignificant changes for the C57 mice. The chronic effect changes of the three response variables for ApoE-/- mice were maximal in the last few weeks. There was also a significant relationship between CAPs exposure concentration and short-term changes of heart rate in ApoE-/- mice during exposure. Response variables were also defined for examining fluctuations of 5-min heart rates within long (i.e., 3-6 h) and short time periods (i.e., approximately 15 min). The results for the ApoE-/- mice showed that heart-rate fluctuation within the longer periods increased to 1.35-fold by the end of exposure experiment, while the heart-rate fluctuation within 15 min decreased to 0.7-fold.