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      1. Author :
        Kadioglu, A.; Brewin, H.; Hartel, T.; Brittan, J. L.; Klein, M.; Hammerschmidt, S.; Jenkinson, H. F.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Mol Oral Microbiol
      6. Products :
      7. Volume :
        25
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen10, Xen 10, Streptococcus pneumoniae Xen10, IVIS, Animals; Bacterial Adhesion; Bacterial Processes; Bacterial Proteins/*physiology; *Carrier State; Colony Count, Microbial; Female; Host-Pathogen Interactions; Lung/microbiology; Meningitis, Pneumococcal/microbiology; Mice; Models, Animal; Mutation; Nasopharynx/*microbiology; Pneumonia, Pneumococcal/complications; Sepsis/*microbiology; Streptococcus pneumoniae/*pathogenicity; Virulence Factors/physiology
      12. Abstract :
        Summary The pneumococcal cell surface protein PavA is a virulence factor associated with adherence and invasion in vitro. In this study we show in vivo that PavA is necessary for Streptococcus pneumoniae D39 colonization of the murine upper respiratory tract in a long-term carriage model, with PavA-deficient pneumococci being quickly cleared from nasopharyngeal tissue. In a pneumonia model, pavA mutants were not cleared from the lungs of infected mice and persisted to cause chronic infection, whereas wild-type pneumococci caused systemic infection. Hence, under the experimental conditions, PavA-deficient pneumococci appeared to be unable to seed from lung tissue into blood, although they survived in blood when administered intravenously. In a meningitis model of infection, levels of PavA-deficient pneumococci in blood and brain following intercisternal injection were significantly lower than wild type. Taken collectively these results suggest that PavA is involved in successful colonization of mucosal surfaces and in translocation of pneumococci across host barriers. Pneumococcal sepsis is a major cause of mortality worldwide so identification of factors such as PavA that are necessary for carriage and for translocation from tissue to blood is of clinical and therapeutic importance.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20331793
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10400
      1. Author :
        Xie, Chao; Liang, Bojian; Xue, Ming; Lin, Angela S.P.; Loiselle, Alayna; Schwarz, Edward M.; Guldberg, Robert E.; O'Keefe, Regis J.; Zhang, Xinping
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Am J Pathol
      6. Products :
      7. Volume :
        175
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen10, Xen 10, Streptococcus pneumoniae Xen10, IVIS
      12. Abstract :
        Although the essential role of cyclooxygenase (COX)-2 in fracture healing is known, the targeted genes and molecular pathways remain unclear. Using prostaglandin E2 receptor (EP)2 and EP4 agonists, we examined the effects of EP receptor activation in compensation for the lack of COX-2 during fracture healing. In a fracture-healing model, COX-2-/- mice showed delayed initiation and impaired endochondral bone repair, accompanied by a severe angiogenesis deficiency. The EP4 agonist markedly improved the impaired healing in COX-2-/- mice, as evidenced by restoration of bony callus formation on day 14, a near complete reversal of bone formation, and an approximately 70% improvement of angiogenesis in the COX-2-/- callus. In comparison, the EP2 agonist only marginally enhanced bone formation in COX-2-/- mice. To determine the differential roles of EP2 and EP4 receptors on COX-2-mediated fracture repair, the effects of selective EP agonists on chondrogenesis were examined in E11.5 long-term limb bud micromass cultures. Only the EP4 agonist significantly increased cartilage nodule formation similar to that observed during prostaglandin E2 treatment. The prostaglandin E2/EP4 agonist also stimulated MMP-9 expression in bone marrow stromal cell cultures. The EP4 agonist further restored the reduction of MMP-9 expression in the COX-2-/- fracture callus. Taken together, our studies demonstrate that EP2 and EP4 have differential functions during endochondral bone repair. Activation of EP4, but not EP2 rescued impaired bone fracture healing in COX-2-/- mice.
