Citations

ABSTRACT Signal peptide peptidase (SPP) is an intramembrane cleaving protease (I‐CLiP) identified by its cleavage of several type II membrane signal peptides. To date, only human SPP has been directly shown to have proteolytic activity. Here we demonstrate that the most closely related human homologue of SPP, signal peptide peptidase like 3 (SPPL3), cleaves a SPP substrate, but a more distantly related homologue, signal peptide peptidase like 2b (SPPL2b), does not. These data provide strong evidence that the SPP and SPPL3 have conserved active sites and suggest that the active sites SPPL2b is distinct. We have also synthesized a cDNA designed to express the single SPP gene present in Plasmodium falciparum and cloned this into a mammalian expression vector. When the malaria SPP protein is expressed in mammalian cells it cleaves a SPP substrate. Notably, several human SPP inhibitors block the proteolytic activity of malarial SPP (mSPP). Studies from several model organisms that express multiple SPP homologs demonstrate that the silencing of a single SPP homologue is lethal. Based on these data, we hypothesize that mSPP is a potential a novel therapeutic target for malaria.—Nyborg, A. C., Ladd, T. B., Jansen, K., Kukar, T., Golde, T. E. Intramembrane proteolytic cleavage by human signal peptide peptidase like 3 and malaria signal peptide peptidase. FASEB J. 20, 1671–1679 (2006)

ABSTRACT Tefibazumab (Aurexis), a humanized monoclonal antibody that binds to the surface-expressed adhesion protein clumping factor A, is under development as adjunctive therapy for serious Staphylococcus aureus infections. Sixty patients with documented S. aureus bacteremia (SAB) were randomized and received either tefibazumab at 20 mg/kg of body weight as a single infusion or a placebo in addition to an antibiotic(s). The primary objective of the study was determining safety and pharmacokinetics. An additional objective was to assess activity by a composite clinical end point (CCE). Baseline characteristics were evenly matched between groups. Seventy percent of infections were healthcare associated, and 57% had an SAB-related complication at baseline. There were no differences between the treatment groups in overall adverse clinical events or alterations in laboratory values. Two patients developed serious adverse events that were at least possibly related to tefibazumab; one hypersensitivity reaction was considered definitely related. The tefibazumab plasma half-life was 18 days. Mean plasma levels were <100 μg/ml by day 14. A CCE occurred in six patients (four placebo and two tefibazumab patients) and included five deaths (four placebo and one tefibazumab patient). Progression in the severity of sepsis occurred in four placebo and no tefibazumab patients. Tefibazumab was well tolerated, with a safety profile similar to those of other monoclonal antibodies. Additional trials are warranted to address the dosing range and efficacy of tefibazumab.

Abstract The use of high energy devices has been suggested for intra‐articular surgery. Experimental studies have been performed using the laser and electrocautery. However, clinical application has primarily been with the use of the electrocautery. Electrosurgery is currently being used for lateral retinacular release as well as meniscal surgery. Inadvertent damage to articular cartilage may occur, especially during meniscal resection. The objective of the current study is to assess the effect of the Concept electrocautery with the meniscal cutting electrode on fresh human articular cartilage. Twenty fresh tibial plateaus removed at the time of total knee arthroplasty were subjected to electrocautery currents ranging from 25 to 82.5 W. The articular cartilage was stained with hematoxylin and eosin. The extent of cartilage necrosis was quantitated as a percentage of the thickness of the articular cartilage. A dose response curve was developed. The extent of articular cartilage necrosis with the electrocautery setting of 20 (24.4 W) commonly used for meniscal resection resulted in only an 11.4%‐injury to the articular cartilage. At the manufacturer's recommended setting of 24 (27 W), a 16% depth of laceration of the articular cartilage may be anticipated. We conclude that the lowest current setting possible should be utilized for meniscal surgery and the risk of articular cartilage damage from inadvertent injury is not excessive.