Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis.

BACKGROUND: [corrected] Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration. To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments. RESULTS: By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination. CONCLUSIONS: These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis

A realist evaluation of a physical activity participation intervention for children and youth with disabilities: What works, for whom, in what circumstances, and how?

Background: The need to identify strategies that facilitate involvement in physical activity for children and youth with disabilities is recognised as an urgent priority. This study aimed to describe the association between context, mechanisms and outcome(s) of a participation-focused physical activity intervention to understand what works, in what conditions, and how. Methods: This study was designed as a realist evaluation. Participant recruitment occurred through purposive and theoretical sampling of children and parents participating in the Local Environment Model intervention at Beitostolen Healthsports Centre in Norway. Ethnographic methods comprising participant observation, interviews, and focus groups were employed over 15 weeks in the field. Data analysis was completed using the context-mechanism-outcome framework of realist evaluation. Context-mechanism-outcome connections were generated empirically from the data to create a model to indicate how the program activated mechanisms within the program context, to enable participation in physical activity. Results: Thirty one children with a range of disabilities (mean age 12y 6 m (SD 2y 2 m); 18 males) and their parents (n=44; 26 mothers and 18 fathers) participated in the study. Following data synthesis, a refined program theory comprising four context themes, five mechanisms, and six outcomes, were identified. The mechanisms (choice, fun, friends, specialised health professionals, and time) were activated in a context that was safe, social, learning-based and family-centred, to elicit outcomes across all levels of the International Classification of Functioning, Disability and Health. Conclusions: The interaction of mechanisms and context as a whole facilitated meaningful outcomes for children and youth with disabilities, and their parents. Whilst optimising participation in physical activity is a primary outcome of the Local Environment Model, the refined program theory suggests the participation-focused approach may act as a catalyst to promote a range of outcomes. Findings from this study may inform future interventions attempting to enable participation in physical activity for children and youth with disabilities

Mutation Accumulation in a Selfing Population: Consequences of Different Mutation Rates between Selfers and Outcrossers

Currently existing theories predict that because deleterious mutations accumulate at a higher rate, selfing populations suffer from more intense genetic degradation relative to outcrossing populations. This prediction may not always be true when we consider a potential difference in deleterious mutation rate between selfers and outcrossers. By analyzing the evolutionary stability of selfing and outcrossing in an infinite population, we found that the genome-wide deleterious mutation rate would be lower in selfing than in outcrossing organisms. When this difference in mutation rate was included in simulations, we found that in a small population, mutations accumulated more slowly under selfing rather than outcrossing. This result suggests that under frequent and intense bottlenecks, a selfing population may have a lower risk of genetic extinction than an outcrossing population

Generation and characterisation of Friedreich ataxia YG8R mouse fibroblast and neural stem cell models

This article has been made available through the Brunel Open Access Publishing Fund.Background: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by GAA repeat expansion in the first intron of the FXN gene, which encodes frataxin, an essential mitochondrial protein. To further characterise the molecular abnormalities associated with FRDA pathogenesis and to hasten drug screening, the development and use of animal and cellular models is considered essential. Studies of lower organisms have already contributed to understanding FRDA disease pathology, but mammalian cells are more related to FRDA patient cells in physiological terms. Methodology/Principal Findings: We have generated fibroblast cells and neural stem cells (NSCs) from control Y47R mice (9 GAA repeats) and GAA repeat expansion YG8R mice (190+120 GAA repeats). We then differentiated the NSCs in to neurons, oligodendrocytes and astrocytes as confirmed by immunocytochemical analysis of cell specific markers. The three YG8R mouse cell types (fibroblasts, NSCs and differentiated NSCs) exhibit GAA repeat stability, together with reduced expression of frataxin and reduced aconitase activity compared to control Y47R cells. Furthermore, YG8R cells also show increased sensitivity to oxidative stress and downregulation of Pgc-1α and antioxidant gene expression levels, especially Sod2. We also analysed various DNA mismatch repair (MMR) gene expression levels and found that YG8R cells displayed significant reduction in expression of several MMR genes, which may contribute to the GAA repeat stability. Conclusions/Significance: We describe the first fibroblast and NSC models from YG8R FRDA mice and we confirm that the NSCs can be differentiated into neurons and glia. These novel FRDA mouse cell models, which exhibit a FRDA-like cellular and molecular phenotype, will be valuable resources to further study FRDA molecular pathogenesis. They will also provide very useful tools for preclinical testing of frataxin-increasing compounds for FRDA drug therapy, for gene therapy, and as a source of cells for cell therapy testing in FRDA mice. © 2014 Sandi et al