      13. URL :
        http://ajp.amjpathol.org/cgi/content/abstract/175/2/772
      14. Call Number :
        PKI @ kd.modi @ 2
      15. Serial :
        10401
      1. Author :
        Bernthal, N. M.; Pribaz, J. R.; Stavrakis, A. I.; Billi, F.; Cho, J. S.; Ramos, R. I.; Francis, K. P.; Iwakura, Y.; Miller, L. S.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        J Orthop Res
      6. Products :
      7. Volume :
        29
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen36, Xen 36, Staphylococcus aureus Xen36, IVIS, Animals; Arthroplasty; Biofilms/growth & development; Bone Wires/microbiology; Interleukin-1beta/*metabolism; Male; Mice; Mice, Congenic; Mice, Inbred C57BL; Myeloid Differentiation Factor 88/metabolism; Neutrophil Infiltration; Prosthesis-Related Infections/*immunology/metabolism; Staphylococcal Infections/*immunology/metabolism; Staphylococcus aureus; Toll-Like Receptor 2/*metabolism
      12. Abstract :
        MyD88 is an adapter molecule that is used by both IL-1R and TLR family members to initiate downstream signaling and promote immune responses. Given that IL-1beta is induced after Staphylococcus aureus infections and TLR2 is activated by S. aureus lipopeptides, we hypothesized that IL-1beta and TLR2 contribute to MyD88-dependent protective immune responses against post-arthroplasty S. aureus infections. To test this hypothesis, we used a mouse model of a post-arthroplasty S. aureus infection to compare the bacterial burden, biofilm formation and neutrophil recruitment in IL-1beta-deficient, TLR2-deficient and wild-type (wt) mice. By using in vivo bioluminescence imaging, we found that the bacterial burden in IL-1beta-deficient mice was 26-fold higher at 1 day after infection and remained 3- to 10-fold greater than wt mice through day 42. In contrast, the bacterial burden in TLR2-deficient mice did not differ from wt mice. In addition, implants harvested from IL-1beta-deficient mice had more biofilm formation and 14-fold higher adherent bacteria compared with those from wt mice. Finally, IL-1beta-deficient mice had approximately 50% decreased neutrophil recruitment to the infected postoperative joints than wt mice. Taken together, these findings suggest a mechanism by which IL-1beta induces neutrophil recruitment to help control the bacterial burden and the ensuing biofilm formation in a post-surgical joint.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21445990
      14. Call Number :
        PKI @ kd.modi @ 5
      15. Serial :
        10411
      1. Author :
        Brand, A. M.; de Kwaadsteniet, M.; Dicks, L. M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Lett Appl Microbiol
      6. Products :
      7. Volume :
        51
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen36, Xen 36, Staphylococcus aureus Xen36, IVIS, Animals; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Nisin/*pharmacology; Peritoneal Cavity/*microbiology; Staphylococcal Infections/*prevention & control; Staphylococcus aureus/*drug effects/growth & development
      12. Abstract :
        AIMS: To determine the ability of nisin F to control systematic infection caused by Staphylococcus aureus, using C57BL/6 mice as a model. METHODS AND RESULTS: Twelve mice were intraperitoneally injected with 1 x 10(8) viable cells of Staph. aureus Xen 36 containing the modified Photorhabdus luminescence luxABCDE operon on plasmid pAUL-A Tn4001. After 4 h, six mice were intraperitoneally injected with 640 arbitrary units (AU) nisin F, and six were injected with sterile saline. Six mice, not infected with Staph. aureus, were treated with nisin F, and six not infected were left untreated. The viability of Staph. aureus Xen 36 was monitored over 48 h by recording photon emission levels. Nisin F suppressed Staph. aureus for 15 min in vivo. No abnormalities were recorded in blood analyses and internal organs of mice treated with nisin F. CONCLUSIONS: Nisin F suppressed the growth of Staph. aureus in the peritoneal cavity for at least 15 min. Re-emergence of Staph. aureus bioluminescence over the next 44 h suggests that nisin F was inactivated, most probably by proteolytic enzymes. SIGNIFICANCE AND IMPACT OF THE STUDY: A single dosage of nisin F administered in the peritoneal cavity controlled the growth of Staph. aureus for at least 15 min in vivo.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21029139
      14. Call Number :
        PKI @ kd.modi @ 2
      15. Serial :
        10410
      1. Author :
        Hosman, A. H.; Bulstra, S. K.; Sjollema, J.; van der Mei, H. C.; Busscher, H. J.; Neut, D.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        J Orthop Res
      6. Products :
