Anti-adhesion molecule therapies in inflammatory bowel disease: touch and go.

Exploration of the mechanisms underlying the inflammatory bowel diseases [N. Mori, Y. Horie, M.E. Gerritsen, D.C. Anderson, D.N. Granger, Anti-inflammatory drugs and endothelial cell adhesion molecule expression in murine vascular beds. Gut 1999;44:186-95] is a leading field of medical research that drives the application of biological therapies to human diseases. Indeed, many inflammatory mediators can be targeted in the gut by monoclonal antibodies. A recent direction for these therapeutics is targeting of the adhesion molecule family. This molecule family mediates the adhesion and extravasation of leukocytes through the endothelium at sites of inflammation. This is a complex multistep process that has been extensively investigated in recent years; thanks to these studies some adhesion molecules have been identified to specifically mediate leukocyte migration to gut inflammatory sites, like alpha(4)beta(7) integrin. This review outlines the scientific basis behind this therapeutic approach, and describes the principal clinical studies that have been carried out on these new molecules in patients with IBD.

Removal of AMPA receptors (AMPARs) from synapses is preceded by transient endocytosis of extrasynaptic AMPARs.

AMPA receptors (AMPARs) are dynamically regulated at synapses, but the time course and location of their exocytosis and endocytosis are not known. Therefore, we have used ecliptic pHluorin-tagged glutamate receptor 2 to visualize changes in AMPAR surface expression in real time. We show that synaptic and extrasynaptic AMPARs respond very differently to NMDA receptor activation; there is a rapid internalization of extrasynaptic AMPARs that precedes the delayed removal of synaptic AMPARs.

Chronic Obstructive Pulmonary Disease--SMi's Second Annual Conference. 10-11 March 2004, London, UK.

Approximately 75 delegates attended this conference over the course of 2 days, the majority of whom were drawn from the pharmaceutical industry. The speakers represented a more varied group, and included clinical physicians and representatives of the British Thoracic Society and the World Health Organisation (WHO). Chronic obstructive pulmonary disease (COPD) is a disease that has only been recognized by physicians for the last 12 years, and consequently it has a low level of public awareness. However, the WHO estimates that COPD will be among the top five factors affecting quality-of-life in industrialized countries by 2020. Clearly this represents a major unmet medical need, and the focus of the presentations reflected this. Presentations were balanced between those that attempted to differentiate the disease state from asthma, and those that discussed the suitability of currently available or indicated asthma therapeutics for the treatment of COPD.

Proteins involved in the trafficking and functional synaptic expression of AMPA and KA receptors.

Alpha-amino-3-hydroxy-5-methylisoxazolepropionate receptors (AMPARs) mediate the majority of fast synaptic transmission in the mammalian central nervous system, play a central role in synapse stabilisation and plasticity, and their prolonged activation is potently neurotoxic. The functional roles of kainate receptors (KARs) are less well defined but they play a role in some forms of synaptic plasticity. Both receptor types have been shown to be highly developmentally and activity-dependently regulated and their functional synaptic expression is under tight cellular regulation. The molecular and cellular mechanisms that regulate the synaptic localisation and functional expression of AMPARs and KARs are objects of concerted research. There has been significant progress towards elucidating some of the processes involved with the discovery of an array of proteins that selectively interact with individual AMPAR and KAR subunits. These proteins have been implicated in, among other things, the regulation of post-translational modification, targeting and trafficking, surface expression, and anchoring. The aim of this review is to present an overview of the major interacting proteins and suggest how they may fit into the hierarchical series of events controlling the trafficking of AMPARs and KARs.

Temporary placement of covered self-expandable metal stents in benign biliary strictures: a new paradigm? (with video).

BACKGROUND: Benign biliary strictures (BBS) are usually managed with plastic stents, whereas placement of uncovered metallic stents has been associated with failure related to mucosal hyperplasia. OBJECTIVE: We analyzed the efficacy and safety of temporary placement of a covered self-expanding metal stent (CSEMS) in BBS. DESIGN: Patients with BBS received temporary placement of CSEMSs until adequate drainage was achieved; confirmed by resolution of symptoms, normalization of liver function tests, and imaging. SETTING: Tertiary-care center with long-standing experience with CSEMSs. PATIENTS: Seventy-nine patients with BBS secondary to chronic pancreatitis (32), calculi (24), liver transplant (16), postoperative biliary repair (3), autoimmune pancreatitis (3), and primary sclerosing cholangitis (1). INTERVENTION: ERCP with temporary CSEMS placement. Removal of CSEMSs was performed with a snare or a rat-tooth forceps. MAIN OUTCOME MEASUREMENTS: End points were efficacy, morbidity, and clinical response. RESULTS: CSEMSs were removed from 65 patients. Resolution of the BBS was confirmed in 59 of 65 patients (90%) after a median follow-up of 12 months after removal (range 3-26 months). If patients who were lost to follow-up, developed cancer, or expired were considered failures, then an intent-to-treat global success rate of 59 of 79 (75%) was obtained. Complications associated with placement included 3 post-ERCP pancreatitis (4%), 1 postsphincterotomy bleed (1%), and 2 pain that required CSEMS removal (2%). In 11 patients (14%), the CSEMS migrated. In 1 patient, CSEMS removal was complicated by a bile leak that was successfully managed with plastic stents. LIMITATION: Pilot study from a single center. CONCLUSIONS: Temporary CSEMS placement in patients with BBS offers a potential alternative to surgery.

