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Publication Record


Metabolic Effects of Diet and Exercise in Patients with Moderate to Severe CKD: A Randomized Clinical Trial.
Ikizler TA, Robinson-Cohen C, Ellis C, Headley SAE, Tuttle K, Wood RJ, Evans EE, Milch CM, Moody KA, Germain M, Limkunakul C, Bian A, Stewart TG, Himmelfarb J
(2018) J Am Soc Nephrol 29: 250-259
MeSH Terms: Adiposity, Aged, Albuminuria, Body Weight, Caloric Restriction, Creatinine, Exercise, F2-Isoprostanes, Female, Glomerular Filtration Rate, Humans, Interleukin-6, Male, Middle Aged, Oxidative Stress, Oxygen Consumption, Pilot Projects, Renal Insufficiency, Chronic
Show Abstract · Added October 24, 2017
CKD is steadily increasing along with obesity worldwide. Furthermore, obesity is a proinflammatory risk factor for progression of CKD and cardiovascular disease. We tested the hypothesis that implementation of caloric restriction and aerobic exercise is feasible and can improve the proinflammatory metabolic milieu in patients with moderate to severe CKD through a pilot, randomized, 2×2 factorial design trial. Of 122 participants consented, 111 were randomized to receive caloric restriction and aerobic exercise, caloric restriction alone, aerobic exercise alone, or usual care. Of those randomized, 42% were women, 25% were diabetic, and 91% were hypertensive; 104 started intervention, and 92 completed the 4-month study. Primary outcomes were a change from baseline in absolute fat mass, body weight, plasma F-isoprostane concentrations, and peak oxygen uptake (VO). Compared with usual care, the combined intervention led to statistically significant decreases in body weight and body fat percentage. Caloric restriction alone also led to significant decreases in these measures, but aerobic exercise alone did not. The combined intervention and each independent intervention also led to significant decreases in F-isoprostane and IL-6 concentrations. No intervention produced significant changes in VO, kidney function, or urine albumin-to-creatinine ratio. In conclusion, 4-month dietary calorie restriction and aerobic exercise had significant, albeit clinically modest, benefits on body weight, fat mass, and markers of oxidative stress and inflammatory response in patients with moderate to severe CKD. These results suggest healthy lifestyle interventions as a nonpharmacologic strategy to improve markers of metabolic health in these patients.
Copyright © 2018 by the American Society of Nephrology.
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2 Members
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18 MeSH Terms
Uric acid correlates to oxidation and inflammation in opposite directions in women.
Wu SH, Shu XO, Milne G, Xiang YB, Zhang X, Cai Q, Fazio S, Linton MF, Chen H, Purdue M, Rothman N, Gao YT, Zheng W, Yang G
(2015) Biomarkers 20: 225-31
MeSH Terms: Aged, Biomarkers, C-Reactive Protein, Case-Control Studies, Chromatography, Liquid, F2-Isoprostanes, Female, Gas Chromatography-Mass Spectrometry, Humans, Inflammation, Inflammation Mediators, Interleukin-6, Middle Aged, Oxidation-Reduction, Tandem Mass Spectrometry, Tumor Necrosis Factor-alpha, Uric Acid
Show Abstract · Added March 10, 2016
OBJECTIVE - To evaluate the association of uric acid (UA) levels with a panel of markers of oxidative stress and inflammation.
METHODS - Plasma UA levels, along with a panel of oxidative stress and inflammatory markers, were measured in 755 Chinese women.
RESULTS - Plasma UA levels were inversely associated with urinary levels of the oxidative stress marker F2-isoprostanes and positively correlated to levels of inflammatory markers, such as C-reactive protein and some proinflammatory cytokines (tumor necrosis factor-α and interleukin-6) in blood as well as prostaglandin E2 metabolites in urine.
CONCLUSIONS - Plasma UA levels correlate to oxidation and inflammation biomarkers in opposite directions in women.
1 Communities
3 Members
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17 MeSH Terms
Timing of solid food introduction is associated with urinary F2-isoprostane concentrations in childhood.
