Adding Bupivacaine to High-potassium Cardioplegia Improves Function and Reduces Cellular Damage of Rat Isolated Hearts after Prolonged, Cold Storage

Background Bupivacaine retards myocardial acidosis during ischemia. The authors measured function of rat isolated hearts after prolonged storage to determine whether bupivacaine improves cardiac protection compared with standard cardioplegia alone. Methods After measuring cardiac function on a Langendorff apparatus, hearts were perfused with cardioplegia alone (controls), cardioplegia containing 500 microm bupivacaine, or cardioplegia containing 2 mm lidocaine; were stored at 4 degrees C for 12 h; and were then reperfused. Heart rate and left ventricular developed pressures were measured for 60 min. Maximum positive rate of change in ventricular pressure, oxygen consumption, and lactate dehydrogenase release were also measured. Results All bupivacaine-treated, four of five lidocaine-treated, and no control hearts beat throughout the 60-min recovery period. Mean values of heart rate, left ventricular developed pressure, maximum positive rate of change in ventricular pressure, rate-pressure product, and efficiency in bupivacaine-treated hearts exceeded those of the control group (P < 0.001 at 60 min for all). Mean values of the lidocaine group were intermediate. Oxygen consumption of the control group exceeded the other groups early in recovery, but not at later times. Lactate dehydrogenase release from the bupivacaine group was less than that from the control group (P < 0.001) but did not differ from baseline. Conclusions Adding bupivacaine to a depolarizing cardioplegia solution reduces cell damage and improves cardiac function after prolonged storage. Metabolic inhibition may contribute to this phenomenon, which is not entirely explained by sodium channel blockade

d=3 Bosonic Vector Models Coupled to Chern-Simons Gauge Theories

We study three dimensional O(N)_k and U(N)_k Chern-Simons theories coupled to a scalar field in the fundamental representation, in the large N limit. For infinite k this is just the singlet sector of the O(N) (U(N)) vector model, which is conjectured to be dual to Vasiliev's higher spin gravity theory on AdS_4. For large k and N we obtain a parity-breaking deformation of this theory, controlled by the 't Hooft coupling lambda = 4 \pi N / k. For infinite N we argue (and show explicitly at two-loop order) that the theories with finite lambda are conformally invariant, and also have an exactly marginal (\phi^2)^3 deformation. For large but finite N and small 't Hooft coupling lambda, we show that there is still a line of fixed points parameterized by the 't Hooft coupling lambda. We show that, at infinite N, the interacting non-parity-invariant theory with finite lambda has the same spectrum of primary operators as the free theory, consisting of an infinite tower of conserved higher-spin currents and a scalar operator with scaling dimension \Delta=1; however, the correlation functions of these operators do depend on lambda. Our results suggest that there should exist a family of higher spin gravity theories, parameterized by lambda, and continuously connected to Vasiliev's theory. For finite N the higher spin currents are not conserved.Comment: 34 pages, 29 figures. v2: added reference

The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1

DMF (dimethyl fumarate) exerts anti-inflammatory and pro-metabolic effects in a variety of cell types, and a formulation (BG-12) is being evaluated for monotherapy in multiple sclerosis patients. DMF modifies glutathione (GSH) levels that can induce expression of the anti-inflammatory protein HO-1 (haem oxygenase-1). In primary astrocytes and C6 glioma cells, BG-12 dose-dependently suppressed nitrite production induced by either LI [LPS (lipopolysaccharide) at 1 \u3bcg/ml plus IFN\u3b3 (interferon \u3b3) at 20 units/ml] or a mixture of pro-inflammatory cytokines, with greater efficacy in C6 cells. BG-12 reduced NOS2 (nitric oxide synthase 2) mRNA levels and activation of a NOS2 promoter, reduced nuclear levels of NF-\u3baB (nuclear factor \u3baB) p65 subunit and attenuated loss of I\u3baB\u3b1 (inhibitory \u3baB\u3b1) in both cell types, although with greater effects in astrocytes. In astrocytes, LI decreased mRNA levels for GSHr (GSH reductase) and GCL (c-glutamylcysteine synthetase), and slightly suppressed GSHs (GSH synthetase) mRNAs. Co-treatment with BG-12 prevented those decreased and increased levels above control values. In contrast, LI reduced GSHp (GSH peroxidase) and GCL in C6 cells, and BG-12 had no effect on those levels. BG-12 increased nuclear levels of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), an inducer of GSH-related enzymes, in astrocytes but not C6 cells. In astrocytes, GSH was decreased by BG-12 at 2 h and increased at 24 h. Prior depletion of GSH using buthionine-sulfoximine increased the ability of BG-12 to reduce nitrites. In astrocytes, BG-12 increased HO-1 mRNA levels and effects on nitrite levels were blocked by an HO-1 inhibitor. These results demonstrate that BG-12 suppresses inflammatory activation in astrocytes and C6 glioma cells, but with distinct mechanisms, different dependence on GSH and different effects on transcription factor activation

