Controlled Release of Vancomycin and Tigecycline from an Orthopaedic Implant Coating Prevents Staphylococcus aureus Infection in an Open Fracture Animal Model.

Introduction:Treatment of open fractures routinely involves multiple surgeries and delayed definitive fracture fixation because of concern for infection. If implants were made less susceptible to infection, a one-stage procedure with intramedullary nailing would be more feasible, which would reduce morbidity and improve outcomes. Methods:In this study, a novel open fracture mouse model was developed using Staphylococcus aureus (S. aureus) and single-stage intramedullary fixation. The model was used to evaluate whether implants coated with a novel "smart" polymer coating containing vancomycin or tigecycline would be colonized by bacteria in an open fracture model infected with S. aureus. In vivo bioluminescence, ex vivo CFUs, and X-ray images were evaluated over a 42-day postoperative period. Results:We found evidence of a markedly decreased bacterial burden with the local release of vancomycin and tigecycline from the PEG-PPS polymer compared to polymer alone. Vancomycin was released in a controlled fashion and maintained local drug concentrations above the minimum inhibition concentration for S. aureus for greater than 7 days postoperatively. Bacteria were reduced 139-fold from implants containing vancomycin and undetected from the bone and soft tissue. Tigecycline coatings led to a 5991-fold reduction in bacteria isolated from bone and soft tissue and 15-fold reduction on the implants compared to polymer alone. Antibiotic coatings also prevented osteomyelitis and implant loosening as observed on X-ray. Conclusion:Vancomycin and tigecycline can be encapsulated in a polymer coating and released over time to maintain therapeutic levels during the perioperative period. Our results suggest that antibiotic coatings can be used to prevent implant infection and osteomyelitis in the setting of open fracture. This novel open fracture mouse model can be used as a powerful in vivo preclinical tool to evaluate and optimize the treatment of open fractures before further studies in humans

Free convective combustion on vertical surfaces-variable property analysis and experiments

This paper treats the problem of free convective combustion of near vertical fuel surfaces in quiescent oxidant atmosphere, both theoretically and experimentally. The theory improves on existing theories in terms of taking into account variable thermodynamic and transport properties. The locally similar solutions obtained numerically are compared with earlier predictions as well as experiments on mass burn rate, flame stand off and other features. While comparison in the case of some fuels seems bettered by the use of variable properties, the not-too good a comparision in other cases is traced to experimental inaccuracies more particularly related to the non-achievement of steady combustion. To remedy this, an experimental apparatus was carefully designed and the results of these experiments show good comparison with theoretical predictions in all cases considered

Enhancement of magnetoresistance in manganite multilayers

Magnanite multilayers have been fabricated using La0.67Ca0.33MnO3 as the ferromagnetic layer and Pr0.7Ca0.3MnO3 and Nd0.5Ca0.5MnO3 as the spacer layers. All the multilayers were grown on LaAlO3 (100) by pulse laser deposition. An enhanced magnetoresistnace (defined (RH- R0)/R0) of more than 98% is observed in these multilayers. Also a low field magnetoresistance of 41% at 5000 Oe is observed in these multilayer films. The enhanced MR is attributed to the induced double exchange in the spacer layer, which is giving rise to more number of conducting carriers. This is compared by replacing the spacer layer with LaMnO3 where Mn exists only in 3+ state and no enhancement is observed in the La0.67Ca0.33MnO3 / LaMnO3 multilayers as double exchange mechanism can not be induced by external magnetic fields.Comment: 13 pages, 5 Figure

Percutaneous pulmonary valve implantation in humans - Results in 59 consecutive patients

Background - Right ventricular outflow tract (RVOT) reconstruction with valved conduits in infancy and childhood leads to reintervention for pulmonary regurgitation and stenosis in later life.Methods and Results - Patients with pulmonary regurgitation with or without stenosis after repair of congenital heart disease had percutaneous pulmonary valve implantation (PPVI). Mortality, hemodynamic improvement, freedom from explantation, and subjective and objective changes in exercise tolerance were end points. PPVI was performed successfully in 58 patients, 32 male, with a median age of 16 years and median weight of 56 kg. The majority had a variant of tetralogy of Fallot (n = 36), or transposition of the great arteries, ventricular septal defect with pulmonary stenosis (n = 8). The right ventricular (RV) pressure (64.4 +/- 17.2 to 50.4 +/- 14 mm Hg, P < 0.001), RVOT gradient (33 +/- 24.6 to 19.5 +/- 15.3, P < 0.001), and pulmonary regurgitation ( PR) (grade 2 of greater before, none greater than grade 2 after, P < 0.001) decreased significantly after PPVI. MRI showed significant reduction in PR fraction (21 +/- 13% versus 3 +/- 4%, P < 0.001) and in RV end-diastolic volume (EDV) (94 +/- 28 versus 82 +/- 24 mL (.) beat(-1) (.) m(-2), P < 0.001) and a significant increase in left ventricular EDV ( 64 +/- 12 versus 71 +/- 13 mL (.) beat(-1.) m(-2), P = 0.005) and effective RV stroke volume ( 37 +/- 7 versus 42 +/- 9 mL (.) beat(-1) (.) m(-2), P = 0.006) in 28 patients (age 19 +/- 8 years). A further 16 subjects, on metabolic exercise testing, showed significant improvement in V(O2)max (26 +/- 7 versus 29 +/- 6 mL (.) kg(-1) (.) min(-1), P < 0.001). There was no mortality.Conclusions - PPVI is feasible at low risk, with quantifiable improvement in MRI-defined ventricular parameters and pulmonary regurgitation, and results in subjective and objective improvement in exercise capacity