Frederiksen BN, Seifert J, Kroehl M, Lamb MM, Milne GL, Rewers M, Norris JM
(2015) Pediatr Res 78: 451-6
MeSH Terms: Age Factors, Biomarkers, Breast Feeding, Child, Child, Preschool, F2-Isoprostanes, Feeding Methods, Female, Humans, Infant, Infant Food, Linear Models, Longitudinal Studies, Male, Prospective Studies, Protective Factors, Risk Factors, Time Factors
Show Abstract · Added March 10, 2016
BACKGROUND - Timing of solid food introduction in infancy has been associated with several chronic diseases. To explore potential mechanisms, we investigated the relationship between timing of solid food introduction and F2-isoprostanes-a marker of oxidative stress.
METHODS - Urinary F2-isoprostanes were assessed in 336 healthy children aged less than 11.5 y with 1,266 clinic visits (mean = 3.8 visits per child) in the Diabetes Autoimmunity Study in the Young. We analyzed the association between F2-isoprostane concentrations and infant diet exposures using linear mixed models adjusted for age, age(2), HLA-DR3/4,DQB1*0302 genotype, first-degree relative with type 1 diabetes, maternal age, maternal education, sex, and exposure to in utero cigarette smoke.
RESULTS - Later solid food introduction was associated with lower F2-isoprostane concentrations in childhood (on average, 0.10 ng/mg per month of age at introduction; estimate: -0.10 (95% confidence interval (CI): -0.18, -0.02) P value = 0.02). Moreover, childhood F2-isoprostane concentrations were, on average, 0.24 ng/mg lower in individuals breastfed at solid food introduction (estimate: -0.24 (95% CI: -0.47, -0.01) P value = 0.04) compared with those who were not. Associations remained significant after limiting analyses to F2-isoprostanes after 2 y of age.
CONCLUSION - Our results suggest a long-term protective effect of later solid food introduction and breastfeeding at solid food introduction against increased F2-isoprostane concentrations throughout childhood.
1 Communities
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18 MeSH Terms
Association of plasma F2-isoprostanes and isofurans concentrations with erythropoiesis-stimulating agent resistance in maintenance hemodialysis patients.
Rivara MB, Ikizler TA, Ellis CD, Mehrotra R, Himmelfarb J
(2015) BMC Nephrol 16: 79
MeSH Terms: Adult, Aged, Anemia, C-Reactive Protein, Drug Resistance, F2-Isoprostanes, Female, Furans, Hematinics, Humans, Inflammation, Interleukin-6, Iron, Kidney Failure, Chronic, Linear Models, Male, Middle Aged, Oxidative Stress, Prospective Studies, Renal Dialysis
Show Abstract · Added August 5, 2015
BACKGROUND - In patients undergoing maintenance hemodialysis (HD), hyporesponsiveness to erythropoiesis stimulating agents (ESAs) is associated with adverse clinical outcomes. Systemic inflammation is highly prevalent in HD patients and is associated with ESA hyporesponsiveness. Oxidative stress is also highly prevalent in HD patients, but no previous study has determined its association with ESA response. This study assessed the association of plasma markers of oxidative stress and inflammation with ESA resistance in patients undergoing maintenance HD.
METHODS - We analyzed data from 165 patients enrolled in the Provision of Antioxidant Therapy in Hemodialysis study, a randomized controlled trial evaluating antioxidant therapy in prevalent HD patients. Linear and mixed-effects regression were used to assess the association of baseline and time-averaged high sensitivity F2-isoprostanes, isofurans, C-reactive protein (hsCRP), and interleukin-6 (IL-6) with ESA resistance index (ERI), defined as the weekly weight-adjusted ESA dose divided by blood hemoglobin level. Unadjusted models as well as models adjusted for potential confounders were examined. Predicted changes in ERI per month over study follow-up among baseline biomarker quartiles were also assessed.
