Three-dimensional outcomes of twin-block appliance treatment and the influence of the postured wax bite

Aims 1 To identify the 3D soft tissue volumetric and linear landmark changes following treatment with the Twin-Block Appliance TBA. 2 To estimate the TBA treatment outcome on the soft tissue facial profile volumetric and linear landmark changes from the Postured Wax Bite (PWB). 3 To identify if there is any association between certain soft tissue landmark variables and successful treatment outcome of the TBA as measured by the reduction in overjet. 4 To assess the effects of TBA treatment on facial expressions. Materials and Methods Forty-seven Caucasian subjects with Class II division 1 were recruited. 3D images captured of each subject, pre-treatment (T1), with the PWB (T2) and at the end of treatment (T3). Soft tissue volumetric and linear changes as well as the correlation between facial parameters and successful treatment were calculated. Results The mean soft tissue volumetric change from T1 to T3 was 22.24 ± 16.73 cm³. Soft tissue profile linear changes from T1-T3 for lower facial landmarks were 4-5 mm. From T1-T3, the mean soft tissue volumetric change of the total sample was 60% of the change produced by the PWB (T1 to T2). Correlations were weak for all 3D facial parameters and successful overjet reduction. Facial expression changes were only significant for the lower landmarks. Conclusions 1 TBA treatment, in growing subjects, increased the lower facial soft tissue volume and caused forward movement of the lower soft tissue facial profile landmarks.2 The PWB can be used to estimate the treatment outcome of the TBA on soft tissue profile changes.3 No association was found between soft tissue landmark variables and successful overjet reduction.4 TBA treatment had no effect on the upper facial landmarks for each facial expression but it changed the lower facial expressions significantly except for maximal smile in males.

An investigation of the molecular interactions between statins and bacterial pathogens, and their combined impact on the human immune system

Statins are a class of drug that inhibits cholesterol biosynthesis, and are used to treat patients with high serum cholesterol levels. They exert this function by competitively binding to the enzyme 3-hydroxy-3-methylglutaryl-CoenzymeA reductase (HMGR), which catalyses the formation of mevalonate, a rate-limiting step in cholesterol biosynthesis. In addition, statins have what are called “pleiotropic effects”, which include the reduction of inflammation, immunomodulation, and antimicrobial effects. Statins can also improve survival of patients with sepsis and pneumonia. Cystic fibrosis (CF) is the most common recessive inherited disease in the Caucasian population, which is characterised by factors including, but not limited to, excessive lung inflammation and increased susceptibility to infection. Therefore, the overall objective of this study was to examine the effects of statins on CFassociated bacterial pathogens and the host response. In this work, the prevalence of HMGR was examined in respiratory pathogens, and several CF-associated pathogens were found to possess homologues of this enzyme. HMGR homology was analysed in Staphylococcus aureus, Burkholderia cenocepacia and Streptococcus pneumoniae, and the HMGR of B. cenocepacia was found to have significant conservation to that of Pseudomonas mevalonii, which is the most widely-characterised bacterial HMGR. However, in silico analysis revealed that, unlike S. aureus and S. pneumoniae, B. cenocepacia did not possess homologues of other mevalonate pathway proteins, and that the HMGR of B. cenocepacia appeared to be involved in an alternative metabolic pathway. The effect of simvastatin was subsequently tested on the growth and virulence of S. aureus, B. cenocepacia and S. pneumoniae. Simvastatin inhibited the growth of all 3 species in a dose-dependent manner. In addition, statin treatment also attenuated biofilm formation of all 3 species, and reduced in vitro motility of S. aureus. Interestingly, simvastatin also increased the potency of the aminoglycoside antibiotic gentamicin against B. cenocepacia. The impact of statins was subsequently tested on the predominant CF-associated pathogen Pseudomonas aeruginosa, which does not possess a HMGR homologue. Mevastatin, lovastatin and simvastatin did not influence the growth of this species. However, sub-inhibitory statin concentrations reduced the swarming motility and biofilm formation of P. aeruginosa. The influence of statins was also examined on Type 3 toxin secretion, quorum sensing and chemotaxis, and no statin effect was observed on any of these phenotypes. Statins did not appear to have a characteristic effect on the P. aeruginosa transcriptome. However, a mutant library screen revealed that the effect of statins on P. aeruginosa biofilm was mediated through the PvrR regulator and the Cup fimbrial biosynthesis genes. Furthermore, proteomic analysis demonstrated that 6 proteins were reproducibly induced by simvastatin in the P. aeruginosa swarming cells. The effect of statins on the regulation of the host-P. aeruginosa immune response was also investigated. Statin treatment increased expression of the pro-inflammatory cytokines IL-8 and CCL20 in lung epithelial cells, but did not attenuate P. aeruginosa-mediated inflammatory gene induction. In fact, simvastatin and P. aeruginosa caused a synergistic effect on CCL20 expression. The expression of the transcriptional regulators KLF2 and KLF6 was also increased by statins and P. aeruginosa, with the induction of KLF6 by simvastatin proving to be a novel effect. Interestingly, both statins and P. aeruginosa were capable of inducing alternative splicing of KLF6. P. aeruginosa was found to induce KLF6 alternative splicing by way of the type 3 secreted toxin ExoS. In addition, a mechanistic role was elucidated for KLF6 in the lung, as it was determined that statin-mediated induction of this protein was responsible for the induction of the host response genes CCL20 and iNOS. Moreover, statin treatment caused a slight increase in infection-related cytotoxicity, and increased bacterial adhesion to cells. Taken together, these data demonstrate that statins can reduce the virulence of CFassociated bacterial pathogens and alter host response effectors. Furthermore, novel statin effectors were identified in both bacterial and host cells.

