New approaches in the management of multiple sclerosis

Multiple sclerosis (MS) is a central nervous system chronic inflammatory disease that is characterized by an extensive and complex immune response. Scientific advances have occurred in immunology, pathophysiology, and diagnostic and clinical assessment tools, and recent discovery of unique therapeutic targets has spurred numerous Phase II and Phase III clinical trials. Reductions in MS relapse rates and improvements in T2 or gadolinium-enhancing lesion burdens have been reported from Phase III trials that include fingolimod, alemtuzumab, cladribine, and rituximab. Promising Phase II trial data exist for teriflunomide, daclizumab, laquinimod, and fumarate. The optimism created by these favorable findings must be tempered with evaluation of the adverse effect profile produced by these new agents. Given the discovery of progressive multifocal leukoencephalopathy with the use of natalizumab, ongoing vigilance for rare and life-threatening reactions due to new agents should be paramount. Patients with MS often experience difficulty with ambulation, spasticity, and cognition. Recent clinical trial data from two Phase III dalfampridine-SR trials indicate certain patients receive benefits in ambulation. This article provides an overview of data from clinical trials of newer agents of potential benefit in MS

Bistability of Slow and Fast Traveling Waves in Fluid Mixtures

The appearence of a new type of fast nonlinear traveling wave states in binary fluid convection with increasing Soret effect is elucidated and the parameter range of their bistability with the common slower ones is evaluated numerically. The bifurcation behavior and the significantly different spatiotemporal properties of the different wave states - e.g. frequency, flow structure, and concentration distribution - are determined and related to each other and to a convenient measure of their nonlinearity. This allows to derive a limit for the applicability of small amplitude expansions. Additionally an universal scaling behavior of frequencies and mixing properties is found. PACS: 47.20.-k, 47.10.+g, 47.20.KyComment: 4 pages including 5 Postscript figure

Subharmonic bifurcation cascade of pattern oscillations caused by winding number increasing entrainment

Convection structures in binary fluid mixtures are investigated for positive Soret coupling in the driving regime where solutal and thermal contributions to the buoyancy forces compete. Bifurcation properties of stable and unstable stationary square, roll, and crossroll (CR) structures and the oscillatory competition between rolls and squares are determined numerically as a function of fluid parameters. A novel type of subharmonic bifurcation cascade (SC) where the oscillation period grows in integer steps as $n (2\pi)/(\omega)$ is found and elucidated to be an entrainment process.Comment: 7 pages, 4 figure

Influence of through-flow on linear pattern formation properties in binary mixture convection

We investigate how a horizontal plane Poiseuille shear flow changes linear convection properties in binary fluid layers heated from below. The full linear field equations are solved with a shooting method for realistic top and bottom boundary conditions. Through-flow induced changes of the bifurcation thresholds (stability boundaries) for different types of convective solutions are deter- mined in the control parameter space spanned by Rayleigh number, Soret coupling (positive as well as negative), and through-flow Reynolds number. We elucidate the through-flow induced lifting of the Hopf symmetry degeneracy of left and right traveling waves in mixtures with negative Soret coupling. Finally we determine with a saddle point analysis of the complex dispersion relation of the field equations over the complex wave number plane the borders between absolute and convective instabilities for different types of perturbations in comparison with the appropriate Ginzburg-Landau amplitude equation approximation. PACS:47.20.-k,47.20.Bp, 47.15.-x,47.54.+rComment: 19 pages, 15 Postscript figure

Influence of the Soret effect on convection of binary fluids

Convection in horizontal layers of binary fluids heated from below and in particular the influence of the Soret effect on the bifurcation properties of extended stationary and traveling patterns that occur for negative Soret coupling is investigated theoretically. The fixed points corresponding to these two convection structures are determined for realistic boundary conditions with a many mode Galerkin scheme for temperature and concentration and an accurate one mode truncation of the velocity field. This solution procedure yields the stable and unstable solutions for all stationary and traveling patterns so that complete phase diagrams for the different convection types in typical binary liquid mixtures can easily be computed. Also the transition from weakly to strongly nonlinear states can be analyzed in detail. An investigation of the concentration current and of the relevance of its constituents shows the way for a simplification of the mode representation of temperature and concentration field as well as for an analytically manageable few mode description.Comment: 30 pages, 12 figure

Convection in Binary Fluid Mixtures. II. Localized Traveling Waves. (Physical Review E, in press)

