Prostaglandin F2α formation is associated with mortality in a Swedish community-based cohort of older males.

AIMS: An increasing number of clinical studies highlight the importance of the inflammatory mediator prostaglandin F2 α (PGF(2α)). Prostaglandin F2 α activity has been suggested to play pivotal roles in the development of cardiovascular diseases and cancer. However, whether systemic PGF(2α) concentrations may signal mortality is unknown. The aim was to evaluate in vivo PGF(2α) formation, by measuring urinary 15-keto-dihydro-PGF(2α), and mortality risk in a community setting. METHODS AND RESULTS: Urinary 15-keto-dihydro-PGF(2α) was measured in a Swedish population of 670 men (aged 77-78 years) and the participants were followed up for a median of 9.7 years (383 died, among them 156 of cardiovascular causes and 102 of cancer). In Cox regression models, urinary 15-keto-dihydro-PGF(2α) was significantly associated with cardiovascular mortality [multivariate hazard ratio (HR) for 1 SD increase of urinary 15-keto-dihydro-PGF(2α): 1.18; 95% CI:1.04-1.34; P = 0.01) independent of established cardiovascular risk factors including C-reactive protein. Urinary 15-keto-dihydro-PGF(2α) was also independently associated with total mortality (multivariate HR for 1 SD increase of urinary 15-keto-dihydro-PGF(2α): 1.11; 95% CI: 1.01-1.21; P = 0.03). The combination of 15-keto-dihydro-PGF(2α) concentrations above the median and high serum high-sensitive C-reactive protein (>3 mg/L) was independently associated with a two-fold increased risk of cancer and total mortality (P = 0.02 and P < 0.001, respectively). CONCLUSION: This is the first study to show that the inflammatory mediator PGF(2α) was independently associated with mortality and specifically cardiovascular mortality 10 years later. The results are in line with the emerging evidence of the importance of the inflammatory mediator PGF(2α) in fatal cardiovascular disease.

Involvement of inflammation in normal pregnancy.

To study the role of inflammation throughout normal pregnancy and postpartum, 37 women with normal pregnancies, including normal neonatal outcome, participated. Blood and urine samples were collected from each woman at least six times during pregnancy and postpartum. Plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and urinary levels of a prostaglandin-F2α (PGF2α ) metabolite were measured. Median, 25th to 75th centile and average change per gestational week of IL-6, TNF-α and the PGF2α metabolite were measured. Levels of IL-6 increased significantly throughout pregnancy and remained high postpartum. No change in TNF-α could be seen. The PGF2α metabolite levels increased significantly throughout pregnancy and decreased postpartum. These results suggest that mild but significant inflammatory activity is involved in the development of normal pregnancy, which might have important physiological roles.

Short-term chamber exposure to low doses of two kinds of wood smoke does not induce systemic inflammation, coagulation or oxidative stress in healthy humans.

INTRODUCTION: Air pollution increases the risk of cardiovascular diseases. A proposed mechanism is that local airway inflammation leads to systemic inflammation, affecting coagulation and the long-term risk of atherosclerosis. One major source of air pollution is wood burning. Here we investigate whether exposure to two kinds of wood smoke, previously shown to cause airway effects, affects biomarkers of systemic inflammation, coagulation and lipid peroxidation. METHODS: Thirteen healthy adults were exposed to filtered air followed by two sessions of wood smoke for three hours, one week apart. One session used smoke from the start-up phase of the wood-burning cycle, and the other smoke from the burn-out phase. Mean particle mass concentrations were 295 µg/m³ and 146 µg/m³, and number concentrations were 140,000/cm³ and 100,000/cm³, respectively. Biomarkers were analyzed in samples of blood and urine taken before and several times after exposure. Results after wood smoke exposure were adjusted for exposure to filtered air. RESULTS: Markers of systemic inflammation and soluble adhesion molecules did not increase after wood smoke exposure. Effects on markers of coagulation were ambiguous, with minor decreases in fibrinogen and platelet counts and mixed results concerning the coagulation factors VII and VIII. Urinary F2-isoprostane, a consistent marker of in vivo lipid peroxidation, unexpectedly decreased after wood smoke exposure. CONCLUSIONS: The effects on biomarkers of inflammation, coagulation and lipid peroxidation do not indicate an increased risk of cardiovascular diseases in healthy adults by short-term exposure to wood smoke at these moderate doses, previously shown to cause airway effects.

