Ulcerative Colitis: Tulassay Z

Herszényi L, Farinati F, Miheller P, Tulassay Z. · 2nd Department of Medicine, Semmelweis University, Hungarian Academy of Science, Budapest, Hungary. · Eur J Cancer Prev. · Pubmed #18941372 No free full text.

Abstract: Chemoprevention means the use of agents to prevent, delay, or reverse carcinogenesis. This review was designed to critically discuss the most promising agents in colorectal cancer (CRC) chemoprevention. Aspirin is the best studied chemopreventive agent for CRC. Optimal chemoprevention requires long-term use and high dose of aspirin that may increase the risk of gastrointestinal bleeding. Nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors may also be candidates for chemoprevention. The regular use of nonsteroidal anti-inflammatory drugs, however, causes adverse effects including gastrointestinal bleeding, and cyclooxygenase-2 inhibitors may increase the risk of cardiovascular events. In patients with ulcerative colitis 5-aminosalicylates reduce the risk of CRC and dysplasia. Ursodeoxycholic acid can reduce the risk of dysplasia or CRC in patients with primary sclerosing cholangitis and ulcerative colitis. Current data are insufficient to support the use of hormone replacement therapy to reduce the risk of CRC. Statins may have chemopreventive effects, but further investigation of their overall benefits in preventing CRC is warranted. Antioxidant supplements cannot prevent CRC. The usefulness of selenium, folate, calcium, and vitamin D awaits further evaluation. Chemoprevention cannot yet be accepted as standard medical practice. Use of chemopreventive agents cannot be a substitute for colorectal surveillance.

Hagymási K, Tulassay Z. · Semmelweis Egyetem, Altalános Orvostudományi Kar, II. Belgyógyászati Klinika, Budapest. · Orv Hetil. · Pubmed #17120688 No free full text.

Abstract: The colorectal cancer is one of the most serious complication of inflammatory bowel disease. Longer duration of the disease, extensive colitis, primary sclerosing cholangitis, family history of colorectal cancer are the main risk factors. The relative risk of colorectal cancer in ulcerative colitis is increased, however, there're marked geographically differences. Relative risk of colorectal cancer is 2.5 and small bowel cancer risk is 31.2 in Crohn's disease. There aren't prospective, randomized, controlled trials that definitively prove the benefit of surveillance of colorectal cancer in IBD. Colonoscopy improve the 5-year survival rate, however, there is no evidence for the reduction of mortality. Meta-analysis showed efficacy of mesalamine in the reduction of risk of colorectal cancer, but prospective trials have been missed. Chemoprotective role of other immunomodulators has not been proven yet.

Lengyel G, Tulassay Z. · Semmelweis Egyetem, Altalános Orvostudományi Kar, II. Belgyógyászati Klinika. · Orv Hetil. · Pubmed #16398312 No free full text.

Abstract: Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease with the segmental inflammation, obliterative fibrosis and cholestasis of intra- and extrahepatic biliary ducts which leads to secondary biliary cirrhosis. Its aetiology is unknown. The disease is accompanied with ulcerative colitis in 70-80 percent. Its clinical progress is variable, the average duration of the disease is between the diagnosis and the final stage (liver transplantation) about 18 years. The prevalence of PSC is 1-5/100 000 inhabitants. Mainly it occurs in male patients (70 %), male-female rate is 2:1. The authors summarise the treatment modalities after reviewing the pathogenesis, clinical picture and the diagnostic procedures. The pathomechanism of the basis therapy with ursodeoxycholic acid (UDCA) is discussed in details, especially its effects on the clinical picture and the laboratory data. The authors review the results of the immunosuppressive therapy and the treatments of specific complications in PSC. They underline the importance and opportunities of the early diagnosis of cholangiocarcinoma, which is very frequent in this disease.

Hagymási K, Tulassay Z. · Semmelweis Egyetem, Altalános Orvostudományi Kar, II. Belgyógyászati Klinika, Budapest. · Orv Hetil. · Pubmed #16184878 No free full text.

Abstract: Inflammatory bowel disease has traditionally been categorized as either ulcerative colitis or Crohn's disease on the basis of clinical, radiological and histological criteria. Emerging data suggest that inflammatory bowel disease comprises a heterogenous family of inflammatory disorders in which the specific clinical manifestations of disease are determined by the interaction of genetic and environmental factors. Interactions of susceptibility and modifying genes influence the specific features of disease phenotype, penetrance, location, behavior, and complication. CARD15/NOD2 mutations are significantly associated with ileal location, whereas certain HLA haplotypes are associated with colonic disease. The associations with CARD15/ND2 mutations and early age at onset, as well as disease behavior (stricturing, fistulizing type) are less consistent. Distinct HLA alleles contribute to the occurrence of extraintestinal manifestation. With the increasing number of genotype-phenotype relationship, it is hoped that a molecular classification can be created, in which various disease subtypes are categorized according to their specific genotypes. In the future, such sheme may permit early, accurate diagnosis, prediction of disease course, complications, prognosis, as well as treatment response.

Sipos F, Molnár B, Zágoni T, Tulassay Z. · Altalános Orvostudományi Kar, II. Belgyógyászati Klinika, Semmelweis Egyetem, Budapest. · Orv Hetil. · Pubmed #12073537 No free full text.

Abstract: INTRODUCTION: The pathogenesis of inflammatory bowel diseases is still unknown, but is accessible from several ways. One possibility is the immunohistochemical analysis of cellular changes in the intestinal mucosa. The increased epithelial cell turnover is connected with false immunological pathways in the subepithelial layer. Behind these disturbances which can lead to chronic remitting inflammatory processes the imbalance of apoptosis and proliferation plays a key role. AIM: Of this study is to summarize our current knowledge of the cell kinetical alterations considering histological activity of disease. CONCLUSIONS: On the basis of current understanding it is known that the apoptosis and proliferation of epithelial cells increase in active inflammation compare to normal, although an uniform standpoint of evaluating is still missing. Some alterations of apoptosis and antigen presentation are described in the mononuclear cells of the subepithelial layer. Getting acquainted with and describing the changes of cell kinetics provide facilities to develop new and effective diagnostical methods and therapies.

