Search

This article explores an emerging strategy by sections of the British radical right towards the LGBTQ+ (lesbian, gay, bisexual, transgender and queer) community, who the radical right claim are existentially threatened by the alleged violent homophobia of Islam and their ostensible betrayal by ‘the left’. Consequently, parts of the radical right present themselves as the ‘true’ protectors of LGBTQ+ individuals through what we term alter-progressivism. By analysing recorded speeches, discussions and interviews by and with key British radical right figures, we demonstrate three themes: (1) the broad radical right discourse of a ‘Great Replacement’ specifically tailored towards LGBTQ+ anxieties, (2) a narrative in which the radical right portray themselves as the defenders of (some) minorities and (3) an emerging distinction between the far-right and radical right concerning LGBTQ+ rights. We conclude that these themes represent a significant rhetorical shift and reveal the flexibility of radical right narratives in an attempt to appeal to diverse communities. This represents a serious challenge, which compels social scientists to adapt their understandings of radical right ideologies, objectives and strategies.

Daily rhythms are observed in humans and almost all other organisms. Most of these observed rhythms reflect both underlying endogenous circadian rhythms and evoked responses from behaviours such as sleep/wake, eating/fasting, rest/activity, posture changes and exercise. For many research and clinical purposes, it is important to understand the contribution of the endogenous circadian component to these observed rhythms.The goal of this manuscript is to provide guidance on best practices in measuring metrics of endogenous circadian rhythms in humans and promote the inclusion of circadian rhythms assessments in studies of health and disease. Circadian rhythms affect all aspects of physiology. By specifying minimal experimental conditions for studies, we aim to improve the quality, reliability and interpretability of research into circadian and daily (i.e., time-of-day) rhythms and facilitate the interpretation of clinical and translational findings within the context of human circadian rhythms. We describe protocols, variables and analyses commonly used for studying human daily rhythms, including how to assess the relative contributions of the endogenous circadian system and other daily patterns in behaviours or the environment. We conclude with recommendations for protocols, variables, analyses, definitions and examples of circadian terminology.Although circadian rhythms and daily effects on health outcomes can be challenging to distinguish in practice, this distinction may be important in many clinical settings. Identifying and targeting the appropriate underlying (patho)physiology is a medical goal. This review provides methods for identifying circadian effects to aid in the interpretation of published work and the inclusion of circadian factors in clinical research and practice.

Foster provides an overview of the hormone melatonin, discussing its role in seasonal biology and its more controversial function in human sleep.

In his fifth-century BCE chronicle of the Graeco-Persian Wars, Herodotus describes a challenge that European scholars have faced for two and a half millennia (Drace-Francis, 2013: 1). Since Antiquity, discussions of just what ‘Europe’ is, descriptively and normatively, have not been resolved and consensus has been reached that multiple ‘Europes’ exist. Recent events in Europe, though, suggest that while the boundaries of Europe are, and will forever remain, quite unknown, the boundaries of EUrope are becoming identifiable.

Is the European Union (EU) in a state of crisis? Over recent years, a series of systemic and spontaneous challenges, including Brexit, the rise of Euroscepticism and the Eurozone and refugee crises, have manifested in landmark moments for European integration. First published as a special issue of the journal Global Discourse, this edited collection investigates whether these crises are isolated phenomena or symptoms of a deeper malaise across the EU. Experts from across disciplines analyse and rethink the forces which pull Europeans together, as well as those which push them apart.

Is the European Union (EU) in a state of crisis? Over recent years, a series of systemic and spontaneous challenges, including Brexit, the rise of Euroscepticism and the Eurozone and refugee crises, have manifested in landmark moments for European integration. First published as a special issue of the journal Global Discourse, this edited collection investigates whether these crises are isolated phenomena or symptoms of a deeper malaise across the EU. Experts from across disciplines analyse and rethink the forces which pull Europeans together, as well as those which push them apart.

