Small Bowel Diverticulosis: Pathogenesis, Clinical Management, and New Concepts.

PURPOSE OF REVIEW: Small bowel diverticulosis is a well-known clinical entity whose diagnosis and management has evolved in recent years. This review covers pathophysiology, incidence, and prevalence, and it also provides an update on modern diagnosis and management. Meckel's diverticula are covered elsewhere in this volume. RECENT FINDINGS: CT scan and MRI have largely supplanted barium follow-through for diagnosis. No intervention is needed in asymptomatic individuals. Endoscopic management is playing an increasing role for both bleeding and resection of intraduodenal diverticula, but surgical intervention remains the only definitive intervention for other complications like diverticulitis and small bowel obstruction. Small bowel diverticulosis is an uncommon condition which is associated with numerous possible complications. While endoscopy is playing an increasingly large role in management, surgical resection remains the treatment of choice for most complications. A high index of suspicion is needed in order to diagnose this entity.

Editorial: not so nosocomial anymore: the growing threat of community-acquired Clostridium difficile.

Clostridium difficile infection is widely accepted to be the leading cause of nosocomial infection-related morbidity and mortality, outpacing both antibiotic-resistant staphylococcus and enterococcus. The existence and prevalence of community-acquired Clostridium difficile infection, on the other hand, is much less well appreciated. Growing evidence now suggests that community-acquired Clostridium difficile infection may account for more than a third of Clostridium difficile-associated diarrhea overall. Similar to nosocomial Clostridium difficile infection, community-acquired cases appear to be increasing in incidence, and although associated mortality is lower than in nosocomial cases, morbidity including hospitalization and recurrence are high. Further, traditional risk factors for Clostridium difficile infection including antibiotic exposure appear to be less important in community-acquired cases and common routes of exposure and infection in the community are yet to be elucidated. In this issue of the American Journal of Gastroenterology, Khanna et al. provide important epidemiological data on the growing threat of community-acquired Clostridium difficile infection.

Adenoma detection rates vary minimally with time of day and case rank: a prospective study of 2139 first screening colonoscopies.

BACKGROUND: Adenoma detection rate is an important measure of colonoscopy quality; however, factors including procedure order that contribute to adenoma detection are incompletely understood. OBJECTIVE: The aim of this study was to prospectively evaluate factors associated with adenoma detection rate. DESIGN: Prospective cohort study. Data were collected on patient and physician characteristics, trainee participation, time of day, and case rank. SETTING: Outpatient tertiary-care center. PATIENTS: This study involved consecutive patients presenting for first screening colonoscopies. MAIN OUTCOME MEASUREMENTS: Adenoma and polyp detection rates (proportion of cases with one or more lesion detected) and ratios (mean number of lesions detected per case). RESULTS: A total of 2139 colonoscopies were performed by 32 gastroenterologists. Detection rates were 42.7% for all polyps, 25.4% for adenomas, and 5.0% for advanced adenomas. Adenoma detection was associated with male sex and increasing age on multivariate analysis. In the overall study cohort, time of day and case rank were not significantly associated with detection rates. In post hoc analysis, polyp and adenoma detection rates appeared lower after the fifth case of the day for endoscopists with low volumes of cases and after the tenth case of the day for endoscopists with high volumes of cases. LIMITATION: Single center. CONCLUSION: Overall, time of day and case rank did not influence adenoma detection rate. We observed a small but significant decrease in detection rates in later procedures, which was dependent on physician typical procedure volume. These findings imply that colonoscopy quality in general is stable throughout the day; however, there may be a novel "stamina effect" for some endoscopists, and interventions aimed at improving colonoscopy quality need to take individual physician practice styles into consideration.

Treatment of Clostridium difficile-associated disease.

Clostridium difficile infection is an increasing burden to the health care system, totaling more than $1 billion/year in the United States. Treatment of patients with C difficile infection with metronidazole or vancomycin reduces morbidity and mortality, although the number of patients that do not respond to metronidazole is increasing. Despite initial response rates of greater than 90%, 15%-30% of patients have a relapse in symptoms after successful initial therapy, usually in the first few weeks after treatment is discontinued. Failure to develop specific antibody response has recently been identified as a critical factor in recurrence. The review discusses the different management strategies for initial and recurrent symptomatic C difficile infections.

Asymptomatic colonization by Clostridium difficile in infants: implications for disease in later life.

