Increase In Inflammatory Markers Research Articles

Abstract 04: Caspase-8 is a novel candidate driver gene in head and neck squamous cell carcinoma

Abstract Integrated genomic analysis of head and neck squamous cell carcinoma (HNSCC) has identified a heterogeneous spectrum of alterations dominated by tumor suppressor genes. An interesting new candidate driver gene is Caspase-8 (CASP8), which is mutated in 18% of oral cavity HPV-negative tumors. CASP8 is not obviously a part of any well-characterized driver pathway in HNSCC, and its role in this tumor type is unknown. In TCGA genomic data CAPS8 mutant tumors have a unique spectrum of alterations and expression changes, including a dramatic increase in markers of inflammation, which suggest they are a genomic subtype of HNSCC. CAPS8 is a key component of the extrinsic apoptotic pathway, but it also has a role in necrotic death, inflammation, and other pathways. We have characterized human and mouse CASP8 knock-out cell lines in vitro and in vivo in order to begin to understand the function of this gene in HNSCC. Loss of CASP8 function prevents extrinsic apoptosis and alters proliferation and tumorigenicity. It may also regulate the antitumor immune response. CASP8 is an exciting new candidate driver gene in HNSCC that may offer new opportunities for therapeutic intervention. Citation Format: Burak Uzunparmak, Antje Lindemann, Mitchell J. Frederick, Jeffrey N. Myers, Curtis R. Pickering. Caspase-8 is a novel candidate driver gene in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 04.

The Hypothalamic Inflammatory/Gliosis Response to Neonatal Overnutrition Is Sex and Age Dependent.

Astrocytes participate in both physiological and pathophysiological responses to metabolic and nutrient signals. Although most studies have focused on the astrocytic response to weight gain due to high-fat/high-carbohydrate intake, surplus intake of a balanced diet also induces excess weight gain. We have accessed the effects of neonatal overnutrition, which has both age- and sex-dependent effects on weight gain, on hypothalamic inflammation/gliosis. Although both male and female Wistar rats accumulate excessive fat mass as early as postnatal day (PND) 10 with neonatal overnutrition, no increase in hypothalamic cytokine levels, markers of astrocytes or microglia, or inflammatory signaling pathways were observed. At PND 50, no effect of neonatal overnutriton was found in either sex, whereas at PND 150, males again weighed significantly more than their controls, and this was coincident with an increase in markers of inflammation and astrogliosis in the hypothalamus. Circulating triglycerides and free fatty acids were also elevated in these males, but not in females or in either sex at PND 10. Thus, the effects of fatty acids and estrogens on astrocytes in vitro were analyzed. Our results indicate that changes in circulating fatty acid levels may be involved in the induction of hypothalamic inflammation/gliosis in excess weight gain, even on a normal diet, and that estrogens could participate in the protection of females from these processes. In conclusion, the interaction of developmental influences, dietary composition, age, and sex determines the central inflammatory response and the associated long-term outcomes of excess weight gain.

Polyphenol supplementation inhibits physiological increase of prostaglandin E2 during reproductive period – A randomized clinical trial

Anti-inflammatory property of polyphenols and their effect on the metabolism of prostaglandins is not established in healthy humans. This study aimed to evaluate the effect of polyphenol supplementation in plasma levels of prostaglandin E2 and other markers of inflammation and oxidative stress in women using contraceptives. In this randomized double-blind clinical trial, women aged 25–35 years were selected. Participants received capsules containing polyphenols or placebo, to be consumed for fifteen days. From 40 women randomized, 28 completed the study. Control group showed a significant increase in the levels of PGE2 (p=0.01) while the polyphenols group showed no change in these levels (p=0.79). There was an increase in hs-CRP (p<0.01) and F2-isoprostane (p=0.04) in the control group. The GSSG to GSH ratio significantly reduced in the polyphenols group (p=0.02). Supplementation with polyphenol capsules inhibited the increase in markers of inflammation and oxidative stress in women of childbearing age using combined hormonal contraceptives.

