Gábor Lakatos

Comparison of the effects of 1,25 dihydroxyvitamin D and 25 hydroxyvitamin D on bone pathology and disease activity in Crohn's disease patients

Background: Vitamin D is essential for osteopenia therapy in Crohns disease (CD). The active form of vitamin‐D (aVD) is the 1,25(OH)2D. There are no data available whether aVD or plain vitamin‐D (pVD) has any advantage in managing osteoporosis in CD or has any effect on the activity of the disease itself. Our work is a prospective study to compare the effects of aVD and pVD on bone metabolism and the clinical course of CD. Methods: In all, 37 inactive CD patients were involved in the study and divided into 2 age‐, gender‐, and t‐score‐matched groups. Group A was treated with aVD while group B received pVD. Osteocalcin, beta‐CrossLaps, osteoprotegerin, and receptor activator nuclear factor kappa‐B ligand concentrations were estimated at the start of the study and at 6 weeks and 3 and 12 months. The activity of CD was also measured clinically and by laboratory parameters. Results: At week 6 the Crohns Disease Activity Index (CDAI) scores and concentration of C‐reactive protein decreased (69.44 ± 58.6 versus 57.0 ± 54.89 and 15.8 ± 23.57 mmol/L versus 7.81 ± 3.91 mmol/L, respectively, P < 0.05) parallel with markers of bone turnover (beta‐CrossLaps: 0.46 ± 0.21 ng/mL versus 0.40 ± 0.25 ng/mL, and osteocalcin: 32.29 ± 15.3 ng/mL versus 29.98 ± 14.14 ng/mL, P < 0.05); however, osteoprotegerin concentration (marker of osteoblast activity) increased (3.96 ± 2.1 pg/mL versus 4.58 ± 2.19 pg/mL) in group A, but did not change in group B. Osteocalcin and beta‐CrossLaps concentrations changed more significantly by the 3rd month; however, these changes disappeared by the 12th month. Conclusions: According to our study, aVD has a more prominent short‐term beneficial effect on bone metabolism and disease activity in CD compared with pVD. (Inflamm Bowel Dis 2009)

The Behavior of Matrix Metalloproteinases and Their Inhibitors in Colorectal Cancer

Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix components crucial for tumor growth, invasion and metastasis. MMPs are controlled by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). We and others have demonstrated that MMPs and TIMPs are especially important in the process of tumor invasion, progression and the metastasis of colorectal cancer (CRC). It has been proposed that MMPs and TIMPs might play a part not only in tumor invasion and initiation of metastasis but also in carcinogenesis from colorectal adenomas. Several recent studies demonstrated that high preoperative serum or plasma MMP-2, MMP-9 and TIMP-1 antigen levels are strong predictive factors for poor prognosis in patients with CRC and their determination might be useful for identification of patients with higher risk for cancer recurrence. MMP-9 and TIMP-1 have significant potential tumor marker impact in CRC. Their diagnostic sensitivity is consistently higher than those of conventional biomarkers. The pharmacological targeting of CRC by the development of a new generation of selective inhibitors of MMPs, that is highly specific for certain MMPs, is a promising and challenging area for the future.

The impact of matrix metalloproteinases and their tissue inhibitors in inflammatory bowel diseases

Background: It has been suggested that matrix metalloproteinases (MMPs) may play a role in the pathogenesis of inflammatory bowel diseases (IBD). However, the impact of serum MMPs and their inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] have scarcely been investigated in the same experimental setting in ulcerative colitis (UC) and Crohn’s disease (CD) as well as their correlation with IBD activity. Methods: MMP-2, MMP-7, MMP-9, TIMP-1 and TIMP-2 serum antigen levels were determined in 23 patients with UC, 25 patients with CD and 10 healthy control patients by enzyme-linked immunoassay technique. Statistical analysis with one-way ANOVA and Student’s t tests was performed. A linear regression analysis or a Spearman’s r test was used to assess correlation. Differences were considered significant with p < 0.05. Results: Serum antigen concentrations of MMP-9, TIMP-1 and TIMP-2 were significantly higher in UC and CD patients compared to controls. MMP-7 was also significantly higher in CD compared with controls. Elevated MMP-9 and TIMP-1 antigen levels showed significant positive correlation with disease activity of IBD. MMP-2 and TIMP-2 levels inversely correlated with CD activity. Significant correlations were found between MMP-9/TIMP-1 and MMP-2/TIMP-2 antigen levels in both UC and CD. Conclusions: We demonstrated that serum antigen concentrations of MMP-9, TIMP-1 and TIMP-2 were significantly increased in patients with UC and CD compared to controls. Our results suggest that MMPs and TIMPs may contribute to the inflammatory and remodeling processes in IBD. Serum MMP-9 and TIMP-1 might be useful as additional biomarkers in the assessment of IBD activity.

