Association between polymorphism in regulatory region of gene encoding tumour necrosis factor alpha and risk of Alzheimer's disease and vascular dementia: a case-control study

BACKGROUND: Deposition of beta-amyloid in the brains of patients with Alzheimer's disease is thought to precede a chain of events that leads to an inflammatory response by the brain. We postulated that genetic variation in the regulatory region of the gene for the proinflammatory cytokine tumour necrosis factor alpha (TNF-alpha) leads to increased risk of Alzheimer's disease and vascular dementia. METHODS: A polymorphism in the regulatory region of the TNF-alpha gene was analysed in a case-control study. The polymorphism (C-850T) was typed in 242 patients with sporadic Alzheimer's disease, 81 patients with vascular dementia, 61 stroke patients without dementia, and 235 normal controls. These groups of individuals were also genotyped for the apolipoprotein E polymorphism, and the vascular dementia and stroke groups were typed at the HLA-DR locus. FINDINGS: The distribution of TNF-alpha genotypes in the vascular dementia group differed significantly from that in the stroke and normal control groups, giving an odds ratio of 2.51 (95% CI 1.49-4.21) for the development of vascular dementia for individuals with a CT or TT genotype. Logistic regression analysis indicated that the possession of the T allele significantly increased the risk of Alzheimer's disease associated with carriage of the apolipoprotein E epsilon4 allele (odds ratio 2.73 [1.68-4.44] for those with apolipoprotein E epsilon4 but no TNF-alpha T, vs 4.62 [2.38-8.96] for those with apolipoprotein E epsilon4 and TNF-alpha T; p=0.03). INTERPRETATION: Possession of the TNF-alpha T allele significantly increases the risk of vascular dementia, and increases the risk of Alzheimer's disease associated with apolipoprotein E. Although further research is needed, these findings suggest a potential role for anti-inflammatory therapy in vascular dementia and Alzheimer's disease, and perhaps especially in patients who have had a stroke.

Global Systemic Risk and International Regulatory Coordination: Squaring Sovereignty and Financial Stability

In recent years much attention has been given to systemic risk and maintaining financial stability. Much of the focus, rightly, has been on market failures and the role of regulation in addressing them. This article looks at the role of domestic policies and government actions as sources of global instability. The global financial system is built upon global markets controlled by national financial and macroeconomic policies. In this context, regulatory asymmetries, diverging policy preferences, and government failures add a further dimension to global systemic risk not present at the national level.
Systemic risk is a result of the interplay between two independent variables: an underlying trigger event, in this analysis a domestic policy measure, and a transmission channel. The solution to systemic risk requires tackling one of these variables. In a domestic setting, the centralization of regulatory power into one single authority makes it easier to balance the delicate equilibrium between enhancing efficiency and reducing instability. However, in a global financial system in which national financial policies serve to maximize economic welfare, regulators will be confronted with difficult policy and legal tradeoffs.
We investigate the role that financial regulation plays in addressing domestic policy failures and in controlling the danger of global financial interdependence. To do so we analyse global financial interconnectedness, and explain its role in transmitting instability; we investigate the political economy dynamics at the origin of regulatory asymmetries and government failures; and we discuss the limits of regulation.

Restraing Regulatory Capture? Anglo America, Crisis Politics and Trajectories of Change in Global Financial Governance

A growing number of respected commentators now argue that regulatory capture of public agencies and public policy by leading banks was one of the main causal factors behind the financial crisis of 2007–2009, resulting in a permissive regulatory environment. This regulatory environment placed a faith in banks own internal risk models, contributed to pro-cyclical behaviour and turned a blind eye to excessive risk taking. The article argues that a form of ‘multi-level regulatory capture’ characterized the global financial architecture prior to the crisis. Simultaneously, regulatory capture fed off, but also nourished the financial boom, in a fashion that mirrored the life cycle of the boom itself. Minimizing future financial booms and crises will require continuous, conscious and explicit efforts to restrain financial regulatory capture now and into the future. The article assesses the extent to which this has been achieved in current global financial governance reform efforts and highlights some of the persistent difficulties that will continue to hamper efforts to restrain regulatory capture. The evidence concerning the extent to which regulatory capture is being effectively restrained is somewhat mixed, and where it is happening it is largely unintentional and accidental. Recent reforms have overlooked the political causes of the crisis and have failed to focus explicitly or systematically on regulatory capture.

