Evaluation of the toxicity of a substituted 2,4-thiazolidinedione moiety to isolated rat hepatocytes : relevance to glitazone toxicity

Troglitazone (TGZ), a 2,4 thiazolidinedione (TZD) anti-diabetic agent, has been associated with hepatotoxicity in type II diabetic patients. The mechanism of toxicity has not yet been established. However, it has been reported (Kennedy et al., 2003) that the incorporation of a sulphur atom in the cyclic imide structure of N-(3,5-dichlorophenyl)succinimide (NDPS), analogous to the 2,4-TZD moiety in TGZ, resulted in hepatotoxicity. In this study we have examined the relative in vitro hepatotoxicity of 3-(3,5-dichlorophenyl)-2,4,thiazolidinedione (DCPT), which contains the 2,4-TZD moiety, and that of its structural analogue NDPS. NDPS and DCPT were synthesised using a modification of the method of Fujinami et al (1971) and characterised by NMR and mass spectrometry. Hepatocytes were prepared from male Sprague-Dawley rats (180-220g), and cell viability was measured using Trypan Blue exclusion. Preparations with initial cell viability above 80% were used in all experiments. Cells were incubated for 3 hours with NDPS and DCPT at (0μM, 100μM, 500μM and 1mM in dimethylsulphoxide (0.1% (v/v)) at 37oC in an atmosphere of 95%O2/5%CO2). Samples were taken at regular time intervals (0, 15, 30, 60 90, 120, 180 minutes) for the measurement of viability, reduced glutathione (GSH) content and lactate dehydrogenase (LDH) activity in the extracellular medium. Statistical analyses (ANOVA followed by Dunnett’s test) of the data (Table 1) obtained for hepatocytes exposed to DCPT and NDPS did not reveal significant differences in GSH content, LDH activity or cell viability over a 3h incubation period. These data indicate that the incorporation of a sulphur atom in the succinamide ring of NDPS to produce the corresponding 2,4 TZD (DCPT) does not result in an increase in hepatotoxic effects in vitro. This finding, together with our previous report on the lack of toxicity of the 2,4-TZD containing, rosiglitazone (Ball et al 2004 ), would suggest that a chemical mechanism of toxicity of TGZ (if feasible) might be a function of the whole molecule rather than the TZD moiety alone

Eigenvalue characterization for a class of boundary value problems

We consider the $n$'th order ordinary differential equation $(-1)^{n-k} y^{(n)}=\lambda a(t) f(y)$, $t\in[0,1]$, $n\geq 3$ together with the boundary condition $y^{(i)}(0)=0$, $0\leq i\leq k-1$ and $y^{(l)}=0$, $j\leq l\leq j+n-k-1$, for $1\leq j\leq k-1$ fixed. Values of $\lambda$ are characterized so that the boundary value problem has a positive solution

Supercooling of the high field vortex phase in single crystalline BSCCO

Time resolved magneto-optical images show hysteresis associated with the transition at the so-called ``second magnetization peak'' at B_sp in single-crystalline Bi_2Sr_2CaCu_2O_8+d. By rapid quenching of the high-field phase, it can be made to persist metastably in the sample down to fields that are nearly half B_sp.Comment: 2 pages, 2 figures Submitted to the conference proceedings of M2S-VI, February 200, Housto

Slow relaxations and history dependence of the transport properties of layered superconductors

We study numerically the time evolution of the transport properties of layered superconductors after different preparations. We show that, in accordance with recent experiments in BSCCO performed in the second peak region of the phase diagram (Portier et al, 2001), the relaxation strongly depends on the initial conditions and is extremely slow. We investigate the dependence on the pinning center density and the perturbation applied. We compare the measurements to recent findings in tapped granular matter and we interpret our results with a rather simple picture.Comment: 4 pages, 4 fig

Adaptive biomedical treatment and robust control

Abstract An adaptive treatment strategy is a set of rules for choosing effective medical treatments for individual patients. In the statistical literature, methods for optimal dynamic treatment (ODT) include Q-learning and A-learning methods, which are linked to machine learning in engineering and computer science. The research project behind this article aims to develop new methodology for both ODT and engineering control, through the integration of techniques and approaches that have been developed in both fields, with a particular focus on the problem of robustness. The methodological framework is based on a regret-regression approach from the statistical literature and non-minimal state-space methods from control. This article provides an introduction to some of these concepts and presents preliminary novel contributions based on the application of robust H∞ methods to ODT problems

