Abdominal computed tomography scoring systems and experienced radiologists in the radiological diagnosis of small bowel and mesenteric injury.

PURPOSE: Blunt bowel and/or mesenteric injury requiring surgery presents a diagnostic challenge. Although computed tomography (CT) imaging is standard following blunt trauma, findings can be nonspecific. Most studies have focused on the diagnostic value of CT findings in identifying significant bowel and/or mesenteric injury (sBMI). Some studies have described scoring systems to assist with diagnosis. Little attention, has been given to radiologist interpretation of CT scans. This study compared the discriminative ability of scoring systems (BIPS and RAPTOR) with radiologist interpretation in identifying sBMI. METHODS: We conducted a retrospective chart review of trauma patients with suspected sBMI. CT images were reviewed in a blinded fashion to calculate BIPS and RAPTOR scores. Sensitivity and specificity were compared between BIPS, RAPTOR, and the admission CT report with respect to identifying sBMI. RESULTS: One hundred sixty-two patients were identified, 72 (44%) underwent laparotomy and 43 (26.5%) had sBMI. Sensitivity and specificity were: BIPS 49% and 87%, AUC 0.75 (0.67-0.81), P < 0.001; RAPTOR 46% and 82%, AUC 0.72 (0.64-0.79), P < 0.001; radiologist impression 81% and 71%, AUC 0.82(0.75-0.87), P < 0.001. The discriminative ability of the radiologist impression was higher than RAPTOR (P = 0.04) but not BIPS (P = 0.13). There was not a difference between RAPTOR vs. BIPS (P = 0.55). CONCLUSION: Radiologist interpretation of the admission CT scan was discriminative of sBMI. Although surgical vigilance, including evaluation of the CT images and patient, remains fundamental to early diagnosis, the radiologist's impression of the CT scan can be used in clinical practice to simplify the approach to patients with abdominal trauma.

Sub-inhibitory fosmidomycin exposures elicits oxidative stress in Salmonella enterica serovar Typhimurium LT2.

Fosmidomycin is a time-dependent nanomolar inhibitor of methylerythritol phosphate (MEP) synthase, which is the enzyme that catalyzes the first committed step in the MEP pathway to isoprenoids. Importantly, fosmidomycin is one of only a few MEP pathway-specific inhibitors that exhibits antimicrobial activity. Most inhibitors identified to date only exhibit activity against isolated pathway enzymes. The MEP pathway is the sole route to isoprenoids in many bacteria, yet has no human homologs. The development of inhibitors of this pathway holds promise as novel antimicrobial agents. Similarly, analyses of the bacterial response toward MEP pathway inhibitors provides valuable information toward the understanding of how emergent resistance may ultimately develop to this class of antibiotics. We have examined the transcriptional response of Salmonella enterica serovar typhimurium LT2 to sub-inhibitory concentrations of fosmidomycin via cDNA microarray and RT-PCR. Within the regulated genes identified by microarray were a number of genes encoding enzymes associated with the mediation of reactive oxygen species (ROS). Regulation of a panel of genes implicated in the response of cells to oxidative stress (including genes for catalases, superoxide dismutases, and alkylhydrogen peroxide reductases) was investigated and mild upregulation in some members was observed as a function of fosmidomycin exposure over time. The extent of regulation of these genes was similar to that observed for comparable exposures to kanamycin, but differed significantly from tetracycline. Furthermore, S. typhimurium exposed to sub-inhibitory concentrations of fosmidomycin displayed an increased sensitivity to exogenous H2O2 relative to either untreated controls or kanamycin-treated cells. Our results suggest that endogenous oxidative stress is one consequence of exposures to fosmidomycin, likely through the temporal depletion of intracellular isoprenoids themselves, rather than other mechanisms that have been proposed to facilitate ROS accumulation in bacteria (e.g. cell death processes or the ability of the antibiotic to redox cycle).

Targeting DXP synthase in human pathogens: enzyme inhibition and antimicrobial activity of butylacetylphosphonate.

The unique methylerythritol phosphate pathway for isoprenoid biosynthesis is essential in most bacterial pathogens. The first enzyme in this pathway, 1-deoxy-D-xylulose 5-phosphate (DXP) synthase, catalyzes a distinct thiamin diphosphate (ThDP)-dependent reaction to form DXP from D-glyceraldehyde 3-phosphate (D-GAP) and pyruvate and represents a potential anti-infective drug target. We have previously demonstrated that the unnatural bisubstrate analog, butylacetylphosphonate (BAP), exhibits selective inhibition of Escherichia coli DXP synthase over mammalian ThDP-dependent enzymes. Here, we report the selective inhibition by BAP against recombinant DXP synthase homologs from Mycobacterium tuberculosis, Yersinia pestis and Salmonella enterica. We also demonstrate antimicrobial activity of BAP against both Gram-negative and Gram-positive strains (including E. coli, S. enterica and Bacillus anthracis), and several clinically isolated pathogens. Our results suggest a mechanism of action involving inhibition of DXP synthase and show that BAP acts synergistically with established antimicrobial agents, highlighting a potential strategy to combat emerging resistance in bacterial pathogens.