| 1. |
- Bergman, Joakim, 1989-
(author)
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Studies of the Biology of Intrathecal Treatment in Progressive MS
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Background: Multiple Sclerosis (MS) is a chronic, inflammatory, autoimmune disease, affecting the central nervous system (CNS). About 85% of afflicted present with a relapsing-remitting form of the disease (RRMS), for which a breakthrough in treatment was made in 2008 with rituximab, an antibody directed towards CD20, a surface antigen on B-cells. These findings also contributed to cementing the importance of the B-cell’s role in MS pathophysiology. However, MS also exist as a progressive phenotype, affecting most MS patients either from onset or after a transition from RRMS, and for progressive MS the same treatment effect of anti-CD20 has not been observed. Still, studies have found follicle-like structures containing B-cells in meninges and subarachnoid space of the cortex in progressive MS brains, supporting the involvement of B-cells. Evidence also support the existence of a chronic, low-grade inflammatory process compartmentalised within the CNS that correlates with the progressive phase of MS, which may present a treatment barrier towards anti-CD20. Peripherally administrated therapeutic antibodies cross the intact blood-brain barrier with low efficiency with only 0.1-0.5% of the plasma concentration occurring in the cerebrospinal fluid (CSF). Intrathecal (IT) administration circumvents the blood-brain barrier, presenting an opportunity to better target the CNS B-cells.Aims: To evaluate the safety and feasibility of intrathecal anti-CD20 therapy with rituximab in progressive MS, its effect on disease progression through clinical parameters, and impact on biomarkers in CSF. Furthermore, this thesis aimed to evaluate the effect on biomarkers representative of cell injury related to insertion of a ventricular catheter for drug administration and to examine the interstitial milieu in the brain through microdialysis (MD).Methods: The thesis is based on the open-label, phase IIb, multicentre clinical trial Intrathecal Treatment Trial in Progressive Multiple Sclerosis (ITT-PMS; EudraCT 2008-002626-11), in which 23 participants received IT treatment with rituximab, and the extended follow-up study, ITT-PMS extension (EudraCT 2012-000721-53). All participants received a ventricular catheter and an Ommaya reservoir for drug administration through a neurosurgical procedure, and 10 participants received a MD catheter in parallel to the ventricular catheter for 10 days. The treatment effect was evaluated by regular clinical evaluations and analyses of CSF. The clinical outcome was evaluated through walking and upper-limb function tests, and by clinical evaluation scales. Levels of selected CSF biomarkers were analysed from the same time-points as the clinical evaluations.Results: After the completion of the extension trial, one clinical parameter (cognitive performance) showed improvement but could most likely be explained by a learning effect. Worsening of walking speed was observed, while the remaining clinical parameters showed no change. Two severe adverse events occurred in the form of low-virulent bacterial meningitis caused by Propionibacterium, but both were treated effectively with antibiotics without residual symptoms. A ‘spike’ was noticed in the level of lumbar CSF neurofilament light (NFL) following surgery but returned to pre-surgery baseline within 6-12 months. No change was observed for any of the other lumbar CSF biomarkers. No meaningful correlation of protein levels was observed when comparing MD samples, ventricular CSF, and lumbar CSF.Conclusions: Intrathecal treatment through intraventricular administration was well tolerated but not without risks. A continued progression was observed in gait impairment. The insertion of the ventricular catheter caused white matter injury, measured through an increase in NFL in lumbar CSF, in direct association with the surgical procedure. No impact was observed on other CSF biomarkers. There was a poor correlation between different CNS compartments regarding protein levels, arguing for caution in drawing conclusions about brain pathophysiology from lumbar CSF samples.
