Samuel M Poloyac

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Are you Samuel M Poloyac?

Claim your profile

Publications (59)230.91 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To examine the relationship between regional cerebral oxygen saturation (rSO2), delayed cerebral ischaemia (DCI), and outcomes after aneurysmal subarachnoid haemorrhage (aSAH).
    Intensive & critical care nursing: the official journal of the British Association of Critical Care Nurses 06/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aneurysmal subarachnoid hemorrhage is a type of stroke with high morbidity and mortality. Increased endothelin-1 (ET-1) levels have been associated with increased risk of cerebral vasospasm, which is associated with increased morbidity. The purpose of this study was to investigate the relationships between ET-1 genotypes and ET-1 protein levels in cerebrospinal fluid (CSF) measured 72 hr before angiographic vasospasm measurement in subjects at high risk of cerebral vasospasm. Specifically, this study evaluated the differences between variant positive and variant negative groups of nine different ET-1 single-nucleotide polymorphisms (SNPs) in relationship with the ET-1 protein exposure rate. The CSF ET-1 protein levels were quantified using enzyme-linked immunosorbent assay. One functional SNP and eight ET-1 tagging SNPs were selected because they represent genetic variability in the entire ET-1 gene. The variant negative group of SNP rs2070699 was associated with a significantly higher ET-1 exposure rate than the variant positive group (p = 0.004), while the variant positive group of the rs5370 group showed a trend toward association with a higher ET-1 exposure rate (p = 0.051). Other SNPs were not informative. This is the first study to show differences in ET-1 exposure rate 72 hr before angiography in relation to ET-1 genotypes. These exploratory findings need to be replicated in a larger study; if replicated, these differences in genotypes may be a way to inform clinicians of those patients at a higher risk of increased ET-1 protein levels, which may lead to a higher risk of angiographic vasospasm.
    Biological Research for Nursing 05/2014; · 1.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The central role of mitochondria in metabolic pathways and in cell-death mechanisms requires sophisticated signalling systems. Essential in this signalling process is an array of lipid mediators derived from polyunsaturated fatty acids. However, the molecular machinery for the production of oxygenated polyunsaturated fatty acids is localized in the cytosol and their biosynthesis has not been identified in mitochondria. Here we report that a range of diversified polyunsaturated molecular species derived from a mitochondria-specific phospholipid, cardiolipin (CL), is oxidized by the intermembrane-space haemoprotein, cytochrome c. We show that a number of oxygenated CL species undergo phospholipase A2-catalysed hydrolysis and thus generate multiple oxygenated fatty acids, including well-known lipid mediators. This represents a new biosynthetic pathway for lipid mediators. We demonstrate that this pathway, which includes the oxidation of polyunsaturated CLs and accumulation of their hydrolysis products (oxygenated linoleic, arachidonic acids and monolysocardiolipins), is activated in vivo after acute tissue injury.
    Nature Chemistry 05/2014; · 21.76 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cytochrome P450 (CYP) 4A and 4F enzymes metabolize arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE). Although CYP4A-derived 20-HETE is known to have prohypertensive and proangiogenic properties, the effects of CYP4F-derived metabolites are not well characterized. To investigate the role of CYP4F2 in vascular disease, we generated mice with endothelial expression of human CYP4F2 (Tie2-CYP4F2-Tr). LC/MS/MS analysis revealed 2-foldincreases in 20-HETE levels in tissues and endothelial cells (ECs), relative to wild-type (WT) controls. Tie2-CYP4F2-Tr ECs demonstrated increases in growth (267.1±33.4 vs. 205.0±13% at 48 h) and tube formation (7.7±1.1 vs. 1.6±0.5 tubes/field) that were 20-HETE dependent and associated with up-regulation of prooxidant NADPH oxidase and proangiogenic VEGF. Increases in VEGF and NADPH oxidase levels were abrogated by inhibitors of NADPH oxidase and MAPK, respectively, suggesting the possibility of crosstalk between pathways. Interestingly, IL-6 levels in Tie2-CYP4F2-Tr mice (18.6±2.7 vs. 7.9±2.7 pg/ml) were up-regulated via NADPH oxidase- and 20-HETE-dependent mechanisms. Although Tie2-CYP4F2-Tr aortas displayed increased vasoconstriction, vasorelaxation and blood pressure were unchanged. Our findings indicate that human CYP4F2 significantly increases 20-HETE production, CYP4F2-derived 20-HETE mediates EC proliferation and angiogenesis via VEGF- and NADPH oxidase-dependent manners, and the Tie2-CYP4F2-Tr mouse is a novel model for examining the pathophysiological effects of CYP4F2-derived 20-HETE in the vasculature.-Cheng, J., Edin, M. L., Hoopes, S. L., Li, H., Bradbury, J. A., Graves, J. P., DeGraff, L. M., Lih, F. B., Garcia, V., Shaik, J. S. B., Tomer, K. B., Flake, G. P., Falck, J. R., Lee, C. R., Poloyac, S. M., Schwartzman, M. L., Zeldin, D. C. Vascular characterization of mice with endothelial expression of cytochrome P450 4F2.
