Gergely Klausz

Investigation of the Prognostic Value of TNF-α Gene Polymorphism among Patients Treated with Infliximab, and the Effects of Infliximab Therapy on TNF-α Production and Apoptosis

Objectives: Infliximab, a chimeric anti-tumor necrosis factor (TNF) antibody, is highly effective for the treatment of Crohn’s disease (CD) and rheumatoid arthritis (RA). Our experiments focused on RA and CD patients receiving infliximab. Since cytokine production is largely determined by genetic factors, the promoter polymorphisms of TNF-α were examined among these patients. Additionally, the changes caused by infliximab in the TNF-α-producing ability and apoptosis of peripheral blood mononuclear cells (PBMCs) were investigated. Methods: The TNF-α genotypes were analyzed by PCR-RFLP. The in vitro TNF-α production of the PBMCs was detected by flow cytometric analysis. The TNF-α concentration in the supernatant was measured by bioassay. Apoptosis was detected by annexin V-fluorescein isothiocyanate labeling. Results and Conclusions: 8 of the 12 nonresponder patients carried the TNF A allele associated with high TNF-α production. We suggest that the determination of TNF polymorphism may help identify more suitable candidates for infliximab treatment. Although in vitro infliximab treatment for 48 h resulted in significant (44.2 ± 1.17%) apoptosis in PBMCs, in ex vivo samples from RA patients who received infliximab, apoptosis was only 13.3 ± 1.6%. Furthermore, infliximab did not result in irreversible inhibition of the TNF-α-producing ability or in the significant apoptosis of PBMCs.

Polymorphism of the heat-shock protein gene Hsp70-2, but not polymorphisms of the IL-10 and CD14 genes, is associated with the outcome of Crohn's disease

Objective. In Crohns disease (CD) a Th-1 dominant immune reaction is induced, which could be associated with genetic predisposition. Several previous studies have investigated the roles of CD14, heat-shock protein (Hsp)70 and IL-10 gene polymorphisms in the development of the disease. The results are contradictory and inter-racial differences are implicated. Therefore, this phenomenon was evaluated in well-documented Caucasian patients with CD in order to verify the clinical importance of these polymorphisms. Material and methods. The genomic DNA of 133 patients with CD and that of 75 healthy controls were examined. CD was divided into subgroups according to the Vienna classification. An arbitrary classification system based on disease severity was also applied, which was determined according to the therapeutic intervention. The CD14 (−159 C→T) promoter gene polymorphism was investigated by melting-point analysis. The IL-10 (−1082 G→A) and Hsp70-2 (1267 A→G) gene polymorphisms were detected by RFLP (restriction fragment length polymorphism). Results. None of the allele frequencies of the examined polymorphisms differed significantly between the patient and control populations. Neither the CD14 nor the IL-10 polymorphisms exhibited any correlation with the development or with the progression of the disease. With regard to Hsp70-2 gene polymorphism, those patients who carry at least one A allele have a significantly lower probability of the need for surgical intervention. Conclusions. Allele A of the Hsp70-2 gene may be associated with a less severe form of CD, suggesting the clinical value of the genotype assessment. The genetic determination of the defense mechanisms in CD appears to be associated with the polymorphism of the Hsp70-2 gene rather than that of the CD14 or IL-10 genes.

Characterization of a novel multifunctional resveratrol derivative for the treatment of atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an increased risk for stroke, heart failure and cardiovascular‐related mortality. Candidate targets for anti‐AF drugs include a potassium channel Kv1.5, and the ionic currents IKACh and late INa, along with increased oxidative stress and activation of NFAT‐mediated gene transcription. As pharmacological management of AF is currently suboptimal, we have designed and characterized a multifunctional small molecule, compound 1 (C1), to target these ion channels and pathways.

Randomized Trial of Intracardiac Echocardiography During Cavotricuspid Isthmus Ablation

Randomized Trial of ICE During CTI Ablation. Introduction: Despite a high success rate, radio‐frequency ablation (RFA) of the cavotricuspid isthmus (CTI) can be unusually challenging in some cases. We postulated that visualization of the CTI with intracardiac echocardiography (ICE) could maximize the succes rate, decrease the procedure and ablation time, and minimize the radiation exposure.

