1. Resources
  2. Citations Library

Headers act as filters

  • Records
      1. Author :
        Ghali, Shadi; Bhatt, Kirit A; Dempsey, Marlese P; Jones, Deidre M; Singh, Sunil; Aarabi, Shahram; Arabi, Shahram; Butler, Peter E; Gallo, Robert L; Gurtner, Geoffrey C
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Plastic and reconstructive surgery
      6. Products :
      7. Volume :
        123
      8. Issue :
        4
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Bioware; Cathelicidins; Chronic Disease; Drug Carriers; Genetic Engineering; Male; Rats; Rats, Inbred F344; Surgical Flaps; Wound Infection; Xen29
      12. Abstract :
        BACKGROUND The success of antimicrobial therapy has been impaired by the emergence of resistant bacterial strains. Antimicrobial peptides are ubiquitous proteins that are part of the innate immune system and are successful against such antibiotic-resistant microorganisms. The authors have previously demonstrated the feasibility of protein delivery via microvascular free flap gene therapy and here they examine this approach for recalcitrant infections. METHODS The authors investigated the production of the human cathelicidin antimicrobial peptide-LL37, delivered by ex vivo transduction of the rodent superficial inferior epigastric free flap with Ad/CMV-LL37. The vascular permeabilizing agent vascular endothelial growth factor (VEGF) was co-administered during ex vivo transduction with adenoviral vectors in an attempt to augment transduction efficiency. A rodent model of chronic wound/foreign body infection seeded with bioluminescent Staphylococcus aureus was used to assess the biological efficacy of delivering therapeutic antimicrobial genes using this technology. RESULTS The authors were successful in demonstrating significant LL37 expression, which persisted for 14 days after ex vivo transduction with Ad/CMV-LL37. Transduction efficiency was significantly improved with the co-administration of 5 micrograms of VEGF during transduction without significantly increasing systemic dissemination of adenovirus or systemic toxicity. They were able to demonstrate in the rodent model of chronic wound/foreign body infections a significant reduction in bacterial loads from infected catheters following transduction with Ad/CMV-LL37 and increased bacterial clearance. CONCLUSION This study demonstrates for the first time that microbicidal gene therapy via microvascular free flaps is able to clear chronic infections such as occurs with osteomyelitis resulting from trauma or an infected foreign body [corrected]
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19337084
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9040
      1. Author :
        Gillrie, Mark R; Zbytnuik, Lori; McAvoy, Erin; Kapadia, Roxna; Lee, Kristine; Waterhouse, Christopher C M; Davis, Shevaun P; Muruve, Daniel A; Kubes, Paul; Ho, May
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        European journal of immunology
      6. Products :
      7. Volume :
        40
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Chemotaxis, Leukocyte; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Humans; Interferon-gamma; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Staphylococcal Infections; Staphylococcus aureus; Teichoic Acids; Toll-Like Receptor 2; Transplantation Chimera; Xen29
      12. Abstract :
        The response of leukocytes to lipoteichoic acid (LTA), a TLR2-dependent major cell wall component of Staphylococcus aureus, is linked to the outcome of an infection. In this study we investigated the role of nonhematopoietic TLR2 in response to LTA and S. aureus by creating bone marrow chimeras. Significant leukocyte recruitment in response to LTA required IFN-gamma priming in WT C57BL/6 and TLR2(-/-)-->WT mice, but was not observed in TLR2(-/-) or WT-->TLR2(-/-) animals. LTA also induced a proinflammatory response in IFN-gamma primed primary human microvascular endothelial cells leading to leukocyte recruitment in vitro. When mice were infected with S. aureus, the most profound elevation of TNF-alpha and IL-6 was seen in TLR2(-/-) and TLR2(-/-)-->WT mice. TLR2(-/-), but not chimeric mice, demonstrated increased IL-17, blood leukocytosis and pulmonary neutrophilia compared to WT mice. Collectively, the results suggest an essential role for IFN-gamma and nonhematopoietic TLR2 for leukocyte recruitment in response to LTA. In contrast, TLR2 on both hematopoietic and nonhematopoietic cells appears to orchestrate an inhibitory response to S. aureus such that in complete TLR2 deficiency, there is an exaggerated proinflammatory response and/or skewing of the immune response towards a Th17 phenotype that may contribute to the decreased survival of TLR2(-/-) mice.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20306471
