Clostridium perfringens gas gangrene is characterized by rapid tissue destruction, impaired host response, and, often, death. Phospholipase C (alpha -toxin) is the virulence factor most responsible for these pathologies. The present study investigated the efficacy of active immunization with the C-terminal domain of alpha -toxin (Cpa247-370) in a murine model of gas gangrene. Primary end points of the study were survival, progression of infection, and tissue perfusion. Secondary end points, which were based on findings of histologic evaluation of tissues, included the extent of tissue destruction and microvascular thrombosis, as well as the magnitude of the tissue inflammatory response. Survival among C-domain-immunized animals was significantly greater than that among sham-immunized control animals. Furthermore, immunization with the C-domain localized the infection and prevented ischemia of the feet. Histopathologic findings demonstrated limited muscle necrosis, reduced microvascular thrombosis, and enhanced granulocytic influx in C-domain-immunized mice. We conclude that immunization with the C-domain of phospholipase C is a viable strategy for the prevention of morbidity and mortality associated with C. perfringens gas gangrene.
The phospholipases C of C. perfringens (alpha-toxin) and C. bifermentans (Cbp) show >50% amino acid homology but differ in their hemolytic and toxic properties. We report here the purification and characterisation of alpha-toxin and Cbp. The phospholipase C activity of alpha-toxin and Cbp was similar when tested with phosphatidylcholine in egg yolk or in liposomes. However, the hemolytic activity of alpha-toxin was more than 100-fold that of Cbp. To investigate whether differences in the carboxy-terminal domains of these proteins were responsible for differences in the hemolytic and toxic properties, a hybrid protein (NbiCα) was constructed comprising the N domain of Cbp and the C domain of alpha-toxin. The hemolytic activity of NbiCαwas 10-fold that of Cbp, and the hybrid enzyme was toxic. These results confirm that the C-terminal domain of these proteins confers different properties on the enzymatically active N-terminal domain of these proteins.
Differences in the biological properties of the Clostridium perfringens phospholipase C (K K-toxin) and the C. bifermentans phospholipase C (Cbp) have been attributed to differences in their carboxy-terminal domains. Three residues in the carboxy-terminal domain of K K-toxin, which have been proposed to play a role in membrane recognition (D 269
We surveyed first-year students at the ANU College of Law on various measures of wellbeing, thinking styles and motivations for attending law school. We followed up our surveys with a student–faculty dialogue retreat. The results of our work confirm that, even in a law school where formal mentoring programs are in place and where resources for student counselling are readily available, law students suffer symptoms of psychological distress at levels higher than their age peers in the general public. During the first year of law school, many students experience psychological struggles, changes in their thinking styles, and changes in self-concept and sense of wellbeing. By the end of the first year many students in our sample showed increased rational thinking and lower experiential thinking. Lower levels of experiential thinking were associated with increased symptoms of psychological distress, while students with a higher propensity toward experiential thinking showed little change in depressive symptoms from the beginning to the end of the year of law study. In extended deliberations on law student wellbeing, faculty and student retreat participants highlighted their sense that law school changed them in important ways, making them more rational, analytical, competitive and adversarial. Law school also promoted feelings of insecurity, inefficacy and isolation. To address these changes, participants made a variety of proposals for curricular reform, which are discussed here. Specific changes in law school curricula – including proposals for greater transparency, clarity and guidance about course work, for more positive and formative feedback, and for more social and intellectual engagement – are identified as having potential to improve law student wellbeing.
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