Eliakim R, Tulassay Z, Kupcinskas L, Adamonis K, Pokrotnieks J, Bar-Meir S, Lavy A, Mueller R, Greinwald R, Chermesh I, Gross V, Anonymous00328. · Gastroenterology Department, Rambam Medical Center, Haifa, Israel. · Aliment Pharmacol Ther. · Pubmed #17944738 No free full text.

Abstract: BACKGROUND: Rectally administered mesalazine (mesalamine; 5-aminosalicylic acid) is the first-line therapy for treatment of distal ulcerative colitis. Recently, a high-volume 5-aminosalicylic acid foam has been shown to be as effective and safe as standard 5-aminosalicylic acid enema. AIM: To study the efficacy and safety of a low-volume vs. a high-volume 5-aminosalicylic acid foam. METHODS: In this investigator-blinded study, patients with active distal ulcerative colitis [Clinical Activity Index (CAI) > 4, Endoscopic Index > or = 4] were randomized to receive 2 x 1 g/30 mL low-volume (n = 163) or 2 x 1 g/60 mL high-volume 5-aminosalicylic acid foam (n = 167) for 42 days. Primary end point was clinical remission (CAI < or = 4) at the final/withdrawal visit (per-protocol). RESULTS: 330 patients were evaluable for efficacy and safety by intention-to-treat, 290 for per-protocol analysis. Clinical remission rates at week 6 (per-protocol) were 77% on low-volume foam vs. 77% on high-volume foam (P = 0.00002 for non-inferiority). The low-volume foam was associated with a lower frequency of severe discomfort, pain and retention problems. CONCLUSIONS: Low-volume 5-aminosalicylic acid foam is as effective and safe as a high-volume 5-aminosalicylic acid foam in the treatment of active distal ulcerative colitis, but offers compliance advantages compared to the high-volume preparation.

Lakner L, Csöngei V, Magyari L, Varga M, Miheller P, Sarlós P, Orosz P, Bári Z, Takács I, Járomi L, Sáfrány E, Sipeky C, Bene J, Tulassay Z, Döbrönte Z, Melegh B. · Vas Megyei Markusovszky Kórház Nonprofit Zrt. Gasztroenterológiai és Belgyógyászati Osztály Szombathely. · Orv Hetil. · Pubmed #19581171 No free full text.

Abstract: The IBD5 locus (MIM#606348) on chromosome 5q31 has been demonstrated to confer increased risk for inflammatory bowel disease. Controversial reports have been published about the significance of individual loci located in this region. Here we investigated the possible genetic association of inflammatory bowel diseases with C1672T of SLC22A4 and G-207C SLC22A5 alleles, and with IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility variants of the IBD5 region located on chromosome 5q31. Patients and methods: Total of 440 patients, 206 with Crohn's disease, 234 with ulcerative colitis, and 279 controls were studied by PCR-RFLP methods. Results: Neither the C1672T, and G-207C alleles, nor the TC haplotype were found to confer risk for Crohn's disease or ulcerative colitis. By contrast, both of the minor allele frequencies of IGR2096a_1 T (48.1%) and IGR2198a_1 C (46.1%) were increased in Crohn's disease subjects as compared with the controls (38.5% and 38.4%, respectively; p<0.05). Using regression analysis adjusted to age and gender these alleles were found to confer risk for Crohn's disease (OR=1.694, 95% CI: 1.137-2.522; p=0.010 for T allele, OR=1.644, 95% CI=1.103-2.449; p=0.015 for C allele of IGRs). In UC no such associations were found. Conclusions: Our results revealed the susceptibility nature of the examined IGR minor alleles in Hungarians, which nation differs historically from the surrounding Caucasian populations in origin of the founders of the state.

Lakner L, Csöngei V, Sarlós P, Járomi L, Sáfrány E, Varga M, Orosz P, Magyari L, Bene J, Miheller P, Tulassay Z, Melegh B. · Department of Medicine and Gastroenterology, Markusovszky Hospital, Szombathely, Hungary. · Int J Colorectal Dis. · Pubmed #19214536 No free full text.

Abstract: BACKGROUND AND AIMS: We investigated the possible association of IBD with C1672T of SLC22A4 and G-207C of SLC22A5 alleles, and with the novel IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility loci, all located on IBD5 locus of chromosome 5q31. MATERIALS AND METHODS: DNA of 217 Crohn's disease, 252 ulcerative colitis, and 290 control patients were analyzed by polymerase chain reaction/restriction fragment length polymorphism methods. RESULTS: Neither the C1672T and G-207C alleles, nor the TC haplotype were found to be risk factors. By contrast, the minor allele frequencies of IGR2096a_1 T (47.2%) and IGR2198a_1 C (45.9%) were increased in Crohn's disease compared with the controls (38.2% and 37.7%, respectively; p < 0.05); multivariate regression analysis revealed a risk nature for Crohn's disease (OR = 1.748, 95% CI 1.186-2.574; p = 0.007 for T allele, OR = 1.646, 95% CI 1.119-2.423, p = 0.011 for C allele of IGRs). CONCLUSION: The data suggest a special haplotype arrangement of susceptibility genes at the IBD5 locus in Hungarians, which nation differs historically from the surrounding Caucasian ethnicities in its origin.

