15-F2t Isoprostane Research Articles

Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies.

ObjectiveTo investigate the efficacy of N-acetylcysteine (NAC) for decreasing elevated oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies (RYR1-RM).MethodsIn this 6-month natural history assessment (n = 37) followed by a randomized, double-blinded, placebo-controlled trial, 33 eligible participants were block-randomized (1:1) to receive NAC (n = 16) or placebo (n = 17), orally for 6 months (adult dose 2,700 mg/d; pediatric dose 30 mg/kg/d). The primary endpoint was urine 15-F2t isoprostane concentration and the clinically meaningful co-primary endpoint was 6-minute walk test (6MWT) distance.ResultsWhen compared to the general population, participants had elevated baseline 15-F2t isoprostane concentrations and most had a decreased 6MWT distance (mean ± SD 3.2 ± 1.5 vs 1.1 ± 1.7 ng/mg creatinine and 468 ± 134 vs 600 ± 58 m, respectively, both p < 0.001). 15-F2t isoprostane concentration and 6MWT distance did not change over the 6-month natural history assessment (p = 0.98 and p = 0.61, respectively). NAC treatment did not improve 15-F2t isoprostane concentration (least squares means difference 0.1 [95% confidence interval [CI] −1.4 to 1.6] ng/mg creatinine, p = 0.88) or 6MWT distance (least squares means difference 24 [95% CI −5.5 to 53.4] m, p = 0.11). NAC was safe and well-tolerated at the doses administered in this study.ConclusionIn ambulatory RYR1-RM–affected individuals, we observed stable disease course, and corroborated preclinical reports of elevated oxidative stress and decreased physical endurance. NAC treatment did not decrease elevated oxidative stress, as measured by 15-F2t isoprostane.Classification of evidenceThis study provides Class I evidence that, for people with RYR1-RM, treatment with oral NAC does not decrease oxidative stress as measured by 15-F2t isoprostane.Clinicaltrials.gov identifierNCT02362425.

A Cross-Sectional Study on 3-(2-Deoxy-β-D-Erythro-Pentafuranosyl)Pyrimido[1,2-α]Purin-10(3H)-One Deoxyguanosine Adducts among Woodworkers in Tuscany, Italy

Occupational exposure to wood dust has been estimated to affect 3.6 million workers within the European Union (EU). The most serious health effect caused by wood dust is the nasal and sinonasal cancer (SNC), which has been observed predominantly among woodworkers. Free radicals produced by inflammatory reactions as a consequence of wood dust could play a major role in SNC development. Therefore, we investigated the association between wood dust and oxidative DNA damage in the cells of nasal epithelia, the target site of SNC. We have analyzed oxidative DNA damage by determining the levels of 3-(2-deoxy-β-D-erythro-pentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine (M1dG), a major-peroxidation-derived DNA adduct and a biomarker of cancer risk in 136 woodworkers compared to 87 controls in Tuscany, Italy. We then examined the association of M1dG with co-exposure to volatile organic compounds (VOCs), exposure length, and urinary 15-F2t isoprostane (15-F2t-IsoP), a biomarker of oxidant status. Wood dust at the workplace was estimated by the Information System for Recording Occupational Exposures to Carcinogens. M1dG was measured using 32P-postlabeling and mass spectrometry. 15-F2t-IsoP was analyzed using ELISA. Results show a significant excess of M1dG in the woodworkers exposed to average levels of 1.48 mg/m3 relative to the controls. The overall mean ratio (MR) between the woodworkers and the controls was 1.28 (95% C.I. 1.03–1.58). After stratification for smoking habits and occupational status (exposure to wood dust alone and co-exposure to VOCs), the association of M1dG with wood dust (alone) was even greater in non-smokers workers, MR of 1.43 (95% C.I. 1.09–1.87). Conversely, not consistent results were found in ex-smokers and current smokers. M1dG was significantly associated with co-exposure to VOCs, MR of 1.95 (95% C.I. 1.46–2.61), and occupational history, MR of 2.47 (95% C.I. 1.67–3.62). Next, the frequency of M1dG was significantly correlated to the urinary excretion of 15-F2t-IsoP, regression coefficient (β) = 0.442 ± 0.172 (SE). Consistent with the hypothesis of a genotoxic mechanism, we observed an enhanced frequency of M1dG adducts in woodworkers, even at the external levels below the regulatory limit. Our data implement the understanding of SNC and could be useful for the management of the adverse effects caused by this carcinogen.

