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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sad reality is that in the year 2012, people are still dying or suffering from the extreme morbidity of ischemic stroke. This tragedy is only compounded by the graveyard full of once promising new therapies. While it is indeed true that the overall mortality from stroke has declined in the United States, perhaps due to increased awareness of stroke symptoms by both the lay public and physicians, it is clear that better therapies are needed. In this regard, progress has been tremendously slowed by the simple fact that experimental models of stroke and the animals that they typically employ, rats and mice, do not adequately represent human stroke. Furthermore, the neuroprotective therapeutic approach, in which potential treatments are administered with the hope of preventing the spread of dying neurons that accompanies a stroke, typically fail for a number of reasons such as there is simply more brain matter to protect in a human than there is in a rodent! For this reason, there has been somewhat of a shift in stroke research away from neuroprotection and toward a neurorepair approach. This too may be problematic in that agents that might foster brain repair could be acutely deleterious or neurotoxic and vice versa, making the timing of treatment administration after stroke critical. Therefore, in our efforts to discover a new stroke therapy, we decided to focus on identifying brain repair elements that were (1) endogenously and actively generated in response to stroke in both human and experimental animal brains, (2) present acutely and chronically after ischemic stroke, suggesting that they could have a role in acute neuroprotection and chronic neurorepair, and (3) able to be administered peripherally and reach the site of stroke brain injury. In this review, I will discuss the evidence that suggests that perlecan domain V may be just that substance, a potential beacon of hope for stroke patients.
ACS Chem Neurosci 2013 Mar 20
PMID:Perlecan domain V therapy for stroke: a beacon of hope? 2350 72

The dosing of anticoagulants is critical when balancing efficacy and safety. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome 2-Thrombolysis In Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) trial was designed to evaluate 2 low doses of rivaroxaban compared with placebo in patients with recent acute coronary syndromes being treated with antiplatelet therapies. Because the 2 doses significantly reduced the primary efficacy end point, a further comparison of the 2 treatment strategies was deemed important. In total, 15,526 patients were randomized to twice-daily rivaroxaban 2.5 mg, rivaroxaban 5 mg, or placebo. Comparing the 2 active doses, there were no significant differences between 2.5 and 5 mg for the primary efficacy end point of cardiovascular death, myocardial infarction, or stroke (9.1% vs 8.8%, p = 0.89), myocardial infarction (6.1% vs 4.9%, p = 0.23), or stent thrombosis (2.2% vs 2.3%, p = 0.59). However, there was a divergence in cardiovascular death, which included ischemic and hemorrhagic events, with the 2.5-mg dose resulting in lower rates than the 5-mg dose (2.7% vs 4.0%, p = 0.009). Notably, with 2.5 versus 5 mg, there were fewer study drug discontinuations (p = 0.004) and fewer non-coronary artery bypass grafting TIMI major or minor bleeds (p = 0.021) and fatal bleeds (p = 0.044). Of the patients who died, 8 in the 2.5-mg group and 20 in the 5-mg group experienced non-coronary artery bypass grafting TIMI major or minor bleeding events before death. In conclusion, the 2 doses of rivaroxaban reduced cardiovascular events in patients with recent acute coronary syndromes treated with antiplatelet therapies; however, the 2.5-mg dose was associated with lower mortality and fewer bleeding complications than the 5-mg dose. Thus, the addition of rivaroxaban 2.5 mg twice daily offers a more favorable balance of efficacy and safety in patients with recent acute coronary syndromes.
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PMID:Comparison of the efficacy and safety of two rivaroxaban doses in acute coronary syndrome (from ATLAS ACS 2-TIMI 51). 2371 4

Rivaroxaban is a factor Xa inhibitor that was recently reviewed by the Food and Drug Administration as a potential therapy to reduce the risk of recurrent atherothrombotic events in patients with acute coronary syndromes. Approval of this drug would represent a paradigm shift away from dual antiplatelet therapy toward long-term triple antithrombotic therapy. However, to date, no other experimental anticoagulant agent has demonstrated a favorable risk-benefit profile in this population, in part because of the expected increased risk in major bleeding by combining aspirin, a P2Y12 receptor inhibitor, and an anticoagulant. Approvability of rivaroxaban was considered largely on the basis of the ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS 2-Thrombolysis In Myocardial Infarction 51) trial, which demonstrated a significant reduction in a composite of cardiovascular death, myocardial infarction, and stroke. Although the primary efficacy endpoint was met, a substantial amount of missing data was observed. We discuss the impact of missing data in this trial, its implications for informative censoring of safety events (major bleeding), and implications for future cardiovascular outcomes trials.
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PMID:The ATLAS ACS 2-TIMI 51 trial and the burden of missing data: (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS 2-Thrombolysis In Myocardial Infarction 51). 2374 77

