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Szodoray P.,University of Oslo | Papp G.,Medical and Health Science Center | Nakken B.,Institute of Basic Medical science | Harangi M.,Debrecen University | Zeher M.,Medical and Health Science Center
Autoimmunity Reviews | Year: 2010

Extracorporeal photochemotherapy, or photopheresis is a low-risk therapeutical intervention, which has been introduced in a variety of hematological malignancies, autoimmune conditions and transplantation. The mode of action of photopheresis encompasses apoptosis-induction and modifications of immunoregulatory processes, leading to the elimination of malignant cells, as well as the down-modulation of harmful immune responses. Although the beneficial effects of the therapy have been depicted in numerous studies, little is known about the exact benefits and the molecular mechanisms behind. The aim of the present review was to portray some aspects of the molecular and clinical rationale of extracorporeal photochemotherapy in autoimmune diseases, malignancies and transplantation, and to provide an overview of the treatment in the modern clinical management of these diseases. © 2009 Elsevier B.V. All rights reserved.


Toth B.,Debrecen University | Wolff A.S.B.,University of Bergen | Halasz Z.,Semmelweis University | Tar A.,Heim Pal Childrens Hospital | And 7 more authors.
Clinical Endocrinology | Year: 2010

Objective Autoimmune polyendocrine syndrome type I (APS I) is a rare primary immunodeficiency disorder characterized by chronic mucocutaneous candidiasis, multi-organ autoimmunity and ectodermal dysplasia. Autoantibodies to parathyroid and adrenal glands and type I interferons (IFN) are hallmarks of APS I, which results from mutations in the autoimmune regulator (AIRE) gene. We wished to study clinical, immunological and genetic features of APS I in Hungarian patients, and to correlate anti-IFN-ω serum concentration with APS I and other multi-organ autoimmune diseases. Design Detailed analysis of patients with APS I and multi-organ autoimmune diseases. Patients Seven patients with APS I and 11 patients with multi-organ autoimmune diseases were studied. Measurements Mutational analysis was performed by bidirectional sequencing of AIRE. Antibodies against IFN-ω and endocrine organ-specific autoantigens were studied with radioimmunoassay. RFLP was performed by digestion of DNA with Hin6I restriction enzyme. Results AIRE sequence analysis revealed homozygous c.769C>T mutations in three patients and compound heterozygous sequence variants (c.769C>T/c.44-66dup26bp; c.769C>T/c.965-977del13bp; c.769C>T/c.1344delC) in four patients with APS I. All the six live patients tested had markedly elevated IFN-ω antibodies, which were not found in heterozygous siblings or parents. One of the identified patients was negative for antibodies against IFN-ω at 6 weeks of age, but became positive at 7 months. At age 1, he is still without symptoms of the disease. In contrast to patients with APS I, no AIRE mutation or elevation of IFN-ω antibodies were detected in patients with multi-organ autoimmune diseases. Conclusion This is the first overview of patients diagnosed with APS I in Hungary. A novel c.1344delC mutation in AIRE was detected. Anti-IFN-ω antibodies seem to appear very early in life and are helpful to differentiate APS I from other multi-organ autoimmune diseases. © 2010 Blackwell Publishing Ltd.


Tromm A.,Ev. Krankenhaus Hattingen GmbH | Bunganic I.,Gastroenterologicka Ambulancia | Tomsova E.,District Hospital Mlada Boleslav | Tulassay Z.,SOTE II Sz Belgyogyaszati Klinika | And 16 more authors.
Gastroenterology | Year: 2011

