Increased synthesis and intestinal expression of IL-39 in patients with inflammatory bowel disease.

IL-39 (Interleukin-39) is a heterodimeric cytokine composed of IL-23p19 and EBI3 (Epstein-Barr virus-induced gene 3) subunits. Despite the evidence that correlates the role of IL-39 in regulating inflammation, its expression in the intestinal microenvironment of IBD (inflammatory bowel disease) patients is still unknown. Thus, this work was focused on characterizing relative mRNA (messenger RNA) IL-39 expression and intestinal synthesis in IBD patients. This study includes 37 patients diagnosed with ulcerative colitis (UC), 15 with Chron's disease (CD), and 22 controls. Gene expression of IL-39 subunits (IL-23p19/EBI3) was measured by RT-PCR (real time polymerase chain reaction). Intestinal synthesis was evaluated by immunohistochemistry and serum levels by ELISA. Statistical analysis was done using Prism GraphPad V6. Relative mRNA IL-39 expression was increased in patients with active UC and active CD compared to the remission UC, remission CD, and control group. High levels of relative mRNA expression of IL-39 (IL-23p19 subunit) were associated with histological activity. IHQ analysis showed increased IL-39 production in mucosa, submucosa, muscular, and serosa layer of patients with active disease. IL-39 serum production was increased in patients with UC. IL-39 gene's upregulation was found in patients with active IBD and was associated with severe histological activity in UC. This is the first report regarding the role of IL-39 in patients with IBD. The findings suggest that IL-39 might play a role as an inflammatory mediator in active IBD and could be considered a new alternative in treating this condition.

Clinical and Endoscopic Differences Between Patients With Barrett's Esophagus With and Without Dysplasia/Adenocarcinoma.

INTRODUCTION: Barrett's esophagus (BE) is the main precursor of esophageal adenocarcinoma (EAC). This study aimed to identify the risk factors associated with BE progression to dysplasia or EAC in a Latin population. METHODS: The study is a retrospective analysis of a single-center cohort of patients with BE, evaluated from 2002 to 2012. RESULTS: We identified 420 patients with BE; 281 (66.9%) of them were men with a mean age of 57.2 ± 15.3 years. Among all BE patients evaluated, 81 (19.3%) had progression to some degree of dysplasia/EAC. The mean follow-up was 5.6 years. Multivariate analysis showed that age (OR = 1.03), cigarette smoking (OR = 3.05), long-segment BE (OR = 4.81), and a visible lesion on BE (OR = 6.94) were associated with progression to dysplasia/EAC. CONCLUSION: In Latin patients with BE, age, cigarette smoking, long-segment BE, and the presence of lesions were associated with the presence of dysplasia/EAC.

ABCC7/CFTR Expression Is Associated with the Clinical Course of Ulcerative Colitis Patients.

Inflammatory bowel disease includes ulcerative colitis (UC) and Crohn's disease (CD) of unknown etiology. The expression of ATP-binding cassette (ABC) family proteins has been associated with drug resistance and development of UC. The cystic fibrosis transmembrane conductance regulator (CFTR) or also known as ABCC7 is involved in the inflammatory chronic response. The aim of this study was to evaluate the role of ABCC7/CFTR in UC patients and normal controls without inflammation. This is an exploratory, observational, and cross-sectional study that included a total of 62 patients with UC and normal controls. Gene expression of CFTR was measured by RT-PCR, and protein expression of CFTR was determined by western blot analysis. We found a significant downregulation of the CFTR gene expression in patients with active UC compared to normal controls without inflammation (P < 0.004); even the gene expression of CFTR was decreased in remission UC patients compared to normal controls without inflammation (P = 0.04). The CFTR gene expression was associated with the clinical course of UC and the protein expression of CFTR was decreased in active UC patients compared to normal controls without inflammation suggesting that this molecule might play a role in the inflammation in UC patients.

Intestinal production of secreted protein acidic and rich in cysteine (SPARC) in patients with ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is an inflammatory disease of the intestine. The genetics factors play an important role in the pathogenesis of UC. SPARC exacerbates colonic inflammatory symptoms in dextran sodium sulphate-induced murine colitis. The aim of the study was to measure the gene expression and intestinal production of SPARC in patients with UC and controls as well as, to determine its correlation with histological activity. METHODS: We included 40 patients with confirmed diagnosis of UC, and 20 controls without endoscopic evidence of any type of colitis or neoplasia. The relative quantification of the gene expression was performed by real time PCR. GAPDH was used as housekeeping gene for normalization purposes and quality controls. Protein expression was determined by immunohistochemistry. RESULTS: The gene expression of SPARC was increased in patients with active UC vs in remission UC and vs. controls (P = 0.005). There was no significant difference between patients with remission UC and controls. The overexpression of SPARC in patients with active UC correlated significantly with mild histological activity (P = 0.06, OR = 7.77, IC = 0.77-77.9) moderate (P = 0.06, OR = 8.1, IC 95%=0.79-82.73), and severe (P = 0.03, OR = 6.5, IC 95%=1.09-38.6). Double positive SPARC+/CD16+ cells were localized mainly in submucosa, muscular layer, and adventitia, and in perivascular inflammatory infiltrates in patients with active UC. CONCLUSION: The gene and protein expression of SPARC is increased in active UC. SPARC could be a marker of intestinal inflammation and its expression correlates with histological activity.

