Macrophage Inflammatory Proteins (MIPs) Contribute to Malignant Potential of Colorectal Polyps and Modulate Likelihood of Cancerization Associated with Standard Risk Factors.

Better understanding of molecular changes leading to neoplastic transformation is prerequisite to optimize risk assessment and chemopreventive and surveillance strategies. Data on macrophage inflammatory proteins (MIPs) in colorectal carcinogenesis are scanty and their clinical relevance remains unknown. Therefore, transcript and protein expression of CCL3, CCL4, CXCL2, and CCL19 were determined in 173 and 62 patients, respectively, using RT-qPCR and immunohistochemistry with reference to polyps' characteristics. The likelihood of malignancy was modeled using probit regression. With the increasing malignancy potential of hyperplastic-tubular-tubulo-villous-villous polyps, the expression of CCL3, CCL4, and CCL19 in lesions decreased. CCL19 expression decreased also in normal mucosa while that of CXCL2 increased. Likewise, lesion CCL3 and lesion and normal mucosa CCL19 decreased and normal CXCL2 increased along the hyperplasia-low-high dysplasia grade. The bigger the lesion, the lower CCL3 and higher CXCL2 in normal mucosa. Singular polyps had higher CCL3, CCL4, and CCL19 levels in normal mucosa. CCL3, CCL4 and CXCL2 modulated the likelihood of malignancy associated with traditional risk factors. There was no correlation between the protein and mRNA expression of CCL3 and CCL19. In summary, the polyp-adjacent mucosa contributes to gaining potential for malignancy by polyps. MIPs may help in specifying cancerization probability estimated based on standard risk factors.

Update on the Role of Rifaximin in Digestive Diseases.

Various environmental factors affecting the human microbiota may lead to gut microbial imbalance and to the development of pathologies. Alterations of gut microbiota have been firmly implicated in digestive diseases such as hepatic encephalopathy, irritable bowel syndrome and diverticular disease. However, while these three conditions may all be related to dysfunction of the gut-liver-brain axis, the precise pathophysiology appears to differ somewhat for each. Herein, current knowledge on the pathophysiology of hepatic encephalopathy, irritable bowel syndrome, and diverticular disease are reviewed, with a special focus on the gut microbiota modulation associated with these disorders during therapy with rifaximin. In general, the evidence for the efficacy of rifaximin in hepatic encephalopathy appears to be well consolidated, although it is less supported for irritable bowel syndrome and diverticular disease. We reviewed current clinical practice for the management of these clinical conditions and underlined the desirability of more real-world studies to fully understand the potential of rifaximin in these clinical situations and obtain even more precise indications for the use of the drug.

Pancreatic Cancer in Celiac Disease Patients-A Systematic Review and Meta-Analysis.

Background: Celiac disease (CD) is an autoimmune enteropathy affecting approximately 1% of the population and is associated with an increased risk of enteropathy-associated T-cell lymphoma and small bowel adenocarcinoma, whereas the association between CD and other malignancies is unclear. Since pancreatic cancer (PC) remains one of the most lethal neoplasms and its incidence is increasing despite numerous ongoing research on diagnostic biomarkers and novel therapies, we aimed to investigate whether CD has an impact on the risk of PC. Material and Methods: We performed a systematic review of the literature published from January 2000 to March 2022 in two databases: Web of Science and Scopus and a meta-analysis of eligible studies. Results: Our search identified eight publications included in the systematic review. A total of five studies involving 47,941 patients, including 6399 CD patients with malignancies and 1231 PC cases were included in the meta-analysis and 221 cases of PC in CD patients with other cancers were recognized. The pooled OR for PC was 1.46 (95% CI 1.26−1.7) with significant heterogeneity (89.1%; p < 0.05), suggesting that CD patients with malignancies were at higher risk for PC. Conclusions: The association between CD and PC is uncertain. However, the results of the current meta-analysis may indicate an increased risk of PC in the group of patients with CD and other cancers. Further multicenter studies are warranted.

Biochemical Intracystic Biomarkers in the Differential Diagnosis of Pancreatic Cystic Lesions.

