Activation of nuclear factor-kappa B subunits c-Rel, p65 and p50 by plasma lipids and fatty acids across the menstrual cycle.

This study focused on a comprehensive analysis of the canonical activation pathway of the redox-sensitive transcription factor nuclear factor-kappa B (NF-κB) in peripheral blood mononuclear cells, addressing c-Rel, p65 and p50 activation in 28 women at early (T1) and late follicular (T2) and mid (T3) and late luteal (T4) phase of the menstrual cycle, and possible relations with fasting plasma lipids and fatty acids. For the first time, strong inverse relations of c-Rel with apolipoprotein B were observed across the cycle, while those with LDL cholesterol, triglycerides as well as saturated (SFA), particularly C14-C22 SFA, monounsaturated (MUFA), and polyunsaturated fatty acids (PUFA) clustered at T2. In contrast, p65 was positively related to LDL cholesterol and total n-6 PUFA, while p50 did not show any relations. C-Rel was not directly associated with estradiol and progesterone, but data suggested an indirect C22:5n-3-mediated effect of progesterone. Strong positive relations between estradiol and individual SFA, MUFA and n-3 PUFA at T1 were confined to C18 fatty acids; C18:3n-3 was differentially associated with estradiol (positively) and progesterone (inversely). Given specific roles of c-Rel activation in immune tolerance, inhibition of c-Rel activation by higher plasma apolipoprotein B and individual fatty acid concentrations could have clinical implications for female fertility.

Identification of blood cell transcriptome-based biomarkers in adulthood predictive of increased risk to develop metabolic disorders using early life intervention rat models.

Calorie restriction during gestation in rats has long-lasting adverse effects in the offspring. It induces metabolic syndrome-related alterations, which are partially reversed by leptin supplementation during lactation. We employed these conditions to identify transcript-based nutrient sensitive biomarkers in peripheral blood mononuclear cells (PBMCs) predictive of later adverse metabolic health. The best candidate was validated in humans. Transcriptome analysis of PBMCs from adult male Wistar rats of three experimental groups was performed: offspring of control dams (CON), and offspring of 20% calorie-restricted dams during gestation without (CR) and with leptin supplementation throughout lactation (CR-LEP). The expression of 401 genes was affected by gestational calorie restriction and reversed by leptin. The changes preceded metabolic syndrome-related phenotypic alterations. Of these genes, Npc1 mRNA levels were lower in CR vs CON, and normalized to CON in CR-LEP. In humans, NPC1 mRNA levels in peripheral blood cells (PBCs) were decreased in subjects with mildly impaired metabolic health compared to healthy subjects. Therefore, a set of potential transcript-based biomarkers indicative of a predisposition to metabolic syndrome-related alterations were identified, including NPC1, which was validated in humans. Low NPC1 transcript levels in PBCs are a candidate biomarker of increased risk for impaired metabolic health in humans.

Urinary Metabolomic Markers of Protein Glycation, Oxidation, and Nitration in Early-Stage Decline in Metabolic, Vascular, and Renal Health.

Glycation, oxidation, nitration, and crosslinking of proteins are implicated in the pathogenic mechanisms of type 2 diabetes, cardiovascular disease, and chronic kidney disease. Related modified amino acids formed by proteolysis are excreted in urine. We quantified urinary levels of these metabolites and branched-chain amino acids (BCAAs) in healthy subjects and assessed changes in early-stage decline in metabolic, vascular, and renal health and explored their diagnostic utility for a noninvasive health screen. We recruited 200 human subjects with early-stage health decline and healthy controls. Urinary amino acid metabolites were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Machine learning was applied to optimise and validate algorithms to discriminate between study groups for potential diagnostic utility. Urinary analyte changes were as follows: impaired metabolic health-increased N ε -carboxymethyl-lysine, glucosepane, glutamic semialdehyde, and pyrraline; impaired vascular health-increased glucosepane; and impaired renal health-increased BCAAs and decreased N ε -(γ-glutamyl)lysine. Algorithms combining subject age, BMI, and BCAAs discriminated between healthy controls and impaired metabolic, vascular, and renal health study groups with accuracy of 84%, 72%, and 90%, respectively. In 2-step analysis, algorithms combining subject age, BMI, and urinary N ε -fructosyl-lysine and valine discriminated between healthy controls and impaired health (any type), accuracy of 78%, and then between types of health impairment with accuracy of 69%-78% (cf. random selection 33%). From likelihood ratios, this provided small, moderate, and conclusive evidence of early-stage cardiovascular, metabolic, and renal disease with diagnostic odds ratios of 6 - 7, 26 - 28, and 34 - 79, respectively. We conclude that measurement of urinary glycated, oxidized, crosslinked, and branched-chain amino acids provides the basis for a noninvasive health screen for early-stage health decline in metabolic, vascular, and renal health.

