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Objective To investigate metabolic syndrome (MetS), disease activity, and adipokine levels among patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and undifferentiated arthritis (UA) at the time of diagnosis and after 1 year of follow-up. Methods Patients with inflammatory joint diseases participating in the Northern Savo 2010 population-based prospective epidemiological study were evaluated for components of MetS (by National Cholesterol Education Program's Adult Treatment Panel III) and clinical parameters of disease activity. The adipokines adiponectin, adipsin, resistin, and leptin were measured at baseline and after 1 year of treatment with disease-modifying antirheumatic drugs. Results Among 176 patients, MetS was detected in 42% of RA, 36% of SpA, and 51% of UA patients. Metabolic syndrome was associated with higher disease activity as measured by patient global assessment in RA and UA patients and increased pain in RA patients. Leptin levels were increased in patients with MetS, showing a linearly increasing trend with the number of components of MetS in SpA and UA, but not in RA. In RA patients, decrease in disease activity correlated with decrease in leptin levels. Resistin did not associate with MetS, but a decrease in resistin correlated with decrease in disease activity in RA and UA. In SpA, increased adiponectin level correlated with relief in disease activity, but not with MetS. Conclusions Metabolic syndrome was common in patients with newly diagnosed arthritides and associated with higher disease activity and increased leptin levels. Resistin responded to treatment of arthritis in RA and UA, leptin in RA, and adiponectin in SpA.

Objective: We investigated lipid concentrations, particle sizes and antibodies binding to periodontal bacteria Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis and to malondialdehyde-acetaldehyde (MAA) modified low-density lipoprotein in immunoglobulin (Ig) class A, G and M among patients with newly diagnosed rheumatoid arthritis (RA) in a population-based cohort.Methods: Concentrations and sizes of lipoprotein particles analysed by proton nuclear magnetic resonance spectroscopy and antibody levels to MAA modified low-density lipoprotein were studied at baseline and after one-year of follow-up. Serum Ig A and G class antibodies to periodontal bacteria were determined at baseline.Results: Sixty-three patients were divided into tertiles according to disease activity by disease activity score with 28 joint count and erythrocyte sedimentation rate (ESR) ( 4.7). Small low-density lipoprotein concentration was lowest in the tertile with the highest disease activity. In high-density lipoprotein, the concentrations of total, medium and small particles decreased with disease activity. The particle size in low-density lipoprotein associated with disease activity and the presence of antibodies to P. gingivalis. Ig G and M antibodies to MAA modified low-density lipoprotein correlated with disease activity. Inflammation associated changes faded by one year.Conclusions: Drug naive RA patients had proatherogenic changes in lipid profiles, but they were reversible, when inflammation diminished.Key messagesPatients with drug naive rheumatoid arthritis showed proatherogenic lipid profiles.Reversible changes in lipid profiles can be achieved as response to inflammation suppression.Active therapy aimed at remission is essential in all patients with rheumatoid arthritis.

Objectives Vascular endothelial growth factor (VEGF) has been related to the etiology of major depressive disorder (MDD). The findings involving the effects of electroconvulsive therapy (ECT) on the VEGF levels have been conflicting. The aim was to examine the possible changes in the VEGF levels and their associations with clinical outcome in patients with MDD during ECT. Methods The study comprised 30 patients suffering from MDD. Their plasma VEGF levels were measured at baseline and 2 and 4 hr after the first, fifth, and last ECT session. The severity of depression was quantified by the Montgomery‐Asberg Depression Rating Scale (MADRS). Results The VEGF levels increased between the 2‐hr and 4‐hr measurements during the first (p = .003) and the fifth (p = .017) sessions. The baseline VEGF levels between individual ECT sessions remained unchanged during the ECT series. No correlations were found between the increased VEGF levels and the clinical outcome. Conclusions Electroconvulsive therapy increased the VEGF levels repeatedly at the same time point in two different ECT sessions. These increases had no association with the response to ECT. Consequently, VEGF may act as a mediator in the mechanism of action of ECT., Plasma VEGF levels of patients suffering from MDD were measured in different time points during ECT series. ECT increased the VEGF levels repeatedly at the same time point in two different ECT sessions but these increases had no association with the response to ECT. Consequently, VEGF may act as a mediator in the mechanism of action of ECT.

Background Transforming growth factor beta 1 (TGF-β1) and platelet-derived growth factor (PDGF) are cytokines involved in fibrotic processes causing radiotherapy (RT)-induced cardiovascular changes. We aimed to investigate the associations between TGF-β1 and PDGF and the echocardiographic changes that occur during RT and during three-year follow-up. Methods The study included 63 women receiving adjuvant RT for early-stage breast cancer or ductal carcinoma in situ. Serum TGF-β1 (ng/ml) and PDGF (ng/ml) levels were measured by enzyme-linked immunoassay and echocardiographic examination was performed before RT, after RT and at 3 years. Patients were grouped by biomarker behavior by a trajectory analysis. Results TGF-β1 decreased from 19.2 (IQR 17.1–22.3) before RT to 18.8 (14.5–22.0) after RT (p = 0.003) and the decrease persisted at 17.2 (13.7–21.2) 3 years after RT (p = 0.101). PDGF decreased from 15.4 (12.6–19.1) before RT to 13.8 (11.7–16.2) after RT, p = 0.001, and persisted at 15.6 (10.4–18.4) at 3 years, p = 0.661. The TGF-β1 level before RT (Spearman’s rho 0.441, p

AIMS Alcohol consumption has been suggested a major role in the pathogenesis and prognosis of depression. However, reliable identification of hazardous drinking continues to be problematic. We compared the accuracy of different biomarkers and self-reports of alcohol consumption in the follow-up study of depression. METHODS Data from 202 patients with major depressive disorder were obtained through self-reports, AUDIT and AUDIT-C questionnaires and biomarker analyses. The clinical assessments and measurements of biomarkers (GT, CDT, GT-CDT-combination, MCV, ALT, AST, hs-CRP, IL-6) were performed at baseline and after six months of treatment. Based on self-reported alcohol intake at baseline the patients were classified to three subgroups. RESULTS About 27.2% of patients were categorized to high-risk drinkers, 26.3% low-risk drinkers and 46.5% abstainers. High-risk drinkers showed significantly higher mean values of GT, CDT, GT-CDT-combination and IL-6 than abstainers, diagnostic accuracy being highest with the combined marker of GT-CDT. The accuracy of AUDIT and AUDIT-C to detect high-risk drinking was also significant. During follow-up, the differences observed in the biomarkers at baseline disappeared together with recovery from depression. CONCLUSIONS Our data suggest the combined use of GT-CDT and AUDIT questionnaires to improve the identification of drinking of patients with depression. This approach could be useful for improving treatment adherence and outcome in depressed patients.

Julkaisua ei hallinnoi Genomibiologian yksikkö, mutta en saanut yksikköä vaihdettua. Päätekijöiden affiliaatio: Department of Rheumatology, University of Helsinki and Helsinki University Hospital , Helsinki, Finland. Oma julkaisuun liittyvä affiliaationi: University of Helsinki, Faculty of Medicine, Clinicum. Objectives: To study whether female patients with active rheumatoid arthritis (RA) have myocardial abnormalities and whether progression of myocardial involvement can be attenuated by disease-modifying anti-rheumatic drugs (DMARDs). Method: Cardiac magnetic resonance (cMR; 1.5 or 3.0 T), including late gadolinium enhancement (LGE), T1 relaxation time, and ventricular functions, was performed in 30 patients with untreated active early RA starting first DMARDs, and 28 patients with chronic RA with inadequate response to conventional synthetic DMARDs starting biological DMARDs. cMR was repeated in RA patients 1 year later. cMR was conducted once in 22 fibromyalgia (FM) subjects and in 35 healthy volunteers serving as controls. All subjects were non-smoking females without coronary heart disease, heart failure, or diabetes. Results: Compared with controls, 58 RA patients had slightly lower ventricular function, although in the normal range, and longer T1 time at baseline. None of the FM subjects had LGE, but it was frequent in RA (67%). During the 1 year DMARD treatment, Disease Activity Score based on 28-joint count-C-reactive protein declined, ventricular functions tended to improve, but the number of patients with LGE remained unchanged. However, the number of LGE-positive heart segments either decreased or stayed the same in 91% of RA patients. In early RA patients, achieving tight remission was associated with LGE stabilization, after adjustment for age, metabolic syndrome, baseline inflammatory activity, and leisure-time physical activity. Conclusion: Treatment targeted to tight remission in early stages of RA seems to be important to prevent not only joint damage but also myocardial abnormalities.