Resveratrol, a natural stilbene present at relatively high concentrations in grape skin and seeds and red wine, is known for its purported antioxidant activity in the vascular and nervous systems. In contrast to its direct antioxidant role within the central nervous system, recent research supports a protective mechanism through increasing endogenous cellular antioxidant defenses, which triggers a cascade of parallel neuroprotective pathways. A growing body of in vitro and in vivo evidence indicates that resveratrol acts through multiple pathways and reduces ischemic damage in vital organs, such as the heart and the brain, in various rodent models. Most of the protective biological actions of resveratrol have been associated with its antioxidative, anti-inflammatory, and antiapoptotic properties and other indirect pathways. Continued public interest and increasing resveratrol supplements on the market warrant a review of the available in vitro and in vivo science reported in the stroke-related literature. Rigorous clinical trials evaluating the effects of resveratrol in stroke are absent, though the general population consumption appears to be relatively safe. Resveratrol has shown potential for treating stroke in laboratory animals and in vitro human cell studies, yet there is still a need for human research in preclinical settings. This review summarizes many of the findings on the neuroprotective potential of resveratrol in cerebral stroke, focusing on both the in vitro and in vivo experimental models and some proposed mechanisms of action.
ACS Chem Neurosci 2013 Aug 21
PMID:Neuroprotective properties and mechanisms of resveratrol in in vitro and in vivo experimental cerebral stroke models. 2375 34

Thrombin is a serine protease and regulator of hemostasis that plays a critical role in the formation of obstructive blood clots, or thrombosis, that is a life-threatening condition associated with numerous diseases such as atherosclerosis and stroke. To detect thrombi in living animals, we design and conjugate thrombin-sensitive peptide substrates to the surface of nanoparticles. Following intravenous infusion, these "synthetic biomarkers" survey the host vasculature for coagulation and, in response to substrate cleavage by thrombin, release ligand-encoded reporters into the host urine. To detect the urinary reporters, we develop a companion 96-well immunoassay that utilizes antibodies to bind specifically to the ligands, thus capturing the reporters for quantification. Using a thromboplastin-induced mouse model of pulmonary embolism, we show that urinary biomarker levels differentiate between healthy and thrombotic states and correlate closely with the aggregate burden of clots formed in the lungs. Our results demonstrate that synthetic biomarkers can be engineered to sense vascular diseases remotely from the urine and may allow applications in point-of-care diagnostics.
ACS Nano 2013 Oct 22
PMID:Nanoparticles that sense thrombin activity as synthetic urinary biomarkers of thrombosis. 2478 37

Leg ulcers (LUs) represent one of the main causes of morbidity in sickle cell anemia (SCA). This manifestation has been related to hemolysis, infections predisposition and inflammation that leads cytokines secretion. In this context, our study aimed to evaluate Th17 related cytokines (IL-6, IL-17A, IL-22 and IL-23) in serum and peripheral mononuclear cells culture supernatants with and without lymphoproliferative stimulation (anti-human CD3 and anti-human CD28). The cytokines levels were also correlated to clinical, hematological and biochemical parameters in SCA patients with and without LUs history (SCALU and SCAWH) as well as in healthy controls. In SCALU patients, high levels of IL-17A were associated with absence of acute chest syndrome (ACS, p=0.0328). The other clinical parameters analyzed (osteonecrosis, stroke, priapism, splenectomy and blood transfusions history) were not significantly related with other cytokine levels. In SCALU patients was also observed that IL-17A increased levels were associated with high levels of LDH (p=0.0130), the same association pattern was found for IL-6 (0.0160) and IL-22 (p=0.0165) in the SCALU group. Interestingly, we did not find statistical correlations with these parameters in SCAWH group. The other hematological parameters (hemoglobin, leucocyte and reticulocyte count) and indirect bilirrubin did not show any correlation with analyzed cytokines in both groups. So, for the first time, we show that IL-17A present in SCALU patients may exert a preventive role in the ACS development. Furthermore, IL-6, IL-17A and IL-22 accompanied the LDH levels only in SCALU patients suggesting to serve as additional markers of hemolysis or to be related with immunity response against extracellular pathogens.
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PMID:Evaluation of Th17 related cytokines associated with clinical and laboratorial parameters in sickle cell anemia patients with leg ulcers. 2437 41

Control is a hallmark of machines; effective control over a nanoscale system is necessary to turn it into a nanomachine. Nanomotors from biology often integrate a ratchet-like passive control and a power-stroke-like active control, and this synergic active-plus-passive control is critical to efficient utilization of energy. It remains a challenge to integrate the two differing types of control in rationally designed nanomotor systems. Recently a light-powered track-walking DNA nanomotor was developed from a bioinspired design principle that has the potential to integrate both controls. However, it is difficult to separate experimental signals for either control due to a tight coupling of both controls. Here we present a systematic study of the motor and new derivatives using different fluorescence labeling schemes and light operations. The experimental data suggest that the motor achieves the two controls autonomously through a mechanics-mediated symmetry breaking. This study presents an experimental validation for the bioinspired design principle of mechanical breaking of symmetry for synergic ratchet-plus-power stroke control. Augmented by mechanical and kinetic modeling, this experimental study provides mechanistic insights that may help advance molecular control in future nanotechnological systems.
ACS Nano 2014 Feb 25
PMID:Autonomous synergic control of nanomotors. 2442 93

