13,672 research outputs found
Exploring the effects of spinal cord stimulation for freezing of gait in parkinsonian patients
Dopaminergic replacement therapies (e.g. levodopa) provide limited to no response for axial motor symptoms including gait dysfunction and freezing of gait (FOG) in Parkinson’s disease (PD) and Richardson’s syndrome progressive supranuclear palsy (PSP-RS) patients. Dopaminergic-resistant FOG may be a sensorimotor processing issue that does not involve basal ganglia (nigrostriatal) impairment. Recent studies suggest that spinal cord stimulation (SCS) has positive yet variable effects for dopaminergic-resistant gait and FOG in parkinsonian patients. Further studies investigating the mechanism of SCS, optimal stimulation parameters, and longevity of effects for alleviating FOG are warranted. The hypothesis of the research described in this thesis is that mid-thoracic, dorsal SCS effectively reduces FOG by modulating the sensory processing system in gait and may have a dopaminergic effect in individuals with FOG. The primary objective was to understand the relationship between FOG reduction, improvements in upper limb visual-motor performance, modulation of cortical activity and striatal dopaminergic innervation in 7 PD participants. FOG reduction was associated with changes in upper limb reaction time, speed and accuracy measured using robotic target reaching choice tasks. Modulation of resting-state, sensorimotor cortical activity, recorded using electroencephalography, was significantly associated with FOG reduction while participants were OFF-levodopa. Thus, SCS may alleviate FOG by modulating cortical activity associated with motor planning and sensory perception. Changes to striatal dopaminergic innervation, measured using a dopamine transporter marker, were associated with visual-motor performance improvements. Axial and appendicular motor features may be mediated by non-dopaminergic and dopaminergic pathways, respectively. The secondary objective was to demonstrate the short- and long-term effects of SCS for alleviating dopaminergic-resistant FOG and gait dysfunction in 5 PD and 3 PSP-RS participants without back/leg pain. SCS programming was individualized based on which setting best improved gait and/or FOG responses per participant using objective gait analysis. Significant improvements in stride velocity, step length and reduced FOG frequency were observed in all PD participants with up to 3-years of SCS. Similar gait and FOG improvements were observed in all PSP-RS participants up to 6-months. SCS is a promising therapeutic option for parkinsonian patients with FOG by possibly influencing cortical and subcortical structures involved in locomotion physiology
BECOMEBECOME - A TRANSDISCIPLINARY METHODOLOGY BASED ON INFORMATION ABOUT THE OBSERVER
ABSTRACT
Andrea T. R. Traldi
BECOMEBECOME
A Transdisciplinary Methodology Based on Information about the Observer
The present research dissertation has been developed with the intention to provide practical strategies and discover new intellectual operations which can be used to generate Transdisciplinary insight. For this reason, this thesis creates access to new knowledge at different scales.
Firstly, as it pertains to the scale of new knowledge generated by those who attend Becomebecome events. The open-source nature of the Becomebecome methodology makes it possible for participants in Becomebecome workshops, training programmes and residencies to generate new insight about the specific project they are working on, which then reinforce and expand the foundational principles of the theoretical background.
Secondly, as it pertains to the scale of the Becomebecome framework, which remains independent of location and moment in time. The method proposed to access Transdisciplinary knowledge constitutes new knowledge in itself because the sequence of activities, described as physical and mental procedures and listed as essential criteria, have never been found organised
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in such a specific order before. It is indeed the order in time, i.e. the sequence of the ideas and activities proposed, which allows one to transform Disciplinary knowledge via a new Transdisciplinary frame of reference.
Lastly, new knowledge about Transdisciplinarity as a field of study is created as a consequence of the heretofore listed two processes.
The first part of the thesis is designated ‘Becomebecome Theory’ and focuses on the theoretical background and the intellectual operations necessary to support the creation of new Transdisciplinary knowledge. The second part of the thesis is designated ‘Becomebecome Practice’ and provides practical examples of the application of such operations. Crucially, the theoretical model described as the foundation for the Becomebecome methodology (Becomebecome Theory) is process-based and constantly checked against the insight generated through Becomebecome Practice.
To this effect, ‘information about the observer’ is proposed as a key notion which binds together Transdisciplinary resources from several studies in the hard sciences and humanities. It is a concept that enables understanding about why and how information that is generated through Becomebecome Practice is considered of paramount importance for establishing the reference parameters necessary to access Transdisciplinary insight which is meaningful to a specific project, a specific person, or a specific moment in time
The applied psychology of addictive orientations : studies in a 12-step treatment context.
