Update on the management of ulcerative colitis: treatment and maintenance approaches focused on MMX® mesalamine

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon that typically manifests as diarrhea, abdominal pain, and bloody stool. Complications, such as colorectal cancer and extraintestinal manifestations, may also develop. The goals of management are to induce and maintain clinical remission and to screen for complications of this disease. Mesalamine is a 5-aminosalicylic acid compound that is the first-line therapy to induce and maintain clinical remission in patients with mild-to-moderate UC. For patients who are refractory to mesalamine or have more severe disease, steroids, azathioprine/mercaptopurine, cyclosporine, or infliximab may be used, induce and/or maintain remission. The various formulations of mesalamine available are primarily differentiated by the methods of delivery of the active compound of the drug to the colon. Mesalamine with Multi-Matrix System® (MMX) technology (Cosmo SpA, Milan, Italy) is an oral (1.2 g), once-daily tablet formulation of mesalamine used for the treatment of UC (Lialda® or Mezavant®, Shire Pharmaceuticals Inc, Wayne, PA). In clinical studies, MMX mesalamine (taken as a once-daily dose of 2.4 or 4.8 g) effectively induced and maintained clinical remission in patients with active mild-to-moderate UC. The overall safety profile of MMX mesalamine is similar to other oral mesalamine formulations. The use of such once-daily formulations has led to intense interest in whether simplified pill regimens can improve patient adherence to mesalamine therapy

Nephrolithiasis in patients with inflammatory bowel disease in the community

Background: Inflammatory bowel disease (IBD) has been associated with renal stone formation. The objective of this study was to determine prospectively the prevalence of nephrolithiasis in a community-based population of patients with IBD and to analyze factors associated with renal calculus formation. Methods: Screening renal ultrasound was performed in a well characterized cohort of patients seen between 2009 and 2012 at an IBD clinic. We enrolled 168 patients, including 93 with Crohn’s disease and 75 with ulcerative colitis. Clinical and phenotypic variables associated with asymptomatic nephrolithiasis were determined. Results: Nephrolithiasis was detected in 36 patients with Crohn’s disease and in 28 patients with ulcerative colitis (38% for both). Although none of the patients had been previously hospitalized for symptomatic nephrolithiasis, nine with Crohn’s disease and five with ulcerative colitis had recurrent urinary tract infections or hydronephrosis. In patients with Crohn’s disease, ileocolonic (L3) disease was associated with a greater risk of nephrolithiasis than was ileal (L1) or colonic (L2) disease (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.8–7). Active ulcerative colitis (regardless of severity) represented a significant risk factor for formation of renal calculi (OR 4.2, 95% CI 1.1–15, P = 0.02). Conclusion: In surgery-naïve patients with IBD in the community, asymptomatic nephrolithiasis is common and should be considered when renal dysfunction or infection is detected

In silico gene expression analysis – an overview

Efforts aimed at deciphering the molecular basis of complex disease are underpinned by the availability of high throughput strategies for the identification of biomolecules that drive the disease process. The completion of the human genome-sequencing project, coupled to major technological developments, has afforded investigators myriad opportunities for multidimensional analysis of biological systems. Nowhere has this research explosion been more evident than in the field of transcriptomics. Affordable access and availability to the technology that supports such investigations has led to a significant increase in the amount of data generated. As most biological distinctions are now observed at a genomic level, a large amount of expression information is now openly available via public databases. Furthermore, numerous computational based methods have been developed to harness the power of these data. In this review we provide a brief overview of in silico methodologies for the analysis of differential gene expression such as Serial Analysis of Gene Expression and Digital Differential Display. The performance of these strategies, at both an operational and result/output level is assessed and compared. The key considerations that must be made when completing an in silico expression analysis are also presented as a roadmap to facilitate biologists. Furthermore, to highlight the importance of these in silico methodologies in contemporary biomedical research, examples of current studies using these approaches are discussed. The overriding goal of this review is to present the scientific community with a critical overview of these strategies, so that they can be effectively added to the tool box of biomedical researchers focused on identifying the molecular mechanisms of disease

Exosomes in Intestinal Inflammation

Exosomes are 30–150 nm sized vesicles released by a variety of cells, and are found in most physiological compartments (feces, blood, urine, saliva, breast milk). They can contain different cargo, including nucleic acids, proteins and lipids. In Inflammatory Bowel Disease (IBD), a distinct exosome profile can be detected in blood and fecal samples. In addition, circulating exosomes can carry targets on their surface for monoclonal antibodies used as IBD therapy. This review aims to understand the exosome profile in humans and other mammals, the cargo contained in them, the effect of exosomes on the gut, and the application of exosomes in IBD therapy