Circadian rhythms are essential for the survival of all organisms, enabling them to predict daily changes in the environment and time their behaviour appropriately. The molecular basis of such rhythms is the circadian clock, a self-sustaining molecular oscillator comprising a transcriptional–translational feedback loop. This must be continually readjusted to remain in alignment with the external world through a process termed entrainment, in which the phase of the master circadian clock in the suprachiasmatic nuclei (SCN) is adjusted in response to external time cues. In mammals, the primary time cue, or “zeitgeber”, is light, which inputs directly to the SCN where it is integrated with additional non-photic zeitgebers. The molecular mechanisms underlying photic entrainment are complex, comprising a number of regulatory factors. This review will outline the photoreception pathways mediating photic entrainment, and our current understanding of the molecular pathways that drive it in the SCN.

Since the early 1990s a dominant modernist narrative has assumed that European integration and the progressive march of secularism, multiculturalism and increased material prosperity would lead to the fading-away of tribal, national, racial and other parochial identities; identities ostensibly incompatible with a meta-national ‘European’ identity founded not in ethnosymbolic myth, but in cosmopolitanism. This has informed not only academic theory but has also guided 60 years of EU policy making, with Ernst Haas’ doctrine of neofunctionalist spill-over dominating European assumptions that a pan-European identity would replace national affiliations. Brexit contradicts this in four ways. First, Brexit demonstrates the renewed appeal of ethnic nationalism on multiple levels: nationalist (British), sub-nationalist (English), and meta-nationalist (white nationalism). Second, Brexit demonstrates shifts in traditional nationalism in the form of gulfs in a neo-medieval society. Third, Brexit demonstrates the existence of multiple and incompatible ‘European’ identities. Finally, Brexit demonstrates how a specifically EUropean identity can be just as hostile and exclusionary as ethnic nationalism. This reappearance of social discord, ethnosymbolic identities, and the praxis of ethnic identity exemplified by the British, but seen across the EU, necessitates a fundamental reconsideration of the apparently irreversible trends of an unfalsifiable theory of modernist, neofunctionalist progressivism in the form of European integration. Using the British as a case study, this paper argues that the very processes of European integration have, by accelerating antagonistic national and EU identities, inadvertently constructed the apparatus for EUrope’s potential disintegration.

This revised and updated tenth edition of the bestselling textbook Politics UK is an indispensable introduction to British politics. It provides a thorough and accessible overview of the institutions and processes of British government, an excellent grounding in British political history and an incisive introduction to the issues and challenges facing Britain today. This edition welcomes three brand new chapters - 'Elites in the United Kingdom', 'Gender and British politics' and 'UK Immigration policy in hostile environment' - alongside rigorously updated revised chapters. It delivers excellent coverage of contemporary events, with significant new material covering: the Johnson premiership and the national challenge of Covid-19, the end of the May premiership and the implementation of Brexit, the Labour Party's transition from Corbyn to Starmer, infrastructure and innovation, 'fake news', populism and nationalism, the UK's place in a post-Brexit world, climate change, social mobility and elite recruitment, devolution and regionalism, constitutional strain, the role of political advisers, abuse and incivility in politics and much more. Other features of the new edition include: A wide range of illustrative material, boxes and case studies providing illuminating examples alongside the analysis. A comprehensive 'who's who' of politics in the form of Profile boxes featuring key political figures. And another thing . . . pieces containing short articles on salient and pressing topics, written by distinguished commentators including Sir John Curtice, Sir Simon Jenkins, Andrew Rawnsley, Baroness Julie Smith of Newnham, and Philip Collins. Online interviews on the book's website see notable figures from British political life discussing the pressing issues of today. With chapters written by highly respected scholars in the field and contemporary articles on real-world politics from well-known political commentators, this textbook is an essential guide for all students of British politics. © 2022 selection and editorial matter, Bill Jones, Philip Norton and Isabelle Hertner;. All rights reserved.

