Aspirin and antagonists of platelet ADP P2Y(12) receptors are often coprescribed for protection against thrombotic events. However, blockade of platelet P2Y(12) receptors can inhibit thromboxane A(2) ...(TXA(2))-dependent pathways of platelet activation independently of aspirin.
To assess in vitro whether aspirin adds additional antiaggregatory effects to strong P2Y(12) receptor blockade.
With the use of platelet-rich plasma from healthy volunteers, determinations were made in 96-well plates of platelet aggregation, TXA(2) production and ADP/ATP release caused by ADP, arachidonic acid, collagen, epinephrine, TRAP-6 amide and U46619 (six concentrations of each) in the presence of prasugrel active metabolite (PAM; 0.1-10 μmol L(-1)), aspirin (30 μmol L(-1)), PAM + aspirin or vehicle. results: PAM concentration-dependently inhibited aggregation; for example, aggregation in response to all concentrations of ADP and U46619 was inhibited by ≥ 95% by PAM at > 3 μmol L(-1) . In further tests of PAM (3 μmol L(-1)), aspirin (30 μmol L(-1)) and PAM + aspirin, aspirin generally failed to produce more inhibition than PAM or additional inhibition to that caused by PAM. The antiaggregatory effects of PAM were associated with reductions in the platelet release of both TXA(2) and ATP + ADP. Similar effects were found when either citrate or lepirudin were used as anticoagulants, and when traditional light transmission aggregometry was conducted at low stirring speeds.
P2Y(12) receptors are critical to the generation of irreversible aggregation through the TXA(2) -dependent pathway. As a result, strong P2Y(12) receptor blockade alone causes inhibition of platelet aggregation that is little enhanced by aspirin. The clinical relevance of these observations remains to be determined.
The emergence and spread of multidrug-resistant strains of Mycobacterium tuberculosis remains a major concern of tuberculosis control programmes worldwide, as treatment depends on low-efficacy, toxic ...compounds that often lead to poor outcomes. M. tuberculosis develops drug resistance exclusively through chromosomal mutations, in particular single-nucleotide polymorphisms. Moreover, in laboratory assays the organism exhibits a spontaneous mutation rate that is at the lower end of the bacterial spectrum. Despite this, whole-genome sequencing technology has identified unexpected genetic diversity among clinical M. tuberculosis populations. This suggests that the mycobacterial mutation rate may be modulated within the host and, in turn, implies a potential role for constitutive and/or transient mutator strains in adaptive evolution. It also raises the possibility that environmental factors might act as key mutagens during M. tuberculosis infection. Here we consider the elements that might influence the mycobacterial mutation rate in vivo and evaluate the potential roles of constitutive and transient mutator states in the generation of drug resistance mutations. In addition, we identify key research questions that will influence future efforts to develop novel therapeutic strategies for a disease that continues to impose a significant global health burden.
In situ transmission electron microscopy observations of uniaxial compression of sub-300nm diameter, cylindrical, single-crystalline 6H-SiC pillars oriented along and at 45 degree with respect to ...reveal that plastic slip occurs at room-temperature on the basal {0001} planes at stresses above 7.8GPa. Using a combination of aberration-corrected electron microscopy, molecular dynamics simulations and density functional theory calculations, we attribute the observed phenomenon to basal slip on the shuffle set along . By comparing the experimentally measured yield stresses with the calculated values required for dislocation nucleation, we suggest that room-temperature plastic deformation in 6H-SiC crystals is controlled by glide rather than nucleation of dislocations.
High doses of COX-2-selective drugs could increase the risk of thrombotic events, but in direct comparisons with traditional NSAIDs at standard doses few differences have been identified.4,5,10,13 ...For example, an analysis of data from the TARGET clinical trial showed that in patients with high risk for thrombotic events lumiracoxib, which has high COX-2-selectivity in vitro, produced no more cardiovascular mortality, non-fatal myocardial infarctions or strokes than did ibuprofen.14 Several mechanisms could underlie any increases in thrombotic risk caused by NSAIDs and COX-2-selective drugs. ... NSAIDs given to people at standard oral or intravenous doses inhibit platelet activity and increase bleeding time1-5,16-18 in accordance with their circulating half-lives, and this could contribute to NSAID-induced gastrointestinal bleeding.\n High doses of some of these drugs might also produce antiplatelet effects through inhibition of COX-1, although these vary widely in extent and duration.4,5,16,17,18 This provides a rational explanation of why, although producing similar maximum levels of inhibition of COX-1 and COX-2, the short-acting5 traditional NSAIDs ibuprofen and diclofenac could increase thrombotic risk at high dose while the longer-acting5 traditional NSAID naproxen does not.5,19 For COX-2-selective drugs, increasing doses increase cardiovascular risk as for the other NSAIDs.
