The side effects of opiates are an important area of study as detriments to activities of daily living and to quality of life might outweigh detriments caused by untreated pain. Furthermore there has been relatively little research into the cognitive effects of opiates. This thesis aims to explore the effects of morphine and oxycodone on memory. Part one of the thesis comprises a literature review of the cognitive effects of opiates. It presents an overview of the current levels of understanding as well as highlighting the clinical importance of furthering our understanding. It also briefly raises the question of how gender may interact with the drug effects. Part 2 comprises the empirical paper. It reports a randomised, placebo-controlled, double-blind study comparing the effects of 10 mg morphine, 5 mg oxycodone and placebo on 18 healthy volunteers. The findings were that these doses did not produce significant impairments in most cognitive measures, and there was no retrograde memory impairment as was seen in a previous similar study involving cancer patients. It found some subtle drug effects on working memory, episodic memory and subjective experiences. More importantly, it revealed some subtle interactions of gender and weight with drug implying that the current practice of prescribing doses of oral opiates that are not determined by weight and gender may be inappropriate. Part 3 comprises a critical appraisal of the research. It includes a description of my personal experience during the research process as well as exploring further issues of validity within the study.

The central effect of nicotine on cardiovascular regulation has been extensively studied. However, due to its unselective nature for nicotinic acetylcholine receptors (nAChR) the involvement of specific nAChRs at sites in the brain, in central nervous cardiovascular regulation remains unclear. The effects of intracerebroventricular (i.c.v.) and intracisternal (i.e.) injections of the a7 selective agonist, PSAB-OFP, and the a4p2 selective agonist, TC-2559, were investigated on blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) compared with nicotine, in the anaesthetised rats. PSAB-OFP and TC-2559 i.c.v. caused a delayed dose-related increase in BP and RSNA. When given i.e. the action was similar except the rise in BP was more immediate. The possibility that the pressor response was partly due to the agonists causing the release of the vasoconstrictor vasopressin into the circulation was tested by repeating the i.c.v. and i.e. injections of the agonists in the presence of a selective vasopressin Via antagonist. In the presence of Vi antagonist (i.v.), PSAB-OFP and TC-2559 (i.c.v.) now induced no change in BP or RSNA however i.e., the increase in BP and RSNA was delayed with TC-2559, while PSAB-OFP caused a decrease in BP and no change in RSNA. The cardiovascular effects of i.c.v. PSAB-OFP and TC-2559 in the presence of Vi receptor antagonist (i.c.v.) were also completely blocked. PSAB-OFP and TC-2559 (i.e.) in rats pre-treated with Vi antagonist (i.e.), no longer produced an increase in BP and RSNA. However, the delayed fall in BP caused by PSAB-OFP was potentiated. Nicotine i.c.v. caused a dose-related increase in BP and renal sympathoinhibition while i.e. the rise in BP was larger and now associated with a bradycardia. In the presence of Vj antagonist (i.v.), nicotine's (i.c.v.) cardiovascular effects were blocked however nicotine i.e. caused a decrease in BP, RSNA and HR. In the presence of Vi antagonist (i.c.v.), nicotine caused no change in RSNA, but BP still increased. In the presence of Vi antagonist (i.e.), nicotine i.e. induced a decrease in RSNA and HR, with no change in BP. This study indicates that activation of a4p2 and <x7 nAChRs in the hindbrain cause an increase in BP due to vasopressin release into the periphery, which is mediated by a central vasopressinergic pathway, possibly involving a pathway from the hindbrain to the PVN. Interestingly, the renal sympathoexcitation was also prevented by blocking Via receptors in the periphery as well as in the brain. A possible mechanism is discussed whereby vasopressin or its antagonist accesses the brain via the circumventricular organs and then indirectly influence the PVN, supra-medulla or supra-spinal vasopressin neurons influencing the renal sympathetic outflow. Nicotine also causes an increase in BP by vasopressin release into the periphery, by acting on nAChR in the forebrain and the hindbrain. Interestingly, the decrease in RSNA is still observed when in the presence of Vj antagonist, suggesting that the decrease in RSNA is partly mediated by an action of nicotine on nAChRs at sites in the hindbrain such as the NTS.

