Introduction: Colorectal cancer surgery involves a period of recovery in hospital followed by convalescence at home. Enhanced recovery programs, in particular the use of laparoscopic surgery have reduced length of inpatient stay. Knowledge regarding the impact of surgery upon functional recovery is lacking. Loss of lean muscle mass and strength may compromise function. We conducted two studies (1) To assess skeletal muscle modulation and functional recovery after potentially curative colon cancer surgery, comparing traditional open surgery (OS) with laparoscopic (LS) techniques and (2) To review return to work (RTW) 1 year post colorectal cancer surgery. Methods: (1) A prospective longitudinal observational study was conducted at a single UK institution (April 2013 and December 2014). Participants undergoing OS and LS for colon cancer were recruited preoperatively and assessed over 6 months. The study was powered to changes in hand grip strength (minimum sample size of 24 patients in each group), and included analysis of serological inflammatory markers (granulocyte lymphocyte ratio (GLR)); muscle architecture (pennation angle (PA), muscle thickness (MT) and fascicle length (FL)), muscle protein synthesis rate and assessment of function (numerical pain score, dukes activity status index (DASI)) and health status (EQ5d5L). (2) A retrospective cohort questionnaire study was conducted. A specific questionnaire was created and dispatched to 204 patients who had undergone surgery with curative intent for colorectal cancer within a single teaching hospital in 2011-2012. Results: (1) Fifty-three patients (OS n=27; LS n=26) were recruited with no statistical differences between groups (age, sex, body mass index, tumour stage, blood loss). LS associated with longer mean operating time (182.5mins v 142.1mins, p<0.05), fewer complications (p<0.05) and shorter length of stay (3 days v 5 days, p<0.05). Hand grip decreased post surgery (maximum decrease day 3 (OS 24% v LS 15%, p<0.05), with OS data significantly lower at 2, 4 and 6 weeks (p<0.05)). GLR peaked on day 1 post surgery with no difference between groups at any time point. Muscle architecture assessment noted OS associated with decreased MT (8% v 1%, p<0.05) and PA (6% v 1%, p<0.05) at 4 and 6 weeks post surgery. Muscle protein synthesis rate for OS was 1.02±0.02%/day. OS pain scores were significantly higher at 2, 4 and 6 weeks (p<0.05). EQ5d5L and DASI scores were significantly lower for OS at 2, 4, 6 weeks and 6 months (p<0.05). (2) Response rate was 75% (OS=82%, LS=51%). LS reported earlier 'return to full fitness' (1-3 months) than OS (>6 months; p<0.05). Recovery from LS was 'better than expected' compared to OS 'worse than expected' (p<0.05). Forty-nine patients were employed preoperatively and 61% (n=30) returned to work. RTW was more frequent after LS (p<0.05). Length of time to RTW was significantly less after LS [44 (6-84) days] than OS [71 (14-252) days] (p<0.05). Conclusions: OS was associated with increased loss of strength, muscle mass and reduced MPS in the first six weeks after surgery, together with poorer functional recovery including RTW. One-third of patients failed to RTW 1 year post colorectal cancer surgery. We must invest more in managing expectations and provide better post discharge support to improve long term functionality.

