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      1. Author :
        Nejadnik, M Reza; Engelsman, Anton F; Saldarriaga Fernandez, Isabel C; Busscher, Henk J; Norde, Willem; van der Mei, Henny C
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        The Journal of antimicrobial chemotherapy
      6. Products :
      7. Volume :
        62
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Anti-Bacterial Agents; Bioware; Colony Count, Microbial; Mice; Mice, Inbred BALB C; Polymers; Prostheses and Implants; Rifampin; Silicone Elastomers; Staphylococcus aureus; Vancomycin; Xen29
      12. Abstract :
        OBJECTIVES Curing biomaterial-associated infection (BAI) frequently includes antibiotic treatment, implant removal and re-implantation. However, revision implants are at a greater risk of infection as they may attract bacteria from their infected surroundings. Polymer brush-coatings attract low numbers of bacteria, but the virtue of polymer brush-coatings in vivo has seldom been investigated. Here, we determine the possible benefits of polymer brush-coated versus pristine silicone rubber in revision surgery, using a murine model. METHODS BAI was induced in 26 mice by subcutaneous implantation of silicone rubber discs with a biofilm of Staphylococcus aureus Xen29. During the development of BAI, half of the mice received rifampicin/vancomycin treatment. After 5 days, the infected discs were removed from all mice, and either a polymer brush-coated or pristine silicone rubber disc was re-implanted. Revision discs were explanted after 5 days, and the number of cfu cultured from the discs and the surrounding tissue was determined. RESULTS None of the polymer brush-coated discs after antibiotic treatment appeared colonized by staphylococci, whereas 83% of the pristine silicone rubber discs were re-infected. Polymer brush-coated discs also showed reduced colonization rates in the absence of antibiotic treatment when compared with pristine silicone rubber discs. Tissue surrounding the discs was culture-positive in all cases. CONCLUSIONS Polymer brush-coatings are less prone to re-infection than pristine silicone rubber when used in revision surgery, i.e. when implanted in a subcutaneous pocket infected by a staphylococcal BAI. Antibiotic pre-treatment during the development of BAI hardly had any effect in preventing the colonization of pristine silicone rubber.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18812426
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9045
      1. Author :
        Ohlsen, Knut; Lorenz, Udo
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Future microbiology
      6. Products :
      7. Volume :
        2
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Anti-Bacterial Agents; Bioware; Community-Acquired Infections; Humans; Methicillin Resistance; Staphylococcal Infections; Staphylococcus aureus; Xen29
      12. Abstract :
        Multiple resistant staphylococci that cause significant morbidity and mortality are the leading cause of nosocomial infections. Meanwhile, methicillin-resistant Staphylococcus aureus (MRSA) also spreads in the community, where highly virulent strains infect children and young adults who have no predisposing risk factors. Although some treatment options remain, the search for new antibacterial targets and lead compounds is urgently required to ensure that staphylococcal infections can be effectively treated in the future. Promising targets for new antibacterials are gene products that are involved in essential cell functions. In addition to antibacterials, active and passive immunization strategies are being developed that target surface components of staphylococci such as cell wall-linked adhesins, teichoic acids and capsule or immunodominant antigens.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18041906
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9049
      1. Author :
        Bucki, Robert; Leszczynska, Katarzyna; Byfield, Fitzroy J; Fein, David E; Won, Esther; Cruz, Katrina; Namiot, Andrzej; Kulakowska, Alina; Namiot, Zbigniew; Savage, Paul B; Diamond, Scott L; Janmey, Paul A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Antimicrobial agents and chemotherapy
      6. Products :
      7. Volume :
        54
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Bacterial Infections; Biofilms; Cathelicidins; Cattle; Cells, Cultured; Dexamethasone; Drug Design; Humans; Interleukins; Macrophages; Microbial Sensitivity Tests; Neutrophils; Phagocytosis; Pseudomonas aeruginosa; Receptors, Glucocorticoid; Spermine; Staphylococcus aureus; Xen5
      12. Abstract :
