Universal logic with encoded spin qubits in silicon.

Quantum computation features known examples of hardware acceleration for certain problems, but is challenging to realize because of its susceptibility to small errors from noise or imperfect control. The principles of fault tolerance may enable computational acceleration with imperfect hardware, but they place strict requirements on the character and correlation of errors1. For many qubit technologies2-21, some challenges to achieving fault tolerance can be traced to correlated errors arising from the need to control qubits by injecting microwave energy matching qubit resonances. Here we demonstrate an alternative approach to quantum computation that uses energy-degenerate encoded qubit states controlled by nearest-neighbour contact interactions that partially swap the spin states of electrons with those of their neighbours. Calibrated sequences of such partial swaps, implemented using only voltage pulses, allow universal quantum control while bypassing microwave-associated correlated error sources1,22-28. We use an array of six 28Si/SiGe quantum dots, built using a platform that is capable of extending in two dimensions following processes used in conventional microelectronics29. We quantify the operational fidelity of universal control of two encoded qubits using interleaved randomized benchmarking30, finding a fidelity of 96.3% ± 0.7% for encoded controlled NOT operations and 99.3% ± 0.5% for encoded SWAP. The quantum coherence offered by enriched silicon5-9,16,18,20,22,27,29,31-37, the all-electrical and low-crosstalk-control of partial swap operations1,22-28 and the configurable insensitivity of our encoding to certain error sources28,33,34,38 all combine to offer a strong pathway towards scalable fault tolerance and computational advantage.

Thyroid homeostasis in B6C3F1 mice upon sub-chronic exposure to trifluoroiodomethane (CF3I).

Trifluoroiodomethane (CF3I) is a fire suppressant gas with potential for use in low global-warming refrigerant blends. Data from studies in rats suggest that the most sensitive health effect of CF3I is thyroid hormone perturbation, but the rat is a particularly sensitive species for disruption of thyroid homeostasis. Mice appear to be less sensitive than rats but still a conservative model with respect to humans. The purpose of this study was to test tolerance and thyroid response to CF3I in B6C3F1 male mice. Male mice were exposed to CF3I for 6 h per day, for 28 days, via whole body exposure at concentrations of 2500, 5000 and 10,000 ppm. A 16-day recovery period was included to evaluate reversibility. No adverse clinical signs were observed throughout the study, and body weights were unaffected by exposure. CF3I exposure had no effect on thyroid histology. An increase in relative thyroid weight was observed at 10,000 ppm on day 28 but not in a separate group of animals evaluated on day 29, and thyroid weight was not different from controls at 44 days. Slight and sporadic changes in serum triiodothyronine, thyroxine, and thyroid-stimulating hormone were observed but did not follow a consistent pattern with respect to timing, dose, or direction. Overall, exposure at up to 10,000 ppm (1.0%) of CF3I gas for 28 days produced no overt general toxicity and only transient, recoverable effects on thyroid weight and hormones at certain concentrations. On the basis of the effect of CF3I exposure on the thyroid, including evaluation of thyroid histopathology, the no observed adverse effect level for this study is 10,000 ppm. Considering the apparently greater toxicity reported in prior studies in male rats, our data suggest a species difference between rats and mice in terms of susceptibility to CF3I-induced thyroid hormone perturbation.

Quantifying error and leakage in an encoded Si/SiGe triple-dot qubit.

Quantum computation requires qubits that satisfy often-conflicting criteria, which include long-lasting coherence and scalable control1. One approach to creating a suitable qubit is to operate in an encoded subspace of several physical qubits. Although such encoded qubits may be particularly susceptible to leakage out of their computational subspace, they can be insensitive to certain noise processes2,3 and can also allow logical control with a single type of entangling interaction4 while maintaining favourable features of the underlying physical system. Here we demonstrate high-fidelity operation of an exchange-only qubit encoded in a subsystem of three coupled electron spins5 confined in gated, isotopically enhanced silicon quantum dots6. This encoding requires neither high-frequency electric nor magnetic fields for control, and instead relies exclusively on the exchange interaction4,5, which is highly local and can be modulated with a large on-off ratio using only fast voltage pulses. It is also compatible with very low and gradient-free magnetic field environments, which simplifies integration with superconducting materials. We developed and employed a modified blind randomized benchmarking protocol that determines both computational and leakage errors7,8, and found that unitary operations have an average total error of 0.35%, with half of that, 0.17%, coming from leakage driven by interactions with substrate nuclear spins. The combination of this proven performance with complete control via gate voltages makes the exchange-only qubit especially attractive for use in many-qubit systems.

