Pseudomonas aeruginosa remains a constant threat both in the community and nosocomially, accounting for approximately 10% of hospital acquired infections (Davies, 2002). In particular, this free living, extremely virulent pathogen is a worry to clinicians involved in the care of patients suffering from cystic fibrosis, the genetically acquired, multi-system disease. Within the CF lung, P. aeruginosa is known to undergo genomic changes resulting in the progression to chronic infection and a worsening prognosis. The most notable example of this phenomenon is the switch to the mucoid phenotype resulting from frame-shift mutations in the mucA gene leading to overproduction of alginate. In this work, we have identified this switch in phenotype as a marker for host adaptation by the bacterium to the CF lung environment and therefore have sequenced three mucoid strains and their non-mucoid progenitors. Using a variety of comparative genomics software, we have identified that two of these pairings are true, isogenic, host adapted counterparts. Each mucoid strain demonstrates evidence associated with such host adaption including genome shrinkage as a result of genomic island and phage loss, as well as decreased virulence and motility. In order to determine the contribution of each genomic anomaly to the change in phenotypes observed, we have utilised a variety of phenotypic analyses including a LC-MS metabolomics analysis of the CF isolates grown in artificial sputum media to mimic chronic lung infection. Further to this, in an attempt at mapping the core genome of P. aeruginosa and providing the community with a greater understanding of the genomic basis of this pathogen, we have also sequenced four well known environmental isolates as well as a further clinical isolate and its rugose small colony variant. With this new data we have developed a new typing method that we believe is superior and more thorough to MLST analysis, noting that P. aeruginosa exists in three distinct groupings.

Propolis, a product from honeybees, is a resinous material composed of beeswax and resin obtained from plant secondary metabolites. It has been used as a folk remedy by humans since ancient times for treatment of many ailments such as wounds, inflammation and peptic ulcer disease. This study investigated the parasiticidal and metabolomic effects of propolis on Trypanosoma brucei, the etiologic agent for sleeping sickness which is an endemic parasitosis in sub-Saharan Africa as well as anti-mycobacterial effects. Propolis samples (n=91) which were mainly from Africa were extracted and profiled by high resolution LC-MS. The active samples which were available in high abundance were subjected to a series of chromatographic separations (open column, MPLC and HPLC) and screening techniques including HR-LCMS and NMR (1D & 2D) in order to separate and identify biologically active compounds present in the extracts. Fractionation was carried out on four samples as follows: S95 (Nigeria), S8 7 (Ghana), P1 (Tanzania) and KSA1 (Saudi Arabian) which possessed high potency against trypanosomes. Metabolomic effects were also investigated on blood stream form trypanosomes for a compound isolated from S87. Two new anti-trypanosomal prenylated stilbenes [(E)-5-(2-(8-hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)-2H-chromen-6-yl)vinyl)-2-(3-methylbut-2-en-1-yl) benzene-1,3-diol (F9) and 5-((E)-3,5-dihydroxystyryl)-3-((E)-3,7-dimethylocta-2,6-dien-1-yl) benzene-1,2-diol] (F13-11) were isolated from ethyl acetate extracts of the Ghanian sample (S87). Both compounds exhibited moderate activity against T. brucei with MICs of 6.73 and 16.45 (So(BM, respectively. A new diterpene propsiadin [(ent)-2-oxo-kaur-16-en-6,18-diol] (4) along with three known flavonoids 3,4-dihydro-2-(3,4-dihydroxyphenyl)-2H-chromene-3,7-diol (1), psiadiarabin (2), psiadiarabin (5) and a known diterpene psiadin (3) were isolated from the Saudi Arabian sample. Compound 1 was inactive at the intial concentration tested against T. brucei and M.marinum while compounds 2-4 had MICs at 30.9, 78.1, and 78.1 (So(BM against T. brucei and 312.1, 312.1 and 69.1 (So(BM against M. marinum, respectively. Psiadiarabin (5) showed considerable activity (0.6 % of control) during the initial screening at 20 (So(Bg/ml concentration. A new stilbene compound (F13-11) exhibited more interesting biological activity and was isolated in higher quantities than F9-1, another stilbene, which made the former a suitable candidate for metabolomic profiling on T. brucei. Treatment of T. brucei with F13-11 revealed significant metabolomic changes including alterations in levels of some of the essential amino acids, elevation of some of the sugars, particularly sedoheptulose, and minor increments in lipids. Overall, this work has revealed new propolis constituents with significant activity against T. brucei and has confirmed the presence of some potential therapeutic compounds in propolis which could be employed as leads in new drug discovery.