        The rising number of antibiotic-resistant bacterial strains represents an emerging health problem that has motivated efforts to develop new antibacterial agents. Endogenous cationic antibacterial peptides (CAPs) that are produced in tissues exposed to the external environment are one model for the design of novel antibacterial compounds. Here, we report evidence that disubstituted dexamethasone-spermine (D2S), a cationic corticosteroid derivative initially identified as a by-product of synthesis of dexamethasone-spermine (DS) for the purpose of improving cellular gene delivery, functions as an antibacterial peptide-mimicking molecule. This moiety exhibits bacterial killing activity against clinical isolates of Staphylococcus aureus, Pseudomonas aeruginosa present in cystic fibrosis (CF) sputa, and Pseudomonas aeruginosa biofilm. Although compromised in the presence of plasma, D2S antibacterial activity resists the proteolytic activity of pepsin and is maintained in ascites, cerebrospinal fluid, saliva, and bronchoalveolar lavage (BAL) fluid. D2S also enhances S. aureus susceptibility to antibiotics, such as amoxicillin (AMC), tetracycline (T), and amikacin (AN). Inhibition of interleukin-6 (IL-6) and IL-8 release from lipopolysaccharide (LPS)- or lipoteichoic acid (LTA)-treated neutrophils in the presence of D2S suggests that this molecule might also prevent systemic inflammation caused by bacterial wall products. D2S-mediated translocation of green fluorescent protein (GFP)-labeled glucocorticoid receptor (GR) in bovine aorta endothelial cells (BAECs) suggests that some of its anti-inflammatory activities involve engagement of glucocorticoid receptors. The combined antibacterial and anti-inflammatory activities of D2S suggest its potential as an alternative to natural CAPs in the prevention and treatment of some bacterial infections.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20308375
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9996
      1. Author :
        Klohs J, Baeva N, Steinbrink J, Bourayou R, Boettcher C, Royl G, Megow D, Dirnagl U, Priller J and Wunder A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Journal of Cerebral Blood Flow and Metabolism
      6. Products :
      7. Volume :
        29
      8. Issue :
        7
      9. Page Numbers :
        N/A
      10. Research Area :
        Neuroscience
      11. Keywords :
        MMPSense; in vivo imaging; matrix metalloproteinases; stroke
      12. Abstract :
        Matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of cerebral ischemia. In this study, we explored whether MMP activity can be visualized by noninvasive near-infrared fluorescence (NIRF) imaging using an MMP-activatable probe in a mouse model of stroke. C57Bl6 mice were subjected to transient middle cerebral artery occlusion (MCAO) or sham operation. Noninvasive NIRF imaging was performed 24 h after probe injection, and target-to-background ratios (TBRs) between the two hemispheres were determined. TBRs were significantly higher in MCAO mice injected with the MMP-activatable probe than in sham-operated mice and in MCAO mice that were injected with the nonactivatable probe as controls. Treatment with an MMP inhibitor resulted in significantly lower TBRs and lesion volumes compared to injection of vehicle. To test the contribution of MMP-9 to the fluorescence signal, MMP9-deficient (MMP9(-/-)) mice and wild-type controls were subjected to MCAO of different durations to attain comparable lesion volumes. TBRs were significantly lower in MMP9(-/-) mice, suggesting a substantial contribution of MMP-9 activity to the signal. Our study shows that MMP activity after cerebral ischemia can be imaged noninvasively with NIRF using an MMP-activatable probe, which might be a useful tool to study MMP activity in the pathophysiology of the disease.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19417756
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4547
      1. Author :
        Thomas Reiner, Rainer H. Kohler, Chong Wee Liew, Jonathan Hill, Jason Gaglia, Rohit Kulkarni and Ralph Weissleder
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Bioconjugate Chemistry
      6. Products :
      7. Volume :
        21
      8. Issue :
        7
      9. Page Numbers :
        N/A
      10. Research Area :
        Metabolic Disorders
      11. Keywords :
        Beta-cells; GLP1-R; imaging; targeting; in vivo imaging; VivoTag; AngioSense; Diabetes
      12. Abstract :
