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Search Results: 1 - 10 of 223996 matches for " Susan C. Fagan "
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Cerebral Neovascularization and Remodeling Patterns in Two Different Models of Type 2 Diabetes
Roshini Prakash, Maribeth Johnson, Susan C. Fagan, Adviye Ergul
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0056264
Abstract: We previously reported intense pial cerebral collateralization and arteriogenesis in a mild and lean model of type 2 diabetes (T2D), Goto-Kakizaki (GK) rats. Increased cerebral neovascularization differed regionally and was associated with poor vessel wall maturity. Building upon these findings, the goals of this study were to determine whether a) glycemic control prevents this erratic cerebral neovascularization in the GK model, and b) this pathological neovascularization pattern occurs in Leprdb/db model, which is the most commonly used model of T2D for studies involving cerebral complications of diabetes. Vascular volume, surface area and structural parameters including microvessel/macrovessel ratio, non-FITC (fluorescein) perfusing vessel abundance, vessel tortuosity, and branch density were measured by 3D reconstruction of FITC stained vasculature in GK rats or Leprdb/db mice. GK rats exhibited an increase in all of these parameters, which were prevented by glycemic control with metformin. In Leprdb/db mice, microvascular density was increased but there was no change in nonFITC-perfusing vessels. Increased PA branch density was associated with reduced branch diameter. These results suggest that T2D leads to cerebral neovascularization and remodeling but some structural characteristics of newly formed vessels differ between these models of T2D. The prevention of dysfunctional cerebral neovascularization by early glucose control suggests that hyperglycemia is a mediator of this response.
Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke
Livia S Machado, Anna Kozak, Adviye Ergul, David C Hess, Cesario V Borlongan, Susan C Fagan
BMC Neuroscience , 2006, DOI: 10.1186/1471-2202-7-56
Abstract: Both MMP-2 and MMP-9 were elevated in the ischemic tissue as compared to the contra-lateral hemisphere after 3 hours occlusion and 21 hours survival (p < 0.0001 for MMP-9). Intraperitoneal minocycline at 45 mg/kg concentration twice a day (first dose immediately after the onset of reperfusion) significantly reduced gelatinolytic activity of ischemia-elevated MMP-2 and MMP-9 (p < 0.0003). Treatment also reduced protein concentration of both enzymes (p < 0.038 for MMP-9 and p < 0.018 for MMP-2). In vitro incubation of minocycline in concentrations as low as 0.1 μg/ml with recombinant MMP-2 and MMP-9 impaired enzymatic activity and MMP-9 was more sensitive at lower minocycline concentrations (p < 0.05).Minocycline inhibits enzymatic activity of gelatin proteases activated by ischemia after experimental stroke and is likely to be selective for MMP-9 at low doses. Minocycline is a potential new therapeutic agent to acute treatment of ischemic stroke.Matrix metalloproteases (MMPs) are a family of zinc dependent proteases responsible for the extracellular matrix turnover and degradation of bioactive proteins. In cerebral ischemia, MMPs 2 and 9, also designated as gelatinases A (72 kDa) and B (92 kDa) have been identified to mediate the degradation of the basal lamina [1,2] and hemorrhagic transformation [3]. MMPs 2 and 9 have been shown to be elevated a few hours after ischemia [4] and to maintain increased activity for days after the onset [2,5]. The inhibition of these enzymes by specific class inhibitors reverts breakdown of laminin [6] and prevents increased barrier permeability, edema, and hemorrhage after ischemic stroke [7-9]. The development of MMP inhibitors as therapeutic agents has been limited by their poor solubility.Minocycline is a commonly used semi-synthetic tetracycline with anti-inflammatory and anti-apoptotic properties [10,11]. Minocycline interferes with MMP activity [12,13] and has been shown to be neuroprotective in cerebral ischemia [14] and in oth
Effect of neutrophil depletion on gelatinase expression, edema formation and hemorrhagic transformation after focal ischemic stroke
Alex K Harris, Adviye Ergul, Anna Kozak, Livia S Machado, Maribeth H Johnson, Susan C Fagan
BMC Neuroscience , 2005, DOI: 10.1186/1471-2202-6-49