Boris Johnson’s electoral victory and the 2020 culmination of Brexit are accelerating Britain’s shift towards the right and towards open criticism of technocracy in the UK and EU. Since 2016 the UK’s political atmosphere has polarised into hostile extremes. The continuation of this toxicity beyond Brexit, the dominance of nationalist narratives as Britain’s new ‘politics of everything’ (Valluvan 2019). While the Conservative Party remains traditionally centre-right and the Brexit Party has ceased to be relevant, the UK continues to witness the growth of the far right and what is called here the ‘Radical Right’, which have been accelerating since 2016, rapidly gaining influence (Norris and Inglehart 2019: 443-472), and ‘mainstreaming’ (Miller-Idriss 2017) in the Conservative majority elected in December 2019. The past four years have seen growing British contempt for technocracy in London and Brussels, while the Leave vote has been represented as a “Will of the People” antithetical to a Remain/Revoke/Second Referendum position, often portrayed as an anti-democratic scheme by “the elite” to frustrate the will of “the people”. This ‘us and them’ populist narrative is deepening as the UK’s volatile political environment moves away from the political procedures and economic values by which the UK has operated since 1945. Since early 2020, this narrative has been significantly accelerated by Covid-19 countermeasures, with anti-EU parties and narratives on the left and right becoming anti-lockdown or anti-vaccine parties and narratives. This paper approaches the radical right as emblematic of British politics’ shift from centrism towards polarised factions defined not by party but by support or contempt for technical governance. In this paper we propose a new explanatory basis for studying the populist radical right not as a temporary phenomenon in response to specific political events and conditions, but as a fluid, amorphous, and heterogeneous set of groups, parties, and narratives whose strategies, appeal, and narratives make them extremely adaptable, and significant as a force with substantial influence of politics into the future.

This article introduces the special issue on populism and technocracy in the integration and governance of the European Union (EU), framing these opposing approaches in the context of polarised debate on the (il)legitimacy of the EU. The special issue was conceived as an interdisciplinary approach to questions of the EU’s legitimacy in the aftermath of structural crises (the eurozone, sovereign debt and the election and appointment of governing agents) and spontaneous crises (migration, external state and non-state security challenges, Brexit and Euroscepticism). Since the special issue’s conception the unanticipated Covid-19 pandemic, and responses from the EU and its member states (current and former) starkly illuminated debates on how the EU should operate, the limits of its power and the limits of its popular legitimacy. The era of passive consensus has been replaced by claims of legitimacy based on active expert-informed intervention, alongside populist claims of the EU’s inherent illegitimacy as an undemocratic technocracy. As such the special issue’s objective is to critically analyse manifold ways in which the populist-technocratic divide is narrated and performed in different regions, disciplines, and social and political systems in an era of growing internal and external challenges to the Union. We observe that the EU’s institutions remain highly adaptable in responding to challenges, but that member-states have continued and accelerated a tendency to nationalise success and Europeanise failure, with the EU acting as a perennial scapegoat largely due to the ease with which it can be narrated as a site of projection for mistrust, resentment, and social grievances. We argue that the relationship between populism and technocracy is rapidly evolving from an imagined binary into a much more fluid, overlapping, and reversible set of political narratives. We conclude that despite the changing nature of populist-technocratic debates and the resilience and adaptability of the EU, it faces accelerating challenges to its legitimacy in the new era of ‘politics of necessity’.

Political geography has an established tradition of engaging with religiously-driven geopolitik. However, despite the remarkable growth in professed atheist beliefs in recent decades and the popular expression of an imagined geopolitical binary between secular/atheist and religious societies, the geopolitics of irreligion have received almost no attention among academic practitioners. This paper outlines the core tenets of ‘New Atheist’ philosophy, before addressing how its key representatives have taken positions on the ‘Global War on Terror.’ In particular, we critically interrogate the works of Richard Dawkins, Sam Harris, and the late Christopher Hitchens and identify a belligerent geopolitical imagination which posits a civilizational clash between an existentially-threatened secular, liberal West with responsibility to use extraordinary violence to protect itself and the world from a backwards oriental Islam. The paper concludes with four possible explanations for the paradox that the New Atheist critique of religion for being violent acts itself as a geopolitical incitement to violence. In so doing, we seek to navigate debates about the nature and purpose of critical geopolitical research given that the historical, intellectual and political contexts in which it was formed have changed.