Insulin-like growth factor binding protein-1 (IGFBP-1) during normal pregnancy.

BACKGROUND: Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is the main binder of IGFs in secretory endometrium and decidualized stromal endometrial cells and IGFBP-1 has been shown to modulate IGF bioactivities and influence fetal growth. To be able to evaluate IGFBP-1 values during pregnancy it is important to establish normal values in pregnant women. MATERIALS & METHODS: We have studied IGFBP-1 concentrations in maternal plasma from 52 healthy women with normal singleton pregnancies. Several plasma samples were collected from each woman and the samples were grouped according to gestational age into the following periods: week 7-17; week 17-24; week 24-28; week 28-31; week 31-34; week 34-38; -2 to 0 weeks prior to delivery and postpartum (>6 weeks after delivery). RESULTS: The 2.5 and 97.5 percentiles for IGFBP-1 were calculated according to the recommendations of the International Federation of Clinical Chemistry on the statistical treatment of reference values. CONCLUSIONS: IGFBP-1 is increased during pregnancy compared to postpartum. Two peaks, at week 17-24 and just before delivery, were observed.

Targeting oxidative injury and cytokines' activity in the treatment with anti-tumor necrosis factor-α antibody for complex regional pain syndrome 1.

Cytokines and oxygen free radicals have been implicated in the potential pathogenic development of complex regional pain syndrome (CRPS). We aimed to analyze the relationship between clinical status, circulating levels of cytokines, and markers of oxidative damage during the treatment with anti-TNFα antibodies. The patient chosen for treatment had not had improvement through a number of conventional therapies and fulfilled the current diagnostic criteria for CRPS-1. We investigated the clinical variables before and after systemic administration of 1.4 mg/kg anti-TNFα antibody (infliximab), repeated after 1 month in a dose of 3 mg/kg. Blood samples were collected before and after anti-TNFα antibodies administration, and plasma was analyzed for 8-isoprostane-prostaglandin F2α (8-iso-PGF2α, a marker of oxidative injury) and cytokines (TNF-α, IL-4, IL-6, IL-7, IL-8, IL-10, IL-17A). Plasma concentrations of 8-iso-PGF2α were measured with radioimmunoassay (RIA), and the kinetics of cytokines were detected in plasma by antibody-based proximity ligation (PLA). Pathologically high levels of 8-iso-PGF2α were found in the patient. Immediately after each administration of infliximab, the levels of 8-iso-PGF2α decreased. Although the patient showed an improvement of the cutaneous dystrophic symptoms and diminished pain associated with these lesions, the levels of circulating TNFα increased after the administration of anti-TNFα antibodies. In a patient with CRPS-1 treated with anti-TNFα antibodies, we report increased levels of circulating TNFα and a temporary mitigation of oxidative stress as measured by plasma F2 -isoprostane. This case report provides evidence 2 supporting the indication of monitoring the oxidative stress biomarkers during treatment with anti-TNFα antibodies in CRPS 1.

Effects of similar intakes of marine n-3 fatty acids from enriched food products and fish oil on cardiovascular risk markers in healthy human subjects.

There is convincing evidence that consumption of fish and fish oil rich in long-chain (LC) n-3 PUFA (n-3 LCPUFA), EPA (20 : 5n-3) and DHA (22 : 6n-3) reduce the risk of CHD. The aim of the present study was to investigate whether n-3 LCPUFA-enriched food products provide similar beneficial effects as fish oil with regard to incorporation into plasma lipids and effects on cardiovascular risk markers. A parallel 7-week intervention trial was performed where 159 healthy men and women were randomised to consume either 34 g fish pâté (n 44), 500 ml fruit juice (n 38) or three capsules of concentrated fish oil (n 40), all contributing to a daily intake of approximately 1 g EPA and DHA. A fourth group did not receive any supplementation or food product and served as controls (n 37). Plasma fatty acid composition, serum lipids, and markers of inflammation and oxidative stress were measured. Compared with the control group, plasma n-3 LCPUFA and EPA:arachidonic acid ratio increased equally in all intervention groups. However, no significant changes in blood lipids and markers of inflammation and oxidative stress were observed. In conclusion, enriched fish pâté and fruit juice represent suitable delivery systems for n-3 LCPUFA. However, although the dose given is known to reduce the risk of CVD, no significant changes were observed on cardiovascular risk markers in this healthy population.