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Drug solubility plays an important role during formulation development; it affects drug delivery and, as many new drug candidates developed have poor water solubility, it is necessary to increase their aqueous solubility for administration. The solubility increases, achieved by prodrugs or salt formation for example, are traditionally measured using the shake-flask method. This thesis investigated the advantages of the CheqSol method for phase-solubility studies. This method, using small pH changes, brings a compound close to its intrinsic solubility then alternates the system between sub- and supersaturated states. It also looked at in silico design and molecular dynamics simulations to investigate the solubilising properties of novel molecules. CheqSol studies were carried out on four compounds, two basic (propranolol HCl and atenolol) and two acidic (gliclazide and ibuprofen), in water and in the presence of HP-β-CD and two poloxamers using the Sirius T3. All three non-ionising excipients used during CheqSol assays were found to increase the solubility of the four example drugs. It was concluded that this method was suitable for phase-solubility studies using non-ionizing excipients. Molecular dynamics were carried out using Materials Studio 5.5. Five novel molecules were investigated to determine if they are predicted to increase the solubility of gliclazide and ibuprofen. The solubility enhancements were compared to HP-β-CD simulations conducted using the software. All five molecules were less effective than HP-β-CD at improving the calculated solubility parameters. Further studies would need to be conducted with excipients, with known solubility effects, for conclusions about the molecular dynamics technique to be drawn.

Background: Children with cancer and their families are frequently confronted with physical and psychosocial late effects resulting from cancer. In recent years, this has been expanded to include posttraumatic stress symptoms (PTSS). However, to date very little research has been completed in the UK to investigate these symptoms. Furthermore, previous research has been limited by lack of adherence to mainstream theoretical accounts of posttraumatic stress disorder (PTSD). Therefore, the current study examined rates of PTSS in children with cancer and their siblings. Secondly, it investigated whether aspects of the Ehlers and Clark (2000) model of PTSD could provide a useful framework for understanding the phenomenon in this population. Methods: A cross-sectional between-groups design was employed to examine the differences in levels of PTSS between children who had been diagnosed with and/or treated for cancer (n = 34) and siblings (n = 26). Participants were aged between 8-18 years. Self-report measures of PTSS, maladaptive appraisals, traumacentred identity, thought suppression, perceived social support and family functioning were completed. Results: There were no significant differences between children with cancer and siblings on measures of PTSS. In support of the hypotheses, maladaptive appraisals, thought suppression and trauma-centred identity were found to significantly correlate with levels of PTSS for both children with cancer and siblings. Perceived social support was found to be significantly correlated with levels of PTSS for siblings only. Contrary to the hypothesis, family functioning was not related to PTSS for either the patient or sibling group. Conclusions: Results failed to evidence differences in levels of PTSS between children with cancer and their siblings. However, provisional support was found for aspects of the Ehlers and Clark (2000) cognitive model of PTSD in explaining PTSS for the current population.

Recent research has established a high prevalence of head injuries in both the adult and youth offending populations. Offenders often have difficulties with tasks that involve executive and frontal lobe functioning compared to non-offenders, but research has often not recorded or controlled for the effect of head injury. This research aimed to investigate whether young offenders in the community, with self-reported traumatic brain injury (TBI), perform differently to young offenders without a TBI on tasks that are associated with frontal lobe functioning. Participants completed a battery of assessment measures that related to four different areas of frontal lobe functioning. In addition measures of mood, socio-economic status (SES) and IQ were taken as possible confounding variables. A total of 20 participants were recruited in the TBI group and 15 in the non-TBI group. Participants were aged between 12-17 years old and had either past or current involvement with Youth Offending Services (YOS). The TBI group had significantly lower IQ and SES than the non-TBI group but similar levels of self-reported depression. The TBI group were more impulsive on an inhibition task and were poorer at intuitive and emotion-based decision making, and reading emotions from the eyes. There were no significant differences between the groups on reaction time tests. The study concluded that within this sample of young offenders, those with a self-reported head injury had poorer performance on some tasks associated with frontal lobe functioning, but not others. The findings are considered in the context of theoretical and clinical implications with suggestions for further research.

Background: Research indicates that there are benefits to both the mother and infant of breastfeeding. Campaigns have been launched in the UK with some efficacy in increasing the numbers reporting an intention to breastfeed, however, breastfeeding continuation rates remain relatively low. It is known that women’s expectations of breastfeeding are important when considering breastfeeding continuation. It is also recognised, that for women there is the potential of impact on postnatal mood and wellbeing when expectations of breastfeeding are not met by experience. Aims: The study aimed to explore the relationship between prenatal breastfeeding self-efficacy, mood and well-being and breastfeeding expectations. It then aimed to explore the relationship between a discrepancy between breastfeeding expectation and experience and postnatal mood and well-being. Method: Participants (N = 63) were first time mothers attending NHS antenatal groups reporting an intention to breastfeed. They completed a measure of breastfeeding expectation, breastfeeding self-efficacy and mood and well-being prenatally. Participants were asked to complete further measures of breastfeeding experience, mood and well-being around 12 weeks postnatally (N=29). Results: It was found that women’s prenatal breastfeeding self-efficacy correlated with their breastfeeding expectations. Breastfeeding social expectations were found to positively correlate with prenatal mood and well-being, while breastfeeding expectations of self were found to be independent of prenatal mood and well-being. Postnatally women’s experiences of breastfeeding were not found to differ significantly from their expectations. Conclusion: Overall, the results suggest that women’s social expectations of breastfeeding may be associated with their mood and well being prenatally. It is considered that breastfeeding expectations of self, however, were not associated with current functioning. It was observed in the current study that breastfeeding expectations were being met by experience, and therefore why an impact on postnatal mood and wellbeing would not be expected is discussed.