      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen36, Xen 36, Staphylococcus aureus Xen36, IVIS
      12. Abstract :
        Wear of metal-on-metal (cobalt-chromium, Co-Cr particles) and metal-on-polyethylene (ultra-high-molecular-weight polyethylene, UHMWPE particles) bearing surfaces in hip prostheses is a major problem in orthopedics. This study aimed to compare the influence of Co-Cr and UHMWPE particles on the persistence of infection. Bioluminescent Staphylococcus aureus Xen36 were injected in air pouches prepared in subcutaneous tissue of immuno-competent BALB/c mice (control), as a model for the joint space, in the absence or presence of Co-Cr or UHMWPE particles. Bioluminescence was monitored longitudinally up to 21 days, corrected for absorption and reflection by the particles and expressed relative to the bioluminescence found in the presence of staphylococci only. After termination, air pouch fluid and air pouch membrane were cultured and histologically analyzed. Bioluminescence was initially lower in mice exposed to UHMWPE particles with staphylococci than in mice injected with staphylococci only, possibly because UHMWPE particles initially stimulated a higher macrophage presence in murine air pouch membranes. For mice exposed to Co-Cr particles with staphylococci, bioluminescence was observed to be higher in two out of six animals compared to the presence of staphylococci alone. In the majority of mice, infection risk in the absence or presence of Co-Cr and UHMWPE particles appeared similar, assuming that the longevity of an elevated bioluminescence is indicative of a higher infection risk. However, the presence of Co-Cr particles yielded a higher bioluminescence in two out of six mice, possibly because the macrophage degradative function was hampered by the presence of Co-Cr particles. (c) 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21866572
      14. Call Number :
        PKI @ kd.modi @ 6
      15. Serial :
        10409
      1. Author :
        Ketonis, C.; Barr, S.; Adams, C. S.; Shapiro, I. M.; Parvizi, J.; Hickok, N. J.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Antimicrob Agents Chemother
      6. Products :
      7. Volume :
        55
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen36, Xen 36, Staphylococcus aureus Xen36, IVIS, Anti-Bacterial Agents/chemistry/*pharmacology; Bacterial Adhesion/drug effects; Biofilms/drug effects/growth & development; *Bone Transplantation; Bone and Bones/*chemistry/*microbiology; Cell Adhesion/drug effects; Cell Line; Colony Count, Microbial; Humans; Microscopy, Confocal; Osteoblasts/cytology; Staphylococcus aureus/drug effects/*growth & development/physiology; Vancomycin/chemistry/*pharmacology
      12. Abstract :
        Infection is an important medical problem associated with the use of bone allografts. To retard bacterial colonization, we have recently reported on the modification of bone allografts with the antibiotic vancomycin (VAN). In this report, we examine the ability of this antibiotic-modified allograft to resist bacterial colonization and biofilm formation. When antibiotic was coupled to the allograft, a uniform distribution of the antibiotic was apparent. Following challenges with Staphylococcus aureus for 6 h, the covalently bonded VAN decreased colonization as a function of inoculum, ranging from 0.8 to 2.0 log(10) CFU. Furthermore, the VAN-modified surface resisted biofilm formation, even in topographical niches that provide a protected environment for bacterial adhesion. Attachment of the antibiotic to the allograft surface was robust, and the bonded VAN was stable whether incubated in aqueous media or in air, maintaining levels of 75 to 100% of initial levels over 60 days. While the VAN-modified allograft inhibited the Gram-positive S. aureus colonization, in keeping with VAN's spectrum of activity, the VAN-modified allograft was readily colonized by the Gram-negative Escherichia coli. Finally, initial toxicity measures indicated that the VAN-modified allograft did not influence osteoblast colonization or viability. Since the covalently tethered antibiotic is stable, is active, retains its specificity, and does not exhibit toxicity, it is concluded that this modified allograft holds great promise for decreasing bone graft-associated infections.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21098245
      14. Call Number :
        PKI @ kd.modi @ 8
      15. Serial :
        10408
      1. Author :
        Ketonis, C.; Barr, S.; Shapiro, I. M.; Parvizi, J.; Adams, C. S.; Hickok, N. J.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Bone
      6. Products :
      7. Volume :
        48