Effect of industrially produced trans fat on markers of systemic inflammation: evidence from a randomized trial in women.

Consumption of industrially produced trans fatty acids (IP-TFA) has been positively associated with systemic markers of low-grade inflammation and endothelial dysfunction in cross-sectional studies, but results from intervention studies are inconclusive. Therefore, we conducted a 16 week double-blind parallel intervention study with the objective to examine the effect of IP-TFA intake on biomarkers of inflammation, oxidative stress, and endothelial dysfunction. Fifty-two healthy overweight postmenopausal women (49 completers) were randomly assigned to receive either partially hydrogenated soybean oil (15.7 g/day IP-TFA) or control oil without IP-TFA. After 16 weeks, IP-TFA intake increased baseline-adjusted serum tumor necrosis factor (TNF) α by 12% [95% confidence interval (CI): 5-20; P = 0.002] more in the IP-TFA group compared with controls. Plasma soluble TNF receptors 1 and 2 were also increased by IP-TFA [155 pg/ml (CI: 63-247); P < 0.001 and 480 pg/ml (CI: 72-887); P = 0.02, respectively]. Serum C-reactive protein, interleukin (IL) 6 and adiponectin and subcutaneous abdominal adipose tissue mRNA expression of IL6, IL8, TNFα, and adiponectin as well as ceramide content were not affected by IP-TFA, nor was urinary 8-iso-prostaglandin-F(2α). In conclusion, this dietary trial indicates that the mechanisms linking dietary IP-TFA to cardiovascular disease may involve activation of the TNFα system.

Use of multiple biomarkers to improve the prediction of death from cardiovascular causes.

BACKGROUND: The incremental usefulness of adding multiple biomarkers from different disease pathways for predicting the risk of death from cardiovascular causes has not, to our knowledge, been evaluated among the elderly. METHODS: We used data from the Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based cohort of elderly men, to investigate whether a combination of biomarkers that reflect myocardial cell damage, left ventricular dysfunction, renal failure, and inflammation (troponin I, N-terminal pro-brain natriuretic peptide, cystatin C, and C-reactive protein, respectively) improved the risk stratification of a person beyond an assessment that was based on the established risk factors for cardiovascular disease (age, systolic blood pressure, use or nonuse of antihypertensive treatment, total cholesterol, high-density lipoprotein cholesterol, use or nonuse of lipid-lowering treatment, presence or absence of diabetes, smoking status, and body-mass index). RESULTS: During follow-up (median, 10.0 years), 315 of the 1135 participants in our study (mean age, 71 years at baseline) died; 136 deaths were the result of cardiovascular disease. In Cox proportional-hazards models adjusted for established risk factors, all of the biomarkers significantly predicted the risk of death from cardiovascular causes. The C statistic increased significantly when the four biomarkers were incorporated into a model with established risk factors, both in the whole cohort (C statistic with biomarkers vs. without biomarkers, 0.766 vs. 0.664; P<0.001) and in the group of 661 participants who did not have cardiovascular disease at baseline (0.748 vs. 0.688, P=0.03). The improvement in risk assessment remained strong when it was estimated by other statistical measures of model discrimination, calibration, and global fit. CONCLUSIONS: Our data suggest that in elderly men with or without prevalent cardiovascular disease, the simultaneous addition of several biomarkers of cardiovascular and renal abnormalities substantially improves the risk stratification for death from cardiovascular causes beyond that of a model that is based only on established risk factors.

A high intake of trans fatty acids has little effect on markers of inflammation and oxidative stress in humans.

