"Biological failure” of the anterior cruciate ligament graft

Anterior cruciate ligament (ACL) reconstruction has the best chance for success when the graft undergoes extensive biologic remodeling and incorporation after implantation. There are many factors that can lead to graft failure and possible revision surgery. These include patient selection; surgical technique such as graft placement and tensioning; the use of allograft versus autograft; mechanical factors such as secondary restraint laxity; lack of a correct, carefully controlled post-operative rehabilitation program; and biological factors. When a patient presents with knee instability following ligament reconstruction and there is no history of a new trauma or identifiable technical error, biological failure should be considered. However, the biologic response of the grafted tissue is closely linked to the mechanical and biochemical environment into which the graft is placed. Thus, the "biological failure” of the ACL graft is a complex pathological entity whose cause is not fully understood. Failure may be initiated by early extensive graft necrosis, disturbances in revascularization, problems in cell repopulation and proliferation, and as well difficulties in the ligamentization process. However, further study of the biological characterization of a failed graft placed in a correct mechanical environment is warrante

Anatomy of the anterior cruciate ligament

The anterior cruciate ligament (ACL) is a band of dense connective tissue which courses from the femur to the tibia. The ACL is a key structure in the knee joint, as it resists anterior tibial translation and rotational loads. When the knee is extended, the ACL has a mean length of 32mm and a width of 7-12mm. There are two components of the ACL, the anteromedial bundle (AMB) and the posterolateral bundle (PLB). They are not isometric with the main change being lengthening of the AMB and shortening of the PLB during flexion. The ACL has a microstructure of collagen bundles of multiple types (mostly type I) and a matrix made of a network of proteins, glycoproteins, elastic systems, and glycosaminoglycans with multiple functional interactions. The complex ultrastructural organization and abundant elastic system of the ACL allow it to withstand multiaxial stresses and varying tensile strains. The ACL is innervated by posterior articular branches of the tibial nerve and is vascularized by branches of the middle genicular arter

One-dimensional Josephson arrays as superlattices for single Cooper pairs

We investigate uniform one-dimensional arrays of small Josephson junctions ($E_J \ll E_C$, $E_C = (2e)^2/2C$) with a realistic Coulomb interaction $U(x) = E_C \lambda \exp( - |x|/\lambda)$ (here $\lambda \gg 1$ is the screening length in units of the lattice constant of the array). At low energies this system can be described in terms of interacting Bose particles (extra single Cooper pairs) on the lattice. With increasing concentration $\nu$ of extra Cooper pairs, a crossover from the Bose gas phase to the Wigner crystal phase and then to the superlattice regime occurs. The phase diagram in the superlattice regime consists of commensurable insulating phases with $\nu = 1/l$ ($l$ is integer) separated by superconducting regions where the current is carried by excitations with {\em fractional} electric charge $q = \pm 2e/l$. The Josephson current through a ring-shaped array pierced by magnetic flux is calculated for all of the phases.Comment: 4 pages (LATEX), 2 figure

Political Regimes and Sovereign Credit Risk in Europe, 1750-1913

This article uses a new panel data set to perform a statistical analysis of political regimes and sovereign credit risk in Europe from 1750 to 1913. Old Regime polities typically suffered from fiscal fragmentation and absolutist rule. By the start of World War I, however, many such countries had centralized institutions and limited government. Panel regressions indicate that centralized and?or limited regimes were associated with significant improvements in credit risk relative to fragmented and absolutist ones. Structural break tests also reveal close relationships between major turning points in yield series and political transformations

ABCC1: a gateway for pharmacological compounds to the ischaemic brain

By preventing access of drugs to the CNS, the blood-brain barrier hampers developments in brain pharmacotherapy. Strong efforts are currently being made to identify drugs that accumulate more efficaciously in ischaemic brain tissue. We identified an ATP-binding cassette (ABC) transporter, ABCC1, which is expressed on the abluminal surface of the brain capillary endothelium and mildly downregulated in response to focal cerebral ischaemia, induced by intraluminal middle cerebral artery occlusion. In biodistribution studies we show that ABCC1 promotes the accumulation of known neuroprotective and neurotoxic compounds in the ischaemic and non-ischaemic brain, ABCC1 deactivation reducing tissue concentrations by up to two orders of magnitude. As such, ABCC1's expression and functionality in the brain differs from the liver, spleen and testis, where ABCC1 is strongly expressed on parenchymal cells, resulting -- in case of liver and testis -- in directed transport from the tissue into the blood. After focal cerebral ischaemia, ABCC1 deactivation abolished the efficacy of both neuroprotective and neurotoxic compounds. Our data indicate that ABCC1 acts as gateway for pharmacological compounds to the stroke brain. We suggest that the tailoring of compounds binding to abluminal but not luminal ABC transporters may facilitate stroke pharmacotherap

Quantum-Phase Transitions of Interacting Bosons and the Supersolid Phase

We investigate the properties of strongly interacting bosons in two dimensions at zero temperature using mean-field theory, a variational Ansatz for the ground state wave function, and Monte Carlo methods. With on-site and short-range interactions a rich phase diagram is obtained. Apart from the homogeneous superfluid and Mott-insulating phases, inhomogeneous charge-density wave phases appear, that are stabilized by the finite-range interaction. Furthermore, our analysis demonstrates the existence of a supersolid phase, in which both long-range order (related to the charge-density wave) and off-diagonal long-range order coexist. We also obtain the critical exponents for the various phase transitions.Comment: RevTex, 20 pages, 10 PostScript figures include

