Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson's disease model.

Parkinson's disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. In the MI2 mice, alterations in gait impairment can be detected by the DigiGait test from 9 months of age, while gross motor deficit was detected by rotarod test at 20 months of age when 50% of dopaminergic neurons in the substantia nigra pars compacta are lost. These changes were associated with an increase in the number and density of 20-500 nm α-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9 to 12 months of age, restored striatal dopamine release, prevented dopaminergic cell death and gait impairment. These effects were associated with a reduction of the inner density of large α-synuclein aggregates and an increase in dispersed small α-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction is associated to fine behavioral motor alterations, precedes dopaminergic axonal loss and neuronal death that become associated with a more consistent motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138b's function in vivo supporting that targeting α-synuclein aggregation is a promising therapeutic approach for PD

Learning To Be Affected: Social suffering and total pain at life’s borders.

The practice of Live Sociology in situations of pain and suffering is the author’s focus. An outline of the challenges of understanding pain is followed by a discussion of Bourdieu’s ‘social suffering’ (1999) and the palliative care philosophy of ‘total pain’. Using examples from qualitative research on disadvantaged dying migrants in the UK, attention is given to the methods that are improvised by dying people and care practitioners in attempts to bridge intersubjective divides, where the causes and routes of pain can be ontologically and temporally indeterminate and/or withdrawn. The paper contends that these latter phenomena are the incitement for the inventive bridging and performative work of care and Live Sociological methods, both of which are concerned with opposing suffering. Drawing from the ontology of total pain, I highlight the importance of (i) an engagement with a range of materials out of which attempts at intersubjective bridging can be produced, and which exceed the social, the material, and the temporally linear; and (ii) an empirical sensibility that is hospitable to the inaccessible and non-relational

Medial gastrocnemius muscle stiffness cannot explain the increased ankle joint range of motion following passive stretching in children with cerebral palsy.

Stretching is often used to increase/maintain joint range of motion (ROM) in children with cerebral palsy (CP) but the effectiveness of these interventions is limited. Therefore, this study aimed to determine the acute changes in muscle-tendon lengthening properties that contribute to increased ROM after a bout of stretching in children with CP. Eleven children with spastic CP (age:12.1(3)y, 5/6 hemiplegia/diplegia, 7/4 GMFCS level I/II) participated in this study. Each child received 3 sets of 5 × 20 s passive, manual static dorsiflexion stretches separated by 30 s rest, and 60 s rest between sets. Pre- and immediately post-stretching, ultrasound was used to measure medial gastrocnemius fascicle lengthening continuously over the full ROM and an individual common ROM pre- to post-stretching. Simultaneously, 3D motion of two marker clusters on the shank and the foot was captured to calculate ankle angle, and ankle joint torque was calculated from manually applied torques and forces on a 6DoF load cell. After stretching, ROM was increased (9.9° (12.0), P = 0.005). Over a ROM common to both pre and post measurements, there were no changes in fascicle lengthening or torque. The maximal ankle joint torque tolerated by the participants increased (2.9(2.4) Nm, P = 0.003) and at this highest passive torque maximal fascicle length was 2.8(2.4) mm greater (P = 0.009) when compared to before stretching. These results indicate that the stiffness of the muscle fascicles in children with CP remain unaltered by an acute bout of stretching. This article is protected by copyright. All rights reserved

Seasonality of Overseas Tourism Demand in Scotland: A Regional Analysis

This paper examines patterns of seasonality in international tourism to the regions of Scotland. Quarterly numbers of overnight stays are disaggregated by trip purpose. Seasonality in vacation tourism to Scotland is shown to be defined by more than a simple rural–urban division. Overseas visiting friends and relatives (VFR) tourism is largely an urban phenomenon and is consequently less seasonal than vacation tourism. Lower seasonal concentration of VFR tourism is not uniform across the regions. Although levels of seasonal intensity of business tourism to the three principal cities of Scotland are approximately the same, there are noticeable variations over time

What should deflationism be when it grows up?