Head and neck squamous cell carcinoma (HNSCC) is the sixth commonest cancer in the UK. Despite recent therapeutic developments, survival rates remain poor, particularly in advanced cancer and Human Papilloma Virus (HPV) negative disease. Novel treatments approaches are therefore urgently required. The type-1 insulin-like growth factor receptor (IGF-1R) regulates cellular growth and survival and is over-expressed in a range of cancer types. Other groups reported that inhibition of IGF-1R reduces HNSCC cell survival and sensitises to ionising radiation, but a clinical trial of IGF-1R inhibition as monotherapy was inactive in unselected palliative patients with HNSCC. These data suggest that predictive biomarkers for response to IGF-1R inhibition are required. The aims of this project were threefold. The first objective was to define factors associated with morbidity and mortality in patients with oropharyngeal cancer (OPSCC) treated with primary surgery alone or with adjuvant chemoradiotherapy. The five-year overall and disease specific survival rates were 68% and 78% respectively. In line with previous data, HPV negative status, current smoking status, high tumour T stage and the presence of perineural spread of tumour or lymphovascular invasion were associated with adverse survival outcomes. In surviving patients, quality of life outcomes were evaluated using the University of Washington Quality of Life score and functional outcomes were assessed with the MD Anderson Dysphagia Inventory. Increasing age, higher tumour T stage, lip-splitting mandibulotomy and free flap reconstruction were associated with reduced quality of life outcome scores following multivariate analysis. The second aim was to assess the significance of IGF-1R expression in HNSCC and test for correlates with clinico-pathological variables. Immunostaining of cores from 346 primary HNSCCs showed that IGF-1R expression was higher in tumour tissue than matched benign epithelium. High IGF-1R was significantly associated with reduced overall and disease specific survival, HPV negative status and high tumour T stage, although was not an independent predictor of survival in multivariate analysis. The final aim was to test the utility of IGF-1R inhibition in HNSCC cell lines as monotherapy and in combination with established treatments, aiming to identify predictive biomarkers for resistance to IGF-1R inhibition. In a panel of 6 HNSCC cell lines, the IGF-1R inhibitor BMS-754807 reduced IGF-1R, AKT and ERK phosphorylation in a dose dependent manner. IGF-1R inhibition with BMS-754807 reduced cell survival and sensitised cells to ionising radiation in clonogenic assay, although the magnitude of this effect varied between cell lines. Combination of BMS-754807 with the EGFR inhibitor Gefitinib caused supra-additive reduction in cell survival. Correlation analysis showed a trend towards an association between high levels of phosphorylated AKT and resistance to BMS-754807 monotherapy. To test the hypothesis that RAS signalling conferred resistance to IGF-1R inhibition, cells were infected with retroviral constructs encoding wild-type or mutant activated HRAS. Cells expressing mutant HRAS were more resistant to BMS-754807 than empty vector or wild-type HRAS infected controls, suggesting that HRAS mutation status may represent a biomarker of resistance to IGF-1R inhibition in HSNCC. Taken together, the results from this project highlight the significance of IGF-1R biology in HNSCC, and form the basis for further in-vivo and clinical research.

Background and aims Pin site infection (PSI) is a common complication of external fixation which can cause significant morbidity. Additional treatment required as a result of PSI can be costly in terms of NHS time and resources, but also personal and financial losses for those undergoing additional treatment. A reduction in PSI would therefore reduce the complications and costs associated with infection. The aim of the study is to determine the feasibility of antimicrobial impregnated collars in preventing PSI in patients with external fixation. Methods Current pin site care practices were identified by using an electronic questionnaire. Assessment of bacteria present at clinically non-infected and infected pin sites was determined through evaluating swabs obtained from the out-patient setting. Bacterial isolates were tested for antimicrobial sensitivity and biofilm capacity. Pre-clinical testing of the antimicrobial collar used bacterial isolates identified from the PSI evaluation. Test strains included S aureus, S epidermidis, corynebacteria and E coli. Pre-clinical tests included SPTT, tK100, and an in-vitro pin site model. A single-centre randomised control feasibility study was conducted with participants allocated to standard care or antimicrobial collar. Primary endpoints included number of participants with PSI, number of infected pin sites and bacteria present at pin sites at 3 months. Main findings Pin site care remains varied across the UK despite the availability of the UK Consensus Guidelines (Timms et al 2011). Pin site care is also inconsistent internationally. The bacterial evaluation identified large number of CoNS (46.2%), corynebacteria (10.7%) and S aureus (4.1%) in clinically non infected pin sites, although the significant increase of S aureus to 17.9% in PSI (p<0.01) suggests that this is a key causative organism in PSI. Antimicrobial sensitivity testing identified that 91.9% CoNS were sensitive to at least two of the antimicrobials used in the collar indicating that the antimicrobial collar has the potential to prevent PSI. SPTT demonstrated the efficacy of the antimicrobial collar in maintaining a zone of bacterial inhibition in excess of three months. TK100 methods also demonstrated the ability of the antimicrobial collar to kill attached bacteria within 72 hours. The feasibility study identified poor participant compliance with the antimicrobial collar. Participants in the antimicrobial collar group had significantly reduced bacteria at pin sites when the antimicrobial collar was retained in place for the duration of treatment (p=0.01). No significant difference was detected with number of participants with pin site infection or number of infected pin sites. Conclusion Results from preliminary testing indicates that the antimicrobial collar may be effective in reducing PSI in participants with external fixation, however further product development is required prior to rigorous testing with an adequately powered randomised control trial and economic evaluation.