Abstract P1-10-07: Prospective longitudinal study of epidermal thickening in breast cancer patients treated with conventional versus hypofractionated radiotherapy

Abstract Purpose: We conducted two prospective longitudinal studies of epidermal thickening in breast cancer (BRCA) patients treated with either conventional (CRT) or hypofractionated radiotherapy (HRT) using ultrasound images to objectively measure radiotherapy (XRT)-induced skin changes. Methods: Following breast conserving surgery, 105 consenting Stage 0-IIIA BRCA patients were enrolled on two studies of whole breast XRT without regional nodal irradiation. In the first, 66 subjects were treated with conventional fractionation (50 Gy plus a sequential 10 Gy boost at 2 Gy per fraction). In the second, subsequent study, 39 patients with characteristics under-represented in trials of HRT were treated to 39.9 Gy at 2.66 Gy per fraction with a simultaneous integrated boost of 8.1 Gy at 0.54 Gy per fraction. Inclusion criteria for this trial included breast separation &amp;gt;25cm, age &amp;lt;50 years, chemotherapy treatment, or non-Caucasian race. Prior to XRT, the last week of XRT, and 12 weeks and 1 year post XRT, subjects underwent objective ultrasound measurements of epidermal thickness over all four quadrants of the treated breast. A skin thickness ratio (STRA) was generated normalizing for corresponding measurements taken of the untreated breast. Pertinent patient, tumor, and treatment characteristics were collected at all time points, as well as peripheral blood for gene expression assays and assessment of inflammatory markers. Results: HRT patients were significantly younger than CRT patients [mean age 52 (38-73) versus (vs.) 56 years (26-75), p=0.03]. There were no other significant differences in patient, tumor, or treatment characteristics. Baseline measurements indicated 68% of CRT (mean increase 27%, SD 0.30) vs. 71% of HRT patients (mean increase 23%, SD 0.29) had skin thickening in the treated versus untreated breast prior to XRT (p=0.50). At all subsequent time points, CRT patients had significantly higher mean STRA than HRT patients [1.53, SD 0.48 vs. 1.33, SD 0.34 during RT (p=0.03); 1.62, SD 0.48 vs. 1.31, SD 0.45 at 12 weeks post RT (p=0.002); and 1.45, SD 0.39 vs. 1.27, SD 0.40 at 1 year post RT (p=0.03), respectively]. At 1 year, 31% of CRT and 38% of HRT patients had an STRA which was either less than or equal to baseline, indicating full recovery. In multivariable analysis, baseline STRA (p&amp;lt;0.001), BMI (p=0.002), chemotherapy (p=0.004) and CRT treatment (p=0.02) predicted for higher STRA 1 year post XRT. Dmax and breast volume receiving 107% of the dose did not predict for STRA. Gene ontology analysis revealed an over-representation of genes, differentially regulated among patients with high and low STRA, involved in the immune and defense responses. Tumor necrosis factor 2 receptor levels were also significantly higher in CRT than HRT treated patients at 1 year (p=0.03). Conclusions: Our findings indicate that CRT is associated with higher and more severe changes in STRA up 1 year after XRT than HRT, even among patients perceived to be at high risk for XRT-induced skin toxicity and who were not well-represented in the original HRT trials. An increase in peripheral markers of inflammation may be one mechanism by which CRT, BMI, and chemotherapy are associated with higher STRA 1 year post XRT. Citation Format: Torres MA, Yang X, Mister D, Ali A, Kahn S, Liu T. Prospective longitudinal study of epidermal thickening in breast cancer patients treated with conventional versus hypofractionated radiotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-07.

Role of genetics in familial Mediterranean fever

Familial Mediterranean fever (FMF) is caused by mutations within the Mediterranean fever (MEFV) gene. These gain of function mutations lead to an increased activation of the inflammasome pyrin with asubsequent disproportional proinflammatory reaction. Classically, in FMF patients two pathogenic mutations affecting both alleles are found in the molecular genetic analysis; however, it is well known that the phenotype can also be caused either by mutations with lower penetrance or unknown significance. Furthermore, in asignificant number of patients only one or even no MEFV mutations can be detected. Heterozygous mutation carriers who do not suffer from classical FMF, can also present with other signs of inflammation, e. g. subclinical increased inflammation markers, associated inflammatory diseases or unclassified symptoms. Thus, FMF does not follow aclassical autosomal recessive inheritance and avariable gene dose effect has to be considered, which is furthermore modulated by other mostly unknown genetic variants and environmental factors. This article summarizes the broad spectrum of clinical presentations associated with MEFV mutations and analyzes the effect of the gene dose on the phenotypical expression. Furthermore, the impact of the molecular genetic analysis on the diagnostics of apatient and on the individualized management of the disease is discussed.