Abstract: Anti-PMN treatment caused successful depletion of neutrophils in treated animals. There was no difference in either infarct volume or hemorrhage between control and PMN depleted animals. While there were significant increases in gelatinase (MMP-2 and MMP-9) expression and activity and edema formation associated with ischemia, neutrophil depletion failed to cause any change.The main finding of this study is that, in the absence of circulating neutrophils, MMP-2 and MMP-9 expression and activity are still up-regulated following focal cerebral ischemia. Additionally, neutrophil depletion had no influence on indicators of ischemic brain damage including edema, hemorrhage, and infarct size. These findings indicate that, at least acutely, neutrophils are not a significant contributor of gelatinase activity associated with acute neurovascular damage after stroke.The matrix metalloproteinases (MMPs) are a family of some 23 zinc dependent proteases that, collectively, possess the ability to degrade nearly every component of the extra-cellular matrix [1-3]. The activity of the MMPs is tightly controlled through proteolytic activation of the zymogen forms and stoichiometric binding of tissue inhibitors of metalloproteinases (TIMPs). The MMPs play an important role in many physiological processes due to their inherent ability to remodel tissues [2,3]. However, in disease states such as vascular disease and stroke, the MMPs may become deleterious due to dysregulation and can result in tissue injury and inflammation. Specifically, the MMPs may be involved in the degradation of the basal lamina in reperfusion injury resulting in disruption of the blood brain barrier and hemorrhagic transformation [4].Recently, several lines of evidence have demonstrated the involvement of the MMPs in cerebral ischemia. Studies in rat, mouse, and baboon models have shown that MMP-9 is up-regulated following transient focal ischemia [5-8]. Additionally, Asahi et al. have shown that MMP-9 knockout as
Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats
Lin Xu, Susan C Fagan, Jennifer L Waller, David Edwards, Cesar V Borlongan, Jianqing Zheng, William D Hill, Giora Feuerstein, David C Hess
BMC Neurology , 2004, DOI: 10.1186/1471-2377-4-7
Abstract: Rats underwent 90 minutes of TMCAO. Minocycline or saline placebo was administered IV starting at 4, 5, or 6 hours post TMCAO. Infarct volume and neurofunctional tests were carried out at 24 hr after TMCAO using 2,3,5-triphenyltetrazolium chloride (TTC) brain staining and Neurological Score evaluation. Pharmacokinetic studies and hemodynamic monitoring were performed on minocycline-treated rats.Minocycline at doses of 3 mg/kg and 10 mg/kg IV was effective at reducing infarct size when administered at 4 hours post TMCAO. At doses of 3 mg/kg, minocycline reduced infarct size by 42% while 10 mg/kg reduced infarct size by 56%. Minocycline at a dose of 10 mg/kg significantly reduced infarct size at 5 hours by 40% and the 3 mg/kg dose significantly reduced infarct size by 34%. With a 6 hour time window there was a non-significant trend in infarct reduction. There was a significant difference in neurological scores favoring minocycline in both the 3 mg/kg and 10 mg/kg doses at 4 hours and at the 10 mg/kg dose at 5 hours. Minocycline did not significantly affect hemodynamic and physiological variables. A 3 mg/kg IV dose of minocycline resulted in serum levels similar to that achieved in humans after a standard 200 mg dose.The neuroprotective action of minocycline at clinically suitable dosing regimens and at a therapeutic time window of at least 4–5 hours merits consideration of phase I trials in humans in view of developing this drug for treatment of stroke.Minocycline is a tetracycline antibiotic with demonstrated anti-inflammatory [1-3], glutamate antagonist [3,4], and anti-apoptotic actions [5-8] in many models of brain injury [2,3,9-11]. These properties, along with its superior human safety and blood-brain-barrier penetration make it an ideal candidate for clinical trials in stroke and other neurological diseases [12]. In focal cerebral ischemia, minocycline has been shown to reduce infarct size by more than 50% when administered up to 4 hours after the onset of ische
Vascular Protection by Angiotensin Receptor Antagonism Involves Differential VEGF Expression in Both Hemispheres after Experimental Stroke
