Platelet‐Oriented Inhibition in New TIA and Minor Ischemic Stroke ( POINT ) Trial: Rationale and design

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99014/1/ijs12129.pd

Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA.

BACKGROUND—Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. METHODS—In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. RESULTS—A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P = 0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P = 0.02). CONCLUSIONS—In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029.

Pharmacological Analysis of the Activation and Receptor Properties of the Tonic GABACR Current in Retinal Bipolar Cell Terminals

GABAergic inhibition in the central nervous system (CNS) can occur via rapid, transient postsynaptic currents and via a tonic increase in membrane conductance, mediated by synaptic and extrasynaptic GABAA receptors (GABAARs) respectively. Retinal bipolar cells (BCs) exhibit a tonic current mediated by GABACRs in their axon terminal, in addition to synaptic GABAAR and GABACR currents, which strongly regulate BC output. The tonic GABACR current in BC terminals (BCTs) is not dependent on vesicular GABA release, but properties such as the alternative source of GABA and the identity of the GABACRs remain unknown. Following a recent report that tonic GABA release from cerebellar glial cells is mediated by Bestrophin 1 anion channels, we have investigated their role in non-vesicular GABA release in the retina. Using patch-clamp recordings from BCTs in goldfish retinal slices, we find that the tonic GABACR current is not reduced by the anion channel inhibitors NPPB or flufenamic acid but is reduced by DIDS, which decreases the tonic current without directly affecting GABACRs. All three drugs also exhibit non-specific effects including inhibition of GABA transporters. GABACR ρ subunits can form homomeric and heteromeric receptors that differ in their properties, but BC GABACRs are thought to be ρ1-ρ2 heteromers. To investigate whether GABACRs mediating tonic and synaptic currents may differ in their subunit composition, as is the case for GABAARs, we have examined the effects of two antagonists that show partial ρ subunit selectivity: picrotoxin and cyclothiazide. Tonic and synaptic GABACR currents were differentially affected by both drugs, suggesting that a population of homomeric ρ1 receptors contributes to the tonic current. These results extend our understanding of the multiple forms of GABAergic inhibition that exist in the CNS and contribute to visual signal processing in the retina

Geology of the Fujairah 1: 50 000 map sheet 50-4, United Arab Emirates

The Fujairah 1:50 000 geological map sheet covers a segment of the Hajar Mountains extending from the Gulf of Oman around the city of Fujairah in the east, to the desert plains of the Rub’ Al Khali in the west. The solid geology predominantly comprises rocks of the Oman-UAE ophiolite complex, with a small area in the centre-north underlain by medium- to high-grade metamorphic rocks (Bani Hamid Group). The ophiolitic rocks comprise an earlier magmatic suite of mantle harzburgite and dunite, overlain by a classic spreading-ridge crustal section of layered gabbro, through “high-level” gabbro (mainly isotropic to varitextured gabbro), to a Sheeted Dyke Complex and topmost pillow basalt. These were intruded by a later magmatic suite comprising some dunite, a predominantly ultramafic “Mixed Unit” (including peridotites and pyroxenites), voluminous wehrlite bodies, and a suite of younger gabbroic rocks and associated minor intrusions (various mafic dykes, tonalites and bodies of magmatic breccia). The metamorphic rocks occur as thin tectonic slices within a major north-west-trending fault zone. They fall within the P4 unit of the Bani Hamid Group of rocks and comprise quartz schists and quartzites, with minor amphibolites and calc-silicate rocks, metamorphosed under amphibolite facies conditions. The solid geology is partially covered by Miocene-Pliocene and Quaternary deposits. These are most extensive in the west, where the Hajar Mountains descend onto the desert plains and comprise palaeo-alluvial fan sands and gravels deposited on variably silicified serpentinite and mantle peridotites. These have been incised by Quaternary fluvial systems and are patchily overlain by Recent alluvial fan deposits. Elsewhere, the Quaternary deposits consist of alluvium and dissected river terraces, with scree and alluvial cones developed on the mountain slopes. Coastal zone deposits of the eastern seaboard include raised beaches and sabkhas, locally overlain by broad, low-angled alluvial fans issuing from the main wadis

Geology of the Khor Fakkan 1:50 000 map sheet 50-3, United Arab Emirates

This report is a description of the 1:50 000 scale Khor Fakkan geological map sheet. It forms part of the published outputs from a contract between the United Arab Emirates (UAE) Federal Government (Ministry of Energy) and the British Geological Survey (BGS) to produce geological maps, at various scales, of the solid and drift geology of the eastern part of the United Arab Emirates. These maps, which have accompanying Sheet Explanations, are listed below. The geological mapping of the Khor Fakkan sheet was undertaken during three winter seasons from 2002 to 2005 (October to December; January to March). The field mapping was carried out largely on transparent overlays on 1:25 000 scale colour aerial photographs, used in conjunction with LANDSAT imagery and 1:50 000 scale topographical base maps. The field data were transferred onto gridded transparent overlays on georectified LANDSAT images at 1: 25 000 scale. K M Goodenough, E R Phillips, D Stephenson, M T Styles, R J Thomas and M Warrak carried out the geological mapping of the Khor Fakkan district. A R Farrant and S L B Arkley contributed to the mapping of the Quaternary deposits. Petrographical analyses were completed by K M Goodenough, E R Phillips, M T Styles and R J Thomas on samples collected by the mapping team. The Sheet Explanation was compiled by K M Goodenough. The word ‘district’ is used here to refer to the area represented by the geological map 1:50 000 series sheet Khor Fakkan. The grid references in the text are UTM Zone 40, using the Nahrawan datum, given in the form [0419633 2826172]. Symbols in brackets after lithostratigraphical names refer to symbols used on the 1:50 000 series geological map. References to other Sheet Explanations in these series are given by Sheet name and number e.g. (Fujairah Sheet, 50-4)

Geology of the Hatta 1:50 000 map sheet, 50-5, United Arab Emirates

This report is a description of the 1:50 000 scale Hatta geological map sheet. It forms part of the published outputs from a contract between the United Arab Emirates (UAE) Federal Government (Ministry of Energy) and the British Geological Survey (BGS) to produce geological maps, at various scales, of the solid and drift geology of the eastern part of the United Arab Emirates. These maps, which have accompanying Sheet Explanations, are listed below. Geological surveying of the Hatta Sheet was completed in three winter field seasons, carried out between October to December and January to March of 2002-2005. Field data was recorded on transparent overlays on 1:25 000 scale colour aerial photographs, used in conjunction with LANDSAT imagery and 1:50 000 topographical base maps. The field data were transferred onto gridded transparent overlays on georectified LANDSAT images at 1:25 000 scale. The mapping team for the Hatta district consisted of M T Styles, R J Thomas, D I Schofield, K M Goodenough, and E R Phillips, with A R Farrant contributing to mapping of the Quaternary deposits. Petrographic analyses were completed by M T Styles, R J Thomas, E R Phillips and K M Goodenough on samples collected by the mapping team. The Sheet Explanation was compiled by M T Styles. The word ‘district’ is used here to refer to the area represented by the geological map 1:50 000 series sheet Hatta. The grid references in the text are UTM Zone 40 using the Nahrawan datum, given in the form [0419633 2826172]. Symbols in brackets after lithostratigraphic names refer to symbols used on the 1:50 000 series geological map. References to other Sheet Explanations in these series are given by Sheet name and number e.g. (Fujairah Sheet, 50-4)