Lakatos PL, Altorjay I, Szamosi T, Palatka K, Vitalis Z, Tumpek J, Sipka S, Udvardy M, Dinya T, Lakatos L, Kovacs A, Molnar T, Tulassay Z, Miheller P, Barta Z, Stocker W, Papp J, Veres G, Papp M, Anonymous00019. · 1st Department of Medicine, Semmelweis University, Budapest, Hungary. · Inflamm Bowel Dis. · Pubmed #18972554 No free full text.

Abstract: BACKGROUND: Pancreatic autoantibodies (PAB) and goblet cell autoantibodies (GAB) are specific for Crohn's disease (CD) and ulcerative colitis (UC), but the sensitivity alone is low. Conventional antibodies and carbohydrates (glycans) are associated with disease phenotype and may be of diagnostic importance in inflammatory bowel disease (IBD). Our aim was to determine the accuracy of PAB and GAB autoantibodies as well as to study relevant phenotype-serotype associations. METHODS: A Hungarian study cohort of 1092 subjects, including 689 well-characterized, unrelated IBD patients (CD: 579, m/f ratio: 274/305, duration: 7.9 +/- 11.2 years; UC: 110, m/f ratio: 53/57, duration: 8.9 +/- 9.8 years), 139 celiac patients, 100 healthy, and 64 non-IBD gastrointestinal controls were investigated. Sera were assayed for PAB-GAB IgA/IgG, anti-Omp, anti-Saccharomyces cerevisiae antibodies (ASCA), and anti-glycans. TLR4 and NOD2/CARD15 was tested by polymerase chain reaction / restriction fragment length polymorphism (PCR-RFLP). Detailed clinical phenotypes were determined. RESULTS: The prevalence of PAB was significantly more frequent in CD (41.1%) versus UC (22.7%), celiac (22.3%), and controls (8% and 4.6%, P < 0.01 for each), while GAB detection was poor in all groups except UC (15.4%). In CD the combination of PAB and/or anti-glycans/ASCA increased the sensitivity to 72% and 59%, respectively, for isolated colonic disease. PAB was associated to gylcans (odds ratio [OR] 1.74,P = 0.002), ASCA IgG/IgA (OR 1.75, P = 0.002), Omp (OR 1.86, P = 0.001) as well as perforating, perianal disease, arthritis, ocular, and cutaneous manifestations (P = 0.002-0.032). In contrast, PAB and GAB antibodies were not associated with NOD2/CARD15 or TLR4, response to medical therapy, or need for surgery. No associations were found in UC. CONCLUSIONS: PAB autoantibodies in combination with ASCA or anti-glycan antibodies increase the sensitivity for detecting CD, especially isolated colonic CD. Antibody response to PAB was associated with complicated disease phenotype and extraintestinal manifestations in this Eastern European IBD cohort.

Sipos F, Galamb O, Herszényi L, Molnár B, Solymosi N, Zágoni T, Berczi L, Tulassay Z. · and Department of Internal Medicine, Semmelweis University, Budapest, Hungary. · Scand J Gastroenterol. · Pubmed #18938767 No free full text.

Abstract: OBJECTIVE: The risk of development of colorectal carcinoma is elevated in chronic, long-standing ulcerative colitis (UC). The changes in regenerative and immortalizing pathways caused by the inflammatory process, and that have been proved to be carcinogenic in other human tissues, have not been fully and uniformly described. We assayed the expression alterations of regenerative signal receptors and cell-aging inhibitory systems within colonic crypts by considering the histological activity of the disease. METHODS: I-type insulin-like growth factor receptor (IGF1R), hepatocyte growth factor receptor (HGFR), telomerase reverse transcriptase (TERT) and telomerase associated protein (TP-1) expression were evaluated immunohistochemically on biopsy specimens from 11 mild, 11 moderate and 12 severe active inflammation of UC cases and from 10 normal colonic tissue cases. Independent colonic biopsies from 5 healthy and 7 severe UC cases were used for TaqMan real-time RT-PCR validation. RESULTS: In mild inflammation, all observed parameters showed significantly elevated epithelial protein expression (IGF1R: 22.3 +/- 9.46%; HGFR: 35.3 +/- 22.8%; TERT/TP-1: 2.1 +/- 1.87%/2 +/- 1.32%) compared to normal (p < 0.005). In moderately active inflammation, only IGF1R expression was significantly higher (50.2 +/- 8.6%) compared to normal and mild inflammation (p < 0.005). In severe inflammation, all parameters showed decreased epithelial expression; IGF1R showed decreased mRNA expression, while HGFR was overexpressed and TERT showed a decreased tendency. CONCLUSIONS: The epithelial expression of IGF1R, HGFR and TERT/TP-1 is elevated in mildly active UC. This phenomenon may allow the epithelial cells that collected genetic defects during severe inflammatory episodes pathologically to survive and proliferate.

Galamb O, Györffy B, Sipos F, Spisák S, Németh AM, Miheller P, Tulassay Z, Dinya E, Molnár B. · 2nd Department of Medicine, Semmelweis University, Budapest, Hungary. · Dis Markers. · Pubmed #18776587 No free full text.

Abstract: Gene expression analysis of colon biopsies using high-density oligonucleotide microarrays can contribute to the understanding of local pathophysiological alterations and to functional classification of adenoma (15 samples), colorectal carcinomas (CRC) (15) and inflammatory bowel diseases (IBD) (14). Total RNA was extracted, amplified and biotinylated from frozen colonic biopsies. Genome-wide gene expression profile was evaluated by HGU133plus2 microarrays and verified by RT-PCR. We applied two independent methods for data normalization and used PAM for feature selection. Leave one-out stepwise discriminant analysis was performed. Top validated genes included collagenIValpha1, lipocalin-2, calumenin, aquaporin-8 genes in CRC; CD44, met proto-oncogene, chemokine ligand-12, ADAM-like decysin-1 and ATP-binding casette-A8 genes in adenoma; and lipocalin-2, ubiquitin D and IFITM2 genes in IBD. Best differentiating markers between Ulcerative colitis and Crohn's disease were cyclin-G2; tripartite motif-containing-31; TNFR shedding aminopeptidase regulator-1 and AMICA. The discriminant analysis was able to classify the samples in overall 96.2% using 7 discriminatory genes (indoleamine-pyrrole-2,3-dioxygenase, ectodermal-neural cortex, TIMP3, fucosyltransferase-8, collectin sub-family member 12, carboxypeptidase D, and transglutaminase-2). Using routine biopsy samples we successfully performed whole genomic microarray analysis to identify discriminative signatures. Our results provide further insight into the pathophysiological background of colonic diseases. The results set up data warehouse which can be mined further.

