Gerard E. Mullin

Increased oxidative stress and decreased antioxidant defenses in mucosa of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation whose cellular components are capable of oxidative respiratory bursts that may result in tissue injury. Mucosal biopsies were analyzed for protein carbonyl content (POPs), DNA oxidation products [8-hydroxy-2′-deoxyguanosine (8-OHdG)], reactive oxygen intermediates (ROIs), trace metals (copper, zinc, and iron) and superoxide dismutase (Cu-Zn SOD). In Crohns disease biopsies, there was an increase in ROIs, POPs, 8-OHdG, and iron, while decreased copper and Cu-Zn SOD activity were found in inflamed tissues compared to controls. For ulcerative colitis, there was an increase in ROIs, POPs, and iron in inflamed tissue compared to controls, while decreased zinc and copper were observed. An imbalance in the formation of reactive oxygen species and antioxidant micronutrients may be important in the pathogenesis and/or perpetuation of the tissue injury in IBD and may provide a rationale for therapeutic modulation with antioxidants.

ACG Clinical Guideline: Nutrition Therapy in the Adult Hospitalized Patient

The value of nutrition therapy for the adult hospitalized patient is derived from the outcome benefits achieved by the delivery of early enteral feeding. Nutritional assessment should identify those patients at high nutritional risk, determined by both disease severity and nutritional status. For such patients if they are unable to maintain volitional intake, enteral access should be attained and enteral nutrition (EN) initiated within 24–48 h of admission. Orogastric or nasogastric feeding is most appropriate when starting EN, switching to post-pyloric or deep jejunal feeding only in those patients who are intolerant of gastric feeds or at high risk for aspiration. Percutaneous access should be used for those patients anticipated to require EN for >4 weeks. Patients receiving EN should be monitored for risk of aspiration, tolerance, and adequacy of feeding (determined by percent of goal calories and protein delivered). Intentional permissive underfeeding (and even trophic feeding) is appropriate temporarily for certain subsets of hospitalized patients. Although a standard polymeric formula should be used routinely in most patients, an immune-modulating formula (with arginine and fish oil) should be reserved for patients who have had major surgery in a surgical ICU setting. Adequacy of nutrition therapy is enhanced by establishing nurse-driven enteral feeding protocols, increasing delivery by volume-based or top-down feeding strategies, minimizing interruptions, and eliminating the practice of gastric residual volumes. Parenteral nutrition should be used in patients at high nutritional risk when EN is not feasible or after the first week of hospitalization if EN is not sufficient. Because of their knowledge base and skill set, the gastroenterologist endoscopist is an asset to the Nutrition Support Team and should participate in providing optimal nutrition therapy to the hospitalized adult patient.

Anti-IL12 imposes the death sentence on Th1 cells in TNBS colitis--is there a light at the end of the tunnel for Crohn's disease?

The intrarectal administration of the hapten trinitrobenzene sulfonic acid (TNBS) into immunocornpetent mice causes a mucosal T-helper type 1 (Thl) T-cell response that is irnmunologically similar to that which is seen in Crohn’s disease (CD) [high interferon (1FN)-y, low interleukin (1L)-41. Through staining of the inflamed intestinal tissue of CD patients, increased numbers of cells secreting IL12, the cytokine that drives Thl T-cell differentiation, have been identified (Gastroenterology 97; 1 12: 1 169-78). It has been demonstrated that when TNBS-treated mice are concomitantly given a systemic administration of anti-IL-12, the onset of colitis is prevented (J Exp Med 1995;182: 1281-90). Additionally, when anti-IL-I2 is given in the presence of known colitis in TNBStreated mice, the colitis abrogated. These findings established that TNBS-induced colitis is a Th 1 T-cell-driven inflammation, and suggested that anti-IL-12 may be a useful agent in the treatment of CD. There are two hypotheses surrounding the mechanism of action of anti-IL12 treatment in TNBS-induced colitis. First, that the anti-IL-12 blocks the induction of new Thl T-cell differentiation needed to sustain chronic intestinal inflammation. Second, that in the absence of IL-12, mucosal Thl T-cells undergo apoptosis. The aim of this study was to define the mechanism of action of anti-IL12 treatment in TNBS-induced colitis. A series of studies were undertaken to analyze cells and tissue obtained from mice with TNBS-induced colitis that had received either anti-IL12, anti-IFN-y, murine Fas-Fc fused to human IgGl Fc, or controls (rat IgG, murine or human IgGl) for phenotype, cytokine production, and apoptosis. The authors found that treatment for TNBS-induced colitis with anti-IL-12 was more effective than with anti-IFN-y, and that anti-IL-12 led to a complete normalization of IFN-y production by the lamina propria T cells ex vivo, whereas anti-IFN-y did not. Treatment with anti-IL-12 also led to an increased number of apoptotic cells in the lamina propria and spleen, suggesting veracity of the hypothesis that anti-IL-12 leads to a reversal of inflammation by elimination of the Thl T cells. The authors further found that the observed apoptosis was mediated by the Fas pathway. Mice with Fas pathway defects responded poorly to anti-IL-12 treatment when compared with controls (p < 0.01). Along these lines, anti-IL-12 treatment was less effective in mice treated with Fas-Fc antibody, which blocks the Fasmediated apoptosis pathway, than those that did not receive Fas-Fc. The authors concluded from their studies that the main mechanism of action of anti-IL-12 in TNBS-induced colitis is the induction of the Fas-mediated apoptosis of the Thl T cells. The elucidation of this pathway is important for treatment of human intestinal diseases with idiopathic chronic inflammation such as CD with anti-IL-I2 antibodies. Comment: Investigation into the mechanisms responsible for the chronic intestinal inflammation in CD and ulcerative colitis (UC) span over two decades of study. Although many plausible theories for the initiation and perpetuation of “uncontrolled” inflammation and tissue injury have been proposed, the potential role of certain regulatory cytokines as administrators of an amplified injurious immune response has been intensely studied. In inflammatory bowel disease (IBD), disturbances in cytokine responses, induction, production, regulation, and secretion have been demonstrated. As an example of the central role of cytokines in IBD pathogenesis, the blockade of cytokine responses by monoclonal antibody to tumor necrosis factor (infliximab) has been demonstrated to successfully treat fistulizing and moderate-to-severe CD (N Engl J Med 1997;337:

