The successful regeneration of damaged or injured tissues is strictly dependent upon the ability to control angiogenesis. The formation of new blood vessels from pre-existing ones is mainly regulated by the vascular endothelial growth factor (VEGF), a mitogen specific for endothelial cells. A number of therapeutic approaches are being pursued to control this process in pathological conditions, including the use of synthetic peptides which have shown their capacity to either promote or inhibit angiogenesis. However, their lack of stability and short half-lives have strictly limited their clinical applications. To address these limitations, here, both anti- and pro- angiogenic peptide sequences (WHLPFKC and YIGSR) were synthesised at the uppermost branching generation of poly-ɛ-lysine dendrons.

Severe back pain caused by intervertebral disc degeneration (IVDD) and disc herniation effects up to 35% of people within their lifetime, of which 10% of cases lead to sufferers being chronically disabled. The impact of these conditions has been estimated in terms of social-economic cost, to be in excess of €12 billion per year in the UK alone. While, the biological processes that cause IVDD are not currently fully understood, IVDD can be characterised as progressive degeneration of the nucleus pulposus tissue, driven by a combination of inflammatory immune processes, enzymatic degradation of extracellular matrix components and changes in cellular phenotype and expression. While there is currently no suitable long-term treatment for IVDD, there has been a new drive of research in the field of tissue engineering and regenerative medicine in an attempt to find a potential treatment for this condition. The aim of this study is to develop a novel bio-active self-assembly hydrogel capable of in situ formation as a potentially injectable treatment for IVDD. The design and intended formulation of this hydrogel was based on both the previous work of (Reches and Gazit, 2003) on the self-assembly peptide, Fmoc-F2, and the design of a novel peptide from the active site of human insulin like growth factor-1.

This research reports the study conducted in Saudi Arabia, which aimed to explore: 1) the perception of the term CP with CP children and their mothers, 2) the implication of the meaning for mothers of children with CP, 3) the experiences of being a child with CP in Saudi Arabia. A qualitative approach was taken using critical ethnography methodology, informed by Bronfenbrenner's (1989, 1992 & 2005) ecological theory framework. Data were collected in two phases: Phase one involved two focus group interviews with 6 mothers of children with CP and follow up semi-structured interviews with three of them. The second phase of the research focused on interviews with children with CP. Semi-structured interviews were conducted with 9 children ranging between 5-17 years of age. Talking Mats, an innovative communication tool, was used to enable two children with difficult verbal communication to give their views.

The development of age appropriate paediatric formulations, particularly those suitable for young children, presents challenges with only limited knowledge available on the acceptability of different medicines and how this affects medication adherence. This thesis describes studies conducted at Alder Hey Children’s Hospital, Liverpool UK, with the aim of determining which factors relating to dose form and organoleptic properties of a medicinal product influence medication adherence in chronically ill children. The research was conducted in two phases comprising 70 chronically ill children aged between 3 and 11 years, 70 primary caregivers, and 33 hospital clinical and technical staff.

Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies, with a five year survival rate of less than five percent. New targets and more effective therapeutic intervention are required to improve diagnosis and prognosis for all patients with pancreatic cancer. Recent studies have established that the tumour suppressor protein Programmed Cell Death Gene 4 (PDCD4) plays a key role in the control of differentiation and neogenesis within the healthy adult pancreas. Pdcd4 was originally identified as a gene up-regulated during the process of apoptosis. However, recent data suggests a function for Pdcd4 as a tumour suppressor, making it a promising target for pancreatic cancer therapy. The present study utilised a novel model of tissue hypoxia, mimicking the oxygen-deprived core of cancerous tumours which is often resistant to conventional chemotherapeutic drugs and which is likely to lead to secondary tumour formation or metastases, especially in pancreatic cancer. Understanding how Pdcd4 regulates pancreatic cell fate, both in healthy pancreatic cells and in conditions of tissue hypoxia, may well arm us with a new weapon in our fight for more effective therapeutic intervention in the treatment and prevention of pancreatic cancer.

Mucus overproduction is an important feature of chronic inflammatory airway diseases including cystic fibrosis, chronic bronchitis, bronchiectasis and severe asthma. Inhaled drugs are often delivered to such diseased airways where mucus hypersecretion is likely to alter the deposition pattern of the drug particles, encouraging more central deposition where more mucus is present than in the airways of the periphery. The effect of the mucus on drug absorption is poorly understood, since there are few in vitro systems capable of modeling the effect of mucus on drug permeability. This project aims to characterize and develop selected lung cell lines as potential models of the airways to study drug permeability in the presence of mucus, whilst also using these models to study potential adverse effects of drug treatment in the airways. Currently there is no published work on drug permeability studies in the presence of mucus, using the chosen lung cell lines.