Background & Aims Comparative data on budesonide vs mesalamine for the treatment of mild-to-moderately active Crohn's disease (CD) are sparse. We assessed the efficacy and safety of each therapy in patients with mildly to moderately active CD. Methods We performed a randomized, double-blind, double-dummy, 8-week, multicenter study in which 309 patients with mildly to moderately active CD received pH-modified-release oral budesonide (9 mg/day once daily or 3 mg/day 3 times daily) or Eudragit-Lcoated oral mesalamine (4.5 g/day). Results The primary efficacy variable, clinical remission (defined as Crohn's Disease Activity Index ≤150), at the final visit occurred in 69.5% (107 of 154) of patients given budesonide vs 62.1% (95 of 153) of patients given mesalamine (difference, 7.4%; 95% repeated confidence interval, -4.6% to 18.0%; P = .001 for noninferiority). Clinical remission rates did not differ significantly between the 2 budesonide groups. Treatment response, defined as Crohn's Disease Activity Index of 150 or less and/or a decrease of 70 or more (Δ70) or 100 or more (Δ100) points from baseline to final visit, did not differ significantly between patients given budesonide vs mesalamine (Δ70, P = .11; Δ100, P = .15), or between the 2 budesonide groups (Δ70, P = .38; Δ100, P = .78). No other efficacy end points differed significantly between groups. Discontinuation because of adverse events occurred in 3% and 5% of budesonide- and mesalamine-treated patients, respectively. There were no clinically relevant differences in adverse events between the 2 budesonide groups. Conclusions Budesonide (9 mg/day) was numerically, but not statistically, more effective than Eudragit-Lcoated mesalamine (4.5 g/day) in patients with mildly to moderately active CD. Budesonide (9 mg/day), administered once daily, was as effective as the standard (3 times daily) regimen. © 2011 AGA Institute.


Schmitt-Hoffmann A.H.,Basilea Pharmaceutica International Ltd. | Roos B.,Basilea Pharmaceutica International Ltd. | Sauer J.,Basilea Pharmaceutica International Ltd. | Schleimer M.,Basilea Pharmaceutica International Ltd. | And 3 more authors.
Clinical and Experimental Dermatology | Year: 2011

Background: Previous studies have shown that concomitant administration of food may enhance the bioavailability of oral retinoids. Aim: To assess the influence of food on the pharmacokinetics (PK) of alitretinoin after a single oral dose. Methods: This was a single-dose, open-label, randomized, crossover study, which enrolled 30 healthy men, aged 18-44years. Subjects received sequential doses of alitretinoin 40mg either after fasting (treatment A) or 5min after completion of a standard breakfast (treatment B), with the dosing sequence randomized (A/B or B/A). The washout period between the two doses was 1week. Plasma concentrations over time were plotted and standard PK variables [area under the curve (AUC) of plasma concentration vs. time, maximum plasma concentration (C max), time to maximum plasma concentration (t max) and elimination half-life (t 1/2)] were determined. Results: Drug exposure was markedly increased when alitretinoin was taken with food compared with fasting, and there were significant increases in mean C max (82.8 vs.25.4ng/mL, respectively) and AUC (220.2 vs. 55.7ng·h/mL). The delaying effect of food on t max was less marked (median of 3.0 vs. 2.0h). Administration with food also increased exposure to drug metabolites. Variability in exposure was markedly reduced if alitretinoin was taken with vs. without food (percentage coefficient of variation 40% vs. 74% for AUC; 49% vs. 85% for C max). Alitretinoin was generally well tolerated, with typical retinoid adverse reactions, mostly comprising headache. Conclusions: Intake of alitretinoin with food substantially increased the bioavailability of alitretinoin, but variability in exposure was reduced. Consequently, oral alitretinoin should be taken with food as outlined in the manufacturer's summary of product characteristics. © 2011 The Author(s). Clinical and Experimental Dermatology © 2011 British Association of Dermatologists.


Bleul T.,University of Heidelberg | Ruhl R.,Medical and Health Science Center | Bulashevska S.,University of Bonn | Karakhanova S.,University of Heidelberg | And 3 more authors.
Molecular Carcinogenesis | Year: 2015

Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. All-trans retinoic acid (ATRA) is the major physiologically active form of vitamin A, regulating expression of many genes. Disturbances of vitamin A metabolism are prevalent in some cancer cells. The main aim of this work was to investigate deeply the components of retinoid signaling in PDAC compared to in the normal pancreas and to prove the clinical importance of retinoid receptor expression. For the study, human tumor tissues obtained from PDAC patients and murine tumors from the orthotopic Panc02 model were used for the analysis of retinoids, using high performance liquid chromatography mass spectrometry and real-time RT-PCR gene expression analysis. Survival probabilities in univariate analysis were estimated using the Kaplan-Meier method and the Cox proportional hazards model was used for the multivariate analysis. In this work, we showed for the first time that the ATRA and all-trans retinol concentration is reduced in PDAC tissue compared to their normal counterparts. The expression of RARα and β as well as RXRα and β are down-regulated in PDAC tissue. This reduced expression of retinoid receptors correlates with the expression of some markers of differentiation and epithelial-to-mesenchymal transition as well as of cancer stem cell markers. Importantly, the expression of RARα and RXRβ is associated with better overall survival of PDAC patients. Thus, reduction of retinoids and their receptors is an important feature of PDAC and is associated with worse patient survival outcomes. © 2014 Wiley Periodicals, Inc..