Nonlinear, spatially localized structures of traveling convection rolls are investigated in quantitative detail as a function of Rayleigh number for two different Soret coupling strengths (separation ratios) with Lewis and Prandtl numbers characterizing ethanol-water mixtures. A finite-difference method was used to solve the full hydrodynamic field equations numerically. Structure and dynamics of these localized traveling waves (LTW) are dominated by the concentration field. Like in the spatially extended convective states ( cf. accompanying paper), the Soret-induced concentration variations strongly influence, via density changes, the buoyancy forces that drive convection. The spatio-temporal properties of this feed-back mechanism, involving boundary layers and concentration plumes, show that LTW's are strongly nonlinear states. Light intensity distributions are determined that can be observed in side-view shadowgraphs. Detailed analyses of all fields are made using colour-coded isoplots, among others. In the frame comoving with their drift velocity, LTW's display a nontrivial spatio-temporal symmetry consisting of time-translation by half an oscillation period combined with vertical reflection through the horizontal midplane of the layer. A time-averaged concentration current is driven by a phase difference between the waves of concentration and vertical velocity in the bulk of the LTW state. The associated large-scale concentration redistribution stabilizes the LTW and controls its drift velocity into the quiescent fluid by generating a buoyancy-reducing concentration "barrier" ahead of the leading LTW front. The selection of the width of the LTW's is investigated and comparisons with experiments are presented.Comment: 18 pages and 6 figures as uuencoded Postscript file (using uufiles) 1 color figure as uuencoded Postscript file, a high resolution version of the color figure (about 10MB) can be requested from [email protected] or [email protected].: (Barten)present address: PSI, CH-5232 Villigen PSI, Switzerlan

Rights, Knowledge, and Governance for Improved Health Equity in Urban Settings

All three of the interacting aspects of daily urban life (physical environment, social conditions, and the added pressure of climate change) that affect health inequities are nested within the concept of urban governance, which has the task of understanding and managing the interactions among these different factors so that all three can be improved together and coherently. Governance is defined as: “the process of collective decision making and processes by which decisions are implemented or not implemented”: it is concerned with the distribution, exercise, and consequences of power. Although there appears to be general agreement that the quality of governance is important for development, much less agreement appears to exist on what the concept really implies and how it should be used. Our review of the literature confirmed significant variation in meaning as well as in the practice of urban governance arrangements. The review found that the linkage between governance practices and health equity is under-researched and/or has been neglected. Reconnecting the fields of urban planning, social sciences, and public health are essential “not only for improving local governance, but also for understanding and addressing global political change” for enhanced urban health equity. Social mobilization, empowering governance, and improved knowledge for sustainable and equitable development in urban settings is urgently needed. A set of strategic research questions are suggested

Amplitude measurements of Faraday waves

A light reflection technique is used to measure quantitatively the surface elevation of Faraday waves. The performed measurements cover a wide parameter range of driving frequencies and sample viscosities. In the capillary wave regime the bifurcation diagrams exhibit a frequency independent scaling proportional to the wavelength. We also provide numerical simulations of the full Navier-Stokes equations, which are in quantitative agreement up to supercritical drive amplitudes of 20%. The validity of an existing perturbation analysis is found to be limited to 2.5% overcriticaly.Comment: 7 figure

Targeting VIP and PACAP receptor signalling: new therapeutic strategies in multiple sclerosis

MS (multiple sclerosis) is a chronic autoimmune and neurodegenerative pathology of the CNS (central nervous system) affecting approx. 2.5 million people worldwide. Current and emerging DMDs (disease-modifying drugs) predominantly target the immune system. These therapeutic agents slow progression and reduce severity at early stages of MS, but show little activity on the neurodegenerative component of the disease. As the latter determines permanent disability, there is a critical need to pursue alternative modalities. VIP (vasoactive intestinal peptide) and PACAP (pituitary adenylate cyclase-activating peptide) have potent anti-inflammatory and neuroprotective actions, and have shown significant activity in animal inflammatory disease models including the EAE (experimental autoimmune encephalomyelitis) MS model. Thus, their receptors have become candidate targets for inflammatory diseases. Here, we will discuss the immunomodulatory and neuroprotective actions of VIP and PACAP and their signalling pathways, and then extensively review the structure–activity relationship data and biophysical interaction studies of these peptides with their cognate receptors