Men’s concerns about body image are increasingly paralleled by a growth in the use of anabolic androgenic steroids (AAS) (Wright & Grogan, 2000) with motivations for such use including enhanced confidence. AAS users are likely to self-objectify their bodies, which might manifest as persistent body surveillance involving constant monitoring and comparison against “internalised standard(s) of attractiveness with a focus on how one’s body looks rather than how it feels or functions” and may result in feelings of body shame (Parent & Moradi, 2011). Experiences of rank and status judgement following self-other comparisons may affect mood states (Gilbert, 2000). Masculinity fundamentally includes perceptions of rank and status and may result in gender role strain, i.e. the experience of distress men experience when feeling that they do not meet constructs about masculinity they value (Kilmartin, 2007). Psychoanalytic approaches suggest that a perceived failure to ‘measure up’ to one’s ego ideal (i.e. the internalisation of admired aspects of one’s parents) produces tension (Piers & Singer, 1953). This may result in shame which is usually related to visible and concrete deficiencies rather than moral deficits (Jacobson, 1964). Kohut (1971) describes how negative comments from one’s caregivers might ultimately result in low self-esteem. The present IPA qualitative study, involving six male AAS users, produced six themes. The participants identified traumatic experiences leading to feelings of weakness, interpreted by participants as being of lower rank and status. These feelings are defended against by wanting to gain size, which results in an increase of perceived strength and, thereby, self-esteem. This, however, remains fragile due to a somewhat dysmorphic misinterpretation of actual size versus internal experiences of weakness, and ultimately shame. AAS use appears to be both motivated and maintained by shame.

Tbx 1, a gene encoding aT-box transcription factor, is required for embryonic development in humans and mice. Half dosage of this gene causes most of the features of the DiGeorge or Velocardiofacial syndrome phenotypes, including aortic arch and cardiac outflow tract abnormalities. Here we show that genetic ablation of Trp53 or pharmacological inhibition of its protein product p53 rescues almost completely aortic arch defects and significantly ameliorates outflow tract defects of Tbx1 mouse mutants. Trp53 deletion rescues the cell proliferation deficit in the second heart field of Tbx1 mutants. In addition, and surprisingly, Tbx1 and p53 proteins can be found on neighboring sites on chromatin, suggesting that they share a set of target genes. In a search for shared targets, we found that the expression of Gbx2, a gene that interacts with Tbx1 during development of the aortic arch arteries, is down regulated by Tbx1 heterozygosity and rescued by Trp53 heterozygosity. In addition, Tbx1 and p53 occupy the Gbx2 gene, indicating that both contribute to its regulation. Overall our data identify unexpected interactions between Tbx1 and Trp53 and provide a proof of principle that developmental defects associated with reduced dosage of Tbx1 can be rescued pharmacologically.

Acute respiratory infections (ART) are among the most frequent infectious diseases in children worldwide, particularly in developing countries. Antibiotics are very often prescribed or purchased without prescription for the treatment of ARl, although viruses are recognised as tbe predominant pathogens [1-7]. The aim of the work presented in this thesis was to quantify antibiotic use 111 outpatients with ARI in Children's Hospital I, Ho Chi Minh City, Vietnam, to identify the viral and bacterial respiratory aetiologic agents and to assess the impact of antibiotic use on the selection of resistant bacteria in the intestinal flora. Two prospective descriptive studies were conducted in the outpatient clinic: one in ARl patients and the other in healthy children. The epidemiology, presentation and treatment characteristics of children with ARI in the outpatient clinic were described. Antibiotics were prescribed in 99.6% of 563 patients while respiratory viruses were detected in 72.5% among these patients with the use of multiplex PCR in respiratory specimens. Antibiotic use was considered inappropriate in 67.7% of cases, according to evidence-based guidelines and detected pathogens. Besides antibiotics, other treatments such as oral bronchodilators, oral corticosteroids, antihistamines, and mucolytic agents were commonly used at the rates of 57.6%, 10.3%, 11 % and 11 %, respectively, and in most of the cases, were not in accordance with the current guidelines. We observed a short-term selection of resistant Enterobacteriaceae in patients' intestinal flora resistant not only to the antibiotic class the patients received but also co-selection of resistance to other rarely used antibiotics. HPLC assays were developed with high sensitivity and specificity to determine the presence of 6 beta- lactam antibiotics in the urine antibiotic use before presentation as determined by HPLC (32%) was significantly higher than that reported by parent interviews (21 %). Antibiotic use in Vietnam is largely unrestricted leading to overuse and overprescription for uncomplicated ARI.

GABA is the ubiquitous inhibitory neurotransmitter in the brain and is involved in a wide variety of brain functions and implicated in many neuropsychiatric disorders. GABA also has a metabolic role such that it is challenging to quantify the function of GABA as a neurotransmitter. This thesis aimed to investigate the neuroimaging modalities available for the measurement of brain GABA in vivo in humans, particularly their sensitivity to changes in synaptic GABA concentration.

No description available.