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| 2. |
- Werner, Petra, 1961-
(author)
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Ett medialt museum : lärandets estetik i svensk television 1956-1969
- 2016
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Doctoral thesis (other academic/artistic)abstract
- This thesis investigates the aesthetic interpretation of learning processes in television produced and broadcast in Sweden between 1956 and 1969. The thesis explores how these programmes are linked to concepts of Bildung by their aesthetics, by which the intangible cultural heritage is entrusted in the form of oral and visual traditions, storytelling and games/play, where learning is the common denominator. The programmes are divided into three categories: aesthetics of attentiveness, aesthetics of tale/storytelling and aesthetics of play. The detailed, thick, descriptions of the programmes emanating from the close-readings shall be, together with the aesthetic categories that I have formulated and expressed in a model, regarded as the survey’s key findings. The starting point of the central theoretical model of the thesis is André Malraux’s idea of an imaginary museum of imagination in which photo reproductions can constitute a collective memory, and thus bepart of an intangible heritage. Based on this idea of an imaginary museum, I have constructed a conceptual model called a medial museum, valid in its own time as well as for posterity. The theoretical models that the study gain support from are characterized by phenomenological and hermeneutical perspectives, as I refer to a phenomenological-hermeneutical method when analysing the programmes, and at the same time underline the phenomenological-hermeneutically based aesthetics in the analysed programmes, where aesthetic interpretation of learning processes in terms of attentiveness, tale and play is of a phenomenological-hermeneutic character. For a broad perspective on learning processes, theoretical support is acquired both from the German philosopher Hans-Georg Gadamer and his hermeneutic of traditions and from the French philosopher Jacques Rancière and his emancipatory ideas of pedagogy and aesthetics. Furthermore, the French philosopher Paul Ricœur and his thoughts on importance of storytelling for knowledge formation have had significant influence on the work. Regarding the concepts of play, I have made use of both Gadamer’s ideas of art experience as play and of Donald W. Winnicott’s theories about play as transitional area. In the programmes’ aesthetics is found a depiction of a broadened interpretation of Bildung, where processes of learning comprise a direct sensual perceiving, attentiveness, storytelling/tale and play. Moreover, within the programmes’ managing of an intangible cultural heritage, I have found an expression of an interplay between modernity and tradition, with emphasis on the historical significance of the present, and rooting in the past of everyday life, where expectation on the future and the memory of the past can co-exist. To summarise, the study suggests the possibility to understand aesthetics as an epistemology using sensuous experience as basis for a conceptual knowledge about how to understand the world. Thereby, one can comprehend aesthetics as pedagogy per se.
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| 3. |
- Ekelund, Alexander, 1979-
(author)
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Kampen om vetenskapen : Politisk och vetenskaplig formering under den svenska vänsterradikaliseringens era
- 2017
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Doctoral thesis (other academic/artistic)abstract
- This thesis examines the relation between politics and science in Sweden during the era of political radicalization in the sixties and seventies. Rooted in the Bourdieuan tradition of cultural sociology the main analysis focuses on relations between different cultural fields. Studying social movements and the political debate as well as the scientific fields makes it possible to identify habitus and strategies that formed the radical student generation. In addition to efforts to understand the historical background of the radicalisation, like the changes within the Education system and the general tendencies of the political debate, certain parts of the Swedish student movement are studied in-depth, like Unga filosofer in Stockholm and other autonomous groups organizing students and young teachers at the university departments. Of particular interest are the collective struggles to gain influence within the academic structures and the alternative forms of education that were initiated in the late sixties and early seventies.Since the young generation of radical academics were not prone to follow the traditional paths – the established order of succession – they had to find ways to compensate for the academic capital that they renounced by challenging their professors or other influential actors. To understand how this came to effect the Social Sciences and Humanities – or in this case more precisely the fields of philosophy, sociology and literary criticism – the other studies focus on analysing three politically motivated projects that were formed at intersections between a movement-context and academia: the first centred on the critique of positivism, the second engaged in the development of the ideas of scientific socialism – inspired by the reception of the philosophy of Louis Althusser – and the third a later feminist project that evolved in the field of literary criticism with the reception of Julia Kristeva’s theories. One thing the three projects had in common was that they created opportunities to channel political engagement in academic strategies by occupying homological positions in the political-intellectual field and the scientific fields – in some cases confronting the same antagonists in the different arenas. Some of the preconditions that made these strategies possible, which are discussed on the basis of the studies of the different fields, are the intellectual infrastructure that enabled conversion of symbolical assets, like magazines and other arenas for theoretical debate, the creation of social networks and the fact that the political radicalization encouraged transnational theoretical investments.
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| 4. |
- Feresiadou, Amalia, et al.
(author)
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Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease
- 2019
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In: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728 .- 1872-8421. ; 332, s. 31-36
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Journal article (peer-reviewed)abstract
- BACKGROUND: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases.METHODS: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease.RESULTS: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL.CONCLUSIONS: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.