Weihua Guan, Payaningal R. Somanath, Anna Kozak, Anna Goc, Azza B. El-Remessy, Adviye Ergul, Maribeth H. Johnson, Ahmed Alhusban, Sahar Soliman, Susan C. Fagan
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024551
Abstract: We identified that the angiotensin receptor antagonist, candesartan, has profound neurovascular protective properties when administered after ischemic stroke and was associated with a proangiogenic state at least partly explained by vascular endothelial growth factor A (VEGFA). However, the spatial distribution of vascular endothelial growth factor (VEGF) isoforms and their receptors remained unknown. Protein analysis identified a significant increase in vascular endothelial grow factor B (VEGFB) in the cerebrospinal fluid (CSF) and the ischemic hemispheres (with increased VEGF receptor 1 activation) of treated animals (p<0.05) which was co-occurring with an increase in protein kinase B (Akt) phosphorylation (p<0.05). An increase in VEGFA protein in the contralesional hemisphere corresponded to a significant increase in vascular density at seven days (p<0.01) after stroke onset. Vascular restoration by candesartan after stroke maybe related to differential regional upregulation of VEGFB and VEGFA, promoting a “prosurvival state” in the ischemic hemisphere and angiogenesis in the contralesional side, respectively. These vascular changes in both hemispheres after effective treatment are likely to contribute to enhanced recovery after stroke.
Increased hemorrhagic transformation and altered infarct size and localization after experimental stroke in a rat model type 2 diabetes
Adviye Ergul, Mostafa M Elgebaly, Mary-Louise Middlemore, Weiguo Li, Hazem Elewa, Jeffrey A Switzer, Christiana Hall, Anna Kozak, Susan C Fagan
BMC Neurology , 2007, DOI: 10.1186/1471-2377-7-33
Abstract: Diabetic Goto-Kakizaki (GK) or control rats underwent 3 hours of middle cerebral artery occlusion and 21 h reperfusion followed by evaluation of infarct size, hemorrhage and neurological outcome.Infarct size was significantly smaller in GK rats (10 ± 2 vs 30 ± 4%, p < 0.001). There was significantly more frequent hematoma formation in the ischemic hemisphere in GK rats as opposed to controls. Cerebrovascular tortuosity index was increased in the GK model (1.13 ± 0.01 vs 1.34 ± 0.06, P < 0.001) indicative of changes in vessel architecture.These findings provide evidence that there is cerebrovascular remodeling in diabetes. While diabetes-induced remodeling appears to prevent infarct expansion, these changes in blood vessels increase the risk for HT possibly exacerbating neurovascular damage due to cerebral ischemia/reperfusion in diabetes.Ischemic stroke is a leading cause of death and disability in the United States and diabetes is the most rapidly increasing risk factor for stroke. Among patients with recent stroke, 70% have overt diabetes or prediabetes characterized by impaired fasting glucose or impaired glucose tolerance [1]. Type 2 diabetes, a disease that affects more than 17 million Americans with an alarming number of new cases, holds a 2–6 fold increased risk for stroke. Not only is the incidence of stroke increased among diabetics, but stroke patients with diabetes have a worse outcome. Mortality is increased in diabetics at one week, one month and three months after stroke, and diabetic stroke survivors have more profound neurologic deficits and disability [2]. In addition, diabetes and hyperglycemia predict early neurologic deterioration following ischemic stroke [3]. A recent study reported that persistent post-stroke hyperglycemia causes infarct expansion and worse clinical outcome [4]. Vascular complications of diabetes characterized by vascular dysfunction and pathological remodeling contribute to increased cardiovascular mortality and morbidity in
Role of Matrix Metalloproteinase Activity in the Neurovascular Protective Effects of Angiotensin Antagonism
Tauheed Ishrat,Anna Kozak,Ahmed Alhusban,Bindu Pillai,Maribeth H. Johnson,Azza B. El-Remessy,Adviye Ergul,Susan C. Fagan
Stroke Research and Treatment , 2014, DOI: 10.1155/2014/560491
