Neurofilament Proteins as Body Fluid Biomarkers of Neurodegeneration in Multiple Sclerosis

Biomarkers of axonal degeneration have the potential to improve our capacity to predict and monitor neurological outcome in multiple sclerosis (MS) patients. Neurofilament proteins, one of the major proteins expressed within neurons and axons, have been detected in cerebrospinal fluid and blood samples from MS patients and are now being actively investigated for their utility as prognostic indicators of disease progression in MS. In this paper, we summarize the current literature on neurofilament structure, assembly, and degeneration and discuss their potential utility as biomarkers for monitoring neurological decline in MS. We also discuss the need to further develop sensitive methods for assaying neurofilaments in blood to improve clinical applicability

Precarious video: historical events, trauma and memory in South African video art (Jo Ractliffe, Penny Siopis, Berni Searle, Minnette Vári)

This dissertation explores four recent examples of video art by four South African women artists. It focuses on Jo Ractliffe’s Vlakplaas: 2 June 1999 (drive-by shooting) [1999/2000], Berni Searle’s Mute (2008), Penny Siopis’ Obscure White Messenger (2010) and Minnette Vári’s Chimera (the white edition, 2001 and the black edition 2001-2002). I consider the visual, sonic, temporal, durational, spatial, sensory and affective capacities of these works, and their encounter with historical events/episodes and figures the significance and affective charge of which move across the eras differentiated as apartheid and post-apartheid. I seek to contribute to critiques of the post-apartheid democracy, and the impetus to move forward from the past, to forgive and reconcile its violence, while not actively and critically engaging historical trauma, and its relation to memory. Each of the videos engaged enter into a dialogue with historical narratives embedded within the experience and memory of violence and racial oppression in South Africa. The study is concerned with the critical significance and temporality of memory in relation to trauma as a historical and psychoanalytical concept applicable to ongoing conditions of historical and political violence and its continuous, apparently irresolvable repetition in political-historical life. This inquiry is underpinned by art historical approaches to the relationship between art and trauma, and, in particular, the work of Jill Bennett (2005) and Griselda Pollock (2013). It is concerned primarily with Bennett and Pollock’s privileging, from their particular theoretical perspectives, of the affects and internal logics/worlds of art objects, which prompt critical thought, and theoretical and historical inquiry. The particular temporality of video is engaged through historical and psychoanalytical concepts of trauma. The videos selected for this dissertation suggest ideas of temporal and spatial disorientation, displacement, collapse, and irresolvable repetitive return. The opacity that characterises the works is a major point of emphasis, and is related to the dissertation’s concern with trauma, racial oppression and historical/epistemic violence. A major concern is how artists and scholars enter into dialogues with history, from the perspectives of their own subjectivities, without reinscribing historical and epistemic violence, and the objectification of marginalised subjects. Situated within the parameters of feminist ethics the study foregrounds women artists. I argue for an ethics that takes into account self-reflexivity, and the artist’s, and the scholar’s, situated relationship to history, in the aftermath of sustained historical racial oppression and authoritarianism. It considers the possibilities of art objects as sites that facilitate empathetic, critical and intellectually engaged encounters with historical trauma and violence in South Africa. The videos explored counter spectacle and didactic, and authoritarian, modes of representation. In the absence of a sustained and visible art historical narrative of the history of video art in South Africa, the study focuses on work representative of the earliest, documented examples of video art by women artists, which emerge out of the transition from apartheid. The tension between history’s relationship to objectivity, detachment and empirical knowledge, and its participation in subjective, imaginary, and performative processes underpins the study

Strip Casting of Sm₂TM₁₇-Type Alloys for Production of the Metastable SmTM₇ Phase

Conventional book casting of Sm2TM17-type alloys (where TM = Co, Fe, Cu, Zr) leads to a coarse, highly segregated microstructure, predominantly due to the slow, variable cooling rate from the mould surface towards the centre of the ingot. These cast alloys require a long homogenisation treatment to remove this segregation and develop a super-saturated, metastable SmTM7-type hexagonal phase. This SmTM7 phase is a vital precursor phase required during magnet production to develop the complex cellular structure responsible for high magnetic properties. In this work, strip casting was employed to facilitate rapid solidification to develop thin flakes (<0.5 mm thick) with a columnar grain structure. Rapid cooling has the potential to produce a homogenous microstructure consisting predominantly of the metastable SmTM7 phase. This could remove or significantly reduce the need for the energy-intensive homogenisation treatment usually required in conventional magnet manufacture. This paper investigates the effect of wheel speed (and hence cooling rate) on flake thickness, microstructure, and phase balance of the cast alloys. It was shown that for wheel speeds between 1.1 and 3.0 m/s, the microstructure showed large variation; however, in all cases, evidence of the columnar SmTM7 phase was presented. The adhesion between the melt and the wheel was deemed to be critical for the nucleation and subsequent columnar growth of SmTM7 grains, where the wheel speed controlled both the flow of the alloy onto the wheel and the thickness of the resultant flake. It was determined that in order to achieve a homogenous columnar SmTM7 structure, the maximum flake thickness should be limited to 270 μm to avoid the formation of equiaxed Sm2TM17 grains through insufficient cooling

