4,864 research outputs found

    The Structure and Function of the Retina in Multiple Sclerosis

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    Background: Multiple sclerosis (MS) is a complex heterogenous autoimmune inflammatory disease with a prolonged and variable time course. The visual system is frequently implicated, either as the presenting symptom, or, with advancement of the disease. This has been documented in the literature with changes in visual acuity (VA) that are accompanied by functional changes in the optic nerve, measured with the visual evoked potential (VEP) and possible retrograde degeneration involving the retinal ganglion cells in the retina, measured with the pattern reversal electroretinogram (PERG). However, inflammatory episodes may be clinical or subclinical in nature and may go unrecognised. Originating from the same embryological origins, the effect of inflammation in MS on the on the retina is less well known. The research hypothesis was that there is a measurable difference in the function of retinal cells in patients with newly diagnosed multiple sclerosis, suggestive of inflammatory retinopathy compared to healthy controls. The overall aim was to investigate any differences in the electrophysiological function of the visual pathway of patients newly diagnosed with MS compared to healthy controls. Methods: The visual system is explored with clinical (VA), electrophysiology (VEP and electroretinography (ERG – pattern and flash) and structural (OCT) measures, in patients presenting with symptoms suggestive of MS to a specialist service. This prospective case control study investigates the visual pathway at the earliest stage of the disease to look for differences in structure and function between patients and healthy volunteers that might serve as a biomarker in the future. Results: There were a number of variables that were significantly different between the two groups, logistic regression analysis found that VA (p 0.038) and VEP P100 peak-time (p 0.014) from the right eye as significant. Dividing the participants by prolongation of the VEP P100 peak-time as defined in clinical practice, found a number of ERG amplitude variables as well as VA that were consistently different between the groups regardless of symptoms. Conclusion: The study confirms optic nerve involvement in MS with VEP and VA abnormalities consistent with the literature in this cohort. Additionally, VA and some ERG amplitude variables were significantly reduced in participants with MS, when grouped according to VEP P100 peak-time, suggesting inner and outer retinal changes. Further work would be required to confirm these findings. No OCT structural changes were found in any of the analysis that included the macula thickness, ganglion cell layer or retinal nerve fibre layer. Keywords: multiple sclerosis (MS), visual evoked potential (VEP), pattern electroretinogram (PERG), electroretinogram (ERG), optical coherence tomography (OCT

    Studying the interplay between ageing and Parkinson's disease using the zebrafish model

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    Parkinson’s disease (PD) is a neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra. Ageing is the major risk factor for developing PD but the interplay between ageing and PD remains elusive. To investigate the effect of ageing on PD-relevant pathological mechanisms, zebrafish mutant lines harbouring mutations in ageing-associated genes (klotho-/-, sirt1-/-, satb1a-/-, satb1b-/- and satb1a-/-;satb1b-/-) were generated, using CRISPR/Cas9 gene editing. Likewise, a chemical model for SIRT1 deficiency was utilised. klotho-/- zebrafish displayed an accelerated ageing phenotype at 3mpf and reduced survival to 6mpf. Dopaminergic neuron number, MPP+ susceptibility and microglial number were unaffected in klotho-/- larvae. NAD+ levels were decreased in 6mpf klotho-/- brains. However, ATP levels and DNA damage were unaffected. sirt1-/- zebrafish did not display a phenotype through adulthood. il-1β and il-6 were not upregulated in sirt1-/- larvae, and chemical inhibition of sirt1 did not increase microglial number. cdkn1a, il-1β and il-6 were not upregulated in satb1a-/- and satb1b-/- larvae. Dopaminergic neuron number and MPP+ susceptibility were unaffected in satb1a-/- larvae. However, satb1b-/- larvae demonstrated a moderate decrease in dopaminergic neuron number but equal susceptibility to MPP+ as satb1b+/+ larvae. Adult satb1a-/- but not adult satb1b-/- zebrafish were emaciated. satb1a-/-;satb1b-/- zebrafish did not display a phenotype through adulthood. Transgenic zebrafish expressing human wildtype α-Synuclein (Tg(eno2:hsa.SNCA-ires-EGFP)) were crossed with klotho-/- and sirt1-/- zebrafish, and treated with a sirt1-specific inhibitor. Neither genetic cross affected survival. The klotho mutation did not increase microglial number in Tg(eno2:hsa.SNCA-ires-EGFP) larvae. Likewise, sirt1 inhibition did not induce motor impairment or cell death in Tg(eno2:hsa.SNCA-ires-EGFP) larvae. In conclusion, the suitability of zebrafish for studying ageing remains elusive, as only 1 ageing-associated mutant line displayed accelerated ageing. However, zebrafish remain an effective model for studying PD-relevant pathological mechanisms due to the availability of CRISPR/Cas9 gene editing, neuropathological and neurobehavioral tools