Immunization with a Recombinant, Pseudomonas fluorescens-Expressed, Mutant Form of Bacillus anthracis-Derived Protective Antigen Protects Rabbits from Anthrax Infection.

Protective antigen (PA), one of the components of the anthrax toxin, is the major component of human anthrax vaccine (Biothrax). Human anthrax vaccines approved in the United States and Europe consist of an alum-adsorbed or precipitated (respectively) supernatant material derived from cultures of toxigenic, non-encapsulated strains of Bacillus anthracis. Approved vaccination schedules in humans with either of these vaccines requires several booster shots and occasionally causes adverse injection site reactions. Mutant derivatives of the protective antigen that will not form the anthrax toxins have been described. We have cloned and expressed both mutant (PA SNKE167-ΔFF-315-E308D) and native PA molecules recombinantly and purified them. In this study, both the mutant and native PA molecules, formulated with alum (Alhydrogel), elicited high titers of anthrax toxin neutralizing anti-PA antibodies in New Zealand White rabbits. Both mutant and native PA vaccine preparations protected rabbits from lethal, aerosolized, B. anthracis spore challenge subsequent to two immunizations at doses of less than 1 µg.

Biologic comparison of inhaled insulin formulations: Exubera™ and novel spray-dried engineered particles of dextran-10.

Inhaled peptides and proteins have promise for respiratory and systemic disease treatment. Engineered spray-dried powder formulations have been shown to stabilize peptides and proteins and optimize aerosol properties for pulmonary delivery. The current study was undertaken to investigate the in vitro and in vivo inhalation performance of a model spray-dried powder of insulin and dextran 10 in comparison to Exubera™. Dextrans are a class of glucans that are generally recognized as safe with optimum glass transition temperatures well suited for spray drying. A 70% insulin particle loading was prepared by formulating with 30% (w/v) dextran 10. Physical characterization revealed a "raisin like" particle. Both formulations were generated to produce a similar bimodal particle size distribution of less than 3.5 µm MMAD. Four female Beagle dogs were exposed to each powder in a crossover design. Similar presented and inhaled doses were achieved with each powder. Euglycemia was achieved in each dog prior and subsequent to dosing and blood samples were drawn out to 245 min post-exposure. Pharmacokinetic analyses of post-dose insulin levels were similar for both powders. Respective dextran 10-insulin and Exubera exposures were similar producing near identical area under the curve (AUC), 7,728 ± 1,516 and 6,237 ± 2,621; concentration maximums (C max), 126 and 121 (µU/mL), and concentration-time maximums, 20 and 14 min, respectively. These results suggest that dextran-10 and other dextrans may provide a novel path for formulating peptides and proteins for pulmonary delivery.

Local and systemic tolerability of a 2'O-methoxyethyl antisense oligonucleotide targeting interleukin-4 receptor-α delivery by inhalation in mouse and monkey.

Antisense oligonucleotides (ASOs) bind and facilitate degradation of RNA and inhibit protein expression in pathways not easily targeted with small molecules or antibodies. Interleukin (IL)-4 and IL-13 potentiate signaling through the shared IL-4 receptor-α (IL-4Rα) subunit of their receptors. ASO targeting of IL-4Rα mRNA in a mouse model of asthma led to attenuation of airway hyperactivity, demonstrating potential benefit in asthma patients. This study focused on tolerability of inhaled IL-4Rα-targeting ASOs. Toxicity studies were performed with mouse- (ISIS 23189) and human-specific (ISIS 369645) sequences administered by inhalation. Four week (monkey) or 13 week (mouse) repeat doses at levels of up to 15 mg/kg/exposure (exp) and 50 mg/kg/exp, respectively, demonstrated dose-dependent effects limited to increases in macrophage size and number in lung and tracheobronchial lymph nodes. The changes were largely non-specific, reflecting adaptive responses that occur during active exposure and deposition of ASO and other material in the lung. Reversibility was observed at a rate consistent with the kinetics of tissue clearance of ASO. Systemic bioavailability was minimal, and no systemic toxicity was observed at exposure levels appreciably above pharmacological doses and doses proposed for clinical trials.

