关键词： ColoPulse   infliximab   drug targeting   topical   ileo-colonic   inflammatory bowel disease  

摘要： Infliximab (IFX) is an intravenously administered monoclonal antibody antagonizing the effects of tumor necrosis factor-alpha (TNF) systemically and is efficacious in the treatment of inflammatory bowel disease (IBD). However, studies suggest that the anti-inflammatory effects result from local immunomodulation in the inflamed regions. Furthermore, topical inhibition of TNF in IBD ameliorates inflammation. We therefore hypothesized that orally administered IFX targeted to the ileo-colonic region in IBD may be an efficacious new treatment option. This study describes the development and validation of the production process of ileo-colonic-targeted 5 mg IFX tablets (ColoPulse-IFX) intended for the oral treatment of IBD by means of producing three consecutive validation batches (VAL1, VAL2, and VAL3, respectively). UV-VIS spectroscopy, HPLC-SEC analysis (content, fragments, aggregates), fluorescence spectroscopy (tertiary protein structure), and ELISA (potency) showed no noticeable deviations of IFX compounded to ColoPulse-IFX compared to fresh IFX stock. The average +/- SD (n = 10) IFX content of VAL1, VAL2, and VAL3 was 96 +/- 2%, 97 +/- 3%, and 96 +/- 2%, respectively, and complied with the European Pharmacopeia (Ph. Eur.) requirements for Content Uniformity. The average +/- SD (n = 3) ColoPulse-IFX potency was 105 +/- 4%, 96 +/- 4%, and 97 +/- 5%, respectively, compared to fresh IFX stock. The IFX release profile from the tablet core was complete (>= 85%) after 10 min in simulated ileum medium. The in vitro coating performance of ColoPulse-IFX showed that the formulation was targeted to the simulated ileo-colonic region. Stability data showed that ColoPulse-IFX was stable for up to 6 months stored at 25 degrees C/60% RH. Based on these results, the production process can be considered validated and its application is discussed in light of the rationale and available evidence for the topical treatment of IBD with IFX.

关键词： inflammatory bowel diseases (IBD)   Janus kinase 2 (JAK2)   thromboembolism   V617F  

摘要： Background Inflammatory bowel disease (IBD) is one of the most important immune-mediated disorders of the gastrointestinal tract. Besides, IBD is associated with numerous extraintestinal complications such as venous thromboembolism (VTE), an important risk factor for vascular complications, which results in the increased morbidity and mortality. The JAK2 (Janus kinase 2) V617F mutation is a well-known point mutation which is involved in the pathogenesis of IBD, and VTE. Therefore, the aims of this study were to evaluate expression of JAK2 and association of V617F mutation in JAK2 of Iranian patients with IBD. Methods Two hundred and forty-six patients with IBD (209 UC and 37 CD) and 206 healthy controls were enrolled in this study. The genomic DNA and total RNA were extracted from peripheral blood mononuclear cells (PBMCs). Then, the JAK2 V617F mutation detection was performed using the restriction fragment length polymorphism (RFLP) method. In addition, the JAK2 mRNA expression was evaluated using a quantitative polymerase chain reaction (q-PCR) using the SYBR Green assay. Results There was no association of V61F mutation in patients with IBD with or without thrombosis compared with healthy control. However, the relative mRNA expression of JAK2 was significantly upregulated in patients with IBD in comparison with healthy control (P < 0.0001). In addition, the JAK2 mRNA expression was significantly decreased in patients with IBD having thrombosis compared with those without thrombosis (P < 0.0001). Conclusions Taken together our findings suggested that JAK2 V61F-independent upregulation of JAK2 mRNA expression in patients with IBD. Moreover, despite the absence of JAK2 V617F mutation in patients with IBD, the increased gene expression of JAK2 can be explained by another molecular mechanism such as regulation of gene expression at the transcriptional level which may play crucial roles in the pathogenesis of IBD.

