Effect of the increase in "alcopops" tax on alcohol-related harms in young people : a controlled interrupted time series

Objective: To measure alcohol-related harms to the health of young people presenting to emergency departments (EDs) of Gold Coast public hospitals before and after the increase in the federal government "alcopops" tax in 2008. Design, setting and participants: Interrupted time series analysis over 5 years (28 April 2005 to 27 April 2010) of 15-29-year-olds presenting to EDs with alcohol-related harms compared with presentations of selected control groups. Main outcome measures: Proportion of 15-29-year-olds presenting to EDs with alcohol-related harms compared with (i) 30-49-year-olds with alcohol-related harms, (ii)15-29-year-olds with asthma or appendicitis, and (iii) 15-29-yearolds with any non-alcohol and non-injury related ED presentation. Results: Over a third of 15-29-year-olds presented to ED with alcohol-related conditions, as opposed to around a quarter for all other age groups. There was no significant decrease in alcohol-related ED presentations of 15-29-year-olds compared with any of the control groups after the increase in the tax. We found similar results for males and females, narrow and broad definitions of alcoholrelated harms, under-19s, and visitors to and residents of the Gold Coast. Conclusions: The increase in the tax on al copops was not associated with any reduction in alcohol-related harms in this population in a unique tourist and holiday region. A more comprehensive approach to reducing alcohol harms in young people is needed.

Characteristics of low-speed vehicle run-over events in children : an 11-year review

Objectives: The purpose of this study was to investigate the characteristics associated with fatal and non-fatal low-speed vehicle run-over (LSVRO) events in relation to person, incident and injury characteristics, in order to identify appropriate points for intervention and injury prevention. Methods: Data on all known LSVRO events in Queensland, Australia, over 11 calendar years (1999–2009) were extracted from five different databases representing the continuum of care ( prehospital to fatality) and manually linked. Descriptive and multivariate analyses were used to analyse the sample characteristics in relation to demographics, health service usage, outcomes, incident characteristics, and injury characteristics. Results: Of the 1641 LSVRO incidents, 98.4% (n=1615) were non-fatal, and 1.6% were fatal (n=26). Over half the children required admission to hospital (56%, n=921); mean length of stay was 3.4 days. Younger children aged 0–4 years were more frequently injured, and experienced more serious injuries with worse outcomes. Patterns of injury (injury type and severity), injury characteristics (eg, time of injury, vehicle type, driver of vehicle, incident location), and demographic characteristics (such as socioeconomic status, indigenous status, remoteness), varied according to age group. Almost half (45.6%; n=737) the events occurred outside major cities, and approximately 10% of events involved indigenous children. Parents were most commonly the vehicle drivers in fatal incidents. While larger vehicles such as four-wheel drives (4WD) were most frequently involved in LSVRO events resulting in fatalities, cars were most frequently involved in non-fatal events. Conclusions: This is the first study, to the authors’ knowledge, to analyse the characteristics of fatal and non-fatal LSVRO events in children aged 0–15 years on a state-wide basis. Characteristics of LSVRO events varied with age, thus age-specific interventions are required. Children living outside major cities, and indigenous children, were over-represented in these data. Further research is required to identify the burden of injury in these groups.

Exploring the re-criminalising of OHS breaches in the context of industrial death

Since the 1980s the calls for further criminalisation of organisational conduct causing harm to workers, the public and the environment have intensified in Australia, Canada and England and Wales.' One focal point of this movement has been the criminal law's response to organisations (and their personnel) failing to comply with occupational health and safety ('OHS') standards, particularly when physical harm (death and serious injury) has resulted from those breaches. Some governments have responded with proposals to enable manslaughter prosecutions to be initiated 'more effectively' against organisations causing the deaths of workers or, in some cases, members of the public (Archibald et al, 2004; Haines and Hall, 2004; Hall et al, 2004; Tombs and Whyte, 2003). In Australia governments have also increased monetary penalties for regulatory OHS offences, a few have introduced other contemporary organisational sanctions, and some have initiated OHS prosecutions more vigorously and with larger fines.

