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Background & aims: Intake assessment in multicenter trials is challenging, yet important for accurate outcome evaluation. The present study aimed to characterize a multicenter randomized controlled trial with a healthy Nordic diet (HND) compared to a Control diet (CD) by plasma and urine metabolic profilesand to associate them with cardiometabolic markers. Methods: During 18e24 weeks of intervention, 200 participants with metabolic syndrome were advised at six centres to eat either HND (e.g. whole-grain products, berries, rapeseed oil, fish and low-fat dairy) or CD while being weight stable. Of these 166/159 completers delivered blood/urine samples. Metabolicprofiles of fasting plasma and 24 h pooled urine were analysed to identify characteristic diet-related patterns. Principal components analysis (PCA) scores (i.e. PC1 and PC2 scores) were used to test their combined effect on blood glucose response (primary endpoint), serum lipoproteins, triglycerides, andinflammatory markers.Results: The profiles distinguished HND and CD with AUC of 0.96 ± 0.03 and 0.93 ± 0.02 for plasma and urine, respectively, with limited heterogeneity between centers, reflecting markers of key foods. Markers of fish, whole grain and polyunsaturated lipids characterized HND, while CD was reflected by lipidscontaining palmitoleic acid. The PC1 scores of plasma metabolites characterizing the intervention is associated with HDL (β = 0.05; 95% CI: 0.02, 0.08; P = 0.001) and triglycerides (β = 0.06; 95% CI: -0.09, -0.03; P < 0.001). PC2 scores were related with glucose metabolism (2 h Glucose, β = 0.1; 95% CI: 0.05, 0.15; P < 0.001), LDL (β = 0.06; 95% CI: 0.01, 0.1; P = 0.02) and triglycerides (β 0.11; 95% CI: 0.06, 0.15; P < 0.001). For urine, the scores were related with LDL cholesterol. Conclusions: Plasma and urine metabolite profiles from SYSDIET reflected good compliance with dietary recommendations across the region. The scores of metabolites characterizing the diets associated with outcomes related with cardio-metabolic risk. Our analysis therefore offers a novel way to approach a per protocol analysis with a balanced compliance assessment in larger multicentre dietary trials.The study was registered at clinicaltrials.gov with NCT00992641.

Anorexia nervosa (AN) is characterised by disrupted and restrictive eating patterns. Recent investigations and meta-analyses have found altered concentrations of inflammatory markers in people with current AN. We aimed to assess nutrient intake in participants with current or recovered AN, as compared to healthy individuals, and explore group differences in dietary inflammatory potential as a possible explanation for the observed alterations in inflammatory markers. We recruited participants with current AN (n = 51), those recovered from AN (n = 23), and healthy controls (n = 49). We used the Food Frequency Questionnaire (FFQ), to calculate a Dietary Inflammatory Index (DII®) score and collected blood samples to measure serum concentrations of inflammatory markers. In current AN participants, we found lower intake of cholesterol, compared to HCs, and lower consumption of zinc and protein, compared to HC and recovered AN participants. A one-way ANOVA revealed no significant group differences in DII score. Multivariable regression analyses showed that DII scores were significantly associated with tumour necrosis factor (TNF)-α concentrations in our current AN sample. Our findings on nutrient intake are partially consistent with previous research. The lack of group differences in DII score, perhaps suggests that diet is not a key contributor to altered inflammatory marker concentrations in current and recovered AN. Future research would benefit from including larger samples and using multiple 24-h dietary recalls to assess dietary intake.

SARS-CoV-2 is the trigger of MIS-C, which suggests that other viruses may trigger different forms of Kawasaki disease. The discovery of inborn errors of immunity underlying MIS-C would facilitate that of inborn errors of immunity to viruses underlying Kawasaki disease., Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.

Soluble urokinase-type plasminogen activator receptor (suPAR) is a chronic inflammation marker associated with the development of a range of diseases, including cancer and cardiovascular disease. The genetics of suPAR remain unexplored but may shed light on the biology of the marker and its connection to outcomes. We report a heritability estimate of 60% for the variation in suPAR and performed a genome-wide association meta-analysis on suPAR levels measured in Iceland (N = 35,559) and in Denmark (N = 12,177). We identified 13 independently genome-wide significant sequence variants associated with suPAR across 11 distinct loci. Associated variants were found in and around genes encoding uPAR (PLAUR), its ligand uPA (PLAU), the kidney-disease-associated gene PLA2R1 as well as genes with relations to glycosylation, glycoprotein biosynthesis, and the immune response. These findings provide new insight into the causes of variation in suPAR plasma levels, which may clarify suPAR’s potential role in associated diseases, as well as the underlying mechanisms that give suPAR its prognostic value as a unique marker of chronic inflammation., Dowsett and colleagues used a genome-wide association approach to investigate the genetic influence on soluble urokinase-type plasminogen activator receptor presence in the plasma of humans. Their findings indicate a 60% heritability factor in British twins, and using a wide sample of Northern European genome samples they identify eleven genetic loci associated with an increase or decrease of this chronic inflammation marker.

Longitudinal analysis of the immune response in COVID-19 patients identifies a myeloid signature associated with severe disease., COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells (PBMCs) of hospitalized patients during the peak of the COVID-19 pandemic in the UK. Here, we report key immune signatures present shortly after hospital admission that were associated with the severity of COVID-19. Immune signatures were related to shifts in neutrophil to T cell ratio, elevated serum IL-6, MCP-1 and IP-10, and most strikingly, modulation of CD14+ monocyte phenotype and function. Modified features of CD14+ monocytes included poor induction of the prostaglandin-producing enzyme, COX-2, as well as enhanced expression of the cell cycle marker Ki-67. Longitudinal analysis revealed reversion of some immune features back to the healthy median level in patients with a good eventual outcome. These findings identify previously unappreciated alterations in the innate immune compartment of COVID-19 patients and lend support to the idea that therapeutic strategies targeting release of myeloid cells from bone marrow should be considered in this disease. Moreover, they demonstrate that features of an exaggerated immune response are present early after hospital admission suggesting immune-modulating therapies would be most beneficial at early timepoints.