Perspective: Quantum Hamiltonians for optical interactions

The multipolar Hamiltonian of quantum electrodynamics is extensively employed in chemical and optical physics to treat rigorously the interaction of electromagnetic fields with matter. It is also widely used to evaluate intermolecular interactions. The multipolar version of the Hamiltonian is commonly obtained by carrying out a unitary transformation of the Coulomb gauge Hamiltonian that goes by the name of Power-Zienau-Woolley (PZW). Not only does the formulation provide excellent agreement with experiment, and versatility in its predictive ability, but also superior physical insight. Recently, the foundations and validity of the PZW Hamiltonian have been questioned, raising a concern over issues of gauge transformation and invariance, and whether observable quantities obtained from unitarily equivalent Hamiltonians are identical. Here, an in-depth analysis of theoretical foundations clarifies the issues and enables misconceptions to be identified. Claims of non-physicality are refuted: the PZW transformation and ensuing Hamiltonian are shown to rest on solid physical principles and secure theoretical ground

Possible Origin of Fermion Chirality and Gut Structure From Extra Dimensions

The fundamental chiral nature of the observed quarks and leptons and the emergence of the gauge group itself are most puzzling aspects of the standard model. Starting from general considerations of topological properties of gauge field configurations in higher space-time dimensions, it is shown that the existence of non-trivial structures in ten dimensions would determine a class of models corresponding to a grand unified GUT structure with complex fermion representations with respect to $SU(3)_C \otimes SU(2)_L \otimes U(1)_Y$. The discussion is carried out within the framework of string theories with characteristic energy scales below the Planck mass. Avoidance of topological obstructions upon continuous deformation of field configurations leads to global chiral symmetry breaking of the underlying fundamental theory, imposes rigorous restrictions on the structure of the vacuum and space-time itself and determines uniquely the gauge structure and matter content.Comment: final version to appear in Phys. Rev.

Immersed boundary-finite element model of fluid-structure interaction in the aortic root

It has long been recognized that aortic root elasticity helps to ensure efficient aortic valve closure, but our understanding of the functional importance of the elasticity and geometry of the aortic root continues to evolve as increasingly detailed in vivo imaging data become available. Herein, we describe fluid-structure interaction models of the aortic root, including the aortic valve leaflets, the sinuses of Valsalva, the aortic annulus, and the sinotubular junction, that employ a version of Peskin's immersed boundary (IB) method with a finite element (FE) description of the structural elasticity. We develop both an idealized model of the root with three-fold symmetry of the aortic sinuses and valve leaflets, and a more realistic model that accounts for the differences in the sizes of the left, right, and noncoronary sinuses and corresponding valve cusps. As in earlier work, we use fiber-based models of the valve leaflets, but this study extends earlier IB models of the aortic root by employing incompressible hyperelastic models of the mechanics of the sinuses and ascending aorta using a constitutive law fit to experimental data from human aortic root tissue. In vivo pressure loading is accounted for by a backwards displacement method that determines the unloaded configurations of the root models. Our models yield realistic cardiac output at physiological pressures, with low transvalvular pressure differences during forward flow, minimal regurgitation during valve closure, and realistic pressure loads when the valve is closed during diastole. Further, results from high-resolution computations demonstrate that IB models of the aortic valve are able to produce essentially grid-converged dynamics at practical grid spacings for the high-Reynolds number flows of the aortic root