The role of university research centres in building road safety capacity : implications for China

In recent decades, highly motorised countries, such as Australia, have witnessed significant improvements in population health through reductions in fatalities and injuries from road traffic crashes. In Australia, concerted efforts have been made to reduce the road trauma burden since road fatalities reached their highest level in in the early 1970s. Since that time, many improvements have been made drawing on various disciplines to reduce the trauma burden (e.g., road and vehicle design, road user education, traffic law enforcement practices and enforcement technologies). While road fatalities have declined significantly since the mid-1970s, road trauma remains a serious public health concern in Australia. China has recently become the largest car market in the world (Ma, Li, Zhou, Duan, & Bishai, 2012). This rapid motorisation has been accompanied by substantial expansion of the road network as well as a large road trauma burden. Road traffic injuries are a major cause of death in China, reported as accounting for one third of all injury-deaths between 2002 and 2006 (Ma et al., 2012). In common with Australia, China has experienced a reported decline in fatalities since 2002 (see Hu, Wen & Baker, 2008). However, there remains a strong need for action in this area as rates of motorisation continue to climb in China. In Australia, a wide range of organisations have contributed to the improvements in road safety including government agencies, professional organisations, advocacy groups and research centres. In particular, Australia has several highly regarded and multi-disciplinary, university-based research centres that work across a range of road safety fields, including engineering, intelligent transportation systems, the psychology of road user behaviour, and traffic law enforcement. Besides conducting high-quality research, these centres fulfil an important advocacy role in promoting safer road use and facilitating collaborations with government and other agencies, at both the national and international level. To illustrate the role of these centres, an overview will be provided of the Centre for Accident Research and Road Safety-Queensland (CARRS-Q), which was established in 1996 and has gone on to become a recognised world-leader in road safety and injury prevention research. The Centre’s research findings are used to provide evidence-based recommendations to government and have directly contributed to promoting safer road use in Australia. Since 2006, CARRS-Q has also developed strong collaborative links with various universities and organisations in China to assist in building understanding, connections and capacity to assist in reducing the road trauma burden. References Hu, G., Wen, M., Baker, T. D., & Baker, S. P. (2008). Road-traffic deaths in China, 1985–2005: threat and opportunity. Injury Prevention, 14, 149-153. Ma, S., Li, Q., Zhou, M., Duan, L., & Bishai, D. (2012). Road Traffic Injury in China: A Review of National Data Sources. Traffic Injury Prevention, 13(S1), 57-63.

The protective mechanisms of first aid training within a school-based program for early adolescents

This thesis was concerned with the protective mechanisms of first aid training in the context of peer support. Using a randomised control trial design the current program of research explores first aid training in the school setting and identifies the key components of effective school-based first aid training programs. In particular, examining whether first aid training and associated knowledge could be protective for early adolescents. This broader framing considered whether first aid impacted on increasing behaviour and attitudes towards helping an injured friend, and reducing personal risk taking and related injury.

Improving the identification of fatigue-related crashes in the Australian Capital Territory

It has been well established nationally and internationally that fatigue-related driving is an important contributory factor in fatal and serious injury crashes. The purpose of this report was to survey a large, representative sample of residents living in both the NSW and ACT to ask about their experience of fatigue and their involvement in fatigue-related crashes and incidents. This will provide valuable data about the number and characteristics of fatigue-related crashes and incidents of ACT residents. Specifically this study assessed the prevalence of incidents of fatigue-related driving for residents of NSW and the ACT, the characteristics surrounding the incident, if the report would fit within the NSW, QLD, or ATSB proxy definition or if it would fall outside of the proxy definition...

The challenge of normative influences for program design for youth in detention

Young people in detention are at greater risk of death and disability from injury sustained while not in custody. Injury prevention and mental health programs have been designed for this group but their theoretical basis is rarely discussed. The present study investigates whether the conceptual basis of the Theory of Planned Behavior (TPB) is relevant to youth in a detention center. Focus group and observational data were collected. A thematic analysis supported central theoretical constructs and emphasized “Subjective Norms.” The challenge of normative influences must be actively addressed in the design of health interventions for youth in detention.