Objectives A history of recurrent miscarriage is associated with future cardiovascular disease. The aim of this study was to determine novel cardiovascular biomarkers in women with a history of recurrent miscarriage as this might lead to a better understanding of the association. Study design Women who visited the recurrent miscarriage clinic at Leiden University Medical Centre (between 2000 and 2010), and had three consecutive miscarriages ≤30 years were invited to participate in this follow-up study (between 2012 and 2014). The reference group consisted of women with at least one uncomplicated pregnancy and a history of no miscarriage, matched on zip code, age, and date of pregnancy. Main outcome measures Cardiovascular biomarkers were determined, classified into; inflammation (HsCRP, lipoprotein-associated phospholipase A2), thrombosis (homocysteine, folate, anti-cardiolipin antibodies and anti-s-2-glycoprotein antibodies), lipid metabolism (lipoprotein(a)), renal function (creatinine, microalbuminuria), myocardial damage (N-terminal pro-brain natriuretic peptide, high sensitive TroponineT) and multiple mechanisms (albumin, vitamin D). Results In both groups, 36 women were included. Women with recurrent miscarriage had a significantly higher median HsCRP (1.49 mg/L) compared to women with no miscarriage (1.01 mg/L, p = 0.03) and a significantly lower mean albumin (46.0 vs 47.6g/L, p = 0.004) and vitamin D (55.6 vs 75.4nmol/L, p = 0.007), respectively. Differences remained after adjustments for classic cardiovascular risk factors (BMI, smoking, diabetes mellitus, and hypertension). Conclusions Our findings suggest a proinflammatory state in women with a history of recurrent miscarriage, which suggests a less optimal health, compared to women with no miscarriage. More research (observational and intervention) is warranted to investigate the association with vitamin D.

Historically, connexin hemichannels have been considered as structural precursors of gap junctions. However, accumulating evidence points to independent roles for connexin hemichannels in cellular signaling by connecting the intracellular compartment with the extracellular environment. Unlike gap junctions, connexin hemichannels seem to be mainly activated in pathological processes. The present study was set up to test the potential involvement of hemichannels composed of connexin32 and connexin43 in acute hepatotoxicity induced by acetaminophen. Prior to this, in vitro testing was performed to confirm the specificity and efficiency of TAT-Gap24 and TAT-Gap19 in blocking connexin32 and connexin43 hemichannels, respectively. Subsequently, mice were overdosed with acetaminophen followed by treatment with TAT-Gap24 or TAT-Gap19 or a combination of both after 1.5 hour. Sampling was performed 3, 6, 24 and 48 hours following acetaminophen administration. Evaluation of the effects of connexin hemichannel inhibition was based on a series of clinically relevant read-outs, measurement of inflammatory cytokines and oxidative stress. Subsequent treatment of acetaminophen-overdosed mice with TAT-Gap19 only marginally affected liver injury. In contrast, a significant reduction in serum alanine aminotransferase activity was found upon administration of TAT-Gap24 to intoxicated animals. Furthermore, co-treatment of acetaminophen-overdosed mice with both peptides revealed an additive effect as even lower serum alanine aminotransferase activity was observed. Blocking of connexin32 or connexin43 hemichannels individually was found to decrease serum quantities of pro-inflammatory cytokines, while no effects were observed on the occurrence of hepatic oxidative stress. This study shows for the first time a role for connexin hemichannels in acetaminophen-induced acute liver failure.

Purpose: Low intake of dietary fibre is associated with the development of type 2 diabetes. Dyslipidaemia plays a key role in the pathogenesis of type 2 diabetes. Knowledge of the impact of dietary fibres on postprandial lipaemia is, however, sparse. This study aimed in subjects with metabolic syndrome to assess the impact on postprandial lipaemia and features of the metabolic syndrome of a healthy carbohydrate diet (HCD) rich in cereal fibre, arabinoxylan and resistant starch compared to a refined-carbohydrate western-style diet (WSD). Methods: Nineteen subjects completed the randomised, crossover study with HCD and WCD for 4-week. Postprandial metabolism was evaluated by a meal-challenge test and insulin sensitivity was assessed by HOMA-IR and Matsuda index. Furthermore, fasting cholesterols, serum-fructosamine, circulating inflammatory markers, ambulatory blood pressure and intrahepatic lipid content were measured. Results: We found no diet effects on postprandial lipaemia. However, there was a significant diet × statin interaction on total cholesterol (P = 0.02) and LDL cholesterol (P = 0.002). HCD decreased total cholesterol (−0.72 mmol/l, 95% CI (−1.29; −0.14) P = 0.03) and LDL cholesterol (−0.61 mmol/l, 95% CI (−0.86; −0.36) P = 0.002) compared with WSD in subjects on but not without statin treatment. We detected no other significant diet effects. Conclusions: In subjects with metabolic syndrome on statins a 4-week diet rich in arabinoxylan and resistant starch improved fasting LDL and total cholesterol compared to subjects not being on statins. However, we observed no diet related impact on postprandial lipaemia or features of the metabolic syndrome. The dietary fibre x statin interaction deserves further elucidation.