Background and Objectives: Pancreatic cystic lesions (PCLs) are frequently incidental findings. The prevalence of PCLs is increasing, mainly due to advancements in imaging techniques, but also because of the aging of the population. PCLs comprise challenging clinical problems, as their manifestations vary from benign to malignant lesions. Therefore, the recognition of PCLs is achieved through a complex diagnostic and surveillance process, which in turn is usually long-term, invasive, and expensive. Despite the progress made in the identification of novel biomarkers in the cystic fluid that also support the differentiation of PCLs, their application in clinical practice is limited. Materials and Methods: We conducted a systematic review of the literature published in two databases, Pubmed and Embase, on biochemical biomarkers in PCLs that may be applied in the diagnostic algorithms of PCLs. Results: Eleven studies on intracystic glucose, twenty studies on intracystic carcinoembryonic antigen (CEA), and eighteen studies on other biomarkers were identified. Low levels of intracystic glucose had high sensitivity and specificity in the differentiation between mucinous and non-mucinous cystic neoplasms. Conclusions: CEA and glucose are the most widely studied fluid biochemical markers in pancreatic cystic lesions. Glucose has better diagnostic accuracy than CEA. Other biochemical biomarkers require further research.

Monocyte Chemotactic Proteins (MCP) in Colorectal Adenomas Are Differently Expressed at the Transcriptional and Protein Levels: Implications for Colorectal Cancer Prevention.

The expression of monocyte chemotactic proteins (MCPs) in colorectal polyps and their suitability as targets for chemoprevention is unknown, although MCP expression and secretion can be modulated by non-steroidal inflammatory drugs. This study was designed to determine the expression patterns of MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7 at the protein (immunohistochemistry; n = 62) and transcriptional levels (RTqPCR; n = 173) in colorectal polyps with reference to the polyp malignancy potential. All chemokines were significantly upregulated in polyps at the protein level but downregulated at the transcriptional level by 1.4-(CCL2), 1.7-(CCL7), and 2.3-fold (CCL8). There was an inverse relation between the immunoreactivity toward chemokine proteins and the number of corresponding transcripts in polyps (CCL2 and CCL7) or in normal mucosa (CCL8). The downregulation of chemokine transcripts correlated with the presence of multiple polyps (CCL2 and CCL8), a larger polyp size (CCL2, CCL7, and CCL8), predominant villous growth patterns (CCL2, CCL7 and CCL8), and high-grade dysplasia (CCL2 and CCL8). In conclusion, MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7 chemokines are counter-regulated at the protein and transcriptional levels. Chemokine-directed chemopreventive strategies should therefore directly neutralize MCP proteins or target molecular pathways contributing to their enhanced translation or reduced degradation, rather than aiming at CCL2, CCL7 or CCL8 expression.

Modulating Properties of Piroxicam, Meloxicam and Oxicam Analogues against Macrophage-Associated Chemokines in Colorectal Cancer.

The mechanisms underlying the antineoplastic effects of oxicams have not been fully elucidated. We aimed to assess the effect of classic and novel oxicams on the expression/secretion of macrophage-associated chemokines (RTqPCR/Luminex xMAP) in colorectal adenocarcinoma cells, and on the expression of upstream the non-steroidal anti-inflammatory drug (NSAID)-activated genes NAG1, NFKBIA, MYD88, and RELA, as well as at the chemokine profiling in colorectal tumors. Meloxicam downregulated CCL4 9.9-fold, but otherwise the classic oxicams had a negligible/non-significant effect. Novel analogues with a thiazine ring substituted with arylpiperazine and benzoyl moieties significantly modulated chemokine expression to varying degree, upregulated NAG1 and NFKBIA, and downregulated MYD88. They inhibited CCL3 and CCL4, and their effect on CCL2 and CXCL2 depended on the dose and exposure. The propylene linker between thiazine and piperazine nitrogens and one arylpiperazine fluorine substituent characterized the most effective analogue. Only CCL19 and CXCL2 were not upregulated in tumors, nor was CXCL2 in tumor-adjacent tissue compared to normal mucosa. Compared to adjacent tissue, CCL4 and CXCL2 were upregulated, while CCL2, CCL8, and CCL19 were downregulated in tumors. Tumor CCL2 and CCL7 increased along with advancing T and CCL3, and CCL4 along with the N stage. The introduction of arylpiperazine and benzoyl moieties into the oxicam scaffold yields effective modulators of chemokine expression, which act by upregulating NAG1 and interfering with NF-κB signaling.

