Mild hypothermia does not attenuate platelet aggregation and may even increase ADP-stimulated platelet aggregation after clopidogrel treatment

<p>Abstract</p> <p>Background</p> <p>Mild hypothermia is currently standard of care for cardiac arrest patients in many hospitals and a common belief is that hypothermia attenuates platelet aggregation. We wanted to examine the effects of clopidogrel on platelet aggregation during hypothermia.</p> <p>Methods</p> <p>Platelet reactivity at 37°C and 33°C was evaluated by light transmission aggregometry and vasodilator-stimulated phosphoprotein (VASP) in blood from healthy volunteers before, and 24 hours after, a 600 mg loading dose of clopidogrel.</p> <p>Results</p> <p>Collagen, 5-HT, epinephrine, U46619 and ADP-induced platelet aggregation was unaltered or even increased by hypothermia. After clopidogrel, there was a significant increase in platelet aggregation for 5 and 20 μM ADP at 33°C compared to 37°C (46 ± 5 vs. 34 ± 5% and 58 ± 4 vs. 47 ± 4%, p < 0.001, n = 8). Hypothermia also increased ADP-induced aggregation after pretreatment with the P2Y₁antagonist MRS2500. The decreased responsiveness to clopidogrel during hypothermia could be overcome by addition of the reversible P2Y₁₂antagonist AZD6140. ADP-induced inhibition of VASP-phosphorylation was unaffected by hypothermia both in the presence and absence of clopidogrel. A dose-response curve for ADP-induced platelet aggregation revealed increased potency for ADP during hypothermia with no difference in efficacy.</p> <p>Conclusion</p> <p>Mild hypothermia did not attenuate platelet aggregation, instead it even increased ADP-stimulated platelet aggregation after clopidogrel treatment. Dual platelet inhibition with aspirin and a P2Y₁₂receptor antagonist is probably needed for patients with acute coronary syndromes treated with mild hypothermia, and it is possible that future ADP blockers could be of benefit.</p

Antagonism of the prostaglandin D(2 )receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

BACKGROUND: Mast cell-derived prostaglandin D(2 )(PGD(2)), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH(2 )cells (CRTH2), a high affinity receptor for prostaglandin D(2), mediates trafficking of TH(2)-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology. METHODS: Affinity for and antagonistic potency of TM30089 on many mouse receptors including thromboxane A(2 )receptor mTP, CRTH2 receptor, and selected anaphylatoxin and chemokines receptors were determined in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model. RESULTS: TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other receptors including the related anaphylatoxin C3a and C5a receptors, selected chemokine receptors and the cyclooxygenase isoforms 1 and 2 which are all recognized players in allergic diseases. Furthermore, TM30089 and ramatroban, the latter used as a reference herein, similarly inhibited asthma pathology in vivo by reducing peribronchial eosinophilia and mucus cell hyperplasia. CONCLUSION: This is the first report to demonstrate anti-allergic efficacy in vivo of a highly selective small molecule CRTH2 antagonist. Our data suggest that CRTH2 antagonism alone is effective in mouse allergic airway inflammation even to the extent that this mechanism can explain the efficacy of ramatroban

Insight into trade‐off between wood decay and parasitism from the genome of a fungal forest pathogen

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91191/1/j.1469-8137.2012.04128.x.pd

Problematik med redovisning hos Bostadsrättsföreningar –K-regelverkens redovisnings- och informationsmässiga påverkan i Bostadsrättsföreningars finansiella rapportering

Bakgrund och problem: Införandet av K-regelverkens potentiella påverkan bidrog till en offentlig debatt bland olika parter. Debatten förekom mellan media, förvaltningsorganisationer och revisorer. Det har gått två år sedan införandet vilket gör det intressant att undersöka de verkliga effekterna. Tidigare forskning har tagit upp problematiken med att applicera regelverk anpassade för vinstorienterade organisationer på icke-vinstdrivande organisationer. Uttalanden från upprättare samt användare av de finansiella rapporterna blir angeläget för studien. Syfte: Syftet med den här studien är att förstå hur redovisningen fungerar i en Brf. Beskriva och analysera vilka konsekvenser införandet av K-regelverken haft, avseende redovisningen samt informationsinnehållet på de finansiella rapporterna. Metod: Kvalitativa intervjuer med tre olika förvaltningsorganisationer, två revisorer, en kreditgivare och en styrelseordförande ligger till grund för denna fallstudie. Genom semistrukturerade intervjuer med frågor vilka grundat sig i rättsutlåtanden och diskussionsartiklar har vi erhållit information. Resultat och slutsatser: Intervjuerna har gett respondenternas åsikter kring redovisningsmässig skillnad och rapporternas funktion som informationskälla. Alla respondenter samtycker om att ett anpassat regelverk skulle behövas. Nuvarande regelverk ger inte någon rättvisande bild och den har stora brister som informationskälla. Att förvaltningsbolagen rekommenderar K2 då föreningarna innehar stora resurser tolkas underligt. Förändringar angående avskrivningar och aktivering av kostnader anses ha gett mest problematik och märkbara skillnader. Förslag till fortsatt forskning: En fjärdedel av nya bostadsrättsföreningars ekonomiska planer klarar inte formaliakraven som Bolagsverket har. Intressant att undersöka är självklart varför och vad innebär det här i längden för bostadsrättsföreningar. Förfinar föreningarna siffrorna för att ge en mer attraktiv bild