Vetting Sexual Offenders: State Over-extension, the Punishment Deficit and the Failure to Manage Risk

This article examines the state regulation of sexual offenders in the particular context of pre-employment vetting. A successive range of statutory frameworks have been put in place, culminating in the Safeguarding Vulnerable Groups Act 2006, to prevent unsuitable individuals from working with the vulnerable, and children in particular. Contemporary legislative and policy developments are set against a backdrop of broader concerns in the area of crime and justice, namely risk regulation, preventative governance and ‘precautionary logic.’ Proponents of these approaches have largely ignored concerns over their feasibility. This article specifically addresses this fissure within the specific field of vetting. It is argued that ‘hyper innovation’ and state over-extension in this area are particularly problematic and have resulted in exceptionally uncertain and unsafe policies. These difficulties relate principally to unrealistic public expectations about the state’s ability to control crime; unintended and ambiguous policy effects; and ultimately the failure of the state to deliver on its self-imposed regulatory mandate to effectively manage risk.

Managing Risk: From Regulation to the Reintegration of Sexual Offenders

In the last number of years the management of the dangerous in the community, particularly sex offenders, has generated enormous concern. This concern has been reflected at a number of different levels - in media and popular responses to the risk posed by released sex offenders in the community and in official discourses where an abundance of legislation and policy reforms have been enacted within a relatively short period of time. This analysis seeks to critically evaluate these developments within the context of contemporary criminal justice policy and practice in relation to the management of sex offenders in the community. The article analyses the contemporary focus on risk management or preventative governance which underpins the current regulatory framework and has been reflected in both the sentencing options and in control in the community initiatives for sex offenders. In this respect, the article highlights the gap between policy and practice in terms of the effective risk management of sex offenders. Given the failure of the traditional justice system with respect to these types of offences, it will be argued that the retributive framework could usefully be supplemented by the theory and practice of reintegrative or restorative community justice, and public education in particular, in order to better manage the risk presented by sex offenders in the community.

The Governance of Sexual Offending Across Europe: Penal Policies, Political Economies and the Institutionalization of Risk

This article examines why England and Wales have comparatively one of the most stringent systems for the governance of sexual offending within Western Europe. While England and Wales, like the USA, have adopted broadly exclusionary, managerialist penal policies based around incapacitation and targeted surveillance, many other Western European countries have opted for more inclusionary therapeutic interventions. Divergences in state approaches to sex offender risk, particularly in relation to notification and vetting schemes, are initially examined with reference to the respective theoretical frameworks of ‘policy transfer’ and differing political economies. Chiefly, however, differences in penal policies are attributed to the social and political construction of risk and its control. There may be multiple expressions of risk relating to expert, lay, moral or emotive aspects. It is argued, however, that it is the particular convergence and alignment of these dimensions on the part of the various stakeholders in the UK – government, media, public and professional – that leads to risk becoming institutionalized in the form of punitive regulatory policies for managing the dangerous.

Genome-wide profiling of methylation identifies novel targets with aberrant hyper-methylation and reduced expression in low-risk myelodysplastic syndromes

Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases.

Mood congruent psychotic symptoms and specific cognitive deficits in carriers of the novel schizophrenia risk variant at MIR-137

Objective: The Schizophrenia Psychiatric Genome-wide Association (GWAS) Consortium recently reported on five novel schizophrenia susceptibility loci. The most significant finding mapped to a micro-RNA, MIR-137, which may be involved in regulating the function of other schizophrenia and bipolar disorder susceptibility genes. Method: We genotyped 821 patients with confirmed DSM-IV diagnoses of schizophrenia, bipolar affective disorder I and schizoaffective disorder for the risk SNP (rs1625579) and investigated the clinical profiles of risk allele carriers using a within-case design. We also assessed neurocognitive performance in a subset of cases (n=399) and controls (n=171). Results: Carriers of the risk allele had lower scores for an OPCRIT-derived positive symptom factor (p=0.04) and lower scores on a lifetime measure of psychosis incongruity (p=0.017). Risk allele carriers also had more cognitive deficits involving episodic memory and attentional control. Conclusion: This is the first evidence that the MIR-137 risk variant may be associated with a specific subgroup of psychosis patients. Although the effect of this single SNP was not clinically relevant, investigation of the impact of carrying multiple risk SNPs in the MIR-137 regulatory network on diagnosis and illness profile may be warranted. © 2012 Elsevier Ireland Ltd.