Manual scoring of polysomnography data is labor-intensive and time-consuming, and most existing software does not account for subjective differences and user variability. Therefore, we evaluated a supervised machine learning algorithm, SomnivoreTM, for automated wake–sleep stage classification. We designed an algorithm that extracts features from various input channels, following a brief session of manual scoring, and provides automated wake-sleep stage classification for each recording. For algorithm validation, polysomnography data was obtained from independent laboratories, and include normal, cognitively-impaired, and alcohol-treated human subjects (total n = 52), narcoleptic mice and drug-treated rats (total n = 56), and pigeons (n = 5). Training and testing sets for validation were previously scored manually by 1–2 trained sleep technologists from each laboratory. F-measure was used to assess precision and sensitivity for statistical analysis of classifier output and human scorer agreement. The algorithm gave high concordance with manual visual scoring across all human data (wake 0.91 ± 0.01; N1 0.57 ± 0.01; N2 0.81 ± 0.01; N3 0.86 ± 0.01; REM 0.87 ± 0.01), which was comparable to manual inter-scorer agreement on all stages. Similarly, high concordance was observed across all rodent (wake 0.95 ± 0.01; NREM 0.94 ± 0.01; REM 0.91 ± 0.01) and pigeon (wake 0.96 ± 0.006; NREM 0.97 ± 0.01; REM 0.86 ± 0.02) data. Effects of classifier learning from single signal inputs, simple stage reclassification, automated removal of transition epochs, and training set size were also examined. In summary, we have developed a polysomnography analysis program for automated sleep-stage classification of data from diverse species. Somnivore enables flexible, accurate, and high-throughput analysis of experimental and clinical sleep studies. ISSN:1662-453X ISSN:1662-4548

Since the inception of the European Coal and Steel Community in the late 1940s, leaders of the European Union have sought a common identity which transcends nation-states. Recent events such as Euromaidan, Brexit, and an ongoing shift towards eurosceptic populism in the EU are focusing attention on this ‘Gospel of Jacques Delors’ and how a “European identity” is expressed. Significant in studies of Europeanness is the role of symbols that express a myth of Europe. Manifestations of this myth have looked backwards to an imagined teleology of European unity in which all Europeans were united regardless of geopolitical divisions, particularly since the dissolution of the Soviet bloc. However, events in Ukraine have demonstrated not only public rejections of the myth of European unity, but also the use of the EU’s symbolism to construct an ‘alter-Europe’ defined by opposition to the EU. This overt use of iconography and iconoclasm to express political identities and affiliations challenges traditional interpretations of how the EU is received by its neighbours, and illustrates that there are multiple, competing versions of “Europe”.

The Earth’s daily rotation affects almost every living creature. From dawn through to dusk, there are changes in light, temperature, humidity, and rainfall. However, these changes are regular, rhythmic, and therefore predictable. Thus, the near 24-hour circadian rhythm is innate: a genetically programmed clock. Circadian Rhythms: A Very Short Introduction explains how organisms can ‘know’ the time and reveals what we now understand of the nature and operation of chronobiological processes. Covering variables such as light, the metabolism, human health, and the seasons, it illustrates how jet lag and shift work can impact on human well-being, and considers circadian rhythms alongside a wide range of disorders, from schizophrenia to obesity.

Geopolitics remains a cornerstone of contemporary human geography, with new introductions on the topic frequently appearing. Among these, Colin Flint's second edition of Introduction to geopolitics...

Drugs that are clinically effective against generalized anxiety disorder preferentially alter rodent risk assessment behavior, whereas drugs that are clinically effective against panic disorder preferentially alter rodent flight behavior. The theoretical principle of “defensive direction” explains the pattern of associations between emotion and defensive behavior in terms of the differing functional demands arising from cautious approach to threat (anxiety) versus departure from threat (fear), offering the prospect that clinically important emotions may be explained using a single rubric of defense. We used a within-subjects, placebo-controlled, design to test this theory, measuring the effects of citalopram and lorazepam on the defensive behavior of 30 healthy adult male humans. We indexed human defensive behavior with a translation of an active avoidance task used to measure rodent defense and found that lorazepam significantly reduced the intensity of defensive behavior during approach to threat (hypothetically anxiety-related) but not departure from threat (hypothetically fear-related). Contrary to prediction, citalopram did not affect either form of defensive reaction. Since lorazepam is a drug with well established anxiety reducing properties, these data support the hypothesis that anxiety is an emotion elicited by threat stimuli that require approach. These data also contribute to the validation of a novel human analog of an established experimental model of rodent fear and anxiety.