CpxR activates MexAB-OprM efflux pump expression and enhances antibiotic resistance in both laboratory and clinical nalB-type isolates of Pseudomonas aeruginosa

Resistance-Nodulation-Division (RND) efflux pumps are responsible for multidrug resistance in Pseudomonas aeruginosa. In this study, we demonstrate that CpxR, previously identified as a regulator of the cell envelope stress response in Escherichia coli, is directly involved in activation of expression of RND efflux pump MexAB-OprM in P. aeruginosa. A conserved CpxR binding site was identified upstream of the mexA promoter in all genome-sequenced P. aeruginosa strains. CpxR is required to enhance mexAB-oprM expression and drug resistance, in the absence of repressor MexR, in P. aeruginosa strains PA14. As defective mexR is a genetic trait associated with the clinical emergence of nalB-type multidrug resistance in P. aeruginosa during antibiotic treatment, we investigated the involvement of CpxR in regulating multidrug resistance among resistant isolates generated in the laboratory via antibiotic treatment and collected in clinical settings. CpxR is required to activate expression of mexAB-oprM and enhances drug resistance, in the absence or presence of MexR, in ofloxacin-cefsulodin-resistant isolates generated in the laboratory. Furthermore, CpxR was also important in the mexR-defective clinical isolates. The newly identified regulatory linkage between CpxR and the MexAB-OprM efflux pump highlights the presence of a complex regulatory network modulating multidrug resistance in P. aeruginosa.

Prostate cancer treatment as an embodied rite of passage: impotence and incontinence as challenges to status reversal and reintegration

Introduction and Rationale: A central argument in the thesis is that performative acts of control, sexual potency and spontaneity are central to the continuous construction of embodied masculine identities. The acts of control, and particularly issues of spontaneity, are central to understandings and addressing the difficulties men face at varying levels of embodied identity. Using Watson’s (2000) ‘Male body schema’, I will explore the challenges and opportunities men face when negotiating normative, pragmatic, and experiential embodiment. I will later then explore the importance of these levels of embodiment to achieving visceral embodiment; or what I would define as a renewed unconscious satisfaction and ability to achieve and maintain normative, pragmatic and experiential forms of embodiment. Purpose and Objectives: Using the concept of liminality, and permanent liminality, the thesis explores how we can interpret and understand men’s experience of prostate cancer diagnosis and treatment, and their struggle to regain power and control in the context of diagnosis, and also the side effects to treatment. The strategies men adopt in seeking out personalised medical programmes of treatment with their doctors are explored in detail. The power and control that can be exercised over medical professionals and treatment options is demonstrated. Method: Collecting responses online from prostate specific discussion boards via gatekeepers, and from interviews on the ‘health talk’ online database, three intersecting conceptual categories - liminality, masculinity and the body/embodiment - are combined in this research. Liminality and ‘time’ are directly linked to notions of ‘success’ and ‘outcome’ during the treatment process, and mark distinct points at which men, and their families, expect measures or limits to have been reached. Exploring liminality within the context of Turner’s ‘rites of passage’, I explore the difficulty men face in concluding the third stage of the rites; reintegration. Results: Prostate cancer diagnosis and treatment, impotence and incontinence, in particular, have profound implications for the continuous construction of embodied masculine identities, and thus identity in general, making the construction of hegemonic ideals in the context of a highly ‘performative’ society highly troublesome. The issue of ‘spontaneity’ in the construction of various forms of embodied identities is of particular concern for men who contributed to this study.