Synthetic and naturally occurring calcium and magnesium carbonate minerals are widely used in a range of industrial and environmental applications where the mineral quality and purity is often critical for their intended use. Hence accurate characterisation of the mineral assemblages is essential. Equally important is an understanding of the chemical and physical pathways leading to mineral formation and their roles in carbon sequestration from greenhouse gases. This study investigates the application of Raman and infrared spectroscopies to Ca-Mg carbonate analysis. A full quantitative calibration has been achieved for quaternary mixtures by Raman spectroscopy (RS) employing monovariable and multivariable methods. The method was validated by X-ray powder diffraction (XRD). The lowest error on component values was obtained by Principal Component Regression with application of Standard Normal Variate. The quantifications show that RS is comparable to XRD. The effect of particle size on the fundamental vibrations of the [CO32-] anion in calcite is investigated by mid-infrared and RS. While the effect of particle size on the infrared signature of internal modes of the [CO32-] anion is well documented, this thesis documents associated changes in Raman spectra as a function of particle size. With decreasing size spectral contrast diminishes and changes in the relative ratios of the internal modes occur. For RS the turnaround from optically thick to thin material occurs in the 42-59 μm size range with further changes occurring at ≤ 5 μm. RS was also utilized to monitor carbonate reaction kinetics after dissolution of [Mg(OH)2] by CO2 sparging in the presence of calcium salts at 35 °C, 30 days duration. Four experiments employing different calcium salts, Ca:Mg ratios and effect of hydromagnesite [Mg5(CO3)4(OH)2.xH2O] seeding were examined utilizing vibrational spectroscopies, XRD and SEM. Results suggest that carbonate mineral paragenesis is driven by geochemical feedback between a range of calcium and magnesium carbonate dissolution-precipitation events where decomposition of nesquehonite [Mg(HCO3,OH)∙2H2O] leads to formation of magnesium carbonate hydrates [Mg5(CO3)4(OH)2.xH2O]. XRD confirmed that these hydrated phases contain 8 and/or 5 molecules of crystalline water. However, RS cannot distinguish these phases. Traces of barringtonite [Mg(CO3)∙2H2O] found at the end of experiments were interpreted as an indicator of incongruent dissolution of nesquehonite. Findings suggest that the Raman active ν1 mode of barringtonite is situated at ca. 1094-1095 cm-1. The limitations of Raman analysis in the context of mineral assemblage quantification, short range ordering and particle size effects are discussed in the context of these findings.

Resveratrol and compounds related to it, known as resveralogues, have been shown to extend healthy lifespan in a number of species. A diverse set of molecular mechanisms have been proposed to account for these effects, including the activation of the NAD+-dependent histone deacetylase SIRT1. However, both resveratrol and some of its derivatives also display potentially detrimental activities including direct DNA damage, toxicity and the induction of cellular senescence. Accordingly, the overall aim of this thesis was to enable the generation of better compounds with minimal detrimental activity and maximum beneficial activity. The data presented in this thesis show my development of a new, convenient, one-pot stereo-selective synthesis of resveratrol and other trans-stilbene derivatives. This synthesis has been used to prepare more than 40 compounds, of which 20 are completely novel and a further 12 previously uncharacterised with regard to their biological effects. This study have evaluated these resveralogues with respect to their cytotoxicity in human fibroblasts using a range of widely-recognised assays. Data on the compounds’ toxicity are presented, together with evidence that two of the assays commonly used to measure cytotoxicity in vitro (the MTT and neutral red assays) are unsuited for cytotoxicity testing with this class of compound. Twenty-two of the (lowest toxicity) compounds have also been assayed for their effects on growth and senescence using indirect immunostaining for the proliferation marker pki-67 and catalytic histochemical visualisation of SA-β-galactosidase activity, respectively. The results indicate that the growth inhibitory activity of resveratrol is abrogated by the removal of the trans-stilbene double bond (no reduction of growth fraction in dihydroresveralogues at 100 μM). Interestingly, at low doses (5-10 μM), many resveralogues induce a significant increase in proliferation compared to control untreated cells. SIRT1 activity in the presence of each compound was measured using an in-vitro deacetylation assay and, whilst most resveralogues are SIRT1 activators, none of the compounds examined produced a significant increase in SIRT1 activation compared to the parent compound. SIRT1 activation was, for the first time, found to be independent of the presence of a trans-stilbene double bond. Some initial characterisation of the ability of the resveralogues to alter pro-inflammatory cytokine expression was also undertaken by using ELISA for interleukin 6. Some difficulties with this assay, with respect to background signal interference, were encountered but parallel data from collaborator (Professor Lynne Cox, University of Oxford) using a human specific IL6 antibody are available. Collabrator data, evaluating a selection of resveralogues, indicate that inhibition of IL6 release is independent of SIRT1 activation, demonstrating that not all potential beneficial effects are SIRT1 mediated. Finally, this work has identified three novel lead compounds (V24, V31, and V34) that have less detrimental activities with retention in SIRT1 activity.

