Moderate Colitis Research Articles

Anti-Inflammatory Properties of Streptococcus salivarius, a Commensal Bacterium of the Oral Cavity and Digestive Tract

Streptococcus salivarius is one of the first colonizers of the human oral cavity and gut after birth and therefore may contribute to the establishment of immune homeostasis and regulation of host inflammatory responses. The anti-inflammatory potential of S. salivarius was first evaluated in vitro on human intestinal epithelial cells and human peripheral blood mononuclear cells. We show that live S. salivarius strains inhibited in vitro the activation of the NF-κB pathway on intestinal epithelial cells. We also demonstrate that the live S. salivarius JIM8772 strain significantly inhibited inflammation in severe and moderate colitis mouse models. These in vitro and in vivo anti-inflammatory properties were not found with heat-killed S. salivarius, suggesting a protective response exclusively with metabolically active bacteria.

Modifications of mesenteric adipose tissue during moderate experimental colitis in mice

AimsAdipose tissue secretes various proteins referred to as adipokines, being involved in inflammation. It was recognized that mesenteric adipose tissue (MAT) is altered by inflammation, and pathologies such as inflammatory bowel disease (IBD). The aim of this study was to investigate the alterations of the mesenteric adipose tissue in two experimental colitis models in mice adapted to obtain moderate colonic inflammation. Main methodsColonic inflammation was obtained using two models, either DSS dissolved in drinking water or intra-colonic instillation of DNBS. The expression of adipokines (leptin and adiponectin) and inflammatory markers (IL-6, MCP-1, F4/80) was studied by qRT-PCR in the MAT of treated and control mice. Key findingsObservations of the colon and IL-6 plasma level determination demonstrated that DNBS treatment led to stronger inflammation. Colitis induced a decrease of mRNA encoding to leptin and adiponectin in MAT. In contrast, colonic inflammation led to an increase of mRNA encoding to IL-6, MCP-1 and F4/80, a specific marker of macrophages. SignificanceThe mesenteric adipose tissue, in two models of moderate colitis, shows a loss of adipose profile and a strong increase of inflammatory pattern, close to the observations made in MAT of IBD patients. These data suggest that these pro-inflammatory modifications of MAT have to be taken into account in the pathophysiology of IBD.

Fatigue Severity and Factors Associated with High Fatigue Levels in Korean Patients with Inflammatory Bowel Disease

Background/AimsMany patients with inflammatory bowel disease (IBD) often complain of fatigue. To date, only a few studies in Western countries have focused on fatigue related to IBD, and fatigue has never been specifically studied in Asian IBD patients. The aim of the present study was to investigate the fatigue level and fatigue-related factors among Korean IBD patients.MethodsPatients in remission or with mild to moderate IBD were included. Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue and the Brief Fatigue Inventory. Corresponding healthy controls (HCs) also completed both fatigue questionnaires.ResultsSixty patients with Crohn disease and 68 patients with ulcerative colitis (UC) were eligible for analysis. The comparison group consisted of 92 HCs. Compared with the HCs, both IBD groups were associated with greater levels of fatigue (p<0.001). Factors influencing the fatigue score in UC patients included anemia and a high erythrocyte sedimentation rate (ESR).ConclusionsGreater levels of fatigue were detected in Korean IBD patients compared with HCs. Anemia and ESR were determinants of fatigue in UC patients. Physicians need to be aware of fatigue as one of the important symptoms of IBD to better understand the impact of fatigue on health-related quality of life.