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9036
      1. Author :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Infection and immunity
      6. Products :
      7. Volume :
        77
      8. Issue :
        7
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animal Structures; Animals; Antibodies, Bacterial; Antigens, Bacterial; Bacterial Proteins; Bioware; Cell Wall; Colony Count, Microbial; Female; Humans; Mice; Mice, Inbred BALB C; Neutrophils; Opsonin Proteins; Proteome; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staphylococcal Infections; Staphylococcal Vaccines; Staphylococcus aureus; Vaccines, Subunit; Vaccines, Synthetic; Whole Body Imaging; Xen29
      12. Abstract :
        Staphylococcus aureus is an important human pathogen with increasing clinical impact due to the extensive spread of antibiotic-resistant strains. Therefore, development of a protective polyvalent vaccine is of great clinical interest. We employed an intravenous immunoglobulin (IVIG) preparation as a source of antibodies directed against anchorless S. aureus surface proteins for identification of novel vaccine candidates. In order to identify such proteins, subtractive proteome analysis (SUPRA) of S. aureus anchorless cell wall proteins was performed. Proteins reacting with IVIG but not with IVIG depleted of S. aureus-specific opsonizing antibodies were considered vaccine candidates. Nearly 40 proteins were identified by this preselection method using matrix-assisted laser desorption ionization--time of flight analysis. Three of these candidate proteins, enolase (Eno), oxoacyl reductase (Oxo), and hypothetical protein hp2160, were expressed as glutathione S-transferase fusion proteins, purified, and used for enrichment of corresponding immunoglobulin Gs from IVIG by affinity chromatography. Use of affinity-purified anti-Eno, anti-Oxo, and anti-hp2160 antibodies resulted in opsonization, phagocytosis, and killing of S. aureus by human neutrophils. High specific antibody titers were detected in mice immunized with recombinant antigens. In mice challenged with bioluminescent S. aureus, reduced staphylococcal spread was measured by in vivo imaging. The recovery of S. aureus CFU from organs of immunized mice was diminished 10- to 100-fold. Finally, mice immunized with hp2160 displayed statistically significant higher survival rates after lethal challenge with clinically relevant S. aureus strains. Taken together, our data suggest that anchorless cell wall proteins might be promising vaccine candidates and that SUPRA is a valuable tool for their identification.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19364833
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9039
      1. Author :
        Hart, Emily; Azzopardi, Kristy; Taing, Heng; Graichen, Florian; Jeffery, Justine; Mayadunne, Roshan; Wickramaratna, Malsha; O'Shea, Mike; Nijagal, Brunda; Watkinson, Rebecca; O'Leary, Stephen; Finnin, Barrie; Tait, Russell; Robins-Browne, Roy
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        The Journal of antimicrobial chemotherapy
      6. Products :
      7. Volume :
        65
      8. Issue :
        5
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Anti-Bacterial Agents; Bioware; Colony Count, Microbial; Disease Models, Animal; Female; Foreign Bodies; Humans; Mice; Mice, Inbred BALB C; Ofloxacin; Polymers; Prosthesis-Related Infections; Staphylococcal Infections; Staphylococcus aureus; Xen29
      12. Abstract :
        OBJECTIVES To assess support discs, comprising polyethylene terephthalate (PET), coated with different polymer/levofloxacin combinations for antimicrobial activity in an animal model of infection, in order to explore the use of specific polymer coatings incorporating levofloxacin as a means of reducing device-related infections. METHODS Aliphatic polyester-polyurethanes containing different ratios of poly(lactic acid) diol and poly(caprolactone) diol were prepared, blended with levofloxacin and then used to coat support discs. The in vitro levofloxacin release profiles from these discs were measured in aqueous solution. Mice were surgically implanted with the coated discs placed subcutaneously and infection was initiated by injection of 10(6) cfu of Staphylococcus aureus into the subcutaneous pocket containing the implant. After 5, 10, 20 and 30 days, the discs were removed, and the number of bacteria adhering to the implant and the residual antimicrobial activity of the discs were determined. RESULTS In vitro, the release of levofloxacin from the coated discs occurred at a constant rate and then reached a plateau at different timepoints, depending on the polymer preparation used. In vivo, none of the discs coated with polymer blends containing levofloxacin was colonized by S. aureus, whereas 94% of the discs coated with polymer alone were infected. All discs coated with levofloxacin-blended polymers displayed residual antimicrobial activity for at least 20 days post-implantation. CONCLUSIONS Bioerodable polyester-polyurethane polymer coatings containing levofloxacin can prevent bacterial colonization of implants in an intra-operative model of device-related infections.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20233779