SGI-110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome.

The DNA methyltransferase (DNMT) inhibitor vidaza (5-Azacytidine) in combination with the histone deacetylase inhibitor entinostat has shown promise in treating lung cancer and this has been replicated in our orthotopic lung cancer model. However, the effectiveness of DNMT inhibitors against solid tumors is likely impacted by their limited stability and rapid inactivation by cytidine deaminase (CDA) in the liver. These studies were initiated to test the efficacy of SGI-110, a dinucleotide containing decitabine that is resistant to deamination by CDA, as a single agent and in combination with entinostat. Evaluation of in vivo plasma concentrations and pharmacokinetic properties of SGI-110 showed rapid conversion to decitabine and a plasma half-life of 4 hr. SGI-110 alone or in combination with entinostat reduced tumor burden of a K-ras/p53 mutant lung adenocarcinoma cell line (Calu6) engrafted orthotopically in nude rats by 35% and 56%, respectively. SGI-110 caused widespread demethylation of more than 300 gene promoters and microarray analysis revealed expression changes for 212 and 592 genes with SGI-110 alone or in combination with entinostat. Epigenetic therapy also induced demethylation and expression of cancer testis antigen genes that could sensitize tumor cells to subsequent immunotherapy. In the orthotopically growing tumors, highly significant gene expression changes were seen in key cancer regulatory pathways including induction of p21 and the apoptotic gene BIK. Moreover, SGI-110 in combination with entinostat caused widespread epigenetic reprogramming of EZH2-target genes. These preclinical in vivo findings demonstrate the clinical potential of SGI-110 for reducing lung tumor burden through reprogramming the epigenome.

Challenges for inhaled drug discovery and development: Induced alveolar macrophage responses.

Alveolar macrophage (AM) responses are commonly induced in inhalation toxicology studies, typically being observed as an increase in number or a vacuolated 'foamy' morphology. Discriminating between adaptive AM responses and adverse events during nonclinical and clinical development is a major scientific challenge. When measuring and interpreting induced AM responses, an understanding of macrophage biology is essential; this includes 'sub-types' of AMs with different roles in health and disease and mechanisms of induction/resolution of AM responses to inhalation of pharmaceutical aerosols. In this context, emerging assay techniques, the utility of toxicokinetics and the requirement for new biomarkers are considered. Risk assessment for nonclinical toxicology findings and their translation to effects in humans is discussed from a scientific and regulatory perspective. At present, when apparently adaptive macrophage-only responses to inhaled investigational products are observed in nonclinical studies, this poses a challenge for risk assessment and an improved understanding of induced AM responses to inhaled pharmaceuticals is required.

STP position paper: interpreting the significance of increased alveolar macrophages in rodents following inhalation of pharmaceutical materials.

The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology (STP) appointed a working group to address risk assessment for increases in alveolar macrophages following inhalation of pharmaceutical materials. This position paper provides recommendations for inhalation study-specific terminology and interpretation based on literature and information from marketed inhaled drugs. Based on a weight-of-the-evidence approach, and with appropriate consideration of the physical and pharmacological characteristics of the compound, uncomplicated increases in the size or number of alveolar macrophages in nonclinical species are interpreted as nonadverse.

Comparison of inhalation toxicity studies of gentamicin in rats and dogs.

