The effect of acute alcohol exposure on hepatic oxidative stress and function: prevention by micronutrients

Alcohol binge drinking, especially in teenagers and young adults is a major public health issue in the UK, with the number of alcohol related liver disorders steadily increasing. Understanding the mechanisms behind liver disease arising from binge-drinking and finding ways to prevent such damage are currently important areas of research. In the present investigation the effect of acute ethanol administration on hepatic oxidative damage and apoptosis was examined using both an in vivo and in vitro approach; the effect of micronutrient supplementation prior and during ethanol exposure was also studied. The following studies were performed: (1) ethanol administration (75 mmol/kg body weight) and cyanamide pre-treatment followed by ethanol to study elevated acetaldehyde levels with liver tissue analysed 2.5, 6 and 24 hours post-alcohol; (2). Using juvenile animals, 2% betaine supplementation followed by acute ethanol with tissue analysed 24 hrs post ethanol; and (3). Micronutrient supplementation during concomitant ethanol exposure to hepG2 cells. It was found that a single dose of alcohol caused oxidative damage to the liver of rats at 2.5 hr post-alcohol as evidenced by decreased glutathione levels and increased malondialdehyde levels in both the cytosol and mitochondria. Liver function was also depressed but there were no findings of apoptosis as cytochrome c levels and caspase 3 activity was unchanged. At 6 hours, the effect of ethanol was reduced suggesting some degree of recovery, however, by 24 hours, increased mitochondrial oxidative stress was apparent. The effect of elevated acetaldehyde on hepatic damage was particularly evident at 24 hours, with some oxidative changes at earlier time points. At 24 hours, acetaldehyde caused a profound drop in glutathione levels in the cytosol and hepatic function was still deteriorating. Studies examining ethanol exposure to juvenile livers showed that glutathione levels were increased, suggesting an overtly protective response not seen in with older animals. It also showed that despite cytochrome c release into the cytosol, caspase-3 levels were not increased. This suggests that ATP depletion is preventing apoptosis initiation. Betaine supplementation prevented almost all of the alcohol-mediated changes, suggesting that the main mechanism behind alcohol-mediated liver damage is oxidative stress. Results using the hepG2 cell line model showed that micronutrients involved in glutathione synthesis can protect against hepatocyte damage caused by alcohol metabolism, with reduced reactive oxygen species and increased/maintained glutathione levels. In summary, these results demonstrate that both acute alcohol and acetaldehyde can have damaging effects to the liver, but that dietary intervention may be able to protect against ethanol induced oxidative stress.

Sex-specific disruption of murine midbrain astrocytic and dopaminergic developmental trajectories following antenatal GC treatment

The mammalian midbrain dopaminergic systems arising in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) are critical for coping behaviours and are implicated in neuropsychiatric disorders where early life challenges comprise significant risk factors. Here, we aimed to advance our hypothesis that glucocorticoids (GCs), recognised key players in neurobiological programming, target development within these systems, with a novel focus on the astrocytic population. Mice received antenatal GC treatment (AGT) by including the synthetic GC, dexamethasone, in the mothers' drinking water on gestational days 16-19; controls received normal drinking water. Analyses of regional shapes and volumes of the adult SNc and VTA demonstrated that AGT induced long-term, dose-dependent, structural changes that were accompanied by profound effects on astrocytes (doubling/tripling of numbers and/or density). Additionally, AGT induced long-term changes in the population size and distribution of SNc/VTA dopaminergic neurons, confirming and extending our previous observations made in rats. Furthermore, glial/neuronal structural remodelling was sexually dimorphic and depended on the AGT dose and sub-region of the SNc/VTA. Investigations within the neonatal brain revealed that these long-term organisational effects of AGT depend, at least in part, on targeting perinatal processes that determine astrocyte density and programmed cell death in dopaminergic neurons. Collectively, our characterisation of enduring, AGT-induced, sex-specific cytoarchitectural disturbances suggests novel mechanistic links for the strong association between early environmental challenge (inappropriate exposure to excess GCs) and vulnerability to developing aberrant behaviours in later life, with translational implications for dopamine-associated disorders (such as schizophrenia, ADHD, autism, depression), which typically show a sex bias

Localism as restorative politics; social capital and anti-politics in the London Borough of Burgundia

