Dirac Quantization of the Pais-Uhlenbeck Fourth Order Oscillator

As a model, the Pais-Uhlenbeck fourth order oscillator with equation of motion $d^4q/dt^4+(\omega_1^2+\omega_2^2)d^2q/dt^2 +\omega_1^2\omega_2^2 q=0$ is a quantum-mechanical prototype of a field theory containing both second and fourth order derivative terms. With its dynamical degrees of freedom obeying constraints due to the presence of higher order time derivatives, the model cannot be quantized canonically. We thus quantize it using the method of Dirac constraints to construct the correct quantum-mechanical Hamiltonian for the system, and find that the Hamiltonian diagonalizes in the positive and negative norm states that are characteristic of higher derivative field theories. However, we also find that the oscillator commutation relations become singular in the $\omega_1 \to \omega_2$ limit, a limit which corresponds to a prototype of a pure fourth order theory. Thus the particle content of the $\omega_1 =\omega_2$ theory cannot be inferred from that of the $\omega_1 \neq \omega_2$ theory; and in fact in the $\omega_1 \to \omega_2$ limit we find that all of the $\omega_1 \neq \omega_2$ negative norm states move off shell, with the spectrum of asymptotic in and out states of the equal frequency theory being found to be completely devoid of states with either negative energy or negative norm. As a byproduct of our work we find a Pais-Uhlenbeck analog of the zero energy theorem of Boulware, Horowitz and Strominger, and show how in the equal frequency Pais-Uhlenbeck theory the theorem can be transformed into a positive energy theorem instead.Comment: RevTeX4, 20 pages. Final version, to appear in Phys. Rev.

Large Eddy Simulation of acoustic pulse propagation and turbulent flow interaction in expansion mufflers

A novel hybrid pressure-based compressible solver is developed and validated for low Mach number acoustic flow simulation. The solver is applied to the propagation of an acoustic pulse in a simple expansion muffler, a configuration frequently employed in HVAC and automotive exhaust systems. A set of benchmark results for experimental analysis of the simple expansion muffler both with and without flow are obtained to compare attenuation in forced pulsation for various mean-flow velocities. The experimental results are then used for validation of the proposed pressure-based compressible solver. Compressible, Unsteady Reynolds Averaged Navier-Stokes (URANS) simulation of a muffler with a mean through flow is conducted and results are presented to demonstrate inherent limitations associated with this approach. Consequently, a mixed synthetic inflow boundary condition is developed and validated for compressible Large Eddy Simulation (LES) of channel flow. The mixed synthetic boundary is then employed for LES of a simple expansion muffler to analyse the flow-acoustic and acoustic-pulse interactions inside the expansion muffler. The improvement in the prediction of vortex shedding inside the chamber is highlighted in comparison to the URANS method. Further, the effect of forced pulsation on flow-acoustic is observed in regard to the shift in Strouhal number inside the simple expansion muffler

Fostering collaborative research for rare genetic disease: The example of Niemann-Pick type C disease

Rare disease represents one of the most significant issues facing the medical community and health care providers worldwide, yet the majority of these disorders never emerge from their obscurity, drawing little attention from the medical community or the pharmaceutical industry. The challenge therefore is how best to mobilize rare disease stakeholders to enhance basic, translational and clinical research to advance understanding of pathogenesis and accelerate therapy development. Here we describe a rare, fatal brain disorder known as Niemann-Pick type C (NPC) and an innovative research collaborative known as Support of Accelerated Research for NPC (SOAR-NPC) which illustrates one pathway through which knowledge of a rare disease and its possible treatments are being successfully advanced. Use of the “SOAR” mechanism, we believe, offers a blueprint for similar advancement for many other rare disorders

Comprehensive Solution to the Cosmological Constant, Zero-Point Energy, and Quantum Gravity Problems