Markers of lipid oxidative damage in the exhaled breath condensate of nano TiO2 production workers

Nanoscale titanium dioxide (nanoTiO2) is a commercially important nanomaterial. Animal studies have documented lung injury and inflammation, oxidative stress, cytotoxicity and genotoxicity. Yet, human health data are scarce and quantitative risk assessments and biomonitoring of exposure are lacking. NanoTiO2 is classified by IARC as a group 2B, possible human carcinogen. In our earlier studies we documented an increase in markers of inflammation, as well as DNA and protein oxidative damage, in exhaled breath condensate (EBC) of workers exposed nanoTiO2. This study focuses on biomarkers of lipid oxidation. Several established lipid oxidative markers (malondialdehyde, 4-hydroxy-trans-hexenal, 4-hydroxy-trans-nonenal, 8-isoProstaglandin F2α and aldehydes C6–C12) were studied in EBC and urine of 34 workers and 45 comparable controls. The median particle number concentration in the production line ranged from 1.98 × 104 to 2.32 × 104 particles/cm3 with ∼80% of the particles <100 nm in diameter. Mass concentration varied between 0.40 and 0.65 mg/m3. All 11 markers of lipid oxidation were elevated in production workers relative to the controls (p < 0.001). A significant dose-dependent association was found between exposure to TiO2 and markers of lipid oxidation in the EBC. These markers were not elevated in the urine samples. Lipid oxidation in the EBC of workers exposed to (nano)TiO2 complements our earlier findings on DNA and protein damage. These results are consistent with the oxidative stress hypothesis and suggest lung injury at the molecular level. Further studies should focus on clinical markers of potential disease progression. EBC has reemerged as a sensitive technique for noninvasive monitoring of workers exposed to engineered nanoparticles.

Stroke Damage Is Exacerbated by Nano-Size Particulate Matter in a Mouse Model.

This study examines the effects of nano-size particulate matter (nPM) exposure in the setting of murine reperfused stroke. Particulate matter is a potent source of inflammation and oxidative stress. These processes are known to influence stroke progression through recruitment of marginally viable penumbral tissue into the ischemic core. nPM was collected in an urban area in central Los Angeles, impacted primarily by traffic emissions. Re-aerosolized nPM or filtered air was then administered to mice through whole body exposure chambers for forty-five cumulative hours. Exposed mice then underwent middle cerebral artery occlusion/ reperfusion. Following cerebral ischemia/ reperfusion, mice exposed to nPM exhibited significantly larger infarct volumes and less favorable neurological deficit scores when compared to mice exposed to filtered air. Mice exposed to nPM also demonstrated increases in markers of inflammation and oxidative stress in the region of the ischemic core. The findings suggest a detrimental effect of urban airborne particulate matter exposure in the setting of acute ischemic stroke.

Impact of NMT1 Gene Polymorphisms on Features of the Metabolic Syndrome among Severely Obese Patients