Author Correction: Acute Heart Failure developed as worsening of Chronic Heart Failure is associated with increased mortality compared to de novo cases.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Serum concentrations of free fatty acids are associated with 3-month mortality in acute heart failure patients.

Background Plasma free fatty acids (FFA) are higher in heart failure (HF) patients compared to healthy controls. Considering that the extent of FFA elevation in HF might mirror the severity of HF, we hypothesized that the serum levels of FFA may be a useful prognostic indicator for 3-month mortality in acute heart failure (AHF). Methods We analyzed the serum samples of AHF patients obtained at admission to the emergency department. Serum levels of FFA were analyzed using an enzymatic reagent on an automatic analyzer. Results Out of 152 included AHF patients that were originally included, serum samples of 132 patients were available for the quantification of FFA. Of these, 35 (26.5%) died within 3 months of onset of AHF. These patients had significantly higher serum levels of FFA compared to AHF patients who were alive 3 months after onset of AHF. Univariable logistic regression analyses showed a significant positive association of FFA levels with 3-month mortality (odds ratio [OR] 2.76 [95% confidence interval 1.32-6.27], p = 0.010). Importantly, this association remained significant after adjusting for age and sex, as well as for further clinical and laboratory parameters that showed a significant association with 3-month mortality in the univariate analyses. Conclusions We conclude that the admission serum levels of FFA are associated with 3-month mortality in AHF patients. Therefore, measurements of circulating FFA levels may help identifying high-risk AHF patients.

Prospective evaluation of three rapid molecular tests for seasonal influenza in patients presenting at an emergency unit.

BACKGROUND: For infection control measures, rapid accurate diagnostics on admission of patients with suspected seasonal influenza is crucial. OBJECTIVE: Prospective comparison of three rapid molecular tests for detection of influenza A/B RNA. STUDY DESIGN: Outpatients presenting at the Medical emergency department of Graz University Hospital with influenza-like illness and a requirement for hospitalization (n = 312) were studied. Nasopharyngeal swabs were collected with the 3 mL-version of the UTM™ Viral Transport Medium (Copan). Specimens were tested for influenza A and B RNA using the Alere™ i Influenza A & B (Abbott), the cobas® Influenza A/B (Roche), and the Xpert® Xpress Flu/RSV (Cepheid) tests. Results were compared to those obtained from the same specimen by the Influenza A/B R-GENE® (bioMerieux) test based on real-time PCR as reference method. RESULTS: Overall sensitivities of the Abbott, Roche, and Cepheid tests were 90.5%, 96.0%, and 97.0%, overall specificities 99.4%, 97.6%, and 98.2% respectively. With the Abbott and the Cepheid tests, all specimens gave valid results, while the Roche test showed invalid results in 37 (12.1%) specimens. Total time to result for the Abbott, Roche, and Cepheid tests was 18 min, 22 min, and 32 min respectively. CONCLUSIONS: The Abbott test lacked sensitivity, the Roche test was impaired by a high number of invalid results. Overall, despite the longest total time to result, the Cepheid test showed the best performance to detect influenza virus RNA in symptomatic patients presenting at an emergency unit in this study.