Wood dust and urinary 15-F2t isoprostane in Italian industry workers

Wood dust is one of the most common occupational exposures, with about 3.6 million of workers in the wood industry in Europe. Wood particles can deposit in the nose and the respiratory tract and cause adverse health effects. Occupational exposure to wood dust has been associated with malignant tumors of the nasal cavity and paranasal sinuses. The induction of oxidative stress and the generation of reactive oxygen species through activation of inflammatory cells could have a role in the carcinogenicity of respirable wood dust. Therefore, we conducted a cross-sectional study to evaluate the prevalence of urinary 15-F2t isoprostane (15-F2t-IsoP), a biomarker of oxidative stress and peroxidation of lipids, in 123 wood workers compared to 57 unexposed controls living in Tuscany region, Italy. 15-F2t-IsoP generation was measured by ELISA. The main result of the present study showed that a statistically significant excess of this biomarker occurred in the workers exposed to 1.48 mg/m3 of airborne wood dust with respect to the unexposed controls. The overall mean ratio (MR) between the workers exposed to wood dust and the controls was 1.36, 95% Confidence Interval (C.I.) 1.18–1.57, after correction for age and smoking habits. A significant increment of 15-F2t-IsoP (43%) was observed in the smokers as compared to the non-smokers. The urinary excretion of 15-F2t-IsoP was significantly associated with co-exposure to organic solvents, i.e., MR of 1.41, 95% C.I. 1.17–1.70, after adjustment for age and smoking habits. A 41% excess was observed in long-term wood workers, 95% C.I. 1.14–1.75. Multivariate regression analysis showed that the level of 15-F2t-IsoP was linearly correlated to the length of exposure, regression coefficient (β) = 0.244 ± 0.002 (SE). The overall increment by exposure group persisted after stratification for smoking habits. For instance, in smokers, a 53% excess was detected in the wood workers as compared to the controls, 95% C.I. 1.23–1.91. Our data support the hypothesis that oxidative stress and lipid peroxidation can have a role in the toxicity of wood dust F2-IsoP measure can be a tool for the evaluation of the effectiveness of targeted interventions aimed to reduce exposures to environmental carcinogens.

Urinary phthalate and phthalate alternative metabolites and isoprostane among couples undergoing fertility treatment

BackgroundEpidemiological data suggest associations between phthalate exposures to a variety of adverse reproductive outcomes including reduced sperm quality and reproductive success. While mechanisms of these associations are not fully elucidated, oxidative stress has been implicated as a potential mediator. We examined associations of urinary metabolites of phthalates and phthalate alternative plasticizers with oxidative stress among couples seeking fertility treatment. MethodsSeventeen urinary plasticizer metabolites and 15-F2t isoprostane, a biomarker of oxidative stress, were quantified in spot samples from 50 couples seeking fertility treatment who enrolled in the Sperm Environmental Epigenetics and Development Study during 2014–2015. ResultsIn multivariable analyses, percent change in isoprostane was positively associated with interquartile range increases for the oxidative metabolites of di-2-ethylhexyl phthalate, [mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP; 20.0%, p=0.02), mono-2-ethyl-5-oxohexyl phthalate (MEOHP; 24.1%, p=0.01), and mono-2-ethyl-5-carboxypentyl phthalate (MECPP; 24.1%, p=0.004)], mono-isobutyl phthalate (MiBP; 17.8%, p=0.02), mono-hydroxyisobutyl phthalate (MHiBP; 27.5%, p=0.003), and cyclohexane-1,2-dicarboxylic acid mono-hydroxy-isononyl ester (MHINCH; 32.3%, p=0.002). Stratification of participants by sex revealed that isoprostane was positively associated with MHiBP (41.4%, p=0.01) and monocarboxy-isononyl phthalate (MCNP; 26.0%, p=0.02) among females and MEOHP (35.8%, p=0.03), MiBP (29.2%, p=0.01), MHiBP (34.7%, p=0.007) and MHINCH (49.0%, p=0.002) among males. ConclusionsOur results suggest that exposure to phthalates and phthalate replacements are associated with higher levels of oxidative stress in a sex-specific manner. Additional studies are needed to replicate our findings and to examine the potential health implications of the use of phthalates and alternative phthalates in consumer end products.