RESULTS - Patients with time-averaged isofurans in the highest quartile had higher adjusted mean ERI compared with patients in the lowest quartile (β = 14.9 ng/ml; 95% CI 7.70, 22.2; reference group <0.26 ng/ml). The highest quartiles of hsCRP and IL-6 were also associated with higher adjusted mean ERI (β = 10.8 mg/l; 95% CI 3.52, 18.1 for hsCRP; β = 10.2 pg/ml; 95% CI 2.98, 17.5 for IL-6). No significant association of F2-isoprostanes concentrations with ERI was observed. Analyses restricted to baseline exposures and ERI showed similar results. Baseline hsCRP, IL-6, and isofurans concentrations in the highest quartiles were associated with greater predicted change in ERI over study follow-up compared to the lowest quartiles (P = 0.008, P = 0.004, and P = 0.04, respectively). There was no association between baseline F2-isoprostanes quartile and change in ERI.
CONCLUSIONS - In conclusion, higher concentrations of isofurans, hsCRP and IL-6, but not F2-isoprostanes, were associated with greater resistance to ESAs in prevalent HD patients. Further research is needed to test whether interventions that successfully decrease oxidative stress and inflammation in patients undergoing maintenance HD improve ESA responsiveness.
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2 Members
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20 MeSH Terms
Randomized, placebo-controlled trial of acetaminophen for the reduction of oxidative injury in severe sepsis: the Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis trial.
Janz DR, Bastarache JA, Rice TW, Bernard GR, Warren MA, Wickersham N, Sills G, Oates JA, Roberts LJ, Ware LB, Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis Study Group
(2015) Crit Care Med 43: 534-41
MeSH Terms: Acetaminophen, Adult, Analgesics, Non-Narcotic, Cell-Free System, Creatinine, Critical Illness, Double-Blind Method, F2-Isoprostanes, Female, Hemoglobins, Hospital Mortality, Humans, Male, Middle Aged, Oxidation-Reduction, Propofol, Respiration, Artificial, Sepsis
Show Abstract · Added January 28, 2015
OBJECTIVES - This trial evaluated the efficacy of acetaminophen in reducing oxidative injury, as measured by plasma F2-isoprostanes, in adult patients with severe sepsis and detectable plasma cell-free hemoglobin.
DESIGN - Single-center, randomized, double-blind, placebo-controlled phase II trial.
SETTING - Medical ICU in a tertiary, academic medical center.
PATIENTS - Critically ill patients 18 years old or older with severe sepsis and detectable plasma cell-free hemoglobin.
INTERVENTIONS - Patients were randomized 1:1 to enteral acetaminophen 1 g every 6 hours for 3 days (n = 18) or placebo (n = 22) with the same dosing schedule and duration.
MEASUREMENTS AND MAIN RESULTS - F2-Isoprostanes on study day 3, the primary outcome, did not differ between acetaminophen (30 pg/mL; interquartile range, 24-41) and placebo (36 pg/mL; interquartile range, 25-80; p = 0.35). However, F2-isoprostanes were significantly reduced on study day 2 in the acetaminophen group (24 pg/mL; interquartile range, 19-36) when compared with placebo (36 pg/mL; interquartile range, 23-55; p = 0.047). Creatinine on study day 3, a secondary outcome, was significantly lower in the acetaminophen group (1.0 mg/dL; interquartile range, 0.6-1.4) when compared with that in the placebo (1.3 mg/dL; interquartile range, 0.83-2.0; p = 0.039). There was no statistically significant difference in hospital mortality (acetaminophen 5.6% vs placebo 18.2%; p = 0.355) or adverse events (aspartate aminotransferase or alanine aminotransferase > 400; acetaminophen 9.5% vs placebo 4.3%; p = 0.599).
CONCLUSIONS - In adults with severe sepsis and detectable plasma cell-free hemoglobin, treatment with acetaminophen within 24 hours of ICU admission may reduce oxidative injury and improve renal function. Additional study is needed to confirm these findings and determine the effect of acetaminophen on patient-centered outcomes.
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1 Members
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18 MeSH Terms
New risk factors for adult-onset incident asthma. A nested case-control study of host antioxidant defense.