We present a solution to the cosmological constant, the zero-point energy, and the quantum gravity problems within a single comprehensive framework. We show that in quantum theories of gravity in which the zero-point energy density of the gravitational field is well-defined, the cosmological constant and zero-point energy problems solve each other by mutual cancellation between the cosmological constant and the matter and gravitational field zero-point energy densities. Because of this cancellation, regulation of the matter field zero-point energy density is not needed, and thus does not cause any trace anomaly to arise. We exhibit our results in two theories of gravity that are well-defined quantum-mechanically. Both of these theories are locally conformal invariant, quantum Einstein gravity in two dimensions and Weyl-tensor-based quantum conformal gravity in four dimensions (a fourth-order derivative quantum theory of the type that Bender and Mannheim have recently shown to be ghost-free and unitary). Central to our approach is the requirement that any and all departures of the geometry from Minkowski are to be brought about by quantum mechanics alone. Consequently, there have to be no fundamental classical fields, and all mass scales have to be generated by dynamical condensates. In such a situation the trace of the matter field energy-momentum tensor is zero, a constraint that obliges its cosmological constant and zero-point contributions to cancel each other identically, no matter how large they might be. Quantization of the gravitational field is caused by its coupling to quantized matter fields, with the gravitational field not needing any independent quantization of its own. With there being no a priori classical curvature, one does not have to make it compatible with quantization.Comment: Final version, to appear in General Relativity and Gravitation (the final publication is available at http://www.springerlink.com). 58 pages, revtex4, some additions to text and some added reference

Donor origin of circulating endothelial progenitors after allogeneic bone marrow transplantation

AbstractEndothelial cell precursors circulate in blood and express antigens found on hematopoietic stem cells, suggesting that such precursors might be subject to transplantation. To investigate, we obtained adherence-depleted peripheral blood mononuclear cells from 3 individuals who had received a sex-mismatched allogeneic bone marrow transplant (BMT) and cultured the cells on fibronectin-coated plates with endothelial growth factors. The phenotype of the spindle-shaped cells that emerged in culture was characterized by immunofluorescent staining, and the origin of the cells was determined using a polymerase chain reaction (PCR)-based assay for polymorphic short tandem repeats (STRs). The cells manifested a number of endothelial characteristics-such as von Wlllebrand factor, CD31, and Flk-1/KDR expression; Bandeiraea simplicifolia lectin 1 binding; and acetylated low-density lipoprotein uptake-but lacked expression of certain markers of activation or differentiation, including intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and the epitope for the anti-endothelial cell antibody P1H12. For each patient and at all time points studied (ranging from 5 to 52 months after transplantation), STR-PCR analysis showed that cultured cells and nucleated blood cells came exclusively from the bone marrow donor. These results demonstrate that circulating endothelial progenitors are both transplantable and capable of long-term repopulation of human allogeneic BMT recipients.Biol Blood Marrow Transplant 2000;6(3A):301-8

Relation of Patients Living Without a Partner or Spouse to Being Physically Active After Acute Coronary Syndromes (from the PULSE Accelerometry Substudy)

Living alone is associated with adverse outcomes after acute coronary syndromes (ACS). One potential mediator of the relation between partner status and outcomes after ACS is physical activity. To evaluate the association of partner status with physical activity after ACS, data from 107 participants enrolled in the Prescription Use, Lifestyle, and Stress Evaluation (PULSE) study, a prospective observational study of post-ACS patients, were analyzed. Accelerometers were used to measure physical activity after hospital discharge. The primary outcome measure was a maximum 10 hours of daytime activity 1 month after discharge. One month after discharge from ACS hospitalizations, participants without a partner or spouse exhibited 24.4% lower daytime activity than those with a partner or spouse (p = 0.003). After controlling for age, gender, body mass index, Charlson co-morbidity index, and traditional psychosocial and clinical cardiovascular correlates of post-ACS physical activity, partner status remained an independent predictor of post-ACS physical activity (20.5% lower daytime activity among those without a partner or spouse, p = 0.008). In conclusion, in this study of accelerometer-measured physical activity after an ACS hospitalization, those without a partner or spouse exhibit significantly less physical activity than those with a partner or spouse 1 month after discharge from the hospital. Low physical activity may be an important mediator of the prognosis associated with partner status after ACS

Detection of Dynamic Spatiotemporal Response to Periodic Chemical Stimulation in a Xenopus Embryonic Tissue