The clinical data for the studies was collected at The PROMIS Recovery Centre, a Minnesota Model treatmentc entre for addictions,w hich encouragesth e membership and use of the 12 step Anonymous Fellowships, and is abstinence based. The area of addiction is contextualised in a review chapter which focuses on research relating to the phenomenon of cross addiction. A study examining the concept of "addictive orientations" in male and female addicts is described, which develops a study conductedb y StephensonM, aggi, Lefever, & Morojele (1995). This presents study found a four factor solution which appeared to be subdivisions of the previously found Hedonism and Nurturance factors. Self orientated nurturance (both food dimensions, shopping and caffeine), Other orientated nurturance (both compulsive helping dimensions and work), Sensation seeking hedonism (Drugs, prescription drugs, nicotine and marginally alcohol), and Power related hedonism (Both relationship dimensions, sex and gambling. This concept of "addictive orientations" is further explored in a non-clinical population, where again a four factor solution was found, very similar to that in the clinical population. This was thought to indicate that in terms of addictive orientation a pattern already exists in this non-clinical population and that consideration should be given to why this is the case. These orientations are examined in terms of gender differences. It is suggested that the differences between genders reflect power-related role relationships between the sexes. In order to further elaborate the significance and meaning behind these orientations, the next two chapters look at the contribution of personality variables and how addictive orientations relate to psychiatric symptomatology. Personality variables were differentially, and to a considerable extent predictably involved with the four factors for both males and females.Conscientiousness as positively associated with "Other orientated Nurturance" and negatively associated with "Sensation seeking hedonism" (particularly for men). Neuroticism had a particularly strong association with the "Self orientated Nurturance" factor in the female population. More than twice the symptomatology variance was explained by the factor scores for females than it was for males. The most important factorial predictors for psychiatric symptomatology were the "Power related hedonism" factor for males, and "Self oriented nurturance" for females. The results are discussed from theoretical and treatment perspectives
Self-help/mutual aid groups in mental health : ideology, helping mechanisms and empowerment
In the last quarter of the twentieth century, self-help/mutual aid groups for mental health issues started to emerge in growing numbers, mainly in Western societies, offering and/or advocating for alternative non-traditional forms of support, and attracted the attention of many researchers and clinicians for their unique characteristics. Among the subjects of interest are typologies of groups, helping mechanisms and benefits from participation. However, there is lack of systematic research in the area and existing studies have been largely confined to the therapeutic value of these groups instead of acknowledging their
socio-political meaning and subsequent psychosocial benefits for their members like personal empowerment.
The present study was conducted during the transitional years from a Conservative to a newly elected Labour Government (1996 -1998), with subsequent policy shifts taking place in the welfare sector. The purpose of the study was to explore the potential of self-help groups as part of a broader new social movement, the service user movement, focussing on the English scene. It addressed this issue examining the relevance of a group typology based on political ideology and focus of change. To test the validity of this classification for members, a set of individual characteristics and group mechanisms as well as their change
through time were examined. The sample consisted of fourteen mental health selfhelp/mutual aid groups from London and South East England, with a variety of structural and organisational features. The methodology used was a combination of both quantitative (self-completion questionnaires) and qualitative techniques (analysis of written material, participant observation and interviews). Measurements were repeated after a one-year interval (Time 1N=67, Time 2 N=56).
Findings showed that, indeed, political ideology of self-help/mutual aid groups provided the basis of a meaningful typology and constitutes a comprehensive way of categorising them. Group ideology was related to specific helping mechanisms and aspects of personal empowerment. Specifically, conservative and combined group members reported more expressive group processes like sharing of feelings and self-disclosure, while radical group members were more empowered and optimistic. Group identification was also associated with specific helping activities and aspects of empowerment in the three group categories. The psychosocial character of group types and the beneficial outcomes for members remained stable through time. In general, prolonged participation was reflected in greater member identification with the group and resulted in improved mental wellbeing, increased social support, companionship and optimism for the future
Studies of strategic performance management for classical organizations theory & practice
Nowadays, the activities of "Performance Management" have spread very broadly in actually every part of business and management. There are numerous practitioners and researchers from very different disciplines, who are involved in exploring the different contents of performance management. In this thesis, some relevant historic developments in performance management are first reviewed. This includes various theories and frameworks of performance management. Then several management science techniques are developed for assessing performance management, including new methods in Data Envelopment Analysis (DEA) and Soft System Methodology (SSM). A theoretical framework for performance management and its practical procedures (five phases) are developed for "classic" organizations using soft system thinking, and the relationship with the existing theories are explored. Eventually these results are applied in three case studies to verify our theoretical development. One of the main contributions of this work is to point out, and to systematically explore the basic idea that the effective forms and structures of performance management for an organization are likely to depend greatly on the organizational configuration, in order to coordinate well with other management activities in the organization, which has seemingly been neglected in the existing literature of performance management research in the sense that there exists little known research that associated particular forms of performance management with the explicit assumptions of organizational configuration. By applying SSM, this thesis logically derives some main functional blocks of performance management in 'classic' organizations and clarifies the relationships between performance management and other management activities. Furthermore, it develops some new tools and procedures, which can hierarchically decompose organizational strategies and produce a practical model of specific implementation steps for "classic" organizations. Our approach integrates popular types of performance management models. Last but not least, this thesis presents findings from three major cases, which are quite different organizations in terms of management styles, ownership, and operating environment, to illustrate the fliexbility of the developed theoretical framework
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Role of Cerebrovascular Cells in Tau Processing Following Traumatic Brain Injury
Repetitive exposure to mild traumatic brain injuries (r-mTBI) sustained through the participation in contact sports can lead to chronic post-concussive symptoms and the development of neurodegenerative diseases such as Alzheimer’s disease and Chronic Traumatic Encephalopathy (CTE). A primary hallmark of CTE is the accumulation of pathogenic tau in neurons and astrocytes that surround small blood vessels in the brain. Chronic exposure to r-mTBI leads to elevated levels of extracellular tau and pathogenic tau accumulation in neurons, ultimately resulting in neuronal death. While the mechanisms responsible for pathogenic tau elimination from the brain are unclear, our prior work demonstrated that cells associated with the cerebrovasculature can interact with extracellular tau and may contribute to the removal of extracellular tau from the brain.
