DSpace Collection:
http://theses.ncl.ac.uk/jspui/handle/10443/4857
2024-02-07T21:43:11ZLong-term outcomes of non-alcoholic fatty liver disease
http://theses.ncl.ac.uk/jspui/handle/10443/6053
Title: Long-term outcomes of non-alcoholic fatty liver disease
Authors: Gallacher, Jennifer Anne
Abstract: Background
Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of chronic liver disease
worldwide and affects a third of Western populations. The rising prevalence of NAFLD has
been associated with an in increased incidence of complications of cirrhosis such as
hepatocellular carcinoma and death and is associated with worrying healthcare and
economic burden. The natural history of NAFLD is varied and remains incompletely
understood. Long-term, large cohort studies with diversity of disease severity are required to
further understanding and improve management of NAFLD.
Aims and Methods
This study aimed to describe the clinical characteristics of a large UK based NAFLD cohort
and explore the frequency and predictors of significant clinical events. Participants were
identified from the Newcastle Hospitals historical clinical database and the European NAFLD
Registry who met the eligibility criteria and had at least 12 months follow up.
Results
Six hundred and five patients were included with a mean follow-up time of 11.8 ± 7.3 years.
One hundred and sixteen (19.2%) were cirrhotic at baseline, which increased to 166 (32.9%)
by the final clinical event. Co-morbidities such as T2DM, HTN and the metabolic syndrome
were common, and the incidence of these rose over the follow-up period. One hundred and
twelve patients died over the course of the study; liver disease was the most common cause
of death (28.6%). Factors that were prognostic for all-cause mortality included fibrosis stage
at baseline (aHR 8.31, 95% CI 4.31-16.01), T2DM (aHR 1.98, 95% CI 1.25-3.14), IHD (aHR 2.31,
95% CI 1.27-4.20) and “high risk” FIB-4 (aHR 10.02, 95% CI 6.14-16.35).
Conclusion
This thesis describes a large, well-characterised NAFLD cohort over a follow-up period of up
to 35 years. Factors that predicted adverse outcomes were identified including T2DM, IHD
and FIB-4 scores, which could help clinicians identify individuals at risk of poor outcomes.
Description: MD Thesis2023-01-01T00:00:00ZExercise tolerance in ageing and hypertrophic cardiomyopathy : from pathophysiology to a lifestyle intervention
http://theses.ncl.ac.uk/jspui/handle/10443/6052
Title: Exercise tolerance in ageing and hypertrophic cardiomyopathy : from pathophysiology to a lifestyle intervention
Authors: Fuller, Amy Susan
Abstract: Ageing and hypertrophic cardiomyopathy (HCM) are characterised by reduced functional
capacity and quality of life (QoL); predictors of long-term outcomes. Chronic inflammation is
a driver of pathophysiological cardiovascular hallmarks in ageing and HCM, including left
ventricular (LV) hypertrophy and diastolic dysfunction. Exercise intolerance in ageing and
HCM is suggested to be aetiological of central and/or peripheral factors. Excess decline in
functional capacity with age can be potentially attenuated with physical activity and exercise.
In addition, lifestyle interventions including exercise training and dietary nitrate (NO3
-
)
supplementation can safely improve exercise tolerance in individuals with heart failure, but few
studies report effects in HCM. The mitochondria play a central role in the initiation and
development of inflammation and may be a driver of pathological cardiac alterations in ageing
and HCM.
The present thesis firstly, investigated the effect of age and sex on mechanisms of exercise
tolerance in healthy individuals, with physical activity level (low, medium, or high) as a
confounding factor. Secondly, it explored determinants of exercise tolerance in HCM compared
to healthy controls. Thirdly, it evaluated the effects of a novel 16-week lifestyle intervention
incorporating increased physical activity (step count) and NO3
- supplementation on
cardiovascular function and QoL in HCM. Finally, in an animal model of cardiac hypertrophy
and inflammageing, the thesis assessed the association between mitochondrial function and
pathological phenotype in an ageing and HCM.
The major findings of the present thesis suggest that i, Part A), the ability of skeletal muscles
to extract delivered oxygen (represented by reduced arteriovenous O2 difference) at peak
oxygen consumption (V̇ O2peak) is the key determinant of exercise tolerance in healthy older
individuals when physical activity level is controlled for. However, no interaction between age
and sex was found for V̇ O2peak and determinants (i.e., cardiac output and arteriovenous O2
difference). In contrast, females present with accelerated age-related vascular change in
comparison to males. i, Part B), in comparison to healthy individuals, arteriovenous O2
difference at V̇ O2peak is the key determinant of exercise tolerance in individuals with HCM. ii)
A 16-week novel lifestyle intervention may significantly improve vasodilation (i.e., blood
pressure), which is related to cardiac remodelling, and QoL. However, no change in exercise
tolerance or cardiac function in individuals with HCM was observed. iii) reduced mitochondrial
complex I (CI) activity and mitochondrial biogenesis may be associated with the cardiac
pathological alterations in ageing and HCM.
xxv
In conclusion, the findings of the present thesis add knowledge about the deficiencies in
cardiovascular function caused by primary ageing with the novel inclusion of physical activity
category as a confounding factor in final analysis. Providing key information for improvement
of clinical interventions to help prevent a state of dependence in our ageing population. Next,
the present thesis helped to further define the underlying mechanisms of exercise intolerance in
individuals with HCM by the novel addition of comparing the clinical population to healthy
individuals, which is imperative to help define therapeutic targets to lessen the burden to those
individuals affected. A novel lifestyle intervention in individuals with HCM combining
increased physical activity and NO3
- supplementation may positively impact long-term
outcomes in this clinical population. Finally, the work provides a platform for further
investigation into the contribution of mitochondrial function in pathological cardiac
hypertrophy in ageing and HCM after the novel assessment of CI and CIV function in an aged
and HCM mouse cardiac phenotype model.