Introduction: N-myristoyltransferase (NMT) is implicated in myristoylation, required for bio- logical activities of several proteins. Its gene N-myristoyltransferase 1 (NMT1) has been found to be overexpressed and hypermethylated in Visceral Adipose Tissue (VAT) of severely obese individuals with Metabolic Syndrome (MetS+) versus without (MetS-). Objective: The aim of this study was to verify the associations between NMT1 gene polymor- phisms Single Nucleotide Polymorphisms (SNPs) and metabolic complications among obese subjects. Methods: Associations between SNPs and determinants of MetS were tested with 1752 obese participants undergoing a bariatric surgery. The effect of selected SNPs on methylation, and correlation with expression levels of NMT1 were verified in subgroups. Results: Rs2239921 was significantly associated with systolic (p=0.03) and diastolic (p<0.0001) blood pressures. Rs2239923 was associated with plasma High Density Lipoprotein-Cholesterol or HDL-Cholesterol (HDL-C) levels (p=0.05), while rs2269746 was associated with Low Den- sity Lipoprotein-Cholesterol or LDL-Cholesterol (LDL-C) (p=0.006) and Total-Cholesterol (Total-C) levels (p=0.004). Rs1005136 (p=0.03), rs8066395 (p=0.03) or rs2157840 (p=0.04) were associated with plasma concentrations of C-Reactive Protein (CRP). Phenotype-associat- ed SNPs were associated with NMT1 methylation levels of six CpG sites. NMT1 methylation levels of one CpG site, cg10755730, correlated with gene expression levels (r=0.57; p=0.04). Conclusion: These results suggest that the presence of NMT1 SNPs is associated with altered plasma lipid levels as well as with increased inflammation markers and blood pressure among severely obese patients.

Experimental Periodontitis Results in Prediabetes and Metabolic Alterations in Brain, Liver and Heart: Global Untargeted Metabolomic Analyses.

Results from epidemiological studies suggest that there is an association between periodontitis and prediabetes, however, causality is not known. The results from our previous studies suggest that induction of periodontitis leads to hyperinsulinemia glucose intolerance and insulin resistance, all hallmarks of prediabetes. However, global effects of periodontitis on critical organs in terms of metabolic alterations are unknown. We determined the metabolic effects of periodontitis on brain, liver, heart and plasma resulting from Porphyromonas gingivalis induced periodontitis in mice. Periodontitis was induced by oral application of the periodontal pathogen, Porphyromonas gingivalis for 22 weeks. Global untargeted biochemical profiles in samples from these organs/plasma were determined by liquid and gas chromatography/mass spectrometry and compared between controls and animals with periodontitis. Oral application of Porphyromonas gingivalis induced chronic periodontitis and hallmarks of prediabetes. The results of sample analyses indicated a number of changes in metabolic readouts, including changes in metabolites related to glucose and arginine metabolism, inflammation and redox homeostasis. Changes in biochemicals suggested subtle systemic effects related to periodontal disease, with increases in markers of inflammation and oxidative stress most prominent in the liver. Signs of changes in redox homeostasis were also seen in the brain and heart. Elevated bile acids in liver were suggestive of increased biosynthesis, which may reflect changes in liver function. Interestingly, signs of decreasing glucose availability were seen in the brain. In all three organs and plasma, there was a significant increase in the microbiome-derived bioactive metabolite 4-ethylphenylsulfate sulfate in animals with periodontitis. The results of metabolic profiling suggest that periodontitis/bacterial products alter metabolomic signatures of brain, heart, liver, and plasma in the prediabetic state. These data provide scientific community valuable metabolic signatures that become the basis for understanding the impact of periodontitis on a systemic disease and potentially targets for therapeutic intervention.

A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents.

The innate immune cell sensor leucine-rich–containing family, pyrin domain containing 3 (NLRP3) inflammasome controls the activation of caspase-1, and the release of proinflammatory cytokines interleukin (IL)-1β and IL-18. The NLRP3 inflammasome is implicated in adipose tissue inflammation and the pathogenesis of insulin resistance. Herein, we tested the hypothesis that adipose tissue inflammation and NLRP3 inflammasome are linked to the downregulation of subcutaneous adipose tissue (SAT) adipogenesis/lipogenesis in obese adolescents with altered abdominal fat partitioning. We performed abdominal SAT biopsies on 58 obese adolescents and grouped them by MRI-derived visceral fat to visceral adipose tissue (VAT) plus SAT (VAT/VAT+SAT) ratio (cutoff 0.11). Adolescents with a high VAT/VAT+SAT ratio showed higher SAT macrophage infiltration and higher expression of the NLRP3 inflammasome–related genes (i.e., TLR4, NLRP3, IL1B, and CASP1). The increase in inflammation markers was paralleled by a decrease in genes related to insulin sensitivity (ADIPOQ, GLUT4, PPARG2, and SIRT1) and lipogenesis (SREBP1c, ACC, LPL, and FASN). Furthermore, SAT ceramide concentrations correlated with the expression of CASP1 and IL1B. Infiltration of macrophages and upregulation of the NLRP3 inflammasome together with the associated high ceramide content in the plasma and SAT of obese adolescents with a high VAT/VAT+SAT may contribute to the limited expansion of the subcutaneous abdominal adipose depot and the development of insulin resistance.

