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

Atorvastatin in stroke: a review of SPARCL and subgroup analysis

Statin therapy in patients with cardiovascular disease is associated with reduced incidence of stroke. The Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) trial showed daily treatment with 80 mg of atorvastatin in patients with a recent stroke or transient ischemic attack (TIA) reduced the incidence of fatal or nonfatal stroke by 16%. Several post hoc analyses of different subgroups followed the SPARCL study. They have not revealed any significant differences when patients were sorted by age, sex, presence of carotid disease or type of stroke, with the exception of intracranial hemorrhage as the entry event. Lower low-density lipoprotein cholesterol levels in addition to possible neuroprotective mechanisms due to atorvastatin treatment correlate with improved risk reduction. Although not predefined subgroups and subject to an insufficient power, these post hoc studies have generated new clinical questions. However, clinicians should avoid denying therapy based on such subgroup analysis. At this point, the best evidence powerfully demonstrates stroke and TIA patients should be prescribed high dose statin therapy for secondary stroke prevention

Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke in the SAINT I trial

<p><b>Background and Purpose:</b> NXY-059 is a free radical-trapping neuroprotectant demonstrated to reduce disability from ischemic stroke. We conducted analyses on additional end points and sensitivity analyses to confirm our findings.</p> <p><b>Methods:</b> We randomized 1722 patients with acute ischemic stroke to a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours of stroke onset. The primary outcome was disability at 90 days, as measured by the modified Rankin Scale (mRS), a 6-point scale ranging from 0 (no residual symptoms) to 5 (bed-bound, requiring constant care). Additional and exploratory analyses included mRS at 7 and 30 days; subgroup interactions with final mRS; assessments of activities of daily living by Barthel index; and National Institutes of Health Stroke Scale (NIHSS) neurological scores at 7 and 90 days.</p> <p><b>Results:</b> NXY-059 significantly improved the distribution of the mRS disability score compared with placebo at 7, 30, and 90 days (Cochran-Mantel-Haenszel test P=0.002, 0.004, 0.038, respectively; 90-day common odds ratio 1.20; 95% CI, 1.01 to 1.42). The benefit was not attributable to any specific baseline characteristic, stratification variable or subgroup interaction. Neurological scores were improved at 7 days (odds ratio [OR], 1.46; 95% CI, 1.13, 1.89; P=0.003) and the Barthel index was improved at 7 and 30 days (OR, 1.55; 95% CI, 1.22, 1.98; P<0.0001; OR, 1.27; 95% CI, 1.01, 1.59; P=0.02).</p> <p><b>Conclusions:</b> NXY-059 within 6 hours of acute ischemic stroke significantly reduced disability. Benefit on neurological scores and activities of daily living was detectable early but not significant at 90 days; however, our trial was underpowered to measure effects on the neurological examination. The benefit on disability is not confounded by interactions and is supported by other outcome measures.</p&gt

Global Drug-Resistance Patterns and the Management of Latent Tuberculosis Infection in Immigrants to the United States

Background: In the United States, an increasingly disproportionate burden of tuberculosis among the foreign-born population has led to calls for improvements in the detection and treatment of latent infection in new immigrants. Current treatment guidelines do not take into account global differences in drug resistance patterns or their implications for the treatment of immigrants. The use of multinational surveillance systems to guide the management of latent infection according to region-specific drug-resistance profiles could improve the efficiency of efforts to reduce the burden of tuberculosis in immigrants to the United States. Methods: We constructed a decision-analysis model by using a hypothetical cohort of all documented immigrants entering the United States from developing nations. Region-specific drug-resistance profiles were derived from data on 30,388 cases of infection. The model examined the effectiveness and cost effectiveness of four strategies: no intervention or tuberculin skin testing followed by treatment with isoniazid, treatment with rifampin, or treatment with rifampin plus pyrazinamide for those with a positive test result. Results: A strategy of detecting and treating latent tuberculosis infection was cost-saving among immigrants from Mexico, Haiti, sub-Saharan Africa, South Asia, and developing nations in East Asia and the Pacific. This strategy was highly cost effective among immigrants from other developing nations. Rifampin plus pyrazinamide was the preferred strategy for treating latent infection in immigrants from Vietnam, Haiti, and the Philippines. Conclusions: For new immigrants to the United States from developing nations, a strategy of detecting and treating latent tuberculosis infection would lead to substantial health and economic benefits. Because of the high prevalence of resistance to isoniazid, treatment with a rifampin-containing regimen should be strongly considered for immigrants from Vietnam, Haiti, and the Philippines

Global Drug-Resistance Patterns and the Management of Latent Tuberculosis Infection in Immigrants to the United States