Szamosi T, Lakatos PL, Anonymous00057, Szilvasi A, Lakatos L, Kovacs A, Molnar T, Altorjay I, Papp M, Szabo O, Satori A, Tulassay Z, Miheller P, Horvath HC, Papp J, Tordai A, Andrikovics H. · 1st Department of Medicine, Semmelweis University, Koranyi st. 2/A, 1083, Budapest, Hungary. · Dig Dis Sci. · Pubmed #18716880 No free full text.

Abstract: PURPOSE: In previous studies the NFKBIA 3'UTR (untranslated region) AA genotype was associated with Crohn's disease (CD), while the NFKB1-94ins/delATTG mutation increased the risk for ulcerative colitis (UC). The aim of our study was to investigate these two polymorphisms and patients' response to medical therapy and/or disease phenotype in Hungarian inflammatory bowel disease (IBD) patients. METHODS: NFKBIA 3'UTR- and NFKB1-94ins/delATTG polymorphisms were investigated in 415 unrelated IBD patients (CD: 266 patients, mean age 35.2 +/- 12.1 years, duration 8.7 +/- 7.5 years; UC patients: 149, mean age 44.4 +/- 15.4 years, duration 10.7 +/- 8.9 years) and 149 controls by PCR-restriction fragment length polymorphism (RFLP) analysis. Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS: The NFKBIA 3'UTR and NFKB1-94ins/delATTG genotypes and allele frequencies were not significantly different among IBD and controls. In patients with UC, the 3'UTR GG genotype was associated with extensive colitis (55.3 vs. 29.4%, odds ratio 2.97, 95% confidence interval 1.45-6.08). The presence of variant alleles did not predict response to steroids, infliximab, or need for surgery. CONCLUSIONS: The NFKBIA 3'UTR GG genotype was associated with an increased risk for extensive colitis in Hungarian patients. In contrast, variant alleles did not predict response to medical therapy or need for surgery.

Herszényi L, Farinati F, Cardin R, István G, Molnár LD, Hritz I, De Paoli M, Plebani M, Tulassay Z. · 2nd Department of Medicine, Semmelweis University, Budapest Hungarian Academy of Science, Clinical Gastroenterology Research Unit, Budapest, Hungary. · BMC Cancer. · Pubmed #18616803 links to  free full text

Abstract: BACKGROUND: Cathepsin B and L (CATB, CATL), urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 play an important role in colorectal cancer invasion. The tumor marker utility and prognostic relevance of these proteases have not been evaluated in the same experimental setting and compared with that of CEA and CA-19-9. METHODS: Protease, CEA and CA 19-9 serum or plasma levels were determined in 56 patients with colorectal cancer, 25 patients with ulcerative colitis, 26 patients with colorectal adenomas and 35 tumor-free control patients. Protease, CEA, CA 19-9 levels have been determined by ELISA and electrochemiluminescence immunoassay, respectively; their sensitivity, specificity, diagnostic accuracy have been calculated and correlated with clinicopathological staging. RESULTS: The protease antigen levels were significantly higher in colorectal cancer compared with other groups. Sensitivity of PAI-1 (94%), CATB (82%), uPA (69%), CATL (41%) were higher than those of CEA or CA 19-9 (30% and 18%, respectively). PAI-1, CATB and uPA demonstrated a better accuracy than CEA or CA 19-9. A combination of PAI-1 with CATB or uPA exhibited the highest sensitivity value (98%). High CATB, PAI-1, CEA and CA 19-9 levels correlated with advanced Dukes stages. CATB (P = 0.0004), CATL (P = 0.02), PAI-1 (P = 0.01) and CA 19-9 (P = 0.004) had a significant prognostic impact. PAI-1 (P = 0.001), CATB (P = 0.04) and CA 19-9 (P = 0.02) proved as independent prognostic variables. CONCLUSION: At the time of clinical detection proteases are more sensitive indicators for colorectal cancer than the commonly used tumor markers. Determinations of CATB, CATL and PAI-1 have a major prognostic impact in patients with colorectal cancer.

Lakatos PL, Szamosi T, Szilvasi A, Molnar E, Lakatos L, Kovacs A, Molnar T, Altorjay I, Papp M, Tulassay Z, Miheller P, Papp J, Tordai A, Andrikovics H, Anonymous00044. · 1st Department of Medicine, Semmelweis University, Budapest, Hungary. · Dig Liver Dis. · Pubmed #18499543 No free full text.