Comparison of a qualitative canine C-reactive protein test to a quantitative test and traditional markers of inflammation - Short communication.

Qualitative tests for C-reactive protein (CRP) are available for use in dogs, and provide a rapid in-house method of detecting acute inflammation. The aim of this study was to compare results from a qualitative CRP lateral flow test (Teco CRP FASTest) to those obtained from a quantitative CRP ELISA and to traditional methods of detecting inflammation, including total leukocyte and neutrophil numbers, presence of immature neutrophils and a left shift, presence or absence of toxic changes in neutrophils and plasma fibrinogen concentration in whole blood and serum samples collected from 113 client-owned dogs. More dogs had CRP FASTest positive results than had quantitatively increased CRP (ELISA) or increases in traditional methods used for measuring inflammation. Few dogs had increases in markers of inflammation but no elevated CRP. The qualitative CRP FASTest was found to be a sensitive test for detecting increased CRP concentration and was positive more frequently than were traditional markers of inflammation.

Effects of glucomannan/spirulina-surimi on liver oxidation and inflammation in Zucker rats fed atherogenic diets.

Cholesterolemia is associated with pro-oxidative and proinflammatory effects. Glucomannan- or glucomannan plus spirulina-enriched surimis were included in cholesterol-enriched high-saturated diets to test the effects on lipemia; antioxidant status (glutathione status, and antioxidant enzymatic levels, expressions and activities); and inflammation biomarkers (endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α)) in Zucker fa/fa rats. Groups of eight rats each received diet containing squid-surimi (C), squid-surimi cholesterol-enriched diet (HC), glucomannan-squid-surimi cholesterol-enriched diet (HG), or glucomannan-spirulina-squid-surimi cholesterol-enriched diet (HGS) over a period of 7 weeks. HC diet induced severe hyperlipemia, hepatomegalia, increased inflammation markers, and impaired antioxidant status significantly (at least p < 0.05) vs. C diet. HG diet decreased lipemia and liver size and normalized antioxidant status to C group levels, but increased TNF-α with respect to HC diet (p < 0.05). In general terms, 3 g/kg of spirulina in diet maintained the positive results observed in the HG diet but, in addition, increased inflammation index [eNOS/(eNOS + iNOS)] and decreased plasma TNF-α (both p < 0.05). In conclusion, glucomannan plus a small amount of spirulina blocks negative effects promoted by hypercholesterolemic diets. Although more studies are needed, present results suggest the utility of including glucomannan and/or spirulina as functional ingredients into fish derivates to be consumed by people on metabolic syndrome risk.

LPS-Stimulated Whole Blood Cytokine Production Is Not Related to Disease Behavior in Patients with Quiescent Crohn's Disease.

IntroductionCrohn’s disease (CD) is a chronic inflammatory disease in which cytokines play a pivotal role in the induction and maintenance of inflammation. Innate cytokine production is genetically determined and varies largely between individuals; this might impact the severity of inflammation. We aimed to assess whether ex-vivo endotoxin-stimulated levels of cytokines could be associated with disease phenotype.MethodsPatients with quiescent CD (Harvey-Bradshaw Index ≤ 4 and negative inflammation markers) who were not using immunomodulating drugs or biologicals were eligible. Historical disease characteristics (localization, behavior, number of bowel resections, drug history, extra-intestinal symptoms) were extracted from medical records. We measured cytokine levels (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-10) in supernatants of lipopolysaccharide (LPS) -stimulated whole blood cultures and correlated these with disease characteristics and age- and sex-matched healthy controls. In addition, we analyzed whether single nucleotide polymorphisms (SNPs) in the promoter region of the TNF-α gene were related to TNF-α levels.ResultsWe included 75 patients with CD and 24 healthy controls. Six patients were excluded because of increased inflammation markers resulting in a total of 69 patients. The mean age (SD) of patients with CD was 51.2 (12.3) years with a mean (SD) disease duration of 24.1 (11.5) years. Disease localization, peri-anal involvement and behavior were not related to LPS-stimulated TNF-α, IL-1β, IL-6 or IL-10 levels. In addition, combination of localization with behavior to differentiate mild from severe disease type showed no significant differences. TNF-α levels were higher in patients with CD (428 pg/ml IQR [267-468]) compared to healthy controls (459 pg/ml IQR [364-570], p=0.02). We found no associations between SNPs in the promoter region and TNF-α levels.ConclusionIn this study, innate cytokine production of TNF-α, IL-1β, IL-6 and IL-10 was not related to historical disease characteristics or disease severity in patients with quiescent CD. These findings suggest that genetically determined levels of these cytokines obtained from LPS-stimulated whole blood cultures are not linked with disease behavior or severity.