Differential metabolism of alprazolam by liver and brain cytochrome (P4503A) to pharmacologically active metabolite

Cytochrome P450 (P450) is a superfamily of enzymes which mediates metabolism of xenobiotics including drugs. Alprazolam, an anti-anxiety agent, is metabolized in rat and human liver by P4503A1 and P4503A4 respectively, to 4-hydroxy alprazolam (4-OHALP, pharmacologically less active) and α-hydroxy alprazolam (α-OHALP, pharmacologically more active). We examined P450 mediated metabolism of alprazolam by rat and human brain microsomes and observed that the relative amount of α-OHALP formed in brain was higher than liver. This biotransformation was mediated by a P450 isoform belonging to P4503A subfamily, which is constitutively expressed in neuronal cells in rat and human brain. The formation of larger amounts of α-OHALP in neurons points to local modulation of pharmacological activity in brain, at the site of action of the anti-anxiety drug. Since hydroxy metabolites of alprazolam are hydrophilic and not easily cleared through blood-CSF barrier, α-OHALP would potentially have a longer half-life in brain

Clustering Approach to Quantify Long-Term Spatio-Temporal Interactions in Epileptic Intracranial Electroencephalography

Abnormal dynamical coupling between brain structures is believed to be primarily responsible for the generation of epileptic seizures and their propagation. In this study, we attempt to identify the spatio-temporal interactions of an epileptic brain using a previously proposed nonlinear dependency measure. Using a clustering model, we determine the average spatial mappings in an epileptic brain at different stages of a complex partial seizure. Results involving 8 seizures from 2 epileptic patients suggest that there may be a fixed pattern associated with regional spatio-temporal dynamics during the interictal to pre-post-ictal transition

Negative diffraction pattern dynamics in nonlinear cavities with left-handed materials

We study a ring cavity filled with a slab of a right-handed material and a slab of a left-handed material. Both layers are assumed to be nonlinear Kerr media. First, we derive a model for the propagation of light in a left-handed material. By constructing a mean-field model, we show that the sign of diffraction can be made either positive or negative in this resonator, depending on the thicknesses of the layers. Subsequently, we demonstrate that the dynamical behavior of the modulation instability is strongly affected by the sign of the diffraction coefficient. Finally, we study the dissipative structures in this resonator and reveal the predominance of a two-dimensional up-switching process over the formation of spatially periodic structures, leading to the truncation of the homogeneous hysteresis cycle.Comment: 8 pages, 5 figure

A topological Josephson junction platform for creating, manipulating, and braiding Majorana bound states

As part of the intense effort towards identifying platforms in which Majorana bound states can be realized and manipulated to perform qubit operations, we propose a topological Josephson junction architecture that achieves these capabilities and which can be experimentally implemented. The platform uses conventional superconducting electrodes deposited on a topological insulator film to form networks of proximity-coupled lateral Josephson junctions. Magnetic fields threading the network of junction barriers create Josephson vortices that host Majorana bound states localized in the junction where the local phase difference is an odd multiple of $\pi$, i.e. attached to the cores of the Josephson vortices. This enables us to manipulate the Majorana states by moving the Josephson vortices, achieving functionality exclusive to these systems in contrast to others, such as those composed of topological superconductor nanowires. We describe protocols for: 1) braiding localized Majorana states by exchange, 2) controlling the separation and hence the coupling of adjacent localized Majorana states to effect non-Abelian rotations via hybridization of the Majorana modes, and 3) reading out changes in the non-local parity correlations induced by such operations. These schemes make use of the application of current pulses and local magnetic field pulses to control the location of vortices, and measurements of the Josephson current-phase relation to reveal the presence of the Majorana bound states. We describe the architecture and schemes in the context of experiments currently underway.Comment: 23 pages, 12 Figures. Significant edits and new subsection added, Accepted version in Annals of Physic

Differential requirement for P2X7R function in IL-17 dependent vs. IL-17 independent cellular immune responses

IL17-dependent autoimmunity to collagen type V (Col V) has been associated with lung transplant obliterative bronchiolitis. Unlike the T helper 1 (Th1)-dependent immune responses to Tetanus Toxoid (TT), the Th17 response to Col V in lung transplant patients and its Th1/17 variant observed in coronary artery disease patients requires IL-1β, tumor necrosis factor α and CD14(+) cells. Given the involvement of the P2X7 receptor (P2X7R) in monocyte IL-1β responses, we investigated its role in Th17-, Th1/17- and Th1-mediated proinflammatory responses. Transfer of antigen-pulsed peripheral blood mononucleated cells (PBMCs) from Col V-reactive patients into SCID mouse footpads along with P2X7R antagonists revealed a selective inhibition of Col V-, but not TT-specific swelling responses. P2X7R inhibitors blocked IL-1β induction from monocytes, including both Col V-α1 peptide-induced (T-dependent), as well as native Col V-induced (T-independent) responses. Significantly higher P2X7R expression was found on CXCR3(neg) CCR4(+)/6(+) CD4(+) [Th17] versus CXCR3(+)CCR4/6(neg) CD4(+) [Th1] subsets in PBMCs, suggesting that the paradigm of selective dependence on P2X7R might extend beyond Col V autoimmunity. Indeed, P2X7R inhibitors suppressed not only anti-Col V, but also Th1/17-mediated alloimmunity, in a heart transplant patient without affecting anti-viral Epstein-Barr virus responses. These results suggest that agents targeting the P2X7R might effectively treat Th17-related transplant pathologies, while maintaining Th1-immunity to infection