Background Hyperglycemia in the setting of an acute coronary syndrome (ACS) impacts short term outcomes, but little is known about longer term effects. We therefore designed this study to firstly determine the association between hyperglycemia and short term and longer term outcomes in patients presenting with ACS and secondly evaluate the prognostic role of diabetes, body mass index (BMI) and the novel biomarker Cyr61 on outcomes. Methods The prospective Special Program University Medicine-Acute Coronary Syndrome (SPUM-ACS) cohort enrolled 2168 patients with ACS between December 2009 and October 2012, of which 2034 underwent PCI (93.8%). Patients were followed up for 12 months. Events were independently adjudicated by three experienced cardiologists. Participants were recruited from four tertiary hospitals in Switzerland: Zurich, Geneva, Lausanne and Bern. Participants presenting with acute coronary syndromes and who underwent coronary angiography were included in the analysis. Patients were grouped according to history of diabetes (or HbA1c greater than 6%), baseline blood sugar level (BSL; 11.1 mmol/L) and body mass index (BMI). The primary outcome was major adverse cardiac events (MACE) which was a composite of myocardial infarction, stroke and all-cause death. Secondary outcomes included the individual components of the primary endpoint, revascularisations, bleeding events (BARC classification) and cerebrovascular events (ischaemic or haemorrhagic stroke or TIA). Results Patients with hyperglycemia, i.e. BSL ≥ 11.1 mmol/L, had higher levels of C-reactive protein (CRP), white blood cell count (WBC), creatinine kinase (CK), higher heart rates and lower left ventricular ejection fraction (LVEF) and increased N-terminal pro-brain natriuretic peptide. At 30 days and 12 months, those with BSL ≥ 11.1 mmol/L had more MACE and death compared to those with BSL Conclusions and relevance In this large, prospective, independently adjudicated cohort of in all comers ACS patients undergoing PCI, both a history of diabetes and elevated entry glucose was associated with inflammation and increased risk of MACE both at short and long-term. The mediators might involve increased sympathetic activation, inflammation and ischemia as reflected by elevated Cyr61 levels leading to larger levels of troponin and lower LVEF. Trial registration Clinical Trial Registration Number: NCT01000701. Registered October 23, 2009

Objectives: Surfactant protein-D (SP-D), an innate immune defence molecule of the collectin family, is expressed in lungs and additional extrapulmonary epithelia. SP-D has immune modulatory and anti-microbial effects depending on its oligomerization. The ratio of high molecular weight (HMW): low molecular weight (LMW) SP-D in serum is mainly determined by the Met11Thr polymorphism (SNP rs721917). We aimed to study the SP-D serum level and the molecular size distribution in patients with untreated axial spondyloarthritis (axSpA) as compared with control subjects.Methods: Thirty-four patients with disease modifier untreated axSpA according to the ASAS criteria, age 19-63 years, disease duration 3.9 (2.2-5.6) years were included. Demographics, smoking habits, HLA-B27 status, ASDAS, BASDAI, BASFI, BASMI and visual analogue scale scores were recorded. SP-D in serum was measured by ELISA. DNA was isolated from whole blood and single nucleotide polymorphism rs721917 was genotyped. SP-D molecular size distribution was determined using gel filtration chromatography.Results: SP-D in serum did not differ between patients with axSpA and healthy controls, 1177 (869, 1536) vs 910 (494, 1682) (P = 0.35) and SP-D did not correlate with disease activity. However, the HMW/LMW ratio of SP-D in serum was significantly lower in axSpA, 0.38 (0.18, 0.53) compared with controls 1.49 (0.37, 3.24) when adjusting for the Met11Thr polymorphism, gender, age, BMI and smoking (P = 0.0004). There was no correlation between HMW/LMW ratio and CRP or composite diseases outcome measures.Conclusion: We suggest that predominance of LMW oligomeric variants of SP-D may enhance local or systemic inflammatory responses in axSpA.

Objective. Due to the localized nature of Charcot foot, systemically altered levels of inflammation markers can be difficult to measure. The aim of this study was to investigate whether it is possible to detect an arteriovenous (A-V) flux in any locally produced inflammatory biomarkers from an acute Charcot foot by comparing local and systemic measurements. Methods. We included patients with acute diabetic Charcot foot. Blood was sampled from the vena saphena magna on the distal part of the crus bilaterally as well as from the arteria radialis. To minimize the A-V shunting effect, the feet were externally cooled with ice water prior to resampling. Results. Both before and after cooling, the A-V flux of interleukin-6 (IL-6) between the Charcot feet and the arterial level was significantly higher than the flux between the healthy feet and the arterial level (Δvaluebefore: 7.25 versus 0.41 pg/mL, resp., p=0.008; Δvalueafter: 10.04 versus 1.68 pg/mL, resp., p=0.032). There were no differences in the fluxes for other markers of inflammation. Conclusion. We have found an increased A-V flux of IL-6 in the acute diabetic Charcot foot compared to the healthy foot in the same patients.

BACKGROUND Venous thromboembolism (VTE) is a major cause of morbidity and mortality in elderly patients. Extracellular DNA is a pro-inflammatory and pro-thrombotic mediator in vitro and in animal models. Levels of circulating extracellular DNA (ceDNA) are increased in VTE patients, but the association of ceDNA with VTE extent and clinical outcome is poorly understood. OBJECTIVES We analyzed the association of ceDNA with the extent of VTE, categorized as distal and proximal deep vein thrombosis and pulmonary embolism, and with the clinical outcomes VTE recurrence and mortality. METHODS We quantified ceDNA by a fluorescent probe, as well as circulating nucleosomes and neutrophil extracellular traps (NETs) by ELISA in plasma from 611 patients aged ≥ 65 years with acute VTE of a prospective cohort study (SWITCO65+). RESULTS Levels of ceDNA and nucleosomes, but not NETs, correlated with VTE extent. Infectious comorbidities independently increased ceDNA levels in VTE. CeDNA strongly correlated with C-reactive protein and leukocytosis, suggesting an association of ceDNA with inflammation in VTE patients. CeDNA furthermore predicted PE-related and all-cause mortality, but not VTE recurrence, during a 3-year follow-up. CONCLUSIONS Our study suggests that ceDNA levels in VTE patients reflect the degree of inflammation and may serve as a biomarker to stratify VTE patients at risk for mortality.