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen36, Xen 36, Staphylococcus aureus Xen36, IVIS, Adsorption/drug effects; Anti-Bacterial Agents/chemistry/*pharmacology; Biological Markers/metabolism; *Bone Transplantation; Cell Differentiation/drug effects; Cell Shape/drug effects; Cells, Cultured; Colony Count, Microbial; Drug Stability; Fetus/cytology; Fluorescence; Gene Expression Profiling; Humans; Microbial Sensitivity Tests; Osteoblasts/cytology/drug effects/metabolism; Phenotype; Time Factors; Transplantation, Homologous; Vancomycin/chemistry/*pharmacology
      12. Abstract :
        Bacterial contamination of bone allograft is a significant complication of orthopedic surgery. To address this issue, we have engineered a method for covalently modifying bone allograft tissue with the antibiotic vancomycin. The goal of this investigation was to compare the biocidal properties of this new allograft material with those of vancomycin physisorbed onto graft material. The duration of antibiotic release from the vancomycin-modified allograft matrix was determined, and no elution was observed. In contrast, the adsorbed antibiotic showed a peak elution at 24h that then decreased over several days. We next used an Staphylococcus aureus disk diffusion assay to measure the activity of the eluted vancomycin. Again we found that no active antibiotic was eluted from the covalently modified allograft. Similarly, when the vancomycin-modified allograft morsel was used in the assay, no measurable elution was observed; amounts of antibiotic released from the adsorbed samples inhibited S. aureus growth for 4-7 days. Probably the most telling property of the allograft was that after 2 weeks, the tethered allograft was able to resist bacterial colonization. Unlike the elution system in which vancomycin was depleted over the course of days-weeks, the antibiotic on the allograft was stably bound even after 300 days, while its biocidal activity remained undiminished for 60 days. This finding was in stark contrast to the antibiotic impregnated allograft, which was readily colonized by bacteria. Finally we chose to evaluate three indicators of cell function: expression of a key transcription factor, expression of selected transcripts, and assessment of cell morphology. Since the tethered antibiotic appeared to have little or no effect on any of these activities, it was concluded that the stable, tethered antibiotic prevented bacterial infection while not modifying bone cell function.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21035576
      14. Call Number :
        PKI @ kd.modi @ 7
      15. Serial :
        10407
      1. Author :
        Penn-Barwell, J. G.; Murray, C. K.; Wenke, J. C.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Bone Joint Surg Br
      6. Products :
      7. Volume :
        94
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen36, Xen 36, Staphylococcus aureus Xen36, IVIS
      12. Abstract :
        Most animal studies indicate that early irrigation and debridement reduce infection after an open fracture. Unfortunately, these studies often do not involve antibiotics. Clinical studies indicate that the timing of initial debridement does not affect the rate of infection but these studies are observational and fraught with confounding variables. The purpose of this study was to control these variables using an animal model incorporating systemic antibiotics and surgical treatment. We used a rat femur model with a defect which was contaminated with Staphylococcus aureus and treated with a three-day course of systemic cefazolin (5 mg/kg 12-hourly) and debridement and irrigation, both of which were initiated independently at two, six and 24 hour time points. After 14 days the bone and hardware were harvested for separate microbiological analysis. No animal that received antibiotics and surgery two hours after injury had detectable bacteria. When antibiotics were started at two hours, a delay in surgical treatment from two to six hours significantly increased the development of infection (p = 0.047). However, delaying surgery to 24 hours increase the rate of infection, but not significantly (p = 0.054). The timing of antibiotics had a more significant effect on the proportion of positive samples than earlier surgery. Delaying antibiotics to six or 24 hours had a profoundly detrimental effect on the infection rate regardless of the timing of surgery. These findings are consistent with the concept that bacteria progress from a vulnerable planktonic form to a treatment-resistant biofilm.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22219257
      14. Call Number :
        PKI @ kd.modi @ 10
      15. Serial :
        10404