Living long-term with acquired brain injury in Ireland: towards a counter discourse

Irish literature on Acquired Brain Injury (ABI) is very scant and is mainly deficits and/or needs based. The focus is generally on how to manage the short term needs of the younger population with ABI. The starting position of my thesis is that people living long-term with ABI are important participants in developing knowledge about this social phenomenon, living with ABI while accepting that their brain injury does not determine them. Six mature adults with ABI and their six significant others participated in this longitudinal study. Using a narrative approach in interviews, over twenty months, five repeat individual interviews with each of the twelve participants was held. From this I gained an understanding of their lived experiences, their life-world and their experiences of our local public ABI/disability services, systems and discourse. Along with this new empirical data, theoretical developments from occupational therapy, occupational science, sociology, and disability studies were also used within a meta-narrative informed by critical theory and critical realism to develop a synthesis of this study. Social analysis of their narratives co-constructed with me, allowed me generate nuanced insights into tendencies and social processes that impacted and continues to impact on their everyday-everynight living. I discuss in some depth here, the relational attitudinal, structural, occupational and environmental supports, barriers or discrimination that they face(d) in their search for social participation and community inclusion. Personal recognition of the disabled participants by their family, friends and/or local community, was generally enhanced after much suffering, social supports, slow recovery, and with some form of meaningful occupational engagement. This engagement was generally linked with pre-injury interests or habits, while Time itself became both a major aid and a need. The present local ABI discourse seldom includes advocacy and inclusion in everyday/every night local events, yet most participants sought both peer-support or collective recognition, and social/community inclusion to help develop their own counter-discourse to the dominant ABI discourse. This thesis aims to give a broad social explanation on aspects of their social becoming, 'self-sameness' and social participation, and the status of the disabled participants wanting to live 'the slow life'. Tensions and dialectical issues involved in moving from the category of a person in coma, to person with a disability, to being a citizen should not demote the need for special services. While individualized short-term neuro-rehabilitation is necessary, it is not sufficient. Along with the participants, this researcher asks that community health and/or social care planners and service-providers rethink how ABI is understood and represented, and how people with ABI are included in their local communities

Investigation of lantibiotic regulation, immunity and synergy

Due to the increasing incidence of antibiotic resistant strains, the use of novel antimicrobials, such as bacteriocins, has become an ever more likely prospect. Lacticin 3147 (of which there are two components, Ltnα and Ltnβ) and nisin belong to the subgroup of bacteriocins called the lantibiotics, which has attracted much attention in recent years. The lantibiotics are antimicrobial peptides that contain unusual amino acids resulting from a series of enzyme-mediated post translational modifications. Given that there have been relatively few examples of lantibiotic-specific resistance; these antimicrobials appear to represent valid alternatives to classical antibiotics. However, the fact that lantibiotics are naturally only produced in small amounts often hinders their commercialisation. In order to overcome this bottleneck, several approaches can be employed. For example, we can create a situation that reduces the quantity of a lantibiotic required to inhibit a target by combining it with other antimicrobials. Here, following an initial screen involving lacticin 3147 and several classical antibiotics, it was observed between lacticin 3147 and the commercial antibiotics polymyxin B/E function synergistically. This reduced the amounts of the individual antimicrobials required for kill and broadened the spectrum of inhibition of both agents. Upon combination with polymyxins, lacticin 3147, which has been associated with Gram positive targets only, actively targeted Gram negative species such as Escherichia coli and Cronobacter sp. An alternative means of addressing problems associated with lantibiotic yield is to better understand how production is regulated, and ultimately use this information to enhance peptide levels. With this in mind the regulation of lacticin 3147 production from the promoter Pbac was investigated using a green fluorescent protein (GFP) expression reporter system. This revealed that elements within both of the divergent operons of the lacticin 3147 gene cluster are involved in Pbac regulation. That is, LtnR, already established as a negative regulator of itself and the lacticin 3147 associated immunity genes, also acts as an activator of Pbac transcription. In contrast, an enhanced level of expression is observed in the absence of the lacticin 3147 structural genes, ltnA1 and ltnA2, indicating that these genes/gene products are involved in Pbac repression. In fact, through complementation of the ltnA2 gene, it was revealed that this regulation is more likely to be dependent on the presence of the gene transcript rather that the corresponding prepropeptide or modified Ltnβ. It may be that if lacticin 3147 production is successfully enhanced, the ability of the producing cell to protect itself may become an issue. To prepare for such a possibility a bioengineered derivative of the lacticin 3147 immunity protein LtnI (LtnI I81V) which provides enhanced protection was discovered through an in depth investigation involving the site and saturation mutagenesis of this protein. In addition, the creation of truncated forms of LtnI allowed the identification of important and essential regions of this immunity protein. Finally, as mentioned, self-immunity is essential to prevent self-killing. However the discovery of nisin U immunity and regulatory gene homologues (spiFEGRR’K) within the pathogenic strain S. infantarius subsp. infantarius is a cause for concern as it represents an example of immune mimicry, a form of lantibiotic-specific resistance. The ability of spiFEG to confer protection was apparent when they successfully provided protection to nisin A, F, Z, Q and U when expressed heterologously in the nisin sensitive L. lactis HP host. As a consequence of the studies presented in this thesis, it is likely that strategies will emerge that will facilitate the production of greater levels of lacticin 3147 production and lead to enhanced immunity in lactococcal backgrounds. Alternatively the need for enhanced production could be avoided through the use of antimicrobial combinations. In addition, providing awareness of the threats of the emergence of resistance through immune mimicry can allow researchers to develop strategies to prevent this phenomenon from leading to the dissemination of lantibiotic resistance.