In this thesis, I examined the mechanisms through which the cerebrovascular cells eliminate extracellular tau from the brain and how those processes are impacted by r-mTBI. I demonstrated that brain vascular mural cells (pericytes and smooth muscle cells) progressively degenerate following exposure to r-mTBI consistent with what is observed in individuals with AD. This mural cell dysfunction impairs the ability of the cerebrovessels to interact with tau. Furthermore, I found that the cerebrovasculature can eliminate extracellular tau from the brain through caveolae-mediated endothelial transcytosis, which is impaired following chronic exposure to r-mTBI. The diminished tau transit across the blood-brain barrier following brain injury may be a contributing factor in the pathogenic tau accumulation observed in CTE.
A significant genetic risk factor for neurodegenerative diseases including AD and CTE is possession of the E4 isoform of Apolipoprotein E (ApoE). Astrocytes are the predominant source of ApoE in the brain, though there is very little understanding regarding their interactions with extracellular tau, particularly after exposure to head trauma. While the ApoE4 isoform has been associated with increased tau accumulation and cerebrovascular dysfunction after TBI, investigations into these associations are limited. The current studies found that while astrocytes internalize and release tau back into the extracellular space under normal conditions, these processes become dysfunctional following r-mTBI leading to astrocytic tau accumulation, which is further exacerbated by the ApoE4 isoform.
In summary, I identified the factors responsible for the elimination of extracellular tau across the BBB, which are impaired after head trauma. Therapeutic interventions that restore these processes may ameliorate the chronic accumulation of tau associated with neurodegenerative disease. These findings may be particularly important for individuals with the ApoE4 isoform, who are more susceptible to the pathophysiological sequelae of tau accumulation, particularly after exposure to r-mTBI
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Know Your Bugs: A Collaborative Evaluation of a Community Health Education Module That Aims to be Accessible to Adults with Learning Disabilities
The right to health should be a fundamental right of everyone. However, despite initiatives to improve the health of adults with learning disabilities, concerns about poorer health and health inequalities remain, and have been exacerbated by the COVID-19 pandemic. Accessible health promotion can help to overcome barriers to healthy behaviour but the effectiveness of health education in infection prevention and self-care is unknown. This research aimed to understand the health education experiences of adults with learning disabilities regarding a module designed to improve knowledge about self-care, infection prevention and antibiotic use.
Beginning with a scoping review of ‘what works’, this research involved observation of the learning context in two locations and semi-structured interviews with 18 course participants to explore health knowledge and behaviour change in the short, medium and longer term. Data were analysed iteratively, addressing the realist concept of context/mechanism/outcome configurations.
Participants had a positive learning experience and gained knowledge about microbes, hand hygiene, self-care, and antibiotic use. Some participants reported behaviour change regarding handwashing and self-care. The contexts that influenced learning were personal, social, physical, active, and external. Mechanisms that interacted with these contexts to trigger learning included: accessible teaching methods, interactive resources, relaxed and effective participant interactions, facilitation of independent thinking and planning, appropriate involvement of supporters, and an inclusive and engaging educator style.