Phthalate Exposure and 15-F2t Isoprostane Concentrations Among Couples Seeking Assisted Reproductive Technologies

INTRODUCTION: Phthalates are a class of environmentally ubiquitous plasticizers and are detected in most populations due to their widespread use. Epidemiological data indicate male and female reproductive health may be negatively impacted by phthalate exposures. Although mechanisms are not fully elucidated, phthalate induced oxidative stress has been implicated as a potential mediator. The objective of this study is to examine associations of urinary phthalate metabolites and isoprostane, a known biomarker of oxidative stress in couples seeking assisted reproductive technologies(ART). METHODS: A total of 49 couples were recruited from Baystate Medical Center’s IVF clinic from 2014 to 2015 as part of the Sperm Environmental Epigenetics and Development Study (SEEDS). Seventeen phthalates metabolites were analyzed from spot urine samples by the CDC. Oxidative stress biomarkers were assessed using Oxford Biomedial Research’s urinary 15 F2t-Isoprostane ELISA kit. Percent change in isoprostane per interquartile range (IQR) increase in each phthalate metabolite was estimated using linear regression and adjusted for BMI, maternal age, and specific gravity. RESULTS: Concentrations of five metabolites (MCNPP, MBzP, MEP, MiBP, and MMP) had positive correlations among couples (Spearman; p&lt;0.05). In adjusted models, isoprostane concentrations were associated with IQR increases in phthalate metabolites: MEOHP(35.8%, p=0.03); MiBP(29.2%, p=0.01); MHiBP(34.7%, p=0.007), and MHiNCH (23.4%, p=0.02) in males and MHiBP(41.4%, p=0.01) and MCNP (26%, p=0.02) in females. Conclusions: These results suggest certain urinary phthalate metabolites influence oxidative stress profiles. To our knowledge, this is the first study to examine the relationship between preconception isoprostane and phthalate metabolite concentrations in couples seeking ART.

Urban air and tobacco smoke as conditions that increase the risk of oxidative stress and respiratory response in youth

BackgroundAir pollution and tobacco smoke can induce negative effects on the human health and often leads to the formation of oxidative stress. ObjectiveThe purpose of this study was to clarify the role of the urbanization degree and of passive exposure to tobacco smoke in the formation of oxidative stress. Thus, a group of non-smoking adolescents was recruited among those who live and attend school in areas with three different population densities. To each subject a spot of urine was collected to quantify 15-F2t isoprostane as a marker of oxidative stress and cotinine as a marker of passive exposure to tobacco smoke. Furthermore, respiratory functionality was also measured. ResultsMultiple linear regression analysis results showed a direct correlation (p<0.0001) of 15-F2t isoprostane with both the urbanization and passive smoke. Lung function parameters proved significantly lower for the subjects living in the most populous city of Torino. ConclusionThis remarks the negative effect that urbanization has on the respiratory conditions. Lastly, lung functionality presented a low inverse correlation with 15-F2t isoprostane, suggesting an independent mechanism than that of the urban factor.

15-F2t isoprostane as biomarker of oxidative stress induced by tobacco smoke and occupational exposure to formaldehyde in workers of plastic laminates

BackgroundFormaldehyde (FA) is a suspected human carcinogen capable of inducing oxidative stress through different metabolic ways. FA may originate from tobacco smoke, several environmental sources, as well as occupational sources, like furnishing industries specialized in the production of pressed-wood and laminate products. ObjectOur aim was to investigate the role of tobacco smoke and occupational exposure to air-FA in the induction of oxidative stress status by comparing FA-exposed with non-exposed subjects who smoked or did not. MethodsEnrollment of 105 subjects was made in an industry of plastic laminates, including both workers directly exposed to FA and non-exposed office personnel, as control group. 15-F2t isoprostane (15-F2t IsoP), detected by ELISA technique and urinary cotinine, detected by GC-MS, were used for evaluating oxidative stress and tobacco smoke exposure, respectively. Air-FA levels were detected by GC-MS. ResultsFA concentrations were significantly higher in subjects occupationally exposed than the controls. Smoking habits and air-FA exposures independently induce the formation of 15-F2t IsoP and increase the oxidative stress level. ConclusionsOur findings show, for the first time, that 15-F2t IsoP presents a dependency from both the smoking habit and air-FA exposures, and consequently, that these breathable pollutants could be considered as two important independent risk factors in increasing the oxidative stress in human beings.