    The FASEB Journal 03/2014; · 5.70 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives To examine the relationship between regional cerebral oxygen saturation (rSO2), delayed cerebral ischaemia (DCI), and outcomes after aneurysmal subarachnoid haemorrhage (aSAH). Research Methodology Subjects (n = 163) with aSAH, age 21–75 years, and Fisher grade >1 were included in the study. Continuous rSO2 monitoring was performed for 5–10 days after injury using near-infrared spectroscopy with sensors over the frontal/temporal cortex. rSO2 < 50 indicated desaturation. DCI was defined as neurological deterioration due to impaired cerebral blood flow. Three- and 12-month functional outcomes were assessed by the modified Rankin scale (MRS) as good (0–3) and poor (4–6). Results DCI occurred in 57% of patients; of these 66% had rSO2 < 50. Overall, 56% had rSO2 < 50 on either side, 21% and 16% had poor MRS at 3 and 12 months. Subjects with rSO2 <50 were 3.25 times more likely to have DCI compared to those with rSO2 >50 (OR 3.25, 95%CI 1.58–6.69), positive predictive value (PPV) = 70%. Subjects with rSO2 <50 were 2.7 times more likely to have poor 3-month MRS compared to those with rSO2 >50 (OR 2.7, 95%CI 1.1–7.2), PPV = 70%. Conclusions These results suggest that NIRS has the potential for detecting DCI after aSAH. This potential needs to be further explored in a larger prospective study.
    Intensive and Critical Care Nursing. 01/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Fatty liver disease is an emerging public health problem without effective therapies, and chronic hepatic inflammation is a key pathologic mediator in its progression. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory effects. Although promoting the effects of EETs elicits anti-inflammatory and protective effects in the cardiovascular system, the contribution of CYP-derived EETs to the regulation of fatty liver disease-associated inflammation and injury is unknown. Using the atherogenic diet model of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), our studies demonstrated that induction of fatty liver disease significantly and preferentially suppresses hepatic CYP epoxygenase expression and activity, and both hepatic and circulating levels of EETs in mice. Furthermore, mice with targeted disruption of Ephx2 (the gene encoding soluble epoxide hydrolase) exhibited restored hepatic and circulating EET levels and a significantly attenuated induction of hepatic inflammation and injury. Collectively, these data suggest that suppression of hepatic CYP-mediated EET biosynthesis is an important pathological consequence of fatty liver disease-associated inflammation, and that the CYP epoxygenase pathway is a central regulator of the hepatic inflammatory response in NAFLD/NASH. Future studies investigating the utility of therapeutic strategies that promote the effects of CYP-derived EETs in NAFLD/NASH are warranted.