Background: In the United States, an increasingly disproportionate burden of tuberculosis among the foreign-born population has led to calls for improvements in the detection and treatment of latent infection in new immigrants. Current treatment guidelines do not take into account global differences in drug resistance patterns or their implications for the treatment of immigrants. The use of multinational surveillance systems to guide the management of latent infection according to region-specific drug-resistance profiles could improve the efficiency of efforts to reduce the burden of tuberculosis in immigrants to the United States. Methods: We constructed a decision-analysis model by using a hypothetical cohort of all documented immigrants entering the United States from developing nations. Region-specific drug-resistance profiles were derived from data on 30,388 cases of infection. The model examined the effectiveness and cost effectiveness of four strategies: no intervention or tuberculin skin testing followed by treatment with isoniazid, treatment with rifampin, or treatment with rifampin plus pyrazinamide for those with a positive test result. Results: A strategy of detecting and treating latent tuberculosis infection was cost-saving among immigrants from Mexico, Haiti, sub-Saharan Africa, South Asia, and developing nations in East Asia and the Pacific. This strategy was highly cost effective among immigrants from other developing nations. Rifampin plus pyrazinamide was the preferred strategy for treating latent infection in immigrants from Vietnam, Haiti, and the Philippines. Conclusions: For new immigrants to the United States from developing nations, a strategy of detecting and treating latent tuberculosis infection would lead to substantial health and economic benefits. Because of the high prevalence of resistance to isoniazid, treatment with a rifampin-containing regimen should be strongly considered for immigrants from Vietnam, Haiti, and the Philippines

Amino-terminal dimerization of an erythropoietin mimetic peptide results in increased erythropoietic activity

AbstractBackground: Erythropoietin (EPO), the hormone involved in red blood cell production, activates its receptor by binding to the receptor's extracellular domain and presumably dimerizing two receptor monomers to initiate signal transduction. EPO-mimetic peptides, such as EMP1, also bind and activate the receptor by dimerization. These mimetic peptides are not as potent as EPO, however. The crystal structure of the EPO receptor (EBP) bound to EMP1 reveals the formation of a complex consisting of two peptides bound to two receptors, so we sought to improve the biological activity of EPO-mimetic peptides by constructing covalent dimers of EMP1 and other peptide mimetics linked by polyethylene glycol (PEG).Results: The potency of the PEG-dimerized EPO peptide mimetics both in vitro and in vivo was improved up to 1,000-fold compared to the corresponding peptide monomers. The dinners were constructed using peptide monomers which have only one reactive amine per molecule, allowing us to conclude that the increase in potency can be attributed to a structure in which two peptides are linked through their respective amino termini to the difunctional PEG molecule. In addition, an inactive peptide was converted into a weak agonist by PEG-induced dimerization.Conclusions: The potency of previously isolated peptides that are modest agonists of the EPO receptor was dramatically increased by PEG-induced dimerization. The EPO receptor is thought to be dimerized during activation, so our results are consistent with the proposed 2:2 receptor : peptide stoichiometry. The conversion of an inactive peptide into an agonist further supports the idea that dimerization can mediate receptor activation

Prevalence and correlates of specialty substance use disorder treatment for Department of Veterans Affairs Healthcare System patients with high alcohol consumption

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78096/1/67.pd

Suicidality and hostility following involuntary hospital treatment

Background Psychiatric patients showing risk to themselves or others can be involuntarily hospitalised. No data is available on whether following hospitalisation there is a reduction in psychopathological indicators of risk such as suicidality and hostility. This study aimed to assess changes in suicidality and hostility levels following involuntary admission and their patient-level predictors. Methods A pooled analysis of studies on involuntary treatment, including 11 countries and 2790 patients was carried out. Suicidality and hostility were measured by the Brief Psychiatric Rating Scale. Results 2790 patients were included; 2129 followed-up after one month and 1864 after three months. 387 (13.9%) patients showed at least moderate suicidality when involuntarily admitted, 107 (5.0%) after one month and 97 (5.2%) after three months. Moderate or higher hostility was found in 1287 (46.1%) patients after admission, 307 (14.5%) after one month, and 172 (9.2%) after three months. Twenty-three (1.2%) patients showed suicidality, and 53 (2.8%) patients hostility at all time-points. Predictors of suicidality three months after admission were: suicidality at baseline, not having a diagnosis of psychotic disorder and being unemployed. Predictors of hostility were: hostility at baseline, not having a psychotic disorder, living alone, and having been hospitalized previously. Conclusions After involuntary hospital admission, the number of patients with significant levels of suicidality and hostility decreases substantially over time, and very few patients show consistently moderate or higher levels of these symptoms. In patients with psychotic disorders these symptoms are more likely to improve. Social factors such as unemployment and isolation could hamper suicidality and hostility reduction and may be targeted in interventions to reduce risk in involuntarily admitted patients