Consumption of industrial trans fatty acids (iTFA) increases LDL cholesterol, decreases HDL cholesterol, and is strongly associated with a higher risk of cardiovascular disease (CVD). However, changes in circulating cholesterol cannot explain the entire effect. Therefore, we studied whether iTFA and conjugated linoleic acid (CLA) affect markers of inflammation and oxidative stress. Sixty-one healthy adults consumed each of 3 diets for 3 wk, in random order. Diets were identical except for 7% of energy provided by oleic acid (control diet), iTFA, or CLA. At the end of the 3 wk, we measured plasma inflammatory markers IL-6, C-reactive protein, tumor necrosis factor receptors I and II (TNF-RI and -RII), monocyte chemotactic protein-1 and E-selectin, and urinary 8-iso-PGF(2α), a marker of lipid peroxidation. Consumption of iTFA caused 4% lower TNF-RI concentrations and 6% higher E-selectin concentrations compared with oleic acid (control) and had no significant effect on other inflammatory markers. CLA did not significantly affect inflammatory markers. The urine concentration of 8-iso-PGF(2α) [geometric mean (95% CI)] was greater after the iTFA [0.54 (0.48, 0.60) nmol/mmol creatinine] and the CLA [1.2 (1.1, 1.3) nmol/mmol creatinine] diet periods than after the control period [0.45 (0.41, 0.50) nmol/mmol creatinine; P < 0.05]. In conclusion, high intakes of iTFA and CLA did not substantially affect plasma concentrations of inflammatory markers, but they increased the urine 8-iso-PGF(2α) concentration. However, it is unlikely this plays a major role in the mechanism by which iTFA increase the risk of CVD. However, more research is needed to fully understand the implications of these findings.

The combined contribution of albuminuria and glomerular filtration rate to the prediction of cardiovascular mortality in elderly men.

BACKGROUND: Cardiovascular risk prediction is particularly important in the primary prevention of cardiovascular disease (CVD). Yet, data on whether the combined addition of albuminuria and estimated glomerular filtration rate (eGFR) improves cardiovascular risk prediction in individuals without CVD in the community is scarce. METHODS: We investigated associations between urinary albumin excretion rate (UAER), cystatin C-based eGFR and cardiovascular mortality in a community-based cohort of elderly men (ULSAM study; n = 1113, mean age 71 years, 208 cardiovascular deaths, median follow-up 12.9 years) with prespecified analyses in participants without CVD (n = 649, 86 cardiovascular deaths). RESULTS: Using multivariable Cox regression, higher UAER and lower eGFR were associated with increased risk for cardiovascular mortality independently of established cardiovascular risk factors in the whole sample and in men without CVD at baseline [subsample without CVD: UAER; hazard ratio (HR) per 1 SD 1.26, 95% confidence interval (CI) 1.05-1.51, P = 0.01; eGFR: HR per 1 SD 0.74, 95% CI 0.59-0.92, P = 0.007]. Analyses of model discrimination, calibration, reclassification and global fit suggested that UAER and eGFR also add relevant prognostic information beyond established cardiovascular risk factors in participants without prevalent CVD. Interestingly, established cutoffs used to diagnose microalbuminuria (UAER > 20 µg/min) and chronic kidney disease Stage 3 (eGFR < 60 mL/min/1.73 m(2)), appeared less suitable for cardiovascular risk prediction [integrated discrimination improvement (IDI) 0.006, P = 0.11], while cutoffs UAER > 6 µg/min and eGFR < 45 mL/min/1.73 m(2) significantly improved IDI (0.047, P < 0.001). CONCLUSIONS: UAER and eGFR improved cardiovascular risk prediction beyond established cardiovascular risk factors, suggesting that these kidney biomarkers may be useful in predicting cardiovascular death in elderly men.

A longitudinal study of plasma levels of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF), sFlt1: PlGF ratio and vascular endothelial growth factor (VEGF-A) in normal pregnancy.