    PLoS ONE 01/2014; 9(10):e110162. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The metabolites of arachidonic acid (AA) produced from the cyclooxygenase (COX) pathway, collectively termed as prostanoids, and from the CYP 450 pathway, eicosanoids, have been implicated in various neuro-degenerative and neuroinflammatory diseases. This study developed a quantitative UPLC-MS/MS method to simultaneously measure 11 prostanoids including prostaglandins and cyclopentenone metabolites in the rat brain cortical tissue. Linear calibration curves ranging from 0.104 to 33.3ng/ml were validated. The inter-day and intra-day variance for all metabolites was less than 15%. The extraction recovery efficiency and matrix (deionized water) effects measured at 12.5ng/ml (750pg on column) ranged from 88 to 100% and 3 to 14%, respectively, with CV% values below 20%. Additionally, applying the processing and extraction conditions of this method to our previous CYP450 eicosanoids method resulted in overall improvement in extraction recovery and reduction in matrix effects at low (0.417ng/ml) and high (8.33ng/ml) concentrations. In rat brain cortical tissue samples, concentrations of prostanoids ranged from 10.2 to 937pmol/g wet tissue and concentration of eicosanoids ranged from 2.23 to 793pmol/g wet tissue. These data demonstrate that the successive measurement of prostanoids and eicosanoids from a single extracted sample of rat brain tissue can be achieved with a UPLC-MS/MS system and that this method is necessary for evaluation of these metabolites to delineate their role in various neuroinflammatory and cerebrovascular disorders.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 11/2013; 945-946C:207-216. · 2.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE: Preclinical and clinical studies have suggested that therapeutic hypothermia, while decreasing neurologic injury, may also lead to drug toxicity that may limit its benefit. Cooling decreases cytochrome P450 (CYP)-mediated drug metabolism, and limited clinical data suggest that drug levels are elevated. Fosphenytoin is metabolized by cytochrome P450 2C, has a narrow therapeutic range, and is a commonly used antiepileptic medication. The objective of this study was to evaluate the impact of therapeutic hypothermia on phenytoin levels and pharmacokinetics in children with severe traumatic brain injury. DESIGN: Pharmacokinetic analysis of subjects participating in a multicenter randomized phase III study of therapeutic hypothermia for severe traumatic brain injury. SETTING: ICU at the Children's Hospital of Pittsburgh. PATIENTS: Nineteen children with severe traumatic brain injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A sum of 121 total and 114 free phenytoin levels were evaluated retrospectively in 10 hypothermia-treated and nine normothermia-treated children who were randomized to 48 hours of cooling to 32-33°C followed by slow rewarming or controlled normothermia. Drug dosing, body temperatures, and demographics were collected during cooling, rewarming, and posttreatment periods (8 d). A trend toward elevated free phenytoin levels in the hypothermia group (p=0.051) to a median of 2.2 mg/L during rewarming was observed and was not explained by dosing differences. Nonlinear mixed-effects modeling incorporating both free and total levels demonstrated that therapeutic hypothermia specifically decreased the time-variant component of the maximum velocity of phenytoin metabolism (Vmax) 4.6-fold (11.6-2.53 mg/hr) and reduced the overall Vmax by ~50%. Simulations showed that the increased risk for drug toxicity extends many days beyond the end of the cooling period. CONCLUSIONS: Therapeutic hypothermia significantly reduces phenytoin elimination in children with severe traumatic brain injury leading to increased drug levels for an extended period of time after cooling. Pharmacokinetic interactions between hypothermia and medications should be considered when caring for children receiving this therapy.
    Critical Care Medicine 10/2013; 41(10):2379-87. · 6.12 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background and purpose: Soluble epoxide hydrolase (sEH) diminishes vasodilatory and neuroprotective effects of epoxyeicosatrienoic acids by hydrolyzing them to inactive dihydroxy metabolites. The primary goals of this study were to investigate the effects of acute sEH inhibition by t-AUCB on infarct volume, functional outcome, and changes in cerebral blood flow (CBF) in a rat model of ischemic stroke. Methods: Focal cerebral ischemia was induced in rats for 90 min followed by reperfusion. At the end of 24 h after reperfusion rat were euthanized for infarct volume assessment by TTC staining. Brain cortical sEH activity was assessed by UPLC-MS/MS. Functional outcome at 24, and 48 h after reperfusion was evaluated by arm flexion, and sticky-tape tests. Changes in CBF were assessed by ASL-MRI at baseline, during ischemia, and at 180 min after reperfusion. Neuroprotective effects of t-AUCB were evaluated in primary rat neuronal cultures by Cytotox-Flour kit and Propidium Iodide staining. Results: t-AUCB significantly reduced cortical infarct volume by 35% (14.5±2.7% vs 41.5±4.5%), elevated cumulative EETs/DHETs ratio in brain cortex by two fold (4.40±1.89 vs 1.97±0.85), and improved functional outcome in arm-flexion test (day 1: 3.28±0.5 s vs 7.50±0.9 s; day 2: 1.71±0.4 s vs 5.28±0.5 s) when compared to the vehicle-treated group. t-AUCB significantly reduced neuronal cell death in a dose dependent manner (vehicle:70.9±7.1% vs t-AUCB0.1µM: 58±5.11% vs t-AUCB0.5µM: 39.9±5.8%). Conclusions: These findings suggest that t-AUCB may exert its neuroprotective effects by affecting multiple components of neurovascular unit including neurons, astrocytes and microvascular flow.