Characterization of Human CD39+ Th17 Cells with Suppressor Activity and Modulation in Inflammatory Bowel Disease

Induced regulatory T-cells (iT-reg) and T helper type 17 (Th17) in the mouse share common CD4 progenitor cells and exhibit overlapping phenotypic and functional features. Here, we show that human Th17 cells endowed with suppressor activity (supTh17) can be derived following exposure of iT-reg populations to Th17 polarizing conditions. In contrast to “pathogenic” Th17, supTh17 display immune suppressive function and express high levels of CD39, an ectonucleotidase that catalyzes the conversion of pro-inflammatory extracellular nucleotides ultimately generating nucleosides. Accordingly, supTh17 exhibit nucleoside triphosphate diphosphohydrolase activity, as demonstrated by the efficient generation of extracellular AMP, adenosine and other purine derivatives. In addition supTh17 cells are resistant to the effects of adenosine as result of the low expression of the A2A receptor and accelerated adenosine catalysis by adenosine deaminase (ADA). These supTh17 can be detected in the blood and in the lamina propria of healthy subjects. However, these supTh17 cells are diminished in patients with Crohn’s disease. In summary, we describe a human Th17 subpopulation with suppressor activity, which expresses high levels of CD39 and consequently produces extracellular adenosine. As these uniquely suppressive CD39+ Th17 cells are decreased in patients with inflammatory bowel disease, our findings might have implications for the development of novel anti-inflammatory therapeutic approaches in these and potentially other immune disorders

Characteristics of Inflammatory Bowel Disease Serology in Patients With Indeterminate Colitis

Goals and Background Inflammatory bowel disease (IBD) serology testing is often used in patients with indeterminate colitis (IC) to help distinguish between ulcerative colitis (UC) and Crohn’s disease (CD). We investigated the performance of serology testing in predicting future diagnosis in this setting. Study Observational study of individuals with IC at a single center who underwent IBD serology testing (pANCA, ASCA and anti-OmpC) and had at least 12 months follow-up from time of serology result. Results 117 individuals with IC and 1 year follow-up data were enrolled. All IC patients had endoscopic and histologic evidence of colitis at enrollment. One year after serology testing, 58 (50%) individuals with IC were diagnosed with UC, 49 (42%) with CD, and 10 (9%) remained labeled with IC. The sensitivity/specificity of an initial positive pANCA for a subsequent diagnosis of UC was 78%/44%. For ASCA and anti-OmpC, the results were 18%/84% and 27%/75%, respectively, for a subsequent diagnosis of CD. A positive pANCA test was associated with a likelihood ratio (LR) of 1.4 (95% CI: 1.1–1.8) for a subsequent diagnosis of UC at 1 year. Neither positive ASCA (LR 1.1; 95% CI: 0.5–2.5) nor anti-OmpC (LR 1.1; 95% CI: 0.6–2.0) was associated with a subsequent diagnosis CD in patients with IC. Conclusions The disease phenotype in the majority of individuals initially labeled with IC evolved to be more consistent with either UC or CD on follow-up. pANCA, ASCA, and anti-OmpC, individually, were of limited utility in predicting a patient’s subsequent disease phenotype

Serum calprotectin levels correlate with biochemical and histological markers of disease activity in TNBS colitis

Background and aim: Serum calprotectin is elevated in patients with inflammatory bowel disease (IBD). Whether it correlates other markers of disease activity is unknown. the aim of this study was to correlate serum calprotectin with biochemical and histological measures of intestinal inflammation.Materials and methods: TNBS colitis was induced in wistar rats, and serial blood samples were collected at 0, 3, and 12 days. Animals were subsequently sacrificed for pathological evaluation at day 12. Serum calprotectin and cytokines were measured by ELISA. Pathologic changes were classified at the macroscopic and microscopic levels.Results: TNBS colitis induced elevated serum calprotectin, TNF and IL-6 within 24 h. Levels of serum calprotectin remained elevated in parallel to persistence of loose stool and weight loss to day 12. Serum calprotectin levels correlated with serum levels of TNF-alpha, and IL6 (p < 0.001), but not CRP. Animals with liquid stool had significantly higher levels of serum calprotectin than control animals. There was a correlation between macroscopic colitis scores, and levels of serum calprotectin.Conclusion: Serum calprotectin levels correlate with biochemical and histological markers of inflammation in TNBS colitis. This biomarker may have potential for diagnostic use in patients with IBD. (C) 2013 Elsevier Inc. All rights reserved.NIHUniversidade Federal de São Paulo, UNIFESP EPM, Dept Gastroenterol, São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP EPM, Dept Nephrol, Basic Res Lab, São Paulo, BrazilHarvard Univ, Beth Israel Hosp, Sch Med, Ctr Inflammatory Bowel Dis, Boston, MA USAUniversidade Federal de São Paulo, UNIFESP EPM, Dept Gastroenterol, São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP EPM, Dept Nephrol, Basic Res Lab, São Paulo, BrazilNIH: K23DK084338Web of Scienc