Cluster analysis for the identification of clinical phenotypes among antiphospholipid antibody-positive patients from the APS ACTION Registry

Objective: This study aimed to use cluster analysis (CA) to identify different clinical phenotypes among antiphospholipid antibodies (aPL)-positive patients. Methods: The Alliance for Clinical Trials and International Networking (APS ACTION) Registry includes persistently positive aPL of any isotype based on the Sydney antiphospholipid syndrome (APS) classification criteria. We performed CA on the baseline characteristics collected retrospectively at the time of the registry entry of the first 500 patients included in the registry. A total of 30 clinical data points were included in the primary CA to cover the broad spectrum of aPL-positive patients. Results: A total of 497 patients from international centres were analysed, resulting in three main exclusive clusters: (a) female patients with no other autoimmune diseases but with venous thromboembolism (VTE) and triple-aPL positivity; (b) female patients with systemic lupus erythematosus, VTE, aPL nephropathy, thrombocytopaenia, haemolytic anaemia and a positive lupus anticoagulant test; and (c) older men with arterial thrombosis, heart valve disease, livedo, skin ulcers, neurological manifestations and cardiovascular disease (CVD) risk factors. Conclusions: Based on our hierarchical cluster analysis, we identified different clinical phenotypes of aPL-positive patients discriminated by aPL profile, lupus or CVD risk factors. Our results, while supporting the heterogeneity of aPL-positive patients, also provide a foundation to understand disease mechanisms, create new approaches for APS classification and ultimately develop new management approaches

Similar dispersal patterns between two closely related birds with contrasting migration strategies

