CCR2 contributes to host defense against Staphylococcus aureus orthopedic implant-associated infections in mice.

C-C motif chemokine receptor 2 (CCR2) is an important mediator of myeloid cell chemotaxis during inflammation and infection. Myeloid cells such as monocytes, macrophages, and neutrophils contribute to host defense during orthopedic implant-associated infections (OIAI), but whether CCR2-mediated chemotaxis is involved remains unclear. Therefore, a Staphylococcus aureus OIAI model was performed by surgically placing an orthopedic-grade titanium implant and inoculating a bioluminescent S. aureus strain in knee joints of wildtype (wt) and CCR2-deficient mice. In vivo bioluminescent signals significantly increased in CCR2-deficient mice compared with wt mice at later time points (Days 14-28), which was confirmed with ex vivo colony-forming unit enumeration. S. aureus γ-hemolysin utilizes CCR2 to induce host cell lysis. However, there were no differences in bacterial burden when the OIAI model was performed with a parental versus a mutant γ-hemolysin-deficient S. aureus strain, indicating that the protection was mediated by the host cell function of CCR2 rather than γ-hemolysin virulence. Although CCR2-deficient and wt mice had similar cellular infiltrates in the infected joint tissue, CCR2-deficient mice had reduced myeloid cells and γδ T cells in the draining lymph nodes. Taken together, CCR2 contributed to host defense at later time points during an OIAI by increasing immune cell infiltrates in the draining lymph nodes, which likely contained the infection and prevented invasive spread.

Interleukin-1ß and tumor necrosis factor are essential in controlling an experimental orthopedic implant-associated infection.

Orthopedic implant-associated infection (OIAI) is a major complication that leads to implant failure. In preclinical models of Staphylococcus aureus OIAI, osteomyelitis and septic arthritis, interleukin-1α (IL-1α), IL-1ß, and tumor necrosis factor (TNF) are induced, but whether they have interactive or distinctive roles in host defense are unclear. Herein, a S. aureus OIAI model was performed in mice deficient in IL-1α, IL-1ß, or TNF. Mice deficient in IL-1ß or TNF (to a lesser extent) but not IL-1α had increased bacterial burden at the site of the OIAI throughout the 28-day experiment. IL-1ß and TNF had a combined and critical role in host defense as mice deficient in both IL-1R and TNF (IL-1R/TNF-deficient mice) had a 40% mortality rate, which was associated with markedly increased bacterial burden at the site of the OIAI infection. Finally, IL-1α- and IL-1ß-deficient mice had impaired neutrophil recruitment whereas IL-1ß-, TNF-, and IL-1R/TNF-deficient mice all had impaired recruitment of both neutrophils and monocytes. Therefore, IL-1ß and TNF contributed to host defense against S. aureus OIAI and neutrophil recruitment was primarily mediated by IL-1ß and monocyte recruitment was mediated by both IL-1ß and TNF.

Cognitive and Affective Responses to Mass-media Based Genetic Risk Information in a Socio-demographically Diverse Sample of Smokers.

Many individuals receive information about genomics from the mass media. When media reports are about conditions that are considered behavioral, such as smoking, they may negatively affect some health-promoting cognitions. We examined how informing adult smokers about the genetic basis for nicotine addiction influenced smoking-related health cognitions and affect and whether responses varied by socio-demographics or genetics beliefs. We recruited 392 smokers (Mage = 44.5, 52.8% African American, 51.3% no college experience, 66.2% women) from public locations in a mid-sized Midwestern city. They were randomly assigned to read a news article describing either a pharmacy's decision to stop selling tobacco (n = 78) or the discovery of a gene associated with increased risk of nicotine addiction and lung cancer (n = 314). Participants also completed a survey assessing socio-demographics, health cognitions (quit intentions, self-efficacy, response efficacy, perceived risk), affect (worry, anticipated regret), genetic determinism, and other genetics beliefs. ANOVAs revealed no statistically significant main effects of genetic information on any health cognitions or affects. Linear regressions revealed that socio-demographics and genetics beliefs moderated very few effects. This suggests that concerns that mass media-based dissemination of genetic discoveries may have detrimental effects on smoking-related cognitions and affects are likely unwarranted.

Efficacy of a Multimechanistic Monoclonal Antibody Combination against Staphylococcus aureus Surgical Site Infections in Mice.

Surgical site infections (SSIs) are commonly caused by Staphylococcus aureus We report that a combination of three monoclonal antibodies (MEDI6389) that neutralize S. aureus alpha-toxin, clumping factor A, and four leukocidins (LukSF, LukED, HlgAB, and HlgCB) plus vancomycin had enhanced efficacy compared with control antibody plus vancomycin in two mouse models of S. aureus SSI. Therefore, monoclonal antibody-based neutralization of multiple S. aureus virulence factors may provide an adjunctive perioperative approach to combat S. aureus SSIs.