Abstract: BACKGROUND: North American and European genome-wide association scans have identified ATG16L1 and IL23R as novel inflammatory bowel disease (IBD) susceptibility genes and subsequent reports confirmed these findings in large independent populations. The aims of this study were to investigate the association and examine genotype-phenotype relationships in a Hungarian IBD cohort. METHODS: 415 unrelated IBD patients (CD: 266, age: 35.2+/-12.1 years, duration: 8.7+/-7.5 years and UC: 149, age: 44.4+/-15.4 years, duration: 10.7+/-8.9 years) and 149 healthy subjects were investigated. IL23R Arg381Gln (R381Q, rs11209026) and ATG16L1 Thr300Ala (T300A, rs2241880) polymorphisms were tested using LightCycler allele discrimination method. Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS: The association between IL23R rs11209026, ATG16L1 rs2241880 and CD was confirmed (OR(IL23R381Q): 0.38, 95% CI: 0.16-0.87; OR(ATG16L1300AA): 1.86, 95% CI: 1.04-3.40). No difference was found between patients with UC and either controls or CD. In CD, IL23R 381Gln heterozygosity was associated with inflammatory disease (70% vs. 34%, p=0.037), while disease restricted to the colon was more prevalent in patients with the ATG16L1 300Ala/Ala homozygosity (33.3% vs. 21.1%, p=0.036). In addition, carriage of the variant alleles did not predict response to steroids, infliximab or need for surgery. CONCLUSIONS: We confirmed that ATG16L1 and IL23R are susceptibility loci for CD in Hungarian CD patients. Further studies are needed to confirm the reported phenotype-genotype associations found in this study.

Ficsor L, Varga VS, Tagscherer A, Tulassay Z, Molnar B. · 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary. · Cytometry A. · Pubmed #18228558 links to  free full text

Abstract: Automated and quantitative histological analysis can improve diagnostic efficacy in colon sections. Our objective was to develop a parameter set for automated classification of aspecific colitis, ulcerative colitis, and Crohn's disease using digital slides, tissue cytometric parameters, and virtual microscopy. Routinely processed hematoxylin-and-eosin-stained histological sections from specimens that showed normal mucosa (24 cases), aspecific colitis (11 cases), ulcerative colitis (25 cases), and Crohn's disease (9 cases) diagnosed by conventional optical microscopy were scanned and digitized in high resolution (0.24 mum/pixel). Thirty-eight cytometric parameters based on morphometry were determined on cells, glands, and superficial epithelium. Fourteen tissue cytometric parameters based on ratios of tissue compartments were counted as well. Leave-one-out discriminant analysis was used for classification of the samples groups. Cellular morphometric features showed no significant differences in these benign colon alterations. However, gland related morphological differences (Gland Shape) for normal mucosa, ulcerative colitis, and aspecific colitis were found (P < 0.01). Eight of the 14 tissue cytometric related parameters showed significant differences (P < 0.01). The most discriminatory parameters were the ratio of cell number in glands and in the whole slide, biopsy/gland surface ratio. These differences resulted in 88% overall accuracy in the classification. Crohn's disease could be discriminated only in 56%. Automated virtual microscopy can be used to classify colon mucosa as normal, ulcerative colitis, and aspecific colitis with reasonable accuracy. Further developments of dedicated parameters are necessary to identify Crohn's disease on digital slides.

Papp M, Altorjay I, Dotan N, Palatka K, Foldi I, Tumpek J, Sipka S, Udvardy M, Dinya T, Lakatos L, Kovacs A, Molnar T, Tulassay Z, Miheller P, Norman GL, Szamosi T, Papp J, Anonymous00071, Lakatos PL. · 2nd Department of Medicine, University of Debrecen, Debrecen, Hungary. · Am J Gastroenterol. · Pubmed #18047543 No free full text.

Abstract: BACKGROUND: Antibodies to Saccharomyces cerevisiae (S. cerevisiae) (ASCA) and porin protein-C of Escherichia coli (anti-OmpC) are associated with disease phenotype and may be of diagnostic importance in inflammatory bowel diseases (IBD). Our aim was to determine whether a panel of new antibodies against bacterial proteins and carbohydrates could help differentiate among the various forms of IBD, and whether they were associated with particular clinical manifestations in a Hungarian cohort of IBD patients. METHODS: Six hundred fifty-two well-characterized, unrelated, consecutive IBD patients (CD [Crohn's disease] 557, men/women 262/295, duration 8.1 +/- 11.3 yr; ulcerative colitis [UC] 95, men/women 44/51, duration 8.9 +/- 9.8 yr) and 100 healthy and 48 non-IBD gastrointestinal (GI) controls were investigated. Sera were assayed for anti-OmpC and antibodies against a mannan epitope of S. cerevisiae (gASCA), laminaribioside (ALCA), chitobioside (ACCA), and mannobioside (AMCA). TLR4 and NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP). Detailed clinical phenotypes were determined by reviewing the patients' medical charts. RESULTS: Sixty-six percent of the CD patients had at least one of the investigated antibodies. Among glycan antibodies, gASCA or the combination of gASCA and atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) was most accurate for differentiating between CD and UC. ASCA and gASCA assays performed similarly. Increasing amount and level of antibody responses toward gASCA, ALCA, ACCA, AMCA, and OmpC were associated with more complicated disease behavior (P < 0.0001) and need for surgery in CD (P= 0.023). A serological dosage effect was also observed. gASCA and AMCA antibodies were associated with NOD2/CARD15, in addition to a gene-dosage effect. No serotype-phenotype associations were found in UC. CONCLUSIONS: Antibody response to this new panel of serological markers was associated with complicated disease phenotype, NOD2/CARD15 genotype, and a need for surgery in this eastern European IBD cohort.

Herszenyi L, Miheller P, Tulassay Z. · Semmelweis University, Second Department of Medicine, Hungarian Academy of Science, Clinical Gastroenterology Unit, Budapest, Hungary. · Dig Dis. · Pubmed #17827953 No free full text.