Objectives: The present study was performed to determine whether lung injury manifests as lung edema in neonates after congenital cardiac surgery and whether a stress-dose corticosteroid (SDC) regimen attenuates postoperative lung injury in neonates after congenital cardiac surgery. Design: A supplementary report of a randomized, double-blinded, placebo-controlled clinical trial. Setting: A pediatric tertiary university hospital. Participants: Forty neonates (age ≤28 days) undergoing congenital cardiac surgery with cardiopulmonary bypass. Interventions: After anesthesia induction, patients were assigned randomly to receive intravenously either 2 mg/kg methylprednisolone or placebo b, which was followed by hydrocortisone or placebo bolus six hours after weaning from CPB for five days as follows: 0.2 mg/kg/h for 48 hours, 0.1 mg/kg/h for the next 48 hours, and 0.05 mg/kg/h for the following 24 hours. Measurements and Main Results: The chest radiography lung edema score was lower in the SDC than in the placebo group on the first postoperative day (POD one) (p = 0.03) and on PODs two and three (p = 0.03). Furthermore, a modest increase in the edema score of 0.9 was noted in the placebo group, whereas the edema score remained at the preoperative level in the SDC group. Postoperative dynamic respiratory system compliance was higher in the SDC group until POD three (p < 0.01). However, postoperative oxygenation; length of mechanical ventilation; and tracheal aspirate biomarkers of inflammation and oxidative stress, namely interleukin-6, interleukin-8, resistin, and 8-isoprostane, showed no differences between the groups. Conclusions: The SDC regimen reduced the development of mild and likely clinically insignificant radiographic lung edema and improved postoperative dynamic respiratory system compliance without adverse events, but it failed to improve postoperative oxygenation and length of mechanical ventilation. publishedVersion

Exhaled nitric oxide (FENO) is a marker of airway inflammation in asthma. Measuring FENO at multiple flow rates enables calculation of NO-parameters like bronchial NO output (JawNO), bronchial wall (CawNO) and alveolar (CANO) NO-concentrations, and bronchial diffusion factor of NO (DawNO). FENO is known to rapidly reduce after administration of inhaled corticosteroids (ICS) in asthma. However, little is known on the effect of ICS on other NO-parameters. We assessed 1) the onset of the ICS-treatment on the NO-parameters and 2) whether the changes in bronchial NO-output are due to changes bronchial wall NO-concentration or diffusion factor. FENO and other NO-parameters were measured in 23 children with asthma or asthma-like symptoms at baseline and after 1, 3 and 7 days of treatment with inhaled fluticasone propionate 250 mg b.i.d. There was a decrease in JawNO (from 680 (244/1791) (median (1st/3rd quartile)) to 357 (165/753) pl/s, p ICS-treatment reduces FENO50 and JawNO rapidly and the decline is caused by decreased bronchial wall NO-concentration while bronchial NO diffusion factor remained unchanged. These findings suggest that CawNO could be a more specific marker of airway inflammation and treatment response than JawNO or FENO50, which are both determined also by DawNO that was found to be resistant to the treatment with ICS.

Objectives To search for biomarkers of RT-induced cardiotoxicity, we studied the behavior of ST2 during RT and three years after RT, and the associations with echocardiographic changes. Materials and methods We measured soluble ST2 (ng/ml) in serum samples from 63 patients receiving RT for early breast cancer. Sampling and echocardiography were performed at baseline, after RT and at the three-year follow-up. Patients were grouped by >15% (group 1) and ≤15% (group 2) relative worsening in global longitudinal strain (GLS). Results ST2 levels tended to increase during RT, from a median (interquartile range; IQR) of 17.9 (12.4–22.4) at baseline to 18.2 (14.1–23.5) after RT (p = 0.075). By the three-year follow up, ST2 levels increased to 18.7 (15.8–24.2), p = 0.018. The increase in ST2 level was associated with worsening cardiac systolic function at three-year follow-up, GLS (rho = 0.272, p = 0.034) and left ventricular ejection fraction (LVEF) (rho = ─0.343, p = 0.006). Group 1 (n = 14) had a significant increase in ST2 levels from 17.8 (12.3–22.5) at baseline to 18.4 (15.6–22.6) after RT, p = 0.035 and to 19.9 (16.0–25.1) three years after RT, p = 0.005. ST2 levels were stable in group 2 (n = 47): 17.8 (12.3–22.0) at baseline, 17.7 (12.6–23.5) after RT and 18.0 (15.5–22.4) at three years. Conclusion ST2 may be useful for determining which patients are at risk for long-term cardiovascular toxicity following adjuvant breast cancer RT, but prospective clinical studies are needed to confirm this hypothesis., Highlights • ST2 levels increase 3 years from adjuvant radiotherapy for breast cancer. • The increase in ST2 levels is associated with a worsening in global longitudinal strain (GLS). • Increase in ST2 levels is seen during radiotherapy in patients with a >15% change in GLS over 3 years.

BACKGROUND AND PURPOSE mPGES1 catalyses the production of PGE2 , the most abundant prostanoid related to inflammation and pain in arthritis. mPGES1 is suggested to be a safer and more selective drug target in inflammatory conditions compared to the COX enzymes inhibited by NSAIDs. In the present study, we investigated the effects of the selective mPGES1 inhibitor MF63 on gene expression in primary human chondrocytes from patients with osteoarthritis (OA). EXPERIMENTAL APPROACH Chondrocytes were isolated from articular cartilage obtained from osteoarthritis patients undergoing knee replacement surgery. The effects of MF63 were studied in the primary chondrocytes with RNA-sequencing based genome-wide expression analysis. The main results were confirmed with qRT-PCR and compared with the effects of the NSAID ibuprofen. Functional analysis was performed with the GO database and interactions between the genes were studied with STRING. KEY RESULTS MF63 enhanced the expression of multiple metallothionein 1 (MT1) isoforms as well as endogenous antagonists of IL-1 and IL-36. The expression of IL-6, by contrast, was down-regulated. These genes were also essential in functional and interaction network analyses. The effects of MF63 were consistent in qRT-PCR analysis, whereas the effects of ibuprofen overlapped only partly with MF63. There were no evident findings of catabolic effects by MF63. CONCLUSION AND IMPLICATIONS Metallothionein 1 has been suggested to have anti-inflammatory and protective effects in cartilage. Up-regulation of the antagonists of IL-1 superfamily and down-regulation of the pro-inflammatory cytokine IL-6 also support novel anti-inflammatory and possibly disease-modifying effects of mPGES1 inhibitors in arthritis.

OBJECTIVE To investigate the impact of anti-rheumatic medications on salivary matrix metalloproteinase (MMP)-8 levels and MMP-8/TIMP (tissue inhibitor of MMPs)-1 ratio in patients with rheumatoid arthritis (RA) and periodontal findings during a 1-year follow-up. MATERIALS AND METHODS Salivary MMP-8 was measured by an immunofluorometric assay and TIMP-1 by an enzyme-linked immunosorbent assay of 53 patients with early untreated RA (ERA), naive to synthetic disease modifying anti-rheumatic drugs (DMARDs), of 28 patients with chronic RA (CRA), candidates for biologic DMARDs and of 43 age- and sex-matched controls. Periodontal health was evaluated by bleeding on probing (BOP), pocket depth (PD), and periodontal inflammatory burden index (PIBI). Examinations were conducted twice for RA patients and once for controls. RESULTS Salivary MMP-8 level and MMP-8/TIMP-1 ratio associated positively with PIBI in patients with chronic RA (MMP-8: p

Patients with depression and alcohol use disorder frequently present with elevated markers of inflammation. Adipose tissue may function as a source for inflammation, yet the interplay between adiposity, alcohol use and depression has remained unknown. We examined 242 patients, referred to treatment for depressive symptoms, and followed for a period of 6 months. The assessments included screening for alcohol use and measurements of body mass index, serum adiponectin, leptin, resistin, progranulin, hs-CRP, IL-6 and MCP-1 at baseline and after 6 months of treatment. During follow-up, mean MADRS and AUDIT scores decreased significantly, whereas BMI increased. The changes in the levels of cytokines and adipokines were influenced by alcohol consumption and adiposity in a gender-dependent manner. The presence of AUD seemed to particularly influence the levels of cytokines. The levels of IL-6, hs-CRP, progranulin, and leptin differed between AUD and non-AUD groups at baseline, but no longer at 6 months. Baseline levels of leptin and resistin were higher in women and changes occurring in leptin, progranulin, and adiponectin were more notable in women. The data indicates significant gender-dependent interactions between depression, alcohol and mediators of inflammation, which should be considered in studies on the pathogenesis of depression and its comorbidities.

