INTERACTIONS AMONG INTERLEUKIN-6, C-REACTIVE PROTEIN AND INTERLEUKIN-6 (-174) G/C POLYMORPHISM IN THE PATHOGENESIS OF CROHN'S DISEASE AND ULCERATIVE COLITIS.

Inflammatory bowel diseases are multifactorial disorders the clinical manifestation of which depends on the interaction among immune response, genetic and environmental factors. There is growing evidence that cytokines and gene polymorphisms have an important role in disease pathogenesis in various populations although molecular mechanism of their signaling and interactions is not fully understood yet. The present study aimed at exploring the effects of interleukin-6, C-reactive protein and interleukin-6 rs1800795 polymorphism on the development of Crohn's disease, ulcerative colitis and inflammatory bowel diseases overall and at determining differences between inflammatory bowel disease patients and healthy controls. A total of 132 inflammatory bowel disease patients and 71 healthy blood donors were investigated. In order to assess the clinical relevance of interleukin-6 and C-reactive protein serum concentration and interleukin-6 rs1800795 single nucleotide polymorphism in patients with Crohn's disease and ulcerative colitis, we performed a cross-sectional, case-control study. Quantitative assessment of serum interleukin-6 and C-reactive protein was performed with solid-phase, enzyme-labeled, chemiluminescent sequential immunometric and immunoturbidimetric assay, respectively. A real-time fluorescence resonance energy transfer-based method on a LightCyclerTM PCR 1.2 was used for genotyping of IL-6 rs1800795 polymorphism. Both interleukin-6 and C-reactive protein serum levels were elevated in Crohn's disease and ulcerative colitis patients. Positive correlations were observed between C-reactive protein and interleukin-6 serum concentration and ulcerative colitis activity index as measured by modified Truelove-Witt's severity index scale. C-reactive protein serum level was higher in Crohn's disease patients without intestinal resection than in Crohn's disease patients with prior intestinal resection. In ulcerative colitis patients, interleukin-6 and C-reactive protein serum levels were statistically significantly higher in CC interleukin-6 genotype in comparison to GG+GC genotype. Analysis of the promoter region of the interleukin-6 rs1800795 gene polymorphism showed no statistically significant difference in allele frequency either between inflammatory bowel disease patients and healthy controls or between the two inflammatory bowel disease phenotypes and healthy controls. Associations presented in this study give a potentially important insight into the role of interleukin-6 and C-reactive protein signaling and interleukin-6 polymorphism in the pathogenesis of Crohn's disease and ulcerative colitis disease.

Interleukin 17A and Toll-like Receptor 4 in Patients with Arterial Hypertension.

BACKGROUND/AIMS: Immune responses are involved in arterial hypertension. An observational cross-sectional case control study was conducted to estimate the association between Toll-like receptor 4 (TLR4) expression and interleukin (IL)-17A serum levels in patients with controlled and non-controlled hypertension. METHODS: We have enrolled 105 non-complicated otherwise healthy hypertensive patients: 53 with well-controlled blood pressure and 52 non-controlled. TLR4 peripheral monocytes expression and serum IL-17A levels were determined by flow cytometry and ELISA, respectively. RESULTS: Non-controlled patients exhibited higher TLR4 expression than well-controlled (25.60 vs. 21.99, P=0.011). TLR4 expression was lower in well-controlled patients who were prescribed beta blockers (18.9 vs. 22.6, P=0.005) and IL-17A concentration was higher in patients using diuretics in either group (1.41 vs. 2.01 pg/ml, P<0.001; well-controlled 1.3 vs. 1.8 pg/ml, P= 0.023; non-controlled 1.6 vs. 2.3 pg/ml, P=0.001). Correlation between IL-17A concentration and hypertension duration was observed in non-controlled patients (Spearman correlation coefficient . ρ=0.566, P<0.001) whereas in well-controlled patients a correlation was found between hypertension duration and TLR4 expression (ρ=0.322, P=0.020). CONCLUSIONS: Arterial hypertension stimulates the immune response regardless of blood pressure regulation status. Prolonged hypertension influences peripheral monocyte TLR4 expression and IL-17A serum levels. Anti-hypertensive drugs have different immunomodulatory effects: diuretics are associated with higher IL-17A concentration and beta-blockers with lower TLR4 expression.

Transcardial gradient of adiponectin, interleukin-6 and tumor necrosis factor-α in overweight coronary artery disease patients.

BACKGROUND: Obesity is associated with coronary artery disease (CAD), where epicardial adipose tissue (EAT) express proatherogenic cytokines (i.e., interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)) and decreases production of beneficial adiponectin. Studies on endocrine role of EAT are mostly based on assessing cytokines' mRNAs, whereas cytokine blood levels might not readily correlate. In order to get better insight into the endocrine role of thickened EAT in CAD, we assessed transcardial gradient of adiponectin, IL-6 and TNF-α. METHODS: We assessed anthropometric and ultrasound measures in cohort of fifty nondiabetic subjects (21 CAD and 29 non-CAD). Blood sampled from aortic root and coronary sinus was assayed for adiponectin, IL-6 and TNF-α, using ELISA. RESULTS: Except thicker EAT in CAD subjects, anthropometric measures were similar (overweight), with higher adiponectin in coronary sinus than in aortic root (p<0.001) in both groups. CAD subjects had lower adiponectin in aortic root (p<0.001) and higher levels of TNF-α in coronary sinus than in aortic root (p=0.05). EAT thickness positively correlated with hip circumference (p=0.038) and negatively correlated with adiponectin levels (for both p<0.05). CONCLUSIONS: Transcardial gradient of adiponectin in non-CAD and CAD overweight subjects was similar, while latter had lower systemic adiponectin level and thicker EAT. EAT with thickening reaches the threshold level of near-maximal down-regulation of adiponectin and its further thickening is not associated with continued decrease of adiponectin production. In CAD patients levels of TNF-α were higher, but IL-6 were not, and these cytokines might be flush out by lymphatic route.

