Progressive Dwindling in Multiple Sclerosis: An Opportunity to Improve Care

Introduction In the general ageing population, 40% of deaths occur following a prolonged trajectory of “progressive dwindling,” characterised by chronic accumulation of disability and frailty, and associated with increased dependency and reduced reserves. Those who progressively dwindle are poorly catered for by current healthcare systems and would benefit from a coordinated approach to their medical and social care, known as formative care. People with multiple sclerosis (pwMS) may be more likely to progressively dwindle, and may be appropriate targets for formative care pathways. Objectives To determine the proportion of pwMS who follow a progressive dwindling trajectory prior to death. To relate trajectory to place of death, and examine what factors predict the progressively dwindling trajectory. Methods A retrospective observational study of 582 deceased pwMS enrolled in the UK MS Tissue Bank, including death certificates and extensive clinical summaries. Results 73.7% of pwMS had a “progressively dwindling” trajectory of dying. This was predicted by those who reach MS disease milestones earlier. 72.5% of pwMS died an MS-related death, which was predicted by an aggressive disease course from onset. Those who progressively dwindled were equally likely to die in hospital as those with other trajectories to death. Conclusions The progressively dwindling trajectory of dying is very common in pwMS, and can be predicted by earlier disease milestones. Pathways could target pwMS in these years prior to death, to improve care

Inference of riverine nitrogen processing from longitudinal and diel variation in dual nitrate isotopes

Longitudinal and diel measurements of dual isotope composition (δ¹⁵N and δ¹⁸O) in nitrate (NO<inf>3</inf>-N) were made in the Ichetucknee River, a large (∼8m³ s ^-1), entirely spring-fed river in North Florida, to determine whether isotopic variation can deconvolve assimilatory and dissimilatory removal. Comparing nitrate concentrations and isotope composition during the day and night we predicted (1) daytime declines in total fractionation due to low assimilatory fractionation and (2) diurnal variation in dual isotope coupling between 1:1 (assimilation) and 2:1 (denitrification). Five daytime longitudinal transects comprising 10 sampling stations showed consistent NO<inf>3</inf>-N removal (25-35% of inputs) and modest fractionation (¹⁵ε <inf>total</inf> between -2 and -6‰, enriching the residual nitrate pool). Lower fractionation (by ∼1‰) during two nighttime transects, suggests higher fractionation due to assimilation than denitrification. Total fractionation was significantly negatively associated with discharge, input [NO<inf>3</inf>-N], N mass removal, and fractional water loss. Despite well-constrained mass balance estimates that denitrification dominated total N removal, isotope coupling was consistently 1:1, both for longitudinal and diel sampling. Hourly samples on two dates at the downstream location showed significant diel variation in concentration ([NO<inf>3</inf>-N] amplitude = 60 to 90 μg N L^-1) and isotope composition (δ¹⁵N amplitude = -0.7‰ to -1.6‰). Total fractionation differed between day and night only on one date but estimated assimilatory fractionation assuming constant denitrification was highly variable and implausibly large (for N, ¹⁵ε = -2 to -25‰), suggesting that fractionation and removal due to denitrification is not diurnally constant. Pronounced counterclockwise hysteresis in the relationship between [NO<inf>3</inf>-N] and δ¹⁵N suggests diel variation in N isotope dynamics. Together, low fractionation, isotope versus concentration hysteresis, and consistent 1:1 isotope coupling suggests that denitrification is controlled by NO <inf>3</inf>^- diffusion into the benthic sediments, the length of which is mediated by riverine oxygen dynamics. While using dual isotope behavior to deconvolve removal pathways was not possible, isotope measurements did yield valuable information about riverine N cycling and transformations. Copyright © 2012 by the American Geophysical Union

Age effect on retina and optic disc normal values

Purpose: To investigate retinal thickness and optic disc parameters by the Retinal Thickness Analyzer (RTA) glaucoma program in older normal subjects and to determine any age effect. Methods: Subjects over 40 years of age without any prior history of eye diseases were recruited. Only subjects completely normal on clinical ophthalmologic examination and on visual field testing by Humphrey Field Analyzer (HFA) using the SITA 24-2 program were included. A total of 74 eyes from 74 subjects with even age distribution over the decades were enrolled and underwent topographic measurements of the posterior pole and of the optic disc by RTA. The `glaucoma full' program in software version 4.11B was applied. Results: Mean patient age was 59.9 +/- 10.3 years with a range from 40 to 80 years. The only parameter intraocular pressure (IOP) correlated with was retinal posterior pole asymmetry (r=0.27, p=0.02). IOP itself increased significantly with age (r=0.341, p=0.003). Mean defect and pattern standard deviation of the HFA did not correlate with any of the retinal or optic disc measurements. Increasing age correlated significantly with some of the morphologic measurements of the RTA: decreasing perifoveal minimum thickness (r=-0.258, p=0.026), increased cup-to-disc area ratio (r=0.302, p=0.016) and increased cup area (r=0.338 p=0.007). Conclusions: An age effect exists for some of the retina and optic disc measurements obtained by the RTA. Copyright (C) 2005 S. Karger AG, Basel

Hydrologie and biotic influences on nitrate removal in a subtropical spring-fed river