Larkin EK, Gao YT, Gebretsadik T, Hartman TJ, Wu P, Wen W, Yang G, Bai C, Jin M, Roberts LJ, Gross M, Shu XO, Hartert TV
(2015) Am J Respir Crit Care Med 191: 45-53
MeSH Terms: 1-Alkyl-2-acetylglycerophosphocholine Esterase, Adult, Age of Onset, Aged, Antioxidants, Asthma, Biomarkers, Case-Control Studies, China, F2-Isoprostanes, Female, Humans, Micronutrients, Middle Aged, Oxidative Stress, Platelet Activating Factor, Prospective Studies, Protective Factors, Risk Factors, alpha-Tocopherol
Show Abstract · Added January 20, 2015
RATIONALE - Host antioxidant defense, consisting of enzymatic antioxidant activity and nonenzymatic antioxidant micronutrients, is implicated in asthma pathogenesis. Studies of antioxidant defense and adult incident asthma have either used measures of antioxidants estimated from questionnaires or not considered enzymatic aspects of host defense.
OBJECTIVES - We conducted the first study designed and powered to investigate the association of antioxidant defenses on adult incident asthma.
METHODS - In a nested case-control study, we followed Shanghai women (aged 40-70 years) without prevalent asthma at baseline, over 8 years. Subjects with incident asthma were ascertained prospectively by gold standard testing of symptomatic women and matched to two asymptomatic control subjects.
MEASUREMENTS AND MAIN RESULTS - Baseline urinary F2-isoprostanes, plasma concentrations of antioxidant micronutrients (tocopherols, xanthines, carotenes, and lycopene), and antioxidant enzyme activity (platelet-activating factor acetylhydrolase [PAF-AH] and superoxide dismutase) were measured from samples collected before disease onset. Among 65,372 women, 150 (0.24%) developed asthma. F2-isoprostane levels before asthma onset were not different between cases and control subjects. Doubling of α-tocopherol concentrations and PAF-AH activity was associated with 50 and 37% decreased risk of incident asthma (α-tocopherol: adjusted odds ratio = 0.52; 95% confidence interval, 0.32-0.84; PAF-AH: adjusted odds ratio = 0.63; 95% confidence interval, 0.42-0.93).
CONCLUSIONS - In this prospective study, α-tocopherol, within normal reference ranges, and PAF-AH enzymatic activity were associated with decreased asthma development. These modifiable risk factors may be an effective strategy to test for primary asthma prevention.
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2 Members
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20 MeSH Terms
A pilot randomized crossover trial assessing the safety and short-term effects of pomegranate supplementation in hemodialysis patients.
Rivara MB, Mehrotra R, Linke L, Ruzinski J, Ikizler TA, Himmelfarb J
(2015) J Ren Nutr 25: 40-9
MeSH Terms: Aged, Beverages, Biomarkers, C-Reactive Protein, Cross-Over Studies, Dietary Supplements, F2-Isoprostanes, Female, Humans, Inflammation, Interleukin-10, Interleukin-1beta, Interleukin-6, Linear Models, Lipids, Lythraceae, Male, Middle Aged, Oxidative Stress, Pilot Projects, Plant Preparations, Prospective Studies, Renal Dialysis, Sensitivity and Specificity, Treatment Outcome, Tumor Necrosis Factor-alpha
Show Abstract · Added September 29, 2014
OBJECTIVE - Oxidative stress and systemic inflammation are highly prevalent in patients undergoing maintenance hemodialysis (MHD) and are linked to excess cardiovascular risk. This study examined whether short-term supplementation with pomegranate juice and extract is safe and well tolerated by MHD patients. The secondary aim was to assess the effect of pomegranate supplementation on oxidative stress, systemic inflammation, monocyte function, and blood pressure.
DESIGN - Prospective, randomized, crossover, pilot clinical trial (NCT01562340).
SETTING - The study was conducted from March to October 2012 in outpatient dialysis facilities in the Seattle metropolitan area.
SUBJECTS - Twenty-four patients undergoing MHD (men, 64%; mean age, 61 ± 14 years) were randomly assigned to receive pomegranate juice or extract during a 4-week intervention period. After a washout period, all patients received the alternative treatment during a second 4-week intervention period.
INTERVENTION - Patients assigned to receive pomegranate juice received 100 mL of juice before each dialysis session. Patients assigned to receive pomegranate extract were given 1,050 mg of extract daily.