Pulmonary aspiration of gastric contents during the perioperative period in infants and children may be associated with postoperative mortality or pulmonary morbidity. There has not been a recent ...determination of the frequency of this event and its outcomes in infants and children.
The authors prospectively identified all cases of pulmonary aspiration of gastric contents during the perioperative courses of 56,138 consecutive patients younger than 18 yr of age who underwent 63,180 general anesthetics for procedures performed in all surgical specialties from July 1985 through June 1997 at the Mayo Clinic.
Pulmonary aspiration occurred in 24 patients (1: 2,632 anesthetics; 0.04%). Children undergoing emergency procedures had a greater frequency of pulmonary aspiration compared to those undergoing elective procedures (1:373 vs. 1:4,544, P < 0.001). Fifteen of the 24 children who aspirated gastric contents did not develop respiratory symptoms within 2 h of aspiration, and none of these 15 developed pulmonary sequelae. Five of these nine children who aspirated and in whom respiratory symptoms developed within 2 h subsequently had pulmonary complications treated with respiratory support (P < 0.003). Three children were treated with mechanical ventilation for more than 48 h, but no child died of sequelae of pulmonary aspiration.
In this study population, the frequency of perioperative pulmonary aspiration in children was quite low. Serious respiratory morbidity was rare, and there were no associated deaths. Infants and children with clinically apparent pulmonary aspiration in whom symptoms did not develop within 2 h did not have respiratory sequelae.
Abstract
Extreme precipitation events impact the Pacific Northwest during winter months, causing flooding, landslides, extensive property damage, and loss of life. Outstanding questions about such ...events include whether there are a range of associated synoptic evolutions, whether such evolutions vary along the coast, and the associated rainfall duration and variability. To answer these questions, this study uses 60 years of National Climatic Data Center (NCDC) daily precipitation observations to identify the top 50 events in two-day precipitation at six coastal stations from northern California to northwest Washington. NCEP–NCAR reanalysis data were used to construct synoptic composite evolutions of these events for each coastal location. Most regional flooding events are associated with precipitation periods of 24 h or less, and two-day precipitation totals identify nearly all major events. Precipitation areas of major events are generally narrow, roughly 200 km in width, and most are associated with atmospheric rivers. Composite evolutions indicate negative anomalies in sea level pressure and upper-level height in the central Pacific, high pressure anomalies over the southwest United States, large positive 850-hPa temperature anomalies along the coast and offshore, and enhanced precipitable water and integrated water vapor fluxes over southwest to northeast swaths. A small subset of extreme precipitation events over the southern portion of the domain is associated with a very different synoptic evolution: a sharp trough in northwesterly flow and post-cold-frontal convection. High precipitable water values are more frequent during the summer, but are not associated with heavy precipitation due to upper-level ridging over the eastern Pacific and weak onshore flow that limit upward vertical velocities.
Our objective was to validate the possibility of detecting SARA from milk Fourier transform mid-infrared spectroscopy estimated fatty acids (FA) and machine learning. Subacute ruminal acidosis is a ...common condition in modern commercial dairy herds for which the diagnostic remains challenging due to its symptoms often being subtle, nonexclusive, and not immediately apparent. This observational study aimed at evaluating the possibility of predicting SARA by developing machine learning models to be applied to farm data and to provide an estimated portrait of SARA prevalence in commercial dairy herds. A first data set composed of 488 milk samples of 67 cows (initial DIM = 8.5 ± 6.18; mean ± SD) from 7 commercial dairy farms and their corresponding SARA classification (SARA+ if rumen pH <6.0 for 300 min, else SARA-) was used for the development of machine learning models. Three sets of predictive variables: i) milk major components (MMC), ii) milk FA (MFA), and iii) MMC combined with MFA (MMCFA) were submitted to 3 different algorithms, namely Elastic net (EN), Extreme gradient boosting (XGB), and Partial least squares (PLS), and evaluated using 3 different scenarios of cross-validation. Accuracy, sensitivity, and specificity of the resulting 27 models were analyzed using a linear mixed model. Model performance was not significantly affected by the choice of algorithm. Model performance was improved by including fatty acids estimations (MFA and MMCFA as opposed to MMC alone). Based on these results, one model was selected (algorithm: EN; predictive variables: MMCFA; 60.4, 65.4, and 55.3% of accuracy, sensitivity, and specificity, respectively) and applied to a large data set comprising the first test-day record (milk major components and FA within the first 70 DIM of 211,972 Holstein cows (219,503 samples) collected from 3001 commercial dairy herds. Based on this analysis, the within-herd SARA prevalence of commercial farms was estimated at 6.6 ± 5.29% ranging from 0 to 38.3%. A subsequent linear mixed model was built to investigate the herd-level factors associated to higher within-herd SARA prevalence. Milking system, proportion of primiparous cows, herd size and seasons were all herd-level factors affecting SARA prevalence. Furthermore, milk production was positively, and milk fat yield negatively associated with SARA prevalence. Due to their moderate levels of accuracy, the SARA prediction models developed in our study, using data from continuous pH measurements on commercial farms, are not suitable for diagnostic purpose. However, these models can provide valuable information at the herd level.
