We assess the potential of the water-soluble fraction of atmospheric fine aerosols in the southeastern United States to generate reactive oxygen species (ROS) and identify major ROS-associated ...emission sources. ROS-generation potential of particles was quantified by the dithiothreitol (DTT) assay and involved analysis of fine particulate matter (PM) extracted from high-volume quartz filters (23 h integrated samples) collected at various sites in different environmental settings in the southeast, including three urban-Atlanta sites, in addition to a rural site. Paired sampling was conducted with one fixed site in Atlanta (Jefferson Street), representative of the urban environment, with the others rotating among different sites, for ~250 days between June 2012 and September 2013 (N=483). A simple linear regression between the DTT activity and aerosol chemical components revealed strong associations between PM ROS-generation potential and secondary organic aerosol (WSOC – water-soluble organic carbon) in summer, and biomass burning markers in winter. Redox-active metals were also somewhat correlated with the DTT activity, but mostly at urban and roadside sites. Positive matrix factorization (PMF) was applied to apportion the relative contribution of various sources to the ROS-generation potential of water-soluble PM2.5 in urban Atlanta. PMF showed that vehicular emissions contribute uniformly throughout the year (12–25%), while secondary oxidation processes dominated the DTT activity in summer (46%) and biomass burning in winter (47%). Road dust was significant only during drier periods (~12% in summer and fall). Source apportionment by chemical mass balance (CMB) was reasonably consistent with PMF, but with higher contribution from vehicular emissions (32%). Given the spatially large data set of PM sampled over an extended period, the study reconciles the results from previous work that showed only region- or season-specific aerosol components or sources contributing to PM ROS activity, possibly due to smaller sample sizes. The ubiquitous nature of the major sources of PM-associated ROS suggests widespread population exposures to aerosol components that have the ability to catalyze the production of oxidants in vivo.
Interindividual variability of platelet inhibition after aspirin or clopidogrel administration has been described. Additionally, aspirin resistance and clopidogrel resistance occur in some ...individuals. Because the prodrug clopidogrel is activated by hepatic cytochrome P450 (CYP) 3A4, we hypothesized that interindividual variability in clopidogrel efficacy might be related to interindividual differences in CYP3A4 metabolic activity.
Platelet aggregation was measured before and after clopidogrel treatment in 32 patients undergoing coronary artery stent implantation and in 35 healthy volunteers. The erythromycin breath test was used to measure CYP3A4 activity in vivo in 25 of the healthy volunteers. Individual platelet aggregation was studied in 10 healthy volunteers after the coadministration of clopidogrel and rifampin (a CYP3A4 inducer). Clopidogrel nonresponders, low responders, and responders were defined by a relative inhibition of adenosine diphosphate (20 micromol/L)-induced platelet aggregation of <10%, 10% to 29%, and > or =30%, respectively. Among patients, 22% were clopidogrel nonresponders, 32% were low responders, and 47% were responders. Among volunteers, 16% were nonresponders, 12% were low responders, and 72% were responders. Percent platelet aggregation after clopidogrel inversely correlated with CYP3A4 activity (r=-0.6, P=0.003). Improved platelet inhibition in volunteers resistant to clopidogrel was observed with the coadministration of clopidogrel and rifampin.
Clopidogrel administration results in interindividual variability in platelet inhibition, which correlates with CYP3A4 metabolic activity. Measurement of antiplatelet drug efficacy with a point-of-care device and alternative antithrombotic strategies for aspirin or clopidogrel nonresponders and low responders could reduce the incidence of thrombotic events that continue to occur despite oral antiplatelet therapy.
Ship and aircraft measurements of aerosol organic matter (OM) and water‐soluble organic carbon (WSOC) were made in fresh and aged pollution plumes from major urban areas in the northeastern United ...States in the framework of the 2004 International Consortium for Atmospheric Research on Transport and Transformation (ICARTT) study. A large part of the variability in the data was quantitatively described by a simple parameterization from a previous study that uses measured mixing ratios of CO and either the transport age or the photochemical age of the sampled air masses. The results suggest that OM was mostly due to secondary formation from anthropogenic volatile organic compound (VOC) precursors in urban plumes. Approximately 37% of the secondary formation can be accounted for by the removal of aromatic precursors using newly published particulate mass yields for low‐NOx conditions, which are significantly higher than previous results. Of the secondary formation, 63% remains unexplained and is possibly due to semivolatile precursors that are not measurable by standard gas chromatographic methods. The observed secondary OM in urban plumes may account for 35% of the total source of OM in the United States and 8.5% of the global OM source. OM is an important factor in climate and air quality issues, but its sources and formation mechanisms remain poorly quantified.