    Management strategies and contributory factors for resistance exercise-induced muscle damage: an exploration of dietary protein, exercise load, and sex

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    The World Health Organisation recommends that resistance exercise be performed at least twice per week to benefit general health and wellbeing. However, resistance exercise is associated with acute muscle damage that potentially can dampen muscle adaptations promoted by chronic resistance training. The extent to which muscle is damaged by exercise is influenced by various factors, including age, training status, exercise type, and – notable to this thesis – sex. To this end, establishing sex-specific management strategies for exercise-induced muscle damage (EIMD) is important to optimise the benefits of exercise. Two EIMD management strategies were focussed on in this thesis: dietary protein supplementation and exercise load manipulation. It was identified in this thesis that research into the impact both of protein supplementation and exercise load on EIMD heavily underrepresent female populations (chapters 3 and 5), despite well-documented sex differences in EIMD responses. Therefore, future research priority should be placed on bridging the sex data gap by conducting high-quality studies centralising around female-focussed and sex-comparative methodological designs. Both peri-exercise protein supplementation and exercise load manipulation in favour of lighter loads were revealed to be effective management strategies for resistance EIMD in males through systematic and scoping review of the current literature (chapters 3 and 5, respectively). Due to a lack of data from females, it is only appropriate for these strategies to be recommended for males at present. To decipher whether protein supplementation and lower exercise loads are beneficial for managing EIMD in females, a randomised controlled trial (RCT) (chapter 4) and a protocol for an RCT (chapter 6) involving male and female participants are presented in this thesis. The incorporation of ecologically-valid resistance exercise in the RCT in chapter 4 highlighted that even mild muscle damage is attenuated in females, reflected in diminished increases in post-exercise creatine kinase concentration and muscle soreness compared with males; however, the reason for this difference requires further investigation. This study, while supporting sex differences, contrasted previous studies, as neither males nor females experienced an attenuation of EIMD during milk protein supplementation. This difference likely owed to the lower severity of muscle damage induced in the current study relative to previous studies, and accordingly, future research should seek to discover alternative management strategies for mild EIMD. A protocol for an RCT examining the impact of exercise load on EIMD in untrained males and females is described in Chapter 6 of this thesis and may be used as guidance for researchers developing similar, sex-comparative studies. It was hypothesised that females will experience attenuated muscle damage relative to males and low-load exercise will induce less muscle damage than high-load exercise in both sexes. A lack of methodological consistency among EIMD studies was a recurring finding throughout this thesis, which posed an issue when attempting to compare between-study outcomes and reach a consensus. Achieving greater uniformity in study designs by adopting comparable methods relating to EIMD markers and time-points of assessment would help improve understanding of the factors influencing the magnitude of EIMD and effective management strategies. While there are limitations with several EIMD markers – for example the variability of biomarkers and subjectivity of perceptual assessments – once the optimal markers are determined, these should be consistently used moving forward. Overall, this thesis has contributed to the current body of knowledge by demonstrating that milk protein ingestion is not an effective management strategy for muscle damage following ecologically-valid resistance exercise; therefore, alternative strategies to mitigate mild muscle damage should be investigated. Further, this work supported previous reports of sex differences in EIMD and indicated that the attenuation of EIMD in females relative to males was not attributed to sex differences in body composition; thus, the aetiology of such differences necessitates further exploration by means of high-quality sex comparative research. Finally, this thesis reached the consensus recommendation that lower exercise loads can be utilised to reduce muscle damage in males; nonetheless, supporting evidence for the application of this recommendation to females is required

    Living with erythropoietic protoporphyria:Bridging the gap between research and clinical practice

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    Analysis of Hippo pathway signalling in schwannoma and meningioma