A comparison of training methods to increase neck muscle strength

Objective To compare two neck strength training modalities. Background Neck injury in pilots flying high performance aircraft is a concern in aviation medicine. Strength training may be an effective means to strengthen the neck and decrease injury risk. Methods The cohort consisted of 32 age-height-weight matched participants, divided into two experimental groups; the Multi-Cervical Unit (MCU) and Thera-Band tubing groups (THER), and a control (CTRL) group. Ten weeks of training were undertaken and pre-and post isometric strength testing for all groups was performed on the MCU. Comparisons between the three groups were made using a Kruskal-Wallis test and effect sizes between the MCU and the THER groups and the THER and CTRL groups were also calculated. Results The MCU group displayed the greatest increase in isometric strength (flexion 64.4%, extension 62.9%, left lateral flexion 53.3%, right lateral flexion 49.1%) and differences were only statistically significant (p<0.05) when compared to the CTRL group. Increases in neck strength for the THER group were lower than that shown in the MCU group (flexion 42.0%, extension 29.9%, left lateral flexion 26.7%, right lateral flexion 24.1%). Moderate to large effect sizes were found between the MCU and THER as well as the THER and CTRL groups. Conclusions This study demonstrated that the MCU was the most effective training modality to increase isometric cervical muscle strength. Thera-Band tubing did however, produce moderate gains in isometric neck strength

Evaluation of the Queensland Minimum Passing Distance Road Rule

The two-year trial of the Queensland minimum passing distance (MPD) road rule began on 7 April 2014. The rule requires motor vehicles to provide cyclists a minimum lateral passing distance of one metre when overtaking cyclists in a speed zone of 60 km/h or less, and 1.5 metres when the speed limit is greater than 60 km/h. This document summarises the evaluation of the effectiveness of the new rule in terms of its: 1. practical implementation; 2. impact on road users’ attitudes and perceptions; and 3. road safety benefits. The Centre for Accident Research and Road Safety – Queensland (CARRS-Q) developed the evaluation framework (Haworth, Schramm, Kiata-Holland, Vallmuur, Watson & Debnath; 2014) for the Queensland Department of Transport and Main Roads (TMR) and was later commissioned to undertake the evaluation. The evaluation included the following components: • Review of correspondence received by TMR; • Interviews and focus groups with Queensland Police Service (QPS) officers; • Road user survey; • Observational study; and • Crash, injury and infringement data analysis.

