|
|
Pathophysiological and genetic factors affecting serum uric acid level.
Hasíková, Lenka ; Závada, Jakub (advisor) ; Hrnčíř, Zbyněk (referee) ; Horák, Pavel (referee)
Introduction: Serum uric acid level (SUA) depends on the balance between its production and excretion. SUA is associated with several transmembrane proteins responsible for reabsorption (mainly URAT1 and GLUT9) and secretion (ABCG2) on the apical and basolateral membranes of the proximal tubules in the kidney, and in the case of ABCG2, it also correlates with its significant excretion through the gastrointestinal tract. Gout is a metabolic disease caused by the deposition of urate crystals in the joints and tissues. Chronic hyperuricemia is a primary risk factor for the development of gout; however, gout patients usually have a lower SUA during an acute gout attack than in the intercritical periods. The exact mechanism of this phenomenon is unknown. It has been speculated that the systemic inflammatory response can explain this discrepancy. The aim of the study is to determine whether treatment with specific inhibitors of the proinflammatory cytokine TNF (TNFi) affects SUA in patients with systemic rheumatic disease (SRD), and whether changes in SUA correlate with changes in selected proinflammatory cytokines or with the biomarker of oxidative stress, allantoin. Another aim is to determine the frequency and effect of allelic variants in the ABCG2 urate transporter gene in patients with primary...
|
|
|
Effectiveness and safety of biological therapy in inflammatory rheumatic diseases
Nekvindová, Lucie ; Závada, Jakub (advisor) ; Hendl, Jan (referee) ; Hrnčíř, Zbyněk (referee)
This thesis focuses on evaluating the effectiveness and safety of biological/targeted treatment in chronic inflammatory rheumatic diseases based on data from the ATTRA registry. The introductory chapters of the thesis give an overview of three rheumatic diseases - rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), characterising clinical manifestation, diagnosis, therapeutical options and current treatment guidelines. The work also contains a brief summary of information about planning, creating and maintaining a clinical registry and characterises specifics related to the analysis of registry data. The practical part of the thesis was aimed at two research questions. Recently, a treat-to-target (T2T) strategy was established for RA, PsA and axSpA. Studies from daily clinical practice concerning the advantage of following T2T over usual care are still lacking. Thus, the first goal of the thesis was to evaluate whether following a treat to target strategy after not reaching low disease activity within the first six months leads to a higher chance of meeting the treatment target at the twelve-month visit. Our second goal in the thesis was to evaluate the association between therapeutic response (achieving remission and drug retention) and patients'...
|
|
|
The Imaging of Brain Pathological Lesions in Systemic Lupus Erythematosus Patients
Podrazilová, Lucie ; Dostál, Ctibor (advisor) ; Hrnčíř, Zbyněk (referee) ; Seidl, Zdeněk (referee)
Objective: Our project study presents the results of measuring the volume of pathological foci in the brain tissue of patients suffering from systemic lupus erytematodes (SLE) with or without neuropsychiatric manifestations (NP). Magnetic resonance (MR) scans of patients with SLE and, in particular, signs of neuropsychiatric involvement show pathological foci in the cerebral white matter. Methods: A total of 53 SLE patients, 29 with signs of neuropsychiatric syndromes (NPSLE), 24 without, and 16 healthy controls underwent prospective volumetric magnetic resonance imaging in a flow attenuated inversion recovery (FLAIR) sequence. The disease activity was expressed in terms of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Results: All of the patients in this study were found to have a larger volume of pathological foci in the brain tissue than the healthy controls. The NPSLE subgroup had a larger volume of pathological foci than the SLE patients without NP (p<0.001). The largest volume of such foci was found in patients with a history of cerebrovascular disease (p<0.05). These were also noted for a correlation between the duration of the disease and the period of time elapsed from the onset of the first signs of neuropsychiatric lupus (p<0.01). Correlation with SLEDAI-rated disease activity...