Commensal bacteria exacerbate intestinal inflammation but are not essential for the development of murine ileitis.

The pathogenesis of Crohn's disease has been associated with a dysregulated response of the mucosal immune system against intraluminal Ags of bacterial origin. In this study, we have investigated the effects of germfree (GF) conditions in the SAMP1/YitFc murine model of Crohn's disease-like ileitis. We show that the bacterial flora is not essential for ileitis induction, because GF SAMP1/YitFc mice develop chronic ileitis. However, compared with disease in specific pathogen-free (SPF) mice, ileitis in GF mice is significantly attenuated, and is associated with delayed lymphocytic infiltration and defective mucosal expression of Th2 cytokines. In addition, we demonstrate that stimulation with purified fecal Ags from SPF, but not GF mice leads to the generation of IL-4-secreting effector lymphocytes. This result suggests that commensal bacteria drive Th2 responses characteristic of the chronic phase of SAMP1/YitFc ileitis. Finally, adoptive transfer of CD4-positive cells from GF, but not SPF mice induces severe colitis in SCID recipients. These effects were associated with a decreased frequency of CD4(+)CD25(+)Foxp3(+) T cells in the mesenteric lymph nodes of GF mice compared with SPF mice, as well as lower relative gene expression of Foxp3 in CD4(+)CD25(+) T cells in GF mice. It is therefore apparent that, in the absence of live intraluminal bacteria, the regulatory component of the mucosal immune system is compromised. All together, our results indicate that in SAMP1/YitFc mice, bacterial flora exacerbates intestinal inflammation, but is not essential for the generation of the chronic ileitis that is characteristic of these mice.

Temporary placement of covered self-expandable metallic stents in patients with biliary leak: midterm evaluation of a pilot study.

BACKGROUND: Management of biliary leaks includes ERCP and stent placement. The ability to temporarily place a partially covered self-expandable metallic stent (CSEMS) might offer an advantage in the treatment of biliary leaks. OBJECTIVE: We analyzed our 2 years' experience when using this innovative technique. DESIGN: Patients in whom a previous ERCP had failed to resolve a bile leak or patients with severe comorbidities were offered CSEMS and were followed prospectively for clinical and radiologic responses. SETTING: Tertiary-care center with long-standing experience of using CSEMS. PATIENTS: A total of 16 patients were included. Of these, 7 had previously undergone unsuccessful plastic stent placement, 3 had previously failed ERCP, and 7 had severe comorbidities that prevented multiple interventions. INTERVENTION: ERCP with placement of a CSEMS covering the cystic duct take-off in the case of a cystic-stump leak. CSEMS were removed after resolution of the leak. MAIN OUTCOME MEASUREMENTS: Efficacy and safety of the CSEMS in bile leaks; complications were also evaluated. RESULTS: Of the patients studied, 15 responded to CSEMS placement with complete resolution of the leak on imaging. One patient with partial cholecystectomy relapsed and underwent drainage; another patient responded to the treatment but required revision because of migration. CSEMS were left in place for a median time of 3 months (range, 1-17 months). Complications included 1 proximal and 1 distal migration. LIMITATIONS: Pilot study from a single center. CONCLUSIONS: CSEMS is an excellent option in this subgroup of patients not responding to plastic stent placement or with severe comorbidities.

Evidence-based medications for the treatment of the inflammatory bowel diseases.

PURPOSE OF REVIEW: Evidence-based medicine is an increasingly important tool to aid the clinician in the treatment of patients. This is particularly true for diseases such as the inflammatory bowel diseases, for which the pathogenesis is unknown and an extensive range of treatment options is available. High quality data may not be available for all decisions, but it is essential that clinicians are aware of well-grounded data that are available. RECENT FINDINGS: The body of data supporting the use of biological therapies in inflammatory bowel disease continues to grow and diversify. Regulatory requirements and academic expectations are evolutionary forces that are resulting in continuous improvement in the quality of studies. SUMMARY: This review will update the reader on several significant analyses that have been published recently. It is intended to raise awareness of the data, helping clinicians to evaluate new treatments and to revisit older treatments with a critical eye.