Lazar V.,Debrecen University | Ecsedi S.,Debrecen University | Ecsedi S.,Hungarian Academy of Sciences | Vizkeleti L.,Debrecen University | And 10 more authors.
Melanoma Research | Year: 2012

Somatic mutations of BRAF and NRAS oncogenes are thought to be among the first steps in melanoma initiation, but these mutations alone are insufficient to cause tumor progression. Our group studied the distinct genomic imbalances of primary melanomas harboring different BRAF or NRAS genotypes. We also aimed to highlight regions of change commonly seen together in different melanoma subgroups. Array comparative genomic hybridization was performed to assess copy number changes in 47 primary melanomas. BRAF and NRAS were screened for mutations by melting curve analysis. Reverse transcription PCR and fluorescence in-situ hybridization were performed to confirm the array comparative genomic hybridization results. Pairwise comparisons revealed distinct genomic profiles between melanomas harboring different mutations. Primary melanomas with the BRAF mutation exhibited more frequent losses on 10q23-q26 and gains on chromosome 7 and 1q23-q25 compared with melanomas with the NRAS mutation. Loss on the 11q23-q25 sequence was found mainly in conjunction with the NRAS mutation. Primary melanomas without the BRAF or the NRAS mutation showed frequent alterations in chromosomes 17 and 4. Correlation analysis revealed chromosomal alterations that coexist more often in these tumor subgroups. To find classifiers for BRAF mutation, random forest analysis was used. Fifteen candidates emerged with 87% prediction accuracy. Signaling interactions between the EGF/MAPK-JAK pathways were observed to be extensively altered in melanomas with the BRAF mutation. We found marked differences in the genetic pattern of the BRAF and NRAS mutated melanoma subgroups that might suggest that these mutations contribute to malignant melanoma in conjunction with distinct cooperating oncogenic events. Copyright © Lippincott Williams & Wilkins.


Csorba R.,Medical and Health Science Center | Tsikouras P.,Democritus University of Thrace | Lampe R.,Medical and Health Science Center | Poka R.,Medical and Health Science Center
Archives of Gynecology and Obstetrics | Year: 2012

Introduction The purpose of this study is to describe the characteristics of female children who experience sexual abuse and explore common features that may assist in developing prevention strategies. Materials and methods Between 1990 and 2010, 266 girls under the age of 18 years, suspected of being sexually abused, visited the Department of Adolescent Gynecology. We retrospectively collected data illustrating the features of all cases. Seventy-eight percent of the victims were primary school students, and 45% of them were between 11 and 14 years of age. Results The perpetrator knew the victim in 67% of the cases and was a stranger in 33%. Seventy-Wve (28%) perpetrators were members of the victims' families. In 14% of cases, the perpetrator was the victim's father and in 9% her stepfather. The abuse had occurred on multiple occasions in 29% of the cases. The occurrence rate of abuse was highest in the summer season (54%). As much as 63% of children experienced vaginal penetration, while 37% experienced a variety of sexual contact that did not involve penetration. Eighty-Wve victims were physically injured, and in 40 cases the presence of sperm was conWrmed in vulvo-vaginal smears. A high proportion of female child sexual abuse takes place within the family and is revealed only after multiple episodes. The true prevalence of sexual abuse is being appreciated now that Hungarian law and society have recognized this societal problem. Conclusion Prevention requires a systematic and lifelong approach to educating children about personal space and privacy and is the responsibility of parents and professionals. © 2012 Springer-Verlag.


Kolozsvari B.L.,Medical and Health science Center | Petrovski G.,Medical and Health science Center | Petrovski G.,Stem Cells and Eye Research Laboratory | Gogolak P.,Medical and Health science Center | And 4 more authors.
Ophthalmic Research | Year: 2013