Emerging Comorbidities in Inflammatory Bowel Disease: Eating Disorders, Alcohol and Narcotics Misuse.

Inflammatory bowel disease (IBD) is a chronic and potentially devastating condition of the digestive tract which is exemplified by increasing prevalence worldwide, byzantine pathogenesis with a poorly defined role of the environmental factors, and complex clinical demonstration. As a systemic disease, IBD may progress with a wide spectrum of extraintestinal manifestations (EMs) and comorbidities affecting different organs and systems, from anaemia, undernutrition, and cancer to those which are often neglected like anxiety and depression. Evolving IBD epidemiology and changing environment are reflected by an expanding list of IBD-related comorbidities. In contrast to the well-established role of smoking the connection between alcohol and IBD is still debatable on many levels, from pathogenesis to complications. Furthermore, little is known about narcotics use in IBD patients, even if there are obvious factors that may predispose them to narcotics as well as alcohol misuse. Last but not least, the question arises what is the prevalence of eating disorders in IBD. In our paper, we aimed to discuss the current knowledge on alcohol and drugs misuse and eating disorders as emerging extraintestinal comorbidities in IBD.

Machine Learning Prediction Model for Inflammatory Bowel Disease Based on Laboratory Markers. Working Model in a Discovery Cohort Study.

Inflammatory bowel disease (IBD) is a chronic, incurable disease involving the gastrointestinal tract. It is characterized by complex, unclear pathogenesis, increased prevalence worldwide, and a wide spectrum of extraintestinal manifestations and comorbidities. Recognition of IBD remains challenging and delays in disease diagnosis still poses a significant clinical problem as it negatively impacts disease outcome. The main diagnostic tool in IBD continues to be invasive endoscopy. We aimed to create an IBD machine learning prediction model based on routinely performed blood, urine, and fecal tests. Based on historical patients' data (702 medical records: 319 records from 180 patients with ulcerative colitis (UC) and 383 records from 192 patients with Crohn's disease (CD)), and using a few simple machine learning classificators, we optimized necessary hyperparameters in order to get reliable few-features prediction models separately for CD and UC. Most robust classificators belonging to the random forest family obtained 97% and 91% mean average precision for CD and UC, respectively. For comparison, the commonly used one-parameter approach based on the C-reactive protein (CRP) level demonstrated only 81% and 61% average precision for CD and UC, respectively. Results of our study suggest that machine learning prediction models based on basic blood, urine, and fecal markers may with high accuracy support the diagnosis of IBD. However, the test requires validation in a prospective cohort.

Ultrasound Elastography in the Assessment of the Intestinal Changes in Inflammatory Bowel Disease-Systematic Review.

Inflammatory bowel disease (IBD) is a chronic condition affecting primarily the gastrointestinal tract and characterized by growing incidence worldwide. Complex diagnostic process of IBD as well as evaluation of disease activity and intestinal complications that are crucial for the therapeutic decisions, require repetitive, invasive, expensive, time-consuming and poorly tolerated tests. In contrast to endoscopy and computed tomography, ultrasound elastography (UE) is non-invasive, non-radiating and non-contrasting dependent tool which might be utilized in IBD patients for the assessment of the intestinal changes. Therefore, we performed the systematic review to evaluate the possible application of the ultrasound elastography for assessment of the intestinal changes in IBD. After the search of three databases: PubMed, World of Knowledge and Scopus, we identified 12 papers which were included in the final analysis. The majority of the studies were focused on the evaluation of the symptomatic ileal/ileocolonic strictures in Crohn's disease patients that required surgical resection. Only one study concerned ulcerative colitis. The authors evaluated different UE techniques: strain elastography (SE), acoustic radiation force impulse (ARFI) and shear wave elastography (SWE). Results were expressed with semi-quantitative color mapping and strain measurement. Histological scores of inflammation and fibrosis in Crohn's disease were used as a reference test in the majority of studies. Ultrasound elastography seems to be a promising novel imaging technique supporting evaluation of the intestinal strictures in Crohn's disease patients in respect to fibrosis detection as well as differentiation between fibrosis and inflammation. However, further research is needed to establish the position of ultrasound elastography in IBD management.

Faecal Calprotectin in Assessment of Mucosal Healing in Adults with Inflammatory Bowel Disease: A Meta-Analysis.

