A SalmoneUla gene encoding a cytolysin has been identified by screening for hemolysis on blood agar. DNA sequence analyses together with genetic mapping in Salmonella suggest that it is unrelated to other toxins or hemolysins. The gene (slyA) is present in every strain of Salmonella examined, in Shigela, and in enteroinvasive Escherichia coli but not in other Enterobacteriaceae. SlyA (salmolysin) purified from a derivative of the original clone has hemolytic and cytolytic activity and has a molecular weight predicted by the DNA sequence. The median lethal dose and infection kinetics in mice suggest that the toxin is required for virulence and facilitates SalmoneUa survival within mouse peritoneal macrophages.
Clostridium difficile is a leading cause of nosocomial infection in North AmericaWith favorable characteristics such as high production yield, potent toxin neutralization, and intrinsic stability, these V H Hs are attractive systemic therapeutics but are more so as oral therapeutics in the destabilizing environment of the gastrointestinal tract.
Purpose: Waldenstrom's macroglobulinemia (WM) is a B-cell disorder. Despite advances in the therapy, WM remains incurable. As such, novel therapeutic agents are needed for the treatment of WM. Experimental Design: In this multicenter study, 27 patients with WM received up to eight cycles of bortezomib at 1.3 mg/m 2 on days 1, 4, 8, and 11. All but one patient had relapsed/or refractory disease. Results: Following therapy, median serum IgM levels declined from 4,660 to 2,092 mg/dL (P <0.0001).The overall response rate was 85%, with10 and13 patients achieving minor and major responses, respectively. Responses were prompt and occurred at median of1.4 months.The median time to progression for all responding patients was 7.9 (range, 3-21.4+) months.The most common grade III/IV toxicities occurring in z5% of patients were sensory neuropathies (22.2%), leukopenia (18.5%), neutropenia (14.8%), dizziness (11.1%), and thrombocytopenia (7.4%). Sensory neuropathies resolved or improved in nearly all patients following cessation of therapy.
Conclusions:The results of these studies show that bortezomib is an active agent in relapsed and refractory WM.
Recombinant beta-toxin from Clostridium perfringens type C was found to increase the conductance of bilayer lipid membranes (BLMs) by inducing channel activity. The channels exhibited a distribution of conductances within the range of 10 to 380 pS, with the majority of the channels falling into two categories of conductance at 110 and 60 pS. The radii of beta-toxin pores found for the conductance states of 110 and 60 pS were 12.7 and 11.1 Å, respectively. The single channels and the steady-state currents induced by beta-toxin across the BLMs exhibited ideal monovalent cation selectivity. Addition of divalent cations (Zn 2؉ , Cd
2؉, or Mg 2؉ ) at a concentration of 2 mM increased the rate of beta-toxin insertion into BLMs and the single-channel conductance, while application of 5 mM Zn 2؉ to a beta-toxin-induced steady-state current decreased the inward current by approximately 45%. The mutation of arginine 212 of beta-toxin to aspartate, previously shown to increase the 50% lethal dose of beta-toxin for mice nearly 13-fold, significantly reduced the ability of beta-toxin to form channels. These data support the hypothesis that the lethal action of beta-toxin is based on the formation of cation-selective pores in susceptible cells.
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