Antitumor necrosis factor treatment for pediatric inflammatory bowel disease

Over the last 10 years, biologic treatment with the antitumor necrosis factor (anti-TNF) antibodies has dramatically changed the therapeutic approach in pediatric patients with inflammatory bowel disease (IBD). Currently, infliximab and adalimumab are the only anti-TNF drugs that have been approved for use in refractory pediatric Crohn’s disease (CD) and infliximab the only anti-TNF agent for use in refractory pediatric ulcerative colitis (UC). According to the current treatment recommendations, anti-TNF therapy is indicated for moderate and severe pediatric IBD when remission is not achieved using conventional treatment or conventional therapy is not tolerated by the patients. Despite the demonstrated efficacy of anti-TNF drugs in pediatric IBD patients, the potential development of serious adverse events, such as severe immune reactions, infections, and malignancies, limit the possibility of a wider use of anti-TNF drugs. Moreover, a substantial percentage of patients gradually develop non-responsiveness to these therapeutics, due to generation of antibodies against anti-TNF antibodies. Therefore, treatment of pediatric IBD patients with biologics should be undertaken in specialized tertiary medical centers, which are specially qualified for this purpose.

Clinical features and treatment of ulcerative colitis-related severe gastroduodenitis and enteritis with massive bleeding after colectomy

Ulcerative colitis (UC) has been recognised as a systemic immune disorder that is not as restricted as colitis. UC-related gastrointestinal lesions with bleeding can develop soon after colectomy and can progress rapidly. Therefore, we considered the clinical features and treatment of these UC-related lesions. We reviewed the patient data in our UC surgery database to evaluate its prevalence and features. We found 7/1,100 patients with UC-related lesions between January 2000 and April 2013. These lesions developed at a mean of 24 (range 8-480) days after colectomy. Six of the seven patients suffered from gastrointestinal bleeding as an initial symptom that rapidly developed into massive bleeding or perforations. All of the patients were diagnosed with pancolitis; at the time of colectomy, fulminant, severe, moderate, and mild colitis were presented by four, one, one, and one patients, respectively. All patients with enteritis had consecutively developed other infectious complications, including anastomotic leakage, pyoderma gangrenosum, wound infection, and pneumonia. Although patients with bleeding did not respond to treatment with corticosteroids, they responded well to infliximab soon after its administration. Although six of the seven patients showed cytomegalo virus re-activation in blood or pathological examinations, ganciclovir was not effective in its elimination. Although UC-related lesions with an unknown aetiology can occur after colectomy, immediate examination and treatment are required if gastrointestinal bleeding is found after surgery. Because gastrointestinal bleeding from UC-related lesions can worsen rapidly and may be related to mortality, early potent immunosuppressive therapy should be considered.

64. Forced treadmill exercise training exacerbates inflammation and causes mortality while voluntary wheel training is protective in a mouse model of colitis

The purpose of this study was to examine whether exercise training reduced inflammation and symptomology in a mouse model of colitis. We hypothesized that moderate forced treadmill running (FTR) and voluntary wheel running (VWR) would reduce colitis symptoms and colon inflammation in response to dextran sodium sulfate (DSS). Mice were randomized to sedentary, moderate intensity FTR, or VWR for 6 wks. DSS was given at 2% (w/v) in drinking water over 5 days. Colons were harvested on Days 6, 8 and 12 in FTR and Day 8 post-DSS in VWR experiments. Interestingly, we found that moderate FTR exacerbated colitis symptomology and inflammation as measured by significant (p < 0.05) increases in diarrhea and IL-6, IL-1β, IL-17 colon gene expression. We also observed higher mortality (3/10 died vs. 0/10, p = 0.07) in the FTR/DSS group. In contrast, VWR alleviated colitis symptoms and reduced inflammatory gene expression in the colons of DSS-treated mice (p < 0.05). While DSS treatment reduced food/fluid intake and body weight, there was a tendency for FTR to exacerbate, and for VWR to attenuate, this effect. FTR (in the absence of DSS) increased gene expression of the chemokine and antibacterial protein CCL6 suggesting that FTR altered gut homeostasis that may be related to the exaggerated response to DSS. In conclusion, we found that FTR exacerbated, whereas VWR attenuated, symptoms and inflammation in response to DSS.