Previous research has found that Cognitive Bias Modification for Interpretation (CBM-I) is effective for modifying interpretation biases and reducing anxiety in adults (e.g., Mathews & Mackintosh, 2000). Beard (2011) recommended investigating the effectiveness of CBM-I in adolescents, particularly those experiencing social anxiety, and enhancing effects of CBM-I. Webb, Ononaiye, Sheeran, Reidy and Lavda (2010) found that implementation intentions (II) could promote rapid disengagement from threatening stimuli and decrease poor self-evaluation for people with high levels of social anxiety. Therefore the current study aimed to investigate the effects of CBM-I with II using a three session CBM-I training programme with adolescents experiencing clinical levels of social anxiety. Curtis (2013) found that adolescents with SAD showed greater reductions in anxiety and negative interpretation bias following a CBM-I programme if they enjoyed the programme. Therefore the study looked at whether adolescents who reported greater enjoyment displayed greater reductions in negative interpretation bias and social anxiety symptoms than those that reported low levels of enjoyment. Overall, CBM-I with IIs did not significantly reduce negative interpretation biases and levels of social anxiety. Still, minimal reductions in negative interpretation bias and social anxiety symptoms were found for some adolescents and the enjoyment level experienced was related to outcomes. The clinical and theoretical implications were discussed (e.g., aetiology of SAD and implications for treatment), alongside limitations of the study (e.g., recruitment and sample considerations) and potential directions for further research were suggested (e.g., increasing the number of CBM-I sessions) to develop our understanding of the variables involved in modifying interpretation bias and social anxiety in adolescents.

Background: People with dementia who have participated in research have reported experiencing shame (Cheston, in press; Mitchell, McCollum & Monaghan, 2013), and other uncomfortable self-conscious experiences, such as self-criticism (Langdon, Eagle & Warner, 2006), embarrassment (Imhof, Wallhagen, Mahrer-Imhof & Monsch, 2006), and fears of stigma (Harman & Clare, 2006). Public Health guidance has emphasised the importance of addressing the stigma and marginalisation of people with dementia (Department of Health, 2009; World Health Organisation & Alzheimer’s Disease International, 2012). Methodology: This study uses Interpretative Phenomenological Analysis to explore experiences of shame for six people in the early stages of dementia, living independently in the community. Data was collected through the use of individual, semi-structured interviews conducted within participants’ homes. The interviews were transcribed by the primary researcher and analysed through an in-depth, interpretive examination. Results: Four superordinate themes emerged from the data. Firstly, Avoidance reveals how the participants made several levels of attempts to hide and distance themselves from shaming experiences. Secondly, the participants’ accounts highlight Negative Self-Perceptions, including a weakening sense of self, a loss of value, and meaninglessness. Thirdly, Relationship Matters involve issues around trust, feeling a burden, and the impact of past relationships on current levels of shame. Fourthly, Uncertainty and loss of control highlights the participants’ search for an understanding of their experiences, and fears about an unknown future and losing control. Conclusion: The study contributes ideas for developing both public and professional awareness for promoting non-shaming experiences for people with dementia. In particular, suggestions are provided for improving communication during the assessment and diagnosis process, as well as options for responding to shame through psychological therapies.

Background and aims Social anxiety is common in people with psychosis. Recent evidence suggests that cognitive behavioural interventions can be used with this population to reduce distress and increase functioning. Imagery rescripting is effective for a range of psychological problems including social anxiety. This study aimed to investigate whether imagery rescripting is effective for social anxiety in people with psychosis. Method A single case series, multiple baseline design was used. Ten participants were recruited from Early Intervention in Psychosis (EIP) and Integrated Delivery Team (IDT) services in Norfolk and Suffolk. The intervention was replicated from previous work in the social anxiety field (Wild et al., 2008; Wild & Clark, 2011). Throughout the study participants completed measures related to social anxiety, beliefs, memory and imagery, psychotic symptoms, depression, social functioning and quality of life. Each participant attended seven sessions including a one month follow-up assessment. Data were analysed using visual inspection and the calculation of reliable and clinical change. Exploratory group statistics and effect sizes were also calculated. Results Five participants achieved reliable and clinical change in social anxiety and were classified as ‘recovered’ (Wise, 2004). Improvements in belief, memory and imagery ratings were observed for most participants following imagery rescripting. Psychotic symptoms, depression, social functioning and quality of life remained largely stable. Those who didn’t recover had more complex needs or comorbid difficulties. Group Imagery rescripting for social anxiety in psychosis D. Heavens iii analyses revealed significant improvements and medium to large effect sizes. However, this should be interpreted with caution due to the small sample size. Conclusion The study offers some support for the use of imagery rescripting for social anxiety in people with psychosis. Those with less complex presentations are likely to benefit most and it may offer a brief yet effective intervention for these individuals. Those with complex difficulties may require longer and more intensive input.