Nebulized gentamicin solution was administered to rats (nose-only) and dogs (face mask) for 14 days with a 14-day recovery period. Control groups of each were exposed to saline aerosols. Mean estimated inhaled lung doses of gentamicin were 39, 123 and 245 mg/kg for rats (deposited doses 6, 17 and 34 mg/kg) over 30, 90 and 180 min, respectively. Since dogs do not tolerate exposures as long as rats, inhaled lung doses were limited to 7, 14 and 41 mg/kg (deposited doses of 1, 3 and 8 mg/kg) over 15, 30 and 60 min. Comparable doses were achieved at the low dose for rats and high dose for dogs. Serum AUCs (14 ± 2 µg/mL h (mean ± SD) at 6 mg/kg in rats and 11 ± 7 µg/mL h at 8 mg/kg in dogs) showed comparable exposure between the two, implying similar absorbed doses and confirming similar deposited lung doses. Rat exposures resulted in dose-related lung pathology (including low dose) manifested as upper respiratory tract irritant reactions with alveolar histiocytosis, inflammation, airway epithelial metaplasia and lymphomegaly in lung tissue. This was associated with high lung tissue gentamicin levels 24 h post-dose on Day 14 (375 ± 33 µg/g at deposited dose of 6 mg/kg). Dose-related kidney tubular necrosis (a well-known toxicity of parenteral gentamicin) was observed, but no test-article related effects on lung histopathology in dogs (even at highest deposited dose of 8 mg/kg) and low levels of lung tissue gentamicin (42 ± 11 µg/g) 24 h post-dose on Day 14.

Safety assessment of nebulized xylitol in beagle dogs.

Xylitol, a potential cystic fibrosis treatment, lowers the salt concentration of airway surface liquid and enhances innate immunity of human airways. The study objective was to evaluate the potential toxicity/recovery from a 14-consecutive day (7 days/week), facemask inhalation administration of nebulized xylitol solution in Beagle dogs. Aerosolized xylitol was generated through three Aerotech II nebulizers operating at approximately 40 psi driving pressure. Test article groups were exposed to the same concentration of aerosolized xylitol for 1, 0.5, or 0.25 h for the high, mid, and low exposures, respectively. A control group was exposed for 1 h to a nebulized normal saline solution. Animals were sacrificed the day following the last exposure or subsequently after 14 non-exposure days. Study endpoints included clinical observations, body weights, ophthalmology, and physical examinations, food consumption, clinical pathology, urinalyses, organ weights, and histopathology. Mean xylitol aerosol concentrations for all groups were approximately 3.5 mg/l. Mean total deposited doses to the pulmonary region were estimated as 21, 11, and 5 mg/kg, for the high-, mid-, and low-exposure groups, respectively. All dogs survived to the scheduled necropsy. No treatment-related findings were observed due to xylitol exposure in any end point examined. Lung findings (mild interstitial infiltration, macrophage hyperplasia, alveolitis, and bronchitis) were consistent among exposed and control groups. No exposure-related effect of xylitol in any parameter assessed was seen during or after the 14-day exposure in Beagle dogs. The No Observed Effect Level was the high-exposure level and suggests that inhaled xylitol is safe for clinical administration.

Effects of simulated downwind coal combustion emissions on pre-existing allergic airway responses in mice.

CONTEXT: Coal-fired power plant emissions can contribute a significant portion of the ambient air pollution in many parts of the world. OBJECTIVE: We hypothesized that exposure to simulated downwind coal combustion emissions (SDCCE) may exacerbate pre-existing allergic airway responses. METHODS: Mice were sensitized and challenged with ovalbumin (OVA). Parallel groups were sham-sensitized with saline. Mice were exposed 6 h/day for 3 days to air (control, C) or SDCCE containing particulate matter (PM) at low (L; 100 µg/m³), medium (M; 300 µg/m³), or high (H; 1000 µg/m³) concentrations, or to the H level with PM removed by filtration (high-filtered, HF). Immediately after SDCCE exposure, mice received another OVA challenge (pre-OVA protocol). In a second (post-OVA) protocol, mice were similarly sensitized but only challenged to OVA before air/SDCCE. Measurement of airway hyperresponsiveness (AHR), bronchoalveolar lavage (BAL), and blood collection were performed ~24 h after the last exposure. RESULTS: SDCCE significantly increased BAL macrophages and eosinophils in OVA-sensitized mice from the post-OVA protocol. However, there was no effect of SDCCE on BAL macrophages or eosinophils in OVA-sensitized mice from the pre-OVA protocol. BAL neutrophils were elevated following SDCCE in both protocols in nonsensitized mice. These changes were not altered by filtering out the PM. In the post-OVA protocol, SDCCE decreased OVA-specific IgG1 in OVA-sensitized mice but increased levels of total IgE, OVA-specific IgE and OVA-specific IgG1 and IgG(2a) in non-sensitized animals. In the pre-OVA protocol, SDCCE increased OVA-specific IgE in both sensitized and non-sensitized animals. Additionally, BAL IL-4, IL-13, and IFN-γ levels were elevated in sensitized mice. CONCLUSION: These results suggest that acute exposure to either the particulate or gaseous phase of SDCCE can exacerbate various features of allergic airway responses depending on the timing of exposure in relation to allergen challenge.