Clostridium difficile colitis acquired in the intensive care unit: outcome and prognostic factors

We assessed factors associated with mortality and complicated course in the case of Clostridium difficile infection (CDI) acquired in the intensive care unit (ICU). Retrospective cohort study conducted from 1 January 2002 through 1 January 2012. All patients who acquired CDI in our ICU were included. Thirty-one patients were included. Twenty patients (65 %) had mild colitis, 8 (25 %) moderate colitis, and 3 (10 %) severe colitis. Initial antibiotherapy was metronidazole (n = 30, 97 %) and vancomycin (n = 1, 3 %). Seventeen patients (55 %) experienced at least one complication: failure of initial treatment (n = 16, 52 %), shock (n = 11, 34 %), need for surgery (n = 1, 3 %) or renal replacement (n = 4, 13 %), or death (n = 8, 26 %). Risk factors of ICU mortality were history of corticosteroids prescription, prolonged ICU stay, low serum albumin level, and high Sequential Organ Failure Assessment (SOFA) score at the time of CDI diagnosis. Factors associated with a complicated course were high Simplified Acute Physiology Score (SAPS II), high SOFA score, and low serum albumin level at the time of CDI onset. Risk factors of poor outcome in patients with CDI acquired in the ICU are different from those in the general population suffering from CDI. The implementation of treatment algorithms taking into account these factors may reduce complication rates in this specific population.

A CASE SERIES OF LISTERIA MONOCYTOGENES INFECTION IN INFLAMMATORY BOWEL DISEASE PATIENTS TREATED WITH ANTI-TNFα THERAPY

IntroductionAnti-TNFα therapy has had a huge impact on the treatment of inflammatory bowel disease. The inhibition of TNFα not only reduces inflammation but also increases the risk of opportunistic infections....

Forced treadmill exercise training exacerbates inflammation and causes mortality while voluntary wheel training is protective in a mouse model of colitis

The purpose of this study was to examine whether exercise training reduced inflammation and symptomology in a mouse model of colitis. We hypothesized that moderate forced treadmill running (FTR) or voluntary wheel running (VWR) would reduce colitis symptoms and colon inflammation in response to dextran sodium sulfate (DSS). Male C57Bl/6J mice were randomized to sedentary, moderate intensity FTR (8-12 m/min, 40 min, 6 weeks, 5x/week), or VWR (30 days access to wheels). DSS was given at 2% (w/v) in drinking water over 5 days. Mice discontinued exercise 24 h prior to and during DSS treatment. Colons were harvested on Days 6, 8 and 12 in FTR and Day 8 post-DSS in VWR experiments. Contrary to our hypothesis, we found that moderate FTR exacerbated colitis symptomology and inflammation as measured by significant (p<0.05) increases in diarrhea and IL-6, IL-1β, IL-17 colon gene expression. We also observed higher mortality (3/10 died vs. 0/10, p=0.07) in the FTR/DSS group. In contrast, VWR alleviated colitis symptoms and reduced inflammatory gene expression in the colons of DSS-treated mice (p<0.05). While DSS treatment reduced food/fluid intake and body weight, there was a tendency for FTR to exacerbate, and for VWR to attenuate, this effect. FTR (in the absence of DSS) increased gene expression of the chemokine and antibacterial protein CCL6 suggesting that FTR altered gut homeostasis that may be related to the exaggerated response to DSS. In conclusion, we found that FTR exacerbated, whereas VWR attenuated, symptoms and inflammation in response to DSS.