Nonlinear analysis of a simple model of temperature evolution in a satellite

We analyse a simple model of the heat transfer to and from a small satellite orbiting round a solar system planet. Our approach considers the satellite isothermal, with external heat input from the environment and from internal energy dissipation, and output to the environment as black-body radiation. The resulting nonlinear ordinary differential equation for the satellite's temperature is analysed by qualitative, perturbation and numerical methods, which show that the temperature approaches a periodic pattern (attracting limit cycle). This approach can occur in two ways, according to the values of the parameters: (i) a slow decay towards the limit cycle over a time longer than the period, or (ii) a fast decay towards the limit cycle over a time shorter than the period. In the first case, an exactly soluble average equation is valid. We discuss the consequences of our model for the thermal stability of satellites.Comment: 13 pages, 4 figures (5 EPS files

V-I characteristics in the vicinity of order-disorder transition in vortex matter

The shape of the V-I characteristics leading to a peak in the differential resistance r_d=dV/dI in the vicinity of the order-disorder transition in NbSe2 is investigated. r_d is large when measured by dc current. However, for a small Iac on a dc bias r_d decreases rapidly with frequency, even at a few Hz, and displays a large out-of-phase signal. In contrast, the ac response increases with frequency in the absence of dc bias. These surprisingly opposite phenomena and the peak in r_d are shown to result from a dynamic coexistence of two vortex matter phases rather than from the commonly assumed plastic depinning.Comment: 12 pages 4 figures. Accepted for publication in PRB rapi

Metastability and Transient Effects in Vortex Matter Near a Decoupling Transition

We examine metastable and transient effects both above and below the first-order decoupling line in a 3D simulation of magnetically interacting pancake vortices. We observe pronounced transient and history effects as well as supercooling and superheating between the 3D coupled, ordered and 2D decoupled, disordered phases. In the disordered supercooled state as a function of DC driving, reordering occurs through the formation of growing moving channels of the ordered phase. No channels form in the superheated region; instead the ordered state is homogeneously destroyed. When a sequence of current pulses is applied we observe memory effects. We find a ramp rate dependence of the V(I) curves on both sides of the decoupling transition. The critical current that we obtain depends on how the system is prepared.Comment: 10 pages, 15 postscript figures, version to appear in PR

Nonlinear analysis of spacecraft thermal models

We study the differential equations of lumped-parameter models of spacecraft thermal control. Firstly, we consider a satellite model consisting of two isothermal parts (nodes): an outer part that absorbs heat from the environment as radiation of various types and radiates heat as a black-body, and an inner part that just dissipates heat at a constant rate. The resulting system of two nonlinear ordinary differential equations for the satellite's temperatures is analyzed with various methods, which prove that the temperatures approach a steady state if the heat input is constant, whereas they approach a limit cycle if it varies periodically. Secondly, we generalize those methods to study a many-node thermal model of a spacecraft: this model also has a stable steady state under constant heat inputs that becomes a limit cycle if the inputs vary periodically. Finally, we propose new numerical analyses of spacecraft thermal models based on our results, to complement the analyses normally carried out with commercial software packages.Comment: 29 pages, 4 figure

Dynamic Vortex Phases and Pinning in Superconductors with Twin Boundaries

We investigate the pinning and driven dynamics of vortices interacting with twin boundaries using large scale molecular dynamics simulations on samples with near one million pinning sites. For low applied driving forces, the vortex lattice orients itself parallel to the twin boundary and we observe the creation of a flux gradient and vortex free region near the edges of the twin boundary. For increasing drive, we find evidence for several distinct dynamical flow phases which we characterize by the density of defects in the vortex lattice, the microscopic vortex flow patterns, and orientation of the vortex lattice. We show that these different dynamical phases can be directly related to microscopically measurable voltage - current V(I) curves and voltage noise. By conducting a series of simulations for various twin boundary parameters we derive several vortex dynamic phase diagrams.Comment: 5 figures, to appear in Phys. Rev.