Achieving mucosal healing in patients with inflammatory bowel disease is related to a higher incidence of sustained clinical remission and it translates to lower rates of hospitalisation and surgery. The assessment methods of disease activity and response to therapy are limited and mainly rely on colonoscopy. This meta-analysis reviews the effectiveness of using faecal calprotectin as a marker for mucosal healing in inflammatory bowel disease. Two meta-analyses were conducted in parallel. The analysis on the use of faecal calprotectin in monitoring mucosal healing in colonic Crohn's disease is based on 16 publications (17 studies). The data set for diagnostic values of faecal calprotectin in ulcerative colitis is composed of 35 original publications (total 49 studies). The DOR for the use of faecal calprotectin in Crohn's disease is estimated to be 11.20 and the area under the sROCis 0.829. In cases of ulcerative colitis, the DOR is 14.48, while the AUC sROC is 0.858. Heterogeneity of the studies was moderatetosubstantial. Collected data show overall good sensitivity and specificity of the faecal calprotectin test, as well as a good DOR. Thus, monitoring of mucosal healing with a non-invasive faecal calprotectin test may represent an attractive option for physicians and patients with inflammatory bowel disease.

Standard versus Endocuff versus cap-assisted colonoscopy for adenoma detection: A randomised controlled clinical trial.

BACKGROUND AND AIMS: Adenoma detection rate (ADR) in colon cancer screening is most important for cancer prophylaxis. This work is the first three-armed randomised controlled clinical trial aimed at comparing a head-to-head setting standard colonoscopy (SC) with Endocuff-assisted colonoscopy (EC) and cap-assisted colonoscopy (CAC) for improvement of ADR. METHODS: Patients from Poland and Germany with independent indication for colonoscopy were randomised into three arms of this trial: EC, CAC and SC. Exclusion criteria were age <18 years, active Crohn's disease or ulcerative colitis, known stenosis and post-colonic resection status. RESULTS: A total of 585 patients (195 SC, 189 EC and 186 CAC) were enrolled in this study. Indications were not different between the groups (colorectal cancer screening 51%, diagnostic colonoscopy in 31% and post-polypectomy follow-up in 18%; p = 0.94). Withdrawal time was a mean of 7 min in all groups (p = 0.658), and bowel preparation did not differ between the groups. The time to reach the caecum was significantly reduced when using the cap (a mean of 6 min for CAC vs. 7 min for SC; p = 0.0001). There was no significant difference in the primary outcome of the ADR between the groups (EC 32%, CAC 30%, SC 30%; p = 0.815). EC proved to be superior (EC vs. SC) in the sigmoid colon and transverse colon for polyp detection. CONCLUSION: The use of EC increased the total number of polyps seen during colonoscopy. In contrast to recent studies, no significant improvement of the ADR was detected.

L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs.

L-arginine/nitric oxide pathway metabolites are altered in colorectal cancer (CRC). We evaluated underlying changes in pathway enzymes in 55 paired tumor/tumor-adjacent samples and 20 normal mucosa using quantitative-PCR and assessed the impact of classic and novel oxicam analogues on enzyme expression and intracellular metabolite concentration (LC-MS/MS) in Caco-2, HCT116, and HT-29 cells. Compared to normal mucosa, ARG1, PRMT1, and PRMT5 were overexpressed in both tumor and tumor-adjacent tissue and DDAH2 solely in tumor-adjacent tissue. Tumor-adjacent tissue had higher expression of ARG1, DDAH1, and DDAH2 and lower NOS2 than patients-matched tumors. The ARG1 expression in tumors increased along with tumor grade and reflected lymph node involvement. Novel oxicam analogues with arylpiperazine moiety at the thiazine ring were more effective in downregulating DDAHs and PRMTs and upregulating ARG2 than piroxicam and meloxicam. An analogue distinguished by propylene linker between thiazine's and piperazine's nitrogen atoms and containing two fluorine substituents was the strongest inhibitor of DDAHs and PRMTs expression, while an analogue containing propylene linker but no fluorine substituents was the strongest inhibitor of ARG2 expression. Metabolic reprogramming in CRC includes overexpression of DDAHs and PRMTs in addition to ARG1 and NOS2 and is not restricted to tumor tissue but can be modulated by novel oxicam analogues.