Long-term results of obstetric brachial plexus surgery

Background: Brachial plexus birth palsy (BPBP) most often occurs as a result of foetal-maternal disproportion. The C5 and C6 nerve roots of the brachial plexus are most frequently affected. In contrast, roots from the C7 to Th1 that result in total injury together with C5 and C6 injury, are affected in fewer than half of the patients. BPBP was first described by Smellie in 1764. Erb published his classical description of the injury in 1874 and his name became linked with the paralysis that is associated with upper root injury. Since then, early results of brachial plexus surgery have been reasonably well documented. However, from a clinical point of view not all primary results are maintained and there is also a need for later follow-up results. In addition most of the studies that are published emanate from highly specialized clinics and no nation wide epidemiological reports are available. One of the plexus injuries is the avulsion type, in which the nerve root or roots are ruptured at the neural cord. It has been speculated whether this might cause injury to the whole neural system or whether shoulder asymmetry and upper limb inequality results in postural deformities of the spine. Alternatively, avulsion could manifest as other signs and symptoms of the whole musculoskeletal system. In addition, there is no available information covering activities of daily living after obstetric brachial plexus surgery. Patients and methods: This was a population-based cross-sectional study on all patients who had undergone brachial plexus surgery with at least 5 years of follow-up. An incidence of 3.05/1000 for BPBP was obtained from the registers for this study period. A total of 1706 BPBP patients needing hospital treatment out of 1 717 057 newborns were registered in Finland between 1971 and 1997 inclusive. Of these BPBP patients, 124 (7.3%) underwent brachial plexus surgery at a mean age of 2.8 months (range: 0.4―13.2 months). Surgery was most often performed by direct neuroraphy after neuroma resection (53%). Depending on the phase of the study, 105 to 112 patients (85-90%) participated in a clinical and radiological follow-up assessment. The mean follow up time exceeded 13 years (range: 5.0―31.5 years). Functional status of the upper extremity was evaluated using Mallet, Gilbert and Raimondi scales. Isometric strength of the upper limb, sensation of the hand and stereognosis were evaluated for both the affected and unaffected sides then the differences and their ratios were calculated and recorded. In addition to the upper extremity, assessment of the spine and lower extremities were performed. Activities of daily living (ADL), participation in normal physical activities, and the use of physiotherapy and occupational therapy were recorded in a questionnaire. Results: The unaffected limb functioned as the dominant hand in all, except four patients. The mean length of the affected upper limb was 6 cm (range: 1-13.5 cm) shorter in 106 (95%) patients. Shoulder function was recorded as a mean Mallet score of 3 (range: 2―4) which was moderate. Both elbow function and hand function were good. The mean Gilbert elbow scale value was 3 (range: -1―5) and the mean Raimondi hand scale was 4 (range:1―5). One-third of the patients experienced pain in the affected limb including all those patients (n=9) who had clavicular non-union resulting from surgery. A total of 61 patients (57%) had an active shoulder external rotation of less than 0° and an active elbow extension deficiency was noted in 82 patients (77%) giving a mean of 26° (range: 5°―80°). In all, expect two patients, shoulder external rotation strength at a mean ratio 35% (range: 0―83%) and in all patients elbow flexion strength at a mean ratio of 41% (range: 0―79%) were impaired compared to the unaffected side. According to radiographs, incongruence of the glenohumeral joint was noted in 15 (16%) patients, whereas incongruence of the radiohumeral joint was found in 20 (21%) patients. Fine sensation was normal for 34/49 (69%) patients with C5-6 injury, for 15/31 (48%) with C5-7 and for only 8/25 (32%) of patients with total injury. Loss of protective sensation or absent sensation was noted in some palmar areas of the hand for 12/105 patients (11%). Normal stereognosis was recorded for 88/105 patients (84%). No significant inequalities in leg length were found and the incidence of structural scoliosis (1.7%) did not differ from that of the reference population. Nearly half of the patients (43%) had asynchronous motion of the upper limbs during gait, which was associated with impaired upper limb function. Data obtained from the completed questionnaires indicated that two thirds (63%) of the patients were satisfied with the functional outcome of the affected hand although one third of all patients needed help with ADL. Only a few patients were unable to participate in physical activities such as: bicycling, cross-country skiing or swimming. However, 71% of the patients reported problems related to the affected upper limb, such as muscle weakness and/or joint stiffness during the aforementioned activities. Incongruity of the radiohumeral joints, extent of the injury, avulsion type injury, age less than three months of age at the time of plexus surgery and inexperience of the surgeon was related to poor results as determined by multivariate analyses. Conclusions: Most of the patients had persistent sequelae, especially of shoulder function. Almost all measurements for the total injury group were poorer compared with those of the C5-6 type injury group. Most of the patients had asymmetry of the shoulder region and a shorter affected upper limb, which is a probable reason for having an abnormal gait. However, BPBP did not have an effect on normal growth of the lower extremities or the spine. Although, participation in physical activities was similar to that of the normal population, two-thirds of the patients reported problems. One-third of the patients needed help with ADL. During the period covered by this study, 7.3% BPBP of patients that needed hospital treatment had a brachial plexus operation, which amounts to fewer than 10 operations per year in Finland. It seems that better results of obstetric plexus surgery and more careful follow-up including opportunities for late reconstructive procedures will be expected, if the treatment is solely concentrated on by a few specialised teams.