Expression of XRCC5 in peripheral blood lymphocytes is upregulated in subjects from a heavily polluted region in the Czech Republic

Air pollution causes oxidative damage to macromolecules, chromosomal aberrations and changes in gene expression. We investigated the levels of oxidative stress markers [8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), 15-F 2t-isoprostane (15-F2t-IsoP), protein carbonyls] and cytogenetic parameters [genomic frequency of translocations ( F G/100), percentage of aberrant cells (%AB.C.) and acentric fragments (ace)] in subjects living in Prague and in the heavily polluted Ostrava region. We also compared the expression of genes participating in base excision repair (BER) and non-homologous end-joining (NHEJ). We analyzed 64 subjects from Prague and 75 subjects from Ostrava. We measured oxidative stress markers by ELISA, cytogenetic parameters by fluorescence in situ hybridization and gene expression by quantitative PCR. The levels of air pollutants (benzo[a]pyrene, B[a]P; carcinogenic polycyclic aromatic hydrocarbons, c-PAHs; benzene) measured by personal monitors were significantly elevated in Ostrava compared to Prague ( p < 0.001). Despite this fact, we observed no differences in biomarkers of oxidative stress between the two locations. Moreover, subjects from Ostrava were less likely to have above-median levels of %AB.C. (OR; 95% CI: 0.18; 0.05–0.67; p = 0.010). Multivariate analyses revealed that subjects living in Ostrava had increased odds of having above-median levels of XRCC5 expression (OR; 95% CI: 3.33; 1.03–10.8; q = 0.046). Above-median levels of 8-oxodG were associated with decreased levels of vitamins C (OR; 95% CI: 0.37; 0.16–0.83; p = 0.016) and E (OR; 95% CI: 0.25; 0.08–0.75; p = 0.013), which were elevated in subjects from Ostrava. We suggest that air pollution by c-PAHs affects XRCC5 gene expression, which probably protects subjects from Ostrava against the induction of a higher frequency of translocations; elevated vitamin C and E levels in the Ostrava subjects decrease the levels of 8-oxodG.

Oxidative stress in twin neonates is influenced by birth weight and weight discordance

Objectives To evaluate the extent of oxidative stress in neonates born from multiple gestation pregnancies who are at high risk of prematurity and growth abnormalities. Design and methods Blood samples were collected from umbilical cord of 72 twins, born at gestational age of 28–38 weeks, and 20 consecutive control singletons. Oxidative stress parameters (15-F 2t-isoprostane, a marker of lipid peroxidation, and total antioxidant capacity, tAOC), were measured in cord plasma. Results Levels of 15-F 2t-isoprostane showed a moderate negative correlation with birth weight and were higher in small co-twins of discordant pairs; tAOC was positively correlated with birth weight but no significant difference was found between co-twins. Conclusions Oxidative stress levels in twins are mainly influenced by birth weight and weight discordance. We suggest that evaluation of cord blood 15-F 2t-isoprostane might be of clinical value as maker of pre- and perinatal distress in twinning.

Oxidative stress and chromosomal aberrations in an environmentally exposed population

We investigated the effect of the seasonal variability of environmental air pollutants on oxidative stress and cytogenetic biomarkers in a group of 59 city policemen working in Prague, Czech Republic. The studied group was monitored in February and May 2007. The exposure to environmental pollutants (carcinogenic polycyclic aromatic hydrocarbons, c-PAHs, including benzo[a]pyrene, B[a]P, and particulate matter of aerodynamic diameter < 2.5 μm, PM2.5) was measured by personal and/or stationary monitors. Levels of c-PAHs were significantly higher in winter than spring, while exposure to PM2.5 was higher in May than in February 2007. We did not observe any significant difference between the two seasons for any biomarker of oxidative stress (8-oxo-7,8-dihydro-2′-deoxyguanosine, 8-oxodG, 15-F 2t-isoprostane, 15-F 2t-IsoP, protein carbonyl levels) or any cytogenetic parameter, including the genomic frequency of translocations ( F G/100), the percentage of aberrant cells (%AB.C.) or the number of acentric fragments (ace). Analyses of associations between oxidative stress biomarkers and cytogenetic parameters showed a negative relationship between protein oxidation and F G/100, as well as protein oxidation and ace. We further analyzed the effect of air pollution on all subjects regardless of the season. Data from stationary monitors showed that 8-oxodG levels were significantly increased by exposure to PM2.5 over a 2-day period before sampling and by exposure to B[a]P over a 28-day period, days 57–84 before sampling. 15-F 2t-IsoP levels were increased after exposure to B[a]P over both 2-day and 3-day periods preceding sample collection and after exposure to c-PAHs over a 2-day period before sampling. %AB.C. was significantly affected by exposure to B[a]P over a 14-day period, days 57–70 before sampling. In summary, our results indicate that the exposure to environmental pollutants affects urinary excretion of 8-oxodG, lipid peroxidation and the frequency of chromosomal aberrations.