Living with acquired brain injury

This study found that natural community supports were comprised of two distinct groupings; firstly immediate families, friends and peer support groups; secondly neighbours and local community groups such as sporting and activity- based organisations and groups. The findings of this study indicate that living with acquired brain injury involves a process where the person moves from acute high intensity health services onto rehabilitative services and then onto re-establishing independent lives. It is evident that smooth transitions and interconnectivity of services are essential in facilitating this recovery process. Instrumental to the recovery is the support of immediate family and close friends, who form people’s immediate natural support network and go a long way towards facilitating individuals in rebuilding their lives. A key finding of this study is that broader natural community supports do not appear to play as central a role in supporting individuals to live independent lives when compared to the role of family and friends. The lack of involvement of broader community groups, in many ways, prompted individuals to contact formal support services. For the majority of participants, independence is facilitated through the combination of immediate natural community supports and formal services. The role of formal support services is key to developing broader community support networks. This study found a blurred division between formal services and broader community support networks. The authors recommended that the role of formal supports services in acting as a bridge between the needs of the individual and the development of meaningful community networks, be formally recognised and further developed. Additionally, they argued that the importance of the role of broader natural community, supports such as those provided by community and sporting groups must be enhanced. Greater awareness of the issues faced by people living with acquired brain injury and its often invisible nature is necessary in this endeavour. The authors stated it is important to recognise that there are multiple issues impacting on independent living and these issues intersect, for instance with age, gender, employment, qualifications and so on. A lack of public awareness of acquired brain injury was found to be a key barrier to independent living, along with issues relating to socialising, access to employment and finances. The findings of this study reflect the complexities of living with acquired brain injury and the need for holistic support that is cognisant of the factors which impact on integration. It is vital that flexible, personalised services are developed which are fit for purpose and meet the needs of not only people with acquired brain injury but also their immediate natural community support network. Recognition of the intersection between immediate/ broader natural community supports and formal services is also key to developing the comprehensive and practical supports required to achieve an independent life. This was a qualitative study and all participants were sourced through Headway, a community based service provider for people with ABI. Data collection was divided into two stages: firstly focus groups, followed by individual interviews. Four focus groups were convened in Cork (2), Dublin (1) and Limerick (1). Each focus group was facilitated by at least two members of the research team and a total of twenty-six individuals participated in the focus groups. Thematic analysis of the data was undertaken to guide and inform the second stage of the study; the individual interviews. Ten interviews were undertaken with individuals who presented with ABI in the Cork and Limerick regions.

Impact of exercise on innate immunity in multiple sclerosis progression and symptomatology

Multiple Sclerosis (MS), an idiopathic progressive immune-mediated neurological disorder of the central nervous system (CNS), is characterized by recurrent episodes of inflammatory demyelination and consequent axonal deterioration. It accounts for functional deterioration and lasting disability among young adults. A body of literature demonstrates that physical activity counteracts fatigue and depression and may improve overall quality of life in MS patients. Furthermore, much data indicates that exercise ameliorates chronic neuroinflammation and its related pathologies by tipping cytokine profiles toward an anti-inflammatory signature. Recent data has focused on the direct impact of exercise training on the innate immune system by targeting toll-like receptors (TLRs), signaling pattern recognition receptors that govern the innate immune response, shedding light on the physiological role of TLRs in health and disease. Indeed, TLRs continue to emerge as players in the neuroinflammatory processes underpinning MS. This review will highlight evidence that physical activity and exercise are potential immunomodulatory therapies, targeting innate signaling mechanism(s) to modulate MS symptom development and progression.