To study prospectively the association of salivary and serum matrix metalloproteinase (MMP)-8, tissue inhibitor of MMPs (TIMP)-1 and interleukin (IL)-6 with periodontal and systemic inflammation in rheumatoid arthritis (RA). We hypothesized that biomarker concentrations reflect inflammation.Fifty three early untreated RA (ERA) and 28 chronic RA (CRA) patients, underwent rheumatological and dental examinations at baseline and one year later after starting first conventional or biological disease modifying antirheumatic drug. We included 43 control subjects. Saliva and serum samples were analyzed for MMP-8, TIMP-1 and IL-6. Periodontal health was assessed by bleeding on probing (BOP), pocket depth (PD) and periodontal inflammatory burden index (PIBI); RA disease activity was assessed by disease activity score DAS28. Joint destruction was analyzed by the modified Sharp-van der Heijde (SHS) method.Serum MMP-8 (p .001; p .001) and IL-6 (p .001; p = .002) were significantly higher in CRA vs. other study groups during the study. Salivary MMP-8 (p = .010) and IL-6 (p = .010) were significantly higher in ERA vs. other study groups at baseline. Salivary MMP-8 was associated with periodontal parameters.Elevated serum concentrations of MMP-8 and IL-6 in CRA patients reflected chronic RA, while elevated salivary concentrations of MMP-8 levels in ERA patients reflected increased periodontal inflammation. Key messages Concentrations of inflammatory biomarkers in serum and saliva were different between patients with RA and healthy controls. Concentrations of MMP-8 and of IL-6 in serum were elevated in patients with chronic RA reflecting joint inflammation and the burden of established RA. Concentrations of MMP-8 in saliva was elevated already at the early stage of RA and the level of salivary MMP-8 was associated with poor periodontal health both in patients with early and in those with chronic RA.

Experimental and clinical reports highlight the role of cytokines in pathophysiological processes in underpinning epilepsy, but the clinical data remains somewhat limited. The levels of Interleukin (IL)-6 were measured in serum from 49 patients with refractory epilepsy [temporal lobe epilepsy (TLE, n=23), extratemporal lobe epilepsy (XLE, n=22), and idiopathic generalized epilepsy (IGE, n=4)] before and after the first verified seizure (IS; index seizure) during inpatient video-electroencephalographic (VEEG) monitoring. The levels of IL-6 increased significantly at all time points between 3h and 24h after the IS compared to the baseline. IL-6 concentrations were significantly higher at the 3h and 6h time point after tonic-clonic seizures (TCS) compared to the situation with simple partial and complex partial seizures. An IS duration longer than 100s, low baseline IL-6 level and10 seizures/month in patients with TLE were associated with an increase in IL-6 concentrations during the 24h after the IS. In patients with TLE, the maximum change in IL-6 levels after IS was significantly higher than in XLE. If the baseline level of IL-6 was low (under 5pg/ml), seizures induced a significant elevation in both absolute and relative values in TLE patients but not in XLE. In patients with ≤10 seizures per month during the last year, the maximum change was higher than in patients with10 seizures. If the total seizure burden during registration was ≥100s, the IL-6 increase was significantly higher than if it were under 100s. The results of this study highlight the complexity of factors involved in the seizure induced production of the inflammatory cytokine, IL-6. The major factor is the epilepsy type i.e. increased production of IL-6 in TLE compared to XLE. The response to a single seizure in TLE is dependent on the previous seizure frequency and the baseline IL-6 concentration.

Metabolic syndrome and related cardiovascular risk factors are well-known comorbidities among patients with schizophrenia. Biomarkers of these antipsychotic-associated metabolic adverse effects and antipsychotic-induced weight gain are needed. Glucagon-like peptide-1 (GLP-1) is involved in insulin secretion, regulation of satiety, inhibition of food intake, and inhibition of gastric emptying. GLP-1 also induces reduction in body weight. Visfatin/ NAMPT/ PBEF is an adipocytokine secreted by several cells and tissues. Increased plasma visfatin levels have been associated with overweight/obesity, type 2 diabetes mellitus, insulin resistance, metabolic syndrome and cardiovascular diseases, low grade inflammation, and proinflammatory markers. Associations between antipsychotic-induced weight gain and serum visfatin and GLP-1 levels have been little studied in patients with schizophrenia. The aim of the present study was to test the possible role of serum GLP-1 and visfatin level alterations as markers of weight gain in association with metabolic and inflammatory markers in 190 patients (109 male, 81 female) with schizophrenia on clozapine treatment. High serum levels of GLP-1 correlated significantly with higher levels of visfatin, leptin, insulin, HOMA-IR, higher BMI, and weight change among men. Associations between serum visfatin levels and BMI or weight change were not found in the present patients. Serum GLP-1 level seems to be a marker of metabolic risk factors among men with schizophrenia on clozapine treatment. Female patients may be more sensitive to suppressive effects of clozapine on GLP-1 secretion. Patients on clozapine would benefit from GLP-1 agonists as preventive treatment. publishedVersion

Intracellular signalling in blood leucocytes shows multiple aberrations in acute pancreatitis (AP) complicated by organ dysfunction (OD). We studied whether the aberrations associate with severity of AP and occur in sepsis complicated by OD. The study comprises 14 sepsis patients (11 with shock), 18 AP patients (nine mild; six moderately severe; three severe) and 28 healthy volunteers. Within 48 h after admission to hospital, phosphorylation of nuclear factor-ĸB (NF-ĸB), signal transducers and activators of transcription (STATs) 1,3, and extracellular signal-regulated kinases 1/2 were measured from stimulated or non-stimulated leucocytes using phosphospecific whole blood flow cytometry. In sepsis, as compared with healthy subjects, phosphorylated NF-ĸB levels of monocytes promoted by bacterial lipopolysaccharides, tumour necrosis factor or Escherichia coli cells were lower (P < 0.001 for all), pSTAT1 levels of monocytes promoted by IL-6 were lower (P < 0.05 for all), and STAT3 was constitutively phosphorylated in monocytes, neutrophils and lymphocytes (P < 0.001 for all). In AP, severity was associated with proportions of pSTAT1-positive monocytes and lymphocytes promoted by IL-6 (P < 0.01 for both), constitutive STAT3 phosphorylation in neutrophils (P < 0.05), but not with any of the pNF-ĸB levels. Monocyte pSTAT3 fluorescence intensity, promoted by IL-6, was lower in sepsis and AP patients with OD than in AP patients without OD (P < 0.001). Collectively, signalling aberrations in sepsis with OD mimic those described previously in AP with OD. Possibility that aberrations in STAT1 and STAT3 pathways provide novel markers predicting evolution of OD warrants studies including patients presenting without OD but developing it during follow-up.

AIM This study evaluated whether 15 allergy, immunology or inflammatory markers predicted the long-term use of cows' milk or milk products seven years after the start of oral immunotherapy (OIT) for cows' milk allergy in children. METHODS The following laboratory parameters were measured before the OIT at Tampere University Hospital, Finland, and after the six-month escalation phase: serum total immunoglobulin (Ig) E, milk-specific IgG and IgG4, eosinophil cationic protein, eosinophil-derived neurotoxin, interleukins 4, 5, 6, 10 and 12p70 and serum adipokines adiponectin, adipsin, leptin and resistin. Follow-up data from a seven-year phone questionnaire in 2015 were available for 24 children: 14 successful and 10 unsuccessful milk users. RESULTS There were no significant differences in any of the 15 markers measured at the start of the study between the subjects who later formed the successful and unsuccessful groups. At the end of the six-month escalation phase of OIT, serum adipsin was higher in the group who were unsuccessful milk users at the seven-year follow-up study. CONCLUSION None of the 15 allergy, immunology or inflammatory markers were useful in predicting the outcome of OIT. Preliminary evidence was found that high serum adipsin after the six-month escalation phase of OIT might predict unsuccessful outcome.

Aims This study explored whether growth was poorer among very low birth weight (VLBW) infants with bronchopulmonary dysplasia (BPD) and assessed adipokine levels as predictors of early growth. Methods We studied 53 VLBW infants born in Tampere University Hospital up to 12 months of corrected age (CA). The mean age of the 21 infants with BPD and 32 infants without BPD was 29 weeks and the mean weights were 930 (635-1,470) and 1,185 (650-1,470) grams. Growth parameters, macronutrients intake and plasma levels of adipokines were measured. Results BPD infants were lighter than controls until 36 weeks of CA, with catch-up growth achieved by three months of CA. Adipsin levels were lower in BPD infants at 28 days of postnatal age. High leptin levels seemed protective for low weight for height at nine months of CA. The duration of ventilator therapy predicted low weight for height, length for age and body mass index and BPD predicted low length for age at 12 months of CA. Conclusions Catch-up growth in VLBW infants with BPD was achieved by three months of CA, but adipokines played a limited role in predicting growth. Shortening ventilator therapy could help growth in VLBW infants. This article is protected by copyright. All rights reserved.