Efeitos cardiovasculares da transferência adotiva de linfócitos T reguladores em camundongos submetidos à infusão crônica de angiotensina II e de aldosterona

A angiotensina (Ang) II e aldosterona induzem hipertensão arterial por mecanismos em parte mediados pela imunidade adaptativa, envolvendo linfócitos T auxiliares respondedores (Tresp). Os linfócitos T reguladores (Treg) são capazes de suprimir os efeitos próinflamatórios do sistema imune. O presente estudo avaliou se a transferência adotiva de Treg é capaz de prevenir a hipertensão e a lesão vascular induzidas pela Ang II ou pela aldosterona, em dois protocolos distintos. No protocolo com Ang II, camundongos machos C57BL/6 sofreram a injeção endovenosa de Treg ou Tresp, sendo depois infundidos com Ang II (1μg/kg/min), ou salina (grupo controle) por 14 dias. No protocolo com aldosterona, um outro conjunto de animais sofreu injeções de Treg ou Tresp, sendo depois infundido com aldosterona (600μg/kg/d) ou salina (grupo controle), pelo mesmo intervalo de tempo. O grupo tratado com aldosterona recebeu salina 1% na água. Tanto o grupo Ang II como aldosterona apresentaram elevação da pressão arterial sistólica (43% e 31% respectivamente), da atividade da NADPH oxidase na aorta (1,5 e 1,9 vezes, respectivamente) e no coração (1,8 e 2,4 vezes, respectivamente) e uma redução da resposta vasodilatadora à acetilcolina (de 70% e 56%, respectivamente), quando comparados com os respectivos controles (P<0,05). Adicionalmente, a administração de Ang II proporcionou um aumento rigidez vascular (P<0,001), na expressão de VCAM-1 nas artérias mesentéricas (P<0,05), na infiltração aórtica de macrófagos e linfócitos T (P<0,001) e nos níveis plasmáticos das citocinas inflamatórias interferon (INF)-γ, interleucina (IL)-6, Tumor necrosis factor (TNF)-α e IL-10 (P<0,05). Ang II causou uma queda de 43% no número de células Foxp3+ no córtex renal, enquanto que a transferência adotiva de Treg aumentou as células Foxp3+ em duas vezes em comparação com o controle. A administração de Treg preveniu o remodelamento vascular induzido pela aldosterona, observado na relação média/lúmen e na área transversal da média das artérias mesentéricas (P<0,05). Todos os parâmetros acima foram prevenidos com a administração de Treg, mas não de Tresp. Estes resultados demonstram que Treg são capazes de impedir a lesão vascular e a hipertensão mediadas por Ang II ou por aldosterona, em parte através de ações antiinflamatórias. Em conclusão, uma abordagem imuno-modulatória pode prevenir o aumento da pressão arterial, o estresse oxidativo vascular, a inflamação e a disfunção endotelial induzidos por Ang II ou aldosterona.

Alterações comportamentais e a análise do estresse oxidativo na idade adulta de animais expostos a hipóxia pré-natal

A Hipóxia-Isquêmica (HI) pré-natal é caracterizada por uma redução no aporte de oxigênio e nutrientes para o feto durante o período gestacional, que pode acarretar, a longo prazo, em dificuldade de concentração e aprendizagem, hiperatividade e déficit de memória. Esses prejuízos podem persistir ou se agravar até a idade adulta, levando ainda ao aparecimento de doenças como epilepsia e paralisia cerebral (PC). A privação de oxigênio e nutrientes, assim como o estresse materno, anemia, eclâmpsia e uso de drogas durante a gestação, podem causar estresse oxidativo durante os períodos críticos do desenvolvimento, e pode ser a principal razão para as mudanças que levam a programação fetal. O objetivo deste estudo foi relacionar a geração de espécies reativas e a consequente formação de estresse oxidativo nos animais adultos, com as alterações da biodisponibilidade do óxido nítrico de forma sistêmica, além de mudanças nos comportamentos motor e de ansiedade, manutenção da memória e aprendizado. Para a hipóxia, foi utilizado o modelo de clampeamento das artérias uterinas das ratas no 18 dia gestacional por 45 min, analisando os filhotes após 90 dias de nascidos. Foram utilizados os testes Open Field e labirinto em cruz elevada para a análise comportamental, e análises das enzimas glutationa peroxidase (GPx), superóxido desmutase (SOD) e catalase, além de quantificação de nitritos, TBARs e carbonilação de proteínas para avaliação de mecanismos oxidantes e antioxidantes. Os resultados demonstraram que o insulto durante a gestação pode acarretar em redução na formação da enzima GPx, além de maior concentração de nitritos analisados nos soros dos animais hipoxiados quando comparados aos controles, contribuindo para o dano oxidativo. Também foi observada redução na memória de habituação e comportamento motor, além de elevado comportamento ansioso em animais hipoxiados, diferentemente de controles. Concluímos assim que a hipóxia isquêmica pré-natal pode alterar permanentemente o estado oxidativo dos animais, além de atuar na formação do comportamento motor, memória de habituação e ansiedade. As descobertas aqui apresentadas contribuem para ampliar o entendimento acerca do evento de hipóxia isquêmica pré-natal, além de prover ferramentas para o desenvolvimento de mecanismos protetores e preventivos aos possíveis danos por ela causados.

