Impaired muscle oxygen use at onset of exercise in peripheral arterial disease

ObjectivesIn patients with peripheral arterial disease (PAD), abnormal muscle metabolism and impaired oxygen delivery distal to the arterial occlusions may contribute to the exercise limitation observed in this population. Muscle tissue hemoglobin saturation (StO2), measured with near-infrared spectroscopy, reflects the relative contributions of oxygen delivery and oxygen use. Thus differences in the kinetics of StO2 in response to exercise may yield important insight into the potential mechanisms associated with the PAD exercise impairment. The purposes of this study were to characterize the muscle oxygenation responses in patients with PAD and in healthy control subjects at the onset of exercise, and to compare the kinetics of StO2 desaturation. We hypothesized that at the onset of exercise the kinetics of StO2 desaturation would be slowed in PAD compared with control responses.Material and methodsSix patients with PAD and 6 healthy control subjects from a university center were examined in a prospective cross-sectional analysis that evaluated the desaturation kinetics of StO2 at the onset of walking exercise. On separate visits subjects performed graded treadmill exercise and 3 constant work rate treadmill tests equivalent to ∼60% (low), ∼80% (medium), and 100% (peak) of their peak exercise work rate. Gastrocnemious muscle StO2 response profiles (InSpectra tissue spectrometer) were measured at rest and across the rest to exercise transition. Muscle StO2 responses were characterized by an exponential mathematical model. The end point value was taken as the time constant of StO2 desaturation after onset of exercise (ie, equivalent to time to reach approximately 63% of StO2 decrease).ResultsThe patients with PAD and the control subjects were of similar age and activity level. The qualitative patterns of StO2 responses at onset of exercise were also similar between patients and control subjects at all work rates. However, the kinetic time constants of StO2 desaturation were prolonged in patients with PAD versus control subjects (averaged time constant across all work rates, 21.9 ± 9.4 seconds vs 4.9 ± 2.2 seconds; P < .01).ConclusionsThe slowed muscle StO2 kinetics in PAD are consistent with an impairment in muscle oxygen use at the onset of walking exercise. Impaired muscle metabolism may contribute to the altered physiologic responses to exercise and to exercise impairment in patients with PAD

Disjoint edges in topological graphs and the tangled-thrackle conjecture

It is shown that for a constant $t\in \mathbb{N}$, every simple topological graph on $n$ vertices has $O(n)$ edges if it has no two sets of $t$ edges such that every edge in one set is disjoint from all edges of the other set (i.e., the complement of the intersection graph of the edges is $K_{t,t}$-free). As an application, we settle the \emph{tangled-thrackle} conjecture formulated by Pach, Radoi\v{c}i\'c, and T\'oth: Every $n$-vertex graph drawn in the plane such that every pair of edges have precisely one point in common, where this point is either a common endpoint, a crossing, or a point of tangency, has at most $O(n)$ edges

Langevin Simulations of Two Dimensional Vortex Fluctuations: Anomalous Dynamics and a New IVIV-exponent

The dynamics of two dimensional (2D) vortex fluctuations are investigated through simulations of the 2D Coulomb gas model in which vortices are represented by soft disks with logarithmic interactions. The simulations trongly support a recent suggestion that 2D vortex fluctuations obey an intrinsic anomalous dynamics manifested in a long range 1/t-tail in the vortex correlations. A new non-linear IV-exponent a, which is different from the commonly used AHNS exponent, a_AHNS and is given by a = 2a_AHNS - 3, is confirmed by the simulations. The results are discussed in the context of earlier simulations, experiments and a phenomenological description.Comment: Submitted to PRB, RevTeX format, 28 pages and 13 figures, figures in postscript format are available at http://www.tp.umu.se/~holmlund/papers.htm

Application of adaptive design and decision making to a phase II trial of a phosphodiesterase inhibitor for the treatment of intermittent claudication