Research into the natural aging process of platelets has garnered much research interest in recent years, and there have long been associations drawn between the proportion of newly formed platelets ...in the circulation and the risk of thrombosis. However, these observations have largely been demonstrated in patient groups in which there may be underlying systemic changes that effect platelet function. Recent advances in technology have allowed in-depth analysis of differently aged platelets isolated from the peripheral blood of healthy individuals and have demonstrated that aged platelets, often referred to as senescent platelets, undergo extensive changes in the transcriptome and proteome. Ultimately, these changes result in platelets whose functions have deteriorated such that they cannot partake in hemostatic responses to the same extent as newly formed platelets. Here, we review transcriptomic and proteomic research in platelet aging in the context of health and how this research sheds light upon alterations in platelet structure and function.
Platelets normally last within the human circulation for approximately 10 days, however there are a number of diseases in which this life span is notably reduced. People who have platelets with such reduced lifespans have higher risks of heart attacks and strokes and reduced responsiveness to standard anti-platelet drugs. Research in recent years has aimed to understand the age-related changes that occur within platelets as they circulate in the bloodstream. In this review article, the authors provide a summary of the changes that occur during the natural aging process of platelets in healthy people, highlighting reductions in the levels of RNA and proteins. Despite these general reductions in their own RNA and proteins, research has shown that as platelets circulate they take up other RNA transcripts and proteins from the bloodstream, and this too seems a hallmark of platelet aging. The authors also discuss age-related declines in various aspects of platelet function which renders them less effective participants in the formation of blood clots.
Phenyl- and bioisosteric ferrocenyl-derived aminoquinoline-benzimidazole hybrid compounds were synthesised and evaluated for their in vitro antiplasmodial activity against the chloroquine-sensitive ...NF54 and multi-drug resistant K1 strains of the human malaria parasite, Plasmodium falciparum. All compounds were active against the two strains, generally showing enhanced activity in the K1 strain, with resistance indices less than 1. Cytotoxicity studies using Chinese hamster ovarian cells revealed that the hybrids were relatively non-cytotoxic and demonstrated selective killing of the parasite. Based on favourable in vitro antiplasmodial and cytotoxicity data, the most active phenyl (4c) and ferrocenyl (5b) hybrids were tested in vivo against the rodent Plasmodium berghei mouse model. Both compounds caused a reduction in parasitemia relative to the control, with 5c displaying superior activity (92% reduction in parasitemia at 4 × 50 mg/kg oral doses). The most active phenyl and ferrocenyl derivatives showed inhibition of β-haematin formation in a NP-40 detergent-mediated assay, indicating a possible contributing mechanism of antiplasmodial action. The most active ferrocenyl hybrid did not display appreciable reactive oxygen species (ROS) generation in a ROS-induced DNA cleavage gel electrophoresis study. The compounds were also screened for their in vitro activity against Mycobacterium tuberculosis. The hybrids containing a more hydrophobic substituent had enhanced activity (<32.7 μM) compared to those with a less hydrophobic substituent (>62.5 μM).
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•Phenyl- and ferrocenyl-derived aminoquinoline-benzimidazole hybrid compounds have been prepared.•These show good in vitro activity (0.2–0.9 μM) as antiplasmodial agents against Plasmodium falciparum and are selective.•Selected compounds showed a reduction (92% for ferrocenyl analogue) in parasitemia in vivo.•The hybrids are also active against the H37Rv strain of Mycobacterium tuberculosis.•Generally, the ferrocenyl analogues (<32.7 μM) were more active than the phenyl derivatives.
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