Feminist contributions on sexual experiences of women with serious mental illness: a literature review

This paper aims to explore the contributions of research that include gender perspective in analysing the sexual experiences of women diagnosed with serious mental illness and to identify any barriers and systems that impede sexual fulfilment. We have developed a qualitative literature review using the PRISMA statement. The databases SCOPUS, WOS and PsychINFO were used in this review. Studies were included if they were published up to March 15, 2022, and only studies in English were included. An initial database search was preformed; upon screening for eligibility, there remained 16 studies that explored the sexual experiences of women with diagnoses of serious mental illness. The studies were analysed by a thematic synthesis. Data was coded line-by-line which generated descriptive themes, resulting in four synthesised findings. The four synthesised findings that derived from the reviewed studies were stigma and subjectivity, the experience of interpersonal relationships, the socialisation of women and the effects of psychiatric hegemony. A feminist perspective highlights the interrelationship between gender and stigma as it relates to serious mental illness and sexuality. A feminist perspective and an intersectional approach should be adopted at the intersubjective and structural level to account for the complexity of human experience and to subvert the heteropatriarchal system

El curso CRISH (Co-Creating Innovative Solutions for Health): una historia de co-creación para la co-creación en salud

En un contexto de fragmentación de los sistemas sanitarios nacionales en Europa, aparece la necesidad de implementar un cambio de paradigma que sitúa al paciente en el centro de la innovación en salud, y que remodele el sistema alrededor del concepto de valor. La participación de los pacientes se vuelve crucial para implementar soluciones innovadoras, legítimas y sostenibles que respondan a los retos actuales y futuros en el campo de la salud y del envejecimiento. Este artículo explica el proceso de creación del curso CRISH (Cocreating Innovative Solutions for Health), un curso de formación para médicos, investigadores y pacientes que tiene el objetivo de capacitarlos para co-crear soluciones innovadoras (procesos, productos o servicios). Basado en un análisis exhaustivo de las necesidades de los actores objetivos del curso, su estructura se diseñó para dotar a los participantes de competencias teóricas, habilidades y herramientas fundamentadas en las metodologías de experiencia del paciente, investigación e innovación responsable, emprendeduría, reciprocidad y co-creación

Differentially regulated pathways by endogenous vitamin D in multiple sclerosis identified by transcriptomics of immune cell subsets

Introduction: Vitamin D deficiency is a risk factor for MS. Apart from its role in skeletal health, vitamin D is also recognised to have immunomodulatory effects, which have predominantly been determined by in vitro studies. It remains unclear how vitamin D regulates immune cells in an in vivo setting. Objectives: We used transcriptomic datasets from immune cell subsets and aimed to identify pathways regulated by vitamin D in vivo, and whether there are differences in pathway regulation between people with MS and healthy controls. Methods: 73 MS cases and 102 healthy controls had microarray transcriptomic datasets available for at least one immune subset (monocyte, B, CD4, CD8, NK cell), and an independent cohort of 35 MS cases and 33 healthy controls had RNAseq datasets available. Latent variables were identified by RUV-4 or RUVg. Gene expression was corelated with serum 25(OH)D level (LIAISON 25 OH Vitamin D TOTAL assay) using Limma or edgeR. Gene set enrichment analysis (GSEA) was performed using ClusterProfiler and MSigDB. To identify differences in vitamin D-regulated pathways between MS cases and controls, genes whose expressions were correlated differently with 25(OH)D level by case/control status were determined and then used in GSEA. Results: Vitamin D-related pathways seen across multiple cell types were involved in RNA processing and splicing, mitochondrial function and oxidative phosphorylation, and immune signalling (FDR<0.05). In monocytes, the Gene Ontology term “vitamin D metabolic process” was enriched by genes downregulated with increasing 25(OH)D level in MS cases compared to controls. The Hallmark gene set “TNF-alpha signalling via NFKB” was enriched by genes downregulated in controls relative to cases. In CD4 cells, interleukin and TNF-alpha signalling gene sets were enriched by genes whose expressions were overall downregulated with increasing 25(OH)D level in cases relative to controls. Conclusions: Our pathway analyses identified signals for vitamin D regulation of immune function in vivo. These inferred differences in pathway regulation by vitamin D in MS cases and controls suggest differences in response to endogenous vitamin D