We use a long-term chemical and hydrologic record in combination with longitudinal sampling and highfrequency nitrate (NO3-) measurements from in situ sensors to describe temporal and spatial patterns of nitrogen (N) inputs and removal in the spring-fed Ichetucknee River (Columbia County, Florida) and to determine the hydrological, geomorphic, and biological factors that influence those dynamics. Over a 20-yr period of record, NO 3-N removal averaged 118 kg N d-1 (0.77 g N m-2 d-1 ) over the upper 5 km of the Ichetucknee River. Three independent estimates of gross autotrophic N assimilation (from gross primary production, diel NO3- variation, and standing biomass) agreed closely but accounted for less than 20% of observed N removal. Longitudinal surveys indicate negligible or negative dissolved organic nitrogen and ammonium (NH4+) production, suggesting that denitrification is the predominant mechanism of N removal in this river. A positive relationship between discharge and the magnitude of NO3-N removal shows that interactions with the surrounding floodplain exert considerable influence at high flows, and longitudinal NO3- patterns indicate that N removal may be influenced by channel morphology. These results suggest a greater role for dissimilatory processes and hydrologic connectivity with hyporheic and floodplain sediments than has been previously recognized in highly productive spring-fed rivers of north Florida. While hydrologic variation is the primary determinant of variation in NO 3- removal within the Ichetucknee River, comparison across systems indicates that biotic characteristics can cause significant deviation from predictions based on purely physical models of relationships between river size and N removal. © 2010 by the American Society of Limnology and Oceanography, Inc

Necrotic tumor growth: an analytic approach

The present paper deals with a free boundary problem modeling the growth process of necrotic multi-layer tumors. We prove the existence of flat stationary solutions and determine the linearization of our model at such an equilibrium. Finally, we compute the solutions of the stationary linearized problem and comment on bifurcation.Comment: 14 pages, 3 figure

Maximum-Reward Motion in a Stochastic Environment: The Nonequilibrium Statistical Mechanics Perspective

We consider the problem of computing the maximum-reward motion in a reward field in an online setting. We assume that the robot has a limited perception range, and it discovers the reward field on the fly. We analyze the performance of a simple, practical lattice-based algorithm with respect to the perception range. Our main result is that, with very little perception range, the robot can collect as much reward as if it could see the whole reward field, under certain assumptions. Along the way, we establish novel connections between this class of problems and certain fundamental problems of nonequilibrium statistical mechanics . We demonstrate our results in simulation examples

Broken symmetry states and divergent resistance in suspended bilayer graphene

Graphene [1] and its bilayer have generated tremendous excitement in the physics community due to their unique electronic properties [2]. The intrinsic physics of these materials, however, is partially masked by disorder, which can arise from various sources such as ripples [3] or charged impurities [4]. Recent improvements in quality have been achieved by suspending graphene flakes [5,6], yielding samples with very high mobilities and little charge inhomogeneity. Here we report the fabrication of suspended bilayer graphene devices with very little disorder. We observe fully developed quantized Hall states at magnetic fields of 0.2 T, as well as broken symmetry states at intermediate filling factors $\nu = 0$, $\pm 1$, $\pm 2$ and $\pm 3$. The devices exhibit extremely high resistance in the $\nu = 0$ state that grows with magnetic field and scales as magnetic field divided by temperature. This resistance is predominantly affected by the perpendicular component of the applied field, indicating that the broken symmetry states arise from many-body interactions.Comment: 23 pages, including 4 figures and supplementary information; accepted to Nature Physic

Ordering phenomena in quasi one-dimensional organic conductors

Low-dimensional organic conductors could establish themselves as model systems for the investigation of the physics in reduced dimensions. In the metallic state of a one-dimensional solid, Fermi-liquid theory breaks down and spin and charge degrees of freedom become separated. But the metallic phase is not stable in one dimension: as the temperature is reduced, the electronic charge and spin tend to arrange themselves in an ordered fashion due to strong correlations. The competition of the different interactions is responsible for which broken-symmetry ground state is eventually realized in a specific compound and which drives the system towards an insulating state. Here we review the various ordering phenomena and how they can be identified by optic and magnetic measurements. While the final results might look very similar in the case of a charge density wave and a charge-ordered metal, for instance, the physical cause is completely different. When density waves form, a gap opens in the density of states at the Fermi energy due to nesting of the one-dimension Fermi surface sheets. When a one-dimensional metal becomes a charge-ordered Mott insulator, on the other hand, the short-range Coulomb repulsion localizes the charge on the lattice sites and even causes certain charge patterns. We try to point out the similarities and conceptional differences of these phenomena and give an example for each of them. Particular emphasis will be put on collective phenomena which are inherently present as soon as ordering breaks the symmetry of the system.Comment: Review article Naturwissenschaften 200

The structure of a resuscitation-promoting factor domain from Mycobacterium tuberculosis shows homology to lysozymes

Resuscitation-promoting factor (RPF) proteins reactivate stationary-phase cultures of (G+C)-rich Gram-positive bacteria including the causative agent of tuberculosis, Mycobacterium tuberculosis. We report the solution structure of the RPF domain from M. tuberculosis Rv1009 (RpfB) solved by heteronuclear multidimensional NMR. Structural homology with various glycoside hydrolases suggested that RpfB cleaved oligosaccharides. Biochemical studies indicate that a conserved active site glutamate is important for resuscitation activity. These data, as well as the presence of a clear binding pocket for a large molecule, indicate that oligosaccharide cleavage is probably the signal for revival from dormancy

Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling

Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size, is associated with defective ATR-dependent DNA damage signaling. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition. We now report that mutations in the gene encoding pericentrin (PCNT)--resulting in the loss of pericentrin from the centrosome, where it has key functions anchoring both structural and regulatory proteins--also cause Seckel syndrome. Furthermore, we find that cells of individuals with Seckel syndrome due to mutations in PCNT (PCNT-Seckel) have defects in ATR-dependent checkpoint signaling, providing the first evidence linking a structural centrosomal protein with DNA damage signaling. These findings also suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function may act in common developmental pathways determining human brain and body size