The Burden of Inflammatory Bowel Disease: A Patient-Reported Qualitative Analysis and Development of a Conceptual Model

Background The aim of this study was to describe the impacts of inflammatory bowel disease (IBD) from the patients’ perspective, and to inform the development of a conceptual model. Methods Focus groups and one-on-one interviews were undertaken in adult patients with IBD. Transcripts from the focus groups and interviews were analyzed to identify themes and links between themes, assisted by qualitative data software MaxQDA. Themes from the qualitative research were supplemented with those reported in the literature and concepts included in IBD-specific patient-reported outcome (PRO) measures. Results Twenty-seven patients participated. Key physical symptoms included pain, bowel-related symptoms such as frequency, urgency, incontinence, diarrhea, passing blood, and systemic symptoms such as weight loss and fatigue. Participants described continuing and variable symptom experiences. IBD symptoms caused immediate disruption of activities but also had ongoing impacts on daily activities, including dietary restrictions, lifestyle changes, and maintaining close proximity to a toilet. More distal impacts included interference with work, school, parenting, social and leisure activities, relationships, and psychological well-being. The inconvenience of rectal medications, refrigerated biologics, and medication refills emerged as novel burdens not identified in existing PRO measures. Conclusions IBD symptoms cause immediate disruption in activities, but patients may continue to experience some symptoms on a chronic basis. The conceptual model presented here may be useful for identifying target concepts for measurement in future studies in IBD

Limit cycles, complex Floquet multipliers and intrinsic noise

We study the effects of intrinsic noise on chemical reaction systems, which in the deterministic limit approach a limit cycle in an oscillatory manner. Previous studies of systems with an oscillatory approach to a fixed point have shown that the noise can transform the oscillatory decay into sustained coherent oscillations with a large amplitude. We show that a similar effect occurs when the stable attractors are limit cycles. We compute the correlation functions and spectral properties of the fluctuations in suitably co-moving Frenet frames for several model systems including driven and coupled Brusselators, and the Willamowski-Roessler system. Analytical results are confirmed convincingly in numerical simulations. The effect is quite general, and occurs whenever the Floquet multipliers governing the stability of the limit cycle are complex, with the amplitude of the oscillations increasing as the instability boundary is approached.Comment: 15 pages, 8 figure

Analysis of candidate genes for macular telangiectasia type 2

Purpose: To find the gene(s) responsible for macular telangiectasia type 2 (MacTel) by a candidate-gene screening approach.Methods: Candidate genes were selected based on the following criteria: those known to cause or be associated with diseases with phenotypes similar to MacTel, genes with known function in the retinal vasculature or macular pigment transport, genes that emerged from expression microarray data from mouse models designed to mimic MacTel phenotype characteristics, and genes expressed in the retina that are also related to diabetes or hypertension, which have increased prevalence in MacTel patients. Probands from eight families with at least two affected individuals were screened by direct sequencing of 27 candidate genes. Identified nonsynonymous variants were analyzed to determine whether they cosegregate with the disease in families. Allele frequencies were determined by TaqMan analysis of the large MacTel and control cohorts.Results: We identified 23 nonsynonymous variants in 27 candidate genes in at least one proband. Of these, eight were known single nucleotide polymorphisms (SNPs) with allele frequencies of >0.05; these variants were excluded from further analyses. Three previously unidentified missense variants, three missense variants with reported disease association, and five rare variants were analyzed for segregation and/or allele frequencies. No variant fulfilled the criteria of being causal for MacTel. A missense mutation, p.Pro33Ser in frizzled homolog (Drosophila) 4 (FZD4), previously suggested as a disease-causing variant in familial exudative vitreoretinopathy, was determined to be a rare benign polymorphism.Conclusions: We have ruled out the exons and flanking intronic regions in 27 candidate genes as harboring causal mutations for MacTel