Comparison of the malaria parasite and mammalian protein prenyltransferases and their cellular substrates is important for establishing this enzyme as a target for developing antimalarial agents. Nineteen heptapeptides differing only in their carboxyl-terminal amino acid were tested as alternative substrates of partially purified Plasmodium falciparum protein farnesyltransferase. Only NRSCAIM and NRSCAIQ serve as substrates, with NRSCAIM being the best. Peptidomimetics, FTI-276 and GGTI-287, inhibit the transferase with IC 50 values of 1 and 32 nM, respectively. Incubation of P. falciparum-infected erythrocytes with [ 3 H]farnesol labels 50-and 22-28-kDa proteins, whereas [ 3 H]geranylgeraniol labels only 22-28-kDa proteins. The 50-kDa protein is shown to be farnesylated, whereas the 22-28-kDa proteins are geranylgeranylated, irrespective of the labeling prenol. Protein labeling is inhibited more than 50% by either 5 M FTI-277 or GGTI-298. The same concentration of inhibitors also inhibits parasite growth from the ring stage by 50%, decreases expression of prenylated proteins as measured with prenyl-specific antibody, and inhibits parasite differentiation beyond the trophozoite stage. Furthermore, differentiation specific prenylation of P. falciparum proteins is demonstrated. Protein labeling is detected predominantly during the trophozoite to schizont and schizont to ring transitions. These results demonstrate unique properties of protein prenylation in P. falciparum: a limited specificity of the farnesyltransferase for peptide substrates compared with mammalian enzymes, the ability to use farnesol to label both farnesyl and geranylgeranyl moieties on proteins, differentiation specific protein prenylation, and the ability of peptidomimetic prenyltransferase inhibitors to block parasite differentiation.Malaria continues to be a major disease in tropical areas of the world. Parasite resistance to current drugs used in the treatment of malaria has lead investigators to seek out new drug targets. Among those targets are proteins and enzymes, which are necessary for cellular division and differentiation. Such targets include the protein prenyltransferases, which are necessary for the post-translational modification of proteins involved in the signal transduction pathways and in regulation of DNA replication and cell cycling (1-3). These enzymes are currently a major focus of efforts to design drugs that inhibit unregulated cell growth in cancer (4, 5). Several candidate compounds show great promise as antitumor drugs and are currently being tested in clinical trials. The potential for the application of such drugs to inhibit malarial parasite division and differentiation motivates one to examine the properties of the protozoan enzyme with the goal of identifying unique features of this enzyme that would make it a target for the development of parasite-specific drugs.A variety of proteins including small G-proteins, such as Ras, Rac, Rap, Rho, Rab (6), heterotrimeric G protein ␥ subunits (7), nuclear lamins (8), prot...

OBJECTIVES: We undertook a process improvement initiative to expedite rapid identification of potential sepsis patients based on triage chief complaint, vital signs, and initial lactate level. DESIGN: Prospective cohort study. SETTING: Seven hundred-bed tertiary care hospital with ≅65,000 patient visits/yr. PATIENTS: Patients presenting to emergency department (ED) triage who met the following criteria: greater than or equal to two of the three systemic inflammatory response syndrome criteria assessable in triage, a chief complaint suggestive of infection, emergency severity index 2 or 3, and ambulatory to ED. INTERVENTIONS: A computer-generated lactate order was created, staff education and resources increased, and point-of-care lactate testing was introduced. MEASUREMENTS AND MAIN RESULTS: Primary endpoints include the following: percent of patients having a lactate level drawn, percent of lactate samples resulting before room placement, and time intervals from triage to lactate blood draw and to lactate result. Secondary endpoints were percentage of patients admitted to the hospital, percentage admitted to the ICU, and in-hospital mortality. Six thousand nine hundred six patients were included: 226 historic controls (HCs) and 6,680 intervention group patients. The mean serum lactate level was 1.77 ± 1.18 mmol/L. The percentage of patients having a lactate resulted increased from 27.4% in the HC period to 79.6%. The percentage of these lactate results available while the patient was still in the waiting room increased from 0.4% during the HC period to 33.7% during Phase 5 ( p < 0.0001). In the intervention period, time from triage to lactate result decreased (78.1–63.4 min; p < 0.0001) and time to treatment room decreased (59.3–39.6 min; p < 0.0001). CONCLUSIONS: Implementation of a computerized lactate order using readily available data obtained during ED triage, combined with point-of-care lactate testing, improves time to lactate blood draw and lactate result in patients at risk for severe sepsis. Initial lactate levels correlated with admission to the hospital, admission to the ICU, and in-hospital mortality.

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