Abstract: Background and Purpose. Oxidative stress and matrix metalloproteinase (MMP) activity have been identified as key mediators of early vascular damage after ischemic stroke. Somewhat surprisingly, the angiotensin II type 1 receptor (AT1) blocker, candesartan, has been shown to acutely increase MMP activity while providing neurovascular protection. We aimed to determine the contribution of MMP and nitrative stress to the effects of angiotensin blockade in experimental stroke. Methods. Wistar rats (n?=?9–14/group; a total of 99) were treated in a factorial design with candesartan 1?mg/kg IV, alone or in combination with either a peroxynitrite decomposition catalyst, FeTPPs, 30?mg/kg IP or GM6001 50?mg/kg IP (MMP inhibitor). Neurological deficit, infarct, size and hemorrhagic transformation (HT) were measured after 3?h of middle cerebral artery occlusion (MCAO) and 21?h of reperfusion. MMP activity and nitrotyrosine expression were also measured. Results. Candesartan reduced infarct size and HT when administered alone ( ) and in combination with FeTPPs ( ). GM6001 did not significantly affect HT when administered alone, but the combination with candesartan caused increased HT ( ) and worsened neurologic score ( ). Conclusions. Acute administration of candesartan reduces injury after stroke despite increasing MMP activity, likely by an antioxidant mechanism. 1. Introduction Ischemic stroke, an obstruction of blood flow in a major cerebral vessel, remains a leading cause of adult disability and death in the United States [1]. Because of its complex pathology, a major research and clinical priority is to develop therapeutic interventions in the ischemic brain through the understanding of underlying mechanisms. Ischemia reperfusion leads to a cascade of pathophysiological processes, resulting in further brain damage. Accumulations of free radicals, oxygen/nitrogen species (ROS/RNS), not only increase the susceptibility of brain tissue to reperfusion-induced damage but also trigger numerous molecular cascades, leading to increased blood-brain barrier (BBB) permeability, brain edema, hemorrhage and inflammation, and brain death [2, 3]. As an important component of free radicals, RNS, including peroxynitrite (ONOO–), play important roles in the process of cerebral ischemia-reperfusion injury. Ischemia reperfusion results in the production of peroxynitrite in ischemic brain, which triggers numerous molecular cascades and leads to vascular damage. In vitro, peroxynitrite strongly activates matrix metalloproteinases (MMPs) [4, 5]. Peroxynitrite formation on
Impact of Adaptive Quizzing as a Practice and Remediation Strategy to Prepare for the NCLEX-RN  [PDF]
Susan Malkemes, Julia C. Phelan
Open Journal of Nursing (OJN) , 2017, DOI: 10.4236/ojn.2017.711093
Abstract:

National Council Licensure Examination-Registered Nurse (NCLEX-RN) outcomes are extremely important to nursing institutions and students for myriad reasons. For students, the NCLEX-RN represents one of the final milestones to conquer before entering a nursing career. Nursing programs monitor NCLEX-RN pass rates as an important gauge of program quality and minimum levels frequently must be met. This study explored the implementation of an adaptive quizzing and learning system as part of an NCLEX-RN preparation strategy designed to increase student engagement and subsequent success on the NCLEX-RN. The adaptive quizzing system was used as part of an ongoing, proactive strategy to student preparation. This strategy is in contrast to the practice of using high-stakes exams scores to try and predict student NCLEX-RN outcomes. In the latter case there is mixed evidence on how scores relate to remediation and moving students toward success based on evidence of need. The study school required students (N = 54) to take regular, adaptive practice quizzes throughout their final year in the nursing program. Students were also given the HESI E2 in their final semester and all but one student achieved the target threshold with a range of scores (772 to 1028). Despite this variability, 90.7% of the students in the study group passed the NCLEX-RN on their first attempt, with a pass rate of 98% when considering those who passed on the second attempt. NCLEX-RN pass rates at the study school increased by 11.55% following the implementation of the system and in the second year of implementation (the data analyzed for this study) increased an additional 3.95% from the previous year. With many factors to consider, we cannot say, unequivocally, that using the AQS resulted in an increase in NCLEX-RN pass rates at the study school. Findings from this retrospective study do, however, support the use of an adaptive quizzing system as a component of the NCLEX-RN preparation strategy. Implications of these findings are discussed.