OBJECTIVE: To describe plasma levels of angiogenic (PlGF, VEGF-A) and anti-angiogenic (sFlt1) factors as well as the sFlt1:PlGF ratio throughout normal pregnancy and postpartum. DESIGN: Longitudinal prospective study. SETTING: One outpatient antenatal clinic in Uppsala, Sweden. POPULATION: Thirty-seven healthy women with normal pregnancies and normal neonatal outcome were included. METHODS: Blood samples were collected from each woman at least six times. Plasma levels of sFlt1, PlGF and VEGF-A were measured using commercially available ELISA kits. MAIN OUTCOME MEASURES: Median plasma levels, the 25th to the 75th percentile and the average change per gestational week of sFlt1, PlGF and the sFlt1:PlGF ratio. RESULTS: sFlt1 levels were relatively constant until weeks 29-30, when they increased, reaching a peak at week 40. An increase of 643pg/ml per week was observed from weeks 30 to 40. Postpartum levels were low. PlGF increased by 16pg/ml per week from early pregnancy until weeks 29-30 and thereafter decreased by 14pg/ml per week until week 40. The sFlt1:PlGF ratio decreased from weeks 9-12, was constantly low from weeks 19-20 to 37-38 and then increased to weeks 39-40. VEGF-A was detectable in only 8% of the samples during pregnancy and in 64% postpartum. CONCLUSION: This longitudinal study demonstrates how sFlt1, PlGF and the sFlt1:PlGF ratio fluctuate throughout normal pregnancy and postpartum and may serve as a reference against which these factors can be studied in complicated pregnancies. VEGF-A levels were more often detectable postpartum.

Association between serum cathepsin S and mortality in older adults.

CONTEXT: Experimental data suggest that cathepsin S, a cysteine protease, is involved in the complex pathways leading to cardiovascular disease and cancer. However, prospective data concerning a potential association between circulating cathepsin S levels and mortality are lacking. OBJECTIVE: To investigate associations between circulating cathepsin S levels and mortality in 2 independent cohorts of elderly men and women. DESIGN, SETTING, AND PARTICIPANTS: Prospective study using 2 community-based cohorts, the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 1009; mean age: 71 years; baseline period: 1991-1995; median follow-up: 12.6 years; end of follow-up: 2006) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 987; 50% women; mean age: 70 years; baseline period: 2001-2004; median follow-up: 7.9 years; end of follow-up: 2010). Serum samples were used to measure cathepsin S. MAIN OUTCOME MEASURE: Total mortality. RESULTS: During follow-up, 413 participants died in the ULSAM cohort (incidence rate: 3.59/100 person-years at risk) and 100 participants died in the PIVUS cohort (incidence rate: 1.32/100 person-years at risk). In multivariable Cox regression models adjusted for age, systolic blood pressure, diabetes, smoking status, body mass index, total cholesterol, high-density lipoprotein cholesterol, antihypertensive treatment, lipid-lowering treatment, and history of cardiovascular disease, higher serum cathepsin S was associated with an increased risk for mortality (ULSAM cohort: hazard ratio [HR] for 1-unit increase of cathepsin S, 1.04 [95% CI, 1.01-1.06], P = .009; PIVUS cohort: HR for 1-unit increase of cathepsin S, 1.03 [95% CI, 1.00-1.07], P = .04). In the ULSAM cohort, serum cathepsin S also was associated with cardiovascular mortality (131 deaths; HR for quintile 5 vs quintiles 1-4, 1.62 [95% CI, 1.11-2.37]; P = .01) and cancer mortality (148 deaths; HR for 1-unit increase of cathepsin S, 1.05 [95% CI, 1.01-1.10]; P = .01). CONCLUSIONS: Among elderly individuals in 2 independent cohorts, higher serum cathepsin S levels were associated with increased mortality risk. Additional research is needed to delineate the role of cathepsin S and whether its measurement might have clinical utility.

Cerebral effects of hyperglycemia in experimental cardiac arrest.

OBJECTIVE: To investigate the effects of cardiac arrest on cerebral perfusion and oxidative stress during hyperglycemia and normoglycemia. DESIGN: Experimental animal model. SETTING: University laboratory. SUBJECTS: Triple-breed pigs (weight, 22-27 kg). INTERVENTIONS: Thirty-three pigs were randomized and clamped at blood glucose levels of 8.5-10 mM (high) or 4-5.5 mM (normal) and thereafter subjected to alternating current-induced 12-min cardiac arrest followed by 8 mins of cardiopulmonary resuscitation and direct-current shock to restore spontaneous circulation. MEASUREMENTS AND MAIN RESULTS: Hemodynamics, regional near-infrared light spectroscopy, regional venous Hbo2, and biochemical markers (Protein S100beta, troponin I, F2-isoprostanes reflecting oxidative stress and inflammation) were monitored and/or sampled throughout an observation period of 4 hrs. No significant differences were seen in hemodynamics or biochemical profile. The cerebral oxygenation by means of regional near-infrared light spectroscopy was higher in the hyperglycemic (H) than in the normal (N) group after restoration of spontaneous circulation (p < .05). However, tendencies toward increased protein S100beta and 15-keto-dihydro-prostaglandin F2alpha were observed in the H group but were not statistically significant. CONCLUSIONS: The responses to 12-min cardiac arrest and cardiopulmonary resuscitation share large similarities during hyperglycemia and normoglycemia. The higher cerebral tissue oxygenation observed in the hyperglycemia needs to be confirmed and the phenomenon needs to be addressed in future studies.