Approximately 60% to 70% of healthy newborns and infants are colonized by the enteric pathogen Clostridium difficile. For reasons that remain obscure, these colonized infants show no ill effects from the potent exotoxins released by this anaerobe, in contrast to older children and adults who are susceptible to severe diarrhea and colitis. The organism is acquired in infancy, as in adults, from environmental contamination in the nursery or home environment. Between 12 and 24 months C difficile is evicted as a commensal, presumably by the gradual development of the adult colonic microflora. The carrier state is well tolerated by infants, and the immunoglobulin G antitoxin response that develops during the carrier state appears to provide durable protection against subsequent C difficile disease.

Clostridium difficile toxin A binds colonocyte Src causing dephosphorylation of focal adhesion kinase and paxillin.

Clostridium difficile toxin A impairs tight junction function of colonocytes by glucosylation of Rho family proteins causing actin filament disaggregation and cell rounding. We investigated the effect of toxin A on focal contact formation by assessing its action on focal adhesion kinase (FAK) and the adapter protein paxillin. Exposure of NCM460 human colonocytes to toxin A for 1 h resulted in complete dephosphorylation of FAK and paxillin, while protein tyrosine phosphatase activity was reduced. Blockage of toxin A-associated glucosyltransferase activity by co-incubation with UDP-2'3' dialdehyde did not reduce toxin A-induced FAK and paxillin dephosphorylation. GST-pull down and in vitro kinase activity experiments demonstrated toxin A binding directly to the catalytic domain of Src with suppression of its kinase activity. Direct binding of toxin A to Src, independent of any effect on protein tyrosine phosphatase or Rho glucosylation, inhibits Src kinase activity followed by FAK/paxillin inactivation. These mechanisms may contribute to toxin A inhibition of colonocyte focal adhesion that occurs in human colonic epithelium exposed to toxin A.

Persistent psychological or physical symptoms following endoscopic procedures: an unrecognized post-endoscopy adverse event.

BACKGROUND: Depression and post-traumatic stress disorder have been described after surgical procedures, but not after gastrointestinal endoscopy. AIMS: The aim of our retrospective survey was to determine if new-onset, persistent (>1 month) psychological and/or physical symptoms develop after gastrointestinal endoscopy. We also sought to assess how endoscopy teams respond to patient discomfort during the procedure. METHODS: We conducted in-person interviews among 57 gastroenterologists and endoscopy nurses at two large academic medical centers and a community hospital. Response rate was 81% (57/70). RESULTS: Among gastroenterologists surveyed, 62% had encountered at least one patient with persistent new-onset unexplained physical symptoms, and 48% had encountered at least one patient with persistent new-onset psychological symptoms that started after an endoscopic procedure. A total of 44 such patients were identified, and most were women between 20 and 40 years of age. Common new symptoms that developed after gastrointestinal endoscopy were abdominal discomfort, diarrhea, globus sensation, anxiety disorder and depression. Duration of these symptoms was 1 month to 3 years. Gastroenterologists reported that 4% and endoscopy nurses reported that 10% of patients undergoing endoscopy gestured or requested that the endoscopic procedure be prematurely stopped due to discomfort. Only 11/29 (38%) physicians reported that while obtaining consent for endoscopic procedures, they routinely discuss the possibility of stopping prematurely if the patient becomes uncomfortable. Conclusion Persistent physical or psychological symptoms can develop in some patients after endoscopic procedures.

gp96 is a human colonocyte plasma membrane binding protein for Clostridium difficile toxin A.

Clostridium difficile toxin A (TxA), a key mediator of antibiotic-associated colitis, requires binding to a cell surface receptor prior to internalization. Our aim was to identify novel plasma membrane TxA binding proteins on human colonocytes. TxA was coupled with biotin and cross-linked to the surface of HT29 human colonic epithelial cells. The main colonocyte binding protein for TxA was identified as glycoprotein 96 (gp96) by coimmunoprecipitation and mass spectrum analysis. gp96 is a member of the heat shock protein family, which is expressed on human colonocyte apical membranes as well as in the cytoplasm. TxA binding to gp96 was confirmed by fluorescence immunostaining and in vitro coimmunoprecipitation. Following TxA binding, the TxA-gp96 complex was translocated from the cell membrane to the cytoplasm. Pretreatment with gp96 antibody decreased TxA binding to colonocytes and inhibited TxA-induced cell rounding. Small interfering RNA directed against gp96 reduced gp96 expression and cytotoxicity in colonocytes. TxA-induced inflammatory signaling via p38 and apoptosis as measured by activation of BAK (Bcl-2 homologous antagonist/killer) and DNA fragmentation were decreased in gp96-deficient B cells. We conclude that human colonocyte gp96 serves as a plasma membrane binding protein that enhances cellular entry of TxA, participates in cellular signaling events in the inflammatory cascade, and facilitates cytotoxicity.

