Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study

BACKGROUND: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. METHODS AND RESULTS: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. CONCLUSIONS: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event.

Subclinical hypothyroidism and cardiovascular risk: how to end the controversy

The indications for screening and TSH threshold levels for treatment of subclinical hypothyroidism have remained a clinical controversy for over 20 years. Subclinical thyroid dysfunction is a common finding in the growing population of older adults, occurring in 10–15% among those age 65 and older, and may contribute to multiple common problems of older age, including cardiovascular disease, muscular impairment, mood problems, and cognitive dysfunction (1). In 2004, both the U.S. Preventive Services Task Force (2) and a clinical consensus group of experts (3) concluded that the existing evidence about the association between subclinical hypothyroidism and cardiovascular risks, primarily cross-sectional or case-control studies (4), was insufficient. For example, a frequently cited analysis from the Rotterdam study found a cross-sectional association between subclinical hypothyroidism and atherosclerosis, as measured by abdominal aortic calcification (odds ratio, 1.7; 95% confidence interval [CI], 1.1–2.6) and prevalent myocardial infarction (MI) (odds ratio, 2.3; 95% CI, 1.3–4.0) (5). Conversely, the prospective part of this study included only 16 incident MIs; the hazard ratio (HR) for subclinical hypothyroidism was 2.50, with broad 95% CIs (0.70–9.10). Potential mechanisms for the associations with cardiovascular diseases among adults with subclinical hypothyroidism include elevated cholesterol levels, inflammatory markers, raised homocysteine, increased oxidative stress, insulin resistance, increased systemic vascular resistance, arterial stiffness, altered endothelial function, and activation of thrombosis and hypercoagulability that have all been reported to be associated with subclinical hypothyroidism (1, 6).

Subklinische Hypothyreose: Risiken, aktuelle Empfehlungen und randomisierte Studie in der Schweiz

Quintessenz: • Die subklinische Hypothyreose ist definiert durch erhöhte TSH und normwertige ThyroxinSpiegel; sie kommt bei älteren Patienten häufig vor (10–15%). • Daten aus Beobachtungsstudien zeigen einen möglichen Zusammenhang zwischen der subklinischen Hypothyreose und verschiedenen Krankheitsbildern wie kardiovaskulären Erkrankungen, Muskelbeschwerden sowie depressiven oder kognitiven Störungen. • Die Indikation zur Thyroxin Substitution bei subklinischer Hypothyreose ist derzeit noch nicht klar, was sich in grossen Unterschieden bezüglich Therapie zwischen verschiedenen Ländern niederschlägt. Es zeigt sich jedoch eine Zunahme der ThyroxinVerschreibungen. • Die Teilnahme an der randomisierten TRUST Studie ist die derzeit beste «Behandlungsoption» für ältere Patienten mit subklinischer Hypothyreose.

Investigation of the inhibitory effects of the benzodiazepine derivative, 5-BDBD on P2X4 purinergic receptors by two complementary methods

BACKGROUND/AIMS ATP-gated P2X4 purinergic receptors (P2X4Rs) are cation channels with important roles in diverse cell types. To date, lack of specific inhibitors has hampered investigations on P2X4Rs. Recently, the benzodiazepine derivative, 5-BDBD has been proposed to selectively inhibit P2X4Rs. However, limited evidences are currently available on its inhibitory properties. Thus, we aimed to characterize the inhibitory effects of 5-BDBD on recombinant human P2X4Rs. METHODS We investigated ATP-induced intracellular Ca(2+) signals and whole cell ion currents in HEK 293 cells that were either transiently or stably transfected with hP2X4Rs. RESULTS Our data show that ATP (< 1 μM) stimulates P2X4R-mediated Ca(2+) influx while endogenously expressed P2Y receptors are not activated to any significant extent. Both 5-BDBD and TNP-ATP inhibit ATP-induced Ca(2+) signals and inward ion currents in a concentration-dependent manner. Application of two different concentrations of 5-BDBD causes a rightward shift in ATP dose-response curve. Since the magnitude of maximal stimulation does not change, these data suggest that 5-BDBD may competitively inhibit the P2X4Rs. CONCLUSIONS Our results demonstrate that application of submicromolar ATP concentrations allows reliable assessment of recombinant P2XR functions in HEK 293 cells. Furthermore, 5-BDBD and TNP-ATP have similar inhibitory potencies on the P2X4Rs although their mechanisms of actions are different.

Detailed insight into Arctic climatic variability during MIS 11c at Lake El'gygytgyn, NE Russia

Here we present a detailed multi-proxy record of the climate and environmental evolution at Lake El'gygytgyn, Far East Russian Arctic during the period 430–395 ka covering the marine isotope stage (MIS) 12/11 transition and the thermal maximum of super interglacial MIS 11c. The MIS 12/11 transition at Lake El'gygytgyn is characterized by initial warming followed by a cold reversal implying similarities to the last deglaciation. The thermal maximum of MIS 11c is characterized by full and remarkably stable interglacial conditions with mean temperatures of the warmest month (MTWM) ranging between ca. 10–15 °C; annual precipitation (PANN) ranging between ca. 300–600 mm; strong in-lake productivity coinciding with dark coniferous forests in the catchment; annual disintegration of the lake ice cover; and full mixis of the water column. Such conditions persisted, according to our age model, for ca. 27 ± 8 kyr between ca. 425–398 ka. The Lake El'gygytgyn record closely resembles the climate pattern recorded in Lake Baikal (SE Siberia) sediments and Antarctic ice cores, implying interhemispheric climate connectivity during MIS 11c.