Objective Patients with aneurysmal subarachnoid hemorrhage (aSAH) experience high mortality and morbidity. Neuroinflammation causes brain damage expansion after aSAH. Due to the complexity of the inflammatory response multiple biomarkers are needed to evaluate its' progression. We studied inflammatory process after aSAH by measuring two inflammatory biomarkers, interleukin-6 (IL-6) and high-mobility group box 1 (HMGB1) at simultaneous time-points after aSAH. Methods In this prospective population-based study, IL-6 and HMGB1 were measured in aSAH patients (n = 47) for up to five days. Plasma concentrations of IL-6 and HMGB1 were measured at 0, 12 and 24 h after hospital admission, and thereafter daily for up to five days or until the patient was transferred from the intensive care unit (ICU). The patients' neurological outcomes were evaluated with the modified Rankin Scale at six months after aSAH. Results A high IL-6 level during the first day after aSAH was associated with a severe initial clinical presentation (p = 0.002) and infection during follow-up (p = 0.031). The HMGB1 level did not associate with these parameters. There was no correlation between IL-6 and HMGB1 levels at any time point during the follow-up. The concentrations of IL-6 and HMGB1 were not associated with neurological outcome. Conclusions High initial IL-6 values seem to reflect the intensity of the inflammatory response but not the brain damage per se. An early inflammatory response might even be beneficial since although elevated IL-6 levels were observed in patients with a more severe initial clinical presentation, they were not associated with neurological outcome. The lack of correlation between IL-6 and HMGB1 questions the role of macrophages in the process of the secretion of these inflammatory markers after aSAH, instead pointing to the activation of alternative pro-inflammatory pathways., Highlights • IL-6 reflects the intensity of inflammation after aSAH without association to neurological outcome. • Early inflammatory response might even be beneficial after aSAH. • Lack of correlation between IL-6 and HMGB1 questions the role of macrophages in inflammatory response after aSAH.

Objective Retinol binding protein 4 (RBP4) is a member of the lipocalin family and a vitamin A carrier in the blood. More recently, RBP4 has been described as an adipokine that is involved in insulin resistance and metabolic syndrome (MetS). As obesity, MetS and some adipokines contribute to the pathogenesis of osteoarthritis (OA), we investigated RBP4 in patients with OA. Materials and methods Cartilage, synovial fluid and blood samples were collected from 100 OA patients undergoing total knee replacement surgery. Primary chondrocytes and cartilage tissue were cultured to measure the RBP4 expression. The concentrations of RBP4, other adipokines (adipsin, adiponectin, leptin and resistin) and biomarkers of OA (COMP, MMP-1, MMP-3 and YKL-40) were measured by immunoassay, and gene expression was measured by next-generation RNA sequencing. Results The OA cartilage samples released RBP4 into the culture medium, and the levels correlated positively with the expression of the adipokines adipsin, adiponectin, leptin and resistin. RBP4 was the most prominently expressed of these adipokines in the OA chondrocytes, and the expression of the RBP4 receptors STRA6 (stimulated by retinoic acid gene homologue 6) and TLR4 (Toll-like receptor 4) was also detected. Within the cartilage culture medium, RBP4 showed a positive correlation with MMP-1, MMP-3 and YKL-40. RBP4 was also present in the synovial fluid from the OA patients and correlated positively with the concentrations of RBP4 found in the plasma and the cartilage culture medium. Plasma RBP4 concentrations also showed a positive correlation with MMP-3 and adipsin. Conclusions We show here, for the first time, that RBP4 is produced within OA joints and that it is associated with increased levels of adipokines and MMPs. The results suggest a role for RBP4 in the pathogenesis of OA and as a possible target for the disease-modifying drugs for the treatment of OA.

Background Angiopoietin growth factors (Angs) regulate angiogenesis and lymphangiogenesis by binding to the endothelial Tie2 receptor. Ang2 expression is elevated in tissue hypoxia and inflammation, which also induce cleavage of the extracellular domain of the orphan Tie1 receptor. Here we have examined if the concentrations of Ang2 and the soluble extracellular domain of Tie1 in patient plasma are associated with the prognosis of patients with metastatic breast cancer. Methods Plasma Tie1 and Ang2 levels were measured in metastatic breast cancer patients treated in a phase II trial with a taxane-bevacizumab combination chemotherapy in the first-line treatment setting. They were analyzed before treatment, after 6 weeks and 6 months of treatment, and at the final study visit. Using the median concentrations as cutoffs, Tie1 and Ang2 data were dichotomized into low and high concentration groups. Additionally, we analyzed Tie1 concentrations in plasma from 10 healthy women participating in a breast cancer primary prevention study. Results Plasma samples were available from 58 (89%) of the 65 patients treated in the trial. The baseline Tie1 levels of the healthy controls were significantly lower than those of the metastatic patients (p

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) are the most widely used medicines globally. NSAIDs relieve pain (analgesic effect) and fever (antipyretic effect). They have also some anti-inflammatory properties, but as anti-inflammatory, they are noticeably less potent than GLUCOCORTICOIDS or DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS (DMARDs). Non-selective NSAIDs also inhibit PLATELET aggregation, and acetylsalicylic acid (aspirin, ASA) is used in the (secondary) prevention of myocardial infarction and stroke.

[Abstract] Objective: To update and expand upon prior Osteoarthritis Research Society International (OARSI) guidelines by developing patient-focused treatment recommendations for individuals with Knee, Hip, and Polyarticular osteoarthritis (OA) that are derived from expert consensus and based on objective review of high-quality meta-analytic data. Methods: We sought evidence for 60 unique interventions. A systematic search of all relevant databases was conducted from inception through July 2018. After abstract and full-text screening by two independent reviewers, eligible studies were matched to PICO questions. Data were extracted and meta-analyses were conducted using RevMan software. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Evidence Profiles were compiled using the GRADEpro web application. Voting for Core Treatments took place first. Four subsequent voting sessions took place via anonymous online survey, during which Panel members were tasked with voting to produce recommendations for all joint locations and comorbidity classes. We designated non-Core treatments to Level 1A, 1B, 2, 3, 4A, 4B, or 5, based on the percentage of votes in favor, in addition to the strength of the recommendation. Results: Core Treatments for Knee OA included arthritis education and structured land-based exercise programs with or without dietary weight management. Core Treatments for Hip and Polyarticular OA included arthritis education and structured land-based exercise programs. Topical non-steroidal anti-inflammatory drugs (NSAIDs) were strongly recommended for individuals with Knee OA (Level 1A). For individuals with gastrointestinal comorbidities, COX-2 inhibitors were Level 1B and NSAIDs with proton pump inhibitors Level 2. For individuals with cardiovascular comorbidities or frailty, use of any oral NSAID was not recommended. Intra-articular (IA) corticosteroids, IA hyaluronic acid, and aquatic exercise were Level 1B/Level 2 treatments for Knee OA, dependent upon comorbidity status, but were not recommended for individuals with Hip or Polyarticular OA. The use of Acetaminophen/Paracetamol (APAP) was conditionally not recommended (Level 4A and 4B), and the use of oral and transdermal opioids was strongly not recommended (Level 5). A treatment algorithm was constructed in order to guide clinical decision-making for a variety of patient profiles, using recommended treatments as input for each decision node. Conclusion: These guidelines offer comprehensive and patient-centered treatment profiles for individuals with Knee, Hip, and Polyarticular OA. The treatment algorithm will facilitate individualized treatment decisions regarding the management of OA.

Objective Interleukin-6 (IL-6) has been reported to be elevated in major depressive disorder (MDD) but decreased by antidepressive medication. IL-6 levels are markedly elevated both after epileptic seizures and single electroconvulsive therapy (ECT) session, but long-term changes in IL-6 levels after ECT have not been studied. The correlation between immediate and long-term changes in proinflammatory cytokines and outcome after ECT was investigated. Method Thirty patients suffering from MDD participated in the study. IL-6, interleukin-1β (IL-1β) and interleukin-1 receptor antagonist (IL-1RA) levels were examined at baseline and at 2 and 4 h after the first, fifth and the last ECT sessions. The response to ECT was measured with Montgomery-Asberg Depression Rating Scale (MADRS). Results ECT repeatedly caused an increase in IL-6 levels at the 4-h time point. However, the baseline IL-6 levels decreased among remitters, but not among non-remitters, towards the end of ECT. IL-1β levels were mostly below detectable level, and IL-1Ra levels did not change during and after ECT. Conclusion ECT has distinct acute and long-term effects on IL-6 levels. Interestingly, the long-term effect of ECT on IL-6 seems to correlate with outcome, providing further evidence of the mechanism of action of ECT and supporting the inflammation theory in MDD.