Colonoscopy and µPET/CT are Valid Techniques to Monitor Inflammation in the Adoptive Transfer Colitis Model in Mice

Preclinical in vivo research on inflammatory bowel diseases requires proper animal models and techniques allowing longitudinal monitoring of colonic inflammation without the need to kill animals. We evaluated colonoscopy and μ-positron emission tomography/computed tomography (μPET/CT) as monitoring tools in a model for chronic colitis in mice. Colitis was induced by adoptive transfer of CD4(+)CD25(-)CD62L(+) T cells in immunocompromised severe combined immunodeficient mice. Three study protocols were designed. In study 1, colonoscopy and µPET/CT were performed once, 4 weeks after transfer. In study 2 and study 3, colitis was sequentially followed up through colonoscopy (study 2) or colonoscopy plus µPET/CT (study 3). Each study included postmortem evaluation of colonic inflammation (macroscopy, microscopy, and myeloperoxidase activity). In study 1, both colonoscopy and µPET/CT detected colitis 4 weeks after transfer. Study 2 showed a gradual increase in colonoscopic score from week 2 (1.4 ± 0.6) to week 8 (6.0 ± 1.1). In study 3, colitis was detected 2 weeks after transfer by µPET/CT (2.0 ± 0.4) but not by colonoscopy, whereas both techniques detected inflammation 4 and 6 weeks after transfer. Colonoscopy correlated with µPET/CT (r = 0.812, 0.884, and 0.781, respectively) and with postmortem analyses in all 3 studies. Adoptive transfer of CD4(+)CD25(-)CD62L(+) T cells in severe combined immunodeficient mice results in a moderate chronic colitis. Evolution of colitis could be monitored over time by both colonoscopy and µPET/CT. µPET/CT seems to detect inflammation at an earlier time point than colonoscopy. Both techniques represent reliable and safe methods without the need to kill animals.

Imaging of Chronic Inflammatory Bowel Disease with 18F-FDG PET in Children and Adolescents

Standard for diagnosis of inflammatory bowel disease (IBD) is the endoscopy of the stomach and the intestine. Aim of this study was to determine the value of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in pediatric patients with mild to moderate IBD.We included 23 children and adolescents between 8 and 17 years (median 15 years, 13 boys, 10 girls) in this retrospective study in a routine clinical setting. Diagnoses were Crohn's disease in 19 and ulcerative colitis in 4 cases.3 children had a conventional FDG-PET, 20 patients a combined FDG-PET-computed tomography exam. All children had upper and lower intestinal endoscopy with biopsy and a Hydro-MRI exam to assess the jejunum and proximal ileum. The gastrointestinal tract was divided in 7 segments: Stomach plus duodenum, jejunum and proximal ileum, terminal ileum, cecum plus ascending colon, transverse colon, descending colon, and rectosigmoid.Superficial gastric lesions were missed, gastric ulcerations were detected. For the stomach, the sensitivity was 0.25, the specificity was 1.00, the positive predictive value was 1.00, for the lower intestine (terminal ileum and colon) the values were 0.74, 0.88, and 0.96; for the terminal ileum 0.89, 0.75 and 0.94, respectively.The sensitivity and specificity for of ileal and colonic lesions is high. FDG-PET has to be discussed as a tool for the determination of extent and degree of inflammation, especially in those parts of the small bowel that are not accessible to endoscopy. This has to be weighed against the additional radiation exposure administrated.

Relevance of TNBS-Colitis in Rats: A Methodological Study with Endoscopic, Histologic and Transcriptomic Characterization and Correlation to IBD