We observed that the prodrug clopidogrel was less effective in inhibiting platelet aggregation with coadministration of atorvastatin during point-of-care platelet function testing. Because ...atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we hypothesized that clopidogrel might be activated by CYP3A4.
Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation treated with clopidogrel or clopidogrel plus pravastatin or atorvastatin, and in 27 volunteers treated with clopidogrel and either erythromycin or troleandomycin, CYP3A4 inhibitors, or rifampin, a CYP3A4 inducer. Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner. Percent platelet aggregation was 34+/-23, 58+/-15 (P=0.027), 74+/-10 (P=0.002), and 89+/-7 (P=0.001) in the presence of clopidogrel and 0, 10, 20, and 40 mg of atorvastatin, respectively. Erythromycin attenuated platelet aggregation inhibition (55+/-12 versus 42+/-12% platelet aggregation; P=0.002), as did troleandomycin (78+/-18 versus 45+/-18% platelet aggregation; P<0.0003), whereas rifampin enhanced platelet aggregation inhibition (33+/-18 versus 56+/-20% platelet aggregation, P=0.001).
CYP3A4 activates clopidogrel. Atorvastatin, another CYP3A4 substrate, competitively inhibits this activation. Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel.
This study aims to investigate functional disparity in the locomotor apparatus of bipedal archosaurs. We use reconstructions of hindlimb myology of extant and extinct archosaurs to generate ...musculoskeletal biomechanical models to test hypothesized convergence between bipedal crocodile-line archosaurs and dinosaurs. Quantitative comparison of muscle leverage supports the inference that bipedal crocodile-line archosaurs and non-avian theropods had highly convergent hindlimb myology, suggesting similar muscular mechanics and neuromuscular control of locomotion. While these groups independently evolved similar musculoskeletal solutions to the challenges of parasagittally erect bipedalism, differences also clearly exist, particularly the distinct hip and crurotarsal ankle morphology characteristic of many pseudosuchian archosaurs. Furthermore, comparative analyses of muscle design in extant archosaurs reveal that muscular parameters such as size and architecture are more highly adapted or optimized for habitual locomotion than moment arms. The importance of these aspects of muscle design, which are not directly retrievable from fossils, warns against over-extrapolating the functional significance of anatomical convergences. Nevertheless, links identified between posture, muscle moments and neural control in archosaur locomotion suggest that functional interpretations of osteological changes in limb anatomy traditionally linked to postural evolution in Late Triassic archosaurs could be constrained through musculoskeletal modelling.
Objective To assess the accuracy of the Wells rule for excluding deep vein thrombosis and whether this accuracy applies to different subgroups of patients.Design Meta-analysis of individual patient ...data. Data sources Authors of 13 studies (n=10 002) provided their datasets, and these individual patient data were merged into one dataset.Eligibility criteria Studies were eligible if they enrolled consecutive outpatients with suspected deep vein thrombosis, scored all variables of the Wells rule, and performed an appropriate reference standard.Main outcome measures Multilevel logistic regression models, including an interaction term for each subgroup, were used to estimate differences in predicted probabilities of deep vein thrombosis by the Wells rule. In addition, D-dimer testing was added to assess differences in the ability to exclude deep vein thrombosis using an unlikely score on the Wells rule combined with a negative D-dimer test result.Results Overall, increasing scores on the Wells rule were associated with an increasing probability of having deep vein thrombosis. Estimated probabilities were almost twofold higher in patients with cancer, in patients with suspected recurrent events, and (to a lesser extent) in males. An unlikely score on the Wells rule (≤1) combined with a negative D-dimer test result was associated with an extremely low probability of deep vein thrombosis (1.2%, 95% confidence interval 0.7% to 1.8%). This combination occurred in 29% (95% confidence interval 20% to 40%) of patients. These findings were consistent in subgroups defined by type of D-dimer assay (quantitative or qualitative), sex, and care setting (primary or hospital care). For patients with cancer, the combination of an unlikely score on the Wells rule and a negative D-dimer test result occurred in only 9% of patients and was associated with a 2.2% probability of deep vein thrombosis being present. In patients with suspected recurrent events, only the modified Wells rule (adding one point for the previous event) is safe.Conclusion Combined with a negative D-dimer test result (both quantitative and qualitative), deep vein thrombosis can be excluded in patients with an unlikely score on the Wells rule. This finding is true for both sexes, as well as for patients presenting in primary and hospital care. In patients with cancer, the combination is neither safe nor efficient. For patients with suspected recurrent disease, one extra point should be added to the rule to enable a safe exclusion.