Ireland were screened for the production of antimicrobials and quorum sensing inhibitors. (QSIs). 37 bacterial isolates were found to inhibit QS-dependent pigment production in Chromobacterium violaceum ATCC12472 or Serratia sp ATCC39006. The organic extracts of five isolates caused a significant decrease in both total biomass and biofilm viable counts displaying a range of growth inhibitory and antimicrobial activities. All five organic extracts caused a reduction in Pyocyanin production while three extracts significantly decreased the production of Pyoverdin in P. aeruginosa PAOI. The ability of the algae Bonnemaisonia hamifera and Halidrys siliquosa to produce antibiofilm bioactives was also investigated. Algal extracts of B. hamifera had varying degrees of antibiofilm activity on P. aeruginosa PAOl, E. coli ATCCl1303 and P. mirabilis ATCC7002. The antibiofilm activity of the chloroform, acetonitrile, and hexane extracts was found to be consistent with the presence of QSls detected using both, QSI reporter strain C. violaceum A TCC 12472 and with the luminescence-based bioreporter strains E. coli JMI09 pSB 1142 and JM 109 pSB536 suggesting a QSI -dependent mechanism. The methanolic extract of the alga H. siliquosa failed to display any QSI activity but was found to possess a broad-spectrum antimicrobial activity against bacteria belonging to the genus Staphylococcus, Streptococcus, Enterococcus and Propionibacterium with MBEC values of 1.25 mg/ml for both S. aureus (MRSA) 33593 and P. acnes lA. Bioassay-guided fractionation of the extract allowed the isolation of three compounds displaying antimicrobial and antibiofilm activity against MRS A ATCC33593. The molecular weights of the compounds was determined by UPLCqTOF- MS (442, 442 and 428 m/z respectively) and found to differ from the meroditerpenoids previously extracted from this alga {{902 Culioli,G. 2008;}}. The MBEC values of MRSA ATCC33593 were 0.028mg/ml (64/lM) for compounds 1 & 2 and 0.055 mg/ml (128 /uM) for compound 3. Structural elucidation of the three antimicrobials is currently underway in collaboration with Prof. Tasdemir, NUIG, Galway.

Secretory leucoprotease inhibitor (SLPI) has multifaceted roles in protecting tissues from the damaging effects of inflammation. In addition to its well characterised role as a protease inhibitor, SLPI has been shown to have anti-inflammatory and anti-microbial properties. The therapeutic potential for SLPI as an anti-inflammatory treatment has previously been assessed in chronic inflammatory conditions and has shown promising results in a clinical trial with cystic fibrosis (CF) patients. There is evidence to suggest that SLPI can also inhibit acute inflammation; however the administration of exogenous SLPI as a therapy during the acute inflammatory response has never been investigated. The work presented in this thesis establishes recombinant human SLPI (rhSLPI) as a wide-acting anti-inflammatory following both systemic and pulmonary inflammation induced by bacterial cell surface components. Additionally, rhSLPI was able to reduce a number of inflammatory parameters following pulmonary Pseudomonas aeruginosa infection; however it had no effect on bacterial burden. It was noted that despite reductions in known pro-inflammatory markers, IL-17 was increased following rhSLPI treatment. This IL-17 was shown to be from double negative (ON) T cells, which have been previously reported to play a protective role following pulmonary infection. The importance of SLPI as an inflammatory regulator is established through the increased susceptibility of SLPI knockout (KO) mice to LPS-induced lung inflammation as well as Pseudomonas and Staphylococcus pulmonary infection. Together this gives evidence that SLPI modulates the acute inflammatory response. It should therefore be considered as an anti-inflammatory therapeutic for acute sterile conditions, such as pancreatitis, or acute infections such as that seen in acute respiratory distress syndrome (AROS) patients where it could be combined with antibiotics.

Epidemiological studies suggest that cannabis is a risk factor for psychotic illness. The main active ingredient is Δ-9-Tetrahydrocannabinol (THC). In healthy humans, the acute administration of THC can elicit transient psychotic symptoms and cognitive impairment. THC stimulates the endocanabinoid CB1 receptor (CB1R). However, beyond CB1Rs, the mechanism underlying the pro-psychotic effects of THC is unknown. <em>The ecploration of candidate mechanisms was the first major theme in this thesis</em>. In Study 1 the pro-psychotic properties of intravenous (IV) THC were confirmed. Thereafter, studies 2and 3 explored whether the pro-psychotic effects were related to excess striatal dopamine release or abnormal neural oscillations respectively. The cannabis plant contains over sixty cannabinoid molecules, one of which, Cannabidiol (CBD) can antagonise some of the pharmacological effects of THC. It has been suggested that the absence of CBD in modern, 'high-potency' forms of cannabis (sinsemilla or 'skunk') underlies the risk of such preparations for mental health. However, the evidence for this is sparse. <em>Characterising the effect of CBD on THC-elicited responses was the second major theme in this thesis</em>. Studies 4 and 5 tested whether CBD inhibited acute THC elicited psychosis. In study 1 the psychotomimetic effects of acute IV THC were confirmed. THC-elicited positive symptoms were distinct from anxiety, and negative symptoms were distinct from sedation. Cognitive performance was impaired under THC conditions. In study 2, THC had no significant effect on striatal dopamine release despite inducing robust positive psychotic symptoms. In study 3, THC-elicited positive psychotic symptoms were related to reduced bi-frontal coherence in the theta (4-8Hz) band. Studies 4 and 5 both showed that CBD pre-treatment inhibits acute THC-elicited psychosis. Overall two major findings emerged. 1. The pro-psychotic effects of THC were related to abnormal neural oscillations, but not to striatal dopamine release; 2. Cannabidiol inhibits acute THC psychosis.