BackgroundRectal instillation of trinitrobenzene sulphonic acid (TNBS) in ethanol is an established model for inflammatory bowel disease (IBD). We aimed to 1) set up a TNBS-colitis protocol resulting in an endoscopic and histologic picture resembling IBD, 2) study the correlation between endoscopic, histologic and gene expression alterations at different time points after colitis induction, and 3) compare rat and human IBD mucosal transcriptomic data to evaluate whether TNBS-colitis is an appropriate model of IBD.Methodology/Principal FindingsFive female Sprague Daley rats received TNBS diluted in 50% ethanol (18 mg/0.6 ml) rectally. The rats underwent colonoscopy with biopsy at different time points. RNA was extracted from rat biopsies and microarray was performed. PCR and in situ hybridization (ISH) were done for validation of microarray results. Rat microarray profiles were compared to human IBD expression profiles (25 ulcerative colitis Endoscopic score demonstrated mild to moderate colitis after three and seven days, but declined after twelve days. Histologic changes corresponded with the endoscopic appearance. Over-represented Gene Ontology Biological Processes included: Cell Adhesion, Immune Response, Lipid Metabolic Process, and Tissue Regeneration. IL-1α, IL-1β, TLR2, TLR4, PRNP were all significantly up-regulated, while PPARγ was significantly down-regulated. Among genes with highest fold change (FC) were SPINK4, LBP, ADA, RETNLB and IL-1α. The highest concordance in differential expression between TNBS and IBD transcriptomes was three days after colitis induction. ISH and PCR results corresponded with the microarray data. The most concordantly expressed biologically relevant pathways included TNF signaling, Cell junction organization, and Interleukin-1 processing.Conclusions/SignificanceEndoscopy with biopsies in TNBS-colitis is useful to follow temporal changes of inflammation visually and histologically, and to acquire tissue for gene expression analyses. TNBS-colitis is an appropriate model to study specific biological processes in IBD.

Plasma concentrations and therapeutic effects of budesonide in dogs with inflammatory bowel disease

To evaluate the pharmacokinetics and clinical efficacy of budesonide in dogs with inflammatory bowel disease (IBD). 11 dogs (mean ± SD age, 5.7 ± 3.9 years; various breeds and body weights) with moderate or severe IBD. Each dog received a controlled-release formulation of budesonide (3 mg/m(2), PO, q 24 h) for 30 days (first day of administration was day 1). The concentration of budesonide and its metabolite (16-α-hydroxyprednisolone) was measured via liquid chromatography-tandem mass spectrometry in plasma and urine samples obtained on days 1 and 8 of treatment. On those days, plasma samples were obtained before the daily budesonide administration and 0.5, 1, 2, 4, and 7 hours after drug administration, whereas urine samples were obtained after collection of the last blood sample. A clinical evaluation was performed on the dogs before onset of drug administration and on days 20 and 30 after start of drug administration. The highest plasma concentration of budesonide and 16-α-hydroxyprednisolone on day 1 was detected at 1 hour and at 2 hours after drug administration, respectively. After standardization on the basis of specific gravity, the ratio between urinary concentrations of budesonide and 16-α-hydroxyprednisolone was 0.006 and 0.012 on days 1 and 8, respectively. The clinical response was adequate in 8 of 11 dogs. Budesonide was rapidly absorbed and metabolized in dogs with IBD. The drug gradually accumulated, and there was an adequate therapeutic response and no adverse effects.

Clinical efficacy of mesalazine enema combined with triple live bacterial agent of Clostridium butyricum, Streptococcus faecalis and Bacillus mesentericus in patients with mild to moderate distal ulcerative colitis

Clinical efficacy of mesalazine enema combined with triple live bacterial agent of <i>Clostridium butyricum</i>, <i>Streptococcus faecalis</i> and <i>Bacillus mesentericus</i> in patients with mild to moderate distal ulcerative colitis

Fecal Bacteriotherapy in a 6 Year Old Patient With Ulcerative Colitis and Clostridium Difficile

