Abstract. Mutations in the adenomatous polyposis coli (APC) gene are linked to polyp formation in familial and sporadic colon cancer, but the functions of the protein are not known. We show that APC protein localizes mainly to clusters of puncta near the ends of microtubules that extend into actively migrating regions of epithelial cell membranes. This subcellular distribution of APC protein requires microtubules, but not actin filaments. APC protein-containing membranes are actively involved in cell migration in response to wounding epithelial monolayers, addition of the motorgen hepatocyte growth factor, and during the formation of cell-cell contacts. In the intestine, APC protein levels increase at the crypt/villus boundary, where cell migration is crucial for enterocyte exit from the crypt and where cells accumulate during polyp formation that is linked to mutations in the microtubule-binding domain of APC protein. Together, these data indicate that APC protein has a role in directed cell migration.

Abstract. Background-Short chain fatty acid (SCFA) deficiency is associated with colitis in animals and humans, and the mucosal metabolism of these compounds is decreased in ulcerative colitis. Aims-To assess the efficacy of topical SCFA treatment in ulcerative colitis. Patients and Methods-103 patients with distal ulcerative colitis were entered into a six week, double-blind, placebo controlled trial of rectal SCFA twice daily; patients who were unchanged on placebo were offered SCFA in an open-label extension trial. Results-Of the 91 patients completing the trial, more patients in the SCFA treated than in the placebo treated group improved (33% v 20%, p=0 14, NS). Those on SCFA also had larger, but statistically non-significant, reductions in every component of their clinical and histological activity scores. In patients with a relatively short current episode of colitis (<6 months, n=42), more responded to SCFA than to placebo (48% v 18%, p=003). These patients also had larger, but statistically non-significant, decreases in their clinical activity index (p=0.08 v placebo). Every patient who improved used at least five of six of the prescribed rectal SCFA irrigations, whereas only 37% who did not improve were as compliant. In the open-label extension trial, 65% improved on SCFA; these patients also had significant reductions (p<0.02) in their clinical and histological activity scores. Conclusions-Although SCFA enemas were not of therapeutic value in this controlled trial, the results suggest efficacy in subsets of patients with distal ulcerative colitis including those with short active episodes. Prolonged contact with rectal mucosa seems to be necessary for therapeutic benefit. (Gut 1997; 40: 485-491) Keywords: short chain fatty acids, distal ulcerative colitis.Treatment of distal ulcerative colitis consists mainly of topical or oral 5-aminosalicylic acid (5-ASA) compounds or corticosteroids, or both. These compounds alter the inflammatory response by decreasing oxygen free radical activity and proinflammatory cytokine release, and by modifying the lipo-and cyclooxygenase pathways of arachidonic acid metabolism.' They are relatively expensive, not uniformly effective, are not free of undesired systemic effects even in their new formula-

There are significant differences in IBD subtypes and serologic markers among racial/ ethnic groups with IBD in the United States.

Chronic diarrhea is a common problem affecting up to 5% of the population at a given time. Patients vary in their definition of diarrhea, citing loose stool consistency, increased frequency, urgency of bowel movements, or incontinence as key symptoms. Physicians have used increased frequency of defecation or increased stool weight as major criteria and distinguish acute diarrhea, often due to self-limited, acute infections, from chronic diarrhea, which has a broader differential diagnosis, by duration of symptoms; 4 weeks is a frequently used cutoff. Symptom clusters and settings can be used to assess the likelihood of particular causes of diarrhea. Irritable bowel syndrome can be distinguished from some other causes of chronic diarrhea by the presence of pain that peaks before defecation, is relieved by defecation, and is associated with changes in stool form or frequency (Rome criteria). Patients with chronic diarrhea usually need some evaluation, but history and physical examination may be sufficient to direct therapy in some. For example, diet, medications, and surgery or radiation therapy can be important causes of chronic diarrhea that can be suspected on the basis of history alone. Testing is indicated when alarm features are present, when there is no obvious cause evident, or the differential diagnosis needs further delineation. Testing of blood and stool, endoscopy, imaging studies, histology, and physiological testing all have roles to play but are not all needed in every patient. Categorizing patients after limited testing may allow more directed testing and more rapid diagnosis. Empiric antidiarrheal therapy can be used to mitigate symptoms in most patients for whom a specific treatment is not available.

Chronic watery diarrhea poses a diagnostic and therapeutic challenge and is often a disabling condition for patients. Although acute diarrhea is likely to be caused by infection, the causes of chronic diarrhea (more than 4 weeks in duration) are more elusive. We review on the pathophysiology, diagnosis, and treatment of chronic diarrhea. Drawing on recent insights into the molecular mechanisms of intestinal epithelial transport and barrier function, we discuss how diarrhea can result from a decrease in luminal solute absorption, an increase in secretion, or both, as well as derangements in barrier properties. We also describe the various extra-epithelial factors that activate diarrheal mechanisms. Finally, clinical evaluation and tests used in assessment of patients presenting with chronic diarrhea are reviewed, and an algorithm guiding therapeutic decisions and pharmacotherapy is presented.

Short-chain fatty acids are the predominant luminal anions in the colon (>75 mM) and thus create a rather unique environment for transporting epithelium. The colon absorbs short-chain fatty acids, either by diffusion of the protonated species across the apical membrane or by an anion exchange process with bicarbonate. Additionally, short-chain fatty acids modulate Na absorption, Cl secretion, intracellular pH, and cell volume.

Common variable immunodeficiency (CVID) is the second most prevalent primary immunodeficiency disorder but clinically the most important. It causes a wide spectrum of symptoms and signs affecting many systems of the body. CVID is a combination of humoral and cell-mediated deficiency, which explains not only why so many systems are affected but also why standard therapy in the form of intravenous immunoglobulin is not always effective. The gastrointestinal tract is the largest immune organ in the body, and it is therefore expected that this immunodeficiency will affect it in some way. The gastrointestinal manifestations of CVID are variable and tend to mimic known diseases, such as celiac sprue, pernicious anemia, and inflammatory bowel disease, but show significant differences on the microscopic level. Many studies continue to confirm a high prevalence of inflammatory, malignant, and infectious gastrointestinal disorders in patients with CVID. The T-cell-mediated defects of this immunodeficiency disorder are thought to be the cause of the majority of the gastrointestinal disorders in CVID and not the antibody deficiency. Therefore, intravenous immunoglobulin alone may be ineffective. Combination therapy with immunomodulators, such as azathioprine and 6-mercaptopurine, may be needed to treat these gastrointestinal manifestations of CVID.

No abstract