The Mental Capacity Act 2007 affects doctors in all areas of practice. The act recognises that capacity is a 'balance of probability rather than certainty', and based on this it attempts to 'maximise capacity' in an individual, so to facilitate a decision-making process. The act comprises five key principles as well as a test to determine lack of capacity. It also alludes to areas such as consent by proxy, restraint and capacity, and regulations regarding clinical research. This paper provides a brief background into the fundamental tenets of the act as well as a simple scheme for assessing capacity in hospital inpatients. It also looks at what physicians should be aware of and what will be required of them, particularly from a medico-legal perspective.

Schizophrenia is associated with a number of pathological changes, including alterations in levels of specific proteins. Calprotectin is a novel 36 kDa calcium-binding protein of the S100 family and appears to be a nonspecific marker of inflammation. Calprotectin has not previously been investigated in brain tissue. Samples of post-mortem brain tissue from Brodmann area 9 were obtained from prefrontal cortex from subjects with schizophrenia, bipolar affective disorder, major depression, and from controls. Calprotectin levels were determined by ELISA. To determine cellular localization, immunocytochemical and fluorescent double-labelling analyses were performed. Exogenous calprotectin was added to retinoic acid-differentiated human SH-SY5Y neuroblastoma cell cultures in order to investigate mechanisms of action of calprotectin. Calprotectin was detectable in all samples, and mean levels were noted to be highest in schizophrenic brains (P < 0.05) and lowest in controls. Levels were intermediate in bipolar affective disorder and major depression. Exogenous calprotectin appeared to induce dendritic extension in SH-SY5Y cell culture in a dose-dependent manner. Calprotectin was found to be localized to microglia. These findings suggest that increased levels of calprotecitn in the brain may reflect inflammatory processes, which play a role in the pathogenesis of major psychiatric disorders. Furthermore, calprotectin may influence dendritic plasticity.

The mechanisms by which the lifestyle risk factors obesity, physical inactivity, and low fiber intake predispose to colorectal cancer (CRC) are unclear. Chronic bowel inflammation predisposes to malignancy in cases of inflammatory bowel disease. Many lifestyle risk factors for CRC are associated with evidence of systemic inflammation as indicated by circulating levels of C-reactive protein (CRP), but it is unknown how this relates to inflammation at tissue level. Little is known about the degree of bowel inflammation in general population and the factors that affect it. Therefore, we aimed to assess the relation of levels of bowel inflammation in the general population and lifestyle risk factors for CRC, and to additionally assess whether these associations, if present, were attenuated by controlling for evidence of systemic inflammation. Average CRC risk subjects (320) of either sex aged 50–70 were recruited in South London. A stool sample was provided for calprotectin measurement (a marker of bowel inflammation), serum for CRP, and a detailed dietary and lifestyle questionnaire completed. There was a significant positive relationship between fecal calprotectin and increasing age (P = 0.002), obesity (P = 0.04), physical inactivity (P = 0.01), and an inverse relationship with fiber intake (P = 0.02) and vegetable consumption (P = 0.04). The relationship with obesity was attenuated by controlling for serum CRP. Fecal calprotectin levels are associated with lifestyle risk factors for colorectal cancer. Low-level asymptomatic bowel inflammation may be the link between lifestyle and the pathogenesis of CRC, and circulating proinflammatory cytokines may be part of the mechanism for this link.

Calprotectin is a calcium and zinc binding protein of the S100 family derived predominantly from neutrophils and monocytes. It is detectable in body fluids and tissue samples and is emerging as a valuable marker in the diagnosis, and the monitoring and determining of the prognosis of commonly encountered gastroenterological conditions. Fecal calprotectin, in particular, has for a long time been regarded as a promising marker of gastrointestinal pathology and has now been established as a routine test in Norway and at several centers in the UK.