Health effects of subchronic inhalation exposure to simulated downwind coal combustion emissions.

CONTEXT: There have been no animal studies of the health effects of repeated inhalation of mixtures representing downwind pollution from coal combustion. Environmental exposures typically follow atmospheric processing and mixing with pollutants from other sources. OBJECTIVE: This was the fourth study by the National Environmental Respiratory Center to create a database for responses of animal models to combustion-derived pollutant mixtures, to identify causal pollutants-regardless of source. METHODS: F344 and SHR rats and A/J, C57BL/6, and BALB/c mice were exposed 6 h/day 7 days/week for 1 week to 6 months to three concentrations of a mixture simulating key components of "downwind" coal combustion emissions, to the highest concentration filtered to remove particulate matter (PM), or to clean air. Emissions from low-sulfur subbituminous coal were modified to create a mixture recommended by an expert workshop. Sulfur dioxide, nitrogen oxides, and PM were the dominant components. Nonanimal-derived PM mass concentrations of nominally 0, 100, 300, and 1000 µg/m(3) were mostly partially neutralized sulfate. RESULTS: Only 17 of 270 species-gender-time-outcome comparisons were significantly affected by exposure; some models showed no effects. There was strong evidence that PM participated meaningfully in only three responses. CONCLUSION: On a total mass or PM mass basis, this mixture was less toxic overall than diesel and gasoline exhausts or wood smoke. The largely sulfate PM contributed to few effects and was the sole cause of none. The study did not allow identification of causal pollutants, but the potential role of NOx in some effects is suggested by the literature.

Hypercholesterolemia potentiates aortic endothelial response to inhaled diesel exhaust.

BACKGROUND: Inhalation of diesel exhaust induces vascular effects including impaired endothelial function and increased atherosclerosis. OBJECTIVE: To examine the in vivo effects of subchronic diesel exhaust exposure on endothelial cell transcriptional responses in the presence of hypercholesterolemia. METHODS: ApoE (-/-) and ApoE (+/+) mice inhaled diesel exhaust diluted to particulate matter levels of 300 or 1000 µg/m³ vs. filtered air. After 30 days, endothelial cells were harvested from dispersed aortic cells by fluorescent-activated cell sorting (FACS). Relative mRNA abundance was evaluated by microarray analysis to measure strain-specific transcriptional responses in mice exposed to dilute diesel exhaust vs. filtered air. RESULTS: Forty-nine transcripts were significantly dysregulated by >2.8-fold in the endothelium of ApoE (-/-) mice receiving diesel exhaust at 300 or 1000 µg/m³. These included transcripts with roles in plasminogen activation, endothelial permeability, inflammation, genomic stability, and atherosclerosis; similar responses were not observed in ApoE (+/+) mice. CONCLUSIONS: The potentiation of diesel exhaust-related endothelial gene regulation by hypercholesterolemia helps to explain air pollution-induced vascular effects in animals and humans. The observed regulated transcripts implicate pathways important in the acceleration of atherosclerosis by air pollution.

Inhaled diesel emissions alter atherosclerotic plaque composition in ApoE(-/-) mice.

Recent epidemiological studies suggest that traffic-related air pollution may have detrimental effects on cardiovascular health. Previous studies reveal that gasoline emissions can induce several enzyme pathways involved in the formation and development of atherosclerotic plaques. As a direct comparison, the present study examined the impact of diesel engine emissions on these pathways, and further examined the effects on vascular lesion pathology. Apolipoprotein E-null mice were simultaneously placed on a high-fat chow diet and exposed to four concentrations, plus a high concentration exposure with particulates (PM) removed by filtration, of diesel emissions for 6 h/day for 50 days. Aortas were subsequently assayed for alterations in matrix metalloproteinase-9, endothelin-1, and several other biomarkers. Diesel induced dose-related alterations in gene markers of vascular remodeling and aortic lipid peroxidation; filtration of PM did not significantly alter these vascular responses, indicating that the gaseous portion of the exhaust was a principal driver. Immunohistochemical analysis of aortic leaflet sections revealed no net increase in lesion area, but a significant decrease in lipid-rich regions and increasing trends in macrophage accumulation and collagen content, suggesting that plaques were advanced to a more fragile, potentially more vulnerable state by diesel exhaust exposure. Combined with previous studies, these results indicate that whole emissions from mobile sources may have a significant role in promoting chronic vascular disease.