采后果实衰老和冷害的机理及调控研究

衰老和冷害是果实采后极易发生的两种重要的生理性失调，严重影响了果实的商品质量和市场价值。本论文选用在采后贮藏期间容易衰老和出现冷害的枇杷、杧果和桃果实作为研究材料，比较深入系统地研究了这些果实采后衰老或冷害的机理和调控。主要的研究内容包括：（1）枇杷果实在不同贮藏条件下（低温、气调）的生理代谢、品质变化、衰老进程和贮藏性;（2）杧果果实采后生理特性及外源草酸和水杨酸处理对杧果冷害、品质和活性氧代谢的影响;（3）桃果实在低温贮藏下冷害发生特征，并从氧化还原平衡和蛋白质组表达方面探讨了桃果实采后冷害的发生机理。 试验结果表明：（1）与自发气调包装（MAP）相比，气调（CA, 10% O2＋1%CO2）能更有效的抑制枇杷果实的腐烂、延缓衰老、保持品质，以及控制多聚半乳糖醛酸酶（PG）和多酚氧化酶（PPO）的活性。枇杷果实在1 ºC气调下贮藏50天，腐烂指数低于7%，并保持固有的风味品质。短时间的高氧处理对果实腐烂和品质影响不大，促进了贮藏后期果实内乙醇的积累;（2）外源草酸和水杨酸处理显著减轻了杧果果实在贮藏期间的冷害程度，但对果实的硬度、可溶性固型物和可滴定酸含量影响不大。外源草酸和水杨酸提高了果实内抗坏血酸和谷胱甘肽的还原状态、提高了H2O2含量、降低了O2-含量和脂氧合酶活性，并提高了超氧化物岐化酶、过氧化氢酶、过氧化物酶、抗坏血酸氧化酶和谷胱甘肽还原酶的活性;（3）与非冷害桃果实相比，冷害桃果实呈现较低的H2O2含量、较高的膜透性、较高的酚类物质含量以及较高的抗坏血酸和谷胱甘肽还原状态。水杨酸对果实内H2O2含量、膜透性、酚类物质含量有显著的影响。冷害桃果实与非冷害桃果实的蛋白质表达也有明显的区别，32个差异表达蛋白依其功能分为8类，分别为能量产生、代谢、次生代谢、抗性、蛋白质的分布、基因转录、细胞结构和细胞生长。水杨酸对其中20个蛋白质的表达有显著影响。烯醇化酶、脂质运载蛋白、脱水蛋白、分支酸变位酶以及桂醇脱氢酶等与桃冷害发生有密切关系。 通过对上述结果的分析，得出如下结论：（1）与MAP相比，CA（10% O2 + 1% CO2）可显著延缓枇杷果实的衰老、腐烂和品质下降，CA延缓枇杷衰老的作用机理可能与其减轻果实内氧胁迫、降低PG和PPO活性有关;（2）用外源草酸或水杨酸处理杧果，可减轻贮藏期间果实的冷害程度，其调控机制可能与提高果实抗坏血酸和谷胱甘肽的还原状态、抑制O2－含量和提高H2O2含量有关;（3）在低温贮藏下，桃冷害发生与果实内较低的H2O2含量、生物膜完整性的破坏以及酚类物质含量增加密切相关，果实生物膜完整性的破坏与烯醇化酶、脂质运载蛋白、过敏蛋白以及脱水蛋白的下调表达有关，而酚类物质含量的增加与分支酸变位酶、桂醇脱氢酶的上调表达有关。