ABSTRACT The purpose of this paper is to explore the political implications of policies and measures designed to promote “localism”. That is to say, the devolution of power down to a neighbourhood level, as enacted under the 2011 Localism Act. The implementation of localism in London boroughs will be examined. The context is the current concern over disengagement in an era of “anti-politics”, so it is intended to gain an understanding of how localism is interpreted and implemented on the ground. A tentative thesis, of a “restorative politics”, is proposed, such that localism is dynamic and is generating healthy political activity which counters anti-politics in the local community. This could have profound implications for the political parties locally and at Westminster. The extant theories about localism include constructivist interpretations suggesting that a neo-liberal localism is anti-political. This is contested. An emerging narrative heralding a new dawn of empowerment, and related themes concerning social capital, subsidiarity and anti-politics are reviewed. A necessarily empirical approach is adopted in an essentially functionalist frame of reference. There is a review of both academic and policy literature, combined with interviews of professionals involved in localism. This paper is designed to scope a future more substantial piece of research. The conference brief asks; “what scales or levels are appropriate for organising politics in this century”. In a century so far characterised by disillusionment, democratic deficits and abstention, the answer may be; local. The Good Life is lived locally in shared experience and familiar surroundings, hitherto not much amenable to local change. Burgundia is a reference to the film “Passport to Pimlico” (1949), when ABSTRACT The purpose of this paper is to explore the political implications of policies and measures designed to promote “localism”. That is to say, the devolution of power down to a neighbourhood level, as enacted under the 2011 Localism Act. The implementation of localism in London boroughs will be examined. The context is the current concern over disengagement in an era of “anti-politics”, so it is intended to gain an understanding of how localism is interpreted and implemented on the ground. A tentative thesis, of a “restorative politics”, is proposed, such that localism is dynamic and is generating healthy political activity which counters anti-politics in the local community. This could have profound implications for the political parties locally and at Westminster. The extant theories about localism include constructivist interpretations suggesting that a neo-liberal localism is anti-political. This is contested. An emerging narrative heralding a new dawn of empowerment, and related themes concerning social capital, subsidiarity and anti-politics are reviewed. A necessarily empirical approach is adopted in an essentially functionalist frame of reference. There is a review of both academic and policy literature, combined with interviews of professionals involved in localism. This paper is designed to scope a future more substantial piece of research. The conference brief asks; “what scales or levels are appropriate for organising politics in this century”. In a century so far characterised by disillusionment, democratic deficits and abstention, the answer may be; local. The Good Life is lived locally in shared experience and familiar surroundings, hitherto not much amenable to local change. Burgundia is a reference to the film “Passport to Pimlico” (1949), when a London neighbourhood declared independence and its citizens temporarily created the Good Life for themselves. Is the 21st century localism generating a restorative politics?

Is the incipient Chinese civil society playing a role in regenerating historic urban areas? Evidence from Nanjing, Suzhou and Shanghai

Urban regeneration in Western countries can count on a long-lasting tradition of experiences in which civil society has played a fundamental role in counterbalancing the system of power, resulting in profound urban governance readjustments. This has been the result of the increasing centrality of horizontal alliances between citizens and associations involved in urban affairs since the late 1960s in the West. Similar theoretical frameworks have been applied in China. However, these have frequently resulted in conceptual shortcuts that depict civil society as immature or lacking and the state as authoritarian. This paper will explore whether these categories are still entirely valid to urban regeneration in China. While the regime has traditionally prevented horizontal linkages of associations in urban governance (supporting their vertical integration to ensure a certain degree of soft control), there are signs of change. In particular, three cases of urban regeneration in historic areas will be used to discuss the changing role played by civil society in China. The ultimate goal is to examine whether horizontal linkages across groups of heterogeneous citizens are arising at the micro-level of urban governance.

Residential heat pump installations: the role of vocational education and training

Meeting European emissions targets is reliant on innovative renewable technologies, particularly ‘renewable heat’ from heat pumps. Heat pump performance is driven by Carnot efficiency and optimum performance requires the lowest possible space heating flow temperatures leading to greater sensitivity to poor design, installation and operation. Does sufficient training and installer capacity exist for this technology? This paper situates the results of heat pump field trial performance in a socio-technical context, identifying how far installer competence requirements are met within the current vocational education and training (VET) system and considers possible futures. Few UK installers have formal heat pump qualifications at National Vocational Qualification (NVQ) level 3 and heat pump VET is generally through short-course provision where the structure of training is largely unregulated with no strict adherence to a common syllabus or a detailed training centre specification. Prerequisites for short-course trainees, specifically the demand for heating system knowledge based on metric design criteria, is limited and proof of ‘experience’ is an accepted alternative to formal educational qualifications. The lack of broader educational content and deficiencies in engineering knowledge will have profound negative impacts on both the performance and market acceptance of heat pumps. Possible futures to address this problem are identified.