Inflammatory bowel disease (IBD) is thought to be a disorder of the innate and reactive immune system, and its interaction with the gastrointestinal microbiome. A growing body of literature supports the use of fecal bacteriotherapy in eradicating Clostridium difficile (C. diff) infections. Its use in IBD has been reported but not established. 20-25% of IBD patients present in childhood. Current available IBD therapies pose significant challenges, especially in young children with IBD, due to their side effects and route of administration. We discuss our experience with fecal bacteriotherapy in a 6 year old child with relapsing Ulcerative Colitis (UC) and recurrent C. diff infection. A 6 year old female was diagnosed with UC after presenting with bloody stools, abdominal pain, anemia and elevated ESR. Initial colonoscopy showed pancolitis and a normal terminal ileum. Due to lack of response to oral mesalamine and steroid dependence, azathioprine was started with rectal mesalamine and rectal steroids. Allopurinol was added after breakthrough symptoms and severe anemia. She continued to have intermittent moderate symptoms (blood, diarrhea) at 1 year out from diagnosis. C. diff antigen and toxin were present, and persisted despite treatment with metronidazole and vancomycin. The family was interested in pursuing fecal bacteriotherapy prior to initiating further antibiotic courses and infliximab. Approval was obtained from bioethics committee. Her mother was the stool donor and was screened for stool infections, viral hepatitis and HIV. At baseline, a sigmoidoscopy showed no pseudomembranes, but microscopic moderate chronic active colitis. A nasogastric (NG) tube was placed. Fresh donor stool was mixed with saline then superfiltrated to 30 cc suspension. The suspension was instilled via NG tube uneventfully post procedure, after which it was removed and the patient discharged home. Symptoms and stool inflammatory markers were followed from baseline to 16 weeks post procedure. No treatments aside from azathioprine and allopurinol were used. Stool calprotectin decreased from 504 at baseline to 76 by week 12. C.diff antigen and toxin were cleared by 3 weeks. Microbiome analysis of the donor stool and the patient's stool before and at 3 periods after bacteriotherapy are pending and will be finalized shortly. We describe a case of successful fecal bacteriotherapy for a child with recalcitrant UC and C diff. The implication of the improved calprotectin will be further explored with reducing her current medications. The relative ease, tolerability and success of the procedure should encourage further study.

Impact on Quality of Life of a Smart Device Mobile Application in Patients with Inflammatory Bowel Disease

Purpose: Web-based monitoring of Inflammatory Bowel Disease (IBD) symptoms has been shown to increase medical adherence. Smart devices (SD), such as smart phones and tablets, allow users to download many health-related apps. The use of SD has increased, and we conducted a randomized trial to determine if a mobile symptom tracking app improves QoL in IBD patients. Methods: Patients with IBD with access to a SD (iPhone®/iPad®/iPod touch® or AndroidTM) were eligible to participate. Patients with Blackberry® smart phones were excluded as the app was not fully optimized for this device. We randomized 90 patients (46 Female and 44 male) ages 20-84 with mild to moderate disease to an experimental group and control group. The experimental group downloaded a free app, GI Monitor (WellApps, New York, NY). Subjects used the app daily to record symptoms, track pain, stress levels, frequency and quality of bowel movements. The control group was educated about websites such as www.ccfa.org for information on IBD. Both groups completed the IBD Questionnaire Survey (IBDQ) at time of enrollment and again at follow-up at 8-38 weeks. Results: The mean disease duration in years was 9.5 ± 7.6 and 11.4 ± 8.5 for the control and experimental groups respectively. Mean time for follow up in person or via phone was 104 days in the control group and 87 days in the experimental group. Mean IBDQ score at times of enrollment and follow up were 158.7 ± 24.7 and 165.9 ± 24.7, and 169.3 ± 29.3 and 172.9 ± 26.8 in the control and experimental groups respectively. The change in pre to post IBDQ score was significant within control group (p<0.03) but not for the experimental group. However, the pre and post IBDQ score was not statistically significant between the two groups. The experimental group did feel that the mobile app was easy to use and subjectively improved their ability to track and correlate symptoms. Conclusion: This is the first study to investigate the use of a smart device in patients with IBD. The data from this small sample did not show comparative improvement in IBDQ scores in the experimental group over the control group. As the study patient population had long-standing IBD with a relatively good QoL at baseline, this may represent a bias toward better QoL among smart device users or improved disease awareness with increasing chronicity of disease. Our study did show that mobile apps can be successfully used in patients with mild to moderate IBD to increase their frequency of clinic visits as their disease status worsens. Further studies investigating long-term use of these tools to monitor symptoms, particularly in newly diagnosed patients, are warranted.