Effects of dietary fat modification on oxidative stress and inflammatory markers in the LIPGENE study.

Subjects with the metabolic syndrome (MetS) have enhanced oxidative stress and inflammation. Dietary fat quality has been proposed to be implicated in these conditions. We investigated the impact of four diets distinct in fat quantity and quality on 8-iso-PGF2α (a major F2-isoprostane and oxidative stress indicator), 15-keto-13,14-dihydro-PGF2α (15-keto-dihydro-PGF2α, a major PGF2α metabolite and marker of cyclooxygenase-mediated inflammation) and C-reactive protein (CRP). In a 12-week parallel multicentre dietary intervention study (LIPGENE), 417 volunteers with the MetS were randomly assigned to one of the four diets: two high-fat diets (38 % energy (%E)) rich in SFA or MUFA and two low-fat high-complex carbohydrate diets (28 %E) with (LFHCC n-3) or without (LFHCC) 1·24 g/d of very long chain n-3 fatty acid supplementation. Urinary levels of 8-iso-PGF2α and 15-keto-dihydro-PGF2α were determined by RIA and adjusted for urinary creatinine levels. Serum concentration of CRP was measured by ELISA. Neither concentrations of 8-iso-PGF2α and 15-keto-dihydro-PGF2α nor those of CRP differed between diet groups at baseline (P>0·07) or at the end of the study (P>0·44). Also, no differences in changes of the markers were observed between the diet groups (8-iso-PGF2α, P = 0·83; 15-keto-dihydro-PGF2α, P = 0·45; and CRP, P = 0·97). In conclusion, a 12-week dietary fat modification did not affect the investigated markers of oxidative stress and inflammation among subjects with the MetS in the LIPGENE study.

Supplementation with fatty acids influences the airway nitric oxide and inflammatory markers in patients with cystic fibrosis.

OBJECTIVES: To obtain a balance in the fatty acid (FA) metabolism is important for the inflammatory response and of special importance in cystic fibrosis (CF), which is characterized by impaired FA metabolism, chronic inflammation, and infection in the airways. Nitric oxide (NO) has antimicrobial properties and low nasal (nNO) and exhaled NO (FENO), commonly reported in CF that may affect bacterial status. The present study investigates the effect of different FA blends on nNO and FENO and immunological markers in patients with CF. PATIENTS AND METHODS: Forty-three patients with CF and "severe" mutations were consecutively enrolled in a randomized double-blind placebo-controlled study with 3 FA blends containing mainly n-3 or n-6 FA or saturated FA acting as placebo. FENO, nNO, serum phospholipid concentrations of FA, and biomarkers of inflammation were measured before and after 3 months of supplementation. RESULTS: Thirty-five patients in clinically stable condition completed the study. The serum phospholipid FA pattern changed significantly in all 3 groups. An increase of the n-6 FA, arachidonic acid, was associated with a decrease of FENO and nNO. The inflammatory biomarkers, erythrocyte sedimentation rate, and interleukin-8 decreased after supplementation with n-3 FA and erythrocyte sedimentation rate increased after supplementation with n-6 FA. CONCLUSIONS: This small pilot study indicated that the composition of dietary n-3 and n-6 FA influenced the inflammatory markers in CF. FENO and nNO were influenced by changes in the arachidonic acid concentration, supporting previous studies suggesting that both the lipid abnormality and the colonization with Pseudomonas influenced NO in the airways.