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9035
      1. Author :
        Heit, Bryan; Robbins, Stephen M; Downey, Charlene M; Guan, Zhiwen; Colarusso, Pina; Miller, B Joan; Jirik, Frank R; Kubes, Paul
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Nature immunology
      6. Products :
      7. Volume :
        9
      8. Issue :
        7
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Arthritis, Experimental; Bioware; Chemotaxis, Leukocyte; Humans; Inflammation; Mice; Mice, Transgenic; Neutrophils; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Protein Transport; PTEN Phosphohydrolase; Xen29
      12. Abstract :
        Neutrophils encounter and 'prioritize' many chemoattractants in their pursuit of bacteria. Here we tested the possibility that the phosphatase PTEN is responsible for the prioritization of chemoattractants. Neutrophils induced chemotaxis by two separate pathways, the phosphatidylinositol-3-OH kinase (PI(3)K) phosphatase and tensin homolog (PTEN) pathway, and the p38 mitogen-activated protein kinase pathway, with the p38 pathway dominating over the PI(3)K pathway. Pten(-/-) neutrophils could not prioritize chemoattractants and were 'distracted' by chemokines when moving toward bacterial chemoattractants. In opposing gradients, PTEN became distributed throughout the cell circumference, which inhibited all PI(3)K activity, thus permitting 'preferential' migration toward bacterial products via phospholipase A(2) and p38. Such prioritization was defective in Pten(-/-) neutrophils, which resulted in defective bacterial clearance in vivo. Our data identify a PTEN-dependent mechanism in neutrophils to prioritize, 'triage' and integrate responses to multiple chemotactic cues.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18536720
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9048
      1. Author :
        Kadurugamuwa, Jagath L; Sin, Lin V; Yu, Jun; Francis, Kevin P; Purchio, Tony F; Contag, Pamela R
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2004
      5. Publication :
        Antimicrobial agents and chemotherapy
      6. Products :
      7. Volume :
        48
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antibiotics, Antitubercular; Biofilms; Bioware; Colony Count, Microbial; Diagnostic Imaging; DNA-Directed RNA Polymerases; Luminescent Measurements; Mice; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Xen29
      12. Abstract :
        Eradication of Staphylococcus aureus biofilms after rifampin treatment was tested in a mouse model of device-related infection by using biophotonic imaging. Following treatment, the bioluminescent signals decreased to undetectable levels, irrespective of the age of the biofilm. After the final treatment, the signals rebounded in a time-dependent manner and reached those for the untreated mice. Readministration of rifampin was unsuccessful in eradicating reestablished infections, with the rifampin MICs for such bacteria being increased and with the bacteria having point mutations in the rpoB gene.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/15155235
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9056
      1. Author :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Annals of the New York Academy of Sciences
      6. Products :
      7. Volume :
        1192
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Biofilms; Bioware; Bone Density Conservation Agents; Chronic Disease; Cytokines; Drug Evaluation, Preclinical; Humans; Immunity; Incidence; Jaw Diseases; Mice; Neovascularization, Physiologic; Osteoclasts; Osteomyelitis; Osteonecrosis; Staphylococcal Infections; Xen29
      12. Abstract :