Role of Lymphokines in Function of Gastrointestinal Mucosal T Cells

Publisher Summary This chapter discusses the role of lymphokines in the function of gastrointestinal mucosal T cells. T cells in the organized and diffuse compartments of the intestinal immune system are thought to play a central role in host defense against pathogens and in the pathogenesis of chronic inflammatory intestinal diseases. Cells in organized lymphoid sites, such as the Peyers patches, mesenteric lymph nodes, and appendix, are thought to carry out specialized tasks necessary for initiating responses to antigens present in the intestinal lumen. Many functions carried out by T cells in the gastrointestinal (GI) immune system are thought to be mediated at least in part by their secreted lymphokines. An important requirement for the mucosal immune system is that it be unresponsive for the large number of harmless but potentially antigenic materials in the gastrointestinal tract and at the same time be able to mount a protective response against pathogens. It is thought that this is accomplished at least in part through the immunoregulatory activity of T cells in the mucosa.

Role of lymphokines in immunoregulatory function of mucosal T cells in humans and nonhuman primates.

SummaryThe findings presented above and in other studies provide substantial evidence that lymphocytes in the intestinal lamina propria differ from lymphocyte populations in the circulation or in other tissue sites in a number of ways. First, lamina propria lymphocytes are phenotypically distinet and have evidence of activation. Lymphocytes in the intestinal lamina propria are different in their potential for expression of lymphokine gene products, since activated cells from the lamina propria have high expression of mRNA for IL-2, IL-4, IL-5 and IFN-γ in comparison to circulating lymphocytes. Mesenteric lymph node T cells also differ from circulating lymphocytes in their high expression of IL-4 and IL-5 mRNA. A further difference between mesenteric lymph node and lamina propria T cells is that the former are capable of proliferating in response to IL-4, whereas the latter are not. These phenotypic and mRNA differences of lamina propria lymphocytes also correlate well with their high helper activity in vitro for immunoglobulin synthesis in the pokeweed mitogen system. Finally, lamina propria T cells at a site of inflammation are able to provide high helper activity in response to specific antigens. These observations are all consistent with the conclusion that T cells in the lamina propria are pleomorphic, but are highly enriched for subpopulations of activated memory cells that are geared for effector functions. These functions are likely to be critical in maintaining normal host defense in the mucosal environment.

The development of pneumoperitoneum as a result of botox injection for treatment of achalasia

The development of pneumoperitoneum as a result of botox injection for treatment of achalasia

Intravenous pantropazole: physician understanding of indications and their prescribing patterns leading to hospital restrictions

Intravenous pantropazole: physician understanding of indications and their prescribing patterns leading to hospital restrictions

Tapeworms Diagnosed by Capsule Endoscopy: An Unusual Cause of Abdominal Pain in a Child

A 7-year-old Caucasian boy with autism spectrum disorder presented with increased agitation and aggressive behavior, which were attributed to abdominal pain. Upper endoscopy and colonoscopy were unrevealing. Capsule endoscopy to evaluate for Crohn’s disease showed tapeworms in the small intestine with at least one identifiable scolex (image). Following the diagnosis of taeniasis, stool ova and parasites were collected on three separate days, but the results of analysis were negative. His parents denied recent travel history or exposure to raw foods. They subsequently divulged his recent ingestion of helminth ova, an experimental immunotherapy suggested to improve autistic behaviors. This therapy was suspected to be the cause of the taeniasis. Because the patient had a tendency to place objects in his mouth, another potential culprit was contamination of these objects with eggs or larvae. While helminthic therapy typically does not utilize Taenia because of their pathogenic potential, the composition of the patient’s helminthic therapy is unknown and the product may have been contaminated. (Informed consent was obtained from the patient to publish these images.)