Expression of TOB/BTG family members in patients with inflammatory bowel disease.

In recent years, the role of anti-proliferative TOB proteins in the regulation of immune response by inhibiting T cell activation has been demonstrated. Nevertheless, no previous studies have explored their expression in patients with IBD. The aim of the study was to characterize the gene and protein expression of the TOB/BTG family in intestinal tissue of patients with IBD. This is an observational and cross-sectional study that included 63 IBD patients. Gene expression of TOB/BTG family was measured by RT-PCR. Protein expression of TOB/CD16 and BTG/Ki-67 was evaluated by immunohistochemistry. TOB/BTG family mRNAs were detected and quantitated by RT-qPCR in rectal and ileum biopsies from UC patients and CD patients, respectively, and non-inflammatory control tissues. Results showed that TOB1 and BTG1 gene expression was decreased in the colonic mucosa from patients with UC compared with the control group. The TOB2 and BTG2 genes were over-expressed in the colonic mucosa of patients with UC in remission compared with the active UC and control group. The high TOB2 gene expression was associated with histological remission (P = .01). TOB1/CD16, TOB2/CD16, BTG1/Ki-67, BTG2/Ki-67 and BTG4/Ki-67 single and double positive cells were mostly NK, macrophages, epithelial cells, connective tissue cells and perivascular inflammatory infiltrates in tissues from patients with UC and CD. This is the first depiction of the TOB/BTG family gene and protein expression in rectal and ileum tissues by a CD16+ subpopulation in IBD.

Increased expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and MMP10, MMP23 in inflammatory bowel disease: Cross-sectional study.

It has been reported that EMMPRIN is involved in the regulation of immune response and the induction of MMPs production by fibroblasts. The aim of this study was to describe the intestinal gene expression and protein production of EMMPRIN, MMP23 and MMP10 in patients with ulcerative colitis (UC) and Crohn's disease (CD) and compared them with a control group. Gene expression of EMMPRIN, MMP10 and MMP23B was measured by RT-PCR. In order to determine EMMPRIN and MMP protein expression, colonic tissues were immunostained. The results of the study showed EMMPRIN gene expression was upregulated in rectal mucosa from active (a)UC versus aCD patients (P = .045), remission (r)CD group (P = .0009) and controls (P < .0001). We detected differences between rUC and aCD (P = .004), rCD (P < .0001) or control group (P < .0001). EMMPRIN showed a higher expression in mucosa (intraepithelial lymphocytes), submucosa and adventitia (endothelial cells) from aCD patients. MMP23 levels were increased in aUC and aCD compared to rUC and rCD and the control group (P = .0001). EMMPRIN+/MMP23+─expressing cells were localized mainly in mucosa, muscular and adventitia from active UC patients. MMP10 gene expression was increased in aUC versus CD patients and the control group (P = .0001). MMP10 gene expression is associated with inflammation in UC patients (P = .0001, r2  = .585). EMMPRIN+/MMP10+─producing cells were found mainly in all intestinal layers and perivascular inflammatory infiltrates from aUC patients. In conclusion, EMMPRIN, MMP23 and MMP10 were upregulated in patients with active UC versus remission UC , CD and control groups suggesting that, they are involved in the inflammatory process.

TRPV Subfamily (TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6) Gene and Protein Expression in Patients with Ulcerative Colitis.