Aim Oral immunotherapy (OIT) is a promising but still experimental method to treat children with cow's milk (CM) allergy (CMA). We evaluated changes in allergic, immunological and inflammatory parameters, which happened during the six-month OIT for CMA. Methods We treated 28 school-aged children with CMA using OIT with a double-blind placebo-controlled design. After the controlled study finished, the placebo group was treated with the same but open-label OIT protocol. Sixteen immune variables were tested before and after the six-month OIT. Results Before OIT, the median serum CM-specific immunoglobulin (Ig) E was 18.0kIU/L in the intervention group and 9.4kIU/L in the placebo group (p=0.46). At six months, interleukin (IL)-6 and IL-10 were significantly higher in the intervention group. When the changes during the blinded and open OIT were analyzed together for both groups, blood eosinophils and serum total IgE decreased and milk-specific IgG and IgG4, serum IL-4 and IL-6, and serum leptin and resistin increased significantly. Conclusion Preliminary evidence was found that markers of allergy like blood eosinophils and serum IgE decreased and milk-specific IgG and IgG4 increased during OIT. Adipokines leptin and resistin, which functionally are cytokines linked to Th1-type response, increased during OIT. This article is protected by copyright. All rights reserved.

Schizophrenia is associated with excess cardiovascular comorbidity and mortality related to lifestyle factors, such as lack of physical activity, poor diet, and smoking. The prevalence of metabolic syndrome is increased among patients with schizophrenia, with the highest rates among patients on clozapine treatment. Smoking, obesity, physical inactivity, airway inflammation and obstruction, and adipose tissue and inflammatory marker activation are related in systemic inflammation. Low-grade inflammation is also associated with schizophrenia. Adipokine resistin is a biomarker involving several acute and chronic inflammatory states. However, the inflammatory role of resistin is so far inconclusive and studies in schizophrenia are scanty.The aim of the present study was to explore the role of serum resistin as an inflammatory marker in patients with schizophrenia on clozapine treatment.Associations between serum levels of resistin and some other selected cytokines/adipokines (adiponectin, leptin, adipsin, IL-6, IL-1Ra, TNF-α, hs-CRP) and metabolic markers in 190 patients with schizophrenia on clozapine treatment were studied using a cross-sectional study design.Among male patients especially, smokers had higher levels of resistin than non-smokers, and among smokers resistin levels were associated with IL-1Ra and hs-CRP levels. In the whole patient group levels of resistin associated with levels of IL-1Ra, and among male patients with low HDL-cholesterol.Resistin is a biomarker of systemic inflammation associated with smoking among patients with schizophrenia on clozapine treatment. Resistin might have a role as a marker of cardiovascular comorbidity.

Background: Interleukin (IL)-8 is a proinflammatory cytokine, and high levels of IL-8 are associated with poor prognosis in many malignancies. The objective of this study was to explore the clinical benefit of monitoring plasma IL-8 levels during breast cancer chemotherapy. Patients and Methods: We conducted an exploratory analysis of several circulating proteins, including IL-8, in the plasma. Plasma samples were obtained from 58 metastatic breast cancer patients who took part in a prospective phase 2 first-line bevacizumab chemotherapy trial. Samples were analyzed before therapy, after 6 weeks and 6 months of treatment, and at the final study visit. On the basis of a trajectory analysis of the plasma IL-8 levels, the patients were divided into 3 trajectory groups. Results: Plasma IL-8, IL-6, IL-18, matrix metalloproteinase (MMP)-2, MMP-9, YKL-40, resistin, and high-mobility group box 1 (HMGB1) concentrations were measured, and the most pronounced predictor of patient survival was IL-8. On the basis of the trajectory analysis of the IL-8 levels, the majority of patients (n = 35, 60%) belonged to trajectory group 1, and these patients had significantly lower IL-8 levels before and during the entire chemotherapy treatment period than did the patients in the other groups. Trajectory group 1 patients had significantly better overall survival compared to patients in trajectory group 2 (n = 17; age-adjusted HR = 2.45; 95% confidence interval, 1.21–5.97; P = .012) and 3 (n = 6; age-adjusted HR = 8.65; 95% confidence interval, 3.16–23.7; P < .001). Conclusion: Low IL-8 levels during chemotherapy treatment might help identify patients with prolonged survival.

Interleukin-6 (IL-6) is involved in the pathogenesis of various inflammatory diseases, like rheumatoid arthritis (RA). In the present study, we investigated the role of IL-6 in osteoarthritis (OA) patients and the effects of the stilbenoids monomethyl pinosylvin and pinosylvin on the expression of the cartilage matrix components aggrecan and collagen II and the inflammatory cytokine IL-6 in human OA chondrocytes. Synovial fluid and plasma samples were obtained from 100 patients with severe&thinsp, OA [BMI 29.7 (8.3) kg/m2, age 72 (14) years, median (IQR), 62/38 females/males] undergoing total knee replacement surgery. IL-6 and matrix metalloproteinase (MMP) concentrations in synovial fluid and plasma were measured by immunoassay. The effects of pinosylvin on the expression of IL-6, aggrecan, and collagen II were studied in primary cultures of human OA chondrocytes. IL-6 levels in synovial fluid from OA patients [119.8&thinsp, (193.5) pg/mL, median (IQR)] were significantly increased as compared to the plasma levels [3.1 (2.7) pg/mL, median (IQR)] and IL-6 levels in synovial fluid were associated with MMPs and radiographic disease severity. Natural stilbenoids monomethyl pinosylvin and pinosylvin increased aggrecan expression and suppressed IL-6 production in OA chondrocytes. The results propose that IL-6 is produced within OA joints and has an important role in the pathogenesis of OA. Stilbenoid compounds monomethyl pinosylvin and pinosylvin appeared to have disease-modifying potential in OA chondrocytes.

Background: Transient receptor potential ankyrin 1 (TRPA1) is an ion channel known to mediate nociception and neurogenic inflammation, and to be activated by reactive oxygen and nitrogen species (ROS and RNS) produced at the sites of inflammation. Because neurogenic inflammation as well as the release of ROS and RNS are typical features of early stages of allergic responses, we hypothesized that TRPA1 may be involved in triggering and/or amplifying allergic inflammation. Objective: This study aims at exploring the role of TRPA1 ion channel in acute ovalbumin-induced allergic inflammation in applicable murine models. Methods: The effects of pharmacological blockade and genetic deletion of TRPA1 in ovalbumin-induced allergic conjunctivitis and acute paw inflammation were studied in mice sensitized to ovalbumin. Results: Ovalbumin-induced allergic conjunctivitis was milder in TRPA1-deficient mice and alleviated in wild-type mice treated with the TRPA1 antagonist TCS 5861528. Subcutaneous challenge with ovalbumin caused a significant paw edema and interleukin (IL)-4 production in sensitized mice; these responses were attenuated in animals treated with the TRPA1 antagonist and in TRPA1-deficient mice. Interestingly, blockade of the major secondary effector of TRPA1, substance P, also resulted in attenuated ovalbumin-induced paw edema and IL-4 production. However, the splenocytes’ responses to ovalbumin were similar in cells from wild-type and TRPA1-deficient mice sensitized to ovalbumin. Conclusion: These results introduce a novel concept that TRPA1 mediates early events in allergic inflammation, but does not seem to affect allergic sensitization, and could therefore be a novel drug target to treat conditions associated with allergic inflammation.

To study oral health in patients with rheumatoid arthritis (RA) with emphasis on disease activity and treatment of RA. In this prospective cohort study 81 RA patients [53 early untreated RA (EURA) and 28 chronic RA (CRA) patients with inadequate response to synthetic disease modifying antirheumatic drugs (DMARDs)], underwent rheumatological [Disease Activity Score (28-joint) DAS28] and dental examinations [Total Dental Index (TDI), Decayed Missing Filled Teeth (DMFT) and Decayed Missing Filled Surfaces (DMFS)]. For controls, 43 volunteers were examined. After the examinations, EURA patients started treatment with synthetic DMARDs, oral and intra-articular glucocorticoids. CRA patients were candidates for biological DMARDs. The patients were re-examined mean 16 months later. Results were analyzed with descriptive statistics and logistic regression. TDI was higher in both RA groups at baseline compared to controls [EURA: 2 (2-3); CRA: 2 (1-3); controls 1 (1-3), p = 0.045]. DMFT [r(s) 0.561 (p = 0.002)] and DMFS [r(s) 0.581 (p = 0.001)] associated with DAS28 at baseline in CRA patients. After follow-up, DAS28 associated positively with DMFT [r(s) 0.384 (p = 0.016)] and DMFS [r(s) 0.334 (p = 0.038)] in EURA patients; as well as in CRA patients DMFT [r (s) 0.672 (p = 0.001)], DMFS [r(s) 0.650 (p = 0.001)]. RA patients already in the early phase of the disease had poorer oral health compared to controls. The caries indices associated with the activity of RA in both patient groups. Oral status may thus contribute to the development and further relate to the activity of RA.