AIMS: Atherosclerosis is the leading cause of death in Western societies and a chronic inflammatory disease. However, the key mediators linking recruitment of inflammatory cells to atherogenesis remain poorly defined. Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme, which plays a role in acute inflammatory diseases. METHODS AND RESULTS: In order to test the role of PARP in atherogenesis, we applied chronic pharmacological PARP inhibition or genetic PARP1 deletion in atherosclerosis-prone apolipoprotein E-deficient mice and measured plaque formation, adhesion molecules, and features of plaque vulnerability. After 12 weeks of high-cholesterol diet, plaque formation in male apolipoprotein E-deficient mice was decreased by chronic inhibition of enzymatic PARP activity or genetic deletion of PARP1 by 46 or 51%, respectively (P < 0.05, n >or= 9). PARP inhibition or PARP1 deletion reduced PARP activity and diminished expression of inducible nitric oxide synthase, vascular cell adhesion molecule-1, and P- and E-selectin. Furthermore, chronic PARP inhibition reduced plaque macrophage (CD68) and T-cell infiltration (CD3), increased fibrous cap thickness, and decreased necrotic core size and cell death (P < 0.05, n >or= 6). CONCLUSION: Our data provide pharmacological and genetic evidence that endogenous PARP1 is required for atherogenesis in vivo by increasing adhesion molecules with endothelial activation, enhancing inflammation, and inducing features of plaque vulnerability. Thus, inhibition of PARP1 may represent a promising therapeutic target in atherosclerosis.

Summary Background Conventional coronary artery disease risk factors might potentially explain at least 90% of the attributable risk of coronary artery disease. To better understand the association between the pre-industrial lifestyle and low prevalence of coronary artery disease risk factors, we examined the Tsimane, a Bolivian population living a subsistence lifestyle of hunting, gathering, fishing, and farming with few cardiovascular risk factors, but high infectious inflammatory burden. Methods We did a cross-sectional cohort study including all individuals who self-identified as Tsimane and who were aged 40 years or older. Coronary atherosclerosis was assessed by coronary artery calcium (CAC) scoring done with non-contrast CT in Tsimane adults. We assessed the difference between the Tsimane and 6814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). CAC scores higher than 100 were considered representative of significant atherosclerotic disease. Tsimane blood lipid and inflammatory biomarkers were obtained at the time of scanning, and in some patients, longitudinally. Findings Between July 2, 2014, and Sept 10, 2015, 705 individuals, who had data available for analysis, were included in this study. 596 (85%) of 705 Tsimane had no CAC, 89 (13%) had CAC scores of 1–100, and 20 (3%) had CAC scores higher than 100. For individuals older than age 75 years, 31 (65%) Tsimane presented with a CAC score of 0, and only four (8%) had CAC scores of 100 or more, a five-fold lower prevalence than industrialised populations (p≤0·0001 for all age categories of MESA). Mean LDL and HDL cholesterol concentrations were 2·35 mmol/L (91 mg/dL) and 1·0 mmol/L (39·5 mg/dL), respectively; obesity, hypertension, high blood sugar, and regular cigarette smoking were rare. High-sensitivity C-reactive protein was elevated beyond the clinical cutoff of 3·0 mg/dL in 360 (51%) Tsimane participants. Interpretation Despite a high infectious inflammatory burden, the Tsimane, a forager-horticulturalist population of the Bolivian Amazon with few coronary artery disease risk factors, have the lowest reported levels of coronary artery disease of any population recorded to date. These findings suggest that coronary atherosclerosis can be avoided in most people by achieving a lifetime with very low LDL, low blood pressure, low glucose, normal body-mass index, no smoking, and plenty of physical activity. The relative contributions of each are still to be determined. Funding National Institute on Aging, National Institutes of Health; St Luke's Hospital of Kansas City; and Paleocardiology Foundation.

Geriatric patients with acute infection show increased muscle weakness and fatigability but the relative contribution of central and peripheral factors is unclear. Hospitalised patients with acute infection (82±6years, N=10) and community-dwelling controls (76±6years, N=19) sustained a maximal voluntary isometric contraction of the M. Adductor Pollicis until strength dropped to 50% of its maximal value. Voluntary muscle activation (VA) was assessed before and at the end of the fatigue protocol using twitch interpolation method and muscle activity was monitored using surface electromyography. Twenty-five circulating inflammatory biomarkers were determined. At pre-fatigue, no significant difference in VA was found between groups. VA decreased to similar levels (~50%) at the end of the fatigue protocol with no association with inflammatory biomarkers. In geriatric patients, muscle activity decreased significantly (p

Background and aims Apelin-APJ signaling reduces cardiovascular disease (CVD) risk. In rheumatoid arthritis (RA), the atherosclerosis burden and plaque vulnerability to rupture are increased. We explored relationships between apelin concentrations and subclinical CVD in RA. Methods Apelin levels were measured in 235 (114 black, 121 white) RA patients. Associations between apelin concentrations and ultrasound determined carotid artery intima-media thickness (cIMT) and plaque, and levels of matrix metalloproteinase (MMP)-2 and -9 that mediate plaque stability and vulnerability respectively, were identified in confounder adjusted multivariate regression analysis. Results In all patients, apelin concentrations were directly associated with those of MMP-2 (β (SE) = 0.324 (0.112), p = 0.004) and inversely with those of MMP-9 (β (SE) = -0.239 (0.060), p = 0.000). Apelin concentration-subclinical CVD relations were influenced by population origin, RA disease activity, erythrocyte sedimentation rate (ESR) and interleukin (IL)-6 concentrations (interaction p = 0.001 to 0.04). Accordingly, the apelin-MMP-2 concentration relationship was reproduced in white (β (SE) = 0.367 (0.146), p = 0.01) but not black RA patients (β (SE) = 0.197 (0.220), p = 0.4), and only in those without (but not with) large erythrocyte sedimentation rates (β (SE) = 0.428 (0.143), p = 0.003) or interleukin-6 levels (β (SE) = 0.485 (0.288), p = 0.04). By contrast, the apelin-MMP-9 concentration relation was reproduced more consistently. Apelin levels were inversely related to cIMT in patients with RA remission or mild (β (SE) = -0.068 (0.033), p = 0.04) but not moderate or high disease activity (β (SE) = 0.015 (0.112), p = 0.7). Conclusions Apelin concentrations are associated with altered plaque stability mediator levels and atherosclerosis in patients with RA. These relations are partially dependent on population origin and systemic inflammatory status.