HDL subclasses and mortality in acute heart failure patients.

The link between HDL subclasses and the prognosis of cardiovascular diseases remains controversial. We thus evaluated the prognostic value of the HDL subclasses 3 and 2 cholesterol (HDL3-C, HDL2-C) as well as of total HDL-C for 3-month mortality in acute heart failure (AHF) patients. The serum levels of HDL3-C and total HDL-C were determined by detergent-based homogeneous assay. HDL2-C was computed by the difference between total HDL-C and HDL3-C. Out of the 132 analyzed patients, 35 (26.5%) died within three months after onset of AHF. Univariate logistic regression analyses revealed a significant inverse association of HDL3-C (odds ratio (OR) 0.46 per 1-SD increase, 95% confidence interval (CI) 0.27-0.72, p = 0.001) with 3-month mortality, whereas concentrations of total HDL-C and HDL2-C showed no significant association. After adjustment for various laboratory and clinical parameters known to be associated with mortality in heart failure patients, HDL3-C concentrations remained significantly associated with 3-month mortality (OR 0.34 per 1-SD increase, 95% CI 0.15-0.74, p =0.010). We conclude that low admission serum levels of HDL3-C are associated with an increased 3-month mortality in AHF patients, whereas total HDL-C and HDL2-C showed no association. HDL3-C might thus be useful as a prognostic parameter in AHF.

Progesterone-associated arginine decline at luteal phase of menstrual cycle and associations with related amino acids and nuclear factor kB activation.

BACKGROUND/OBJECTIVES: Given their role in female reproduction, the effects of progesterone on arginine and related amino acids, polyamines and NF-κB p65 activation were studied across the menstrual cycle. METHODS: Arginine, ornithine and citrulline as well as putrescine, spermidine, spermine, and N-acetyl-putrescine were determined in plasma, NF-κB p65 activation in peripheral blood mononuclear cells and progesterone in serum of 28 women at early (T1) and late follicular (T2) and mid (T3) and late (T4) luteal phase. RESULTS: Arginine and related amino acids declined from T1 and T2 to T3 and T4, while progesterone increased. At T3, arginine, ornithine, and citrulline were inversely related with progesterone. Changes (ΔT3-T2) in arginine, ornithine, and citrulline were inversely related with changes (ΔT3-T2) in progesterone. Ornithine and citrulline were positively related with arginine, as were changes (ΔT3-T2) in ornithine and citrulline with changes (ΔT3-T2) in arginine. At T2, NF-κB p65 activation was positively related with arginine. Polyamines did not change and were not related to progesterone. All results described were significant at P < 0.001. CONCLUSIONS: This study for the first time provides data, at the plasma and PBMC level, supporting a proposed regulatory node of arginine and related amino acids, progesterone and NF-κB p65 at luteal phase of the menstrual cycle, aimed at successful preparation of pregnancy.

Acute Heart Failure developed as worsening of Chronic Heart Failure is associated with increased mortality compared to de novo cases.

Acute heart failure (AHF) emerges either de novo or from worsening of chronic heart failure (CHF). The aim of the present study was to evaluate the association between worsening of CHF and mortality in AHF patients. Out of 152 included AHF patients, 47 (30.9%) were de novo AHF patients and 105 (69%) were AHF patients with worsening of CHF. The proportion dying in hospital (19.0% vs. 4.3%, p = 0.023) and within 3 months after hospitalization (36.6% vs. 6.7%, p < 0.001) was significantly higher in AHF patients with worsening of CHF. Logistic regression analyses also showed a significant positive association of AHF emerging as worsening of CHF with hospital mortality [odds ratio (OR) and 95% confidence interval (CI): 5.29 (1.46-34.10), p = 0.029] and 3-month mortality [8.09 (2.70-35.03), p = 0.001]. While the association with hospital mortality was no longer significant after adjusting for comorbidities and clinical as well as laboratory parameters known to be associated with mortality in heart failure patients, the association with 3-month mortality remained significant. We conclude that compared to de novo AHF, AHF evolved from worsening of CHF is a more severe condition and is associated with increased mortality.