Objective We present a case of psychosis in an individual with known HIV infection whose symptoms developed approximately 1 month following the commencement of combination antiretroviral therapy consisting of abacavir (ABC), nevirapine and combivir. She presented with severe persecutory delusions, accompanied by mutism, posturing and catatonia. Following cessation of therapy and the introduction of a low-dose antipsychotic, her mental state resolved to a stable premorbid level, and no further disturbances of behaviour were noted. Furthermore, when re-challenged with the above combination minus ABC, there were no further episodes of psychosis. It is proposed that the aetiology of the psychosis was related to her antiretroviral therapy. Methods Cessation of antiretroviral medication and initiation of antipsychotic medication with appropriate monitoring and assessment. Results Subjective and objective improvements in psychotic symptoms and presentation. Conclusion The current case suggests that sudden onset psychotic disturbances in HIV-infected individuals in the absence of other known organic or other causal factors could be related to treatment with antiretroviral therapy, and that cessation of this can markedly improve psychiatric morbidity. Furthermore, treatment with antipsychotic medication can lead to alleviation of psychotic symptoms and enable the re-introduction of antiretroviral medication.

The fundamental pathological process behind ulcerative colitis and Crohn's disease is intestinal inflammation. As the precise cause of this is not yet completely understood, current treatment strategies are aimed at reducing or eliminating the inflammation. Endoscopic examination and histological analysis of biopsy specimens remain the 'gold standard' methods for detecting and quantifying bowel inflammation; however, these techniques are costly, invasive, and repeated examinations are unpopular with patients. Disease activity questionnaires and laboratory 'inflammatory markers', although widely used, show an unreliable correlation with endoscopy and histology. New markers need to be developed to detect and quantify bowel inflammation. These would be of use diagnostically and also an aid to pharmacological treatment.

BACKGROUND AND AIMS—Assessing the presence and degree of intestinal inflammation objectively, simply, and reliably is a significant problem in gastroenterology. We assessed faecal excretion of calprotectin, a stable neutrophil specific marker, as an index of intestinal inflammation and its potential use as a screening test to discriminate between patients with Crohn's disease and those with irritable bowel syndrome. METHODS—The validity of faecal calprotectin as a marker of intestinal inflammation was assessed in 22 patients with Crohn's disease (35 studies) by comparing faecal excretions and concentrations using four day faecal excretion of 111indium white cells. A cross sectional study assessed the sensitivity of faecal calprotectin concentration for the detection of established Crohn's disease (n=116). A prospective study assessed the value of faecal calprotectin in discriminating between patients with Crohn's disease and irritable bowel syndrome in 220 patients referred to a gastroenterology clinic. RESULTS—Four day faecal excretion of 111indium (median 8.7%; 95% confidence interval (CI) 7-17%; normal

Background The pathogenesis of NSAID-induced gastrointestinal damage is believed to involve a nonprostaglandin dependent effect as well as prostaglandin dependent effects. One suggestion is that the nonprostaglandin mechanism involves uncoupling of mitochondrial oxidative phosphorylation. Aims To assess the role of uncoupling of mitochondrial oxidative phosphorylation in the pathogenesis of small intestinal damage in the rat. Methods We compared key pathophysiologic events in the small bowel following (i) dinitrophenol, an uncoupling agent (ii) parenteral aspirin, to inhibit cyclooxygenase without causing a 'topical' effect and (iii) the two together, using (iv) indomethacin as a positive control. Results Dinitrophenol altered intestinal mitochondrial morphology, increased intestinal permeability and caused inflammation without affecting gastric permeability or intestinal prostanoid levels. Parenteral aspirin decreased mucosal prostanoids without affecting intestinal mitochondria in vivo, gastric or intestinal permeability. Aspirin caused no inflammation or ulcers. When dinitrophenol and aspirin were given together the changes in intestinal mitochondrial morphology, permeability, inflammation and prostanoid levels and the macro- and microscopic appearances of intestinal ulcers were similar to indomethacin. Conclusions These studies allow dissociation of the contribution and consequences of uncoupling of mitochondrial oxidative phosphorylation and cyclooxygenase inhibition in the pathophysiology of NSAID enteropathy. While uncoupling of enterocyte mitochondrial oxidative phosphorylation leads to increased intestinal permeability and low grade inflammation, concurrent decreases in mucosal prostanoids appear to be important in the development of ulcers.