Targeted alpha therapy with 212Pb or 225Ac: Change in RBE from daughter migration.

Targeted α-therapy (TAT) could be delivered early to patients who are at a high-risk for developing brain metastases, targeting the areas of the vasculature where tumor cells are penetrating into the brain. We have utilized a Monte Carlo model representing brain vasculature to calculate physical dose and DNA damage from the α-emitters 225Ac and 212Pb. The micron-scale dose distributions from all radioactive decay products were modeled in Geant4, including the eV-scale interactions using the Geant4-DNA models. These interactions were then superimposed on an atomic-scale DNA model to estimate strand break yields. In addition to 225Ac having a higher dose per decay than 212Pb, it also has a double strand break yield per decay that is 4.7 ±â€¯0.5 times that of 212Pb. However, the efficacy of both nuclides depends on retaining the daughter nuclei at the target location in the brain vasculature. The relative biological effectiveness (RBE) of 225Ac and 212Pb are similar when the entire decay chains are included, with maxima of 2.7 ±â€¯0.6 and 2.5 ±â€¯0.5 (respectively), and RBE values of about 2 to a depth of 80 µm. If the initial daughter is lost, the RBE of 212Pb is completely reduced to 1 or lower and the RBE of 225Ac is approximately 2 only for the first 40 µm.

Dosimetric evaluation of radionuclides for VCAM-1-targeted radionuclide therapy of early brain metastases.

Brain metastases develop frequently in patients with breast cancer, and present a pressing therapeutic challenge. Expression of vascular cell adhesion molecule 1 (VCAM-1) is upregulated on brain endothelial cells during the early stages of metastasis and provides a target for the detection and treatment of early brain metastases. The aim of this study was to use a model of early brain metastasis to evaluate the efficacy of α-emitting radionuclides, 149Tb, 211At, 212Pb, 213Bi and 225Ac; ß-emitting radionuclides, 90Y, 161Tb and 177Lu; and Auger electron (AE)-emitters 67Ga, 89Zr, 111In and 124I, for targeted radionuclide therapy (TRT). METHODS: Histologic sections and two photon microscopy of mouse brain parenchyma were used to inform a cylindrical vessel geometry using the Geant4 general purpose Monte Carlo (MC) toolkit with the Geant4-DNA low energy physics models. Energy deposition was evaluated as a radial function and the resulting phase spaces were superimposed on a DNA model to estimate double-strand break (DSB) yields for representative ß- and α-emitters, 177Lu and 212Pb. Relative biological effectiveness (RBE) values were determined by only evaluating DNA damage due to physical interactions. RESULTS: 177Lu produced 2.69 ± 0.08 DSB per GbpGy, without significant variation from the lumen of the vessel to a radius of 100 µm. The DSB yield of 212Pb included two local maxima produced by the 6.1 MeV and 8.8 MeV α-emissions from decay products, 212Bi and 212Po, with yields of 7.64 ± 0.12 and 9.15 ± 0.24 per GbpGy, respectively. Given its higher DSB yield 212Pb may be more effective for short range targeting of early micrometastatic lesions than 177Lu. CONCLUSION: MC simulation of a model of early brain metastases provides invaluable insight into the potential efficacy of α-, ß- and AE-emitting radionuclides for TRT. 212Pb, which has the attributes of a theranostic radionuclide since it can be used for SPECT imaging, showed a favorable dose profile and RBE.

Radioluminescence from Tc-99m in glass predicts local dose.

The widely-used gamma-emitter Tc-99m has been shown to lead to optical emissions in mice and glass. We investigated the possibility that these emissions are due to the Cerenkov effect and whether the light emitted is proportional to local dose. By using a Geant4 Monte Carlo model matched to an experimental measurement, we show that the light detected by a small animal optical imaging system provides a 2D map of the dose throughout a glass sample. We conclude that radioluminescence from Tc-99m can be used to quantitatively measure dose in transparent materials, which could have applications in dosimetry and quality assurance.

Monte Carlo simulations support non-Cerenkov radioluminescence production in tissue.

There is experimental evidence for the production of non-Cerenkov radioluminescence in a variety of materials, including tissue. We constructed a Geant4 Monte Carlo simulation of the radiation from P32 and Tc99m interacting in chicken breast and used experimental imaging data to model a scintillation-like emission. The same radioluminescence spectrum is visible from both isotopes and cannot otherwise be explained through fluorescence or filter miscalibration. We conclude that chicken breast has a near-infrared scintillation-like response with a light yield three orders of magnitude smaller than BGO.