Importance of interleukin 6 in pathogenesis of inflammatory bowel disease.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is an uncontrolled chronic inflammation of the gastrointestinal tract caused by an interaction of diverse genes and environmental factors. There is growing evidence that cytokine production plays an important role in IBD. One of the key roles in signaling pathway in development of IBD is performed by interleukin 6 (IL-6), although molecular mechanism of this pathway is not yet fully understood. In order to assess the clinical relevance of IL-6 serum concentration in patients with CD and UC we performed cross-sectional, case-control study of IL-6 levels in patients' and healthy blood donors' sera. A total of 100 CD and UC patients and 71 healthy blood donors were investigated. Clinical activity of CD and UC was evaluated using the Crohn's disease activity index and Truelove-Witt's criteria, respectively. Quantitative assessment of serum IL-6 was performed with solid-phase, enzyme-labeled, chemiluminescent sequential immunometric assay. Our results indicate that serum IL-6 is a clinically relevant parameter for CD and UC that strongly correlates with inflammatory activity of disease. We confirmed and extended the role of cytokine production patterns for IBD presentation in Croatian population.

Polymorphisms of interleukin-23 receptor in patients with inflammatory bowel disease in a Croatian tertiary center.

The Interleukin-23 signalling pathway is important for the differentiation of TH17 lymphocytes and is involved in the pathogenesis of Inflammatory bowel disease. Polymorphisms in the IL-23 receptor gene were previously found to be associated with Inflammatory bowel disease in various populations. The aim of this study was to determine whether the specific rs11209026 and rs7530511 single-nucleotide polymorphisms in the Interleukin-23 receptor gene are associated with Crohn's disease and ulcerative colitis in a Croatian patient population. A total of 50 patients with Crohn's disease and 93 patients with ulcerative colitis, as well as 99 healthy control subjects were included in the study. The results determined a significantly higher occurrence of rs11209026 in control group compared to patients with inflammatory bowel disease, suggesting a protective effect of this polymorphism. The rs11209026 variant was strongly associated with Crohn's disease, but it was absent in ulcerative colitis. However, there was no significant association between the rs7530511 polymorphism with either ulcerative colitis or Crohn's disease. Associations presented in this study give potentially important insight into the roles of specific Interleukin-23 receptor polymorphisms in Crohn's disease pathogenesis in the Croatian population.

Position and orientation tracking in a ubiquitous monitoring system for Parkinson disease patients with freezing of gait symptom.

BACKGROUND: Freezing of gait (FoG) is one of the most disturbing and least understood symptoms in Parkinson disease (PD). Although the majority of existing assistive systems assume accurate detections of FoG episodes, the detection itself is still an open problem. The specificity of FoG is its dependency on the context of a patient, such as the current location or activity. Knowing the patient's context might improve FoG detection. One of the main technical challenges that needs to be solved in order to start using contextual information for FoG detection is accurate estimation of the patient's position and orientation toward key elements of his or her indoor environment. OBJECTIVE: The objectives of this paper are to (1) present the concept of the monitoring system, based on wearable and ambient sensors, which is designed to detect FoG using the spatial context of the user, (2) establish a set of requirements for the application of position and orientation tracking in FoG detection, (3) evaluate the accuracy of the position estimation for the tracking system, and (4) evaluate two different methods for human orientation estimation. METHODS: We developed a prototype system to localize humans and track their orientation, as an important prerequisite for a context-based FoG monitoring system. To setup the system for experiments with real PD patients, the accuracy of the position and orientation tracking was assessed under laboratory conditions in 12 participants. To collect the data, the participants were asked to wear a smartphone, with and without known orientation around the waist, while walking over a predefined path in the marked area captured by two Kinect cameras with non-overlapping fields of view. RESULTS: We used the root mean square error (RMSE) as the main performance measure. The vision based position tracking algorithm achieved RMSE = 0.16 m in position estimation for upright standing people. The experimental results for the proposed human orientation estimation methods demonstrated the adaptivity and robustness to changes in the smartphone attachment position, when the fusion of both vision and inertial information was used. CONCLUSIONS: The system achieves satisfactory accuracy on indoor position tracking for the use in the FoG detection application with spatial context. The combination of inertial and vision information has the potential for correct patient heading estimation even when the inertial wearable sensor device is put into an a priori unknown position.

A system for inference of spatial context of Parkinson's disease patients.

This work proposes a concept for indoor ambulatory monitoring for Parkinson's disease patients. In the proposed concept, a wearable inertial sensor is kept as the main monitoring device through the day, and it is expanded by an ambient sensor system in the specific living areas with high estimated probability of occurrence of freezing of gait episode. The ambient sensor system supports decisions of the wearable sensor system by providing relevant spatial context information of the user, which is obtained through precise localization.