Ticagrelor increases APC in ACS patients compared with clopidogrel by inhibiting adenosine uptake by red blood cells.

“Nanobacteria” are nanometer-scale spherical and ovoid particles which have spurred one of the biggest controversies in modern microbiology. Their biological nature has been severely challenged by both geologists and microbiologists, with opinions ranging from considering them crystal structures to new life forms. Although the nature of these autonomously replicating particles is still under debate, their role in several calcification-related diseases has been reported. In order to gain better insights on this calciferous agent, we performed a large-scale project, including the analysis of “nanobacteria” susceptibility to physical and chemical compounds as well as the comprehensive nucleotide, biochemical, proteomic, and antigenic analysis of these particles. Our results definitively ruled out the existence of “nanobacteria” as living organisms and pointed out the paradoxical role of fetuin (an anti-mineralization protein) in the formation of these self-propagating mineral complexes which we propose to call “nanons.” The presence of fetuin within renal calculi was also evidenced, suggesting its role as a hydroxyapatite nucleating factor.

High adenosine plasma concentrations are found in patients with septic shock but not during traumatic shock, or in healthy volunteers. Intermediate values of circulating adenosine are found in patients with severe sepsis. APC may be a prognostic index for outcome in septic patients, with much higher values being found in nonsurvivors.

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: Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. Oxidative stress seems to play a pivotal role in this process, and purine metabolism may be involved in CKD-related oxidative stress. Xanthine oxidase (XO) is an enzyme involved in purine metabolism and is also responsible for the production of reactive oxygen species. Methods: This prospective study aimed to analyze the relation between plasma dosages of molecules involved in redox balance, purine metabolism and cardiovascular events in patients with non-diabetic CKD stages 3-5 or on chronic hemodialysis (HD). CKD (n = 51) and HD (n = 50) patients were compared to matched healthy controls (n = 38) and followed-up for 3 years. Results: Both CKD and HD patients had decreased plasma levels of antioxidants (selenium, zinc, vitamin C). HD patients had decreased levels of the antioxidant enzyme superoxide dismutase and increased levels of oxidation products (ischemia-modified albumin, malondialdehyde [MDA]). The following substrates and enzymes involved in purine metabolism were increased in the HD cohort: adenosine, adenosine deaminase and the pro-oxidant XO. XO activity was negatively correlated with super oxide dismutase and positively with MDA. Interestingly, XO activity was an independent predictor of cardiovascular events in CKD and HD patients, regardless of uric acid levels. Uric acid was not predictive of events. Conclusion: This highlights a possible role of XO itself in CKD-related cardiovascular disease (CVD) and raises the hypothesis that beneficial effects observed with XO inhibitors on CVD in CKD may also be due to the reduction of oxidative stress.

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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.

Background-Previous reports that used head-up tilt testing and adenosine administration have suggested that adenosine may be an important endogenous mediator that may trigger a vasovagal response in susceptible patients. However, little is known regarding endogenous adenosine plasma levels (APLs) during vasovagal syncope provoked by tilt testing. The aim of this study was to determine whether APLs differ in patients with a positive head-up tilt test compared with those with a negative test and whether APLs are modified during tilt-induced vasovagal syncope. Methods and Results-APLs (meanϮSEM) were measured during head-up tilt test in 26 patients who presented with unexplained syncope. In the 15 patients with a negative test, APLs were 0.39Ϯ0.03 mol/L at baseline, 0.22Ϯ0.03 mol/L immediately after tilting, and 0.44Ϯ0.03 mol/L after 45 minutes. APLs were significantly higher in the 11 patients with a positive test (2.66Ϯ0.67 mol/L at baseline and 3.22Ϯ0.85 mol/L immediately after tilting) than in those with a negative test. During tilt testing-induced syncope, APLs increased to reach 4.03Ϯ0.66 mol/L (ie, a 52% increase compared with baseline levels; PϽ0.02). Furthermore, we observed that the higher the APL during syncope, the shorter the time to appearance of symptoms. Conclusions-This study showed that APLs were higher in patients with a positive tilt test than in patients with a negative test and that they increased during tilt testing-induced syncope. These observations suggest that adenosine release may be involved in the triggering mechanism of syncope induced during tilt testing. (Circulation. 2002;106:569-574.)