关键词： gingival tissue-derived mesenchymal stem cell s   inflammatory bowel disease   interleukin-10   regulatory T cells  

摘要： Current evidence indicates that inflammatory bowel disease (IBD) is caused primarily by impaired mucosal immunity, resulting in an imbalance between epithelial barrier function and tissue inflammation. Human gingiva-derived mesenchymal stem cells (GMSCs) exhibit immunomodulatory and anti-inflammatory effects in a variety of immunity- and inflammation-associated diseases. However, the role of GMSCs in treating IBD has not been elucidated. Our study, therefore, examined the therapeutic effect and mechanism of GMSCs in a murine colitis model of IBD. Our results indicate that the infusion of GMSCs significantly prolonged survival and relieved symptoms. Phenotype analyses showed that the frequencies of NK1.1(+) and CD11b(+) cells, as well as CD4 T cells in the spleen, were suppressed in GMSC-treated mice compared with the PBS- or fibroblast-treated control groups. Additionally, GMSC treatment markedly increased the numbers of interleukin (IL)-10(+) regulatory T cells, reduced the secretion of pro-inflammatory cytokines, and increased production of anti-inflammatory cytokines. A mechanistic study revealed that anti-IL-10R antibody abolished the protective effect of GMSCs compared with mice treated with anti-IgG antibody. Thus, our results indicate that GMSCs play a critical role in alleviating colitis by modulating inflammatory immune cells via IL-10 signalling.

摘要： Uncontrolled interferon gamma (IFN gamma)-mediated T-cell responses to commensal microbiota are a driver of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is crucial for controlling these T-cell responses, but the precise mechanism of inhibition remains unclear. A better understanding of how IL-10 exerts its suppressive function may allow identification of individuals with suboptimal IL-10 function among the heterogeneous population of IBD patients. Using cells from patients with an IL10RA deficiency or STAT3 mutations, we demonstrate that IL-10 signaling in monocyte-derived dendritic cells (moDCs), but not T cells, is essential for controlling IFN gamma-secreting CD4(+) T cells. Deficiency in IL-10 signaling dramatically increased IL-1 beta release by moDCs. IL-1 beta boosted IFN gamma secretion by CD4(+) T cells either directly or indirectly by stimulating moDCs to secrete IL-12. As predicted a signature of IL-10 dysfunction was observed in a subgroup of pediatric IBD patients having higher IL-1 beta expression in activated immune cells and macroscopically affected intestinal tissue. In agreement, reduced IL10RA expression was detected in peripheral blood mononuclear cells and a subgroup of pediatric IBD patients exhibited diminished IL-10 responsiveness. Our data unveil an important mechanism by which IL-10 controls IFN gamma-secreting CD4(+) T cells in humans and identifies IL-1 beta as a potential classifier for a subgroup of IBD patients.

关键词： inflammatory bowel disease   amino acids profiling   clinical analysis   human urine   capillary zone electrophoresis   mass spectrometry  

摘要： Urine represents a convenient biofluid for metabolomic studies due to its noninvasive collection and richness in metabolites. Here, amino acids are valuable biomarkers for their ability to reflect imbalances of different biochemical pathways. An impact of amino acids on pathology, prognosis and therapy of various diseases, including inflammatory bowel disease (IBD), is therefore the subject of current clinical research. This work is aimed to develop a capillary electrophoresis-tandem mass spectrometry (CE-MS/MS) method for the quantification of the 20 proteinogenic amino acids in human urine samples obtained from patients suffering from IBD and treated with thiopurines. The optimized CE-MS/MS method, with minimum sample preparation (just dilute and shoot), exhibited excellent linearity for all the analytes (coefficients of determination were higher than 0.99), with inter-day and intra-day precision yielding relative standard deviations in the range of 0.91-15.12% and with accuracy yielding relative errors in the range of 85.47-112.46%. Total analysis time, an important parameter for the sample throughput demanded in routine practice, was shorter in ca. 17% when compared to established CE-MS methods. Favorable performance of the proposed CE-MS/MS method was also confirmed by the comparison with corresponding ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) method. Consistent data for the investigated amino acid metabolome were obtained using both methods. For the first time, the amino acid profiling by CE-MS approach was applied on the clinical IBD samples. Here, significant differences observed in the concentration levels of some amino acids between IBD patients undergoing thiopurine treatment and healthy volunteers could result from the simultaneous action of the disease and the corresponding therapy. These findings indicate that amino acids analysis could be a valuable tool for the study of mechanism of the IBD treatment by thiopurines.