Effects of gasoline engine emissions on preexisting allergic airway responses in mice.

Gasoline-powered vehicle emissions contribute significantly to ambient air pollution. We hypothesized that exposure to gasoline engine emissions (GEE) may exacerbate preexisting allergic airway responses. Male BALB/c mice were sensitized by injection with ovalbumin (OVA) and then received a 10-min aerosolized OVA challenge. Parallel groups were sham-sensitized with saline. Mice were exposed 6 h/day to air (control, C) or GEE containing particulate matter (PM) at low (L), medium (M), or high (H) concentrations, or to the H level with PM removed by filtration (high-filtered, HF). Immediately after GEE exposure mice received another 10-min aerosol OVA challenge (pre-OVA protocol). In a second (post-OVA) protocol, mice were similarly sensitized but only challenged to OVA before air or GEE exposure. Measurements of airway hyperresponsiveness (AHR), bronchoalveolar lavage (BAL), and blood collection were performed approximately 24 h after the last exposure. In both protocols, M, H, and HF GEE exposure significantly decreased BAL neutrophils from nonsensitized mice but had no significant effect on BAL cells from OVA-sensitized mice. In the pre-OVA protocol, GEE exposure increased OVA-specific IgG(1) but had no effect on BAL interleukin (IL)-2, IL-4, IL-13, or interferon (IFN)-gamma in OVA-sensitized mice. Nonsensitized GEE-exposed mice had increased OVA-specific IgG(2a), IgE, and IL-2, but decreased total IgE. In the post-OVA protocol, GEE exposure reduced BAL IL-4, IL-5, and IFN-gamma in nonsensitized mice but had no effect on sensitized mice. These results suggest acute exposure to the gas-vapor phase of GEE suppressed inflammatory cells and cytokines from nonsensitized mice but did not substantially exacerbate allergic responses.

Health effects of inhaled gasoline engine emissions.

Despite their prevalence in the environment, and the myriad studies that have shown associations between morbidity or mortality with proximity to roadways (proxy for motor vehicle exposures), relatively little is known about the toxicity of gasoline engine emissions (GEE). We review the studies conducted on GEE to date, and summarize the findings from each of these studies. While there have been several studies, most of the studies were conducted prior to 1980 and thus were not conducted with contemporary engines, fuels, and driving cycles. In addition, many of the biological assays conducted during those studies did not include many of the assays that are conducted on contemporary inhalation exposures to air pollutants, including cardiovascular responses and others. None of the exposures from these earlier studies were characterized at the level of detail that would be considered adequate today. A recent GEE study was conducted as part of the National Environmental Respiratory Center (www.nercenter.org). In this study several in-use mid-mileage General Motors (Chevrolet S-10) vehicles were purchased and utilized for inhalation exposures. An exposure protocol was developed where engines were operated with a repeating California Unified Driving Cycle with one cold start per day. Two separate engines were used to provide two cold starts over a 6-h inhalation period. The exposure atmospheres were characterized in detail, including detailed chemical and physical analysis of the gas, vapor, and particle phase. Multiple rodent biological models were studied, including general toxicity and inflammation (e.g., serum chemistry, lung lavage cell counts/differentials, cytokine/chemokine analysis, histopathology), asthma (adult and in utero exposures with pulmonary function and biochemical analysis), cardiovascular effects (biochemical and electrocardiograph changes in susceptible rodent models), and susceptibility to infection (Pseudomonas bacteria challenge). GEE resulted in significant biological effects for upregulation of MIP-2, clearance of Pseudomonas bacteria, development of allergic response after in utero exposure, and cardiovascular indicators of vasoconstriction, oxidant stress, and damage.

Effects of hardwood smoke exposure on allergic airway inflammation in mice.