Knowledge gain and changed behaviour intentions were achieved through an engaging, interactive, and focused learning environment, underpinned by a complex and changing combination of interactions. However, further research is needed to understand effective ways of communicating health information in an education context, to understand the impact of education on behaviour change, and to identify ways in which the longer-term retention of learning can be achieved. The research proposes a draft model that can guide effective community health education provision
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Decellularised Normal and Tumour Scaffolds for Cancer Organoid Cultures as a Model of Colorectal Peritoneal Metastases
Peritoneal metastasis (PM) is one of the most common routes of dissemination for colorectal cancer and remains a lethal disease. PM development is caused by a cross-talk between invading cancer cells and the rearrangement of the extracellular matrix (ECM). This interplay is governed by biochemical and biomechanical events that allow the development of a specific microenvironment: the so-called metastatic niche. ECM remodeling may be critical for PM spread. In fact, it has been demonstrated that ECMs are not only able to provide structural support to the exfoliated neoplastic cells, but also to trigger specific molecular pathways, paving the path for the seed of cancer cells, directly to their "pre-educated" soil. The mechanisms that determine the interactions within cancer cells and the ECM are still obscure and could be elucidated by an in vitro 3D-culture system that integrates all the elements involved in PM development. Cancer organoids have shown a profound impact in the field of oncology since they better reflect the main characteristics of the native organs compared to the traditional cell culture models. However, they still fail to represent the heterogeneity of the microenvironment. Methodologies have been recently established to remove cells from tissues and obtain matrices in which ECM and tissue architecture are maintained (dECM models), that could be used as the most representative scaffold on which implant 3D cultures.
I aimed to obtain a 3D-model that closely recapitulates the microenvironment where the PM develops and includes d-ECM repopulated with PM-derived organoids (3D-dECM model). I removed the cellular component of ECMs derived from peritoneal cavity obtained from both PM samples and r matched normal peritoneum using detergents and enzymatic methods. dECMs analyses demonstrated that the procedure maintained the specific characteristics of their tissue of origin also in terms of distribution, localization, and architectural organization of ECM-related proteins. The obtained dECMs showed a different spatial rearrangement between normal and PM-derived peritoneum, suggesting that dECM scaffolds closely recapitulate the native PM microenvironment. Moreover, when I repopulated dECMs with PM-derived organoids I found that PM- and normal peritoneum-derived dECMs differentially regulated the localization and organization of the seeded organoids, which was the same as in the original tissue. The two 3D-ECM models presented different ability in supporting cell proliferation, where PM-derived 3D-dECMs showed a higher proliferation index and a major ability to maintain the stemness phenotype. PM- and normal peritoneum-derived 3D-dECMs differently modulated cell homeostasis and proliferation ratio.
A gene expression analysis of organoids, grown on different substrates reflected faithfully the clinical and biological characteristics of the organoids. The impact of the ECM on the response to standard chemotherapy treatment for PM was also observed.
This demonstrated the value of ex vivo 3D models obtained by combining patient-derived extracellular matrices depleted of cellular components and organoids to mimic the metastatic niche, which could provide tools to develop new therapeutic strategies in a biologically relevant context, to personalize treatments and increase their efficacy
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Characterization of Lipid Bioenergetic Markers in Alzheimer's Disease (AD) in Apolipoprotein E4 (<i>APOE</i>) and non-E4 Carriers.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease of ageing with an estimated prevalence of 36 million worldwide. Individuals carrying one ε4 allele of the apolipoprotein E gene (APOE) are 6 times more likely to develop AD than ε3 homozygotes. Further, ε4 carriers have an abnormal increased reliance on fatty acid oxidation (FAO). The L-carnitine system consisting of L-carnitine and its esters (acylcarnitines) plays an important role in FAO. We therefore hypothesized that changes in blood and brain levels of L-carnitine, its metabolites (TMAO and GBB) as well as acylcarnitines would be indicative of dysfunctional FAO in ageing ε4 carriers influencing AD onset and progression. The L-carnitine system was evaluated in blood and brain in association with APOE in multiple cohorts of controls and patients over the continuum of AD. To investigate the influence of age and APOE on this system a mouse model of AD with human APOE was examined. In this model ex vivo cerebrovascular uptake of L-carnitine metabolites and fatty acids (FAs) were also investigated in relation to APOE. Additionally, a 1-week L-carnitine oral challenge was performed to evaluate the influence of APOE on L-carnitine metabolism. These data suggested that the L-carnitine pathway is dysregulated early on in AD, particularly among ε4 carriers. In the brain, changes in the L-carnitine system were related to AD pathology in an APOE-dependent manner. In mouse models APOE did not affect cerebrovascular uptake of L-carnitine metabolites and FAs or the metabolism of L-carnitine after oral challenge. However, acylcarnitines were differentially affected in different genotypes after cerebrovascular uptake of compounds and L-carnitine challenge suggesting altered in FAO flux in different APOE genotypes.
Understanding disturbances in the L-carnitine system with age, in relation to APOE genotypes, and their collective contributions to AD will help develop targeted prevention and therapeutic strategies
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