It is suggested that the gastrointestinal toxicity of conventional non-steroid anti-inflammatory drugs (NSAIDs) is due to a 'topical' effect in addition to inhibition of the mucosal constitutive cyclo-oxygenase-1 (COX-1) enzyme. COX-2 selective inhibitors have been shown to have excellent gastrointestinal tolerability, but it is not known whether this is due to their selectivity and/or a lack of a 'topical' effect. We assessed the effects of celecoxib (a highly selective COX-2 inhibitor) on key pathophysiologic events in NSAID enteropathy.The 'topical' effects of indomethacin and celecoxib were assessed in vitro (coupled mitochondrial respiration) and in vivo (mitochondrial electron microscopy) and the consequences by study of intestinal permeability (51-Cr-labelled ethylenediamine-tetraacetic acid urinary excretion) and inflammation. We also assessed intestinal prostanoid levels (prostaglandin E, PGE) and the propensity of the drugs to induce intestinal ulcers.Indomethacin uncoupled mitochondrial oxidative phosphorylation in vitro and in vivo, caused a significant (P0.0001) increase in intestinal permeability, caused mucosal inflammation and a 90% decline in intestinal PGE levels, and was associated with multiple small intestinal ulcers. Celecoxib caused no significant increase in any of these parameters, did not decrease intestinal PGE levels, and caused no intestinal ulcers.The intestinal tolerability of celecoxib appears to be due to a combination of the absence of a 'topical' damaging effect and selective COX inhibition.

BACKGROUNDThe diagnosis of non-steroidal anti-inflammatory drug (NSAID) induced enteropathy is difficult, requiring enteroscopy or the use of four day faecal excretion of 111In labelled white cells.AIMSTo assess faecal calprotectin (a non-degraded neutrophil cytosolic protein) as a method for diagnosing NSAID enteropathy.METHODSSingle stool faecal calprotectin concentrations were compared with the four day faecal excretion of 111In labelled white cells in 47 patients taking NSAIDs. The prevalence and severity of NSAID enteropathy was assessed using this method in 312 patients (192 with rheumatoid arthritis, 65 with osteoarthritis, 55 with other conditions) taking 18 different NSAIDs.RESULTSThe four day faecal excretion of 111In white cells correlated significantly with faecal calprotectin concentrations. In the group of 312 patients on NSAIDs faecal calprotectin concentrations were significantly higher than in controls, the prevalence of NSAID enteropathy being 44%. The prevalence and severity of NSAID enteropathy was independent of the particular type or dose of NSAID being taken or other patient variables.CONCLUSIONSAssay of faecal calprotectin provides a simple practical method for diagnosing NSAID enteropathy in man. Forty four per cent of patients receiving these drugs had NSAID induced enteropathy when assessed by this technique; 20% of these had comparable levels of inflammation to that previously reported in patients with inflammatory bowel disease.

The predicted gastrointestinal tolerability of specific cyclooxygenase-2 inhibitors could be due to either a lack of 'topical' irritation and/or lack of effect on cyclooxygenase-1.Key pathophysiologic steps (in vitro and in vivo uncoupling, intestinal prostanoid levels (prostaglandin E, thromboxane B2, and 6-keto-prostaglandin F1alpha), intestinal permeability (51Cr-ethylenediaminetetraacetic acid), inflammation (faecal excretion of a granulocyte marker protein), and ulcer counts) in enteropathy induced by nonsteroidal anti-inflammatory drugs were assessed after administration of indomethacin, 10 mg/kg, and 15 (roughly equipotent), 30, and 60 mg/kg of the preferential cyclooxygenase-2 inhibitor nimesulide.Indomethacin uncoupled oxidative phosphorylation at lower concentrations than nimesulide in vitro. Indomethacin was associated with electron microscopy changes suggestive of uncoupling in 60%-70% of enterocytes examined, whereas nimesulide affected 10%-30% of enterocytes, depending on the dose. Indomethacin increased intestinal permeability and caused inflammation and ulcers with 71%-96% reductions in prostanoid levels. Nimesulide at 15 mg/kg caused no damage, whereas 30 and 60 mg/kg nimesulide were associated with significant decreases in mucosal prostanoids (46%-75%), but only the 60-mg/kg dose caused a transient increase in intestinal permeability. However, at none of the doses did nimesulide cause intestinal inflammation or ulcers.These results endorse the idea that selective cyclooxygenase-2 inhibitors may be associated with some gastrointestinal tolerance due to their selectivity for cyclooxygenase-2, inhibiting cyclooxygenase-1 at only very high doses, and reduced topical irritation.