    AJP Heart and Circulatory Physiology 09/2013; · 4.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prostaglandin D2 (PGD2) is the most abundant prostaglandin in brain but its effect on neuronal cell death is complex and not completely understood. PGD2 may modulate neuronal cell death via activation of DP receptors or its metabolism to the cyclopentenone prostaglandins (CyPGs) PGJ2, △(12)-PGJ2 and 15-deoxy-△(12,14)-PGJ2, inducing cell death independently of prostaglandin receptors. This study aims to elucidate the effect of PGD2 on neuronal cell death and its underlying mechanisms. PGD2 dose-dependently induced cell death in rat primary neuron-enriched cultures in concentrations of ≥ 10μM, and this effect was not reversed by treatment with either DP1 or DP2 receptor antagonists. Antioxidants N-acetylcysteine (NAC) and glutathione which contain sulfhydryl groups that can bind to CyPGs, but not ascorbate or tocopherol, attenuated PGD2-induced cell death. Conversion of PGD2 to CyPGs was detected in neuronal culture medium; treatment with these CyPG metabolites alone exhibited effects similar to those of PGD2, including apoptotic neuronal cell death and accumulation of ubiquitinated proteins. Disruption of lipocalin-type prostaglandin D synthase (L-PGDS) protected neurons against hypoxia. These results support the hypothesis that PGD2 elicits its cytotoxic effects through its bioactive CyPG metabolites rather than DP receptor activation in primary neuronal culture.
    NeuroToxicology 08/2013; · 2.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Cyclopentenone prostaglandins have been identified as potential neurotoxic agents in the setting of hypoxia-ischemia. Cyclooxygenase-2 (COX-2), the upstream enzyme responsible for prostaglandin production is upregulated following hypoxic-ischemic brain injury. However, the temporal production and concentration of cyclopentenone prostaglandins has not been described following global brain ischemia. METHODS: Global brain ischemia was induced in rats by asphyxial cardiac arrest (ACA) followed by resuscitation. Rats were sacrificed between 24 hours and 7 days following resuscitation and their brains removed. Western blot, immunohistochemistry, and mass spectroscopy were performed. A cohort of rats was pretreated with the COX-2 inhibitor SC58125. RESULTS: COX-2 is induced in hippocampus at 24 hours following ACA. Multiple prostaglandins, including cyclopentenone prostaglandin species, are increased in hippocampus as 24 hours following ACA. Prostaglandin and cyclopentenone prostaglandin concentrations are returned to baseline at 3 and 7 days post-ischemia. The COX-2 inhibitor SC58125 completely abrogates the post-ischemic increase in prostaglandins and cyclopentenone prostaglandins. CONCLUSIONS: Prostaglandins, including cyclopentenone prostaglandins, are increased in ischemic brain, peak at 24 hours and can be attenuated by the COX-2 inhibitor SC58125. These data establish the presence of potentially neurotoxic cyclopentenone prostaglandins in post-ischemic brains, thus identifying a target and therapeutic window for neuroprotective therapies.