Interplay between Th1 and Th17 effector T-cell pathways in the pathogenesis of spontaneous colitis and colon cancer in the G i2-deficient mouse

Gαi2-deficient mice spontaneously develop colitis. Using xMAP technology and RT-PCR, we investigated cytokine/chemokine profiles during histologically defined phases of disease: (i) no/mild, (ii) moderate, (iii) severe colitis without dysplasia/cancer and (iv) severe colitis with dysplasia/cancer, compared with age-matched wild-type (WT) littermates. Colonic dysplasia was observed in 4/11 mice and cancer in 1/11 mice with severe colitis. The histology correlated with progressive increases in colon weight/cm and spleen weight, and decreased thymus weight, all more advanced in mice with dysplasia/cancer. IL-1β, IL-6, IL-12p40, IL-17, TNF-α, CCL2 and CXCL1 protein levels in colons, but not small intestines increased with colitis progression and were significantly increased in mice with moderate and severe colitis compared with WT mice, irrespective of the absence/presence of dysplasia/cancer. CCL5 did not change during colitis progression. Colonic IL-17 transcription increased 40- to 70-fold in all stages of colitis, whereas IFN-γ mRNA was gradually up-regulated 12- to 55-fold with colitis progression, and further to 62-fold in mice with dysplasia/cancer. IL-27 mRNA increased 4- to 15-fold during the course of colitis, and colonic IL-21 transcription increased 3-fold in mice with severe colitis, both irrespective of the absence/presence of dysplasia/cancer. FoxP3 transcription was significantly enhanced (3.5-fold) in mice with moderate and severe colitis, but not in mice with dysplasia/cancer, compared with WT mice. Constrained correspondence analysis demonstrated an association between increased protein levels of TNF-α, CCL2, IL-1β, IL-6 and CXCL1 and dysplasia/cancer. In conclusion, colonic responses are dominated by a mixed T(h)1/T(h)17 phenotype, with increasing T(h)1 cytokine transcription with progression of colitis in Gαi2(-/-) mice.

A quantitative study of the mechanisms behind thymic atrophy in Gαi2-deficient mice during colitis development.

Mice deficient for the G protein subunit Gαi2 spontaneously develop colitis, a chronic inflammatory disease associated with dysregulated T cell responses. We and others have previously demonstrated a thymic involution in these mice and an aberrant thymocyte dynamics. The Gαi2−/− mice have a dramatically reduced fraction of double positive thymocytes and an increased fraction of single positive (SP) thymocytes. In this study, we quantify a number of critical parameters in order to narrow down the underlying mechanisms that cause the dynamical changes of the thymocyte development in the Gαi2−/− mice. Our data suggest that the increased fraction of SP thymocytes results only from a decreased number of DP thymocytes, since the number of SP thymocytes in the Gαi2−/− mice is comparable to the control littermates. By measuring the frequency of T cell receptor excision circles (TRECs) in the thymocytes, we demonstrate that the number of cell divisions the Gαi2−/− SP thymocytes undergo is comparable to SP thymocytes from control littermates. In addition, our data show that the mature SP CD4+ and CD8+ thymocytes divide to the same extent before they egress from the thymus. By estimating the number of peripheral TREC+ T lymphocytes and their death rate, we could calculate the daily egression of thymocytes. Gαi2−/− mice with no/mild and moderate colitis were found to have a slower export rate in comparison to the control littermates. The quantitative measurements in this study suggest a number of dynamical changes in the thymocyte development during the progression of colitis.