Background: Claudication secondary to peripheral artery disease (PAD) is associated with substantial functional impairment. Phosphodiesterase (PDE) inhibitors have been shown to increase walking performance in these patients. K-134 is a selective PDE 3 inhibitor being developed as a potential treatment for claudication. The use of K-134, as with other PDE 3 inhibitors, in patients with PAD raises important safety and tolerability concerns, including the induction of cardiac ischemia, tachycardia, and hypotension. We describe the design, oversight, and implementation of an adaptive, phase II, dose-finding trial evaluating K-134 for the treatment of stable, intermittent claudication. Methods: The study design was a double-blind, multi-dose (25 mg, 50 mg, and 100 mg of K-134), randomized trial with both placebo and active comparator arms conducted in the United States and Russia. The primary objective of the study was to compare the highest tolerable dose of K-134 versus placebo using peak walking time after 26 weeks of therapy as the primary outcome. Study visits with intensive safety assessments were included early in the study period to provide data for adaptive decision making. The trial used an adaptive, dose-finding strategy to efficiently identify the highest dose(s) most likely to be safe and well tolerated, based on the side effect profiles observed within the trial, so that less promising doses could be abandoned. Protocol specified criteria for safety and tolerability endpoints were used and modeled prior to the adaptive decision making. The maximum target sample size was 85 subjects in each of the retained treatment arms. Results: When 199 subjects had been randomized and 28-day data were available from 143, the Data Monitoring Committee (DMC) recommended termination of the lowest dose (25 mg) treatment arm. Safety evaluations performed during 14- and 28-day visits which included in-clinic dosing and assessments at peak drug concentrations provided core data for the DMC review. At the time of review, no subject in any of the five treatment arms (placebo, three K-134-containing arms, and cilostazol) had met pre-specified definitions for resting tachycardia or ischemic changes on exercise ECG. If, instead of dropping the 25-mg K-134 treatment arm, all arms had been continued to full enrollment, then approximately 43 additional research subjects would have been required to complete the trial. Conclusions: In this phase II, dose-finding trial of K-134 in the treatment of stable intermittent claudication, no concerning safety signals were seen at interim analysis, allowing the discontinuation of the lowest-dose-containing arm and the retention of the two highest-dose-containing arms. The adaptive design facilitated safe and efficient evaluation of K-134 in this high-risk cardiovascular population

Bond breaking in vibrationally excited methane on transition metal catalysts

The role of vibrational excitation of a single mode in the scattering of methane is studied by wave packet simulations of oriented CH4 and CD4 molecules from a flat surface. All nine internal vibrations are included. In the translational energy range from 32 up to 128 kJ/mol we find that initial vibrational excitations enhance the transfer of translational energy towards vibrational energy and increase the accessibility of the entrance channel for dissociation. Our simulations predict that initial vibrational excitations of the asymmetrical stretch (nu_3) and especially the symmetrical stretch (nu_1) modes will give the highest enhancement of the dissociation probability of methane.Comment: 4 pages REVTeX, 2 figures (eps), to be published in Phys. Rev. B. (See also arXiv:physics.chem-ph/0003031). Journal version at http://publish.aps.org/abstract/PRB/v61/p1565

Anisotropic vortex pinning in superconductors with a square array of rectangular submicron holes

We investigate vortex pinning in thin superconducting films with a square array of rectangular submicron holes ("antidots"). Two types of antidots are considered: antidots fully perforating the superconducting film, and "blind antidots", holes that perforate the film only up to a certain depth. In both systems, we observe a distinct anisotropy in the pinning properties, reflected in the critical current Ic, depending on the direction of the applied electrical current: parallel to the long side of the antidots or perpendicular to it. Although the mechanism responsible for the effect is very different in the two systems, they both show a higher critical current and a sharper IV-transition when the current is applied along the long side of the rectangular antidots

Moving glass phase of driven lattices

We study periodic lattices, such as vortex lattices, driven by an external force in a random pinning potential. We show that effects of static disorder persist even at large velocity. It results in a novel moving glass state with topological order analogous to the static Bragg glass. The lattice flows through well-defined, elastically coupled, {\it % static} channels. We predict barriers to transverse motion resulting in finite transverse critical current. Experimental tests of the theory are proposed.Comment: Revised version, shortened, 8 pages, REVTeX, no figure

Lines, Circles, Planes and Spheres

Let $S$ be a set of $n$ points in $\mathbb{R}^3$, no three collinear and not all coplanar. If at most $n-k$ are coplanar and $n$ is sufficiently large, the total number of planes determined is at least $1 + k \binom{n-k}{2}-\binom{k}{2}(\frac{n-k}{2})$. For similar conditions and sufficiently large $n$, (inspired by the work of P. D. T. A. Elliott in \cite{Ell67}) we also show that the number of spheres determined by $n$ points is at least $1+\binom{n-1}{3}-t_3^{orchard}(n-1)$, and this bound is best possible under its hypothesis. (By $t_3^{orchard}(n)$, we are denoting the maximum number of three-point lines attainable by a configuration of $n$ points, no four collinear, in the plane, i.e., the classic Orchard Problem.) New lower bounds are also given for both lines and circles.Comment: 37 page