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| 5. |
- Myrebøe, Synne, 1972-
(author)
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Kultiveringens politik : Martha Nussbaum, antiken och filosofins praktik
- 2019
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Doctoral thesis (other academic/artistic)abstract
- The Politics of Cultivation is a study on how the American philosopher Martha Nussbaum actualizes Ancient political philosophy to re-negotiate core assumptions in her own contemporary ethical-political discussions. The aim is to explore the potentiality Nussbaum discerns in Ancient philosophy and how this potentiality is actualized in her thoughts on cultivation as a critique of what she sees as reductive cultures of knowledge. Also, I highlight what Nussbaum’s philosophical practice can contribute to a Swedish discourse on bildning as resistance. Following Nussbaum’s philosophy of cultivation from her first articles on Heraclitus in 1972 to her recent work, I focus on how she emphasizes the role of sensibility, sexuality and emotions for reason. The thesis is divided in six chapters. The first chapter gives an overview of cultivation as a recurrent theme throughout Nussbaum’s authorship. In the second chapter I explore her reading of Heraclitus and how this reading highlight her philosophy of cultivation. The third and fourth chapters study how Nussbaum mobilizes Plato and Aristotle to point at some of the problems she finds at the core of her contemporary political philosophy. The fifth chapter investigates how Nussbaum renegotiates Stoic and Epicurean philosophy in her defence of a therapeutic philosophical approach. The last chapter exposes how aesthetical, ethical and political dimensions are weaved into Nussbaum’s thoughts on cultivation. Here, I study her reading of two tragedies and one comedy, showing how Nussbaum’s philosophical practice can be understood as an art of memory.Set in a contemporary, Swedish discussion on bildning [Bildung], and the role of education for liberal democracy, I argue that Nussbaum lay bare the constructed division between education and self-formation where she calls for the urgency to scrutinize educational politics and educational practice. Hence, what Nussbaum emphasizes, is that everywhere people meet, we are already embedded in a process of cultivation of thoughts, emotions and perceptions. The central question on how we can live together in a pluralistic world will thus have different answers depending on what can be seen and heard within the epistemological and political regulation of the sensible. Nussbaum’s politics of cultivation insists not only on being a gadfly on the back of power, but also to change the political structures from a reductive masculinity to the dialectics of love.
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| 6. |
- Emami Khoonsari, Payam, et al.
(author)
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Interoperable and scalable data analysis with microservices : Applications in metabolomics
- 2019
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In: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 35:19, s. 3752-3760
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Journal article (peer-reviewed)abstract
- MotivationDeveloping a robust and performant data analysis workflow that integrates all necessary components whilst still being able to scale over multiple compute nodes is a challenging task. We introduce a generic method based on the microservice architecture, where software tools are encapsulated as Docker containers that can be connected into scientific workflows and executed using the Kubernetes container orchestrator.ResultsWe developed a Virtual Research Environment (VRE) which facilitates rapid integration of new tools and developing scalable and interoperable workflows for performing metabolomics data analysis. The environment can be launched on-demand on cloud resources and desktop computers. IT-expertise requirements on the user side are kept to a minimum, and workflows can be re-used effortlessly by any novice user. We validate our method in the field of metabolomics on two mass spectrometry, one nuclear magnetic resonance spectroscopy and one fluxomics study. We showed that the method scales dynamically with increasing availability of computational resources. We demonstrated that the method facilitates interoperability using integration of the major software suites resulting in a turn-key workflow encompassing all steps for mass-spectrometry-based metabolomics including preprocessing, statistics and identification. Microservices is a generic methodology that can serve any scientific discipline and opens up for new types of large-scale integrative science.
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| 7. |
- Herman, Stephanie, et al.