The Behavior of Matrix Metalloproteinase-9 in Lymphocytic Colitis, Collagenous Colitis and Ulcerative Colitis

Matrix metalloproteinases play an important role in extracellular matrix remodelling. It has been proposed that matrix metalloproteinase-9 (MMP-9) is involved in epithelial damage in ulcerative colitis (UC). However, to our knowledge, no data are available in terms of MMP-9 expression in microscopic colitis. Determination of mucosal protein expression levels of MMP-9 in lymphocytic colitis (LC), collagenous colitis (CC) and UC. MMP-9 immunohistochemical expressions were analyzed in paraffin-embedded tissue samples by immunohistochemistry including patients with LC, CC, UC, active diverticulitis, inactive diverticular disease and healthy control subjects. UC was also subgrouped according to the severity of inflammation. Immunostaining was determined semiquantitatively. Independent colonic biopsies from healthy and severe UC cases were used for gene expression analyses. For further comparison MMP-9 serum antigen levels were also determined in patients with UC and control patients without macroscopic or microscopic changes during colonoscopy. MMP-9 mucosal expression was significantly higher in UC (26.7 ± 19.5%) compared to LC (6.6 ± 9.3%), CC (6.4 ± 7.6%), active diverticulitis (5.33 ± 2.4%), inactive diverticular disease (5.0 ± 2.2%) and controls (6.3 ± 2.6%) (P < 0.001). The immunohistochemical expression of MMP-9 in LC and CC was similar as compared to controls. MMP-9 expression was significantly higher in each inflammatory group of UC compared to controls (mild: 11.0 ± 2.8%, moderate: 23.9 ± 3.7%, severe UC: 52.6 ± 3.9% and 6.3 ± 2.6%, respectively, P < 0.005). The gene expression microarray data and RT-PCR results demonstrated a significantly higher expression of MMP-9 in severely active UC compared to healthy controls (P < 0.001). Significantly higher MMP-9 serum antigen concentrations were observed in UC patients compared with the control group (P < 0.05). MMP-9 seems to play no role in the inflammatory process of LC and CC. In contrast, the mucosal up-regulation of MMP-9 correlated with the severity of inflammation in UC. The increased MMP-9 expression could contribute to the severity of mucosal damage in active UC.

The role of inflammation and proteinases in tumor progression

Chronic inflammation is an important risk factor for the development of cancers. The link between chronic inflammation and the risk of developing cancer is now well established. At least 20% of all cancers arise in association with infection and chronic inflammation. Inflammation and cancer are linked both along intrinsic (driven by genetic events causing malignancy) and extrinsic (driven by inflammatory conditions predisposing to tumor) pathways. Proteinases are key contributors to the breakdown and reconstitution of extracellular matrix components in physiological processes and pathological conditions, including destructive diseases and tumor progression. Matrix metalloproteinases are especially essential in the complex process of coregulation between cellular components of the tumor environment, and they are considered as potential diagnostic and prognostic biomarkers in many types and stages of cancer. Although the link between chronic inflammation, proteinases and risk of developing cancer is now well established, several open questions remain. The most exciting challenge is to find the best approach to target cancer-associated inflammation in patients with cancer. With respect to matrix metalloproteinases, the development of a new generation of selective inhibitors is a promising area of research.

Increased p53 expression in the malignant transformation of Barrett's esophagus is accompanied by an upward shift of the proliferative compartment.

Neoplastic progression in Barrett’s esophagus (BE) occurs by a multistep process associated with early molecular and morphological changes. This study evaluated cell proliferation and p53 expression and their correlation in the development and progression of esophageal adenocarcinoma. PCNA and p53 expressions were analyzed in biopsy samples by immunohistochemistry including patients with reflux esophagitis, BE, BE with concomitant esophagitis, Barrett’s dysplasia, esophageal adenocarcinoma and a control group without any histological changes. Progressive increase in cell proliferation and p53 expression was found in the sequence of malignant transformation of the esophageal mucosa. While cell proliferation was significantly lower in the control group compared with all other groups, there was no increase in p53 expression of esophageal tissues that were negative for dysplasia. Dysplastic BE tissues revealed significantly higher cell proliferation and p53 expression levels compared to BE, reflux esophagitis or BE with concomitant esophagitis. Both, cell proliferation and p53 expression were significantly higher in adenocarcinoma compared to BE or Barrett’s dysplasia. Interestingly, while just BE with concomitant esophagitis showed significantly higher p53 expression levels than BE, both, BE with concomitant esophagitis and reflux esophagitis revealed significantly higher cell proliferation levels compared to BE. Alterations of cell proliferation and p53 expression showed a strong correlation. Simultaneous activation of cell proliferation and p53 expression strongly suggest their association with esophageal epithelial tumor genesis and particularly, their specific role in the biology of esophageal adenocarcinoma. Quantification of these parameters in BE is thought to be useful to identify patients at higher risk for progression to adenocarcinoma.