Non-antibiotic therapy for Clostridium difficile infection.

Treatment of Clostridium difficile infection with metronidazole or vancomycin is successful in the majority of cases, but relapse occurs in 15% to 20% of patients, and in some the infection can remain chronic for months or years. The use of non-antibiotic therapies for this infection is theoretically attractive, as they would enable the normal colonic microflora to be reconstituted which is a requirement for permanent eradication of this pathogen. Over the past decade a number of non-antibiotic approaches to eliminate or neutralize C. difficile or its toxins have been proposed, including probiotic therapy with non-pathogenic microorganisms and several forms of immunotherapy. These alternative approaches are in their infancy, but initial reports appear to support efficacy against this stubborn infection.

Theodore E. Woodward Award. How bacterial enterotoxins work: insights from in vivo studies.

Clostridium difficile is a spore forming, gram-positive anaerobic bacillus first described in 1935 by Hall and O'Toole as a commensal organism in the fecal flora of healthy newborn infants (1). The organism was given its unusual name because it grew slowly and was difficult to isolate in pure culture. Its presence in the stool of healthy neonates suggested that C. difficile was a nonpathogen, even though it produced toxins in broth culture. Following its original description, C. difficile passed quickly into relative obscurity in the 1960's and 1970's when antibiotic-associated pseudomembranous colitis became prevalent following the introduction into clinical practice of broad spectrum antibiotics. The frequent association of clindamycin and lincomycin therapy with pseudomembranous colitis led to the term "clindamycin colitis" (2). A breakthrough occurred in 1978 when C. difficile was identified as the source of a cytotoxin in the stool of patients with pseudomembranous colitis (3). During the two decades since its rediscovery, a great deal has been learned about the pathophysiology, epidemiology and management of C. difficile infection, yet many challenges remain. Currently this organism infects over 30% of individuals admitted to United States hospitals, making C. difficile colitis one of the most common nosocomial infections (4). It is estimated that approximately 10-12 million adults are infected with this organism each year in the United States, about a third of whom become symptomatic. The disease burden in the elderly is particularly severe as they are hospitalized more frequently and for longer duration. The pathophysiology of C. difficile diarrhea requires alteration of the colonic microflora by antibiotics, colonization by C. difficile, and release of two potent enterotoxins designated A and B (5). The toxins of Clostridium difficile are required virulence factors in both animals and humans since non-toxigenic strains do not cause disease. Recent cloning and sequencing of the toxin genes reveals extensive amino acid homology between them that is reflected in common molecular and cellular mechanisms. Both toxins damage cells by modifying the rho family of proteins, key regulators of cellular actin. C. difficile infection causes a florid acute inflammatory response seen in patients with pseudomembranous colitis. It is now realized that neurons and immune cells of the lamina propria are major determinants of toxin-induced diarrhea and mucosal damage. Early critical events following toxin exposure are release of the neuropeptides substance P and calcitonin gene related peptide (CGRP) from sensory afferent neurons and activation of lamina propria macrophages and intestinal mast cells. These peptides in turn release a complex cascade of other inflammatory mediators from lamina propria cells (5). The importance of the host immune response, specifically serum IgG directed against toxin A, is now recognized as a critical determinant of disease expression in man.

Clostridium difficile infection: a worldwide disease.

Clostridium difficile, an anaerobic toxigenic bacterium, causes a severe infectious colitis that leads to significant morbidity and mortality worldwide. Both enhanced bacterial toxins and diminished host immune response contribute to symptomatic disease. C. difficile has been a well-established pathogen in North America and Europe for decades, but is just emerging in Asia. This article reviews the epidemiology, microbiology, pathophysiology, and clinical management of C. difficile. Prompt recognition of C. difficile is necessary to implement appropriate infection control practices.

Overview of Clostridium difficile infection: implications for China.

The incidence and severity of Clostridium difficile infection (CDI) have dramatically increased in the Western world in recent years. In contrast, CDI is rarely reported in China, possibly due to under-diagnosis. This article briefly summarizes CDI incidence, management and preventive strategies. The authors intend to raise awareness of this disease among Chinese physicians and health workers, in order to minimize the medical and economic burden of a potential epidemic in the future.