INTRODUCTION: TRPVs are a group of receptors with a channel activity predominantly permeable to Ca2+. This subfamily is involved in the development of gastrointestinal diseases such as ulcerative colitis (UC). The aim of the study was to characterize the gene and protein expression of the TRPV subfamily in UC patients and controls. METHODS: We determined by quantitative PCR the gene expression of TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6 in 45 UC patients (29 active UC and 16 remission UC) and 26 noninflamed controls. Protein expression was evaluated in 5 µm thick sections of formalin-fixed, paraffin-embedded tissue from 5 customized severe active UC patients and 5 control surgical specimens. RESULTS: TRPV2 gene expression was increased in the control group compared with active UC and remission patients (P = 0.002 and P = 0.05, respectively). TRPV3 gene expression was significantly higher in controls than in active UC patients (P = 0.002). The gene expression of TRPV4 was significantly higher in colonic tissue from patients with remission UC compared with active UC patients (P = 0.05) and controls (P = 0.005). TRPV5 had significantly higher mRNA levels in a control group compared with active UC patients (P = 0.02). The gene expression of TRPV6 was significantly higher in the colonic tissue from patients with active UC compared with the control group (P = 0.05). The protein expression of TRPV2 was upregulated in the mucosa and submucosa from the controls compared with the UC patients (P ≤ 0.003). The protein expression of TRPV3 and TRPV4 was upregulated in all intestinal layers from the controls compared with the UC patients (P < 0.001). TRPV5 was upregulated in the submucosa and serosa from the controls vs. UC patients (P < 0.001). TRPV6 was upregulated in all intestinal layers from the UC patients vs. controls (P ≤ 0.001). CONCLUSION: The TRPV subfamily clearly showed a differential expression in the UC patients compared with the controls, suggesting their role in the pathophysiology of UC.

The Transient Receptor Potential Vanilloid 1 Is Associated with Active Inflammation in Ulcerative Colitis.

The transient receptor potential vanilloid 1 (TRPV1) may play a role in the pathogenesis of ulcerative colitis (UC). The aim of the study was to determine the gene and protein expression of TRPV1 in UC patients and noninflamed controls. Gene expression was performed by RT-PCR, and protein expression was performed by immunohistochemistry. The gene expression of TRPV1 was significantly increased in the remission UC group compared to active UC patients (P = 0.002), and an upregulation of the TRPV1 gene was associated with clinical outcomes such as age at diagnosis (<40 years) (P = 0.02) and clinical disease course characterized by relapsing and continuous activity (P = 0.07). TRPV1 immunoreactive cells were conspicuously higher in all intestinal layers from active UC patients compared with noninflamed control tissue. These findings suggest that TRPV1 might be involved in UC pathogenesis.

Caspase recruitment domain (CARD) family (CARD9, CARD10, CARD11, CARD14 and CARD15) are increased during active inflammation in patients with inflammatory bowel disease.

BACKGROUND: The CARD family plays an important role in innate immune response by the activation of NF-κB. The aim of this study was to determine the gene expression and to enumerate the protein-expressing cells of some members of the CARD family (CARD9, CARD10, CARD11, CARD14 and CARD15) in patients with IBD and normal controls without colonic inflammation. METHODS: We included 48 UC patients, 10 Crohn's disease (CD) patients and 18 non-inflamed controls. Gene expression was performed by RT-PCR and protein expression by immunohistochemistry. CARD-expressing cells were assessed by estimating the positively staining cells and reported as the percentage. RESULTS: The CARD9 and CARD10 gene expression was significantly higher in UC groups compared with CD (P < 0.001). CARD11 had lower gene expression in UC than in CD patients (P < 0.001). CARD14 gene expression was higher in the group with active UC compared to non-inflamed controls (P < 0.001). The low expression of CARD14 gene was associated with a benign clinical course of UC, characterized by initial activity followed by long-term remission longer than 5 years (P = 0.01, OR = 0.07, 95%CI:0.007-0.70). CARD15 gene expression was lower in UC patients versus CD (P = 0.004). CARD9 protein expression was detected in inflammatory infiltrates; CARD14 in parenchymal cells, while CARD15 in inflammatory and parenchymal cells. CARD9-, CARD14- and CARD15 - expressing cells were significantly higher in patients with active UC versus non-inflamed controls (P < 0.05). CONCLUSION: The CARD family is involved in the inflammatory process and might be involved in the IBD pathophysiology.

Higher adenoma detection rate with the endocuff: a randomized trial.

Background and study aim Different techniques have been introduced to improve the endoscopist's view and enhance the detection of polyps. The endocuff is a polymer sleeve cap that is connected to the tip of the colonoscope in order to improve visualization of the mucosa during colonoscopy. The aim of the study was to compare adenoma detection rates (ADR) of endocuff-assisted colonoscopy and conventional colonoscopy. Patients and methods Patients 50 years or older were randomized into two groups: an endocuff-assisted colonoscopy group and a conventional colonoscopy group without the endocuff. Results A total of 337 patients were included: 174 in the endocuff group and 163 in the conventional group. The median age was 61 years (interquartile range 55 - 70 years), and 74 % were women. The ADR was higher in the endocuff group than in the conventional group (22.4 % vs. 13.5 %; P = 0.02). The mean number of adenomas was 0.30 (SD 0.25) in the endocuff group and 0.21 (SD 0.26) in the conventional group (P â€Š= 0.02). The rate of ileal intubation was lower in the endocuff group (73 % vs. 87 %; P < 0.001). No serious adverse events occurred with the use of the endocuff. Conclusions Endocuff colonoscopy achieved a greater ADR than conventional colonoscopy.Trial registered at ClinicalTrials.gov (NTC02387593).