Abstract: Patients with longstanding ulcerative colitis (UC) and Crohn's disease (CD) have an increased risk of colorectal cancer (CRC). CRC accounts for approximately 15% of all deaths in patients with inflammatory bowel disease (IBD). The molecular pathway leading to CRC in IBD appears to differ from the well-known adenoma-to-CRC sequence, given the fact that these cancers appear to arise from either flat dysplastic tissue or dysplasia-associated lesions or masses. The risk of CRC for patients with IBD increases by 0.5-1% yearly, 8-10 years after diagnosis. Patients with a young age at disease onset, more extensive colitis, greater inflammatory burden, concomitant primary sclerosing cholangitis, and a family history of CRC are at greatest risk. Most cancers arise in pancolitis and there is little or no increased risk associated with proctitis while left-sided colitis carries an intermediate cancer risk. The CRC risk in patients with colonic CD is similar to that of UC. Colonic dysplasia is a precursor to CRC in IBD. There is no clear evidence that surveillance colonoscopy prolongs survival in patients with extensive colitis. Newer endoscopic and molecular techniques are being assessed for their effectiveness in augmenting conventional surveillance.

Fischer S, Lakatos PL, Anonymous00281, Lakatos L, Kovacs A, Molnar T, Altorjay I, Papp M, Szilvasi A, Tulassay Z, Osztovits J, Papp J, Demeter P, Schwab R, Tordai A, Andrikovics H. · 1st Department of Medicine, Semmelweis University, Budapest, Hungary. · Scand J Gastroenterol. · Pubmed #17505995 No free full text.

Abstract: OBJECTIVE: MDR1 (ABCB1), a member of the ATP-binding cassette (ABC) transporters, is an attractive candidate gene for the pathogenesis of inflammatory bowel diseases (IBD) and perhaps for response to therapy. Since limited data are available on MDR1 and ABCG2 polymorphisms in East European IBD patients, the aim of this study was to investigate ABCG2 and MDR1 variants and responses to medical therapy and/or disease phenotype in Hungarian patients. MATERIAL AND METHODS: A total of 414 unrelated IBD patients (Crohn's disease (CD): 265, age: 35.2+/-12.1 years, duration: 8.7+/-7.6 years and ulcerative colitis (UC): 149, age: 44.4+/-15.4 years, duration: 10.7+/-8.9 years) and 149 healthy subjects were investigated. ABCG2 G34A, C421A and MDR1 C3435T, G2677T/A single nucleotide polymorphisms (SNPs) were detected using real-time polymerase chain reaction (PCR). Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS: The frequency of the ABCG2 and MDR1 SNPs was not significantly different among IBD, CD, UC patients and controls. There was no difference in risk for steroid resistance in CD patients carrying variant ABCG2 (19.6% versus non-carriers 18.4%, p=NS) or MDR1 3435T (CC: 22.2% versus CT/TT: 17.6%) alleles. In addition, carriage of the variant allele was not associated with disease phenotype, presence of extra-intestinal manifestations, smoking, response to infliximab therapy or the need for surgery. In UC, the carriage of variant ABCG2 alleles seemed to be preventive for arthritis (15.5% versus 31.7%, OR: 0.39, 95% CI: 0.16-0.98). CONCLUSIONS: MDR1 and ABCG2 SNPs were not associated with disease susceptibility or disease phenotype in Hungarian patients, and variant alleles did not predict the response to medical therapy or the need for surgery. Further studies are needed to clarify the association between the presence of ABCG2 variants and arthritis in UC.

Papp M, Altorjay I, Norman GL, Shums Z, Palatka K, Vitalis Z, Foldi I, Lakos G, Tumpek J, Udvardy ML, Harsfalvi J, Fischer S, Lakatos L, Kovacs A, Bene L, Molnar T, Tulassay Z, Miheller P, Veres G, Papp J, Anonymous00415, Lakatos PL. · 2nd Department of Medicine, University of Debrecen, Debrecen, Hungary. · Inflamm Bowel Dis. · Pubmed #17417801 links to  free full text

Abstract: BACKGROUND: Antibodies directed against Saccharomyces cerevisiae (ASCA), perinuclear components of neutrophils (pANCA), and porin protein C of Escherichia coli (anti-OmpC) are reported to be associated with disease phenotype and may be of diagnostic importance in inflammatory bowel disease (IBD). Since limited data are available from Eastern Europe, we assessed the above antibodies in Hungarian IBD patients. METHODS: In all, 653 well-characterized, unrelated consecutive IBD patients (Crohn's disease [CD]: 558, m/f: 263/295, duration: 8.1 +/- 10.7 years; ulcerative colitis [UC]: 95, m/f: 44/51, duration: 8.9 +/- 9.8 years) and 100 healthy subjects were investigated. Sera were assayed for anti-Omp and ASCA by enzyme-linked immunosorbent assay (ELISA) and ANCA by indirect immunofluorescence assay (IIF). TLR4 and NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP). Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS: Anti-Omp, ASCA, and atypical pANCA antibodies were present in 31.2%, 59.3%, and 13.8% of CD, 24.2%, 13.7%, and 48.5% of UC patients, and in 20%, 16%, and 5.6% of controls, respectively. ASCA and anti-Omp positivity were associated with increased risk for CD (odds ratio [OR](ASCA) = 7.65, 95% confidence interval [CI]: 4.37-13.4; OR(Omp) = 1.81, 95% CI: 1.08-3.05). In a logistic regression analysis, anti-Omp and ASCA were independently associated with ileal and noninflammatory disease, but not with a risk for surgery or response to steroids or infliximab. A serology dosage effect was also observed. ASCA and anti-Omp antibodies were associated with NOD2/CARD15, in addition to a gene dosage effect. No associations were found in UC. CONCLUSIONS: Serological markers were useful in the differentiation between CD and UC in an Eastern European IBD cohort. Reactivity to microbial components was associated with disease phenotype and NOD2/CARD15 genotype, further supporting the role of altered microbial sensing in the pathogenesis of CD.

Sipos F, Molnár B, Zágoni T, Miheller P, Tulassay Z. · Semmelweis Egyetem, Altalános Orvostudományi Kar, II Belgyógyászati Klinika, Magyar Tudományos Akadémia, Budapest. · Orv Hetil. · Pubmed #17066600 No free full text.