Schizophrenia is a severe psychiatric disorder with a world-wide prevalence of 1%. The pathophysiology of the illness is not understood, but is thought to have a strong genetic component with some ...environmental influences on aetiology. To gain further insight into disease mechanism, we used microarray technology to determine the expression of over 30 000 mRNA transcripts in post-mortem tissue from a brain region associated with the pathophysiology of the disease (Brodmann area 10: anterior prefrontal cortex) in 28 schizophrenic and 23 control patients. We then compared our study (Charing Cross Hospital prospective collection) with that of an independent prefrontal cortex dataset from the Harvard Brain Bank. We report the first direct comparison between two independent studies. A total of 51 gene expression changes have been identified that are common between the schizophrenia cohorts, and 49 show the same direction of disease-associated regulation. In particular, changes were observed in gene sets associated with synaptic vesicle recycling, transmitter release and cytoskeletal dynamics. This strongly suggests multiple, small but synergistic changes in gene expression that affect nerve terminal function.
To determine if histo-blood group antigens (HBGA) present in oyster gastrointestinal (GI) cells mediate accumulation of human noroviruses (NoV) in oyster GI cells. HBGA-specific monoclonal antibodies ...(MAbs) were used to determine the presence of the corresponding HBGA in oyster GI cells. All oyster samples tested contained type A-like HBGA in GI tissue as measured by ELISA. Recombinant Norwalk virus viral like particles (rNVLP) were bound to plates coated with oyster GI homogenate. The binding was inhibited when rNVLPs were pre-incubated with MAbs specific for type A HBGA, or samples of human saliva from type A individuals. Co-localization of rNVLP and type A-like HBGA, but not type B-like or type H-like HBGA, on GI epithelial cells was observed by immunofluorescent histochemical staining and three-channel confocal scanning laser microscopy. Type A-like HBGA is present in oyster GI cells and responsible for binding of rNVLP. This is the first report of the presence of type A-like HBGA in oyster GI cells and the specific binding of rNVLP to type A-like HBGA on oyster GI cells. The results of this study suggest that human NoV concentrate in oyster GI cells by specific binding to concentrated type A-like HBGA rather than by a nonmolecular entrapment within the tissues.
Measurements were made on board the NOAA RV Ronald H. Brown during the second New England Air Quality Study (NEAQS 2004) to determine the source of the aerosol in the region and how sources and aging ...processes affect submicrometer aerosol chemical composition and optical properties. Using the Lagrangian particle dispersion model FLEXPART in combination with gas phase tracer compounds, local (urban), regional (NE U.S. urban corridor of Washington, D.C.; New York; and Boston), and distant (midwest industries and North American forest fires) sources were identified. Submicrometer aerosol measured near the source region (Boston Harbor) had a molar equivalence ratio near one with respect to NH4+, NO3−, and SO4=, had a large mass fraction of particulate organic matter (POM) relative to SO4=, and had relatively unoxidized POM. As distance from the source region increased, the submicrometer aerosol measured in the marine boundary layer became more acidic and had a lower POM mass fraction, and the POM became more oxidized. The relative humidity dependence of light extinction reflected the change in aerosol composition being lower for the near‐source aerosol and higher for the more processed aerosol. A factor analysis performed on a combined data set of aerosol and gas phase parameters showed that the POM measured during the experiment was predominantly of secondary anthropogenic origin.
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