Ticagrelor increases APC in ACS patients compared with clopidogrel by inhibiting adenosine uptake by red blood cells.
Severe acute malnutrition (SAM) is associated with inadequate diet, low levels of plasma antioxidants and gut microbiota alterations. The link between gut redox and microbial alterations, however, remains unexplored. By sequencing the gut microbiomes of 79 children of varying nutritional status from three centers in Senegal and Niger, we found a dramatic depletion of obligate anaerobes in malnutrition. This was confirmed in an individual patient data meta-analysis including 107 cases and 77 controls from 5 different African and Asian countries. Specifically, several species of the Bacteroidaceae, Eubacteriaceae, Lachnospiraceae and Ruminococceae families were consistently depleted while Enterococcus faecalis, Escherichia coli and Staphylococcus aureus were consistently enriched. Further analyses on our samples revealed increased fecal redox potential, decreased total bacterial number and dramatic Methanobrevibacter smithii depletion. Indeed, M. smithii was detected in more than half of the controls but in none of the cases. No causality was demonstrated but, based on our results, we propose a unifying theory linking microbiota specificity, lacking anaerobes and archaea, to low antioxidant nutrients, and lower food conversion.
Background Many arguments suggest that neutrophils could play a prominent role in COVID‐19. However, the role of key components of neutrophil innate immunity in severe forms of COVID‐19 has deserved insufficient attention. We aimed to evaluate the involvement of neutrophil elastase, histone‐DNA, and DNases in systemic and multi‐organ manifestations of COVID‐19. Methods We performed a multicenter study of markers of neutrophil innate immunity in 155 cases consecutively recruited in a screening center, local hospitals, and two regional university hospitals. The cases were evaluated according to clinical and biological markers of severity and multi‐organ manifestations and compared to 35 healthy controls. Results Blood neutrophil elastase, histone‐DNA, myeloperoxidase‐DNA, and free dsDNA were dramatically increased, and DNase activity was decreased by 10‐fold, compared with controls. Neutrophil elastase and histone‐DNA were associated with intensive care admission, body temperature, lung damage, and markers of cardiovascular outcomes, renal failure, and increased interleukin‐6 (IL‐6), IL‐8, and CXCR2. Neutrophil elastase was an independent predictor of the computed tomography score of COVID‐19 lung damage and the number of affected organs, in multivariate analyses. The increased blood concentrations of NE and neutrophil extracellular traps were related to exacerbation of neutrophil stimulation through IL‐8 and CXCR2 increased concentrations and increased serum DAMPs, and to impaired degradation of NETs as a consequence of the dramatic decrease in blood DNase activity. Conclusion Our results point out the key role of neutrophil innate immunity exacerbation in COVID‐19. Neutrophil elastase and DNase could be potential biomarkers and therapeutic targets of severe systemic manifestations of COVID‐19.
During exercise, cardiac oxygen consumption increases and the resulting low oxygen level in the myocardium triggers coronary vasodilation. This response to hypoxia is controlled notably by the vasodilator adenosine and its A 2A receptor (A 2A R). According to the "spare receptor" pharmacological model, a strong A 2A R-mediated response can occur in the context of a large number of receptors remaining unoccupied, the activation of only a weak fraction of A 2A R (evaluated using K D ), which results in maximal cAMP production (evaluated using EC 50 ), and hence in maximal coronary vasodilation. In coronary artery disease (CAD), myocardial ischemia limits adaptation to exercise, which is commonly detected using the exercise stress test (EST). We hypothesized that spare A 2A R is present in CAD patients to correct ischemia. Seventeen patients with angiographically documented CAD and 17 control subjects were studied. We addressed adenosine-plasma concentration and A 2A R-expression at the mononuclear cell-surface, which reflects cardiovascular expression. The presence of spare A 2A R was tested using an innovative pharmacological approach based on a homemade monoclonal antibody with agonist properties. EST was positive in 82% of patients and in none of the controls. Adenosine plasma concentration increased by 60% at peak exercise in patients and in none of the controls (p < 0.01). Most patients (65%), and none of the controls, had spare A 2A R (identified when EC 50 /K D ≤ 0.1) and a low A 2A R-expression (mean: -37% versus controls; p < 0.01). All patients with spare A 2A R had a positive EST whereas the subjects without spare A 2A R had a negative EST (p < 0.05). Spare A 2A R is therefore associated with positive EST in CAD patients and its detection may be used as a diagnostic marker.
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