Allergen-induced formation of F2-isoprostanes in a murine asthma model identifies oxidative stress in acute airway inflammation in vivo.

F(2)-isoprostanes have been associated with various forms of oxidant stress. The levels of F(2)-isoprostanes in a murine asthma model were studied both in situ and in vivo and further investigated whether the formation of F(2)-isoprostanes was associated with increased ovalbumin (OVA)-induced airway inflammation after a 17-day (OVA-17) or a 24-day (OVA-24) protocol. Bronchial reactivity was assessed by using a ventilator (FlexiVent). OVA-treated animals had higher lung resistance and lung compliance compared to control groups (P<0.001). 8-Iso-PGF(2)(alpha) levels in bronchoalveolar lavage (BAL) and 8-iso-PGF(2)(alpha) immunoreactivity in lung tissue were analyzed. OVA-17 mice showed a 2.5-fold increased level of 8-iso-PGF(2)(alpha) in BAL compared to PBS-17 mice (P=0.023). Lung tissue from OVA-24 mice had more intense 8-iso-PGF(2)(alpha) staining compared to OVA-17 mice. This study showed an accumulation of F(2)-isoprostanes in acute airway inflammation and a markedly increased tissue damage caused by oxidative stress in an ongoing inflammation.

Low dietary intake of beta-carotene, alpha-tocopherol and ascorbic acid is associated with increased inflammatory and oxidative stress status in a Swedish cohort.

Fruit and vegetable consumption has been associated with a reduced risk of several diseases including CVD. A part of these effects seen could be linked to anti-inflammatory and antioxidative effects, although this has not been thoroughly investigated. The present study was designed to investigate the effects of the dietary intake of beta-carotene, alpha-tocopherol and ascorbic acid on in vivo biomarkers of inflammation (PGF2alpha, high-sensitive C-reactive protein (hsCRP) and IL-6 formation) and oxidative stress (F2-isoprostane formation), the two important factors associated with accelerated atherosclerosis. The dietary intake of 704 participants in the Uppsala Longitudinal Study of Adult Men (ULSAM) at age 70 years was registered and inflammatory and oxidative stress biomarkers were quantified 7 years later. The registered dietary intakes of ascorbic acid and alpha-tocopherol were negatively associated linearly and in quartiles with both PGF2alpha, hsCRP, IL-6 and F2-isoprostanes, where ascorbic acid intake generally was more strongly associated. Dietary intake of beta-carotene was only significantly negatively associated with F2-isoprostanes. In conclusion, the present study is the first to suggest that the intake of food rich in antioxidants is associated with reduced cyclo-oxygenase- and cytokine-mediated inflammation and oxidative stress at 7 years of follow-up. These associations could be linked to the beneficial effects of fruit and vegetables observed on CVD.

Blackcurrant seed press residue increases tocopherol concentrations in serum and stool whilst biomarkers in stool and urine indicate increased oxidative stress in human subjects.

Berry seeds are a tocopherol-rich by-product of fruit processing without specific commercial value. In a human intervention study, the physiological impact of blackcurrant seed press residue (PR) was tested. Thirty-six women (aged 24 +/- 3 years; twenty non-smokers, sixteen smokers) consumed 250 g bread/d containing 8% PR for a period of 4 weeks (period 3). Comparatively, a control bread without PR (250 g/d) was tested (period 2) and baseline data were obtained (period 1). Blood, stool and 24 h urine were collected during a 5 d standardised diet within each period. Tocopherol and Fe intakes were calculated from food intake. In serum, tocopherol concentration and Fe parameters were determined. In urine, oxidative stress markers 8-oxo-2'-deoxyguanosine, 8-iso-PGF2alpha and inflammatory response marker 15-keto-dihydro-PGF2alpha were analysed. Stool tocopherol concentration, genotoxicity of faecal water (comet assay) and antioxidant capacity of stool (aromatic hydroxylation of salicylic acid) were determined. Fe and total tocopherol intake, total tocopherol concentrations in serum and stool, and genotoxicity of faecal water increased with PR bread consumption (P < 0.05). The antioxidant capacity of stool decreased between baseline and intervention, expressed by increased formation of 2,3- and 2,5-dihydroxybenzoic acid in vitro (P < 0.05). In smokers, 8-oxo-2'-deoxyguanosine increased with PR consumption (P < 0.05). Prostane concentrations were unaffected by PR bread consumption. In summary, the intake of bread containing blackcurrant PR for 4 weeks increased serum and stool total tocopherol concentrations. However, various biomarkers indicated increased oxidative stress, suggesting that consumption of ground berry seed may not be of advantage.