Studying dispersal is crucial to understand metapopulation and sink-source dynamics and invasion processes. The capability to disperse is especially important for species living in fragmented habitats like wetlands. We investigated the distribution of natal and breeding dispersal distances and philopatry in Spanish populations of two closely related reedbed-nesting birds, the Moustached Warbler Acrocephalus melanopogon and the Eurasian Reed Warbler Acrocephalus scirpaceus. These warblers are morphologically very similar, but differ in migration strategy and, in our study area, in population size. Our aims were to find the best model for dispersal distances and to assess the occurrence of intra- or interspecific differences in dispersal patterns. We used ringing data from the Spanish marking scheme and selected recaptures to avoid including migrating individuals. In both species, most individuals were philopatric but dispersing birds were able to cross large distances (up to more than 100 km), suggesting the capability to compensate for habitat fragmentation. We found the heavy-tailed Cauchy distribution to be the best conceptual description for our data, in all cases but natal dispersal of Moustached Warblers. Among Eurasian Reed Warblers, natal philopatry was lower than breeding philopatry. We found no significant interspecific differences. This does not confirm the hypothesis of higher dispersal ability in long distance migrants (like Eurasian Reed Warblers) than in resident/short distance migrant bird species (like Moustached Warblers). The similarity in dispersal patterns among the two warblers may be explained by their close phylogenetic relatedness, similar constraints imposed on both species by a patchy habitat or similar evolutionary pressures.We are grateful to the many ringers who collected the data during years of fieldwork in Spain. Francesco Ceresa is supported by an "Atraent talent'' grant from the University of Valencia.Ceresa, F.; Belda, E.; Monrós González, JS. (2016). Similar dispersal patterns between two closely related birds with contrasting migration strategies. Population Ecology. 58(3):421-427. doi:10.1007/s10144-016-0547-0S421427583Banco de datos de anillamiento del remite ICONA – Ministerio de Medio Ambiente (2015) Datos de anillamiento y recuperaciones en España. Ministerio de Agricultura, Alimentación y Medio Ambiente, SEO/BirdLife, ICO, EBD-CSIC y GOB. Madrid (in Spanish)Begon M, Townsend CR, Harper JL (2006) Ecology: from individual to ecosystems, 4th edn. Blackwell Publishing, OxfordBlomqvist D, Fessl B, Hoi H, Kleindorfer S (2005) High frequency of extra-pair fertilisation in the moustached warbler, a songbird with a variable breeding system. Behaviour 142:1133–1148Bohonak AJ (1999) Dispersal, gene flow, and population structure. Q Rev Biol 74:21–45Burnham KP, Anderson DR (2002) Model selection and multi-model inference: a practical information-theoretic approach. Springer Verlag, New YorkCantos FJ, Tellería JL (1994) Stopover site fidelity of four migrant warblers in the Iberian Peninsula. J Avian Biol 25:131–134Carrascal LM, Palomino D (2008) Las aves comunes reproductoras en España. Población en 2004–2006. SEO/BirdLife, Madrid (in Spanish with English abstract)Carrascal LM, Weykam S, Palomino D, Lobo JM, Díaz L (2005) Atlas Virtual de las Aves Terrestres de España. http://www.vertebradosibericos.org/atlasaves.html . Accessed 16 Feb 2016Castany J (2003) El carricerín real (Acrocephalus melanopogon) en el P. N. del Prat de Cabanes-Torreblanca. Doctoral thesis. University of Valencia, Valencia (in Spanish)Castany J, López G (2006) El carricerín real en España. I Censo Nacional (2005). SEO/BirdLife, Madrid (in Spanish with English abstract)Ceresa F, Belda EJ, Kvist L, Rguibi-Idrissi H, Monrós JS (2015) Does fragmentation of wetlands affect gene flow in sympatric Acrocephalus warblers with different migration strategies? J Avian Biol 46:577–588Cooper NW, Murphy MT, Redmond LJ, Dolan AC (2009) Density-dependent age at first reproduction in the eastern kingbird. Oikos 118:413–419Delignette-Muller ML, Dutang C (2015) fitdistrplus: An R Package for fitting distributions. J Stat Softw 64:1–34. http://www.jstatsoft.org/v64/i04/ . Accessed 2 Sep 2015Frankham R, Ballou JD, Briscoe DA (2010) Introduction to conservation genetics, 2nd edn. Cambridge University Press, CambridgeHengeveld R (1994) Small step invasion research. Trends Ecol Evol 9:339–342Hodges MF Jr, Krementz DG (1996) Neotropical migratory breeding bird communities in riparian forests of different widths along the Altamaha River, Georgia. Wilson Bulletin 108:496–506Ibrahim KM, Nichols RA, Hewitt GM (1996) Spatial patterns of genetic variation generated by different forms of dispersal during range expansion. Heredity 77:282–291Kennerley P, Pearson D (2010) Reed and bush warblers. Christopher Helm Publishers Ltd., LondonKoenig WD, Van Vuren D, Hooge PN (1996) Detectability, philopatry, and the distribution of dispersal distances in vertebrates. Trends Ecol Evol 11:514–517Kralj J, Procházka P, Fainová D, Patzenhauerová H, Tutiš V (2010) Intraspecific variation in the wing shape and genetic differentiation of reed warblers Acrocephalus scirpaceus in Croatia. Acta Ornithologica 45:51–58Lambrechts MM, Blondel J, Caizergues A, Dias PC, Pradol R, Thomas DW (1999) Will estimates of lifetime recruitment of breeding offspring on small-scale study plots help us to quantify processes underlying adaptation? Oikos 86:147–151Machtans CS, Villard MA, Hannon SJ (1996) Use of riparian buffer strips as movement corridors by forest birds. Conserv Biol 10:1366–1379Nathan R, Perry G, Cronin JT, Strand AE, Cain ML (2003) Methods for estimating long-distance dispersal. Oikos 103:261–273Newton I (1992) Experiments on the limitation of bird numbers by territorial behaviour. Biol Rev 67:129–173Norberg UM (1990) Vertebrate flight, mechanics, physiology, morphology, ecology and evolution. Springer Verlag, BerlinParacuellos M, Tellería JL (2004) Factors affecting the distribution of a waterbird community: the role of habitat configuration and bird abundance. Waterbirds 27:446–453Paradis E, Baillie SR, Sutherland WJ, Gregory RD (1998) Patterns of natal and breeding dispersal in birds. J Anim Ecol 67:518–536Paradis E, Baillie SR, Sutherland WJ (2002) Modeling large-scale dispersal distances. Ecol Model 151:279–292Peirò IG (2003) Intraspecific variation in the wing shape of the long-distance migrant Reed Warbler Acrocephalus scirpaceus: effects of age and distance of migration. Ardeola 50:31–37Plissner JH, Gowaty PA (1996) Patterns of natal dispersal, turnover, and dispersal costs in eastern bluebirds. Anim Behav 51:1307–1322Procházka P, Stokke BG, Jensen H, Fainová D, Bellinvia E, Fossøy F, Vikan JR, Bryja J, Soler M (2011) Low genetic differentiation among reed warbler Acrocephalus scirpaceus populations across Europe. J Avian Biol 42:103–113R Core Team (2014) R: A language and environment for statistical computing. R foundation for statistical computing, ViennaRobinson WD (1999) Long-term changes in the avifauna of Barro Colorado Island, Panama, a tropical forest isolate. Conserv Biol 13:85–97SEO/BirdLife (2016a) Acrocephalus melanopogon. Anillamientos por década. http://www.anillamientoseo.org/ . Accessed 19 Feb 2016 (in Spanish)SEO/BirdLife (2016b) Acrocephalus scirpaceus. Anillamientos por década. http://www.anillamientoseo.org/ . Accessed 19 Feb 2016 (in Spanish)Shigesada N, Kawasaki K, Takeda Y (1995) Modeling stratified diffusion in biological invasions. Am Nat 146:229–251Silva JP, Phillips L, Jones W, Eldridge J, O’Hara E (2007) Life and Europe’s wetlands, restoring a vital ecosystem. Office for Official Publications of the European Communities, LuxembourgSutherland GD, Harestad AS, Price K, Lertzman KP (2000) Scaling of natal dispersal distances in terrestrial birds and mammals. Conservation ecology 4:16. http://www.consecol.org/vol4/iss1/art16 . Accessed 23 Oct 2015Vadász C, Német Á, Karcza Z, Loránt M, Biró C, Csörgő T (2008) Study on breeding site fidelity of Acrocephalus Warblers in Central Hungary. Acta Zool Acad Sci H 54(Suppl. 1):167–175Van Houtan KS, Pimm SL, Halley JM, Bierregaard RO Jr, Lovejoy TE (2007) Dispersal of Amazonian birds in continuous and fragmented forest. Ecol Lett 10:219–229Van Houtan KS, Bass OL Jr, Lockwood J, Pimm SL (2010) Importance of estimating dispersal for endangered bird management. Conservation Letters 3:260–266Van Vessem J, Hecker N, Tucker GM (1997) Inland wetlands. In: Tucker GM, Evans MI (eds) Habitats for birds in Europe: A conservation strategy for the wider environment. BirdLife Conservation Series 6. BirdLife International, Cambridge, pp 125–158Waser PM, Creel SR, Lucas JR (1994) Death and disappearance: estimating mortality risk associated with philopatry and dispersal. Behav Ecol 5:135–141Willis EO (1974) Populations and local extinctions of birds on Barro Colorado Island, Panama. Ecol Monogr 44:153–169Winkler DW, Wrege PH, Allen PE, Kast TL, Senesac P, Wasson MF, Llambías PE, Ferretti V, Sullivan PJ (2004) Breeding dispersal and philopatry in the tree swallow. Condor 106:768–776Winkler DW, Wrege PH, Allen PE, Kast TL, Senesac P, Wasson MF, Sullivan PJ (2005) The natal dispersal of tree swallows in a continuous mainland environment. J Anim Ecol 74:1080–109