    Brain research 04/2013; · 2.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVES:: Pathological increases in asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, have been implicated in endothelial dysfunction and vascular diseases. Reduced nitric oxide early after traumatic brain injury may contribute to hypoperfusion. Currently, methods to quantify asymmetric dimethylarginine in the cerebrospinal fluid have not been fully explored. We aimed to develop and validate a method to determine asymmetric dimethylarginine in the cerebrospinal fluid of a pediatric traumatic brain injury population and to use this method to assess the effects of 1) traumatic brain injury and 2) therapeutic hypothermia on this mediator. DESIGN, SETTING, AND PATIENTS:: An ancillary study to a prospective, phase II randomized clinical trial of early hypothermia in a tertiary care pediatric intensive care unit for children with Traumatic brain injury admitted to Children's Hospital of Pittsburgh. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: A UPLC-MS/MS method was developed and validated to quantitate asymmetric dimethylarginine. A total of 56 samples collected over 3 days with injury onset were analyzed from the cerebrospinal fluid of consented therapeutic hypothermia (n = 9) and normothermia (n = 10) children. Children undergoing diagnostic lumbar puncture (n = 5) were enrolled as controls. Asymmetric dimethylarginine was present at a quantifiable level in all samples. Mean asymmetric dimethylarginine levels were significantly increased in normothermic Traumatic brain injury children compared with that in control (0.19 ± 0.08 µmol/L and 0.11 ± 0.02 µmol/L, respectively, p = 0.01), and hypothermic children had significantly reduced mean asymmetric dimethylarginine levels (0.11 ± 0.05 µmol/L) vs. normothermic (p = 0.03) measured on day 3. Patient demographics including age, gender, and nitric oxide levels (measured as nitrite and nitrate using liquid chromatography coupled with Griess reaction) did not significantly differ between normothermia and hypothermia groups. Also, nitric oxide levels did not correlate with asymmetric dimethylarginine concentrations. CONCLUSIONS:: Asymmetric dimethylarginine levels were significantly increased in the cerebrospinal fluid of traumatic brain injury children. Early hypothermia attenuated this increase. The implications of attenuated asymmetric dimethylarginine on nitric oxide synthases activity and regional cerebral blood flow after traumatic brain injury by therapeutic hypothermia deserve future study.
    Pediatric Critical Care Medicine 02/2013; · 2.35 Impact Factor
  • Samuel M Poloyac, Philip E Empey
    Pediatric Critical Care Medicine 02/2013; 14(2):228-9. · 2.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The advancement of research from basic science discovery to clinical application requires the extensive collaboration of individuals from multiple disciplines, therefore the ability to work as an effective interprofessional team is essential for researchers in clinical and translational science (CTS). Courses that build interprofessional skills are a key component in CTS education, but the development of these courses poses numerous administrative and educational challenges. This paper describes the processes of designing, implementing, and evaluating an innovative graduate-level course that combines online lectures and in-class facilitated group discussions to promote interprofessional interactions. The course offers students the opportunity to interact with and learn from individuals in a variety of disciplines, and it requires students to engage in interprofessional group work to meet the course objectives. During the past 4 years, 96 students from the schools of medicine, pharmacy, nursing, public health, and health and rehabilitation sciences at a large urban university have completed the course. The course has been well-received, with 87% of students rating its overall quality as excellent, good, or satisfactory. The course offers educators a model to teach graduate students the skills that are essential for becoming effective CTS researchers. Clin Trans Sci 2012; Volume #: 1-7.
    Clinical and Translational Science 02/2013; 6(1):50-6. · 2.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The cyclopentenone prostaglandin (CyPG) J(2) series, including prostaglandin J(2) (PGJ(2)), Δ(12)-PGJ(2), and 15-deoxy-∆(12,14)-prostaglandin J(2) (15d-PGJ(2)), are active metabolites of PGD(2), exerting multiple effects on neuronal function. However, the physiologic relevance of these effects remains uncertain as brain concentrations of CyPGs have not been precisely determined. In this study, we found that free PGD(2) and the J(2) series CyPGs (PGJ(2), Δ(12)-PGJ(2), and 15d-PGJ(2)) were increased in post-ischemic rat brain as detected by UPLC-MS/MS with 15d-PGJ(2) being the most abundant CyPG. These increases were attenuated by pre-treating with the cyclooxygenase (COX) inhibitor piroxicam. Next, effects of chronic exposure to 15d-PGJ(2) were examined by treating primary neurons with 15d-PGJ(2), CAY10410 (a 15d-PGJ(2) analog lacking the cyclopentenone ring structure), or vehicle for 24 to 96 h. Because we found that the concentration of free 15d-PGJ(2) decreased rapidly in cell culture medium, freshly prepared medium containing 15d-PGJ(2), CAY10410, or vehicle was changed twice daily to maintain steady extracellular concentrations. Incubation with 2.5 μM 15d-PGJ(2), but not CAY10410, increased the neuronal cell death without the induction of caspase-3 or PARP cleavage, consistent with a primarily necrotic mechanism for 15d-PGJ(2)-induced cell death which was further supported by TUNEL assay results. Ubiquitinated protein accumulation and aggregation was observed after 96 h 15d-PGJ(2) incubation, accompanied by compromised 20S proteasome activity. Unlike another proteasome inhibitor, MG132, 15d-PGJ(2) treatment did not activate autophagy or induce aggresome formation. Therefore, the cumulative cytotoxic effects of increased generation of CyPGs after stroke may contribute to delayed post-ischemic neuronal injury.