Corneal Allograft Rejection:Risk Factors, Diagnosis, Prevention, and Treatment

Recent advances in corneal graft technology, including donor tissue retrieval, storage and surgical techniques, have greatly improved the clinical outcome of corneal grafts. Despite these advances, immune mediated corneal graft rejection remains the single most important cause of corneal graft failure. Several host factors have been identified as conferring a "high risk" status to the host. These include: more than two quadrant vascularisation, with associated lymphatics, which augment the afferent and efferent arc of the immune response; herpes simplex keratitis; uveitis; silicone oil keratopathy; previous failed (rejected) grafts; "hot eyes"; young recipient age; and multiple surgical procedures at the time of grafting. Large grafts, by virtue of being closer to the host limbus, with its complement of vessels and antigen-presenting Langerhans cells, also are more susceptible to rejection. The diagnosis of graft rejection is entirely clinical and in its early stages the clinical signs could be subtle. Graft rejection is largely mediated by the major histocompatibility antigens, minor antigens and perhaps blood group ABO antigens and some cornea-specific antigens. Just as rejection is mediated by active immune mediated events, the lack of rejection (tolerance) is also sustained by active immune regulatory mechanisms. The anterior chamber associated immune deviation (ACAID) and probably, conjunctiva associated lymphoid tissue (CALT) induced mucosal tolerance, besides others, play an important role. Although graft rejection can lead to graft failure, most rejections can be readily controlled if appropriate management is commenced at the proper time. Topical steroids are the mainstay of graft rejection management. In the high-risk situations however, systemic steroids, and other immunosuppressive drugs such as cyclosporin and tacrolimus (FK506) are of proven benefit, both for treatment and prevention of rejection.

Large-scale association analysis identifies new risk loci for coronary artery disease

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2)

Risk, Regulation and the Reintegration of Sexual Offenders

Media reporting of and public concern about sexual offending, particularly relating to children, affects and reflects political, policy and organisational responses to those convicted of such crimes. The development of regulatory policies on sexual offending has taken place within a highly emotive and overtly politicized public and policy discourse. This chapter charts the various ways in which the risks imagined or posed by sexual offenders have been conceptualised within public discourses and regulated and managed under the legislative and organisational ‘risk paradigm.’ Ultimately, it argues that risk-based responses to sexual offending are at best uncertain in their effects and at worst counterproductive, in that they often reduce the potential for successful reintegration. In seeking to look ‘beyond risk’, the chapter also explores the usefulness of restorative and related practices in supporting sex offender reintegration aimed at the primary and secondary levels of harm prevention.

Study on risk assessment and management and prevention of conflicts of interest in the prevention and fight against betting-related match fixing in the EU 28: Final Report

This report concerns the provisions and practices on betting-related match fixing in sports
within the 28 Member States. Carried out in late 2013/early 2014, respondents in each Member
State reported on that state’s gambling-related provisions in respect of football and tennis and
(in each country) a third sport determined on the basis of either its popularity (in terms of
participation or television viewing) or the existence of betting-related “scandals” in that sport
within that particular jurisdiction. Those reports helped the authors to compare the Member
States’ regulatory and self-regulatory frameworks relating to risk assessment and conflict of
interest management, with a view to indicating areas of best practice, identifying particularly
good legislative frameworks and highlighting areas where change was either desirable or
necessary. While some individual Member States have legislation which might provide
templates that others could adapt for their own use, the authors were not convinced that “more
law”, whether at the national or European level, was desirable. Rather, more effective
cooperation among the stakeholders was identified as being more likely to provide tangible
benefits than would new legal frameworks.

Understanding Risk: Contributions from the Journal of Risk and Governance

During recent years, news headlines have been rife with criticisms of the risk management practices of public and private sector entities. These criticisms have often been accompanied by calls for greater transparency in the way government entities manage risks and communicate dangers to the public. Similarly, in the private sector, the internationalisation of economic activity has heightened concerns over the potential adverse implications of mismanagement and financial scandals, and has led to calls for greater regulation and supervision. While the responses of public sector agencies and private sector actors to these challenges have differed, they share a common acknowledgement that effective governance relies on the pro-active identification, assessment, and management of risks as well as appropriate regulatory frameworks.

This edited book covers a number of divergent topics illustrating the emergence of several novel themes in the area of economic and social risks. As a communality, these novel themes relate to the complexity in which human activity in this late stage of capitalist development is embedded. This risk-generating complexity, in turn, can be observed at several levels, including workplace hazards, governance problems within the private sector or the intersection between public and private, and in relation to the economic risks faced by larger entities such as national governments.