Myotonic dystrophy (DM) is a progressive multisystemic genetic disorder which is inherited as an autosomal dominant trait. There are two subtypes of the disorder, DM type 1 and DM type 2. DM type1 is caused by an expansion of a CTG repeat located in the 3' untranslated region of the DMPK gene on chromosome 19q13.3, whereas DM type 2 is caused by a CCTG expansion in intron 1 of ZNF9 gene located on chromosome 3q. The mutant RNAs containing the expanded CTG/CCTG repeats alters the activity of various alternative splicing factors like Muscleblind-like (MBNL) proteins, which are sequestered in the ribonuclear foci in nucleus by the expanded mutant transcripts resulting in a number of splicing defects observed in DM patients. In first part of my thesis, I have assessed the nuclear and cytosolic distribution of MBNL proteins in both normal and DM cells. In both DM1 and DM2 cells the amount of nuclear MBNL1 was found to be at least 50% greater than seen in normal cells. In addition to this, I studied the distribution of MBNL1 protein in nuclear and cytosolic fractions of DM cells before and after treatment with compounds chromomycin A3, gemcitabine, IMOX, RO 31-8220 and hypericin which were highlighted in the primary screen. Treatment with the compounds produced a significant reduction in the proportion of nuclear MBNL1 compared to DMSO treated cells in DM fibroblast and myoblasts. In second part of this thesis I have examined the effect of MBNL1/2 down regulation on both RNA and MBNL1 foci in DM cells. MBNL1 and MBNL2 double knockdown resulted in a 40% increase of nuclear RNA foci than observed in scrambled siRNA treated cells, though a significant reduction was observed in case of MBNL (protein) foci. Also, MBNL 1 and MBNL2 down regulation did not result in the release of mutant transcript from the nucleus to the cytoplasm in KB-Telo MyoD (DM) cells as seen in BpmI restriction polymorphism assay. However, it had a degradative effect on the mutant DMPK transcript.

Aggregation of the abundant neural protein α-synuclein contributes to cellular toxicity in Parkinson‘s disease. We have created transgenic nematodes carrying fusion constructs encoding human α-synuclein (S) tagged with YFP (V) and/or CFP (C) as a fluorescent marker. Using the unc-54 myosin promoter, a synuclein-YFP (unc-54::SV (NI)) fusion construct was abundantly expressed in the body wall muscles of Caenorhabditis elegans. Permanent integrated lines were successfully generated for unc-54::V (NI), unc-54::S+V (I), unc-54::SC+SV (I), unc-54::C+V (I), and unc-54::CV (I) using gamma irradiation. The outcrossed transgenic synuclein strains were radiation sensitive and have shorter life span and lower pharyngeal pumping compared to wild type N2 and unc-54::V (I) worms. Fluorescence Resonance Energy Transfer (FRET) was measured for all the transgenic strains. The unc-54::SC+SV (I) worms showed FRET signals intermediate between the negative (unc-54::C+V (I)) and positive (unc-54::CV (I)) control strains. Confocal images were taken to confirm the presence of FRET. FRET signals increase markedly during early adult life in unc-54::SC+SV (I) worms. RNA interference by feeding was performed in unc-54::SC+SV (I) worms to knock out the Hip-1 co-chaperone function, thereby increasing the FRET signal. unc-54::SC+SV (I) fusion worms were also exposed to pesticides such as chlorpyrifos and rotenone, and we observed an increase in the size and intensity of fluorescent aggregates thereby increasing the FRET signal. Finally we have quantified reactive oxygen species (ROS) for unc-54::SC+SV (I) fusion worms and NL5901 strains by using the H2DCF-DA assay, showing that ROS levels were increased by pesticide exposure.