Embryonic development is guided by a complex and integrated set of stimuli that results in collective system-wide organization that is both time and space regulated. These regulatory interactions result in the emergence of highly functional units, which are correlated to frequency-modulated stimulation profiles. We have determined the dynamic response of vertebrate embryonic tissues to highly controlled, time-varying localized chemical stimulation using a microfluidic system with feedback control. Our approach has enabled localized spatiotemporal manipulation of the steroid hormone dexamethasone (DEX) in Animal Cap (AC) tissues isolated from gastrulating Xenopus embryos. Using this approach we investigated cell-scale responses to precisely controlled stimulation by tracking the redistribution of a GFP-tagged DEX-reporter constructed from the human glucocorticoid receptor (GR). We exposed defined regions of a single AC explant to different stimulation conditions—continuous stimulation, periodic stimulation, and no stimulation. We observed collective behavior of the GR transport into the nucleus was first-order. Furthermore, the dynamic response was well-modeled by a first-order differential equation with a single time derivative. The model predicted that responses to periodic stimulations closely matched the results of the frequency-based experiments. We find that stimulation with localized bursts versus continuous stimulation can result in highly distinct responses. This finding is critical as controlled space and time exposure to growth factors is a hallmark of complex processes in embryonic development. These complex responses to cellular signaling and transport machinery were similar to emergent behaviors in other complex systems, suggesting that even within a complex embryonic tissue, the overall system can converge toward a predictive first-order response

Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism : a pooled analysis of the EINSTEIN-DVT and PE randomized studies

Background: Standard treatment for venous thromboembolism (VTE) consists of a heparin combined with vitamin K antagonists. Direct oral anticoagulants have been investigated for acute and extended treatment of symptomatic VTE; their use could avoid parenteral treatment and/or laboratory monitoring of anticoagulant effects. Methods: A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies compared the efficacy and safety of rivaroxaban (15 mg twice-daily for 21 days, followed by 20 mg once-daily) with standard-therapy (enoxaparin 1.0 mg/kg twice-daily and warfarin or acenocoumarol). Patients were treated for 3, 6, or 12 months and followed for suspected recurrent VTE and bleeding. The prespecified noninferiority margin was 1.75. Results: 8282 patients were enrolled. 4151 received rivaroxaban and 4131 received standard-therapy. The primary efficacy outcome occurred in 86 rivaroxaban-treated patients (2.1%) compared with 95 (2.3%) standard-therapy-treated patients (hazard ratio, 0.89; 95% confidence interval [CI], 0.66-1.19; pnoninferiority<0.001). Major bleeding was observed in 40 (1.0%) and 72 (1.7%) patients in the rivaroxaban and standard-therapy groups, respectively (hazard ratio, 0.54; 95% CI, 0.37-0.79; p=0.002). In key subgroups, including fragile patients, cancer patients, patients presenting with large clots and those with a history of recurrent VTE, the efficacy and safety of rivaroxaban was similar compared with standard-therapy. Conclusion: The single-drug approach with rivaroxaban resulted in similar efficacy to standard-therapy and was associated with a significantly lower rate of major bleeding. Efficacy and safety results were consistent among key patient subgroups

Implantation of a Novel Cryopreserved Viable Osteochondral Allograft for Articular Cartilage Repair in the Knee

Restoration and repair of articular cartilage injuries remain a challenge for orthopaedic surgeons. The standard first-line treatment of articular cartilage lesions is marrow stimulation; however, this procedure can often result in the generation of fibrous repair cartilage rather than the biomechanically superior hyaline cartilage. Marrow stimulation is also often limited to smaller lesions, less than 2 cm2. Larger lesions may require implantation of a fresh osteochondal allograft, though a short shelf life, size-matched donor requirements, potential challenges of bone healing, limited availability, and the relatively high price limit the wide use of this therapeutic approach. We present a straightforward, single-stage surgical technique of a novel reparative and restorative approach for articular cartilage repair with the implantation of a cryopreserved viable osteochondral allograft (CVOCA). The CVOCA contains full-thickness articular cartilage and a thin layer of subchondral bone, and maintains the intact native cartilage architecture with viable chondrocytes, growth factors, and extracellular matrix proteins to promote articular cartilage repair. We report the results of a retrospective case series of three patients who presented with articular cartilage lesions more than 2 cm2 and were treated with the CVOCA using the presented surgical technique. Patients were followed up to 2 years after implantation of the CVOCA and all three patients had satisfactory outcomes without adverse events. Controlled randomized studies are suggested for evaluation of CVOCA efficacy, safety, and long-term outcomes