Long-term moderate intervention with n-3 long-chain PUFA-supplemented dairy products: effects on pathophysiological biomarkers in patients with rheumatoid arthritis.

n-3 long-chain PUFA (n-3 LC-PUFA) may improve cardiovascular and inflammatory diseases. The effects of n-3 LC-PUFA-supplemented dairy products on inflammation and immunological parameters, biomarkers of oxidative stress, serum lipids, and on disease activity were determined in patients with rheumatoid arthritis (RA). Forty-five subjects (forty-three females and two males) were randomly divided into two groups in a double-blind, placebo-controlled cross-over study. Both groups received placebo or verum products consecutively for 3 months with a 2-month washout phase between the two periods. Blood samples were taken at the beginning and at the end of each period. The dairy products generally improved serum lipids by increasing HDL and lowering lipoprotein a. The n-3 LC-PUFA supplements act to lower TAG. Additionally, a decreased lipopolysaccharide-stimulated cylo-oxygenase-2 expression was found in patients who had consumed the enriched dairy products. The majority of the CD analysed were not influenced, although n-3 LC-PUFA did suppress the immune response as lymphocytes and monocytes were found to be significantly decreased. The n-3 LC-PUFA did not increase the biomarkers of oxidative stress such as 8-iso-PGF(2alpha) and 15-keto-dihydro PGF(2alpha), and DNA damage like 7,8-dihydro-8-oxo-2'-deoxyguanosine. The long-term consumption of dairy products (2 x 12 weeks) diminished the excretion of hydroxypyridinium crosslinks, and favoured the diastolic blood pressure. The consumption of moderate doses of n-3 LC-PUFA in combination with dairy products did not improve the disease activity. However, there is evidence of cardioprotective effects. Furthermore, the long-term consumption of dairy products acts against the cartilage and bone destruction in RA.

Glycaemic status in relation to oxidative stress and inflammation in well-controlled type 2 diabetes subjects.

The aim of the present observational study was to investigate the relationships between glycaemic status and levels of oxidative stress and inflammation in well-controlled type 2 diabetes subjects. Metabolic variables (weight, BMI, waist circumference (waist), blood glucose, glycated Hb (HbA(1c)), insulin, blood lipids), biomarkers of oxidative stress (8-iso-PGF(2alpha), malondialdehyde, 8-oxo-7,8-dihydro-2'-deoxyguanosine, formamido pyrimidine glycosylase-sites, frequency of micronucleated erythrocytes, nitrotyrosine) and inflammatory markers (high sensitivity C-reactive protein (hsCRP), IL-6, cyclo-oxygenase-catalyzed PGF(2alpha)-metabolite) were measured. Fifty-six patients (thirty women and twenty-six men, age 62.3 (SD 7.0) years, HbA(1c) 6.1 (SD 0.9) %, BMI 28.3 (SD 3.8) kg/m(2), waist 99.6 (SD 11.1) cm) were included in the study. HbA(1c) (r 0.29, P=0.03) and blood glucose (r 0.33, P=0.01) correlated positively with 8-iso-PGF(2alpha). Positive correlations were also observed between HbA(1c) and nitrotyrosine (r 0.42, P=0.01), waist and hsCRP (r 0.37, P=0.005), hsCRP and IL-6 (r 0.61, P<0.0001) and between PGF(2alpha)-metabolite and 8-iso-PGF(2alpha) (r 0.27, P=0.048). The present study indicates that glycaemic status is associated with oxidative stress even in subjects with well-controlled type 2 diabetes. Furthermore, inflammation was more related to abdominal obesity than to glycaemic control. A large number of biomarkers of oxidative stress and inflammation were investigated, but only a few associations were found between the markers. This could be due to the fact that none of these biomarkers biosynthesises via similar pathways or simultaneously owing to their diverse nature and origin.