|
|
|
The role of S100 proteins in the pathogenesis of rheumatic diseases
Andrés Cerezo, Lucie ; Šenolt, Ladislav (advisor) ; Hrnčíř, Zbyněk (referee) ; Horák, Pavel (referee)
Introduction: Recent findings and better understanding to the pathogenesis of rheumatic diseases contributed to the development of biological therapies targeting cytokines and immune cells. Several S100 proteins exert cytokine-like effects and participate in the regulation of the inflammatory process. The aim of this work was to study the role of selected S100 proteins in the activity and in the pathogenesis of the rheumatic diseases. Results: Our data show for the first time an association of S100A4 proteinwith RA disease activity and decrease of the bioactive form, but not the total amount of S100A4, after aplication of tumour necrosis factor (TNF) blocking biologic therapy in patients with RA. We demonstrated that in vitro S100A4 acts as a potent pro-inflammatory mediator inducing production of TNFα, interleukin (IL)-1β and IL-6 in PBMCs via Toll-like receptor 4 (TLR-4), transcription factor NFκB and tyrosine kinases erk1/2 and p38. Moreover, S100A4 can play an important role in the pathogenesis of inflammatory myopathies. S100A4 is present in the inflammatory infiltrate of the affected muscles and in the regenerating muscles and may act as a cytokine-like factor indirectly promoting muscle fiber damage by stimulating mononuclear cells to increase the synthesis of pro-inflammatory cytokines. We...
|
|
| |
|
|
Molecular Pathophysiology of Primary Hyperuricemia and Gout
Bohatá, Jana ; Stibůrková, Blanka (advisor) ; Hrnčíř, Zbyněk (referee) ; Friedecký, David (referee)
Primary hyperuricemia, as a condition of elevated serum uric acid levels, is caused by various factors and necessarily precedes a form of inflammatory arthritis referred to as gout. Uric acid is the end product of purine catabolism and requires specialized proteins for its transport. Pathogenic variants in the genes for these transport proteins can have a major negative impact on their function, thereby affecting the resulting serum uric acid levels. However, chronically elevated uric acid levels are not the only predisposition to the development of gout. Other factors, such as epigenetic mechanisms or genetic predispositions to inflammatory conditions caused by immune dysregulation, are likely to play a role in disease progression. The aim of the study was to analyse damaging variants in genes for important urate transporters ABCG2, SLC22A12 and SLC2A9, which may cause impaired excretion or reabsorption of uric acid and thus contribute to the development of primary hyperuricemia and gout, or rare hereditary renal hypouricemia. We also focused on circulating miRNAs in the plasma of patients with primary hyperuricemia, gout and gout attack. We identified and functionally characterized over ten rare nonsynonymous variants in the ABCG2 gene. Most of these variants had a negative impact on protein...
|
|
|
Circulating miRNAs as biomarkers in the diagnosis and treatment of rheumatic diseases
Prajzlerová, Klára ; Filková, Mária (advisor) ; Hrnčíř, Zbyněk (referee) ; Procházková, Leona (referee)
Background: MicroRNAs (miRNAs) are small non-coding single-stranded RNAs involved in the posttranscriptional inhibition of gene expression and thereby regulating all cellular functions. Their dysregulation contributes to the pathophysiology of many diseases, including rheumatic diseases. MiRNAs can also be found extracellularly in body fluids and represent promising diagnostic and prognostic biomarkers. Our study aimed to investigate miRNAs as biomarkers of stage and activity and predictors of therapeutic response of two most common inflammatory rheumatic diseases: spondyloarthritis (SpA) and rheumatic arthritis (RA). Results: We found several circulating miRNAs differentially expressed in SpA patients reflecting the severity of axial involvement and/or disease activity. The decrease in circulating miR-145 in plasma of patients with ankylosing spondylitis 3 months of anti-TNF therapy predicted a good therapeutic response and low disease activity after a year of therapy. Circulating and intracellular expression of miR-125b in peripheral blood mononuclear cells (PBMC) was lower in treatment-naïve patients with early RA than in healthy controls. Baseline expression of miR-125 in PBMC predicted a (non)adequate therapeutic response. We also found the increased expression of miR-451 in PBMC in...