        The effects of antiresorptive agents (e.g., alendronate [Aln], osteoprotegerin [OPG]) on bone infection are unknown. Thus, their effects on implant-associated osteomyelitis (OM) were investigated in mice using PBS (placebo), gentamycin, and etanercept (TNFR:Fc) controls. None of the drugs affected humoral immunity, angiogenesis, or chronic infection. However, the significant (P < 0.05 vs. PBS) inhibition of cortical osteolysis and decreased draining lymph node size in Aln- and OPG-treated mice was associated with a significant (P < 0.05) increase in the incidence of high-grade infections during the establishment of OM. In contrast, the high-grade infections in TNFR:Fc-treated mice were associated with immunosuppression, as evidenced by the absence of granulomas and presence of Gram(+) biofilm in the bone marrow. Collectively, these findings indicate that although antiresorptive agents do not exacerbate chronic OM, they can increase the bacterial load during early infection by decreasing lymphatic drainage and preventing the removal of necrotic bone that harbors the bacteria.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20392222
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9034
      1. Author :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Journal of orthopaedic research: official publication of the Orthopaedic Research Society
      6. Products :
      7. Volume :
        26
      8. Issue :
        1
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antibody Formation; Bacterial Proteins; Bioware; Disease Models, Animal; DNA, Bacterial; Endonucleases; Female; Mice; Mice, Inbred C57BL; Micrococcal Nuclease; Osteolysis; Osteomyelitis; Prosthesis-Related Infections; Reverse Transcriptase Polymerase Chain Reaction; Staphylococcal Infections; Staphylococcus aureus; Tibia; Xen29
      12. Abstract :
        Although osteomyelitis (OM) remains a serious problem in orthopedics, progress has been limited by the absence of an in vivo model that can quantify the bacterial load, metabolic activity of the bacteria over time, immunity, and osteolysis. To overcome these obstacles, we developed a murine model of implant-associated OM in which a stainless steel pin is coated with Staphylococcus aureus and implanted transcortically through the tibial metaphysis. X-ray and micro-CT demonstrated concomitant osteolysis and reactive bone formation, which was evident by day 7. Histology confirmed all the hallmarks of implant-associated OM, namely: osteolysis, sequestrum formation, and involucrum of Gram-positive bacteria inside a biofilm within necrotic bone. Serology revealed that mice mount a protective humoral response that commences with an IgM response after 1 week, and converts to a specific IgG2b response against specific S. aureus proteins by day 11 postinfection. Real-time quantitative PCR (RTQ-PCR) for the S. aureus specific nuc gene determined that the peak bacterial load occurs 11 days postinfection. This coincidence of decreasing bacterial load with the generation of specific antibodies is suggestive of protective humoral immunity. Longitudinal in vivo bioluminescent imaging (BLI) of luxA-E transformed S. aureus (Xen29) combined with nuc RTQ-PCR demonstrated the exponential growth phase of the bacteria immediately following infection that peaks on day 4, and is followed by the biofilm growth phase at a significantly lower metabolic rate (p < 0.05). Collectively, these studies demonstrate the first quantitative model of implant-associated OM that defines the kinetics of microbial growth, osteolysis, and humoral immunity following infection.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17676625
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9047
      1. Author :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Microbes and infection / Institut Pasteur
      6. Products :
      7. Volume :
        10
      8. Issue :
        3
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bacterial Proteins; Biofilms; Bioware; Catheterization, Central Venous; Male; Mice; Point Mutation; Sigma Factor; Staphylococcal Infections; Staphylococcus aureus; Virulence; Xen29
      12. Abstract :
        The impact of the alternative sigma factor sigma B (SigB) on pathogenesis of Staphylococcus aureus is not conclusively clarified. In this study, a central venous catheter (CVC) related model of multiorgan infection was used to investigate the role of SigB for the pathogenesis of S. aureus infections and biofilm formation in vivo. Analysis of two SigB-positive wild-type strains and their isogenic mutants revealed uniformly that the wild-type was significantly more virulent than the SigB-deficient mutant. The observed difference in virulence was apparently not linked to the capability of the strains to form biofilms in vivo since wild-type and mutant strains were able to produce biofilm layers inside of the catheter. The data strongly indicate that the alternative sigma factor SigB plays a role in CVC-associated infections caused by S. aureus.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18328762
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9046