Oxidative damage to biological macromolecules in Prague bus drivers and garagemen: Impact of air pollution and genetic polymorphisms

DNA integrity was investigated in the lymphocytes of 50 bus drivers, 20 garagemen and 50 controls using the comet assay with excision repair enzymes. In parallel, 8-oxo-7,8-dihydro-2′-deoxyguanosine and 15-F 2t-isoprostane levels in the urine and protein carbonyl levels in the plasma were assessed as markers of oxidative damage to DNA, lipids and proteins. Exposure to carcinogenic polycyclic aromatic hydrocarbons (cPAHs) and volatile compounds was measured by personal samplers for 48 and 24 h, respectively, before the collection of biological specimens. Both exposed groups exhibited a higher levels of DNA instability and oxidative damage to biological macromolecules than the controls. The incidence of oxidized lesions in lymphocyte DNA, but not the urinary levels of 8-oxodG, correlated with exposure to benzene and triglycerides increased this damage. Oxidative damage to lipids and proteins was associated with exposure to cPAHs and the lipid peroxidation levels positively correlated with age and LDL cholesterol, and negatively with vitamin C. The carriers of at least one variant hOGG1 (Cys) allele tended to higher oxidative damage to lymphocyte DNA than those with the wild genotype, while XPD23 (Gln/Gln) homozygotes were more susceptible to the induction of DNA strand breaks. In contrast, GSTM1 null variant seemed to protect DNA integrity.

Oxidative damage induced by carcinogenic polycyclic aromatic hydrocarbons and organic extracts from urban air particulate matter

We investigated the role of oxidative damage in the mechanism of action of selected individual carcinogenic PAHs (c-PAHs: benzo[ a]pyrene, B[ a]P; dibenzo[ a, l]pyrene, DB[ a, l]P), an artificial mixture of c-PAHs (c-PAHs mix) and extractable organic matter (EOM) from urban air particulate matter (PM). Two cell lines (human hepatoma cells, HepG2; human diploid lung fibroblasts, HEL) were treated for 24 and 48 h with various concentrations of compounds and mixtures. A panel of oxidative stress markers included 8-oxodeoxyguanosine (8-oxodG), 15-F 2t-isoprostane (15-F 2t-IsoP) and protein carbonyl groups. The response of the cell lines to the test compounds was substantially different. In HepG2 cells, oxidative damage to DNA was generally not induced by individual c-PAHs and the c-PAHs mix, but EOM increased 8-oxodG levels in these cells. In HEL cells, none of the compounds induced oxidative DNA damage. Lipid peroxidation, measured as the level of 15-F 2t-IsoP, was induced by c-PAHs in HepG2 cells only after 48 h of incubation, while the effect of EOM was detected already after 24 h. In HEL cells, individual c-PAHs and the c-PAH mix generally decreased 15-F 2t-IsoP levels. This effect was even stronger for EOM treatment. Protein oxidation, assessed as carbonyl levels in cell lysates, was not induced after 24 h of treatment with any compound in either cell line. Individual c-PAHs and the c-PAH mix generally induced protein oxidation in both cell lines after 48 h treatment, with the exception of DB[ a, l]P in HepG2 cells. Oxidative damage to proteins caused by EOM was generally increased in HepG2 cells after 48 h of incubation, while in HEL cells the effect was observed for only one dose of EOM. In summary, our results demonstrate the ability of EOM to induce oxidative damage to DNA and lipids after 24 h of treatment, and to proteins after 48 h, in HepG2 cells, while the effect of c-PAHs was substantially less. The induction of oxidative stress by c-PAHs and EOM in HEL cells was weak.