MAIN OUTCOME MEASURES - The main outcome measures were safety and tolerability of pomegranate juice and extract. Additional secondary outcomes assessed included serum lipids, laboratory biomarkers of inflammation (C-reactive protein and interleukin 6) and oxidative stress (plasma F2 isoprostanes and isofurans), monocyte cytokine production, and predialysis blood pressure.
RESULTS - Both pomegranate juice and extract were safe and well tolerated by study participants. Over the study period, neither treatment had a significant effect on lipid profiles, plasma C-reactive protein, interleukin 6, F2-isoprostane or isofuran concentrations, predialysis systolic or diastolic blood pressure nor changed the levels of monocyte cytokine production.
CONCLUSIONS - Both pomegranate juice and extract are safe and well tolerated by patients undergoing MHD but do not influence markers of inflammation or oxidative stress nor affect predialysis blood pressure.
Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
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26 MeSH Terms
Pigmented rice bran and plant sterol combination reduces serum lipids in overweight and obese adults.
Hongu N, Kitts DD, Zawistowski J, Dossett CM, Kopeć A, Pope BT, Buchowski MS
(2014) J Am Coll Nutr 33: 231-8
MeSH Terms: Adult, Basal Metabolism, Blood Pressure, Body Composition, Body Mass Index, C-Reactive Protein, Caloric Restriction, Cholesterol, HDL, Cholesterol, LDL, Diet, Reducing, Dietary Fiber, Double-Blind Method, F2-Isoprostanes, Female, Humans, Insulin, Leptin, Male, Middle Aged, Motor Activity, Obesity, Overweight, Patient Compliance, Phytosterols, Triglycerides, Weight Loss, Young Adult
Show Abstract · Added July 30, 2015
OBJECTIVE - This study investigated the dietary effect of including pigmented rice bran with or without plant sterols on lipid profiles during energy restriction-induced weight loss in overweight and obese adults not taking cholesterol-lowering medication. In addition, the study examined the effect of intervention on biomarkers of oxidative stress and inflammation.
METHODS - A group of 24 overweight and obese adults (age: 43 ± 6 years, body mass index 32 ± 1 kg/m(2), 18 females) were randomized to a 25% calorie-restricted diet containing either pigmented rice bran (RB) or the RB with addition of plant sterols (RB+PS) snack bars for 8 weeks. The individualized nutrient-balanced diet contained ∼70% of daily energy needs assessed from indirect calorimetry measured resting energy expenditure (EE) and physical activity-related EE assessed using accelerometry. Anthropometrics, blood pressure, blood lipids, glucose, urinary F2-isoprostanes, C-reactive protein, insulin, and leptin were measured at baseline and after 8 weeks of intervention.
RESULTS - Participants lost approximately 4.7 ± 2.2 kg (p < 0.001). Weight loss was not significant between the RB+PS and RB group (p = 0.056). Changes in body fat corresponded to changes in body weight. Average decrease in total cholesterol was significantly higher in the RB+PS group than in the RB group (difference 36 ± 25 g/dL vs 7 ± 16 g/dL; p = 0.044). A similar pattern was observed for the decrease in low-density lipoprotein (LDL) cholesterol (difference 22.3 ± 25.2 g/dL vs 4.4 ± 18.9 g/dL; p = 0.062). Changes in systolic blood pressure, serum levels of leptin, and F2-isoprostanes were significant between baseline values and after 8 weeks on the diet in both groups (p < 0.05) but did not differ between the 2 groups.
CONCLUSIONS - A nutrient-balanced and energy-restricted diet supplemented with rice bran and plant sterols resulted in a significant decrease in total and LDL cholesterol in overweight and obese adults.
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1 Members
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27 MeSH Terms
Urinary biomarkers of oxidative stress and breast cancer survival.
Nechuta S, Cai Q, Zheng Y, Milne GL, Cai H, Dai Q, Yang G, Zheng W, Lu W, Shu XO
(2014) Cancer Causes Control 25: 701-7
MeSH Terms: Adult, Aged, Biomarkers, Tumor, Breast Neoplasms, Case-Control Studies, China, F2-Isoprostanes, Female, Humans, Middle Aged, Oxidative Stress, Prognosis, Survival Analysis, Survivors, Young Adult
Show Abstract · Added May 27, 2014
PURPOSE - Systemic oxidative stress has been implicated in the pathogenesis and progression of many chronic diseases, including breast cancer. No studies have investigated F2-isoprostanes (F2-IsoPs), valid biomarkers of systemic oxidative stress, in association with breast cancer prognosis. We conducted a nested case-control study in a prospective breast cancer survivor cohort to investigate systemic oxidative stress and survival.