Cosmic Physics: The High Energy Frontier

Cosmic rays have been observed up to energies $10^8$ times larger than those of the best particle accelerators. Studies of astrophysical particles (hadrons, neutrinos and photons) at their highest observed energies have implications for fundamental physics as well as astrophysics. Thus, the cosmic high energy frontier is the nexus to new particle physics. This overview discusses recent advances being made in the physics and astrophysics of cosmic rays and cosmic gamma-rays at the highest observed energies as well as the related physics and astrophysics of very high energy cosmic neutrinos. These topics touch on questions of grand unification, violation of Lorentz invariance, as well as Planck scale physics and quantum gravity.Comment: Topical Review Paper to be published in the Journal of Physics G, 50 page

Gentamicin affects the bioenergetics of isolated mitochondria and collapses the mitochondrial membrane potential in cochlear sensory hair cells

Aminoglycoside antibiotics are widely prescribed to treat a variety of serious bacterial infections. They are extremely useful clinical tools, but have adverse side effects such as oto- and nephrotoxicity. Once inside a cell they are thought to cause mitochondrial dysfunction, subsequently leading to apoptotic cell death due to an increase in reactive oxygen species (ROS) production. Here we present evidence of a direct effect of gentamicin (the most commonly prescribed aminoglycoside) on the respiratory activities of isolated rat liver and kidney mitochondria. We show that gentamicin stimulates state 4 and inhibits state 3u respiratory rates, thereby reducing the respiratory control ratio (RCR) whilst simultaneously causing a collapse of the mitochondrial membrane potential (MtMP). We propose that gentamicin behaves as an uncoupler of the electron transport chain (ETC) – a hypothesis supported by our evidence that it reduces the production of mitochondrial ROS (MtROS). We also show that gentamicin collapses the MtMP in the sensory hair cells (HCs) of organotypic mouse cochlear cultures

Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells

Immunotherapy using checkpoint-blocking antibodies against targets such as CTLA-4 and PD-1 can cure melanoma and non-small cell lung cancer in a subset of patients. The presence of CD8 T cells in the tumor correlates with improved survival. We show that immuno-positron emission tomography (immuno-PET) can visualize tumors by detecting infiltrating lymphocytes and, through longitudinal observation of individual animals, distinguish responding tumors from those that do not respond to therapy. We used 89 Zr-labeled PEGylated single-domain antibody fragments (VHHs) specific for CD8 to track the presence of intratumoral CD8 + T cells in the immunotherapy-susceptible B16 melanoma model in response to checkpoint blockade. A 89 Zr-labeled PEGylated anti-CD8 VHH detected thymus and secondary lymphoid structures as well as intratumoral CD8 T cells. Animals that responded to CTLA-4 therapy showed a homogeneous distribution of the anti-CD8 PET signal throughout the tumor, whereas more heterogeneous infiltration of CD8 T cells correlated with faster tumor growth and worse responses. To support the validity of these observations, we used two different transplantable breast cancer models, yielding results that conformed with predictions based on the antimelanoma response. It may thus be possible to use immuno-PET and monitor antitumor immune responses as a prognostic tool to predict patient responses to checkpoint therapies.National Institutes of Health (U.S.) (Grant R01-AI087879-06)National Institutes of Health (U.S.) (Grant DP1-GM106409-03)National Institutes of Health (U.S.) (Grant R01-GM100518-04)National Institutes of Health (U.S.) (Grant P01 CA080111

Numerical approach to a model for quasistatic damage with spatial BV-regularization

We address a model for rate-independent, partial, isotropic damage in quasistatic small strain linear elasticity, featuring a damage variable with spatial BV-regularization. Discrete solutions are obtained using an alternate time-discrete scheme and the Variable-ADMM algorithm to solve the constrained nonsmooth optimization problem that determines the damage variable at each time step. We prove convergence of the method and show that discrete solutions approximate a semistable energetic solution of the rate-independent system. Moreover, we present our numerical results for two benchmark problems