|
|
|
Pathophysiology of urate transporters in primary gout
Pavelcová, Kateřina ; Stibůrková, Blanka (advisor) ; Doležel, Zdeněk (referee) ; Hrnčíř, Zbyněk (referee)
There are localised proteins (so-called urate transporters) in the renal proximal tubules and in the intestine, which excrete and reabsorb uric acid. Polymorphisms in the genes coding these proteins can result in the disruption of the transport function and development of hyperuricemia and gout. However the serum level of uric acid is also determined by other factors which include the intake of exogenous purines in food, synthesis of endogenous purines and degradation of nucleic acids, but also certain conditions. In 250 patients with primary hyperuricemia and gout we used Sanger sequencing to analyse the exons and adjacent intron regions in ten genes coding urate transporters: ABCG2, ABCC4, SLC2A9, SLC22A12, SLC22A11, SLC22A13, SLC17A1, SLC17A3, SLC22A6 and SLC22A8. We examined a possible connection between the identified genetic variants and primary hyperuricemia and gout based on a comparison of allele frequencies with the European population, according to topological models, according to programs predicting the functional impacts of variants and searches in specialised literature. We also took into account the conclusions of functional studies analysing the impact of nonsynonymous variants in the ABCG2 and SLC2A9 genes. We also focused on the effect of the concomitant occurrence of several...
|
|
|
Mechanisms of muscle inflammation and clinical manifestations in patients polymyositis and dermatomyositis
Studýnková-Tomasová, Jana ; Vencovský, Jiří (advisor) ; Bartůňková, Jiřina (referee) ; Hrnčíř, Zbyněk (referee)
Idiopathic inflammatory myopathies (IIM) is a heterogeneous group of acquired diseases with varying course and prognosis nehnisavým caused by inflammation of striated muscle. Clinically they are characterized primarily by proximal muscular weakness. On the basis of specific clinical, histopathological, immunological and demographic features of the breakers can be divided into three subgroups dermatomyositis (DM), polymyositis (PM) and inclusion bodies with myositis (IBM). The aetiology of these diseases is unknown and there is also rooted difficulties with their treatment. The common objective of the project was to try to map out the mechanisms leading to inflammatory infiltration of muscles, muscle tissue edema and tissue damage, and subsequently to clinical manifestations of disease in patients with PM and DM.
|
|
|
Immunogenetic and hormonal markers of predisposition to systemic rheumatic diseases particularly systemic lupus erythematosus
Fojtíková, Markéta ; Pavelka, Karel (advisor) ; Hrnčíř, Zbyněk (referee) ; Rovenský, Jozef (referee)
Fojtikova 2011 INTRODUCTION: Several factors like genetic susceptibility is required for systemic rheumatic diseases development. Immunomodulatory PRL effect supports autoimmunity. AIMS: 1. To detect the immunogenetic background (alleles HLA class I, II and microsatellite polymorphism of the transmembrane part exon 5 of MIC-A gene) of SLE and PsA. 2. To detect PRL serum and synovial fluid with regard to clinical and laboratory RA activity. 3. To find the role of the functional polymorphism -1149G/T SNP PRL of extrapituitary promoter of PRL gene in SLE, RA, PsA, SSc and inflammatory myopathies development. METHODS: Genetic analyses of pateints with SLE (n=156), RA (n=173), PsA (n=100), SSc (n=75), PM (n=47) a DM (n=68) and 123 healthy individuals: PCR-SSP (HLA clase I and II), PCR-fragment analysis (MIC-A) a PCR-RFLP (-1149 G/T SNP PRL). In 29 RA a 26 OA PRL serum and synovial fluid concentrations were detected using immunoradiometric assay. RESULTS: 1. The allele HLA-DRB1*03 (pc=0.008; OR 2.5) and haplotype HLA-DRB1*03-DQB1*0201 (pc <0.001; OR 4.54) were determined as risk immunogenetic markers for SLE in Czech population. In SLE versus controls allele MIC-A5.1 was increased (pc =0.005; OR 1.88). MIC-A5.1 together with HLA-DRB1*03 increases the risk for SLE development, pc <0.000001; OR 9.71....
|
guest ::