Hardwood smoke (HWS) from wood burning stoves and fireplaces can be a significant contributor to the composition of ambient air pollution. We hypothesize that the inhalation of HWS by ovalbumin (OVA)-sensitized mice with preexisting lung inflammation leads to the exacerbation of allergic airway responses. Two different models were employed to characterize the effects of inhaled wood smoke on allergic airway inflammation. In both models, male BALB/c mice were sensitized by injection with OVA and alum. In one model, mice were challenged by inhalation with OVA 1 day prior to exposure to HWS (30, 100, 300, or 1000 microg particulate matter [PM]/m(3)) for 6 h/day on 3 consecutive days. In the other model, mice were exposed by inhalation to OVA, rested for 11 days, were exposed to HWS for 3 consecutive days, and then were exposed to OVA immediately after the final HWS exposure. Bronchoalveolar lavage (BAL), and blood collection were performed approximately 18 h after the last HWS or OVA exposure. HWS exposure after the final allergen challenge (first model) led to a significant increase in BAL eosinophils only at the 300 microg/m(3) level. In contrast, changes in BAL cells did not reach statistical significance in the second model. There were no HWS-induced changes in BAL interleukin (IL)-2, IL-4, IL-13, and interferon (IFN)gamma levels in either model following OVA challenge. These results suggest that acute HWS exposure can minimally exacerbate some indices of allergic airway inflammation when a final OVA challenge precedes HWS exposure, but does not alter Th1/Th2 cytokine levels.

Fresh gasoline emissions, not paved road dust, alter cardiac repolarization in ApoE-/- mice.

Fresh vehicular emissions potentially represent a ubiquitous environmental concern for cardiovascular health. We compared electrocardiographic effects of fresh gasoline engine emissions with resuspended paved road dust in a mouse model of coronary insufficiency. Apolipoprotein E (ApoE)-/- mice on a high fat diet were exposed by whole-body inhalation to either gasoline emissions at 60 microg/m3 particulate matter (PM), an equivalent atmosphere with particles filtered out of the whole exhaust, or paved road dust at 0.5 and 3.5 mg /m3 for 6 h/d for 3 d. Radiotelemetry recordings of electrocardiogram (ECG) were analyzed for changes in T-wave morphology (QT interval, T-wave amplitude, and T-wave Area). Following exposures, lung lavage and blood samples were obtained to assay for markers of pulmonary and systemic inflammation. No exposure induced significant changes in heart rate and only the high concentration of road dust induced signs of pulmonary inflammation. T-wave area exhibited significant deviation from baseline values during exposure to gasoline exhaust particulates, but not to either concentration of road dust or gasoline emissions sans particulates. Gasoline-exposed mice demonstrated elevated plasma endothelin-1, but did not cause systemic inflammation. These data support the hypothesis that freshly-generated engine emissions, as opposed to resuspended paved road dust, may drive cardiac effects that have been observed at road-sides in the environment. The absence of ECG effects for both very high concentrations of road dust PM and equivalent concentrations of the vapor/gas phase of gasoline engine exhaust further indicate the specific risk conferred by fresh vehicular PM.

Low-level subchronic exposure to wood smoke exacerbates inflammatory responses in allergic rats.

Epidemiological studies have implicated wood smoke as a risk factor for exacerbating asthma. However, comparisons of findings in animal models with those in humans are currently not possible, because detailed clinically relevant measurements of pulmonary function are not available in animal studies. Brown Norway rats were immunized with ovalbumin and exposed to either filtered air or wood smoke at 1 mg particulate matter/m(3) for 70 days and challenged with allergen during the last 4 days of exposure. Baseline values for dynamic lung compliance were lower while functional residual capacity was increased in rats exposed to wood smoke compared to rats exposed to filtered air. IFN-gamma levels were reduced and IL-4 levels increased in the bronchoalveolar lavage fluid and blood plasma, inflammatory lesions in the lungs were 21% greater, and airway mucous cells/mm basal lamina were non-significantly increased in rats exposed to wood smoke compared to controls. Collectively, these studies suggest that the pulmonary function was affected in rats by exposure to wood smoke and this decline was associated with only minor increases in inflammation of the lung. Therefore, this animal model may be useful to elucidate the mechanisms of the decline in pulmonary function caused by environmental pollutants when asthmatics are exposed to allergen.