Cardiovascular diseases actually remain the leading cause of death and morbidity in Western countries, and it is the most common cause of death in American women accounting for about one third of all deaths. Women remain underrepresented in published trial literature relative to their disease prevalence. Strong evidence do exists demonstrating gender differences in efficacy (ischemic risk) and safety (bleeding risk) associated with antithrombotic treatment, mostly related to different values of body mass, and renal function in women than men. Several data show a higher platelet reactivity in females and a higher prevalence of high platelet reactivity on aspirin and clopidogrel therapy. In primary prevention, the use of aspirin is associated with a higher reduction of risk for ischemic stroke in females and for myocardial infarction in males. In the setting of ACS, female gender is associated with a significantly higher risk of bleeding. In summary, there are some gender-related aspects of guidance in the complex spectrum of the net clinical benefit related to antithrombotic treatment.
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PMID:Gender and anti-thrombotic therapy: from biology to clinical implications. 2446 54

Rivaroxaban, a direct factor Xa inhibitor, is a novel oral anticoagulant approved for stroke prevention in patients with nonvalvular atrial fibrillation and also approved in Europe (but not in the United States) to prevent recurrent ischemic events in patients with recent acute coronary syndromes. Advantages of rivaroxaban over oral anticoagulants such as warfarin are the lack of need for ongoing monitoring, a fixed-dose regimen, and fewer drug and food interactions. Drawbacks include a lack of an antidote and the absence of a widely available method to reliably monitor the anticoagulant effect. In patients at risk of stroke due to atrial fibrillation, rivaroxaban was noninferior compared to warfarin in preventing stroke/systemic embolism in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial and was associated with a similar risk of major bleeding; the incidence of intracranial hemorrhage was 33% lower with rivaroxaban. Concerns raised about the trial were the adequacy of warfarin management and the increase in event rate at the end of the trial. The drug acquisition cost of rivaroxaban is higher than that of warfarin although decision-analytic models suggest that it is cost effective in atrial fibrillation. In patients with recent acute coronary syndrome, low-dose rivaroxaban reduced mortality and the composite end point of death from cardiovascular causes, myocardial infarction and stroke, but this was accompanied by an increased risk of intracranial hemorrhage and major bleeding in the Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Patients With Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction (ATLAS ACS 2-TIMI) 51 trial. Thus, rivaroxaban appears to be a valuable addition to the therapeutic armamentarium in atrial fibrillation although caution should be exercised, given the limited experience in combination with novel oral antiplatelet agents. The role of rivaroxaban as part of a modern regimen in acute coronary syndrome continues to be evaluated.
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PMID:The role of rivaroxaban in atrial fibrillation and acute coronary syndromes. 2465 84

Targeted nanomedicine holds promise to find clinical use in many medical areas. Endothelial cells that line the luminal surface of blood vessels represent a key target for treatment of inflammation, ischemia, thrombosis, stroke, and other neurological, cardiovascular, pulmonary, and oncological conditions. In other cases, the endothelium is a barrier for tissue penetration or a victim of adverse effects. Several endothelial surface markers including peptidases (e.g., ACE, APP, and APN) and adhesion molecules (e.g., ICAM-1 and PECAM) have been identified as key targets. Binding of nanocarriers to these molecules enables drug targeting and subsequent penetration into or across the endothelium, offering therapeutic effects that are unattainable by their nontargeted counterparts. We analyze diverse aspects of endothelial nanomedicine including (i) circulation and targeting of carriers with diverse geometries, (ii) multivalent interactions of carrier with endothelium, (iii) anchoring to multiple determinants, (iv) accessibility of binding sites and cellular response to their engagement, (v) role of cell phenotype and microenvironment in targeting, (vi) optimization of targeting by lowering carrier avidity, (vii) endocytosis of multivalent carriers via molecules not implicated in internalization of their ligands, and (viii) modulation of cellular uptake and trafficking by selection of specific epitopes on the target determinant, carrier geometry, and hydrodynamic factors. Refinement of these aspects and improving our understanding of vascular biology and pathology is likely to enable the clinical translation of vascular endothelial targeting of nanocarriers.
ACS Nano 2014 May 27
PMID:Vascular targeting of nanocarriers: perplexing aspects of the seemingly straightforward paradigm. 2478 60


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