Increasing body condition score is positively associated interleukin-6 and monocyte chemoattractant protein-1 in Labrador retrievers

The accumulation of excess body fat is a growing problem in dogs as well as people. Contrary to prior understanding of adipose tissue, fat is now considered to be an active endocrine organ that promotes a chronic low-grade inflammatory state often characterized by an increase in pro-inflammatory cytokines and chemokines. These have been implicated in several obesity-related disorders such as insulin resistance, cardiovascular disease, and neoplasia. The purpose of this study was to characterize fasting plasma cytokine concentrations in ninety-two healthy client-owned Labrador retriever dogs of various ages and body condition scores. The dogs were grouped according to body condition score (BCS) into three categories, lean, overweight and obese. The following cytokines and chemokines were evaluated; tumor necrosis factor-alpha, interleukin-2, interleukin-6, interleukin-8, and monocyte chemotactic protein-1 (TNF-α, IL-2, IL-6, IL-8, MCP-1). Our results indicated that fasting plasma IL-6 and MCP-1 concentrations are associated with increasing BCS. This data suggest that certain markers of inflammation increase with increasing body condition score, and that dogs, similar to humans, may be fostering a chronic inflammatory state due to obesity.

TERAPIE CLASICĂ MODIFICATOARE A BOLII DE BAZĂ SAU TERAPIE BIOLOGICĂ ÎN POLIARTRITA REUMATOIDĂ?

Objectives. The purpose of this study is the evaluation of a group of patients suffering from rheumatoid arthritis depending on the administered treatment, classical remissive therapy or biological therapy. Materials and methods. We have performed a retrospective study on a group of 214 patients diagnosed with rheumatoid arthitis, admitted in the Internal Medicine and Rheumatology Clinic of „Dr. I. Cantacuzino“ Clinical Hospital Bucharest, 92 of whom were being administered biological therapy (etanercept, infliximab, adalimumab or rituximab) along with classical remissive therapies (methotrexate, leflunomide, sulfasalazine), and 122 of whom were only being administered classical treatment. We have studied and supervised the influence of these therapies on disease evolution, together with paying attention to several other health risks present in rheumatoid arthritis patients (cardiovascular risk, osteoporosis, joint replacement surgery, neoplasms). Results. In the studied group, the seropositive disease forms predominated (72%), in stages 2 and 3, the average patient age being 59.29±11.52 years. Systemic manifestations were present in patients who underwent biological therapy, presented seropositive disease forms, as well as a more aggresive evolution and a more decreased BMI. Female patients more frequently presented ischemic heart disease, dyslipidemia and increased cholesterol levels, thus comprising multiple cardiovascular risk factors as well as associated cardiovascular pathology. Patients treated with biological therapy have presented a significantly lower incidence of ischemic stroke as well as slightly decreased cholesterol levels, data which correlate with specialty literature. Treatment using statins was more frequently used in these cases. Although statistically unsignificant, the most decreased cholesterol levels were recorded in patients treated with etanercept. Smokers presented a weaker response to biological therapy as compared to non-smokers. Osteoporosis was more frequent in the group of patients treated with classical remissive therapy as well as in those with an increased disease activity, evaluated through the DAS 28 score and increased inflammation markers. DAS 28 was decreased in patients treated with biological treatment (infliximab, adalimumab, rituximab), and those in the third stage of disease, probably because of the more aggeresive treatement administered in these situations. Conclusions. Biological therapy has positively influenced disease evolution, patients presenting decreased values for inflammation markers as well as disease activity, evaluated using the DAS 28 score, in comparison with patients treated with classical remissive therapy. Cholesterol levels were lower in the group treated with biological therapy, as patients underwent statin treatment more frequently, thus presenting a reduced incidence of stroke. Moreover, osteoporosis was less frequent in the group treated with biological agents. These biological therapies did not influence the number of viral hepatitis infections, but in some cases have determined the reactivation of a series of tuberculosis infections. Neoplasms have not presented a significantly increased incidence in the group treated with biological therapy. Adverse effects of biological treatment will be further studied, but the beneficial effect on disease evolution as well as other disease-associated risks is certain.