Background Radiation-induced heart disease is mainly caused by activation of the fibrotic process. Transforming growth factor-beta 1 (TGF-β1) and platelet-derived growth factor (PDGF) are pro-fibrotic mediators. The aim of our study was to evaluate the behavior of TGF-β1 and PDGF during adjuvant radiotherapy (RT) for breast cancer and the association of these cytokines with echocardiographic changes. Methods Our study included 73 women with early-stage breast cancer or ductal carcinoma in situ (DCIS) receiving post-operative RT but not chemotherapy. TGF-β1 and PDGF levels in serum samples taken before and on the last day of RT were measured by an enzyme-linked immunosorbent assay. Echocardiography was also performed at same time points. Patients were grouped according to a ≥ 15% worsening in tricuspid annular plane systolic excursion (TAPSE) and pericardium calibrated integrated backscatter (cIBS). Results In all patients, the median TGF-β1 decreased from 25.0 (IQR 21.1–30.3) ng/ml to 23.6 (IQR 19.6–26.8) ng/ml (p = 0.003), and the median PDGF decreased from 18.0 (IQR 13.7–22.7) ng/ml to 15.6 (IQR 12.7–19.5) ng/ml (p

Objectives Brain‐derived neurotrophic factor (BDNF) has been associated with depression and its treatment response. The aim of the present study was to explore the effect of electroconvulsive therapy (ECT) on serum and plasma BDNF levels and change of Montgomery–Asberg Depression Rating Scale (MADRS) and their associations in patients with major depressive disorder (MDD). Methods The study included thirty patients suffering from MDD. Their serum and plasma BDNF levels were examined before ECT (baseline) and after the first, fifth, and last ECT session. The severity of the depression and the response to ECT were measured with MADRS. Results Electroconvulsive therapy caused no significant changes in serum BDNF levels. Plasma BDNF levels decreased during the fifth ECT session between the baseline and the 2‐hr samples (p = 0.019). No associations were found between serum or plasma BDNF levels and remission. The correlations between plasma and serum BDNF levels in each measurement varied between 0.187 and 0.636. Conclusions Neither serum nor plasma BDNF levels were systematically associated with the clinical remission. However, the plasma BDNF levels somewhat varied during the ECT series. Therefore, the predictive value of BDNF for effects of ECT appears to be at least modest.

Joint replacement surgery is a standard treatment of advanced osteoarthritis (OA). Since 2000, cobalt-chromium (CoCr) metal-on-metal (MoM) implants were widely used in hip arthroplasties. Some patients developed "adverse reaction to metal debris" (ARMD) around the prosthesis, resulting in a need for revision surgery. In the present study, we addressed the pathogenesis of ARMD by genome-wide expression analysis. Pseudosynovial ARMD tissue was obtained from revision surgery of Articular Surface Replacement (ASR, DePuy, Warsaw, IN, USA) hip arthroplasties. Control tissue was 1) OA synovium from primary hip arthroplasties and 2) inflammatory pseudosynovial tissue from metal-on-plastic (MoP) implant revisions. In ARMD tissue, the expression of 1446 genes was significantly increased and that of 1881 decreased as compared to OA synovium. Genes associated with immune response, tissue development and certain leukocyte signaling pathways were enriched in the differently (FC > 2) expressed genes. The network analysis proposed PRKACB, CD2, CD52 and CD53 as the central regulators of the greatest (FC > 10) differences. When ARMD tissue was compared to MoP tissue, the expression of 16 genes was significantly higher and that of 21 lower. Many of these genes were associated with redox homeostasis, metal ion binding and transport, macrophage activation and apoptosis. Interestingly, genes central to myofibroblast (AEBP1 and DES) and osteoclast (CCL21, TREM2 and CKB) development were upregulated in the MoP tissue. In network analysis, IL8, NQO1, GSTT1 and HMOX1 were identified as potential central regulators of the changes. In conclusion, excessive amounts of CoCr debris produced by MoM hip implants induces in a group of patients a unique adverse reaction characterized with enhanced expression of genes associated with inflammation, redox homeostasis, metal ion binding and transport, macrophage activation and apoptosis.

OBJECTIVES Perioperative myocardial infarction (MI) with ischaemia-reperfusion injury (IRI) is a devastating entity occurring in 1-2% of patients after cardiac surgery. The molecular pathway leading to myocardial cellular destruction after MI may include monoamine oxidases. We experimentally investigated whether moclobemide, a monoamine oxidase inhibitor, enhances myocardial recovery after cardiac arrest and MI. METHODS Fifty-six syngeneic Fischer rats underwent heterotopic cardiac transplantation to induce reversible IRI after cardiac arrest. Twenty-eight rats also underwent permanent ligation of the left anterior descending coronary artery to induce MI after cardiac arrest. Twenty-eight rats with or without MI were treated with subcutaneous moclobemide 10 mg/kg/day. Methods used to study myocardial recovery were microdialysis for intramyocardial metabolism, histology and quantitative reverse-transcription polymerase chain reaction for high-mobility group box-1 (HMGB1), haeme oxygenase-1 (HO-1), interleukin-6, hypoxia-inducible factor 1α and macrophages (CD68). RESULTS Pyruvate increased in MI treated with moclobemide versus IRI with moclobemide (29.19 ± 7.64 vs 13.86 ± 8.49 µM, P = 0.028), reflecting metabolic activity after cardiac arrest and reperfusion. Myocardial inflammation increased in MI compared with IRI after 1 h (0.80 ± 0.56 vs 0, point score units [PSUs], P = 0.003), but decreased after 5 days in MI treated with moclobemide versus MI alone (0.80 ± 0.83 vs 2.00 ± 0.70, PSU, P = 0.033). Expressions of HMGB1, CD68 and HO-1 decreased in MI treated with moclobemide versus MI alone (1.33 ± 0.20 vs 1.75 ± 0.24, fold changes [FCs], P = 0.028; 5.15 ± 1.10 vs 9.59 ± 2.75, FC, P = 0.050; 10.41 ± 4.17 vs 21.28 ± 10.01, FC, P = 0.047), indicating myocardial recovery and increased cellularity of remote intramyocardial arteries. CONCLUSIONS Moclobemide enhances myocardial recovery after cardiac arrest and MI; inhibition of remote myocardial changes may be achieved by targeting treatment against monoamine oxidase.

Low mitochondrial number and activity have been suggested as underlying factors in obesity, type 2 diabetes, and metabolic syndrome. However, the stage at which mitochondrial dysfunction manifests in adipose tissue after the onset of obesity remains unknown. Here we examined subcutaneous adipose tissue (SAT) samples from healthy monozygotic twin pairs, 22.8–36.2 years of age, who were discordant (ΔBMI >3 kg/m2, mean length of discordance 6.3 ± 0.3 years, n = 26) and concordant (ΔBMI

Fibroblast growth factor (FGF)-2 is a member of the FGF family and is found in the synovial fluid of patients with osteoarthritis (OA). The aim of this study was to investigate the effects of FGF-2 on human OA cartilage/chondrocytes by examining the association between FGF-2 and the cartilage degrading enzymes matrix metalloproteinase (MMP)-1 and MMP-13 and the major cartilage matrix components aggrecan and collagen II.Cartilage samples were obtained from 97 OA patients undergoing total knee replacement surgery. Cartilage tissue cultures were conducted and levels of FGF-2, MMP-1, and MMP-13 released into the culture medium were measured by immunoassay. The effects of FGF-2 on the expression of MMP-1, MMP-13, aggrecan, and collagen II were further investigated in cultures of primary human OA chondrocytes.FGF-2, MMP-1, and MMP-13 were released into the culture medium from cartilage samples obtained from patients with OA. FGF-2 concentrations correlated positively with the concentrations of MMP-1 (r = 0.414, p0.001) and MMP-13 (r = 0.362, p0.001). FGF-2 also up-regulated the production of MMP-1 and MMP-13, and down-regulated the expression of aggrecan and collagen II, in human OA chondrocyte cultures. Furthermore, FGF receptor antagonists AZD4547 and NVP-BGJ398 down-regulated the expression of MMP-1 and MMP-13 and up-regulated aggrecan and collagen II both in the absence and in the presence of exogenous FGF-2.Our results suggest that, in contrast to its growth factor-like effects in some other tissues, FGF-2 induces catabolic effects in human OA cartilage. Moreover, FGF receptor antagonists showed promising beneficial effects on the balance of catabolic and anabolic factors within OA cartilage.

To assess whether cumulative dust exposure in foundry work is associated with airway inflammation measured by the analysis of fractionated exhaled nitric oxide (NO) concentration, or by inflammatory markers in exhaled breath condensate or serum.We examined 476 dust-exposed and nonexposed foundry workers, and assessed the individual cumulative exposure to dusts and respirable quartz. Bronchial and alveolar NO production and inflammatory markers in exhaled breath condensate and in serum samples were also analyzed.After adjusting for pack-years of smoking, increased levels of alveolar NO, serum C-reactive protein, and interleukin-8 were associated with a higher level of cumulative exposure to dust. The referents had higher serum myeloperoxidase levels, bronchial NO output, and 8-isoprostane levels in exhaled breath condensate than in the dust-exposed groups.Dust exposure in foundry work may induce both systemic and alveolar inflammation.