The feasibility of a single-blinded fast-track pragmatic randomised controlled trial of a complex intervention for breathlessness in advanced disease
Morag C Farquhar, Irene J Higginson, Petrea Fagan, Sara Booth
BMC Palliative Care , 2009, DOI: 10.1186/1472-684x-8-9
Abstract: A single-blinded fast-track pragmatic randomised controlled trial was conducted for patients with chronic obstructive pulmonary disease referred to the service. Patients were randomised to either receive the intervention immediately for an eight-week period, or receive the intervention after an eight-week period on a waiting list during which time they received standard care. Outcomes examined included: response rates to the trial; response rates to the individual questionnaires and items; comments relating to the trial functioning made during interviews with patients, carers, referrers and service providers; and, researcher fieldwork notes.16 of the 20 eligible patients agreed to participate in a recruitment visit (16/20); 14 respondents went on to complete a recruitment visit/baseline interview. The majority of those who completed a recruitment visit/baseline interview completed the RCT protocol (13/14); 12 of their carers were recruited and completed the protocol. An unblinding rate of 6/25 respondents (patients and carers) was identified. Missing data were minimal and only one patient was lost to follow up. The fast-track trial methodology proved feasible and acceptable. Two of the baseline/outcome measures proved unsuitable: the WHO performance scale and the Schedule for the Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW).This study adds to the evidence that fast-track randomised controlled trials are feasible and acceptable in evaluations of palliative care interventions for patients with non-malignant conditions. Reasonable response rates and low attrition rates were achieved. Further, with adequate preparation of the research and randomisation teams, clinicians, and responders, and effective liaison with the clinicians, single-blinding proved possible. Methods were identified to reduce unblinding through careful attention to the type of data collected at unblinded measurement points; the content of interviews should be carefully conside
Co-Fuelling of Peat with Meat and Bone Meal in a Pilot Scale Bubbling Bed Reactor
Kevin McDonnell,Enda J. Cummins,Colette C. Fagan,Markku Orjala
Energies , 2010, DOI: 10.3390/en3071369
Abstract: Co-combustion performance trials of Meat and Bone Meal (MBM) and peat were conducted using a bubbling fluidized bed (BFB) reactor. In the combustion performance trials the effects of the co-combustion of MBM and peat on flue gas emissions, bed fluidization, ash agglomeration tendency in the bed and the composition and quality of the ash were studied. MBM was mixed with peat at 6 levels between 15% and 100%. Emissions were predominantly below regulatory limits. CO concentrations in the flue gas only exceeded the 100 mg/m 3 limit upon combustion of pure MBM. SO 2 emissions were found to be over the limit of 50 mg/m 3, while in all trials NO x emissions were below the limit of 300 mg/m 3. The HCl content of the flue gases was found to vary near the limit of 30 mg/m 3. VOCs however were within their limits. The problem of bed agglomeration was avoided when the bed temperature was about 850 °C and only 20% MBM was co-combusted. This study indicates that a pilot scale BFB reactor can, under optimum conditions, be operated within emission limits when MBM is used as a co-fuel with peat. This can provide a basis for further scale-up development work in industrial scale BFB applications.
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