Association of urinary 15-F 2t-isoprostane level with oxygen desaturation and carotid intima–media thickness in nonobese sleep apnea patients

Obstructive sleep apnea (OSA) is characterized by recurrent apnea during sleep that may unbalance oxidative stress, increasing atherosclerosis. Among oxidative stress markers, 15-F 2t-isoprostane is considered one of the most sensitive and specific metabolites of lipid peroxidation. To explore the relationship between urinary 15-F 2t-isoprostane with sleep apnea severity and carotid modifications in nonobese OSA patients, 31 nonobese sleep apnea patients were studied, along with 10 lean subjects without OSA. Patients were assessed by polysomnography, blood pressure measurement, and ultrasonography to determine the carotid intima–media thickness (IMT). Urinary 15-F 2t-isoprostanes were measured by liquid chromatography–tandem mass spectrometry. Urinary 15-F 2t-isoprostane concentrations were increased in severe OSA patients compared to control subjects (20.2 ± 7.3 vs 12.3 ± 2.8 ng/mmol creatinine; P = 0.020). Mean carotid IMT was correlated with 15-F 2t-isoprostane ( r = 0.532; P < 0.001) and with the apnea–hypopnea index ( r = 0.345; P = 0.029). 15-F 2t-Isoprostane level was related to the night time spent at SaO 2 < 90% ( r = 0.478; P = 0.002), the apnea–hypopnea index ( r = 0.465; P = 0.003), and the mean nocturnal SaO 2 ( r = − 0.424; P = 0.007). These results showed a relationship between lipid peroxidation, carotid intima–media thickness, and intermittent hypoxia in nonobese OSA patients, thus reinforcing the hypothesis that oxidative stress could be involved in the early atherosclerotic process.

Biomarkers of exposure to tobacco smoke and environmental pollutants in mothers and their transplacental transfer to the foetus. Part II. Oxidative damage

Oxidative damage to macromolecules may have numerous negative health consequences. We measured oxidative damage to DNA, proteins and lipids in 80 newborns and 79 mothers, analyzed the effect of mother's tobacco smoke exposure on oxidative stress, and assessed correlations between oxidative stress markers and bulky and PAH (polycyclic aromatic hydrocarbons)-specific DNA adducts. Mean levels (±S.D.) of 8-oxodeoxyguanosine (8-oxodG) per 10 5 dG in the placenta were 2.85 ± 0.78; we did not see a difference between 8-oxodG levels in newborns born to mothers exposed and unexposed to tobacco smoke. Protein carbonyl levels, a marker of protein oxidation, were comparable in the umbilical cord and in maternal venous blood plasma (17.4 ± 3.2 and 17.6 ± 4.2 nmol/ml plasma in newborns and mothers, respectively, p = 0.66). Lipid peroxidation measured as levels of 15-F 2t-isoprostane (15-F 2t-IsoP) in plasma was significantly higher in newborns than in mothers (362 ± 129 and 252 ± 130 pg/ml in newborns and mothers, respectively, p < 0.001). We did not find any effect of tobacco smoke exposure on either biomarker in any group. Levels of both protein carbonyls and 15-F 2t-IsoP in cord blood significantly correlated with those in maternal plasma ( p < 0.001). 8-oxodG levels positively correlated with plasma carbonyls in cord plasma, as well as with cotinine levels (marker of tobacco smoke exposure) in maternal plasma. 8-oxodG levels also correlated with bulky DNA adducts in lymphocyte DNA of newborns and mothers and with PAH-DNA adducts in the placenta. Our results showed higher lipid peroxidation in newborns than in mothers, close correlation of analyzed oxidative stress markers between newborns and mothers, and a relationship between oxidative stress and induction of DNA adducts.