Oxidative Stress Markers in Inflammatory Bowel Diseases: Systematic Review.

Precise diagnostic biomarker in inflammatory bowel diseases (IBD) is still missing. We conducted a comprehensive overview of oxidative stress markers (OSMs) as potential diagnostic, differential, progression, and prognostic markers in IBD. A Pubmed, Web of Knowledge, and Scopus search of original articles on OSMs in IBD, published between January 2000 and April 2020, was conducted. Out of 874 articles, 79 eligible studies were identified and used to prepare the interpretative synthesis. Antioxidants followed by lipid peroxidation markers were the most popular and markers of oxidative DNA damage the least popular. There was a disparity in the number of retrieved papers evaluating biomarkers in the adult and pediatric population (n = 6). Of the reviewed OSMs, a promising performance has been reported for serum total antioxidant status as a mucosal healing marker, mucosal 8-OHdG as a progression marker, and for multi-analyte panels of lipid peroxidation products assessed non-invasively in breath as diagnostic and differential markers in the pediatric population. Bilirubin, in turn, was the only validated marker. There is a desperate need for non-invasive biomarkers in IBD which, however, will not be met in the near future by oxidative stress markers as they are promising but mostly at the early research phase of discovery.

L-Arginine/NO Pathway Metabolites in Colorectal Cancer: Relevance as Disease Biomarkers and Predictors of Adverse Clinical Outcomes Following Surgery.

The L-Arginine/NO pathway is involved in carcinogenesis and immunity. Its diagnostic and prognostic value in colorectal cancer (CRC) was determined using tandem mass spectrometry in 199 individuals (137 with CRC) and, during a three-day follow up, in 60 patients undergoing colorectal surgery. Citrulline was decreased and asymmetric (ADMA) and symmetric (SDMA) dimethylarginines and dimethylamine (DMA) were increased in CRC. The DMA increase corresponded with CRC advancement while arginine, ADMA, and SDMA levels were higher in left-sided cancers. Arginine, citrulline, ADMA, and DMA dropped and SDMA increased post incision. Females experienced a more substantial drop in arginine. The arginine and ADMA dynamics depended on blood loss. The initial SDMA increase was higher in patients requiring transfusions. Postoperative dynamics in arginine and dimethylarginines differed in robot-assisted and open surgery. Concomitant SDMA, citrulline, and DMA quantification displayed a 92% accuracy in detecting CRC. Monitoring changes in arginine, ADMA, and SDMA in the early postoperative period predicted postoperative ileus with 84% and surgical site infections with 90% accuracy. Changes in ADMA predicted operative morbidity with 90% and anastomotic leakage with 77% accuracy. If positively validated, L-arginine/NO pathway metabolites may facilitate CRC screening and surveillance, support differential diagnosis, and assist in clinical decision-making regarding patients recovering from colorectal surgery.

Biochemical Biomarkers of Mucosal Healing for Inflammatory Bowel Disease in Adults.

Mucosal healing (MH) is the key therapeutic target of inflammatory bowel disease (IBD). The evaluation of MH remains challenging, with endoscopy being the golden standard. We performed a comprehensive overview of the performance of fecal-, serum-, and urine-based biochemical markers in colonic IBD to find out whether we are ready to replace endoscopy with a non-invasive but equally accurate instrument. A Pubmed, Web of Knowledge, and Scopus search of original articles as potential MH markers in adults, published between January 2009 and March 2020, was conducted. Finally, 84 eligible studies were identified. The most frequently studied fecal marker was calprotectin (44 studies), with areas under the curves (AUCs) ranging from 0.70 to 0.99 in ulcerative colitis (UC) and from 0.70 to 0.94 in Crohn`s disease (CD), followed by lactoferrin (4 studies), matrix metalloproteinase-9 (3 studies), and lipocalin-2 (3 studies). The most frequently studied serum marker was C-reactive protein (30 studies), with AUCs ranging from 0.60 to 0.96 in UC and from 0.64 to 0.93 in CD. Fecal calprotectin is an accurate MH marker in IBD in adults; however, it cannot replace endoscopy and the application of calprotectin is hampered by the lack of standardization concerning the cut-off value. Other markers are either not sufficiently accurate or have not been studied extensively enough.