Background: Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease (CVD) with poor parasympathetic function being implicated as an underlying factor. Factors related to parasympathetic function, commonly assessed by heart rate recovery (HRR) following maximal exercise, are currently not known in RA. We aimed to explore the association between HRR with CVD risk factors, inflammatory markers, and wellbeing in patients with RA. Methods: Ninety-six RA patients (54.4 ± 12.6 years, 68 % women) completed a treadmill exercise test, during which heart rate (HR) was monitored. HRR1 and HRR2 were defined as the absolute change from HR peak to HRR 1 min post HR peak and 2 min post HR peak, respectively. Cardiorespiratory fitness, CVD risk factors, and serological markers of inflammation were measured in all patients. The Framingham Risk Score (FRS) was used as an assessment of global risk for CVD events, and wellbeing was assessed by questionnaires. Results: Mean HRR1 and HRR2 were 29.1 ± 13.2 bpm and 46.4 ± 15.3 bpm, respectively. CVD risk factors as well as most inflammatory markers and measures of wellbeing were inversely correlated with HRR1 and HRR2. Multivariate regression analyses revealed that 27.9 % of the variance in HRR1 and 37.9 % of the variance in HRR2 was explained collectively by CVD risk factors, measures of inflammation, and wellbeing (p = 0.009, p = 0.001 respectively), however no individual measure was independently associated with HRR1 or HRR2. Conclusion: Parasympathetic activation was associated with overall CVD risk, arthritis-related burden and wellbeing in patients with RA. Trial Registration: [Exercise, cardiovascular disease and rheumatoid arthritis, ISRCTN04121489 ]

Chemotherapy-induced gastrointestinal (GI) toxicity is a common adverse effect of cancer treatment. We used preweaned piglets as models to test our hypothesis that the immunomodulatory and GI trophic effects of bovine colostrum would reduce the severity of GI complications associated with doxorubicin (DOX) treatment. Five-day-old pigs were administered DOX (1 × 100 mg/m2) or an equivalent volume of saline (SAL) and either fed formula (DOX-Form, n = 9, or SAL-Form, n = 7) or bovine colostrum (DOX-Colos, n = 9, or SAL-Colos, n = 7). Pigs were euthanized 5 days after initiation of chemotherapy to assess markers of small intestinal function and inflammation. All DOX-treated animals developed diarrhea, growth deficits, and leukopenia. However, the intestines of DOX-Colos pigs had lower intestinal permeability, longer intestinal villi with higher activities of brush border enzymes, and lower tissue IL-8 levels compared with DOX-Form (all P < 0.05). DOX-Form pigs, but not DOX-Colos pigs, had significantly higher plasma C-reactive protein, compared with SAL-Form. Plasma citrulline was not affected by DOX treatment or diet. Thus a single dose of DOX induces intestinal toxicity in preweaned pigs and may lead to a systemic inflammatory response. The toxicity is affected by type of enteral nutrition with more pronounced GI toxicity when formula is fed compared with bovine colostrum. The results indicate that bovine colostrum may be a beneficial supplementary diet for children subjected to chemotherapy and subsequent intestinal toxicity.

OBJECTIVES: Endovascular aneurysm repair (EVAR), may elicit an unexpected systemic inflammatory response, which has been named post-implantation syndrome (PIS). The aim of this study was to prospectively evaluate the association of PIS with clinical and laboratory parameters in patients who underwent EVAR for abdominal aortic aneurysms (AAA). METHODS: Forty consecutive patients who underwent EVAR for AAA were studied. Complete blood count, fibrinogen, high sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-1, tumor necrosis factor-alpha were determined before and after surgery. Several parameters regarding the operation, as well as the hospitalization days were recorded. RESULTS: PIS was diagnosed in 35% of the patients. Patients with PIS showed significant greater changes of inflammation marker levels, including hs-CRP and IL-6, as compared with the non-PIS group. PIS was associated with longer hospitalization. CONCLUSION: PIS is a relatively common complication of EVAR used to treat AAAs and it is associated with features of a systemic inflammatory response and prolongation of hospitalization. Further studies are necessary towards understanding the underlying pathophysiology and evaluating effective preventive strategies. Interact Cardiovasc Thorac Surg

OBJECTIVE: Uric acid (UA) is a cardiovascular risk marker associated with oxidative stress and inflammation. Recently, atrial fibrillation (AF) has been associated with inflammation and oxidative stress. The objective of this observational study was to investigate the association between UA levels and AF in hypertensive patients. METHODS: Consecutive patients with hypertension were screened. We excluded subjects with coronary artery disease, congestive heart failure, diabetes, valvular heart disease, congenital heart disease, cardiomyopathy, renal failure, inflammatory conditions, thyroid dysfunction, respiratory diseases, and those who were taking drugs that affect UA metabolism (apart from diuretics). The final study population consisted of 451 patients. Fifty of them (11%) had AF (paroxysmal: 38; persistent: 8; permanent: 4). Demographic, clinical, laboratory, and echocardiographic characteristics were carefully recorded. RESULTS: After univariate analysis, age, duration of hypertension, serum creatinine, serum UA, left atrial diameter (LAD), interventricular septum thickness, and left ventricular posterior wall thickness were significantly increased in patients with AF compared with non-AF patients, while the estimated glomerular filtration (eGFR) level was much lower in patients with AF than in those without AF. After multivariate logistic regression analysis, the independent predictors of AF were UA (OR: 1.008; 95% CI: 1.003-1.013, p=0.002) and LAD (OR: 1.160; 95% CI: 1.068-1.260; p