Consequences of delayed pump infusion line change in patients with type 1 diabetes mellitus treated with continuous subcutaneous insulin infusion

Objective To systematically investigate the effect of lack of adherence to the recommended change in insulin pump infusion line use beyond 48 h and determine whether the type of insulin made a difference. Research design and methods This was a double-blind, randomized, crossover trial with 20 patients with diabetes mellitus I using insulins aspart and lispro without a line change for up to 100 h. Using retrospective continuous glucose monitoring, we analyzed the average glucose over the day. Changes in serum 1,5-anhydroglucitol, carboxymethyllysine, and free 15-F 2t isoprostane were also studied. Results From Day 2 to Day 5 of the pump line use, the daily average glucose level increased from 122.7 to 163.9 mg/dl ( P<.05), fasting glucose from 120.3 to 154.5 mg/dl ( P<.05), postprandial glucose from 114.6 to 172.1 mg/dl ( P<.05), and the daily maximum glucose from 207.7 to 242.8 dl ( P<.05 for the trend). Time period that the glucose was >180 mg/dl increased from 14.5% to 38.3% ( P<.05). Loss of control occurred despite increase in total daily insulin dose from 48.5±11.8 to 55.3±17.9 U ( P=.05). There was no difference in loss of control between insulin types, and biomarkers measured did not change significantly. Conclusions The insulin pump infusion should be changed every 48 h in patients using continuous subcutaneous insulin infusion (CSII), to avoid loss of glycemic control. In the short-term, this loss of glycemic control has no impact on oxidative stress and glycation.

Enhanced leukocyte HIF-1α and HIF-1 DNA binding in humans after rapid ascent to 4300 m

Hypoxia plays a crucial role in the pathogenesis of a multitude of diseases and clinical conditions such as cancer, diabetes, cardiovascular disease, stroke, pulmonary disease, inflammation, organ transplant, and wound healing. Investigations into the role of hypoxia-inducible transcription factor (HIF) in disease development have been conducted with the basic premise that HIF is activated in vivo during hypoxia in humans, yet this basic physiologic premise has never verified. Thus, we hypothesized that HIF-1 DNA binding would be enhanced in vivo in humans in response to acute global hypoxia. Fourteen human subjects were exposed to normoxia (1600 m) and hypoxia (4300 m, ≈ 12% O 2) in a hypobaric hypoxic chamber (8 h). HIF-1 DNA binding and HIF-1α protein were evaluated in circulating leukocytes. Oxidative markers were evaluated by plasma metabolomics using nuclear magnetic resonance and by urinary 15-F 2t-isoprostane concentrations. Leukocyte HIF-1 DNA binding was increased ( p = 0.007) and HIF-1α was greater during hypoxia compared to normoxia. Circulating total glutathione was reduced by 35% ( p = 0.001), and lactate and succinate were increased by 29 and 158%, respectively ( p = 0.007 and 0.001), as were urinary 15-F 2t-isoprostanes ( p = 0.037). HIF-1 DNA binding and HIF-1α were elevated in vivo in leukocytes of healthy human subjects exposed to 12% oxygen, in association with plasma and urinary markers of hypoxic stress.

Randomized, Blinded, Placebo-Controlled Clinical Trial of N-Acetylcysteine in Dogs With Spinal Cord Trauma From Acute Intervertebral Disc Disease

The effect of N-acetylcysteine administration intravenously before hemilaminectomy surgery on neurologic outcome and 15F 2t isoprostane excretion in dogs was examined in a blinded, placebo-controlled trial. To determine the effect of N-acetylcysteine administration on urinary 15F 2t isoprostane excretion and neurologic outcome following hemilaminectomy for intervertebral disc disease. Oxidative stress is a mediator of secondary injury to the spinal cord following trauma. Acute intervertebral disc disease is associated with increased oxidative damage in dogs. N-acetylcysteine has preserved neurologic function following experimental spinal cord injury. Seventy dogs with naturally occurring acute intervertebral disc disease were administered either with saline placebo or N-acetylcysteine intravenously before hemilaminectomy surgery. Serial neurologic examinations were performed before and 1, 2, 7, 14, and 42 days following treatment. Urinary excretion of 15F 2t isoprostane excretion was determined before treatment and 1 hour after surgery. Analysis of subjective data did not reveal any significant effect of N-acetylcysteine on neurologic outcome or rate of improvement of neurologic score in the 42 days following treatment. Urinary 15F 2t isoprostane excretion was not significantly different between treatment groups (P > 0.05). N-acetylcysteine intravenously before hemilaminectomy has no effect on urinary 15F 2t isoprostane excretion or neurologic outcome. Treatment of dogs with the antioxidant N-acetylcysteine before hemilaminectomy, while not detrimental, does not affect neurologic outcome in the 42 days following surgery.