Pneumatosis cystoides intestinalis.

A 54-year-old woman underwent colonoscopy for colon cancer screening. Colonoscopy showed multiple cysts in the sigmoid colon, with the largest being 4 cm in diameter. One of the cysts was biopsied. Cyst walls were observed; during biopsy, the gas was released and the cyst collapsed. Computed tomography of the abdomen confirmed a diagnosis of pneumatosis cystoides intestinalis. Pneumatosis cystoides intestinalis is a rare disease characterized by the presence in the intestinal submucosa or subserosa of multiple cysts filled with gas (nitrogen, oxygen, carbon dioxide and hydrogen). This condition occurs more often in males than in females, with cysts most frequently located in the colon. Causes may include elevated intraluminal pressure, pulmonary diseases, bacterial gas production, malnutrition, chemotherapy, connective tissue diseases, among others. Symptoms of pneumatosis cystoides intestinalis include abdominal pain, diarrhea, bloating and gastrointestinal bleeding. This condition is diagnosed by endoscopy or computed tomography of the abdomen. Conservative treatment is successful in 93% of patients. However, 3% of patients develop complications such as intestinal obstruction or perforation.

Neumatosis quística intestinal / Pneumatosis cystoides intestinalis

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Diagnostic yield and therapeutic impact of rectal retroflexion: a prospective, single-blind study conducted in three centers.

BACKGROUND/AIMS: No clear data have been established and validated regarding whether rectal retroflexion has an important and therapeutic impact. The aim of the present study was to evaluate the diagnostic yield and therapeutic impact of rectal retroflexion compared with straight view examination. METHODS: A prospective single-blind study was conducted. Consecutive patients evaluated between October 2011 and April 2012 were included. RESULTS: A total of 934 patients (542 women, 58%) were included. The mean age was 57.4±14.8 years. Retroflexion was successful in 917 patients (98.2%). Distinct lesions in the anorectal area were detected in 32 patients (3.4%), of which 10 (1%) were identified only on retroflex view and 22 (2.4%) on both straight and retroflex views. Of the 32 identified lesions, 16 (50%) were polyps, nine (28.1%) were angiodysplasias, six (18.8%) were ulcers, and one (3.1%) was a flat lesion. All 10 patients (1%) in whom lesions were detected only by rectal retroflexion showed a therapeutic impact. CONCLUSIONS: Rectal retroflexion has minimal diagnostic yield and therapeutic impact. However, its low rate of major complications and the possibility of detecting lesions undetectable by straight viewing justify its use.

Transcript levels of Toll-Like Receptors 5, 8 and 9 correlate with inflammatory activity in Ulcerative Colitis.

BACKGROUND: Dysregulation of innate immune response by Toll-Like Receptors (TLRs) is a key feature in Ulcerative Colitis (UC). Most studies have focused on TLR2, TLR3, and TLR4 participation in UC. However, few studies have explored other TLRs. Therefore, the aim of this study was to evaluate the mRNA profiles of TLR1 to 9 in colonic mucosa of UC patients, according to disease activity. METHODS: Colonic biopsies were taken from colon during colonoscopy in 51 patients with Ulcerative Colitis and 36 healthy controls. mRNA levels of TLR1 to 9, Tollip, inflammatory cytokines IL6 and TNF were assessed by RT-qPCR with hydrolysis probes. Characterization of TLR9 protein expression was performed by Immunohistochemistry. RESULTS: Toll-like receptors TLR8, TLR9, and IL6 mRNA levels were significantly higher in the colonic mucosa from UC patients (both quiescent and active) as compared to healthy individuals (p < 0.04). In the UC patients group the TLR2, TLR4, TLR8 and TLR9 mRNA levels were found to be significantly lower in patients with quiescent disease, as compared to those with active disease (p < 0.05), whereas TLR5 showed a trend (p = 0.06). IL6 and TNF mRNA levels were significantly higher in the presence of active disease and help to discriminate between quiescent and active disease (p < 0.05). Also, IL6 and TNF mRNA positively correlate with TLRs mRNA with the exception for TLR3, with stronger correlations for TLR5, TLR8, and TLR9 (p < 0.0001). TLR9 protein expression was mainly in the lamina propria infiltrate. CONCLUSIONS: This study demonstrates that TLR2, TLR4, TLR8, and TLR9 expression increases in active UC patients, and that the mRNA levels positively correlate with the severity of intestinal inflammation as well as with inflammatory cytokines.