Characteristics of Antiphospholipid Antibody Positive Patients in AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking

OBJECTIVE: To describe baseline characteristics of antiphospholipid antibody (aPL)-positive patients, overall and by clinical and laboratory subtypes, enrolled in an international registry. METHODS: AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking Registry includes persistently aPL-positive adults. We evaluated baseline sociodemographic and aPL-related (APS classification criteria and "non-criteria") characteristics of patients overall and in subgroups (aPL-positive without APS, APS overall, thrombotic APS [TAPS] only, obstetric APS [OAPS] only, and both TAPS/OAPS). We assessed baseline characteristics of patients tested for three aPL (lupus anticoagulant test [LA], anticardiolipin antibody [aCL], and anti-β2 -Glycoprotein-I [aβ2 GPI]) by aPL profiles (LA only, single, double, and triple aPL positivity). RESULTS: Of 804 aPL-positive patients (mean age: 45 ± 13y; female: 74%; white 68%; other systemic autoimmune diseases: 36%), 80% were classified as APS (55% TAPS, 9% OAPS, and 15% TAPS/OAPS). In the overall cohort, 71% had vascular thrombosis, 50% with pregnancy history had obstetric morbidity, and 56% had at least one non-criteria manifestation. Among those with three aPL tested (n: 660), 42% were triple aPL positive. While single, double and triple aPL positive subgroups had similar frequencies of vascular, obstetric, and non-criteria events, these events were lowest in the single aPL subgroup consisting of aCL or aβ2 GPI only. CONCLUSION: Our study demonstrates the heterogeneity of aPL-related clinical manifestations and laboratory profiles in a multicenter, international cohort. Within single aPL-positivity, LA may be a major contributor to clinical events. Future prospective analyses, using standardized core laboratory aPL tests, will help clarify aPL risk profiles and improve risk stratification

