Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety.

Dual antiplatelet therapy, composed of aspirin plus a P2Y12 -receptor antagonist, is the cornerstone of treatment for patients with acute coronary syndrome (ACS). A number of U.S. Food and Drug Administration-approved P2Y12 -receptor antagonists are available for treating patients with ACS, including the thienopyridine compounds clopidogrel and prasugrel. Ticagrelor, the first of a new class of antiplatelet agents, is a noncompetitive, direct-acting P2Y12 -receptor antagonist. Unlike the thienopyridine compounds, ticagrelor does not require metabolism for activity. Also, whereas clopidogrel and prasugrel are irreversible inhibitors of the P2Y12 receptor, ticagrelor binds reversibly to inhibit receptor signaling and subsequent platelet activation. In pharmacodynamic studies, ticagrelor demonstrated faster onset and more potent inhibition of platelet aggregation than clopidogrel. These properties of ticagrelor may contribute to reduced rates of thrombotic outcomes compared with clopidogrel, as demonstrated in a phase III clinical trial. However, in addition to bleeding, distinctive adverse effects of this new chemical entity have not been reported with the thienopyridine P2Y12 -receptor inhibitors. Although ticagrelor represents an advancement in P2Y12 -receptor inhibition therapy, a thorough understanding of this compound as an antiplatelet therapy remains to be elucidated

Microstructural changes in the reward system are associated with post-stroke depression

Background: Studies of lesion location have been unsuccessful in identifying mappings between single brain regions and post-stroke depression (PSD). Based on studies implicating the reward system in major depressive disorder without stroke, we investigated structural correlates within this system and their associations with PSD. Methods: The study enrolled 16 healthy controls, 12 stroke patients with PSD and 34 stroke patients free of PSD. Participants underwent 3T structural and diffusion MRI. Graph theoretical measures were used to examine global topology and whole-brain connectome analyses were employed to assess differences in the interregional connectivity matrix between groups. Structural correlates specific to the reward system were examined from grey matter volumes and by reconstructing its main white matter pathways, namely the medial forebrain bundle and cingulum connections, using deterministic tractography. Fractional anisotropy (FA) was derived as a measure of microstructural organization, and extracellular free-water (FW) as a possible proxy of neuroinflammation. Results: Subnetworks of decreased FA-weighted and increased FW-weighted connectivity were observed in patients with PSD relative to healthy controls. These networks subsumed the majority of regions constituting the reward system. Within the reward system, FA and FW of major connection pathways and grey matter volume were collectively predictive of PSD, explaining 37.8% of the variance in depression severity. Conclusions: PSD is associated with grey matter volume loss, reduced FA and increased extracellular FW in the reward system, similar to features observed in major depression without stroke. Structural characterization of the reward system is a promising biomarker of vulnerability to depression after stroke

Impact of a high-fat meal on assessment of clopidogrel-induced platelet inhibition in healthy subjects.

BACKGROUND: Ideal conditions for platelet reactivity testing are critical for optimal selection of a P2Y12 inhibitor. Data are inconsistent regarding the impact of high-fat meals on test assessment. METHODS: Participants included 12 healthy subjects not taking antiplatelet drugs after a 12-hour fast. After baseline assessment, subjects were given a 600 mg dose of clopidogrel. Four hours later, maximum platelet inhibition was tested in the fasting state by light transmission aggregometry (LTA), VerifyNow P2Y12, vasodilator-stimulated phosphoprotein (VASP), and whole blood aggregometry (WBA). Subjects were then provided a high-fat meal, and platelet function was evaluated two hours later. Change in measured platelet aggregation by LTA was the primary endpoint of the study. The Wilcoxon Rank Sum test was used to compare the change in platelet reactivity between fasting and non-fasting conditions. The Spearman rho (ρ) correlation coefficient was used to evaluate the association between fasting platelet reactivity and the change following a high-fat meal. RESULTS: No significant change occurred in maximal light transmission, as assessed by LTA with 5 μM ADP (p = 0.15) and with 20 μM ADP (p = 0.07). There was a significant change in the area under the curve with 5 μM ADP (p = 0.03) but not with 20 μM ADP (p = 0.18). Although there was no significant change with the VerifyNow P2Y12 assay (p = 0.16), the change was correlated with the initial fasting value (Spearman\u27s rho p = 0.008). The VASP assay and WBA varied minimally. CONCLUSION: The high-fat meal did not significantly alter platelet function assessment of commonly used platelet function tests. Greater intra-subject variability existed for the optically-dependent compared with non-optically dependent tests. TRIAL REGISTRATION: NCT01307657

Post-mortem whole body computed tomography of opioid (heroin and methadone) fatalities: frequent findings and comparison to autopsy