Metabolic Syndrome Modulates Association between Endothelial Lipase and Lipid/Lipoprotein Plasma Levels in Acute Heart Failure Patients.

We hypothesised that the established association of endothelial lipase (EL) plasma levels with atherogenic lipid profile is altered in acute heart failure (AHF) and additionally affected by overlapping metabolic syndrome (MetS). We examined the association of EL plasma levels and lipid/lipoprotein plasma levels in AHF patients without and with overlapping MetS. The study was performed as a single-centre, observational study on 152 AHF patients, out of which 85 had overlapping MetS. In the no-MetS group, EL plasma levels were significantly positively correlated with plasma levels of atherogenic lipids/lipoproteins, including total cholesterol, low-density lipoprotein (LDL)-cholesterol, total LDL particles and triglycerides, but also with plasma levels of antiatherogenic high-density lipoprotein (HDL)-cholesterol, total HDL particles and small HDL particles. In the MetS group, EL plasma levels were positively correlated with triglyceride and small LDL-particle levels, and significantly negatively correlated with plasma levels of large HDL particles as well as with LDL- and HDL-particle size, respectively. EL- and lipid/lipoprotein- plasma levels were different in the no-MetS patients, compared to MetS patients. The association of EL with atherogenic lipid profile is altered in AHF and additionally modified by MetS, which strongly modulates EL- and lipid/lipoprotein-plasma levels in AHF.

Endothelial lipase plasma levels are increased in both sexes in stable coronary artery disease and only in women with acute coronary syndrome but not associated with the severity of coronary artery disease.

AIM: To investigate whether endothelial lipase (EL) plasma levels are increased in stable coronary artery disease (sCAD) and acute coronary syndrome (ACS) patients, as well as to test the association of EL plasma levels and the severity of CAD and sex. METHODS: The study was performed as a single-center, cross-sectional, observational research on 72 sCAD and 187 ACS patients in the Sisters of Charity University Hospital Centre, Zagreb, Croatia, between December 1, 2011 and December 1, 2012. EL plasma levels were measured using ELISA. RESULTS: EL plasma levels were significantly higher in sCAD patients (median 311.3 pg/mL, interquartile range [IQR] 250.4-422.6 pg/mL) than in ACS patients (median=258.7 pg/mL, IQR=162.1-356.0 pg/mL; P<0.001). EL levels in female ACS patients were significantly higher (median 314.5 pg/mL, IQR 218.3-420.8 pg/mL) than in male ACS patients (median 225.4 pg/mL, IQR 148.7320.1 pg/mL; P<0.001) and similar to the EL levels in the sCAD patients. There was no significant correlation between EL plasma levels and the GENSINI score and between EL plasma levels and the number of atherosclerotic coronary artery segments in either the ACS (rho=-0.09, P=0.247; rho=0.12, P=0.106, respectively) or sCAD group (rho=0.04, P=0.771; rho=0.06, P=0.643, respectively). CONCLUSION: Our results suggest that EL plasma levels discriminate male but not female patients with different clinical presentations of CAD, as well as female and male ACS patients. EL plasma levels are not significantly correlated with CAD severity.

Metrics of High-Density Lipoprotein Function and Hospital Mortality in Acute Heart Failure Patients.