Critical properties of two-dimensional Josephson junction arrays with zero-point quantum fluctuations

We present results from an extensive analytic and numerical study of a two-dimensional model of a square array of ultrasmall Josephson junctions. We include the ultrasmall self and mutual capacitances of the junctions, for the same parameter ranges as those produced in the experiments. The model Hamiltonian studied includes the Josephson, $E_J$, as well as the charging, $E_C$, energies between superconducting islands. The corresponding quantum partition function is expressed in different calculationally convenient ways within its path-integral representation. The phase diagram is analytically studied using a WKB renormalization group (WKB-RG) plus a self-consistent harmonic approximation (SCHA) analysis, together with non-perturbative quantum Monte Carlo simulations. Most of the results presented here pertain to the superconductor to normal (S-N) region, although some results for the insulating to normal (I-N) region are also included. We find very good agreement between the WKB-RG and QMC results when compared to the experimental data. To fit the data, we only used the experimentally determined capacitances as fitting parameters. The WKB-RG analysis in the S-N region predicts a low temperature instability i.e. a Quantum Induced Transition (QUIT). We carefully simulations and carry out a finite size analysis of $T_{QUIT}$ as a function of the magnitude of imaginary time axis $L_\tau$. We find that for some relatively large values of $\alpha=E_C/E_J$ ($1\leq \alpha \leq 2.25)$, the $L_\tau\to\infty$ limit does appear to give a {\it non-zero} $T_{QUIT}$, while for $\alpha \ge 2.5$, $T_{QUIT}=0$. We use the SCHA to analytically understand the $L_\tau$ dependence of the QMC results with good agreement between them. Finally, we also carried out a WKB-RG analysis in the I-N region and found no evidence of a low temperature QUIT, up to lowest order in ${\alpha}^{-1}$Comment: 39 pages, 18 postscript figures, to appear in Phys. Rev.

Photo-antagonism of the GABAA receptor

Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation. These compounds are based on the competitive antagonist gabazine and incorporate a variety of photoactive groups. By using site-directed mutagenesis and ligand-docking studies, they reveal new areas of the GABA binding site at the interface between receptor β and α subunits. These compounds enable the selected inactivation of native GABAA receptor populations providing new insight into the function of inhibitory synapses and extrasynaptic receptors in controlling neuronal excitation

The superconductor-insulator transition in 2D dirty boson systems

Universal properties of the zero temperature superconductor-insulator transition in two-dimensional amorphous films are studied by extensive Monte Carlo simulations of bosons in a disordered medium. We report results for both short-range and long-range Coulomb interactions for several different points in parameter space. In all cases we observe a transition from a superconducting phase to an insulating Bose glass phase. {}From finite-size scaling of our Monte Carlo data we determine the universal conductivity $\sigma^*$ and the critical exponents at the transition. The result $\sigma^* = (0.55 \pm 0.06) (2e)^2/h$ for bosons with long-range Coulomb interaction is roughly consistent with experiments reported so far. We also find $\sigma^* = (0.14 \pm 0.03) (2e)^2/h$ for bosons with short-range interactions.Comment: Revtex 3.0, 54 pages, 17 figures included, UBCTP-93-01

Mapping the contribution of β3-containing GABA(A )receptors to volatile and intravenous general anesthetic actions

BACKGROUND: Agents belonging to diverse chemical classes are used clinically as general anesthetics. The molecular targets mediating their actions are however still only poorly defined. Both chemical diversity and substantial differences in the clinical actions of general anesthetics suggest that general anesthetic agents may have distinct pharmacological targets. It was demonstrated previously that the immobilizing action of etomidate and propofol is completely, and the immobilizing action of isoflurane partly mediated, by β3-containing GABA(A )receptors. This was determined by using the β3(N265M) mice, which carry a point mutation known to decrease the actions of general anesthetics at recombinant GABA(A )receptors. In this communication, we analyzed the contribution of β3-containing GABA(A )receptors to the pharmacological actions of isoflurane, etomidate and propofol by means of β3(N265M) mice. RESULTS: Isoflurane decreased core body temperature and heart rate to a smaller degree in β3(N265M) mice than in wild type mice, indicating a minor but significant role of β3-containing GABA(A )receptors in these actions. Prolonged time intervals in the ECG and increased heart rate variability were indistinguishable between genotypes, suggesting no involvement of β3-containing GABA(A )receptors. The anterograde amnesic action of propofol was indistinguishable in β3(N265M) and wild type mice, suggesting that it is independent of β3-containing GABA(A )receptors. The increase of heart rate variability and prolongation of ECG intervals by etomidate and propofol were also less pronounced in β3(N265M) mice than in wild type mice, pointing to a limited involvement of β3-containing GABA(A )receptors in these actions. The lack of etomidate- and propofol-induced immobilization in β3(N265M) mice was also observed in congenic 129X1/SvJ and C57BL/6J backgrounds, indicating that this phenotype is stable across different backgrounds. CONCLUSION: Our results provide evidence for a defined role of β3-containing GABA(A )receptors in mediating some, but not all, of the actions of general anesthetics, and confirm the multisite model of general anesthetic action. This pharmacological separation of anesthetic endpoints also suggests that subtype-selective substances with an improved side-effect profile may be developed