Low bone mass in microscopic colitis

BackgroundMicroscopic colitis presents with similar symptoms to classic inflammatory bowel diseases. Osteoporosis is a common complication of Crohns disease but there are no data concerning bone metabolism in microscopic colitis.AimsThe aim of the present study was to evaluate bone density and metabolism in patients with microscopic colitis.MethodsFourteen patients microscopic colitis were included in the study, and 28 healthy persons and 28 age and gender matched Crohns disease patients were enrolled as controls. Bone mineral density was measured using dual x-ray absorptiometry at the lumbar spine, femoral neck and the radius. Serum bone formation and bone resorption markers (osteocalcin and beta-crosslaps, respectively) were measured using immunoassays.ResultsLow bone mass was measured in 57.14% patients with microscopic colitis. Bone mineral density at the femoral neck in patients suffering from microscopic colitis and Crohns disease was lower than in healthy controls (0.852 ± 0.165 and 0.807 ± 0.136 vs. 1.056 ± 0.126 g/cm2; p < 0.01). Bone mineral density at the non-dominant radius was decreased in microscopic colitis patients (0.565 ± 0.093 vs. 0.667 ± 0.072 g/cm2; p < 0.05) but unaffected in Crohns disease patients (0.672 ± 0.056 g/cm2). Mean beta-crosslaps concentration was higher in microscopic colitis and Crohns disease patients than controls (417.714 ± 250.37 and 466.071 ± 249.96 vs. 264.75 ± 138.65 pg/ml; p < 0.05). A negative correlation between beta-crosslaps concentration and the femoral and radius t-scores was evident in microscopic colitis patients.ConclusionsLow bone mass is frequent in microscopic colitis, and alterations to bone metabolism are similar to those present in Crohns disease. Therefore, microscopic colitis-associated osteopenia could be a significant problem in such patients.

The epidemiology of pancreatic cancer

Pancreatic cancer is a relatively uncommon tumor, but even with early diagnosis, mortality rates are high, explaining why this form of cancer has now become a common cause of cancer mortality. There are no screening tests for early detection of pancreatic cancer. It is more common in men than women and is predominantly a disease of elderly people. There is wide variation in the incidence of pancreatic cancer around the world, suggesting that environmental factors are important in the pathogenesis. Smoking is the major known risk factor for pancreatic cancer, while dietary factors seem to be less important. Other possible risk factors include chronic pancreatitis, obesity and type 2 diabetes. Numerous inherited germ line mutations are associated with pancreatic cancer. Of these, hereditary pancreatitis confers the greatest risk, while BRCA2 mutations are the commonest inherited disorder. Polymorphisms in genes that control detoxification of environmental carcinogens and metabolic pathways may alter the risk of pancreatic cancer.

[The safety of COX-2 inhibitors].

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs worldwide, but they can cause serious gastrointestinal (GI) side effects. NSAIDs are capable of damaging the whole gastrointestinal tract. Cyclooxygenase-2 (COX-2) inhibitors (coxibs) have been developed with the aim of maintaining the anti-inflammatory benefits but reducing gastrotoxicity. There is a good evidence that these drugs effectively prevent gastroduodenal ulcers and ulcer complications. Little is known about the side effects of these agents in the small and large intestine. There is an increasing evidence that COX-2 is constitutively expressed in the gastrointestinal tract and is important for the maintenance of bowel integrity. There have also been growing concerns about the potential for coxibs to increase the frequency of adverse cardiovascular events. The purpose of this review is to summarize recent knowledge about the safety profile of selective COX-2 inhibitors.

Probiotics in gastrointestinal disorders

Probiotics are preparations containing viable microorganisms that confer potential health benefits for the host. Alteration of bacterial flora both in terms of specific content and concentration may be beneficial in many gastrointestinal disorders. Probiotics are widely used for the management of these conditions in many countries. However, mechanisms of probiotics are incompletely understood. Benefits observed clinically with one species or combinations of species can not be generalized. The optimal dose of treatment has to be determined. Although probiotics are generally regarded safe, caution is needed when using these supplements routinely. It has been proved, that severe adverse events can occur as a complication of probiotic treatment. This review summarizes the recent knowledge concerning the use of probiotics in gastrointestinal disorders.