An important aspect of health visitors’ (HVs’) role and responsibility is to identify and respond to domestic violence and abuse (DVA). To date, there has been limited exploration of HVs’ practice knowledge and the nature of their professional relationships during their day-to-day practice in addressing incidents of DVA in black and minority ethnic (BME) communities. Aim - The aim of the study was to explore the nature of HVs’ practice knowledge and professional encounters when trying to define, identify and respond to incidents of DVA in BME communities. Design - This study adopts the interpretative lens of a postcolonial feminist theoretical perspective as the focus for analysing the nature of HVs’ knowledge and their practices in addressing issues of DVA in BME communities. Postcolonial feminist thinkers offer the conjecture that knowledge about BME women’s lives must be analysed within the intersecting racialised, gendered and political contexts of their lives. The study utilises a mixed-method approach by conducting semi-structured interviews with twenty health visitors (HV) and documentary analysis of four key professional practice guidance documents on addressing DVA. Findings - The findings revealed the extent to which HVs’ theoretical and personal knowledge and practice in addressing DVA in BME communities are informed by the racialised, familial, gendered and political settings in which they work. The findings illuminate the complexities that are shaped by the neoliberalist approach to tackling health inequalities in the modern National Health Service (NHS). In particular, the study conceptualise the nature of HVs’ professional relationships with BME women to uncover DVA as a form of hegemonic representation. The findings offer the potential to transform the education and practice of current and future health professionals for the benefit of BME and other marginalised patients or service users. Implication for Practice - This research recommends a practice model which seeks to prioritise emancipatory knowledge. In particular, there are recommendations on the specific context in which HVs work with BME women to uncover DVA. It is suggested that further research in this area of practice should also explore the impact of a proposed Intersectionality framework for uncovering DVA in marginalised groups. This study represents an original contribution to knowledge by increasing understanding of the ways in which HVs work to address DVA in BME communities. Although implied in the literature, the understanding of HVs’ work at the intersection of DVA, familial and political perspectives have never previously been articulated in HV literature in this way.

Low back pain (LBP) is the most common form of chronic pain. Approximately 85% to 90% of chronic low back pain (CLBP) episodes in primary care cannot be related to serious pathology or neurocompression, being described as nonspecific chronic low back pain (NSCLBP). This disorder involves continuous pain or recurrent flare-ups that are responsible for high levels of distress, functional disability and work absenteeism. It has also a significant impact on health care systems and society in general. Considering the complexity inherent in the experience of NSCLBP, where personal and cultural contexts play a major role, research has highlighted the need to study this phenomenon in contexts that have not yet been investigated. This study aimed to explore the Portuguese individuals` experiences and perceptions of NSCLBP. An interpretative phenomenological analysis (IPA) was employed to explore the experiences of eight participants, who were recruited purposefully from three Portuguese health sites. Semi-structured one-to-one interviews were carried out in order to collect data. The interviews were audiorecorded and transcribed verbatim. Following an inductive process of data analysis, five themes emerged as interrelated parts of an extended account that explored the Portuguese individuals` experiences and perceptions of NSCLBP. In the first theme the disruptive nature of the NSCLBP experience was emphasised. In the second, the participants` meaning making of NSCLBP and their need to understand it were highlighted. In the third, the clinical encounters and their contribution to maintaining the lack of participants’ understanding about NSCLBP were emphasised. In the fourth, the meaning making of NSCLBP contribution to reshaping the participants` social interactions was explored. In the fifth, the participants` definition of their sense of self through the meaning making of NSCLBP was highlighted. In order to promote the transparency of data analysis, an audit trail was developed to document all relevant steps of this process. This study has offered the first insights into the Portuguese individuals’ experiences of NSCLBP disorder, which may help clinicians in transferring this knowledge to the therapeutic approach to patients with similar experiences. The knowledge produced may be used to inform recommendations for NSCLBP management.