OBJECTIVE: The functionality of high-density lipoprotein (HDL) is impaired in chronic ischaemic heart failure (HF). However, the relationship between HDL functionality and outcomes in acute HF (AHF) has not been studied. The present study investigates whether the metrics of HDL functionality, including HDL cholesterol efflux capacity and HDL-associated paraoxonase (PON)-1 arylesterase (AE) activity are associated with hospital mortality in AHF patients. METHODS AND RESULTS: The study was performed as a prospective, single-centre, observational research on 152 patients, defined and categorised according to the ESC and ACCF/AHA Guidelines for HF by time of onset, final clinical presentation and ejection fraction. The mean age of the included patients (52% female) was 75.2 years (SD 10.3) and hospital mortality was 14.5%. HDL cholesterol efflux capacity was examined by measuring the capacity of apoB depleted serum to remove tritium-labelled cholesterol from cultured macrophages. The AE activity of the HDL fraction was examined by a photometric assay. In a univariable regression analysis, low cholesterol efflux, but not AE activity, was significantly associated with hospital mortality [odds ratio (OR) 0.78, 95% confidence interval (CI) 0.64-0.96, p = 0.019]. In multivariable analysis progressively adjusting for important clinical and laboratory parameters the association obtained for cholesterol efflux capacity and hospital mortality by univariable analysis, despite a stable OR, did not stay significant (p = 0.179). CONCLUSION: Our results suggest that HDL cholesterol efflux capacity (but not AE activity) contributes to, but is not an independent risk factor for, hospital mortality in AHF patients. Larger studies are needed to draw firm conclusions.

Circulating leptin and NF-κB activation in peripheral blood mononuclear cells across the menstrual cycle.

Using the menstrual cycle as a model, this study focused on longitudinal changes and associations within a physiological network known to play a role in female fertility, including, as biologically active nodes, NF-κB, leptin and adiponectin, ß-carotene, adipose tissue, and progesterone. In 28 women, leptin, adiponectin, ß-carotene, and progesterone concentrations, NF-κB p65 and p50 activation in peripheral blood mononuclear cells (known to possess estrogen, progesterone and leptin receptors), total body fat (TBF) and subcutaneous adipose tissue (SAT) mass were determined at early (T1) and late follicular (T2) and mid (T3) and late (T4) luteal phase. Leptin and adiponectin concentrations were higher, while NF-κB p65 activation was lower at T3 compared with T1. NF-κB p65 activation was inversely related to leptin concentrations at T1, T3, and T4. ß-Carotene was inversely related to leptin (T1,T2,T4) and SAT (T1,T3,T4). NF-κB p50 activation was inversely related to TBF (T4) and SAT (T3,T4), and leptin was positively related to TBF and SAT (T1-T4). Progesterone was inversely related to leptin (T2,T3), adiponectin (T3), TBF (T3,T4), and SAT (T2,T3,T4). By providing evidence of luteal phase-specific reduced NF-κB p65 activation in women under physiological conditions, this study bridges the gap between existing evidence of a Th1-Th2 immune response shift induced by reduced NF-κB p65 activation and a Th1-Th2 shift previously observed at luteal phase. For the first time, inverse regressions suggest inhibitory effects of leptin on NF-κB p65 activation at luteal phase, along with inhibitory effects of leptin as well as adiponectin on progesterone production in corpus luteum. © 2016 The Authors BioFactors published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology. 24(4):376-387, 2016.

Increased expression of endothelial lipase in symptomatic and unstable carotid plaques.

The aim of this study was to evaluate endothelial lipase (EL) protein expression in advanced human carotid artery plaques (HCAP) with regard to plaque (in)stability and the incidence of symptoms. HCAP were collected from 66 patients undergoing carotid endarterectomy (CEA). The degree of plaque (in)stability was estimated by ultrasound and histology. In HCAP sections, EL expression was determined by immunostaining and the intensity was assessed on a semi-quantitative scale (low: <25%, high: >25% positive cells). Monocytes and macrophages in adjacent HCAP sections were stained with a CD163 specific antibody. High EL staining was more prevalent in histologically unstable plaques (in 33.3% of fibrous plaques, 50% of ulcerated non-complicated plaques and 79.2% of ulcerated complicated plaques; χ(2) test, p = 0.004) and in the symptomatic group (70.8 vs. 42.9% in the asymptomatic group; χ(2) test, p = 0.028). The majority of EL immunostaining was found in those HCAP regions exhibiting a strong CD163 immunostaining. EL in HCAP might be a marker and/or promoter of plaque instability and HCAP-related symptomatology.