关键词： Disease Activity Index   SF-36   PRO   Management  

摘要： BACKGROUND & AIMS: Inflammatory bowel disease (IBD) scoring systems combine patient-reported data with physi- cians' observations to determine patient outcomes, but these systems are believed to have limitations. We used real-world data from a large IBD cohort in Switzerland to compare results between patients and healthcare professionals from scoring systems for Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We collected data from the Swiss IBD cohort, beginning in 2006, using 2453 reports for 1385 patients (52% female, 58% with CD). During office visits, physicians asked patients about signs and symptoms and recorded their answers (health care professional-reported outcomes). On a later date, patients received a questionnaire at home (independently of the medical visit), complete it, and sent it back to the data center. Patients also completed the short form 36 and IBD quality of life (QoL) questionnaires. We calculated Cohen's kappa (kappa) statistics to assess the level of agreement in scores between patients and health care professionals (Delta t between reports collected less than 2 months apart). We used Spearman correlation coefficients (rho) to compare general well-being (GWB) and QoL scores determined by patients vs health care professionals. Our primary aim was to investigate the overall and individual level of agreement on signs and symptoms reported by health care professionals vs patients. RESULTS: The best level of agreement (although moderate) was observed for number of stools last week in patients with CD (kappa = 0.47), and nocturnal diarrhea in patients with UC (kappa = 0.52). Agreement was low on level of abdominal pain (kappa = 0.31 for patients with CD and kappa = 0.37 for patients with UC) and GWB (kappa = 0.23 for patients with CD and kappa = 0.26 for patients with UC). Patients reported less severe abdominal pain and worse GWB (CD) or better GWB (UC) than that determined by health care professionals. Patient self-rated GWB correl

关键词： Delivery of health care   inflammatory bowel diseases   risk   vaccination  

摘要： Background: Although it is well established that patients with inflammatory bowel disease (IBD) are at increased risk of complicating diseases and vaccination-preventable infections, whether gastroenterologists (GIs) or primary care providers (PCPs) assume responsibility for these patients' health maintenance is not clear. Methods: We anonymously surveyed a convenience sample of 94 PCPs and 61 GIs at Saint Louis University School of Medicine in St. Louis, MO, about their practice and perception of the health maintenance and vaccination of patients with IBD. Results: Response rates were 82% and 93% for GIs and PCPs, respectively. GIs were as likely as PCPs to screen for smoking (88% vs 89%) and were significantly less likely to screen for depression/anxiety (24% vs 54%) or to provide pertussis (14% vs 44%) or diphtheria (20% vs 48%) vaccines. GIs were significantly more likely than PCPs to assess for colonoscopy need (94% vs 80%);to screen for nonmelanoma skin cancer (62% vs 14%), melanoma (56% vs 7%), osteoporosis (72% vs 51%), or tuberculosis (94% vs 44%);to prescribe calcium/vitamin D (74% vs 53%);to perform nutritional assessment (78% vs 33%);or to provide hepatitis A (60% vs 39%) or hepatitis B (86% vs 56%) vaccines. GIs were as likely as PCPs (64% vs 75%) to perceive that PCPs should order vaccinations and significantly more likely to perceive that GIs should track vaccinations (58% vs 16%) and other health maintenance issues (90% vs 49%). We found positive associations between performing the various health maintenance and vaccination tasks and the perception of responsibility. Conclusion: Several health maintenance aspects are inadequately addressed by GIs and PCPs, in part because of conflicting perceptions of responsibility. Clear guidelines and better GI/PCP communication are required to ensure effective health maintenance for patients with IBD.

关键词： Eradication   Autoimmunity   Immune Response   Bacteria  

摘要： BACKGROUND & AIMS: Helicobacter pylori induces immune tolerance and is associated with a lower risk for immune- mediated disorders, such as autoimmune and inflammatory bowel diseases (IBD). We aimed to determine the effects of treatment for H pylori infection on the incidence of autoimmune disease and IBD. METHODS: We collected data from the National Health Insurance Research Database in Taiwan on patients younger than 18 years old without a prior diagnosis of autoimmune disease or IBD. Patients with peptic ulcer disease (PUD) with treatment of H pylori infection (PUD + HPRx), PUD without H pylori treatment (PUD-HPRx), a urinary tract infection (UTI) treated with cephalosporin, or without PUD (controls) were matched for age, sex, insurance, and Charlson's comorbidity index score. RESULTS: Of the 1 million patients we collected data from in 2005, we included 79,181 patients in the study. We compared the effects of treatment for H pylori infection on the risk of autoimmunity or IBD and found that PUD + HPRx has the highest adjusted hazard risk (aHR) for autoimmunity or IBD (aHR, 2.36), compared to PUD-HPRx (aHR, 1.91) or UTI (aHRs, 1.71) (P < .001). The increased risk of autoimmune disease was not completely accounted for by antibiotic therapy alone, because PUD + HPRx had a higher aHR than UTI (P < .001). A small but significant increase in mortality was observed in the PUD + HPRx cohort (aHR, 1.11;P = .001). CONCLUSION: In an analysis of data from the National Health Insurance Research Database in Taiwan, we found that treatment for H pylori infection is associated with a significant increase in the risk for autoimmune disease, including IBD.