In individuals with HCM, the present thesis suggests that lifestyle interventions incorporating
NO3
- supplementation and increased physical activity may improve factors associated with
long-term outcomes such as QoL and blood pressure. Following the completion of a clinical
trial including a larger study population and dissecting of the combined intervention, lifestyle
behaviours may be implemented into clinical care after the completion of a clinical trial with a
larger study population.
Description: PhD Thesis2023-01-01T00:00:00ZInvestigating the role of CEP164 in ciliopathies through characterisation of a novel Cep164 mouse model
http://theses.ncl.ac.uk/jspui/handle/10443/6046
Title: Investigating the role of CEP164 in ciliopathies through characterisation of a novel Cep164 mouse model
Authors: Devlin, Laura Alice
Abstract: Ciliopathies are a group of rare, genetic disorders caused by mutations affecting
the biogenesis, functioning or maintenance of the ciliary complex. Cilia are found
on almost all cell types in the mammalian body where they orchestrate a
multitude of cellular processes. There are two main classes of cilia, primary cilia,
and motile cilia, which function through their respective roles in signal
transduction and motility. Accordingly, ciliopathies are associated with a plethora
of overlapping, multi-system, clinical manifestations. Moreover, ciliopathies
display an extensive genotype-phenotype heterogeneity, which remains poorly
understood.
CEP164 was initially identified as encoding a centrosomal distal appendage
protein, essential for ciliogenesis. Subsequently, CEP164 mutations have been
found in patients with nephronophthisis (NPHP)–related ciliopathies. These
patients have NPHP, a fibrotic cortico-medullary cystic kidney disease that can
lead to end-stage kidney disease, associated with retinal degeneration and
neurological defects. More recently, CEP164 has been implicated in wider
ciliopathy phenotypes, providing a paradigm for understanding the genetic
complexity of multisystem ciliopathies.
CEP164 expression in human and mouse development revealed that CEP164
expression correlates with tissues affected in CEP164-ciliopathy patients, and
that the expression pattern of CEP164 is conserved between human and mouse.
To examine the role of Cep164, an inducible Cep164 knockout mouse was
developed that revealed a mixed-ciliopathy phenotype, affecting both primary and
motile cilia, which are traditionally associated with separate disease syndromes.
Specifically, inactivation of Cep164 resulted in a number of phenotypes including:
cystic kidney disease, retinal dystrophy, abnormal cerebellar folding, obesity and
male infertility. Many of these phenotypes were consistent with the expanding
human CEP164-disease spectrum, confirming specific roles for CEP164 in organ
development and an ongoing requirement in adult tissue homeostasis. The
murine obesity phenotype and male infertility guided interrogation of wider patient
cohorts to assess the contribution of CEP164 alleles in common disease
phenotypes.
These data reveal that Cep164 is involved in primary and motile cilia function and
that Cep164 mutations alone can lead to complex mixed-ciliopathy phenotypes,
potentially including non-syndromic and adult-onset disease. This serves as a
striking example of the phenotypic heterogeneity that can be caused by a single
gene, and the importance of functional analyses to inform genetic interpretation
of ciliopathies.
Description: PhD Thesis2023-01-01T00:00:00ZInvestigation of somatic genomic abnormalities and the tumour microenvironment in paediatric B-cell non-Hodgkin lymphoma
http://theses.ncl.ac.uk/jspui/handle/10443/6037
Title: Investigation of somatic genomic abnormalities and the tumour microenvironment in paediatric B-cell non-Hodgkin lymphoma
Authors: Blain, Alexandra
Abstract: Over 90% of children diagnosed with B-cell non-Hodgkin lymphoma (B-NHL)
respond well to front-line therapy. However, survival for patients with primary
refractory or relapsed disease remains dismal and treatment options limited. This
project aimed to investigate the genomics and microenvironment of newly identified
B-NHL subtypes associated with poor (tumours with TP53 abnormalities) and good
(Burkitt-like lymphoma with 11q aberration (BLL-11q)) outcomes to identify
prognostic biomarkers and gain insight into the biology of paediatric B-NHL.
Genomic analysis of sporadic Burkitt lymphoma (sBL) patients identified TP53
abnormalities associated with inferior overall (p=0.016) and progression-free
(p=0.0047) survival. Analysis of matched diagnostic and relapse samples revealed
TP53 abnormalities in all cases at diagnosis which were maintained at relapse,
indicating a role for TP53 in sBL relapse. TP53 abnormalities were present within
a cohort of endemic BL (eBL) but were not associated with outcome. Care pathway
analysis involving semi-structured interviews with UK clinicians indicated positive
responses to our TP53 study and recommended validation within a prospective
clinical trial.
BLL-11q tumours harbour copy number gain and loss patterns on chromosome
11q. Previous studies identified genes of interest within the loss region but the
gene/s of interest within 11q gain remain unclear. Copy number analysis redefined
the minimum region of gain on 11q, which included IL10RA. Gene expression
analysis revealed significantly higher expression of IL-10 pathway members – IL10,
IL10RA, JAK2, STAT3 – in BLL-11q samples compared to sBL. High surface
expression of IL10RA in cell-lines with 11q gain/loss abnormalities was confirmed
by flow cytometry. In contrast, sBL cell-lines had low/absent IL10RA surface
expression.
Together, this project has shown that TP53 abnormalities offer substantial clinical
utility as a potential prognostic biomarker in sBL but not eBL, and has identified
IL10RA as a candidate gene of interest warranting further investigation as a
potential novel treatment target for patients with BLL-11q.
Description: PhD Thesis2023-01-01T00:00:00Z