Analysing cell-free plasma DNA and SLE disease activity.

BACKGROUND: Over the years, the demonstration and confirmation of cell-free DNA in the circulation has increasingly been recognized as a valuable diagnostic tool. Likewise, it has been known for some time that DNA structures that are targeted by auto-antibodies play a central role in systemic lupus erythematosis (SLE) and that DNA-antibody complexes in the circulation are one of the hallmarks of SLE. Investigating whether and to what degree fluctuations in free plasma DNA levels in patients with SLE might correspond to disease severity was therefore the goal of this investigation. METHODS: Blood from 13 patients with SLE and from 13 healthy controls was taken and analysed for the presence of anti-dsDNA, anti-ssDNA, anti-nucleosome, anti-histone antibodies as well as for cell-free DNA concentrations. For each patient, the SLE disease activity index (SLEDAI) was calculated. RESULTS: As demonstrated herein, compared to healthy subjects, cell-free DNA plasma levels in patients with SLE were significantly increased and so were anti-dsDNA, anti-ssDNA, anti-histone and anti-nucleosome antibodies. Furthermore, a statistically significant correlation was noted between cell-free DNA and anti-histone antibodies in patients with SLE. However, no correlation was noted between disease activity and anti-dsDNA, anti-ssDNA and anti-nucleosome antibody concentrations. Surprisingly, and more important in the context of this study, there was no correlation between cell-free DNA levels and SLEDAI scores. CONCLUSIONS: The presented data seem to exclude measuring free plasma DNA as an inexpensive, simple and quick tool to assess disease activity in patients with SLE. Further studies on a larger patient population would be needed to confirm our results.

Multicentric validation of proteomic biomarkers in urine specific for diabetic nephropathy.

BACKGROUND: Urine proteome analysis is rapidly emerging as a tool for diagnosis and prognosis in disease states. For diagnosis of diabetic nephropathy (DN), urinary proteome analysis was successfully applied in a pilot study. The validity of the previously established proteomic biomarkers with respect to the diagnostic and prognostic potential was assessed on a separate set of patients recruited at three different European centers. In this case-control study of 148 Caucasian patients with diabetes mellitus type 2 and duration ≥5 years, cases of DN were defined as albuminuria >300 mg/d and diabetic retinopathy (n = 66). Controls were matched for gender and diabetes duration (n = 82). METHODOLOGY/PRINCIPAL FINDINGS: Proteome analysis was performed blinded using high-resolution capillary electrophoresis coupled with mass spectrometry (CE-MS). Data were evaluated employing the previously developed model for DN. Upon unblinding, the model for DN showed 93.8% sensitivity and 91.4% specificity, with an AUC of 0.948 (95% CI 0.898-0.978). Of 65 previously identified peptides, 60 were significantly different between cases and controls of this study. In <10% of cases and controls classification by proteome analysis not entirely resulted in the expected clinical outcome. Analysis of patient's subsequent clinical course revealed later progression to DN in some of the false positive classified DN control patients. CONCLUSIONS: These data provide the first independent confirmation that profiling of the urinary proteome by CE-MS can adequately identify subjects with DN, supporting the generalizability of this approach. The data further establish urinary collagen fragments as biomarkers for diabetes-induced renal damage that may serve as earlier and more specific biomarkers than the currently used urinary albumin.

Cell-free plasma DNA and purine nucleotide degradation markers following weightlifting exercise.