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    Images from Figures 3.7.1, 3.7.2, 3.7.3, 3.9.3 and 3.11.2 and quantification data from Figures 3.7.5, 3.9.4 and 3.11.4 published in Laraba et al. 2022 in the scientific journal BrainThis project focuses on two tumours of the nervous system, schwannoma and meningioma. A large group of schwannomas and meningiomas display the inactivation of the NF2 gene. The NF2 gene codes for the tumour suppressor protein Merlin and its loss is associated with a multitude of pro-tumourigenic mechanisms leading to the occurrence of schwannomas and meningiomas. The loss of Merlin function causes augmented Hippo signaling i.e. interaction of YAP and TAZ, both co-activators of gene expression and the two main effectors of the Hippo signalling pathway, and TEAD, a group of transcription factors binding to YAP and TAZ. There resulting gene expression is associated with increased proliferation and evasion of cell death. This makes the YAP/TAZ-TEAD complex an excellent therapeutic target. Since therapy options for schwannomas and meningiomas are limited to surgery and radiosurgery, both carrying additional risks for the patient, new therapy approaches are desperately needed. Therefore, we explored if a schwannoma mouse model and cell culture and primary meningioma cells would be suitable systems to allow the testing of two potential new therapy options. Macrophages, especially tumour associated macrophages (TAMs), have been shown to promote tumour growth in various ways. Therefore, macrophage depletion is considered a promising therapy option. To see whether elimination of macrophages could be effective in our chosen schwannoma mouse model, a connection between increased TAM numbers and equally heightened proliferation within the developing schwannomas would need to be and was established. Additionally, Nf2 gene knockout and the additional knockout of either Yap or Taz genes also had distinct effects on proliferation, TAM numbers and overall schwannoma structure and cell numbers. Macrophage infiltration and resulting support of tumour growth has also been shown to be partly YAP/TAZ-TEAD signaling dependent. Therefore, in order to simultaneously reduce TAM-derived growth support and directly impair tumour cell proliferation, the second approach targets the Hippo signaling pathway using TEAD S-autopalmitoylation inhibitors by Vivace Therapeutics which interfere with YAP/TAZ-TEAD interaction. I could show that these TEAD palmitoylation inhibitors efficiently inhibit cell proliferation of human meningioma cell lines and primary human meningioma cells.Peninsula Schools of Medicine and DentistryBrain Tumour Researc

    Nutrient Intake and Physical Exercise as Modulators of Healthy Women

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    Cumulative evidence demonstrates that healthy nutrient intake and regular physical exercise are both powerful lifestyle strategies that modulate lifelong health through their ability to improve body composition, musculoskeletal health, sex steroid hormones, sleep quality, and physical and cognitive performance, as well as to prevent chronic diseases across the lifespan, especially in women. While the benefits of nutrition and physical exercise are commonly studied separately, the integration of nutrition and physical exercise has the potential to produce greater benefits in women than strategies focusing only on one or the other. Studying the specificities of women in response to interventions is of the utmost importance for providing optimal healthcare and aids the design of guidelines that are better suited for women. A better knowledge regarding nutrient intake and physical exercise and their interaction in women is therefore needed. This Special Issue entitled “nutrient intake and physical exercise as modulators of healthy women” will comprise manuscripts that highlight this integrational approach as a potential modulator of lifelong outcomes in women

    An exploration of adherence and persistence in overactive bladder and other long-term conditions

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    Background and aims Overactive bladder is a common, bothersome, and chronic condition associated with symptoms of urinary urgency, incontinence, increased daytime micturition frequency and nocturia. Despite exerting a significant burden on quality of life, adherence, and persistence behaviours with OAB are particularly poor in comparison with other long-term conditions. The aims of the present work were to explore themes relating to medicine-taking behaviours in OAB and other long-term conditions and to suggest ways to improve them. Methods A systematic literature review was undertaken to understand the current landscape of qualitative work exploring adherence and persistence with OAB patients. A qualitative study involving 1:1 semi-structured interviews was conducted with OAB patients to explore the context and drivers for adherence and persistence behaviours using thematic analysis. A comparative analysis was then undertaken with qualitative papers exploring medicinetaking behaviours in a chronic bowel condition, type II diabetes, and multimorbidity to explore the themes identified in the OAB study for convergence and divergence in other conditions and to contextualise the learnings from the former study. Results The systematic literature review revealed a gap in the literature of qualitative exploration of adherence and persistence behaviours in OAB patients. The OAB study found a range of drivers for non-adherent behaviours including a perceived lack of treatment efficacy, side effects, unclear instructions, and drug and condition hierarchies, as well as the rich context within which these themes sit. The comparative analysis study supported the findings of the OAB study demonstrating evidence of key themes transcending across conditions, including a perceived lack of treatment efficacy and side effects, as well as nuances associated with the OAB experience. Conclusions The present work has identified key drivers for non-adherent behaviours in OAB patients and sets out a number of recommendations categorised within the World Health Organisation’s 5 dimensions of adherence. These include addressing the poor understanding and illness perception of OAB by patients and others, by improving the provision and availability of information, as well as the work of patient support groups; scrutiny on the support within primary care to OAB patients before and after diagnosis; and the encouragement of realistic expectations of the condition and treatment with mindful use of prescriber’s language at the point of prescribing. The present work has further highlighted the utility of conceptual models of adherence such as COM-B and the NCF in understanding medicine-taking behaviours in the context of OAB
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