Seasonal variability of oxidative stress markers in city bus drivers: Part II. Oxidative damage to lipids and proteins

The aim of the present study was to investigate the seasonal variability of markers of oxidative damage to lipids (15-F 2t-isoprostane, 15-F 2t-IsoP) and proteins (protein carbonyl levels) in 50 bus drivers and 50 controls from Prague, Czech Republic, and to identify factors affecting oxidative stress markers. The samples were collected in three seasons with different levels of air pollution. The exposure to environmental pollutants (carcinogenic polycyclic aromatic hydrocarbons, c-PAHs, particulate matter, PM2.5 and PM10, and volatile organic compounds, VOC) was monitored by personal and/or stationary monitors. For the analysis of both markers, ELISA techniques were used. The median levels of individual markers in bus drivers versus controls were as follows: 15-F 2t-IsoP (nmol/mmol creatinine): winter 2005, 0.81 versus 0.68 ( p < 0.01); summer 2006, 0.62 versus 0.60 ( p = 0.90); winter 2006, 0.76 versus 0.51 ( p < 0.001); carbonyl levels (nmol/ml plasma): winter 2005, 14.1 versus 12.9 ( p = 0.001); summer 2006, 17.5 versus 16.6 ( p = 0.26); winter 2006, 13.5 versus 11.7 ( p < 0.001). Multivariate logistic regression identified PM levels measured by stationary monitors over a period 25–27 days before urine collection as a factor positively associated with lipid peroxidation, while protein oxidation levels correlated negatively with both c-PAHs and PM levels. In conclusion, markers of oxidative damage to lipids and proteins were increased in bus drivers in winter seasons, but not in summer. Lipid peroxidation was positively correlated with c-PAHs and PM exposure; protein oxidation correlated negatively and was highest in summer suggesting another factor(s) affecting protein carbonyl levels.

Plasma 15-F 2t isoprostane concentrations are increased during acute fructose loading in type 2 diabetes

Objective Fructose consumption is increasing worldwide and is likely to play a role in metabolic disorders. Dietary fructose is often recommended for diabetic patients, as this form of carbohydrate leads to a lower postprandial rise in plasma glucose and insulin. However, fructose contributes to the generation of free radicals. The aim of this work was to investigate the acute effects of a fructose load in patients with type 2 diabetes mellitus (T2DM), compared with healthy controls, on several metabolic oxidative biomarkers, particularly plasma 15-F 2t isoprostanes (15-F 2t isoPs). Research design and methods Six T2DM patients and six healthy subjects were recruited. All patients underwent a single fructose tolerance test (75 g of anhydrous fructose). Plasma 15-F 2t isoPs concentrations, plasma total antioxidant capacity (TAS) and thiobarbituric acid reactive substances (TBARS) were measured at baseline, and at 60, 120, 180 and 240 min after fructose absorption. Results Baseline plasma 15-F 2t isoPs concentrations were significantly increased in T2DM patients compared with controls (310 ± 47 versus 237 ± 20 pg/mL, respectively; P < 0.01) and rose significantly ( P < 0.01) to 414 ± 45 pg/mL in diabetic patients. No change in TAS or TBARS was observed in either group. Conclusion Plasma 15-F 2t isoPs are increased during acute fructose loading in T2DM. Knowing the potentially deleterious effect of plasma 15-F 2t isoPs—in particular, vascular lesions—and in light of our results, it is necessary to reconsider fructose consumption in T2DM patients, as we can now show, for the first time, a possible association between acute fructose loading and deleterious effects in such patients.

Plasma levels of 15-F 2t-isoprostane in newborn infants are affected by mode of delivery

Objective To investigate how the mode of delivery affects the level oxidative stress in newborns. Design and methods 15-F 2t-isoprostane, as index of oxidative stress, was measured in umbilical cord plasma samples from 37 infants born after vaginal delivery or caesarian section, using specific immuno-affinity extraction and immunoassay. Results 15-F 2t-isoprostane levels were higher in infants born after vaginal delivery ( n = 18) compared to those delivered by elective caesarian section ( n = 19). Conclusions 15-F 2t-isoprostane is a sensitive biomarker of fetal oxidative stress during labor.