Endoscopic Features of Gastrointestinal Disease in Chronic Granulomatous Disease: A Distinct Entity

Purpose: Chronic granulomatous disease (CGD) is a genetically inherited disorder with a defect in NADPH oxidase of phagocytic cells predisposing to bacterial and fungal infections. Gastrointestinal involvement is seen in about 40% of patients with CGD presenting as an inflammatory bowel disease or motility disorder. Aim: To characterize the endoscopic features and the role of endoscopy in diagnosis and management of gastrointestinal CGD. Methods: A database was created with all patients seen at NIH with CGD. Their clinical, pathologic and endoscopic data was gathered and analyzed. Colitis was defined endoscopically as mild, moderate or severe. Mild disease was characterized by erythema, mucosal friability, nodularity or alteration in vascular pattern. Moderate disease was characterized by erosions, aphthous ulcers or small linear ulcers. Severe disease was characterized by extensive ulcerations with or without complications such as fistulae and strictures. Results: A total of 222 endoscopies: 100 EGDs, 89 colonoscopies and 33 flexible sigmoidoscopies have been performed at NIH, in 81 patients with CGD, between 1990 and 2010. CGD related inflammatory bowel disease, assessed endoscopically, extended from the esophagus to the anus. Esophageal, gastric and duodenal inflammation was seen in 25%, 73% and 39%, respectively, with gastric and duodenal ulcers in 16% and 30%, respectively. Esophageal dysmotility and structural abnormalities were noted in 25% and 29% respectively with only 11% of them being symptomatic. Colonic inflammatory bowel disease characterized by skip lesions was seen in 73% of patients with presence of ano-rectal disease in 96% of patients. Mild, moderate and severe colitis was seen in 17%, 34% and 49% of patients, respectively. CGD related inflammatory bowel disease being a transmural process led to enteric fistulae in 15% of patients with 75% of these being present in the perianal area. Anorectal strictures were noted in 26% patients requiring serial dilations. No patient has developed colonic premalignant lesions or malignancy. Conclusion: Endoscopy helped in characterizing CGD related IBD as a distinct entity which primarily involves the anus and rectum with skip lesions in the remaining bowel. Fistulae and strictures are primarily located in the anorectal area and particular attention needs to be directed towards this area during evaluation of CGD patients. Upper GI tract inflammatory disease is common though not as severe as colonic disease. Endoscopic extent of disease activity and severity helped in guiding medical management, selection of patients for surgical diversion and consideration for hematopoietic stem cell transplantation.

Prognostic Factors of Ischemic Colitis After Infrarenal Aortic Surgery

Postoperative ischemic colitis (POIC) remains a frequent and extremely severe complication of infrarenal abdominal aorta surgery. However, its diagnosis and treatment are not always consensual because the incidence is very small. The aim of this retrospective study was to evaluate the prognostic factors of severe colitis after infrarenal aorta surgery. We analyzed peroperative and perioperative data of the patients who, between 1998 and 2004, underwent infrarenal abdominal aorta surgery and were presented with confirmed POIC. We set two distinct groups: acute colitis group (operated POIC, perioperative deaths, or evolution toward a colic stenosis secondarily operated on) and a moderate colitis group (recovery without aftereffects and no surgery). The main goal was to individualize the prognostic factors of acute colitis. Using the Student's t-test or the Fisher's exact test, the potential prognostic factors were compared between these two groups. Between 1998 and 2004, 679 patients underwent infrarenal abdominal aorta surgery. Among these patients, 28 POIC cases were confirmed: 20 patients had acute POIC and eight had moderate POIC. Demographic and peroperative data were similar in the two groups. Among the 20 patients with acute POIC, 17 were operated on with a postoperative mortality rate of 58.8%. All the patients had at least a left colitis. In 59% of the cases, Hartmann's procedure was performed with a mortality rate of 50%. Early digestive symptoms (p = 0.05), use of vasopressors (p = 0.0377), diagnosis in intensive care unit (p = 0.0095), and a pH <7.35 at D1 (p = 0.0261) were independently associated with acute ischemic colitis. Moreover, we could observe the important role of endoscopy aiming at making diagnosis and prognosis. This study highlighted significant prognosis factors of severe colitis. These factors could help take the decision to operate POIC, especially to lower the effect of multiple organ failure syndrome (MOFS).