Abstract: BACKGROUND: The risk of colorectal carcinoma development is elevated in chronic, longstanding ulcerative colitis. The changes of such regenerative and immortalizing pathways caused by the inflammatory process that are proved to be carcinogenic in other human tissues have not been fully and uniformly described. Aim of the study was to describe the expression alterations of regenerative signal receptors and cell aging inhibitory systems within colonic crypts considering the histological activity of the disease. MATERIALS AND METHODS: I-type insulin-like growth factor receptor (IGF1R), hepatocyte derived growth factor receptor (HGFR), telomerase reverse transcriptase (TERT) and telomerase associated protein (TP-1) expression were evaluated immunohistochemically on formalin fixed paraffin embedded biopsy specimen from 10 mild, 10 moderate, and 10 severe active inflammation of ulcerative colitis and from 10 normal colonic tissue. RESULTS: In mild inflammation all observed parameter showed significantly elevated protein expression in protein level compared to normal (p <0.005). In moderately active inflammation only IGF1R expression was significantly higher compared to normal and to mild inflammation (p <0.005). There were no regenerative signal expression alteration in severe inflammation compared to normal, and epithelial telomerase expression was not detectable in these cases. CONCLUSION: The expression of regenerative signal receptors and immortalizing factors is elevated in mildly (and moderately) inflamed ulcerative colitis. This phenomenon let the genetically defected epithelial cells to pathologically survive and proliferate, so thus favours the development of tumors.

Lakatos PL, Fischer S, Claes K, Kovacs A, Molnar T, Altorjay I, Demeter P, Tulassay Z, Palatka K, Papp M, Rutgeerts P, Szalay F, Papp J, Vermeire S, Lakatos L, Anonymous00243. · First Department of Medicine, Semmelweis University, Budapest, Hungary. · Inflamm Bowel Dis. · Pubmed #16670524 links to  free full text

Abstract: BACKGROUND: Recent data suggest that haplotypic variants of the DLG5 gene on 10q23 are associated with susceptibility to inflammatory bowel disease (IBD) in Germany. In view of the geographical differences in frequency of genetic markers and the absence of data in Central European patients, our aim was to determine the DLG5 R30Q variant in Hungarian IBD patients. MATERIALS AND METHODS: We investigated 773 unrelated IBD patients (age 38.1 +/- 10.3 years; duration, 8.8 +/- 7.5 years; Crohn's disease [CD]: 639; male/female, 309/330; duration, 8.4 +/- 7.1 years; ulcerative colitis [UC]: 134; male/female, 63/71; duration, 10.6 +/- 8.9 years) and 150 healthy subjects. DLG5 R30Q and TLR4 D299G variants were tested by polymerase chain reaction/restriction fragment length polymorphism. DNA was screened for NOD2/CARD15 mutations by denaturing high-performance liquid chromatography. Detailed clinical phenotype was determined by reviewing the medical charts. RESULTS: The frequency of the R30Q variant allele was not significantly different in IBD (22.0%), CD (20.8%), and UC (27.6%) patients compared with healthy control subjects (28.0%). In CD, the 113A variant allele was associated with steroid resistance (16.3% vs noncarriers, 7.6%; odds ratio [OR], 2.4; 95% CI 1.3-4.5; P = 0.013). In a logistic regression model carriage of DLG5 R30Q, perianal involvement and frequent relapses were independently associated with steroid resistance. No phenotype-genotype associations were found in UC patients, although a trend toward more extensive disease was observed in carriers of the variant allele (OR = 2.1; 95% CI 0.95-4.4; P = 0.07). CONCLUSIONS: The present data strongly contrast previous data from Germany. DLG5 113A is not associated with disease susceptibility, but there was a tendency for this allele to confer resistance to steroids. Further studies are required to evaluate the significance of DLG5 in other populations from geographically diverse regions.

Gross V, Bar-Meir S, Lavy A, Mickisch O, Tulassay Z, Pronai L, Kupcinskas L, Kiudelis G, Pokrotnieks J, Kovács A, Faszczyk M, Razbadauskas A, Margus B, Stolte M, Müller R, Greinwald R, Anonymous00134. · Hospital St. Marien, Amberg, Germany. · Aliment Pharmacol Ther. · Pubmed #16393311 No free full text.

Abstract: BACKGROUND: Rectal budesonide is an effective treatment of active ulcerative proctitis or proctosigmoiditis. AIM: To compare the therapeutic efficacy, tolerability and safety, and patient's preference of budesonide foam vs. budesonide enema. METHODS: Patients with active ulcerative proctitis or proctosigmoiditis (clinical activity index > 4 and endoscopic index > or = 4) were eligible for this double-blind, double-dummy, randomized, multicentre study. They received 2 mg/25 mL budesonide foam and placebo enema (n = 265), or 2 mg/100 mL budesonide enema and placebo foam (n = 268) for 4 weeks. Primary endpoint was clinical remission (clinical activity index < or = 4) at the final/withdrawal visit (per protocol). RESULTS: A total of 541 patients were randomized--533 were evaluable for intention-to-treat analysis and 449 for per protocol analysis. Clinical remission rates (per protocol) were 60% for budesonide foam and 66% for budesonide enema (P = 0.02362 for non-inferiority of foam vs. enema within a predefined non-inferiority margin of 15%). Both formulations were safe and no drug-related serious adverse events were observed. Because of better tolerability and easier application most patients preferred foam (84%). CONCLUSION: Budesonide foam is as effective as budesonide enema in the treatment of active ulcerative proctitis or proctosigmoiditis. Both budesonide formulations are safe, and most patients prefer foam.