T-251A polymorphism of IL-8 relating to the development of histological gastritis and G-308A polymorphism of TNF-α relating to the development of macroscopic erosion

Objectives Genetic variations of the inflammatory IL-8 and TNF-&agr; genes can influence the outcome of gastric alterations. Our aims were to determine the prevalence and effect of the T-251A functional polymorphism of IL-8 and the G-308A polymorphism of TNF-&agr; in histological and macroscopic gastric diseases related to Helicobacter pylori infection. Methods Genomic DNA was extracted from biopsy samples from patients with gastritis (n=86, H. pylori positive=41), atrophy (n=32, H. pylori positive=13), intestinal metaplasia (IM) (n=43, H. pylori positive=22) and from histologically negative patients (n=57). The samples were divided by macroscopic diagnosis into erosion and negative groups. The T-251A polymorphism was examined with the amplification refractory mutation system method; the G-308A polymorphism was determined by the polymerase chain reaction-restriction fragment length polymorphism method. For statistical evaluation, Fischers exact test was used. Results In the case of T-251A of IL-8, the frequency of the A/A genotype was significantly increased in gastritis (P=0.049) and IM (P=0.038) groups as compared with the histologically negative ones. No relationship was found between macroscopic erosions and H. pylori infection. In the case of G-308A, the G/G genotype frequency was statistically increased in erosions as compared with negative groups (P=0.035). No difference in the distribution of G-308A genotypes in relation to histological alterations and the H. pylori infection was observed. Conclusions The effect of the polymorphism of IL-8 seems to be relevant in the pathogenesis of histological gastritis and IM, and the effect of the polymorphism of TNF-&agr; is relevant in the pathogenesis of macroscopic erosive gastritis.

Intracardiac echocardiography in a case with previous failed cavotricuspid isthmus ablation

The Eustachian ridge (ER) can present an obstacle to cavotricuspid isthmus (CTI) ablation. We describe a case, where intracardiac echocardiography revealed a prominent ER as a likely reason for a previous failed CTI ablation and guided the looping of the ablation catheter around the ER, resulting in an ultimately successful ablation.

Electrogram analysis at the His bundle region and the proximal coronary sinus as a tool to predict left atrial origin of focal atrial tachycardias

AIMS Early activation at the His bundle (HB) region or proximal coronary sinus (CS) during focal atrial tachycardias (FATs) often necessitates biatrial mapping. Analysis of CS electrograms (EGMs) consisting of a near-field (N) component from CS musculature and a far-field (F) component from left atrial (LA) myocardium can uncover LA activation preceding right atrial (RA) activation. A similar pattern might be observed at the HB. METHODS AND RESULTS Eight patients underwent RA and LA pacing testing the hypothesis that N and F components originating from the RA and LA septum are present in the HB atrial EGM (Pacing group). In this group N preceded F (N-F sequence) in all, while F preceded N (F-N sequence) in seven of eight patients during RA and LA pacing, respectively. Twenty-seven patients with FAT demonstrating earliest activation at the HB or proximal CS during limited RA mapping were also studied (FAT group). Two observers analysed the EGMs at the earliest site during FAT. They found an N-F sequence in 17 (94%) and 16 (89%) of 18 RA FAT and an F-N sequence in seven (78%) and eight (89%) of nine LA FAT, respectively. The F-N sequence predicted the need for LA access with a sensitivity of 78 and 89% and a specificity of 94 and 89%. CONCLUSION Near-field and F components from RA and LA activation can be identified in the HB atrial EGM. Earliest atrial EGM analysis at the HB or CS can predict the need for LA access during FAT ablation.

Role of triggering pulmonary veins in the maintenance of sustained paroxysmal atrial fibrillation.

Triggers from thoracic veins have been implicated not only in the initiation, but also in the perpetuation of paroxysmal atrial fibrillation (PAF). To investigate their role we studied the distribution and stability of dominant frequencies (DFs) during PAF and the response to isolation of the triggering pulmonary vein (PV).

Loss of Biventricular Pacing and Inappropriate Therapy by a Cardiac Resynchronization Implantable Defibrillator

The following tracings were recorded from a patient implanted with a Lumax 540 HFT (Biotronik GmbH, Berlin, Germany) cardiac resynchronization implantable cardioverter defibrillator (ICD). The patient has received an ICD shock without any antecedent symptoms. On the first tracing (Fig. 1A) only right ventricular pacing (RVP) is carried out during tracking of atrial rhythm, presumably sinus tachycardia. Subsequently ventricular fibrillation (VF) is detected and capacitor charging is initiated. The second tracing (Fig. 1B) was recorded before another (aborted) episode. Initially there is only RVP again. After two ventricular premature complexes (PVCs) biventricular (BiV) pacing is restored but lost again after a ventricular sensed event falling in the VF zone. What anomaly(ies) explain the VF detection and loss of BiV pacing?