Novel Agonists and Antagonists of Platelet Receptors

Platelets are central for the primary haemostatis. The platelet has surface bound receptors that are vital for the platelet activation. One of these receptors, the purinergic ADP-activated G-protein coupled receptor (GPCR) P2Y12 is a key receptor for platelet activation, and thus for thrombus formation, which makes P2Y12 a target in pharmaceutical antiplatelet therapies. As a complement during revascularization surgery, mild hypothermia has been accepted, but its effect on platelet activation is unclear. We performed a comparative ex vivo study on platelets, treated with mild hypothermia and normothermia in the presence of P2Y12 inhibitors. We found that mild hypothermia increased platelet P2Y12 activation and that the P2Y12 inhibitor, clopidogrel, lost in efficiency. The P2Y12 receptor is also present on vascular smooth muscle cells (VSMC), promoting contractions. We initiated a comparative study on human and murine artery tissue to evaluate if any of the antiplatelet substances, clopidogrel and ticagrelor (AZD6140) a reversibly non-prodrug P2Y12 inhibitor, could inhibit P2Y12 signaling also on VSMC. The results showed that ticagrelor was able to inhibit P2Y12 stimulated vasoconstriction, while clopidogrel had no effect. The succinate GPCR (SUCNR1) mRNA has been found at high levels in platelets. We performed a study on SUCNR1 to investigate its function in platelets. The study showed that the succinate receptor was expressed as a membrane bound Gαi-protein. Succinate per se could mediate platelet activation. It was dependent on P2Y12 activation, tromboxane A2 release and PI3Kβ signaling. By screening intermediates in the mevalonate pathway, i.e. the cholesterol synthesis, we found that one of them, farnesyl pyrophosphate (FPP), had an antagonistic effect on ADP induced platelet activation. Further investigation on FPP with [35S]GTPγS binding and docking studies confirmed that FPP is an endogenous antagonist on the platelet P2Y12 receptor

Small pieces of flint : mesolithic contact patterns on the Småland highlands in south Sweden

This text discusses a small assemblage of flint from an excavation of a Mesolithic site in the Småland highlands dated to c. 9.200 cal BP. Flint does not occur naturally in the area and the flint assemblage was brought to the site from the coast, about 45 kilometres to the west. The ambition of the study was to analyse a Mesolithic site with few and fragmented artefacts . By means of analyses of distribution patterns and detailed analyses of reduction processes and use-wear analysis it could be established that a variety of tasks had been performed at the site. The distribution of burnt flint together with there mains of a hut demonstrate that the site was spatially organized. Even though the number of flint pieces from the site is small, there are no indications that the find material is the result of short visits on the site. Instead, it is more likely a place that was used for stays of some duration. The use of non-local raw material indicates mobility and contact patterns that links present day west coast of Halland and south-east Scandinavia (Skåne and the Danish islands), with the Småland highland and the Markaryd area at the time of the settlement. The technological analys is indicates that stays in the inland lasted long enough to force the group to use and curate the flint tools in a careful way to make them last. But the visits were not so long that locally available raw materials, as for example quartz, had to be used. A general conclusion to be drawn from the result is that the number of lithic pieces in an assemblage, is not in proportion to the interpretative potential of a site

Effect of Local Anesthetic Lidocaine on Electrostatic Properties of a Lipid Bilayer

The influence of local anesthetic lidocaine on electrostatic properties of a lipid membrane bilayer was studied by molecular dynamics simulations. The electrostatic dipole potential, charge densities, and orientations of the headgroup angle have been examined in presence of different amounts of charged or uncharged forms of lidocaine. Important differences of the membrane properties caused by the presence of the both forms of lidocaine are presented and discussed. Our simulations have shown that both charged and uncharged lidocaine cause almost the same increase of the dipole electrostatic potential in the middle of membrane though for different reasons. The increase, being about 90 mV for 9 mol % of lidocaine and 220 mV for 28 mol% of lidocaine, is of the size which may affect the functioning of voltage-gated ion channels.Advanced computer simulation methods for theoretical description of molecular system

A modeling system for simulation of dial-a-ride services

We present a modeling system for simulation of dial-a-ride services. It can be used as a tool for understanding and study how different designs, and different ways to operate a dial-a-ride service, affect the performance and efficiency of the service. The system simulates the operation of a dynamic dial-a-ride service that operates with multiple fleets of vehicles with different capacities, schedules and depots. It can be used to investigate how the setting of service and cost parameters and the design of the service affect the total cost for the operator and level of service for the customer. We describe the different modules in the system and the possible uses of the system. A short simulation study is performed to exemplify how it can be used. In this study the effects of including costs for customer discomfort are evaluated