rLOAD: does sex mediate the effect of acute antiplatelet loading on stroke outcome.

BackgroundBiologic sex can influence response to pharmacologic therapy. The purpose of this proof-of-concept study was to evaluate the medicating effects of estrogen in the efficacy of acute antiplatelet loading therapy on stroke outcome in the rabbit small clot embolic model.MethodsFemale and male (20/group) New Zealand White rabbits were embolized to produce embolic stroke by injecting small blood clots into the middle cerebral artery via an internal carotid artery catheter. Two hours after embolization, rabbits were treated with standard dose antiplatelet loading (aspirin 10 mg/kg plus clopidogrel 10 mg/kg). Primary outcome measures were platelet inhibition, behavioral outcome P 50 (the weight of microclots (mg) that produces neurologic dysfunction in 50% of a group of animals), and effect of endogenous estrogen on outcome.ResultsFor the first time in a non-rodent model of stroke, it was found that higher endogenous estrogen levels resulted in significantly better behavioral outcome in female subjects (r s -0.70, p < 0.011). Platelet inhibition in response to collagen, arachidonic acid, and adenosine diphosphate (ADP) was not significantly different in females with higher vs. lower estrogen levels.ConclusionsBehavioral outcomes are improved with females with higher endogenous estrogen levels treated with standard dose antiplatelet loading. This is the first non-rodent study to demonstrate that higher endogenous estrogen levels in female rabbits appear to be neuroprotective in ischemic stroke. This research supports the further study of the effect of endogenous estrogen levels on outcome with standard dose antiplatelet loading in stroke patients not eligible for revascularization therapies

Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease.

Altered brain metabolism is associated with progression of Alzheimer's Disease (AD). Mitochondria respond to bioenergetic changes by continuous fission and fusion. To account for three dimensional architecture of the brain tissue and organelles, we applied 3-dimensional electron microscopy (3D EM) reconstruction to visualize mitochondrial structure in the brain tissue from patients and mouse models of AD. We identified a previously unknown mitochondrial fission arrest phenotype that results in elongated interconnected organelles, "mitochondria-on-a-string" (MOAS). Our data suggest that MOAS formation may occur at the final stages of fission process and was not associated with altered translocation of activated dynamin related protein 1 (Drp1) to mitochondria but with reduced GTPase activity. Since MOAS formation was also observed in the brain tissue of wild-type mice in response to hypoxia or during chronological aging, fission arrest may represent fundamental compensatory adaptation to bioenergetic stress providing protection against mitophagy that may preserve residual mitochondrial function. The discovery of novel mitochondrial phenotype that occurs in the brain tissue in response to energetic stress accurately detected only using 3D EM reconstruction argues for a major role of mitochondrial dynamics in regulating neuronal survival

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The cholesterol ester cycle regulates signalling complexes and synapse damage caused by amyloid-ß

Cholesterol is required for the formation and function of some signalling platforms. In synaptosomes, amyloid-β (Aβ) oligomers, the causative agent in Alzheimer's disease, bind to cellular prion proteins (PrPC) resulting in increased cholesterol concentrations, translocation of cytoplasmic phospholipase A2 (cPLA2, also known as PLA2G4A) to lipid rafts, and activation of cPLA2. The formation of Aβ-PrPC complexes is controlled by the cholesterol ester cycle. In this study, Aβ activated cholesterol ester hydrolases, which released cholesterol from stores of cholesterol esters and stabilised Aβ-PrPC complexes, resulting in activated cPLA2. Conversely, cholesterol esterification reduced cholesterol concentrations causing the dispersal of Aβ-PrPC complexes. In cultured neurons, the cholesterol ester cycle regulated Aβ-induced synapse damage; cholesterol ester hydrolase inhibitors protected neurons, while inhibition of cholesterol esterification significantly increased Aβ-induced synapse damage. An understanding of the molecular mechanisms involved in the dispersal of signalling complexes is important as failure to deactivate signalling pathways can lead to pathology. This study demonstrates that esterification of cholesterol is a key factor in the dispersal of Aβ-induced signalling platforms involved in the activation of cPLA2 and synapse degeneration

Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret

Anti-nausea effects and pharmacokinetics of ondansetron, maropitant and metoclopramide in a low-dose cisplatin model of nausea and vomiting in the dog: a blinded crossover study

Nausea is a subjective sensation which is difficult to measure in non-verbal species. The aims of this study were to determine the efficacy of three classes of antiemetic drugs in a novel low dose cisplatin model of nausea and vomiting and measure change in potential nausea biomarkers arginine vasopressin (AVP) and cortisol. A four period cross-over blinded study was conducted in eight healthy beagle dogs of both genders. Dogs were administered 18 mg/m2 cisplatin intravenously, followed 45 min later by a 15 min infusion of either placebo (saline) or antiemetic treatment with ondansetron (0.5 mg/kg; 5-HT3 antagonist), maropitant (1 mg/kg; NK1 antagonist) or metoclopramide (0.5 mg/kg; D2 antagonist). The number of vomits and nausea associated behaviours, scored on a visual analogue scale, were recorded every 15 min for 8 h following cisplatin administration. Plasma samples were collected to measure AVP, cortisol and antiemetic drug concentrations

Ekonomikos samprata, ekonominės politikos ribos ir dimensijos

Whilst discussing measures of economic policy we implicitly or explicitly base our arguments on one or another perception of the economy. Therefore this link between conceptual, theoretical, paradigmatic side of human activities on the one hand, and practical side on the other, is worthwhile to explore. It is even more the case if we concede that economic science pays little attention to the definition of the key economic concept “economy”.Author of the article argues that it is a major breakaway from classical tradition (A. Smith), which prescribes to link economic reality with flows and movement of national wealth. Defining economy as an aspect of social life reflecting the movement of wealth, author defines the latter as a combination of the private, public and natural goods. Accordingly in he discriminates between market, public and natural regimes in economy, stressing that none of them exist in their pure form.Assumption that economy encompasses the goods and regimes mentioned above, serves as a basis for wider than usual understanding of economic policy. Traditionally economic policy is understood as concerned mainly or even exclusively with production of private goods, with market Other aspects of life education, science. politics. legal sphere etc. – are assumed as external to economy. Even if they are included to the sphere of economic policy this inclusion is one-sided – only costs to society are considered and benefits are not taken into account It is serious distortion of the philosophy of economic policy. This distortion is felt especially acutely in the domain of public finances. when public sector is treated as a financial burden and when benefits (utility) produced in the public sector are taken for granted or neglected as non-economic. Such a neglect of public as well as natural goods almost unavoidably makes economic development unbalanced and unsustainable. and could be the reason for future turbulences.Dabar yra plačiai paplitusi tvarios (sustainable) ekonominės plėtros sąvoka. Ji suponuoja, kad galima ir netvari (unsustainable) ekonominė plėtra. Viena į galimos netvarios ekonominės plėtros priežasčių – jos nesubalansuotumas, kuris, be kitų, gali turėti ir gnoseologines priežastis – vienpusišką, iškreiptą ekonominės tikrovės suvokimą. Tai savo ruožtu gali lemti nesubalansuotą ekonominę politiką (economic policy) ir kartu neadekvatų ekonominių, pirmiausiai finansinių, išteklių paskirstymą. Tokiai deformuotai, iškeiptai ūkinei praktikai užtrukus, ekonominis augimas gali sulėtėti ar net patirti nuosmukį. O tai gali sukelti socialinę, politinę trinti ar konfliktus