METHODS - Urinary levels of F2-IsoPs and its major urinary metabolite (2,3-dinor-5,6-dihydro-15-F2t-IsoP, F2-IsoP-M) were measured post-cancer treatment using gas chromatography/negative ion chemical ionization mass spectrometry for 57 deceased breast cancer patients (cases) and 103 surviving patients (controls) matched 1:2 on age at diagnosis, stage, and diagnosis year. Odds ratios (ORs) and 95 % confidence intervals (CIs) were derived from conditional logistic regression models.
RESULTS - In unadjusted models, elevated F2-IsoP levels categorized based on the median value [≥1.73; <1.73 (reference)] were nonsignificantly inversely associated with mortality (OR 0.51, 95 % CI 0.24-1.10). After adjustment for potential confounders, elevated F2-IsoP levels were significantly associated with mortality (OR 0.36, 95 % CI 0.14-0.96). The inverse association was marginally significant when F2-IsoP was categorized based on tertiles (p trend = 0.08). In contrast, elevated F2-IsoP-M levels, categorized based on the median level [≥0.91; < 0.91(reference)], were associated with a statistically nonsignificant increased risk of mortality in both unadjusted and adjusted models (adjusted OR 1.39, 95 % CI 0.62-3.09).
CONCLUSION - Results suggest a role for oxidative stress biomarkers in breast cancer survival; however, as this is the first study to date, additional larger studies are needed.
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4 Members
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15 MeSH Terms
F2-isoprostanes as a biomarker of oxidative stress in the mouse bladder.
Clayton DB, Stephany HA, Ching CB, Rahman SA, Tanaka ST, Thomas JC, Pope JC, Adams MC, Brock JW, Clark PE, Hayward SW, Matusik RJ, Milne GL
(2014) J Urol 191: 1597-601
MeSH Terms: Aging, Animals, Biomarkers, Disease Models, Animal, Disease Progression, F2-Isoprostanes, Female, Mice, Oxidative Stress, Reactive Oxygen Species, Urinary Bladder Neck Obstruction
Show Abstract · Added April 8, 2014
PURPOSE - We theorized that progressive bladder dysfunction due to clinical diagnoses such as outlet obstruction occurs as a result of cyclical oxidative stress events. We hypothesized that measurement of F2-isoprostane, a marker of lipid peroxidation, could serve as a biomarker of oxidative stress in the murine bladder.
MATERIALS AND METHODS - At age 5 to 6 weeks oophorectomized female mice were subjected to 1 of 2 bladder injury models, that is partial bladder outlet obstruction or acute bladder distension. The time points studied after injury included 4, 8 and 16 weeks after obstruction, and 0 to 48 hours after acute bladder distension. In a separate group short-term repetitive acute bladder distension was performed every other day for 14 days. Bladder samples were analyzed for F2-isoprostane using gas chromatography and mass spectroscopy. Mean tissue F2-isoprostane levels were compared.
RESULTS - F2-isoprostane increased significantly after 4 weeks of partial bladder outlet obstruction from 1.46 ng/gm in controls to 2.31 ng/gm at 4 weeks (p = 0.01). Eight and 16 weeks after partial bladder outlet obstruction F2-isoprostane remained significantly elevated (2.39 and 2.48 ng/gm, respectively). Acute bladder distension resulted in a significant increase in F2-isoprostane immediately after distension compared to controls (1.6 vs 0.75 ng/gm, p = 0.04). In mice that underwent repetitive acute bladder distension F2-isoprostane did not change.
CONCLUSIONS - Measurement of tissue F2-isoprostane in the bladder reflects the progression of oxidative stress, primarily in chronic injury models such as partial bladder outlet obstruction. The usefulness of F2-isoprostane measurements in shorter term injury models requires further study.
Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
1 Communities
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11 MeSH Terms