Causes of Multiple Sclerosis: a functional genomics approach

Multiple Sclerosis (MS) is the most common disabling neurological disease affecting young adults in Western Society. To date, 55 strongly associated single nucleotide polymorphisms have been discovered. We now need to identify causal genes. While T-cells as targets for therapeutic intervention have rarely proven useful, there is strong clinical and in-vitro data identifying NK cell deficiencies in patients, and key roles for monocytes in myelin and axon destruction and autoantigen presentation. RNA extracted from magnetic bead sorted monocytes and NK cells, of healthy controls (HC) and untreated patients with relapsing remitting MS (RRMS), was labelled and hybridised to Affymetrix Human Gene 1.0 ST arrays. Expression values were standardized across chips using RMA and quantile normalization as implemented in GenePattern. Genes were ranked by expression difference significance by Mann Whitney U test and ANOVA. To date, we have analysed monocytes of 30 patients and 39 HC, and NK cells from 25 patients and 32 HC. Expression differences of those genes adjacent to MS associated risk SNPs lying between 110kb upstream and 40kb downstream of a candidate gene were considered. We have identified three genes worthy of further analysis on this basis: RGS1, HHEX and THEMIS. To test the relevance of these candidates to central nervous system (CNS) autoimmunity, we aim to mimic phenotypes associated with these expression quantitative trait loci (eQTL) in in-vitro cultures of purified NK cells and monocytes, and in-vivo in a mouse model of MS - experimental autoimmune encephalomyelitis (EAE)

Multiple sclerosis risk variants regulate gene expression in innate and adaptive immune cells

At least 200 single-nucleotide polymorphisms (SNPs) are associated with multiple sclerosis (MS) risk. A key function that could mediate SNP-encoded MS risk is their regulatory effects on gene expression. We performed microarrays using RNA extracted from purified immune cell types from 73 untreated MS cases and 97 healthy controls and then performed Cis expression quantitative trait loci mapping studies using additive linear models. We describe MS risk expression quantitative trait loci associations for 129 distinct genes. By extending these models to include an interaction term between genotype and phenotype, we identify MS risk SNPs with opposing effects on gene expression in cases compared with controls, namely, rs2256814 MYT1 in CD4 cells (q = 0.05) and rs12087340 RF00136 in monocyte cells (q = 0.04). The rs703842 SNP was also associated with a differential effect size on the expression of the METTL21B gene in CD8 cells of MS cases relative to controls (q = 0.03). Our study provides a detailed map of MS risk loci that function by regulating gene expression in cell types relevant to MS

Soluciones para el manejo de la disnea basadas en la co-creación: la metodología del proyecto CALMA

La disnea es un síntoma presente en varias enfermedades respiratorias y cardíacas. Alterna periodos asintomáticos con crisis de distinta intensidad que interfieren en las actividades diarias. A veces, estas crisis requieren atención en Urgencias o son una amenaza para la vida. Este comportamiento cíclico se asocia con la aparición de exacerbaciones. Los pacientes conviven frecuentemente con un cuidador y la relación entre ambos (o su ausencia) influencia su comprensión, competencia y habilidad al manejar la disnea. Actualmente, la gestión de esta sintomatología presenta ámbitos mejorables como la utilización de estrategias no farmacológicas que activen a pacientes y cuidadores. Se ha descrito la necesidad de compartir con la ciudadanía el desarrollo de estrategias de salud para que estas alcancen su potencial. En consecuencia, CALMA involucró a profesionales, instituciones, pacientes y cuidadores, en su creación y validación como estrategia capacitadora para gestionar la disnea. Se desarrolló en tres fases: co-creación entre profesionales, pacientes y cuidadores, desarrollo especializado y validación. Las sesiones de co-creación se celebraron en Coimbra (Facultad de Medicina de la Universidad de Coimbra) y Barcelona (Hospital Clínic de Barcelona). La participación de ciudadanos y profesionales se planteó separada -pero relacionada- para evitar sesgos. Surgieron dos programas de capacitación: los talleres participativos de formación AULA CALMA y el proceso de reflexión durante el alta, CALMA COACHING. Posteriormente, se realizaron 4 sesiones de validación con todos los perfiles involucrados. El resultado permitió completar ambos programas e iniciar su validación (2020) en los hospitales participantes, el Hospital Arnau de Vilanova (Lleida) y la Medical University Lodz (Polonia)