        The ability to image and ultimately quantitate beta-cell mass in vivo will likely have far reaching implications in the study of diabetes biology, in the monitoring of disease progression or response to treatment, as well as for drug development. Here, using animal models, we report on the synthesis, characterization of, and intravital microscopic imaging properties of a near infrared fluorescent exendin-4 analogue with specificity for the GLP-1 receptor on beta cells (E4K12-Fl). The agent demonstrated sub-nanomolar EC50 binding concentrations, with high specificity and binding could be inhibited by GLP-1R agonists. Following intravenous administration to mice, pancreatic islets were readily distinguishable from exocrine pancreas, achieving target-to-background ratios within the pancreas of 6:1, as measured by intravital microscopy. Serial imaging revealed rapid accumulation kinetics (with initial signal within the islets detectable within 3 minutes and peak fluorescence within 20 minutes of injection) making this an ideal agent for in vivo imaging.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912453/?tool=pubmed
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4561
      1. Author :
        Farouc A. Jaffer, Peter Libby and Ralph Weissleder
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Arteriosclerosis, Thrombosis, and Vascular Biology
      6. Products :
      7. Volume :
        29
      8. Issue :
        7
      9. Page Numbers :
        N/A
      10. Research Area :
        Cardiovascular Research
      11. Keywords :
        In vivo imaging; fluorescence molecular tomography; FMT; ProSense; OsteoSense; atherosclerosis; molecular imaging; optical, fluorescence; multimodality; nanoparticle
      12. Abstract :
        Imaging approaches that visualize molecular targets rather than anatomic structures aim to illuminate vital molecular and cellular aspects of atherosclerosis biology in vivo. Several such molecular imaging strategies stand ready for rapid clinical application. This review describes the growing role of in vivo optical molecular imaging in atherosclerosis and highlights its ability to visualize atheroma inflammation, calcification, and angiogenesis. In addition, we discuss advances in multimodality probes, both in the context of multimodal imaging as well as multifunctional, or “theranostic,” nanoparticles. This review highlights particular molecular imaging strategies that possess strong potential for clinical translation.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2733228/?tool=pubmed
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4642
      1. Author :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Clinical & experimental metastasis
      6. Products :
      7. Volume :
        26
      8. Issue :
        7
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        4T1-luc2; Animals; Bioware; Cell Line, Tumor; Disease Models, Animal; DNA-Binding Proteins; Female; Flow Cytometry; Killer Cells, Natural; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, SCID; Neoplasm Metastasis; Rats
      12. Abstract :
        The occurrence of metastases is a critical determinant of the prognosis for breast cancer patients. Effective treatment of breast cancer metastases is hampered by a poor understanding of the mechanisms involved in the formation of these secondary tumor deposits. To study the processes of metastasis, valid in vivo tumor metastasis models are required. Here, we show that increased expression of the EGF receptor in the MTLn3 rat mammary tumor cell-line is essential for efficient lung metastasis formation in the Rag mouse model. EGFR expression resulted in delayed orthotopic tumor growth but at the same time strongly enhanced intravasation and lung metastasis. Previously, we demonstrated the critical role of NK cells in a lung metastasis model using MTLn3 cells in syngenic F344 rats. However, this model is incompatible with human EGFR. Using the highly metastatic EGFR-overexpressing MTLn3 cell-line, we report that only Rag2(-/-)gammac(-/-) mice, which lack NK cells, allow efficient lung metastasis from primary tumors in the mammary gland. In contrast, in nude and SCID mice, the remaining innate immune cells reduce MTLn3 lung metastasis formation. Furthermore, we confirm this finding with the orthotopic transplantation of the 4T1 mouse mammary tumor cell-line. Thus, we have established an improved in vivo model using a Rag2(-/-) gammac(-/-) mouse strain together with MTLn3 cells that have increased levels of the EGF receptor, which enables us to study EGFR-dependent tumor cell autonomous mechanisms underlying lung metastasis formation. This improved model can be used for drug target validation and development of new therapeutic strategies against breast cancer metastasis formation.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19466569
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8940
      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 :
        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