A sexually dimorphic hypothalamic response to chronic high-fat diet consumption.

In this review, we discuss the observations that, following chronic high-fat diet (HFD) exposure, male mice have higher levels of saturated fatty acids (FAs) and total sphingolipids, whereas lower amounts of polyunsaturated FAs in the central nervous system (CNS) than females. Furthermore, males, when compared with female mice, have higher levels of inflammatory markers in the hypothalamus following exposure to HFD. The increase in markers of inflammation in male mice is possibly due to the reductions in proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and estrogen receptor alpha (ERα), which is not recapitulated in female mice. Consistently, hypothalamic inflammation is induced both in male and female ERα total-body knockout mice when exposed to a HFD, thus confirming the key role of ERα in the regulation of HFD-induced hypothalamic inflammation. Finally, the HFD-induced depletion of hypothalamic ERα is associated with dysregulation in metabolic homeostasis, as evidenced by reductions in glucose tolerance and decrements in myocardial function.

Acute Exercise Improves Insulin Action in Parallel with Increases in Markers of Inflammation in Liver from Mice Fed a High Fat Diet

Exercise training in high fat fed mice is protective against liver inflammation and insulin resistance, which occurs in parallel with attenuation in weight gain. The objective of this study was to determine if acute exercise induces an insulin sensitizing effect in parallel with changes in the inflammatory profile of liver in obese mice. C57BL/6 male mice were fed a low fat diet (LFD, 10% kcals from lard) or high fat diet (HFD, 60% kcals from lard) for 7 weeks. Mice from the HFD group were then subjected to 2 hours of treadmill exercise at 15 m·min‐1. At 2 hours post‐exercise, or cage control, mice were injected with insulin (1U/kg BW) and livers were harvested. After 7 weeks, mice fed the HFD were significantly heavier than mice fed the LFD, had impaired glucose clearance during a glucose tolerance test, and had attenuated insulin‐induced phosphorylation of AKT. In mice fed a HFD, acute exercise recovered the impaired phosphorylation of AKT, suggesting improved insulin action. This was accompanied by increased phosphorylation of the mitogen‐activated protein kinase JNK1 and p38. Further, both socs3 and mcp‐1 mRNA were up regulated, along with increased phosphorylation of stat3. The results from this study suggest that in an obese mouse, acute exercise improves liver insulin action in parallel with increases in inflammatory signaling. Funded by NSERC. DCW is a Tier 2 CRC. REKM is funded by an Alzheimer Society PDF.

Dyslipidemia and chronic inflammation markers are correlated with telomere length shortening in Cushing's syndrome.