Sipos F, Molnár B, Zágoni T, Berczi L, Tulassay Z. · 2nd Department of Medicine, Semmelweis University, Budapest, Hungary. · Dis Colon Rectum. · Pubmed #15747078 No free full text.

Abstract: PURPOSE: Epithelial cell turnover related differences between ulcerative colitis, Crohn's colitis, and aspecific colitis are not known yet. METHODS: Totally 345 formalin-fixed, paraffin-embedded biopsy specimens from 33 ulcerative colitis, 26 Crohn's colitis, 30 aspecific colitis, and 10 healthy patients were observed with the TdT-mediated dUTP nick end labeling method and proliferating cell nuclear antigen-, p53-, and epithelial growth factor receptor immunohistochemistry. Because of epithelial growth factor receptor positivity of subepithelial cells epithelial growth factor receptor and CD45, CD68, or CD83 double fluorescence immunohistochemistry were performed on 16 freshly frozen samples from 8 severely active ulcerative colitis and 8 severely active Crohn's colitis patients to describe lamina propria's mononuclear cells, respectively. RESULTS: The epithelial growth factor receptor expression was significantly lower in each inflammatory group compared with normal (P < 0.005) and decreased significantly in mild ulcerative colitis compared with mild Crohn's colitis or aspecific colitis (P < 0.005). Numerous epithelial growth factor receptor and CD45 double-positive submucosal mononuclear cells were observed in moderate-severe inflammations. The p53-expression was significantly higher in each inflammatory group compared with normal (P < 0.05). Significant differences were found between mildly, moderately, and severely inflamed samples in ulcerative colitis (P < 0.05) compared with Crohn's colitis or aspecific colitis. Apoptotic/proliferative rates increased significantly in line with the inflammatory process (P < 0.0001/0.05), but the TdT-mediated dUTP nick end labeling and proliferating cell nuclear antigen-labeling characteristics did not show disease type specificity. CONCLUSIONS: Based on our results, the alterations of epithelial growth factor receptor and p53 expression show ulcerative colitis specificity, whereas the rate of epithelial apoptosis and proliferation are determined by the histologic activity of the inflammation. The increased epithelial growth factor receptor expression by the lamina propria's mononuclear cells in inflammation may suggest its role as an autoantigen.

Prónai L, Schandl L, Orosz Z, Magyar P, Tulassay Z. · 2nd Department of Medicine, Semmelweis University, Hungarian Academy of Science, Gastroenterology Research Unit, Budapest, Hungary. · Helicobacter. · Pubmed #15165265 No free full text.

Abstract: BACKGROUND: Patients with inflammatory bowel disease have lower prevalence of Helicobacter pylori infection, but the exact reason for this is not yet clear. AIM: To examine whether the antibiotics frequently used in inflammatory bowel disease are responsible for the lower prevalence of H. pylori infection. Patients with chronic obstructive pulmonary disease on prolonged previous antibiotic therapy were used for comparison. METHODS: Presence/absence of H. pylori infection was detected by a (13)C-urea breath test in 133 patients with inflammatory bowel disease (82 ulcerative colitis, and 51 Crohn's disease) and compared with that of 135 patients with chronic obstructive pulmonary disease and with two age-matched control groups (200 patients each). Primary disease location, duration of disease and detailed analysis of previous and current medication (dose and duration of antibiotics, steroids, 5-aminosalicylic acid) were analysed in each cases. RESULTS: Seventeen of the 133 patients with inflammatory bowel disease [12.2% (10/82) of ulcerative colitis and 13.7% (7/51) of Crohn's disease] and 90/135 patients with chronic obstructive pulmonary disease (66.7%) were positive for H. pylori. A total of 78/200 (39%) for the inflammatory-bowel-disease-group-matched controls and 110/210 (55%) for the chronic-obstructive-pulmonary-disease-matched controls were positive for H. pylori. The history of any antibiotic or steroid therapy had no influence on H. pylori status of patients with inflammatory bowel disease. CONCLUSION: The prevalence of H. pylori compared to the age-matched controls is significantly lower in patients with inflammatory bowel disease but not in those with chronic obstructive pulmonary disease. Antibiotic use is not responsible for the lower prevalence of H. pylori infection in patients with inflammatory bowel disease.

Molnar B, Bocsi J, Karman J, Nemeth A, Pronai L, Zagoni T, Tulassay Z. · Clinical Gastroenterology Unit, Second Department of Medicine, Semmelweis University of Medicine, 1088 Budapest, Hungary. · Anticancer Res. · Pubmed #12680163 No free full text.

Abstract: BACKGROUND: Quantitative DNA analysis of fresh biopsy material can contribute to a more accurate diagnosis and prognosis. The authors aimed to develop and test a mechanical, nuclear preparation protocol for quantitative DNA analysis. PATIENTS AND METHODS: Altogether 32 gastric (10 healthy, 17 gastritis, 7 adenocarcinoma) and 48 colon (21 healthy, 20 colitis ulcerosa, 7 adenocarcinoma) biopsy specimens were evaluated. The mechanical disruption was performed by Medimachine (DAKO, Denmark). The flow cytometry analysis was performed on a BD FACSStar flow cytometer. RESULTS: DNA Aneuploidy was found in gastric samples only in tumours. The S-phase fraction of the normal cases was 5.9 +/- 2.1%, 5.1% +/- 1.2% in gastritis and 10.7 +/- 1.6% in carcinomas. Seven out of 20 colitis ulcerosa and 4 out of 7 colon cancer samples were aneuploid. The S-phase fraction of normal colon cases was 5.7 +/- 3.4%, in colitis 8.1 +/- 4.2% and 15.1 +/- 5.7% in carcinomas, respectively. CONCLUSION: Mechanical nuclear isolation is a useful method for flow cytometric DNA ploidy analysis of fresh biopsy samples.