    Neurotoxicity Research 01/2013; · 2.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease that affects approximately 30,000 people a year in the United States. Delayed cerebral ischemia (DCI) and cerebral vasospasm (CV) are common complications after aSAH. In addition, aSAH patients have a high risk of poor long-term outcomes. Endothelin-1 (ET-1), a potent vasoconstrictor, or its two types of receptors, ET receptor A (ET(A) ) and ET receptor B (ET(B)), may play a role in the pathogenesis of DCI and CV. Genetic variations within the ET-1,ET(A), or ET(B) genes may also account for variance observed in the outcomes of aSAH patients. The purpose of this study was to describe the distribution of the Lys198Asn polymorphism, a known functional SNP in the ET-1 gene, and tagging SNPs of the ET-1, ET(A), and ET(B) genes in individuals recovering from aSAH. This study also investigated the relationships among the ET polymorphisms, DCI, and global functional outcomes measured at 3 and 6 months after aSAH. Participants included individuals aged 18-75 years with a diagnosis of aSAH. There was a trend found between the variant allele of an ET-1 SNP (rs6912834) and angiographic vasospasm. There were also associations found between two ET(B) SNPs (rs9574124 and rs3027111) and poor outcomes as measured by the Glasgow Outcome scale at 3 months. These findings support the role of ET-1 and ET(B) in recovery following aSAH.
    Biological Research for Nursing 09/2012; · 1.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: A typology of cerebral vasospasm has been proposed based on distinct clinical manifestations: delayed cerebral ischemia, symptomatic 'vasospasm', angiographic vasospasm, and transcranial Doppler vasospasm. We examined each distinct clinical manifestation in a nonparametric genetic association study. AIMS: The purpose of this study was to examine and compare each four distinct acute clinical manifestations and test its perspectives in genetic association studies. METHODS: Two hundred forty-five Caucasian patients with sub-arachnoid hemorrhage were evaluated for these four distinct clinical manifestations along with 906 600 single-nucleotide polymorphisms across the human genome. RESULTS: The four clinical manifestations were significantly associated with each other as P-values ranged from 3·31 × 10(-4) to 8·10 × 10(-15) . Transcranial Doppler vasospasm showed significant genetic association with single nucleotide polymorphism (SNP) (rs999662, P = 3·39 × 10(-8) ). Statistical P-value of rs999662 in association with delayed cerebral ischemia, symptomatic 'vasospasm', and angiographic vasospasm was 0·0017, 0·0017, and 0·19, respectively. CONCLUSIONS: Despite different criteria for each of the four clinical manifestations, they are significantly associated with each other. Our results suggest transcranial Doppler vasospasm may be an appropriate intermediate but still clinically relevant phenotype for genetic association studies. Association with SNP rs999662 indicates a potential role for the region containing the solute carrier family 12 member 3 (SLC12A3) gene in transcranial Doppler vasospasm following sub-arachnoid hemorrhage.