http://philpapers.org/rec/HORWSDI argue that a popular brand of deflationism about truth, disquotationalism, does not adequately account for some central varieties of truth ascription. For example, given Boyle's Law is ''The product of pressure and volume is exactly a constant for an ideal gas'', disquotationalism does not explain why the blind ascription ''Boyle's Law is true'' implies that the product of pressure and volume is exactly a constant for an ideal gas, and given Washington said only ''Birds sing'', disquotationalism does not explain why the existentially quantified ascription ''Something Washington said is true'' implies that birds sing. Thus disquotationalism fails to account for all the facts about truth.This project was supported by a grant from the University of Missouri Research Board

Feminist phenomenology and the woman in the running body

Modern phenomenology, with its roots in Husserlian philosophy, has been taken up and utilised in a myriad of ways within different disciplines, but until recently has remained relatively under-used within sports studies. A corpus of sociological-phenomenological work is now beginning to develop in this domain, alongside a longer standing literature in feminist phenomenology. These specific social-phenomenological forms explore the situatedness of lived-body experience within a particular social structure. After providing a brief overview of key strands of phenomenology, this article considers some of the ways in which sociological, and particularly feminist phenomenology, might be used to analyse female sporting embodiment. For illustrative purposes, data from an autophenomenographic project on female distance running are also included, in order briefly to demonstrate the application of phenomenology within sociology, as both theoretical framework and methodological approach

One Specialty’s Collaborative Approach to Competency-Based Curriculum Development

The authors describe a seven-step consensus development process used to create the two most recent editions of the Academic Pediatric Association’s (APA’s) educational guidelines for pediatric residency. The 1996 (printed) and 2004 (online) editions of the guidelines were designed as flexible tools to help residency programs meet changing accreditation requirements by providing lists of goals and objectives and objective-based evaluation tools. The guidelines were developed in seven steps: (1) centralized national leadership combined with coordinated, disseminated authorship, (2) clear definition of targeted users and repeated assessment of their needs, (3) incorporation of up-to-date information from the literature and national experts, (4) responsive consultation with the national Pediatric Residency Review Committee on the latest accreditation requirements, (5) wide distribution for prepublication review, to obtain broad organizational buy-in and end-user acceptance, (6) intensive dissemination and faculty development through multiple national workshops over several years, and (7) careful evaluation of utilization and user feedback. Representatives of all major organizations involved in pediatric education helped to refine the guidelines. User surveys conducted for the 1996 edition, and Web site user data collected for the 2004 edition, demonstrate that both editions have been used by most residency programs throughout the country. The authors believe that the multifaceted approach to consensus development and the customizable design of the curricular tools in the APA’s guidelines are directly associated with their broad national use. These methods may help to guide educators in other disciplines who are interested in developing and implementing educational products for national dissemination and use

The four qualities of life: Ordering concepts and measures of the good life

The terms 'quality-of-life', 'wellbeing' and 'happiness' denote different meanings; sometimes they are used as an umbrella term for all of value, and the other times to denote special merits. This paper is about the specific meanings of the terms. It proposes a classification based on two bi-partitions; between life 'chances' and life 'results', and between 'outer' and 'inner' qualities. Together these dichotomies imply four qualities of life: 1) livability of the environment, 2) life-ability of the individual, 3) external utility of life and 4) inner appreciation of life. This fourfold matrix is applied in three ways: firstly to place related notions and alternative classifications, secondly to explore substantive meanings in various measures for quality of life and thirdly to find out whether quality-of-life can be measured comprehensively. This last question is answered in the negative. Current sum-scores make little sense. The most inclusive summary measure is still how long and happily people live

In-vivo monitoring for electrical expression of plant living parameters by an impedance lab system

We present a complete in-lab system to monitor the plant and its surrounding environment. The plant impedance is directly measured in a continuous manner, while, simultaneously surrounding environment parameters known to affect plant status, are monitored. This is done combining a new in-vivo direct measurement of the plant together with an embedded system using available sensor technology and a designated interface for continuous data acquisition. Furthermore, the next versions this system can be deployed as a field monitoring device, with simple adaptations