Whole blood ACTB, B2M and GAPDH expression reflects activity of inflammatory bowel disease, advancement of colorectal cancer, and correlates with circulating inflammatory and angiogenic factors: Relevance for real-time quantitative PCR.

BACKGROUND: The effect of bowel inflammation and cancer on the expression of the most prevalent internal controls: ACTB, GAPDH and B2M in whole blood is unknown, although at least GAPDH occurred to be tightly regulated and suspected of supporting cancer growth, challenging its suitability as a reference. OBJECTIVES: To evaluate the effect of colorectal cancer (CRC) and active inflammatory bowel disease (IBD) on the stability of ACTB, B2M, GAPDH, HPRT1, SDHA, and TBP leukocyte expression. MATERIAL AND METHODS: Gene expression in controls and CRC and IBD patients (n = 21/18/25) was evaluated in real-time quantitative polymerase chain reaction (RT-qPCR) using NormFinder, geNorm, BestKeeper, and comparative ΔCt method, and validated by comparison with absolute quantification of interleukin 1ß (IL-1ß) and CCL4. RESULTS: HPRT1, SDHA and TBP were superior normalizers in CRC and IBD. The highest expression variability was noted in active IBD. B2M was significantly lower in CRC but higher in IBD. GAPDH was higher in CRC and IBD. ACTB and GAPDH corresponded with CRC advancement (ρ = 0.52 and ρ = 0.53) and with clinical activity in Crohn's disease (ρ = 0.44 and ρ = 0.57) and ulcerative colitis (GAPDH: ρ = 0.72). ACTB, B2M and GAPDH correlated with circulating inflammatory/angiogenic indices, differently in IBD and CRC. CONCLUSIONS: Leukocyte GAPDH, ACTB, and B2M expression is affected by bowel inflammation and cancer, rendering them unsuitable as a reference in CRC and IBD.

Transcriptional and Metabolomic Analysis of L-Arginine/Nitric Oxide Pathway in Inflammatory Bowel Disease and Its Association with Local Inflammatory and Angiogenic Response: Preliminary Findings.

L-arginine/nitric oxide pathway in Crohn's disease (CD) and ulcerative colitis (UC) is poorly investigated. The aim of current study is to quantify pathway serum metabolites in 52 CD (40 active), 48 UC (33 active), and 18 irritable bowel syndrome patients and 40 controls using mass spectrometry and at determining mRNA expression of pathway-associated enzymes in 91 bowel samples. Arginine and symmetric dimethylarginine decreased (p < 0.05) in active-CD (129 and 0.437 µM) compared to controls (157 and 0.494 µM) and active-UC (164 and 0.52 µM). Citrulline and dimethylamine increased (p < 0.05) in active-CD (68.7 and 70.9 µM) and active-UC (65.9 and 73.9 µM) compared to controls (42.7 and 50.4 µM). Compared to normal, CD-inflamed small bowel had downregulated (p < 0.05) arginase-2 by 2.4-fold and upregulated dimethylarginine dimethylaminohydrolase (DDAH)-2 (1.5-fold) and arginine N-methyltransferase (PRMT)-2 (1.6-fold). Quiescent-CD small bowel had upregulated (p < 0.05) arginase-2 (1.8-fold), DDAH1 (2.9-fold), DDAH2 (1.5-fold), PRMT1 (1.5-fold), PRMT2 (1.7-fold), and PRMT5 (1.4-fold). Pathway enzymes were upregulated in CD-inflamed/quiescent and UC-inflamed colon as compared to normal. Compared to inflamed, quiescent CD-colon had upregulated DDAH1 (5.7-fold) and ornithine decarboxylase (1.6-fold). Concluding, the pathway is deregulated in CD and UC, also in quiescent bowel, reflecting inflammation severity and angiogenic potential. Functional analysis of PRMTs and DDAHs as potential targets for therapy is warranted.

The emerging role of mood disorders in inflammatory bowel diseases.