Purpose Adipokines, especially leptin and adiponectin, have gained increasing importance in pathophysiology of various neurological diseases including epilepsy. There are experimental data suggesting a role for leptin in the genesis of seizures and neuroprotection related to seizures. However there are no clinical studies on the effects of epileptic seizures on adipokines. Methods We measured cerebrospinal fluid (CSF) and plasma levels of leptin, adiponectin and adipsin after provoked or unprovoked primary or secondarily generalized tonic–clonic seizures in 13 female patients and seven controls. The samples were taken within 24h after the seizure onset. Results Leptin plasma levels correlated negatively with the time to sample withdrawal, i.e. the longer the time interval between the seizure and the sample the lower the leptin levels in the patients. Interestingly, plasma adiponectin levels were significantly increased after the seizure episode. Conclusion This study provides further evidence that there are seizure-induced acute changes in adipokine metabolism. Leptin concentrations seem to decrease during the first 24h after the seizure whereas adiponectin levels increase. The meaning of this response is far from clear, but it might be an endogenous attempt to prevent harmful effects of epileptic seizures in the central nervous system.

The studies on the relationship between alcohol consumption, the status of inflammation, and depression have produced conflicting results. In this study, we followed patients with major depressive disorders by monitoring biomarkers of inflammation together with biomarkers of heavy alcohol use.The levels of IL-6 (interleukin-6), IL-8 (interleukin-8), hs-CRP (high sensitivity C-reactive protein), YKL-40 (also known as Chitinase-3-like protein 1 or CHI3L1), and biomarkers of alcohol consumption and liver status (GT, CDT, ALT, alkaline phosphatase) were measured at baseline and after 6 months of psychiatric treatment from 242 patients suffering from current major depressive disorder (MDD) with (n = 99) or without (n = 143) alcohol use disorder (AUD).At baseline, the patients with MDD + AUD showed higher levels of inflammatory biomarkers IL-6 (p 0.001), hs-CRP (p 0.01), YKL-40 (p 0.05), and biomarkers of alcohol consumption, than the corresponding group of non-AUD patients. These differences disappeared during follow-up and recovery from depression. The level of IL-8 decreased significantly in both AUD (p 0.05) and non-AUD (p 0.05) patients. During follow-up, the biomarkers of alcohol consumption, GT and CDT, in AUD patients were found to decrease in parallel with serum YKL-40 levels.Alcohol consumption appears to modulate the status of inflammation in depressive patients. A more systematic use of biomarkers of inflammation together with biomarkers of alcohol consumption and liver status may prove to be of value in a more comprehensive assessment and treatment of patients with depression.

Aim To identify patients with breast cancer at risk for cardiotoxicity, we evaluated homoarginine (HA) behavior during adjuvant treatment. Patients and methods Eighty-one patients received radiotherapy (RT) with or without endocrine treatment, and 19 received chemotherapy, RT and endocrine therapy. Serum HA, asymmetric dimethylarginine (ADMA) and high-sensitivity cardiac troponin T (hscTnT) were measured and echocardiography was performed before chemotherapy, and before and after RT. Results In chemo-naive tamoxifen users HA increased during RT from a median (IQR) of 2.47 (1.61-3.35) to 2.86 (1.93-4.23) μM (p=0.028) and remained stable in patients with aromatase inhibitor and in those without endocrine therapy. Tamoxifen users were mostly spared from echocardiographic changes. In chemotherapy-treated patients, HA decreased during chemotherapy (p=0.001) from 1.46 (1.01-2.18) to 0.91 (0.71-1.29) μM, and increased (p=0.004) to 1.19 (0.83-1.63) μM during RT, remaining lower than at baseline (p=0.014). Echocardiographic changes were observed during chemotherapy. Conclusion HA decrease during chemotherapy could indicate an increased risk of cardiovascular morbidity. Additionally, HA increase in tamoxifen users may reflect a cardioprotective effect of tamoxifen.

INTRODUCTION Assessment of the central and peripheral nitric oxide (NO) dynamics of the lung provides information on the severity and anatomical site of pulmonary inflammation. Several mathematical methods for calculating alveolar and bronchial NO parameters have been introduced. Our aim was to compare these methods. METHODS The study included 69 healthy adults, 66 healthy children, 73 asbestos-exposed subjects and 72 subjects with chronic obstructive pulmonary disease (COPD). Exhaled NO was measured at multiple flow rates and we used five mathematical methods (Tsoukias and George, Pietropaoli, Condorelli, Hogman and Merilainen, and Silkoff) to estimate alveolar and bronchial NO parameters. RESULTS The Hogman and Merilainen method was less frequently feasible than the other methods but it had the highest degree of agreement with the measured data. The methods were most often feasible in healthy or asbestos-exposed adults but distinctly more infrequently in children and adults with COPD, suggesting difficulties in NO measurements in these groups. The linear methods (Tsoukias and George, Pietropaoli) yielded higher alveolar NO concentration and lower bronchial NO flux than the two non-linear methods (Hogman and Merilainen, Silkoff) and a linear method with correction for axial back-diffusion of NO (Condorelli). CONCLUSION In differentiating central and peripheral NO sources we recommend using linear methods, as low flow rates are not needed and the feasibility of the methods is good. If bronchial wall NO concentration (C awNO) and diffusing capacity (D awNO) are of interest, non-linear methods are needed, and we recommend using the Hogman and Merilainen method as only three flow rates are needed. However, the agreement between the model and measured data needs to be checked in real time to ensure feasibility. If the subject has difficulties with the extremely low or high flow rates, we then recommend using the Silkoff method to improve feasibility, but more flow rates and measurements are then needed and the agreement between the model and the measured data may be poorer.

YKL-40 is an inflammation-associated glycoprotein supposed to have a role in cell survival and angiogenesis. Renal cell carcinoma (RCC) is characterized by varying prognosis and risk of relapse after a disease-free period of years. Prognostic markers are critically needed. This study investigated whether YKL-40 could be a useful biomarker in RCC patients.Blood samples from 82 patients with RCC were collected at the time of diagnosis and 3, 5 and 9 months and 2 and 3 years after nephrectomy. YKL-40 levels were determined by enzyme-linked immunosorbent assay. Survival of patients and relapse of RCC were followed up to 15 years.Circulating YKL-40 levels were increased in patients with metastatic RCC at the time of diagnosis (median 115.7 ng/ml, interquartile range 61.0-221.6 ng/ml). Among patients primarily diagnosed with non-metastatic RCC, baseline YKL-40 levels were significantly higher in patients who experienced a relapse during follow-up (103.7, 59.3-242.0 ng/ml) than in patients without relapse (50.6, 33.8-97.1 ng/ml). High baseline YKL-40 was highly associated with poor prognosis in RCC: in age-adjusted univariate analysis, YKL-40 over 120 ng/ml (highest tertile) predicted over five-fold mortality in 5 years, and in multivariate analysis high YKL-40 remained a statistically significant independent risk factor for 5 and 15 year survival.Increased circulating YKL-40 levels were significantly associated with poor survival in patients with RCC. The results suggest YKL-40 as a useful novel biomarker in evaluating prognosis and relapse risk in RCC, being especially beneficial in patients primarily diagnosed with non-metastatic RCC.

Osteoarthritis (OA) has long been viewed as a degenerative “wear-and-tear” disease of cartilage. There is, however, increasing evidence to confirm that inflammation has a critical role in the pathogenesis and symptoms of the disease. Inflammation in osteoarthritis is distinct from that typical for rheumatoid arthritis; it is generally low-grade in its nature but characterized by exacerbations with joint effusions and more severe symptoms. Osteoarthritis shares many features of innate immunity but the inflammatory mechanisms eventually leading to anatomical and functional changes and symptoms typical for osteoarthritis are not known in detail; but their further understanding is essential for the development of disease-modifying treatments for osteoarthritis. Transient receptor potential ankyrin 1 (TRPA1) is a ligand-gated membrane-bound cation channel. It has been widely studied in sensory neurons where it acts as a chemosensor for harmful exogenous compounds and mediates pain and neurogenic inflammation. More recently, TRPA1 has been found to be activated also by endogenous compounds formed in inflammation, such as reactive oxygen and nitrogen species. That prompted us to investigate the role of TRPA1 in inflammatory conditions including osteoarthritis. Monosodium iodoacetate (MIA) -induced arthritis is a widely used animal model of osteoarthritis. We found that MIA evoked acute inflammation, degenerative cartilage changes and joint pain in wild type mice; but interestingly, those responses were significantly attenuated in TRPA1 deficient animals. Furthermore, TRPA1 was found to be expressed and inducible by inflammatory factors including IL-1 and IL-17 in primary human OA chondrocytes; and the TRPA1 channel was shown to be functional based on calcium influx assays. Pharmacological inhibition and genetic depletion of TRPA1 downregulated the production of inflammatory factors and MMP enzymes in mouse cartilage and primary human OA chondrocytes. The present results introduce TRPA1 as a plausible factor involved in the pathogenesis of OA and provide a novel target for analgesic and anti-inflammatory drugs with disease modifying potential in OA. Disclosure of Interest None declared