The present study aimed to investigate the acute effects of a single bout of high-intensive strength training on the production of cell-free plasma DNA (cf-DNA), as well as on the degradation of purine nucleotides as assessed by the concentration of xanthine (XA) and hypoxanthine (HX) in urine and serum. Twelve trained weightlifters performed six sets of six lifting exercises with 90-95% of the one repetition maximum. Blood samples and urine were obtained 1 h before training, immediately after finishing the exercise session and following 2 h of recovery. Cf-DNA, HX, and XA (in serum) significantly increased (P < 0.05-P < 0.001) immediately after heavy lifting exercise when compared with baseline levels, and significantly decreased (P < 0.05-P < 0.001) after 2 h of recovery. These results indicate that, cf-DNA and oxypurines might be relevant biomarkers for cellular damage, mechanical, energetic, and/or ischemic stress in context with exercise.

Efficacy and safety of anticoagulation with heparin versus heparin plus epoprostenol in patients undergoing extracorporeal liver support with Prometheus.

Anticoagulation for extracorporeal liver support is delicate due to underlying coagulation disorders in patients with liver failure and to the associated elevated bleeding risk. To date, there has been no detailed report on anticoagulation issues in patients treated with Prometheus, a device based on the principle of fractionated plasma separation and adsorption. We studied 17 patients from two centers treated with Prometheus, comparing standard anticoagulation with heparin (15 treatments) and a combination of heparin and the synthetic prostacyclin epoprostenol (22 treatments). Standard coagulation tests, proteins C and S, and thrombin-antithrombin (TAT) complex were determined, and adverse events were recorded. All but two treatments could be completed as scheduled, although filter exchange due to filter clotting was required in 24% of the treatments. Three out of 17 patients developed severe bleeding complications within 24 h of treatment. There were no overt thrombotic events. Addition of epoprostenol neither reduced coagulation-related adverse events nor improved standard coagulation parameters. Protein C, but not protein S, showed a significant reduction (23 +/- 18%) after Prometheus treatments, but levels rebounded to baseline within 18 h. TAT levels--a measure for activation of coagulation--were only altered by Prometheus in patients where TAT was already elevated before treatment. In conclusion, anticoagulation of Prometheus with heparin is feasible but still associated with a relatively high frequency of filter clotting and a considerable risk of severe bleeding in this high-risk patient population. As addition of epoprostenol did not prove beneficial, other strategies, such as regional anticoagulation with citrate, should be further evaluated.

Antioxidant status of patients on peritoneal dialysis: associations with inflammation and glycoxidative stress.

BACKGROUND: Patients on peritoneal dialysis (PD) frequently exhibit oxidant-antioxidant imbalance, advanced glycation end-product overload, and subclinical inflammation but the interrelations between these pathophysiological changes have not been fully elucidated. SUBJECTS AND METHODS: To study possible associations, a cross-sectional study of antioxidant status, glycoxidative stress, and inflammation, using HPLC and ELISA methods, was undertaken in 37 PD patients and age- and sex-matched healthy controls. RESULTS: Plasma ascorbate concentrations were low in patients not taking at least low-dose vitamin C supplements. In patients taking vitamin C supplements, there was a positive relation between ascorbate and pentosidine concentrations. Vitamin E and carotenoid concentrations were comparable between patients and controls, while lycopene and lutein/zeaxanthin concentrations were lower. Interleukin-6, C-reactive protein (CRP), and pentosidine concentrations were elevated in PD patients. beta-Cryptoxanthin, lycopene, and lutein/zeaxanthin concentrations were inversely related to interleukin-6 concentrations. beta-Cryptoxanthin concentrations were also inversely related to CRP concentrations. Pentosidine showed a low dialysate-to-plasma ratio, indicating low peritoneal clearance. Pentosidine concentrations increased with duration of PD therapy, while alpha- and beta-carotene concentrations decreased. Malondialdehyde concentrations were elevated compared to controls but remained within the normal range. Retinol concentrations decreased with PD therapy and were inversely related to interleukin-6 and CRP concentrations. CONCLUSIONS: Low-dose vitamin C supplements and a carotenoid-rich diet should be recommended for PD patients to maintain normal antioxidant status and efficiently counteract the chronic inflammatory response, rather than high doses of vitamin C, which could play a role as a precursor of pentosidine.