Accumulating evidence suggests that periodontal infections may have an impact on systemic health. In patients with untreated periodontitis, very high values for several inflammatory markers in serum are expressed simultaneously. We investigated to what extent these peak values change after nonsurgical and surgical periodontal treatment, with adjunctive antibiotics administered during the first or the second treatment phase. In a single-center, randomized, placebo-controlled, and double-masked clinical trial, 80 patients with chronic or aggressive periodontitis were randomized into 2 treatment groups: group A, receiving systemic amoxicillin and metronidazole during the first, nonsurgical phase of periodontal therapy (phase 1), and group B, receiving the antibiotics during the second, surgical phase (phase 2). Serum samples were obtained at baseline (BL), 3 mo after phase 1 (M3), and 6 and 12 mo after phase 2 (M6, M12). Samples were evaluated for 15 cytokines and 9 acute-phase proteins using the Bio-Plex bead array multianalyte detection system. For each analyte, peak values were defined as greater than mean +2 SD of measurements found in 40 periodontally healthy persons. Sixty-six patients showed a peak value of at least 1 analyte at BL. At M12, the number of these patients was only 36 ( P = 0.0002). This decrease was stronger in group A (BL: 35, M12: 19, P = 0.0009) than in group B (BL: 31, M12: 17, P = 0.14). Twenty patients displayed peak values of at least 4 biomarkers at BL. The nonsurgical therapy delivered in the first phase reduced most of these peaks (group A, BL: 9, M3: 4, P = 0.17; group B, BL: 11, M3: 2, P = 0.01), irrespective of adjunctive antibiotics. The reductions obtained at M3 were maintained until M12 in both groups. Initial, nonsurgical periodontal therapy reduced the incidence of peak levels of inflammatory markers. Antibiotics and further surgical therapy did not enhance the effect ( Clinicaltrials.gov NCT02197260).

OBJECTIVE: Recent studies show that sublingual microcirculation is altered in patients resuscitated from cardiac arrest (CA). The objective of this study was to investigate whether the cerebral microcirculation is disturbed in the early post resuscitation period.METHODS: Male Sprague-Dawley rats were randomized to either 10 min of CA or uninterrupted circulation, and observed for 120 or 360min after return of spontaneous circulation (ROSC). At 120 and 360min, cerebral microcirculation was evaluated by side stream dark field microscopy (SDF) through a craniotomy. Plasma samples were analyzed for endothelial adhesion molecules and inflammatory markers, and brains were fixated for histological analysis.RESULTS: Cerebral microcirculation, evaluated by total vessel density, perfused vessel density, proportion of perfused vessels, and microvascular flow index did not differ between groups (p>0.16). Plasma samples drawn 360 min after ROSC displayed a significant increase in sE-selectin, sL-selectin, sI-CAM1, IL-1β, IL-6, IL-10, and elastase compared to controls. In the CA animals, sE-selectin and elastase increased between 120 and 360 min after resuscitation (pCONCLUSION: When evaluated by SDF, the cerebral microcirculation appears unaffected in the early post CA period despite hypotension, systemic inflammation, endothelial activation, and neuronal injury. This article is protected by copyright. All rights reserved.

Background: The risk of cardiovascular disease is tremendously high in dialysis patients. Dialysis patients treated with vitamin D analogs show decreased cardiovascular morbidity and mortality compared with untreated patients. We examined the influence of two common vitamin D analogs, alfacalcidol and paricalcitol, on important cardiovascular biomarkers in hemodialysis patients. Anti-inflammatory effects and the influence on regulators of vascular calcification as well as markers of heart failure were examined.Methods. In 57 chronic hemodialysis patients enrolled in a randomized crossover trial comparing paricalcitol and alfacalcidol, we examined the changes in osteoprotegerin, fetuin-A, NT-proBNP, hs-Crp, IL-6 and TNF-, during 16 weeks of treatment.Results: NT-proBNP and osteoprotegerin increased comparably in the paricalcitol and alfacalcidol-treated groups. Fetuin-A increased significantly in the alfacalcidol-treated group compared with the paricalcitol-treated group (difference 32.84 μmol/l (95% C.I.; range 0.21-67.47)) during the first treatment period. No difference was found between the groups during the second treatment period, and IL-6, TNF- and hs-Crp were unchanged in both treatment groups.Conclusions: Paricalcitol and alfacalcidol modulate regulators of vascular calcification. Alfacalcidol may increase the level of the calcification inhibitor fetuin-A. We did not find any anti-inflammatory effect or difference in changes of NT-proBNP. Trial registry. ClinicalTrials.gov NCT00469599 May 3 2007.

Purpose: The purpose of this study was to describe levels of inflammation markers in Norwegian children and to examine the associations of adiposity, aerobic fitness, and muscle fitness with markers of inflammation. Methods: In 2005-2006, 1467 nine-year-olds were randomly selected from all regions in Norway. The participation rate was 89%. The inflammatory markers evaluated included C-reactive protein (CRP), leptin, adiponectin, plasminogen activator inhibitor-1, tumor necrosis factor-α, hepatocyte growth factor, resistin, and interleukin-6. We assessed muscular strength by measuring explosive, isometric, and endurance strength. Aerobic fitness was measured directly during a maximal cycle ergometer test. Adiposity was expressed as waist circumference (WC). Results: The girls had significantly higher levels of CRP, leptin, adiponectin, and resistin and lower levels of tumor necrosis factor-α compared with the boys. We observed a graded association of CRP and leptin levels across quintiles of WC, aerobic fitness, and muscle fitness (P ≤ 0.001 for all participants). The regression analyses revealed that WC, aerobic fitness, and muscle fitness were independently associated with the CRP (WC β = 0.158, P < 0.001; aerobic fitness β = -0.190, P < 0.001; muscle fitness β = -0.122, P < 0.002) after adjustments for sex, age, Tanner pubertal stage, and the other independent variables. The same pattern was observed for leptin levels (WC β = 0.406, P < 0.001; aerobic fitness β = -0.298, P < 0.001; muscle fitness β = -0.064, P < 0.036). Conclusions: These data represent a reference material with respect to inflammatory markers. Our results show that adiposity, aerobic fitness, and muscle fitness were independently associated with the CRP and leptin levels.