    International Journal of Stroke 05/2012; · 2.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Preclinical and genetic epidemiologic studies suggest that modulating cytochrome P450 (CYP)-mediated arachidonic acid metabolism may have therapeutic utility in the management of coronary artery disease (CAD). However, predictors of inter-individual variation in CYP-derived eicosanoid metabolites in CAD patients have not been evaluated to date. Therefore, the primary objective was to identify clinical factors that influence CYP epoxygenase, soluble epoxide hydrolase (sEH), and CYP ω-hydroxylase metabolism in patients with established CAD. Plasma levels of epoxyeicosatrienoic acids (EETs), dihydroxyeicosatrienoic acids (DHETs), and 20-hydroxyeicosatetraenoic acid (20-HETE) were quantified by HPLC-MS/MS in a population of patients with stable, angiographically confirmed CAD (N=82) and healthy volunteers from the local community (N=36). Predictors of CYP epoxygenase, sEH, and CYP ω-hydroxylase metabolic function were evaluated by regression. Obesity was significantly associated with low plasma EET levels and 14,15-EET:14,15-DHET ratios. Age, diabetes, and cigarette smoking also were significantly associated with CYP epoxygenase and sEH metabolic activity, while only renin-angiotensin system inhibitor use was associated with CYP ω-hydroxylase metabolic activity. Compared to healthy volunteers, both obese and non-obese CAD patients had significantly higher plasma EETs (P<0.01) and epoxide:diol ratios (P<0.01), whereas no difference in 20-HETE levels was observed (P=NS). Collectively, these findings suggest that CYP-mediated eicosanoid metabolism is dysregulated in certain subsets of CAD patients, and demonstrate that biomarkers of CYP epoxygenase and sEH, but not CYP ω-hydroxylase, metabolism are altered in stable CAD patients relative to healthy individuals. Future studies are necessary to determine the therapeutic utility of modulating these pathways in patients with CAD.
    Atherosclerosis 03/2012; 222(2):530-6. · 3.71 Impact Factor
  • Samuel M Poloyac
    Pediatric Critical Care Medicine 01/2012; 13(1):118-9. · 2.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Metabolism of arachidonic acid by cytochrome P450 (CYP) to biologically active eicosanoids has been recognized increasingly as an integral mediator in the pathogenesis of cardiovascular and metabolic disease. CYP epoxygenase-derived epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EET + DHET) and CYP ω-hydroxylase-derived 20-hydroxyeicosatetraenoic acid (20-HETE) exhibit divergent effects in the regulation of vascular tone and inflammation; thus, alterations in the functional balance between these parallel pathways in liver and kidney may contribute to the pathogenesis and progression of metabolic syndrome. However, the impact of metabolic dysfunction on CYP-mediated formation of endogenous eicosanoids has not been well characterized. Therefore, we evaluated CYP epoxygenase (EET + DHET) and ω-hydroxylase (20-HETE) metabolic activity in liver and kidney in apoE(-/-) and wild-type mice fed a high-fat diet, which promoted weight gain and increased plasma insulin levels significantly. Hepatic CYP epoxygenase metabolic activity was significantly suppressed, whereas renal CYP ω-hydroxylase metabolic activity was induced significantly in high-fat diet-fed mice regardless of genotype, resulting in a significantly higher 20-HETE/EET + DHET formation rate ratio in both tissues. Treatment with enalapril, but not metformin or losartan, reversed the suppression of hepatic CYP epoxygenase metabolic activity and induction of renal CYP ω-hydroxylase metabolic activity, thereby restoring the functional balance between the pathways. Collectively, these findings suggest that the kinin-kallikrein system and angiotensin II type 2 receptor are key regulators of hepatic and renal CYP-mediated eicosanoid metabolism in the presence of metabolic syndrome. Future studies delineating the underlying mechanisms and evaluating the therapeutic potential of modulating CYP-derived EETs and 20-HETE in metabolic diseases are warranted.
    AJP Endocrinology and Metabolism 12/2011; 302(5):E500-9. · 4.51 Impact Factor

Publication Stats

643 Citations
230.91 Total Impact Points

Institutions

  • 2001–2014
    • University of Pittsburgh
      • • School of Pharmacy
      • • Pharmaceutical Sciences
      • • School of Nursing
      • • Department of Emergency Medicine
      Pittsburgh, Pennsylvania, United States
    • Procter & Gamble
      Cincinnati, Ohio, United States
  • 2012
    • The University of Arizona
      • College of Nursing
      Tucson, AZ, United States
  • 2010–2012
    • University of North Carolina at Chapel Hill
      • Division of Pharmacotherapy and Experimental Therapeutics
      Chapel Hill, NC, United States
  • 2006
    • Childrens Hospital of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 1999–2001
    • University of Kentucky
      • • Department of Pharmaceutical Sciences
      • • College of Pharmacy
      Lexington, KY, United States
    • Minneapolis Veterans Affairs Hospital
      Minneapolis, Minnesota, United States