Investigation of toll-like receptor tolerance in the regulation of inflammation

Inflammation is a complex and highly organised immune response to microbes and tissue injury. Recognition of noxious stimuli by pathogen recognition receptor families including Toll-like receptors results in the expression of hundreds of genes that encode cytokines, chemokines, antimicrobials and regulators of inflammation. Regulation of TLR activation responses is controlled by TLR tolerance which induces a global change in the cellular transcriptional expression profile resulting in gene specific suppression and induction of transcription. In this thesis the plasticity of TLR receptor tolerance is investigated using an in vivo, transcriptomics and functional approach to determine the plasticity of TLR tolerance in the regulation of inflammation. Firstly, using mice deficient in the negative regulator of TLR gene transcription, Bcl-3 (Bcl-3-/-) in a model of intestinal inflammation, we investigated the role of Bcl-3 in the regulation of intestinal inflammatory responses. Our data revealed a novel role for Bcl-3 in the regulation of epithelial cell proliferation and regeneration during intestinal inflammation. Furthermore this data revealed that increased Bcl-3 expression contributes to the development of inflammatory bowel disease (IBD). Secondly, we demonstrate that lipopolysaccharide tolerance is transient and recovery from LPS tolerance results in polarisation of macrophages to a previously un-described hybrid state (RM). In addition, we identified that RM cells have a unique transcriptional profile with suppression and induction of genes specific to this polarisation state. Furthermore, using a functional approach to characterise the outcomes of TLR tolerance plasticity, we demonstrate that cytokine transcription is uncoupled from cytokine secretion in macrophages following recovery from LPS tolerance. Here we demonstrate a novel mechanism of regulation of TLR tolerance through suppression of cytokine secretion in macrophages. We show that TNF-α is alternatively trafficked towards a degradative intracellular compartment. These studies demonstrate that TLR tolerance is a complex immunological response with the plasticity of this state playing an important role in the regulation of inflammation.

Novel insights into the inflammatory basis of gastrointestinal disease

It has become clear that inflammation is beneficial to man, there are situations though that the inflammatory response causes damage to the host that is harmful to health. When the inflammatory response fails or is too strong, the health of the host is damaged and disease can occur. The implication of intestinal disease caused by an ineffective immune response is of great social and economic burden to society. The overarching purpose of this thesis is to assess inflammatory signalling targets associated with immune mediated disorders such as IBD, IBS and inflammatory liver disease. By assessing these targets and modifying their function I hope to contribute and expand further the pre-existing information on these disorders and improve the therapeutic interventions available in these debilitating conditions. I will assess the role of inflammation in disorders of the GI tract and liver IBD, IBS, hepatic inflammatory injury and furthermore, I will use pharmaceutical agents to activate and suppress components of the immune system. I will examine the inflammatory response in experimental models of disease for IBD and liver injury, I will attempt to alter these pathways using pharmaceutical intervention to delineate the disease causing mechanism that may lead to clinically relevant therapeutic interventions. In regards to IBS, I will attempt to improve the existing knowledge that exists in relation to the pathogenesis of this functional bowel disorder. I will attempt to define a mechanism by which the low grade mucosal inflammation that has been demonstrated by others arises and what this inflammation is induced by. The overall aim of this thesis is to attempt to further understand the mechanisms behind GI and liver disease. Looking at the inflammatory response in these specific conditions and how they can be altered may lead to exciting new therapies for inflammatory conditions in the gastrointestinal tract.