Inflammatory bowel diseases (IBD) are chronic, devastating conditions of the gastrointestinal tract characterized by a complex pathogenesis, increasing worldwide prevalence, a wide spectrum of extraintestinal manifestations, and a reduced health-related quality of life (HRQoL). Furthermore, mood disorders, specifically anxiety and depression, are more prevalent among IBD patients compared to the general population. The connection between mental disorders and IBD is compound, bidirectional and still not fully understood. The IBD may impact psychological health, whereas anxiety and depression are associated with a more aggressive course of IBD. The inflammation process, gut microbiota alterations and drug side effects are factors that influence the mental state of patients with IBD. Importantly, despite the high prevalence of depression and anxiety in IBD, many of the current guidelines do not include clear recommendation for assessment of mental problems in patients and further management. Therefore, monitoring for mood disorders should become a part of the multi-disciplinary and holistic approach to patients with IBD. This review is based on current literature searched in PubMed, mainly considering publications from the last 10 years.

The immunoreactivity of TGF-b1 in non-alcoholic fatty liver disease.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease which becomes a rapidly growing health problem in the Western countries. The development of the disease is most often connected to obesity. NAFLD is also considered as the hepatic manifestation of metabolic syndrome. Transforming growth factor b1 (TGF-b1) plays an important role in the pathogenesis of liver fibrosis, being involved in activation of hepatic stellate cells, stimulation of collagen gene transcription, and suppression of matrix metalloproteinase expression. The objective of the study was to evaluate by immunohistochemistry the expression of TGF-b1 in the liver tissue of NAFLD patients and correlate it with anthropometric, biochemical and routine histological parameters. MATERIAL AND METHODS: The study group consisted of 48 patients with diagnosed NAFLD. Liver steatosis, NAFLD Activity Score (NAS) and METAVIR score of fibrosis were evaluated in liver biopsies. The immunoreactivity of TGF-b1 was evaluated semi-quantitatively separately in portal, septal, lobular hepatocytic and lobular sinu-soidal liver compartments. The results were analyzed in regard to patients' clinical and biochemical parameters. RESULTS: Neither steatosis nor NAS correlated with TGF-b1 expression in any liver compartment, whereas METAVIR score of fibrosis was associated with increased immunoreactivity of TGF-b1 in most of the studied liver compartments. TGF-b1 immunoreactivity showed positive correlation with patients' age and its expression in septal compartment disclosed positive correlation with body mass index, and waist and hip circumference. Hyaluronic acid serum level was positively and iron concentration was negatively associated with TGF-b1 ex-pression in the selected consecutive liver compartments. CONCLUSIONS: The immunohistochemical expression of TGF-b1 may be complementary to routine methods of liver fibrosis evaluation.

Nonenzymatic Serum Antioxidant Capacity in IBD and Its Association with the Severity of Bowel Inflammation and Corticosteroids Treatment.

Background and objectives: Oxidative stress signalling plays a monumental role in inflammatory bowel disease (IBD). Reduction of oxidative stress might control inflammation, block tissue damage, and reverse natural history of IBD. We assessed the serum concentrations of free thiols (FT) and uric acid (SUA), together constituting a large part of nonenzymatic serum antioxidant capacity, as well as total antioxidant status (TAS) with reference to IBD phenotype, activity, co-occurrence of anemia, and treatment with azathioprine (AZA) and corticosteroids (CS). Additionally, we appraised the potential of uric acid, thiol stress, and TAS as mucosal healing (MH) markers in ulcerative colitis. Materials and methods: SUA, FT, and TAS were measured colorimetrically using, respectively, uricase, Ellman's and 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) methods. Results: The study group consisted of 175 individuals: 57 controls, 71 ulcerative colitis (UC), and 47 Crohn's disease (CD) patients. When compared to controls, SUA levels were significantly lower in patients with CD, and FT and TAS levels were significantly lower in patients with CD and UC. In UC patients, SUA, FT, and TAS inversely correlated with the severity of bowel inflammation. As MH markers, SUA displayed better overall accuracy and higher specificity than FT. In active CD, FT, and SUA were significantly lower in patients with anemia. FT was significantly lower in patients treated with corticosteroids. Conclusions: IBD patients, regardless the disease phenotype, have systemic thiol stress, depleted total antioxidant capacity, and reduced concentrations of uric acid, reflecting, to various degrees, clinical and local disease activity as well as presence of anaemia, the most common extraintestinal manifestation of IBD. Evaluation of systemic total antioxidant status may be useful in noninvasive assessment of mucosal healing. Our findings on thiol stress provide an additional aspect on adverse effects of corticosteroids therapy.