« Nous ? ». Interroger l’apparition diffuse du phénomène collectif, à-plusieurs, « nous ». Utiliser les parenthèses de la méthode (epoché) pour entrevoir le soi du phénomène collectif et échapper aux guillemets métaphysiques, « nous », et à la rature ontologique, nous. Penser le Nous ! depuis l’évolution des différentes réductions phénoménologiques, retracer une histoire de la méthode au travers le phénomène de l’inter-subjectivité. D’abord, par la tentative de la réduction transcendantale à l’objectité d’un « nous transcendantal » obtenu par « analogie accouplante » : envers l’autre comme moi (Husserl). Heidegger et la réduction ontologique à l’étantité comme déploiement de la question d’un Dasein avec des autres (Mitdasein). Lévinas et la réduction éthique au visage de l’autre, pour l’autre. Socialité première, au-delà de l’essence, autrement qu’être, ancrée dans la dissymétrie originaire d’un « nous responsable : Je-Vous, vous-Je ». Enfin, la réduction érotique (Marion) au visage de l’autre aimé, détaché du visage universel de l’éthique car individué par son amour ; lui aussi aimant comme moi : « nous amoureux : Je-Tu, Tu-Je ». Mais pas encore Nous ! Le « nous » transcendantal en reste aux vécus de conscience du sujet constituant. Le Mitdasein n’atteint pas l’autre en tant que tel, nous. L’universel de l’éthique se perd dans l’anonymat et l’érotique comporte la déception du tiers en départ. Pouvons nous penser le Nous ! en phénoménologie ? Tout « Je » est un « nous », tout « Vous » est un « nous », mais Nous !? Qu’en est-il de Nous !? Serait-ce un « nos-otros », un Nos-otros des-plazados ? / “We?”. To question the confusing appearance of the collective phenomenon, ‘by-many’, “we”. Utilize the method’s brackets (epoché) in order to investigate the self of the collective phenomenon and escape thus the metaphysical quotation marks “we”, and the ontological deletion, we. To think the “we” throughout the evolution of the different phenomenological reductions, retrace a history of its method focusing on the inter-subjective phenomenon. First of all, through the endeavor of the transcendental reduction to objectity of a “transcendental we” obtained by “analogical pairing”: towards the other as me (Husserl). Heidegger and his ontological reduction to being-ness as the deployment of the questioning of a Dasein with others (Mitdasein). Lévinas and the ethical reduction to the face of the other, for the other. The initial sociability, beyond essence, otherwise than being, anchored in the original dissymmetry of a “responsible we: I-Thou, Thou-I”. Finally, the erotic reduction (Marion) to the face of the loved one, detached from the universal face of ethics thus individuated by its love ; him loving as me : “enamored we: I-You, You-I”. But not yet We! The transcendental “we” rests in the conscience of the constituting subject. The Mitdasein does not reach the other as such, we. The ethical universal losses itself in the anonymity and the erotic entails the deception of the departing third person. Can we think the We! In phenomenology? Every “I” is a “we”, every “You” is a “we”, but We!? What about We!? Could it be a “nos-otros”, a Nos-otros des-plazados?

<p>This essay is based on Edward Saids magnum opus, Orientalism. Orientalism is the notion on the division between the Occident (west) and the Orient (east) stemming primarily from the colonial age. Said states that the great colonial powers of the 19^th and 18^th century, through various science projects, created a view of the east as its own opposite, I.e. as everything opposite to modernization and so called enlightenment, two components affiliated with the west. According to Said these moral and intellectual standards, to this day, penetrate all aspects of western society and are observed in all kinds of institutions, for example the academic world and the media. The essay observes several rapports in two of Sweden leading papers, Expressen and Aftonbladet, concerning the terrorist attacks in London 2005 and analyzes them through a discourse analysis. The purpose of the essay is to find out whether the rapports show any signs of what Said defines as orientalism. The main focus is on the power structures which make up the language used in the rapports and analyzing them through the lens of Orientalism. The analysis show that the rapports in Expressen clearly express a view which verifies Saids theory. The division between”we” I.e. the west and ”them”, the east, is sharp in this case. However the rapports in Aftonbladet show no clear signs of Orientalism and are quite different from the ones presented in Expressen.</p>

This essay is based on Edward Saids magnum opus, Orientalism. Orientalism is the notion on the division between the Occident (west) and the Orient (east) stemming primarily from the colonial age. Said states that the great colonial powers of the 19th and 18th century, through various science projects, created a view of the east as its own opposite, I.e. as everything opposite to modernization and so called enlightenment, two components affiliated with the west. According to Said these moral and intellectual standards, to this day, penetrate all aspects of western society and are observed in all kinds of institutions, for example the academic world and the media. The essay observes several rapports in two of Sweden leading papers, Expressen and Aftonbladet, concerning the terrorist attacks in London 2005 and analyzes them through a discourse analysis. The purpose of the essay is to find out whether the rapports show any signs of what Said defines as orientalism. The main focus is on the power structures which make up the language used in the rapports and analyzing them through the lens of Orientalism. The analysis show that the rapports in Expressen clearly express a view which verifies Saids theory. The division between”we” I.e. the west and ”them”, the east, is sharp in this case. However the rapports in Aftonbladet show no clear signs of Orientalism and are quite different from the ones presented in Expressen.

This study addresses how agrivisitors' social interactions affect satisfaction and, in turn, revisit intention. Adopting social exchange theory and resource theory, the study proposes that social interactions with service providers, local residents, companion visitors, and other customers influence satisfaction, which in turn affects revisit intentions. Revisit intentions, in particular, are considered as social intentions which are shared with other people who travel together. Furthermore, this study argues that the effect of social interactions on satisfaction is stronger for visitors who have greater environmental concerns than those who are less concerned. An onsite and online survey were conducted to examine the proposed model and test the hypotheses. Subjects (N= 400) were visitors who visited organic farms with their companions. Structural Equation Modeling (SEM) was used to test the proposed model and hypothesized relationships among the constructs. The analyses were performed with Analysis of Moment Structures (AMOS 7.0). One construct (i.e., social interaction with local residents) was removed due to its high nonresponse rate, so the two hypotheses associated with this construct were not tested. Other than that most hypotheses except one were supported or partially supported by the data and the proposed model also had an acceptable fit to the data. Results of the present study provide a direction for the development of a theoretical framework to understand revisit intentions by seeking to improve the social exchange relationships with visitors. In addition, practical implications are presented for organic farms involved in or considering tourism businesses.