Sleep is a complex process: the timing of sleep is regulated by two systems (the sleep homeostat and the circadian clock) and there are many potential functions of sleep. The aim of this thesis was to investigate: the impact of light on the regulation of sleep timing (study 1) and the role of sleep in emotional processing (study 2). Study 1 used natural variations in environmental light levels at different geographical locations, to examine the influence of daily light irradiance on sleep timing and chronotype using the Munich chronotype questionnaire (MCTQ). 6443 students were included in this study from six universities from the northern and southern hemispheres. Students in southern hemisphere cities had earlier sleep timings than those in the northern cities. Daily irradiance was higher in the southern hemisphere cities. The amount of time spent outside, age and sex, but not daily irradiance, influenced sleep timings. Study 2 explored the impact of an analogue traumatic event (trauma film) in students who were either sleep deprived or not sleep deprived on intrusive memories ("flashbacks"), sleep physiology and the impact of an increased risk of a mood disorder on this relationship. In this study the sleep deprived participants (n=19) reported fewer intrusive memories to the trauma film than those not sleep deprived (n=22). A change in sleep physiology was observed in the first sleep period following the trauma film, which was more pronounced in the sleep deprived group: increased levels of arousal, REM density and activity in the occipital region. Only three participants at-risk of a mood disorder completed study 2: their data are presented as case studies. In conclusion this research has demonstrated that differences in sleep timings exist between cities in the southern and northern hemispheres and has confirmed that many factors can influence sleep timing. It has also been demonstrated that following a highly emotional event not sleeping may have a beneficial effect, which has implications for the treatment of people after trauma.

It was recently observed that dehydration causes shrinkage of brain tissue and an associated increase in ventricular volume. Negative effects of dehydration on cognitive performance have been shown in some but not all studies, and it has also been reported that an increased perceived effort may be required following dehydration. However, the effects of dehydration on brain function are unknown. We investigated this question using functional magnetic resonance imaging (fMRI) in 10 healthy adolescents (mean age = 16.8, five females). Each subject completed a thermal exercise protocol and nonthermal exercise control condition in a cross‐over repeated measures design. Subjects lost more weight via perspiration in the thermal exercise versus the control condition (P < 0.0001), and lateral ventricle enlargement correlated with the reduction in body mass (r = 0.77, P = 0.01). Dehydration following the thermal exercise protocol led to a significantly stronger increase in fronto‐parietal blood‐oxygen‐level‐dependent (BOLD) response during an executive function task (Tower of London) than the control condition, whereas cerebral perfusion during rest was not affected. The increase in BOLD response after dehydration was not paralleled by a change in cognitive performance, suggesting an inefficient use of brain metabolic activity following dehydration. This pattern indicates that participants exerted a higher level of neuronal activity in order to achieve the same performance level. Given the limited availability of brain metabolic resources, these findings suggest that prolonged states of reduced water intake may adversely impact executive functions such as planning and visuo‐spatial processing. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

Just as daily events are timed by living creatures through circadian rhythms, so seasonal events are timed through an internal calendar that signals birds to return to nesting grounds, salmon to spawn, plants to flower, squirrels to hibernate, kelp to stop growing. In this fascinating book, Russell G. Foster and Leon Kreitzman draw on remarkable recent scientific advances to explain how seasonal change affects organisms, and how plants and animals over countless generations have evolved exquisite sensitivities and adaptations to the seasons. The authors also highlight the impact of seasonal change on human health and well-being. They conclude with a discussion of the dangers posed when climate changes disrupt the seasonal rhythms on which so much life depends. © 2009 by Russell G. Foster and Leon Kreitzman.