Pathophysiology And Genomics Of Virulence Determinants

C. difficile's main virulence determinants are two exotoxins: toxins A and B. In animal models, toxin A was shown to be an enterotoxin inducing both diarrhea and inflammation. By contrast, in tissue culture, toxin B was much more cytotoxic than toxin A and was designated as cytotoxin. The genes for toxin A (tcdA) and toxin B (tcdB) are highly homologous, and the carboxy-terminal regions of both toxins encode a glucosyltransferase specific for the host small GTP-binding proteins of the Rho family. Glucosylation of these small GTP-binding proteins leads to a disorganization of the cytoskeleton and provokes cell death. The toxins also trigger inflammatory response and fluid secretion. Epithelial damages such as necrosis and ulceration can eventually lead to the formation of the characteristic pseudomembranes observed in pseudomem-branous colitis.[5] The level of humoral response against C. difficile toxins appears to confer a certain amount of protection to the host, which may explain why certain individuals remain asymptomatic carriers of toxigenic strains, others only develop mild diarrhea, and some suffer from severe colitis.[6]

Sequence analysis revealed that both toxin genes are part of a multigene operon located within a 19.6-kb pathogenicity locus (PaLoc) inserted into the chromosome of C. difficile. PaLoc genes are conserved in toxigenic strains and are systematically absent from nontoxigenic strains.[7] Restriction enzyme mapping analysis of the PaLoc revealed variant C. difficile strains, which differ in length and restriction sites from the reference strain. Twenty groups of such variants have been described and defined as toxinotypes I-XX.[8] Although tcdB restriction sites are more variable than those of tcdA, deletions and insertions are more frequently observed in tcdA. In fact, some toxinotypes are associated with a toxin A-negative, toxin B-positive phenotype. These strains, which were first isolated from asymptomatic children, are now increasingly recovered from patients presenting symptoms ranging from diarrhea to pseudomembranous colitis.[9] Therefore the presence of toxin A is not required to cause the disease, and toxin B, by itself, can induce significant damage to human intestines.[10]

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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