Bcl-2 protein family: Implications in vascular apoptosis and atherosclerosis

Apoptosis has been recognized as a central component in the pathogenesis of atherosclerosis, in addition to the other human pathologies such as cancer and diabetes. The pathophysiology of atherosclerosis is complex, involving both apoptosis and proliferation at different phases of its progression. Oxidative modification of lipids and inflammation differentially regulate the apoptotic and proliferative responses of vascular cells during progression of the atherosclerotic lesion. Bcl-2 proteins act as the major regulators of extrinsic and intrinsic apoptosis signalling pathways and more recently it has become evident that they mediate the apoptotic response of vascular cells in response to oxidation and inflammation either in a provocative or an inhibitory mode of action. Here we address Bcl-2 proteins as major therapeutic targets for the treatment of atherosclerosis and underscore the need for the novel preventive and therapeutic interventions against atherosclerosis, which should be designed in the light of molecular mechanisms regulating apoptosis of vascular cells in atherosclerotic lesions

Plant Diversity Changes during the Postglacial in East Asia: Insights from Forest Refugia on Halla Volcano, Jeju Island

Understanding how past climate changes affected biodiversity is a key issue in contemporary ecology and conservation biology. These diversity changes are, however, difficult to reconstruct from paleoecological sources alone, because macrofossil and pollen records do not provide complete information about species assemblages. Ecologists therefore use information from modern analogues of past communities in order to get a better understanding of past diversity changes. Here we compare plant diversity, species traits and environment between late-glacial Abies, early-Holocene Quercus, and mid-Holocene warm-temperate Carpinus forest refugia on Jeju Island, Korea in order to provide insights into postglacial changes associated with their replacement. Based on detailed study of relict communities, we propose that the late-glacial open-canopy conifer forests in southern part of Korean Peninsula were rich in vascular plants, in particular of heliophilous herbs, whose dramatic decline was caused by the early Holocene invasion of dwarf bamboo into the understory of Quercus forests, followed by mid-Holocene expansion of strongly shading trees such as maple and hornbeam. This diversity loss was partly compensated in the Carpinus forests by an increase in shade-tolerant evergreen trees, shrubs and lianas. However, the pool of these species is much smaller than that of light-demanding herbs, and hence the total species richness is lower, both locally and in the whole area of the Carpinus and Quercus forests. The strongly shading tree species dominating in the hornbeam forests have higher leaf tissue N and P concentrations and smaller leaf dry matter content, which enhances litter decomposition and nutrient cycling and in turn favored the selection of highly competitive species in the shrub layer. This further reduced available light and caused almost complete disappearance of understory herbs, including dwarf bamboo

Frequent Arousal from Hibernation Linked to Severity of Infection and Mortality in Bats with White-Nose Syndrome

White-nose syndrome (WNS), an emerging infectious disease that has killed over 5.5 million hibernating bats, is named for the causative agent, a white fungus (Geomyces destructans (Gd)) that invades the skin of torpid bats. During hibernation, arousals to warm (euthermic) body temperatures are normal but deplete fat stores. Temperature-sensitive dataloggers were attached to the backs of 504 free-ranging little brown bats (Myotis lucifugus) in hibernacula located throughout the northeastern USA. Dataloggers were retrieved at the end of the hibernation season and complete profiles of skin temperature data were available from 83 bats, which were categorized as: (1) unaffected, (2) WNS-affected but alive at time of datalogger removal, or (3) WNS-affected but found dead at time of datalogger removal. Histological confirmation of WNS severity (as indexed by degree of fungal infection) as well as confirmation of presence/absence of DNA from Gd by PCR was determined for 26 animals. We demonstrated that WNS-affected bats aroused to euthermic body temperatures more frequently than unaffected bats, likely contributing to subsequent mortality. Within the subset of WNS-affected bats that were found dead at the time of datalogger removal, the number of arousal bouts since datalogger attachment significantly predicted date of death. Additionally, the severity of cutaneous Gd infection correlated with the number of arousal episodes from torpor during hibernation. Thus, increased frequency of arousal from torpor likely contributes to WNS-associated mortality, but the question of how Gd infection induces increased arousals remains unanswered