Purpose: To study the association between different types of mediators in the tear fluid and topographic indices characterizing the severity of keratoconus (KC). Methods: In this study, nonstimulated tear fluid samples were collected from 14 eyes of 11 patients with KC. The following indices were measured by corneal topography: maximum K value, average K value, Klyce/Maeda keratoconus index (KCI), Smolek/Klyce keratoconus severity index, opposite sector index, center/surround index, keratoconus prediction index and standard deviation of corneal power. The concentrations of interleukin (IL)-6, IL-13, CXCL8 (IL-8), chemokine (C-C motif) ligand 5 (CCL5, regulated and normal T cell expressed and secreted), matrix metalloproteinase-9 (MMP-9), MMP-13, tissue inhibitor of metalloproteinase-1, nerve growth factor (NGF) and epidermal growth factor were measured by cytometric bead array technology. Release of mediators was calculated from their concentrations and the volume of tears collected over 2 min. Results: Significant positive associations were found between CCL5, MMP-13 and NGF and several topographic indices. Significant negative correlations were found between IL-6 and KCI. Age-dependent associations were observed between IL-13, CXCL8, CCL5 and MMP-13 and the topographic data. Conclusion: Several correlations were observed between the mediators and the topographic indices, suggesting possible roles in the pathophysiology of KC. Our data indicate that some mediators have different effects on the severity of disease in an age-dependent manner. © 2013 S. Karger AG, Basel.


Glant T.T.,Rush University Medical Center | Besenyei T.,Rush University Medical Center | Kadar A.,Rush University Medical Center | Kurko J.,Rush University Medical Center | And 9 more authors.
Arthritis and Rheumatism | Year: 2013

Objective To identify epigenetic factors that are implicated in the pathogenesis of rheumatoid arthritis (RA), and to explore the therapeutic potential of the targeted inhibition of these factors. Methods Polymerase chain reaction (PCR) arrays were used to investigate the expression profile of genes that encode key epigenetic regulator enzymes. Mononuclear cells from RA patients and mice were monitored for gene expression changes, in association with arthritis development in murine models of RA. Selected genes were further characterized by quantitative reverse transcription-PCR, Western blot, and flow cytometry methods. The targeted inhibition of the up-regulated enzymes was studied in arthritic mice. Results A set of genes with arthritis-specific expression was identified by the PCR arrays. Aurora kinases A and B, both of which were highly expressed in arthritic mice and treatment-naive RA patients, were selected for detailed analysis. Elevated aurora kinase expression was accompanied by increased phosphorylation of histone H3, which promotes proliferation of T lymphocytes. Treatment with VX-680, a pan-aurora kinase inhibitor, promoted B cell apoptosis, provided significant protection against disease onset, and attenuated inflammatory reactions in arthritic mice. Conclusion Arthritis development is accompanied by changes in expression of a number of epigenome-modifying enzymes. Drug-induced down-regulation of the aurora kinases, among other targets, seems to be sufficient to treat experimental arthritis. Development of new therapeutics that target aurora kinases can potentially improve RA management. Copyright © 2013 by the American College of Rheumatology.


PubMed | Medical and Health Science Center
Type: | Journal: Cytometry. Part B, Clinical cytometry | Year: 2014

Background: Myelofibrosis (MF) is characterized by accumulation of stromal cells and extracellular matrix. Progression of fibrosis is an important clinical issue and monitoring is required for new therapeutic approaches. Currently the quantification is based on semi-quantitative evaluation of reticulin silver stained slides. We recently reported that platelet derived growth factor receptor beta (PDGFR) expression in fibroblasts is a useful marker of stromal activation. PDGFR expression based scores represent significant differences in different myelofibrosis grade which provides optimal source of quantification. In this study slide based measurements were performed in order to support correlations of PDGFR expression with MF grade. Methods: Scanned image tiles from 79 bone marrow samples (BM) with different myelofibrosis grades were evaluated for PDGFR-related IHC parameters. Following the determination of immunopositive (brown component) and total area (region of interest) of the BM, PDGFR related image parameters were defined and evaluated in comparison to the classical reticulin based grading. Results: Eight PDGFR expression related image parameters showed excellent correlation with the MF grade (correlation coefficient ranging between 0.79 and 0.83) and with PDGFR score (0.76-0.87). Despite the significant sample heterogeneity the parameters showed significant differences between fibrotic and non-fibrotic cases and between mild and advanced fibrosis. Distribution of values within a particular specimen emphasizes the heterogeneity of bone marrow involvement which may cause difficulties in semi-quantitative methods. Conclusions: Our results clearly demonstrated the correlation between myelofibrosis and PDGFR expression considering all relevant areas in BM samples. This method provides good basis for follow-up comparison of the fibrotic samples. 2014 Clinical Cytometry Society.

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