OBJECTIVE: Chronic inflammatory diseases in adults have been associated with increased cardiovascular risk and impaired vascular function. We aimed to assess the presence of early vascular dysfunction in patients with juvenile idiopathic arthritis (JIA) and investigate the role of inherent inflammatory process of JIA in vascular health. METHODS: Thirty patients with JIA (age range 7-18 years) were compared to 33 age- and sex-matched controls. Endothelial function (brachial artery flow-mediated dilation [FMD]), carotid intima-media thickness (IMT), and arterial stiffness were examined. Endothelial inflammation was assessed by intercellular adhesion molecule 1 (ICAM-1) and P-selectin measurements. RESULTS: Patients with JIA showed decreased FMD compared to controls (P = 0.001), independent of age (P = 0.9 among age subgroups). Baseline differences in erythrocyte sedimentation rate, ICAM-1, and glucose between the 2 groups accounted for the difference in FMD. The presence of systemic JIA was associated with greater IMT compared to patients with oligoarticular disease, polyarticular disease, or controls (P = 0.014, P = 0.069, and P = 0.046, respectively). The difference in IMT between systemic versus oligoarticular/polyarticular JIA was attributed to the following risk factors: age, body mass index, blood pressure, disease activity, and corticosteroids use. There were no differences in arterial stiffness indices between JIA patients and controls or between patients with systemic versus nonsystemic disease. CONCLUSION: Endothelial function is impaired in patients with JIA at a very young age, while IMT is increased only in the presence of systemic JIA. Vascular dysfunction may be partly attributed to the effects of disease-related characteristics (inflammation, disease activity, and medications). Arthritis Care Res (Hoboken)

While recent scans for genetic variation associated with human disease have been immensely successful in uncovering large numbers of loci, far fewer studies have focused on the underlying pathways of disease pathogenesis. Many loci which are associated with disease and complex phenotypes map to non-coding, regulatory regions of the genome, indicating that modulation of gene transcription plays a key role. Thus, this study generated genome-wide profiles of both genetic and transcriptional variation from the total blood extracts of over 500 randomly-selected, unrelated individuals. Using measurements of blood lipids, key players in the progression of atherosclerosis, three levels of biological information are integrated in order to investigate the interactions between circulating leukocytes and proximal lipid compounds. Pair-wise correlations between gene expression and lipid concentration indicate a prominent role for basophil granulocytes and mast cells, cell types central to powerful allergic and inflammatory responses. Network analysis of gene co-expression showed that the top associations function as part of a single, previously unknown gene module, the Lipid Leukocyte (LL) module. This module replicated in T cells from an independent cohort while also displaying potential tissue specificity. Further, genetic variation driving LL module expression included the single nucleotide polymorphism (SNP) most strongly associated with serum immunoglobulin E (IgE) levels, a key antibody in allergy. Structural Equation Modeling (SEM) indicated that LL module is at least partially reactive to blood lipid levels. Taken together, this study uncovers a gene network linking blood lipids and circulating cell types and offers insight into the hypothesis that the inflammatory response plays a prominent role in metabolism and the potential control of atherogenesis., Wellcome Trust (London, England) (WT089061), Wellcome Trust (London, England) (WT089062), Academy of Finland (129680), Academy of Finland (213506)

Interleukin (IL)-1 was first cloned in the 1980s, and rapidly emerged as a key player in the regulation of inflammatory processes. The term IL-1 refers to two cytokines, IL-1alpha and IL-1beta, which are encoded by two separate genes. The effects of IL-1 are tightly controlled by several naturally occurring inhibitors, such as IL-1 receptor antagonist (IL-1Ra), IL-1 receptor type II (IL-1RII), and other soluble receptors. Numerous IL-1 inhibitors have been developed and tested primarily in rheumatoid arthritis, with only modest effects. By contrast, the use of IL-1 antagonists has been uniformly associated with beneficial effects in patients with hereditary autoinflammatory conditions associated with excessive IL-1 signaling, such as cryopyrinopathies and IL-1Ra deficiency. Successful treatment with IL-1 blockers has also been reported in other hereditary autoinflammatory diseases, as well as in nonhereditary inflammatory diseases, such as Schnizler syndrome, systemic-onset juvenile idiopathic arthritis and adult Still disease. The role of microcrystals in the regulation of IL-1beta processing and release has provided the rationale for the use of IL-1 inhibitors in crystal-induced arthritis. Finally, preliminary results indicating that IL-1 targeting is efficacious in type 2 diabetes and smoldering myeloma have further broadened the spectrum of IL-1-driven diseases.

OBJECTIVES: To study the effect of pentoxifylline and octreotide administration on serum levels of TNF-alpha and IL-6, in patients who underwent endoscopic retrograde cholangiopancreatography (ERCP), whether they developed pancreatitis or not. METHODS: Out of 590 patients undergoing ERCP, 30 who developed pancreatitis and 25 who did not (controls) were enrolled. Pentoxifylline was given to 23 patients (15 with and eight without pancreatitis) and octreotide to 19 patients (nine with and 10 without pancreatitis, respectively). Thirteen patients did not receive any preventive medication (six with and seven without pancreatitis, respectively). Blood samples were collected at baseline, 6 and 24 h after ERCP. RESULTS: IL-6 increased significantly in patients with pancreatitis at the 6 h (4.2 pg/ml SD: 5.8) and at the 24 h (6.6 pg/ml SD: 9.8) compared with patients without pancreatitis at the 6 h (2.1 pg/ml SD: 3.6) and 24 h (1.9 pg/ml SD: 2.5) (P < 0.01). No significant difference in the values of TNF-alpha and IL-6 obtained among the three study groups in patients with or without pancreatitis was observed. TNF-alpha levels at the 24 h were lower than baseline in patients with pancreatitis who received octreotide (P = 0.04). CONCLUSION: IL-6 increased in the first 24 h of post-ERCP pancreatitis. Pentoxifylline and octreotide cannot prevent IL-6 elevation but octreotide reduces TNF-alpha levels, which may have an impact on the severity of post-ERCP pancreatitis. Eur J Gastroenterol Hepatol

BACKGROUND: The aim of our present study was to compare the association of a wide range of 17 biomarkers of inflammation, hemostasis, and blood rheology with incident heart disease and stroke after accounting for an indicator of subclinical atherosclerotic disease and traditional risk factors and also to determine their incremental predictive ability. METHODS AND RESULTS: We used data from the Edinburgh Artery Study, a population cohort study started in 1987 that comprised 1592 men and women aged 55 to 74 years. Subjects were followed for a mean of 17 years, and 416 of them suffered at least 1 cardiovascular event. In analyses adjusted for cardiovascular risk factors and history of cardiovascular disease (CVD): C-reactive protein, interleukin-6, fibrinogen, fibrin D-dimer, tissue plasminogen activator (t-PA), leukocyte elastase, and lipoprotein(a) (all P