Objective: To investigate frequent findings in cases of fatal opioid intoxication in whole-body post-mortem computed tomography (PMCT). Methods: PMCT of 55 cases in which heroin and/or methadone had been found responsible for death were retrospectively evaluated (study group), and were compared with PMCT images of an age- and sex-matched control group. Imaging results were compared with conventional autopsy. Results: The most common findings in the study group were: pulmonary oedema (95%), aspiration (66%), distended urinary bladder (42%), cerebral oedema (49%), pulmonary emphysema (38%) and fatty liver disease (36%). These PMCT findings occurred significantly more often in the study group than in the control group (p < 0.05). The combination of lung oedema, brain oedema and distended urinary bladder was seen in 26% of the cases in the study group but never in the control group (0%). This triad, as indicator of opioid-related deaths, had a specificity of 100%, as confirmed by autopsy and toxicological analysis. Conclusions: Frequent findings in cases of fatal opioid intoxication were demonstrated. The triad of brain oedema, lung oedema and a distended urinary bladder on PMCT was highly specific for drug-associated cases of death. Key Points : • Frequent findings in cases of fatal opioid intoxication were investigated. • Lung oedema, brain oedema and full urinary bladder represent a highly specific constellation. • This combination of findings in post-mortem CT should raise suspicion of intoxication

Arrhythmic effects of Epac-mediated ryanodine receptor activation in Langendorff-perfused murine hearts are associated with reduced conduction velocity

Recent papers have attributed arrhythmic substrate in murine RyR2-P2328S hearts to reduced action potential (AP) conduction velocities (CV), reflecting acute functional inhibition and/or reduced expression of sodium channels. We explored for acute effects of direct exchange protein directly activated by cAMP (Epac)-mediated ryanodine receptor-2 (RyR2) activation on arrhythmic substrate and CV. Monophasic action potential (MAP) recordings demonstrated that initial steady (8 Hz) extrinsic pacing elicited ventricular tachycardia (VT) in 0 of 18 Langendorff-perfused wild-type mouse ventricles before pharmacological intervention. The Epac activator 8-CPT (8-(4-chlorophenylthio)-2′-O-methyladenosine-3′,5′-cyclic monophosphate) (VT in 1 of 7 hearts), and the RyR2 blocker dantrolene, either alone (0 of 11) or with 8-CPT (0 of 9) did not then increase VT incidence (P>.05). Both progressively increased pacing rates and programmed extrasystolic (S2) stimuli similarly produced no VT in untreated hearts (n=20 and n=9 respectively). 8-CPT challenge then increased VT incidences (5 of 7 and 4 of 8 hearts respectively; P.05). 8-CPT but not dantrolene, whether alone or combined with 8-CPT, correspondingly increased AP latencies (1.14±0.04 (n=7), 1.04±0.03 (n=10), 1.09±0.05 (n=8) relative to respective control values). In contrast, AP durations, conditions for 2:1 conduction block and ventricular effective refractory periods remained unchanged throughout. We thus demonstrate for the first time that acute RyR2 activation reversibly induces VT in specific association with reduced CV.We thank the Medical Research Council (UK) (CLH), Wellcome Trust (UK) (CLH), British Heart Foundation (UK) (CLH), McVeigh Benefaction (CLH and AG), and Sudden Arrhythmic Death Syndrome (SADS) UK (CLH and AG) for support

Currículo e MST: conflitos de saberes e estratégias na produção de sujeitos

Este artigo trata dos conflitos em torno dos saberes disponibilizados nos curr&#237;culos de duas escolas do Movimento dos Trabalhadores Rurais Sem Terra (MST) e das estrat&#233;gias ali inscritas para a produ&#231;&#227;o de sujeitos. Insere-se no campo do curr&#237;culo na vertente p&#243;s-cr&#237;tica, incorporando ferramentas conceituais dos Estudos Culturais e dos estudos de Michel Foucault. O argumento desenvolvido &#233; o de que apesar de as rela&#231;&#245;es de poder-saber forjadas no curr&#237;culo das escolas investigadas serem marcadas pela presen&#231;a predominante dos conhecimentos autorizados, h&#225; ali um esfor&#231;o de ensinar outros saberes que contribuem para disponibilizar algumas posi&#231;&#245;es de sujeito que s&#227;o de import&#226;ncia estrat&#233;gica para a produ&#231;&#227;o do sujeito Sem Terra

Interaction of language, auditory and memory brain networks in auditory verbal hallucinations

Auditory verbal hallucinations (AVH) occur in psychotic disorders, but also as a symptom of other conditions and even in healthy people. Several current theories on the origin of AVH converge, with neuroimaging studies suggesting that the language, auditory and memory/limbic networks are of particular relevance. However, reconciliation of these theories with experimental evidence is missing. We review 50 studies investigating functional (EEG and fMRI) and anatomic (diffusion tensor imaging) connectivity in these networks, and explore the evidence supporting abnormal connectivity in these networks associated with AVH. We distinguish between functional connectivity during an actual hallucination experience (symptom capture) and functional connectivity during either the resting state or a task comparing individuals who hallucinate with those who do not (symptom association studies). Symptom capture studies clearly reveal a pattern of increased coupling among the auditory, language and striatal regions. Anatomical and symptom association functional studies suggest that the interhemispheric connectivity between posterior auditory regions may depend on the phase of illness, with increases in non-psychotic individuals and first episode patients and decreases in chronic patients. Leading hypotheses involving concepts as unstable memories, source monitoring, top-down attention, and hybrid models of hallucinations are supported in part by the published connectivity data, although several caveats and inconsistencies remain. Specifically, possible changes in fronto-temporal connectivity are still under debate. Precise hypotheses concerning the directionality of connections deduced from current theoretical approaches should be tested using experimental approaches that allow for discrimination of competing hypotheses