Background: Osteoarthritis (OA) is a highly prevalent joint degenerative disorder among the older population. The main symptoms of OA are chronic pain, swelling and stiffness of joint. OA histopathology is characterized by cartilage damage, synovial inflammation and remodelling of subchondral bone. Resolvins are endogenous lipid mediators produced from Ω-3 poly-unsaturated fatty acids (PUFAs) during resolution of inflammation. The main biological functions of resolvins include anti-inflammation and resolution of inflammation. Currently, the emerging anti-nociceptive roles of some resolvins have been reported in various models of pain. However, roles of resolvins and the resolvin receptor system on osteoarthritic pain are unknown. Objectives: This thesis assesses the therapeutic potential of a resolvin precursor on OA pain and investigates the underlying mechanisms of action and resolvin receptor system in OA. Methods: Monosodium iodoacetate (MIA) and medial meniscus transection (MNX) -induced joint damage was used as models of OA pain. 17(R)-HDoHE (300ng/300μl) or vehicle (1% ethanol in saline, 300μl) was acutely or chronically administered at day 14 post model induction and pain behaviour was measured to determine the analgesic effects of the drug in these models. Haematoxylin and eosin (H&E) staining was used to assess joint histopathology. Gene expression of resolvin receptors, inflammatory cytokines and metabolic enzymes were measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in associated tissues from the models and human OA samples. Results: Pain behaviour and joint histopathology were established in both the MIA and MNX models. Expression of chemokine-like receptor 1(ChemR23) was lower in the synovia and higher in the spinal cord in the MIA model. 15-lipoxygenase (15-LOX) was expressed at a lower level in both synovia and spinal cord in the MIA model. Negative correlations were revealed between synovial ChemR23 expression and pain behaviour at both day 14 and 35 in the MIA model. ChemR23 expression in the spinal cord was positively correlated with pain behaviour at day 35 in the MIA model. Expression of formyl peptide receptor 2 (ALX), some inflammatory cytokines and metabolic enzymes was lower in the synovia in the MNX model but expression of 5-lipoxygenase-activating protein (FLAP) was higher. Expression of ALX in the synovia was positively correlated with tumor necrosis factor alfa (TNFα), interleukin 1 beta (IL1β) and cyclooxygenase 2(COX2) but negatively correlated with 5-LOX expression in the MIA model. Expression of ALX in the spinal cord was positively correlated with pain behaviour at day 14 but then the converse was true at day 35. Expression of ALX in the spinal cord was negatively correlated with IL6 in the MIA model. 17(R)HDoHE attenuated pain behaviour in both the MIA and MNX models following acute, chronic and discontinuous administration. Effects of acute administration of 17(R)HDoHE on pain behaviour were associated with an up-regulation in the expression of IL6 and decreased 5-LOX expression in the synovia of MIA model. A trend towards down-regulation of pro-inflammatory cytokines and associated enzymes by 17(R)HDoHE was observed in the acute study in the MIA model. Repeated administration of 17(R)HDoHE produced robust and sustained inhibitory effects on pain behaviour, but no change in joint histopathology. Pain behaviour was attenuated when 17(R)HDoHE was administered but returned to levels seen in vehicle treated rats after 7 days after drug cessation. In human OA samples, expression of ChemR23 was significantly higher than expression of ALX in both synovia and medial tibial plateau. ChemR23 expression was positively correlated with expression of 5-LOX in both synovia and medial tibial plateau and negatively correlated with 15-LOX2 expression in the medial tibial plateau from OA patients. There was a significantly positive correlation between ChemR23 expression and IL6 and 15-LOX1 expression in the medial tibial plateau. In addition, there was a significantly positive correlation between ALX and IL6 and 15-LOX1 expression in both synovia and medial tibial plateau. Expression of ALX, TNFα, IL6, COX2 and 5-LOX in the medial tibial plateau from OA patients was lower, compared to expression in bone from femoral heads obtained from trauma patients. Conclusions: These findings support anti-nociceptive and anti-inflammatory roles of resolvins and provide evidence that resolvins may be potential novel drugs to treat OA pain.