(author)
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A biochemical signature of progressive multiple sclerosis
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Other publication (other academic/artistic)abstract
- Currently, very few treatments for patients in the progressive phases of multiple sclerosis (PMS) are available. To enable sensitive evaluation of future treatments, prognostic and predictive markers for therapeutic response are needed, as well as robust markers for early detection of PMS. We have previously demonstrated that a signature of 28 cerebrospinal fluid (CSF) biochemical markers could distinguish PMS from relapsing-remitting multiple sclerosis (RRMS) patients.Herein, we aimed to characterize the 28 previously extracted metabolites by assessing independent differences between 35 PMS and 35 RRMS patients as well as 49 healthy control subjects. Twenty-two of the PMS patients were part of a controlled clinical trial evaluating the effect of intrathecal rituximab for PMS. Using follow-up assessments, we related the metabolites to clinical outcomes of the trial and investigated if they could predict a poor or beneficial treatment response. Finally, we investigated the metabolites’ associations to a panel of six CSF protein biomarkers of axonal, myelin and astrocyte damage as well as T- and B- cell activation and differentiation.The composite signature was predominantly classifying patients as having a poor treatment outcome, achieving an estimated area under the curve (AUC) of 0.63 (sensitivity = 0.90, specificity = 0.38). Univariately, C4H6N6O4 and phenolic phosphate were significantly (p-value<0.05) increased in patients with a poor outcome. We also demonstrated that a majority (n=22) of the metabolites showed PMS distinctive alterations, including increased CSF levels of 4-acetamidobutanoate, 4-hydroxybenzoate and thymine. 4-Acetamidobutanoate did also display significant associations with the results from the symbol digit modalities test (SDMT) and the 9-hole peg test (9-HPT) using the dominant hand, and the protein markers myelin basic protein (MBP), neurofilament light (NFL) and glial fibrillary acidic protein (GFAp), whereas 4-hydroxybenzoate displayed significant associations with NFL. Only six metabolites showed significant differences between RRMS and healthy control subjects, suggesting that this is a PMS specific signature.To summarize, most of the individual metabolites did show significantly distinctive CSF levels in the PMS patients and some of them were also related to cognitive and motoric performance. This suggests that some of the investigated metabolites might have potential as individual markers.
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| 8. |
- Herman, Stephanie, et al.
(author)
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Disease phenotype prediction in multiple sclerosis
- 2023
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In: iScience. - : Cell Press. - 2589-0042. ; 26:6
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Journal article (peer-reviewed)abstract
- Progressive multiple sclerosis (PMS) is currently diagnosed retrospectively. Here, we work toward a set of biomarkers that could assist in early diagnosis of PMS. A selection of cerebrospinal fluid metabolites (n = 15) was shown to differentiate between PMS and its preceding phenotype in an independent cohort (AUC = 0.93). Complementing the classifier with conformal prediction showed that highly confident predictions could be made, and that three out of eight patients developing PMS within three years of sample collection were predicted as PMS at that time point. Finally, this methodology was applied to PMS patients as part of a clinical trial for intrathecal treatment with rituximab. The methodology showed that 68% of the patients decreased their similarity to the PMS phenotype one year after treatment. In conclusion, the inclusion of confidence predictors contributes with more information compared to traditional machine learning, and this information is relevant for disease monitoring.
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| 9. |
- Herman, Stephanie, et al.
(author)
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Integration of magnetic resonance imaging and protein and metabolite CSF measurements to enable early diagnosis of secondary progressive multiple sclerosis
- 2018
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In: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 8:16, s. 4477-4490
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Journal article (peer-reviewed)abstract
- Molecular networks in neurological diseases are complex. Despite this fact, contemporary biomarkers are in most cases interpreted in isolation, leading to a significant loss of information and power. We present an analytical approach to scrutinize and combine information from biomarkers originating from multiple sources with the aim of discovering a condensed set of biomarkers that in combination could distinguish the progressive degenerative phenotype of multiple sclerosis (SPMS) from the relapsing-remitting phenotype (RRMS). Methods: Clinical and magnetic resonance imaging (MRI) data were integrated with data from protein and metabolite measurements of cerebrospinal fluid, and a method was developed to sift through all the variables to establish a small set of highly informative measurements. This prospective study included 16 SPMS patients, 30 RRMS patients and 10 controls. Protein concentrations were quantitated with multiplexed fluorescent bead-based immunoassays and ELISA. The metabolome was recorded using liquid chromatography-mass spectrometry. Clinical follow-up data of the SPMS patients were used to assess disease progression and development of disability. Results: Eleven variables were in combination able to distinguish SPMS from RRMS patients with high confidence superior to any single measurement. The identified variables consisted of three MRI variables: the size of the spinal cord and the third ventricle and the total number of T1 hypointense lesions; six proteins: galectin-9, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor alpha (TGF-alpha), tumor necrosis factor alpha (TNF-alpha), soluble CD40L (sCD40L) and platelet-derived growth factor AA (PDGF-AA); and two metabolites: 20 beta-dihydrocortisol (20 beta-DHF) and indolepyruvate. The proteins myelin basic protein (MBP) and macrophage-derived chemokine (MDC), as well as the metabolites 20 beta-DHF and 5,6-dihydroxyprostaglandin F1a (5,6-DH-PGF1), were identified as potential biomarkers of disability progression. Conclusion: Our study demonstrates, in a limited but well-defined and data-rich cohort, the importance and value of combining multiple biomarkers to aid diagnostics and track disease progression.
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