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Progesterone in transient ischemic stroke: a dose-response study.

ABSTRACT: Previous studies demonstrate the neuroprotective effects of progesterone in numerous animal injury models, but a systematic dose-response study in a transient ischemic stroke model is lacking.We investigated the effects of progesterone at different doses on post-stroke brain infarction and functional deficits in middle-aged rats.Cerebral ischemia was induced in 13-month-old male Sprague-Dawley rats by right middle cerebral artery occlusion for 2 h followed by reperfusion. Rats received intraperitoneal injections of 8, 16, or 32 mg/kg of progesterone (P8, P16, P32) or vehicle at 2 h post-occlusion followed by subcutaneous injections at 6 h and every 24 h post-injury for 7 days. Functional recovery was evaluated at intervals over 22 days using motor, sensory, and cognitive tests. Infarct size was evaluated at 22 days post-stroke.Repeated-measures ANOVA showed significant group effects on grip strength, rotarod, and sensory neglect. All progesterone-treated groups had improved (p?

SUBMITTER: Yousuf S

PROVIDER: S-EPMC4134953 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Progesterone in transient ischemic stroke: a dose-response study.

Yousuf Seema S Atif Fahim F Sayeed Iqbal I Tang Huiling H Stein Donald G DG

Psychopharmacology 20140422 17

<h4>Rationale</h4>Previous studies demonstrate the neuroprotective effects of progesterone in numerous animal injury models, but a systematic dose-response study in a transient ischemic stroke model is lacking.<h4>Objectives</h4>We investigated the effects of progesterone at different doses on post-stroke brain infarction and functional deficits in middle-aged rats.<h4>Methods</h4>Cerebral ischemia was induced in 13-month-old male Sprague-Dawley rats by right middle cerebral artery occlusion for ...[more]

PMID: 24752655

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Project description:BackgroundPatients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease.MethodsIn this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction.ResultsBy 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003).ConclusionsIn this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).

Project description:Background and purposePremature death after transient ischemic attack or stroke is more often because of heart disease or cancer than stroke. Previous studies found blood biomarkers not usefully predictive of nonfatal stroke but possibly of all-cause death. This association might be explained by potentially treatable occult cardiac disease or cancer. We therefore aimed to validate the association of a panel of biomarkers with all-cause death, particularly cardiac death and cancer death, despite the absence of associations with risk of nonfatal vascular events.MethodsFifteen biomarkers were measured in 929 consecutive patients in a population-based study (Oxford Vascular Study), recruited from 2002 and followed up to 2013. Associations were determined by Cox regression. Model discrimination was assessed by c-statistic and the integrated discrimination improvement.ResultsDuring 5560 patient-years of follow-up, none of the biomarkers predicted risk of nonfatal vascular events. However, soluble tumor necrosis factor α receptor-1, von Willebrand factor, heart-type fatty-acid-binding protein, and N-terminal pro-B-type natriuretic peptide were independently predictive of all-cause death (n=361; adjusted hazard ratio per SD, 95% confidence interval: heart-type fatty-acid-binding protein: 1.31, 1.12-1.56, P=0.002; N-terminal pro-B-type natriuretic peptide: 1.34, 1.11-1.62, P=0.002; soluble tumor necrosis factor α receptor-1: 1.45, 1.26-1.66, P=0.02; von Willebrand factor: 1.19, 1.04-1.36, P=0.01). The independent contribution of the four biomarkers taken together added prognostic information and improved model discrimination (integrated discrimination improvement=0.028, P=0.0001). N-terminal pro-B-type natriuretic peptide was most predictive of vascular death (adjusted hazard ratio=1.80, 95% confidence interval, 1.34-2.41, P<0.0001), whereas heart-type fatty-acid-binding protein predicted cancer deaths (1.64, 1.26-2.12, P=0.0002). Associations were strongest in patients without known prior cardiac disease or cancer.ConclusionsSeveral biomarkers predicted death of any cause after transient ischemic attack and minor stroke. N-terminal pro-B-type natriuretic peptide and heart-type fatty-acid-binding protein might improve patient selection for additional screening for occult cardiac disease or cancer, respectively. However, our results require validation in future studies.

Project description:BACKGROUND AND PURPOSE:Chronic kidney disease (CKD) is strongly associated with stroke risk, but the mechanisms underlying this association are unclear and might be informed by subtype-specific analyses. However, few studies have reported stroke subtypes in CKD according to established classification systems, such as the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria. We, therefore, aimed to determine which transient ischemic attack and ischemic stroke subtypes using the TOAST classification occur most frequently in patients with CKD. METHODS:In a population-based study of all transient ischemic attack and stroke (OXVASC [Oxford Vascular Study]; 2002-2017), all ischemic events were classified by TOAST subtypes (cardioembolism, large artery disease, small vessel disease, undetermined, multiple, other etiology, or incompletely investigated). Logistic regression was used to determine the relationship between CKD (defined as an estimated glomerular filtration rate <60 mL/min per 1.73 m2) and transient ischemic attack/stroke subtypes adjusted for age, sex, and hypertension and then stratified by age and estimated glomerular filtration rate category. RESULTS:Among 3178 patients with transient ischemic attack (n=1167), ischemic stroke (n=1802), and intracerebral hemorrhage (n=209), 1267 (40%) had CKD. Although there was a greater prevalence of cardioembolic events (31.8% versus 21.2%; P<0.001) in patients with CKD, this association was lost after adjustment for age, sex, and hypertension (adjusted odds ratio=1.20 [95% CI, 0.99-1.45]; P=0.07). Similarly, although patients with CKD had a lower prevalence of small vessel disease (8.8% versus 13.6%; P<0.001), undetermined (26.1% versus 39.4%; P<0.001), and other etiology (1.0% versus 3.6%; P<0.001) subtypes, these associations were also lost after adjustment (adjusted odds ratio=0.86 [0.65-1.13]; P=0.27 and 0.73 [0.36-1.43]; P=0.37 for small vessel disease and other defined etiology, respectively) for all but undetermined (adjusted odds ratio=0.81 [0.67-0.98]; P=0.03). CONCLUSIONS:There were no independent positive associations between CKD and specific TOAST subtypes, which suggest that renal-specific risk factors are unlikely to play an important role in the etiology of particular subtypes. Future studies of stroke and CKD should report subtype-specific analyses to gain further insights into potential mechanisms.

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Progesterone in transient ischemic stroke: a dose-response study.

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Progesterone in transient ischemic stroke: a dose-response study.

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