Background Scleroderma is a chronic connective tissue disease of unknown aetiology. In early stages, vascular injury and inflammation lead to fibrosis, resulting in irreversible damage in various organs. Inflammation is believed to be necessary in order to activate fibroblasts to over-produce extracellular matrix components. At the present, there is no effective standard treatment to reverse or slow down the progression of scleroderma but one of the feasible approaches is to target key inflammatory pathways that are involved in the pathogenesis of the disease. MKP-1 (Mitogen-Activated Protein Kinase Phosphatase-1) is a nuclear phosphatase present in most cell types and tissues. Studies with MKP-1 deficient mice have undoubtedly shown that MKP-1 is an important regulator of innate and adaptive immune responses to limit and suppress inflammation (1) but its role in fibrosing diseases has not been studied. Objectives In the present study, we aimed to investigate the potential protective role of MKP-1 in the pathogenesis of scleroderma by using MKP-1 deficient mice and a widely studied experimental model of scleroderma. Methods We used bleomycin-induced dermal fibrosis in the mouse as an experimental model of scleroderma (2). Wild type (WT) and MKP-1 deficient mice were injected subcutaneously with bleomycin every other day for 28 days. Dermal thickness and collagen accumulation were determined by histological analyses. The expression of several inflammatory and pro-fibrotic mediators were measured by quantitative RT-PCR. Results We found that bleomycin-induced dermal thickness and lipodystrophy were increased in MKP-1 deficient mice. Collagen accumulation in the dermis and mRNA expression of collagens 1A1 and 3A1 were enhanced in the skin from MKP-1 deficient mice as compared to the skin from WT animals. Affected skin from MKP-1 deficient mice presented increased expression of factors related to inflammation and fibrosis, namely IL-6, TGF-β1, fibronectin-1 and YKL-40 as well as chemokines MCP-1, MIP-1α and MIP-2. Conclusions This study demonstrates, for the first time, that MKP-1 deficient mice develop more severe bleomycin-induced dermal fibrosis than their WT counterparts, indicating that MKP-1 regulates the inflammatory and fibrotic processes typical for experimentally-induced scleroderma. These findings suggest that compounds which enhance expression/activity of MKP-1 have potential as novel drugs for the stage-specific modulation of the pathogenesis of scleroderma. References Korhonen R, Moilanen E. Mitogen-activated protein kinase phosphatase 1 as an inflammatory factor and drug target. Basic Clin Pharmacol Toxicol. 2014; 114:24–36. Yamamoto T et al. Animal model of sclerotic skin. I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma. J Invest Dermatol. 1999; 112:456–62. Disclosure of Interest None declared

Object Aneurysmal subarachnoid hemorrhage (aSAH) is a common cause of death or long-term disability. Despite advances in neurocritical care, there is still only a very limited ability to monitor the development of secondary brain injury or to predict neurological outcome after aSAH. Soluble urokinase-type plasminogen activator receptor (suPAR) has shown potential as a prognostic and as an inflammatory biomarker in a wide range of critical illnesses since it displays an association with overall immune system activation. This is the first time that suPAR has been evaluated as a prognostic biomarker in aSAH. Methods In this prospective population-based study, plasma suPAR levels were measured in aSAH patients (n = 47) for up to 5 days. suPAR was measured at 0, 12, and 24 h after patient admission to the intensive care unit (ICU) and daily thereafter until he/she was transferred from the ICU. The patients’ neurological outcome was evaluated with the modified Rankin Scale (mRS) at 6 months after aSAH. Results suPAR levels (n = 47) during the first 24 h after aSAH were comparable in groups with a favorable (mRS 0–2) or an unfavorable (mRS 3–6) outcome. suPAR levels during the first 24 h were not associated with the findings in the primary brain CT, with acute hydrocephalus, or with antimicrobial medication use during 5-days’ follow-up. suPAR levels were associated with generally accepted inflammatory biomarkers (C-reactive protein, leukocyte count). Conclusion Plasma suPAR level was not associated with either neurological outcome or selected clinical conditions. While suPAR is a promising biomarker for prognostication in several conditions requiring intensive care, it did not reveal any value as a prognostic biomarker after aSAH.

Patients with rheumatoid arthritis (RA) have increased oxidative stress, decreased antioxidant levels, and impaired antioxidant capacity. Cold treatments are used to relieve joint inflammation and pain. Therefore, we measured the effect of cold treatments on the antioxidative capacity of RA patients with active disease. Sixty patients were randomized to (1) whole body cryotherapy at -110 A degrees C, (2) whole body cryotherapy at -60 A degrees C, or (3) local cryotherapy. Each treatment was given three times daily for 7 consecutive days in addition to the conventional rehabilitation. Blinded rheumatologist evaluated disease activity before the first and after the last cryotherapy. We collected plasma samples daily immediately before the first and after the second cryotherapy and measured total peroxyl radical trapping antioxidant capacity of plasma (TRAP), which reflects global combined antioxidant capacity of all individual antioxidants in plasma. Baseline morning TRAP levels (mean, 95% CI), adjusted for age, body mass index, disease activity, and dose of prednisolone, were 1244 (1098-1391) A mu M/l in the local cryotherapy, 1133 (1022-1245) A mu M/l in the cryotherapy at -60 A degrees C, and 989 (895-1082) A mu M/l in the cryotherapy at -110 A degrees C groups (p = 0.006). After the first treatment, there was a rise in 1-h TRAP of 14.2 (-4.2 to 32.6) A mu M/l, 16.1 (-7.4 to 39.6) A mu M/l, and 23.6 (4.1-43.2) A mu M/l, respectively. The increase was significant in the whole-body cryotherapy -110 A degrees C group (p

YKL-40 is a chitinase-like glycoprotein produced by alternatively activated macrophages that are associated with wound healing and fibrosis. Asbestosis is a chronic asbestos-induced lung disease, in which injury of epithelial cells and activation of alveolar macrophages lead to enhanced collagen production and fibrosis. We studied if YKL-40 is related to inflammation, fibrosis, and/or lung function in subjects exposed to asbestosis. Venous blood samples were collected from 85 men with moderate or heavy occupational asbestos exposure and from 28 healthy, age-matched controls. Levels of plasma YKL-40, CRP, IL-6, adipsin, and MMP-9 were measured with enzyme-linked immunosorbent assay (ELISA). Plasma YKL-40 levels were significantly higher in subjects with asbestosis (n=19) than in those with no fibrotic findings in HRCT following asbestos exposure (n=66) or in unexposed healthy controls. In asbestos-exposed subjects, plasma YKL-40 correlated negatively with lung function capacity parameters FVC (Pearson’s r −0.259, p=0.018) and FEV1 (Pearson’s r −0.240, p=0.028) and positively with CRP (Spearman’s rho 0.371, p<0.001), IL-6 (Spearman’s rho 0.314, p=0.003), adipsin (Spearman’s rho 0.459, p<0.001), and MMP-9 (Spearman’s rho 0.243, p=0.025). The present finding suggests YKL-40 as a biomarker associated with fibrosis and inflammation in asbestos-exposed subjects.

Objectives: We aimed to study if interleukin (IL) 8 and hepatocyte growth factor (HGF) predict development of severe acute pancreatitis (SAP) among patients without organ dysfunction (OD) at presentation, and if they discriminate transient OD from persistent OD among patients presenting with OD. Methods: From prospectively collected cohort of 176 AP patients and 32 healthy controls, plasma levels of IL-8 and HGF were determined within 5 days after symptom onset using an enzyme-linked immunosorbent assay. Results: AP was severe in 23 patients, of whom 10 did not have clinical signs of OD at presentation. IL-8 and HGF levels increased along with the severity of AP (P

Key messages #### What is already known about this subject? #### What does this study add? #### How might this impact on clinical practice? Transient receptor potential ankyrin 1 (TRPA1) is a ligand-gated membrane-bound cation channel. TRPA1 has been largely studied in neurons, where it mediates pain and neurogenic inflammation and acts as a chemosensor for harmful exogenous compounds.1 2 More recently, TRPA1 has been found to be activated also by endogenous compounds formed in inflammatory conditions characteristic to arthritis, such as reactive oxygen and nitrogen species.3 We have recently discovered that TRPA1 is functionally expressed in primary human osteoarthritic chondrocytes,4 where it upregulated the production of mediators related to arthritis: interleukin (IL)-6, prostaglandin E2 and matrix metalloproteinases 1, 3 and 13.4 Furthermore, we showed in monosodium iodoacetate-induced experimental arthritis that TRPA1 activation mediates inflammation, cartilage degradation and …