IntroductionCushing’s syndrome (CS) increases cardiovascular risk (CVR) and adipocytokine imbalance, associated with an increased inflammatory state. Telomere length (TL) shortening is a novel CVR marker, associated with inflammation biomarkers. We hypothesized that inflammatory state and higher CVR in CS might be related to TL shortening, as observed in premature aging.AimTo evaluate relationships between TL, CVR and inflammation markers in CS.MethodsIn a cross-sectional study, 77 patients with CS (14 males, 59 pituitary-, 17 adrenal- and 1 ectopic-origin; 21 active disease) and 77 age-, gender-, smoking-matched controls were included. Total white blood cell TL was measured by TRF-Southern technique. Clinical data and blood samples were collected (lipids, adrenal function, glucose). Adiponectin, interleukin-6 (IL6) and C-reactive protein (CRP) were available in a subgroup of patients (n=32). Correlations between TL and clinical features were examined and multiple linear regression analysis was performed to investigate potential predictors of TL.ResultsDyslipidemic CS had shorter TL than non-dyslipidemic subjects (7328±1274 vs 7957±1137 bp, p<0.05). After adjustment for age and body mass index, cured and active CS dyslipidemic patients had shorter TL than non-dyslipidemic CS (cured: 7187±1309 vs 7868±1104; active: 7203±1262 vs 8615±1056, respectively, p<0.05). Total cholesterol and triglycerides negatively correlated with TL (r-0.279 and -0.259, respectively, p<0.05), as well as CRP and IL6 (r-0.412 and -0.441, respectively, p<0.05). No difference in TL according the presence of other individual CVR factors (hypertension, diabetes mellitus, obesity) were observed in CS or in the control group. Additional TL shortening was observed in dyslipidemic obese patients who were also hypertensive, compared to those with two or less CVR factors (6956±1280 vs 7860±1180, respectively, p<0.001). Age and dyslipidemia were independent negative predictors of TL.ConclusionTL is shortened in dyslipidemic CS patients, further worse if hypertension and/or obesity coexist and is negatively correlated with increased inflammation markers. Increased lipids and a “low” grade inflammation may contribute to TL shortening and consequently to premature ageing and increased morbidity in CS.

Low level of trans-10, cis-12 conjugated linoleic acid decreases adiposity and increases browning independent of inflammatory signaling in overweight Sv129 mice

The objective of this study was to determine the extent to which a low level of trans-10, cis-12 (10,12) conjugated linoleic acid (CLA) decreases adiposity and increases browning in overweight mice, its dependence on inflammatory signaling and potential synergistic effects of daily exercise. Young, Sv129 male mice were fed a high-fat diet for 5 weeks to make them fat and glucose intolerant and then switch them to a low-fat diet with or without 0.1% 10,12 CLA, sodium salicylate or exercise for another 7 weeks. 10,12 CLA decreased white adipose tissue (WAT) and brown adipose tissue mass, and increased the messenger RNA and protein levels, and activities of enzymes associated with thermogenesis or fatty acid oxidation in WAT. Mice fed 10,12 CLA had lower body temperatures compared to controls during cold exposure, which coincided with decreased adiposity. Although sodium salicylate decreased 10,12 CLA-mediated increases in markers of inflammation in WAT, it did not affect other outcomes. Exercise had no further effect on the outcomes measured. Collectively, these data indicate that 10,12 CLA-mediated reduction of adiposity is independent of inflammatory signaling, and possibly due to up-regulation of fatty acid oxidation and heat production in order to regulate body temperature. Although this low level of 10,12 CLA reduced adiposity in overweight mice, hepatomegaly and inflammation are major health concerns.

Relationship Between Neutrophil to Lymphocyte Ratio, Platelet to Lymphocyte Ratio and Obstructive Sleep Apnea Syndrome.

Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) give information about many diseases. An increase in inflammation markers occurs in patients with obstructive sleep apnea syndrome (OSAS). The aim of this study is to determine the relationship between OSAS and NLR and PLR values. Two hundred eighty four patients with complaints of snoring and excessive daytime sleepiness were included in the study. Polysomnography had been performed on all patients and the control group. Fourty eight of these patients with apnea-hypopnea index (AHI) less than 5 (pure snoring) were included in the control group, 67 patients with AHI between 5 and 14.9 in the mild OSAS group, 61 patients with AHI between 15 and 29.9 in the moderate OSAS group and 108 patients with AHI more than 30 in the severe OSAS group. NLR and PLR values were calculated from the complete blood count (CBC) analysis of the patients and control group. The OSAS and control groups were compared by age, gender, body mass index (BMI) and PSG parameters as well as NLR and PLR values. The PLR value in the OSAS group was found to be less than in the control group (p=0.006). As the non-REM AHI increased, the value of PLR decreased. As the nocturnal time spent with arterial oxygen saturation<90% increased, the value of NLR was determined to increase. NLR and PLR values can give valuable information in OSAS.