We have previously demonstrated that exercise training prevents the development of Angiotensin (Ang) II-induced atherosclerosis and vulnerable plaques in Apolipoprotein E-deficient (ApoE-/-) mice. In this report, we investigated whether exercise attenuates progression and promotes stability in pre-established vulnerable lesions. To this end, ApoE-/- mice with already established Ang II-mediated advanced and vulnerable lesions (2-kidney, 1-clip [2K1C] renovascular hypertension model), were subjected to sedentary (SED) or voluntary wheel running training (EXE) regimens for 4 weeks. Mean blood pressure and plasma renin activity did not significantly differ between the two groups, while total plasma cholesterol significantly decreased in 2K1C EXE mice. Aortic plaque size was significantly reduced by 63% in 2K1C EXE compared to SED mice. Plaque stability score was significantly higher in 2K1C EXE mice than in SED ones. Aortic ICAM-1 mRNA expression was significantly down-regulated following EXE. Moreover, EXE significantly down-regulated splenic pro-inflammatory cytokines IL-18, and IL-1β mRNA expression while increasing that of anti-inflammatory cytokine IL-4. Reduction in plasma IL-18 levels was also observed in response to EXE. There was no significant difference in aortic and splenic Th1/Th2 and M1/M2 polarization markers mRNA expression between the two groups. Our results indicate that voluntary EXE is effective in slowing progression and promoting stabilization of pre-existing Ang II-dependent vulnerable lesions by ameliorating systemic inflammatory state. Our findings support a therapeutic role for voluntary EXE in patients with established atherosclerosis.

BACKGROUND: The objective of this study was to measure associations of circulating interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) levels with anthropometric and abdominal fat distribution in overweight or obese postmenopausal women. METHODS: One hundred eight overweight or obese postmenopausal were evaluated. Demographic and anthropometric measurements were done. Serum IL-6, TNF-alpha, glucose, and insulin levels were measured. Insulin resistance was calculated by using homeostasis model assessment-insulin resistance (HOMA-IR). The assessment of abdominal fat distribution was performed by ultrasonography. Statistical analysis was made with Pearson and partial correlation analysis. RESULTS: There was a positive correlation between serum IL-6 and TNF-alpha (r = .19; p = .047). IL-6 was positively correlated with body mass index (BMI) (r = .43; p = .0001), waist circumference (r = .41; p = .0001), and visceral fat layer (r = .33; p = .0001) measurements and HOMA-IR index (r = .31, p = .001). A positive relationship between HOMA-IR and visceral fat layer thickness was observed (r = .320; p = .0001). TNF-alpha was positively associated with BMI but not with any measures of central obesity. When adjustment for BMI was performed, there were no significant relationships between the studied parameters. CONCLUSIONS: There are no significant correlations between abdominal fat distributions measured by ultrasonography and circulating IL-6 and TNF-alpha levels. BMI may have a stronger association with circulating inflammatory cytokine concentrations than with different measures of central obesity in overweight or obese postmenopausal women.

In the present study, the changes in circulating IGF-1 and its binding protein IGFBP-3 were determined in adult patients with active inflammatory bowel disease (IBD) in order to assess the effect of this inflammatory condition on the IGF system. IGF-1 and IGFBP-3, as well as interleukin-6 (IL-6) were measured in serum obtained from 22 consecutive newly diagnosed patients (mean age 41.3 years) with active IBD, including 10 patients with Crohn's disease (CD), and 12 with ulcerative colitis (UC). For comparison the same parameters were determined in 30 healthy volunteers matched for age, sex and Body Mass Index (BMI). Serum IGF-1 and IGFBP-3 levels were similar in the two subgroups of patients and the values from all patients were combined for comparison with those from the control group. The mean (+/- SD) serum IGF-1 concentration (178 +/- 91 ng/ml) in the patients with IBD was lower compared with that in the controls (227 +/- 79 ng/ml, P

Endothelial activation and subclinical microvascular occlusions are an ongoing process during steady-state sickle cell disease, leading to interleukin production and an acute-phase response. Alpha-2-macroglobulin (alpha2M) is an acute-phase protein mainly regulated by interleukin-6 (IL-6). On the other hand, alpha2M acts as a carrier protein for IL-6 during inflammatory stress. The purpose of this study is to further assess the interactions between IL-6 and alpha2M as potent modulators of inflammatory reactions during the steady state of sickle cell disease. We measured alpha2M and IL-6 levels in 21 patients (12 male, 9 female; age range 12-44 years) in the steady state of sickle cell disease. Four patients had homozygous sickle cell anaemia and 17 had double heterozygous sickle cell/beta-thalassaemia. Diagnostic quantification of alpha2M was performed by rate nephelometry. Commercial enzyme immunoassay test kits were used for the quantitative measurement of IL-6. The alpha2M and IL-6 levels were compared to the values obtained from healthy volunteers. Mean values (+/- SD) of alpha2M and IL-6 were found to be significantly increased (p < 0.0005) in the patients (alpha2M: 337.2 +/- 104 mg/dl; IL-6: 4 +/- 2.1 pg/ml) compared to the healthy controls (alpha2M: 204.2 +/- 45.8 mg/dl; IL-6: 1.15 +/- 2.5 pg/ml). IL-6 values were positively correlated with alpha2M levels (r = 0.61, p < 0.01). We observed increased alpha2M and IL-6 levels in steady-state sickle cell disease and a positive correlation between these two inflammatory mediators. We suggest that alpha2M is a potent modulator of the inflammatory reaction and tissue repair mechanism during steady-state microvascular occlusions. Elucidating the role of alpha2M in sickle cell disease could lead to the development of novel strategies and therapies for preventing the harmful systemic or local effects of excess cytokine production. Acta Haematol