Publications

The removal of edema from the air spaces is a critical function of the alveolar barrier requiring intact tight junctions. Alveolar fluid clearance contributes to graft function after transplantation and is associated with survival in patients with acute lung injury. Claudin-4 concentrations are known to increase during lung injury and the loss of claudin-4 decreases alveolar fluid clearance in mice. This study was therefore undertaken to evaluate whether differences in lung expression of the tight junction protein claudin-4 are associated with alveolar fluid clearance or clinical measures of lung function. Alveolar fluid clearance rates were measured in ex vivo perfused human lungs not used for transplantation and were compared with histological lung injury and clinical measures of lung injury in the donors. Claudin-4 staining demonstrated a positive correlation with alveolar fluid clearance (Spearman rank correlation [r(s)] = 0.71; P < 0.003); however, claudin-4 staining was not strongly associated with histological measures of lung injury. The expression of other tight junction proteins (including ZO-1) was not associated with alveolar fluid clearance or claudin-4 levels. Claudin-4 staining was lower in lungs from donors with greater impairment in respiratory physiology. These data suggest that claudin-4 may promote alveolar fluid clearance and demonstrate that the amount of claudin-4 expressed may provide specific information regarding alveolar epithelial barrier function that strengthens the link between histological changes and physiological impairment.

GspB is a serine-rich repeat (SRR) adhesin of Streptococcus gordonii that mediates binding of this organism to human platelets via its interaction with sialyl-T antigen on the receptor GPIbα. This interaction appears to be a major virulence determinant in the pathogenesis of infective endocarditis. To address the mechanism by which GspB recognizes its carbohydrate ligand, we determined the high-resolution x-ray crystal structure of the GspB binding region (GspB(BR)), both alone and in complex with a disaccharide precursor to sialyl-T antigen. Analysis of the GspB(BR) structure revealed that it is comprised of three independently folded subdomains or modules: 1) an Ig-fold resembling a CnaA domain from prokaryotic pathogens; 2) a second Ig-fold resembling the binding region of mammalian Siglecs; 3) a subdomain of unique fold. The disaccharide was found to bind in a pocket within the Siglec subdomain, but at a site distinct from that observed in mammalian Siglecs. Confirming the biological relevance of this binding pocket, we produced three isogenic variants of S. gordonii, each containing a single point mutation of a residue lining this binding pocket. These variants have reduced binding to carbohydrates of GPIbα. Further examination of purified GspB(BR)-R484E showed reduced binding to sialyl-T antigen while S. gordonii harboring this mutation did not efficiently bind platelets and showed a significant reduction in virulence, as measured by an animal model of endocarditis. Analysis of other SRR proteins revealed that the predicted binding regions of these adhesins also had a modular organization, with those known to bind carbohydrate receptors having modules homologous to the Siglec and Unique subdomains of GspB(BR). This suggests that the binding specificity of the SRR family of adhesins is determined by the type and organization of discrete modules within the binding domains, which may affect the tropism of organisms for different tissues.

Angiostrongylus cantonensis was first discovered in 1935 and has become an important emerging pathogen causing human angiostrongyliasis. Major outbreaks of human angiostrongyliasis have been reported in endemic regions. Thousands of cases of human angiostrongyliasis have been documented worldwide. A. cantonensis has spread from its traditional endemic regions of the Pacific islands and Southeast Asia to the American continent including the USA, Caribbean islands and Brazil. Humans acquire A. cantonensis by consumption of raw or undercooked intermediate snail hosts or paratenic hosts. The main clinical manifestations of human angiostrongyliasis are eosinophilic meningitis and ocular angiostrongyliasis. The treatment of this disease includes supportive treatment, corticosteroid therapy, and combined therapy with corticosteroids and anthelminthics. The most effective method for prevention is to persuade people not to eat raw or undercooked intermediate and paratenic hosts.

This publication reports the proceedings of the preliminary meeting of the working party that met at Gastro 2009 during the World Congress in London. The purpose of the preliminary meeting was to consider the areas that require attention, to discuss some of the findings that have already been published and to agree on the way forward. Our reason for publishing these proceedings is to stimulate interest in this venture and to provide the opportunity for input from the endoscopy community worldwide. The next meeting of the working party will be at the JGES Society meeting in Aomori in April 2011 when we hope to prepare a preliminary classification. This will be presented for general discussion and debate at the International Congress of Endoscopy (ICE) in Los Angeles in September 2011.