Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

In Search of a Trade Mark: Search Practices and Bureaucratic Poetics

Trade marks have been understood as quintessential ‘bureaucratic properties’. This article suggests that the making of trade marks has been historically influenced by bureaucratic practices of search and classification, which in turn were affected by the possibilities and limits of spatial organisation and technological means of access and storage. It shows how the organisation of access and retrieval did not only condition the possibility of conceiving new trade marks, but also served to delineate their intangible proprietary boundaries. Thereby they framed the very meaning of a trade mark. By advancing a historical analysis that is sensitive to shifts, both in actual materiality and in the administrative routines of trade mark law, the article highlights the legal form of trade mark as inherently social and materially shaped. We propose a historical understanding of trade mark law that regards legal practice and bureaucratic routines as being co-constitutive of the very legal object itself

The merchants of York, Beverley and Hull in the fourteenth and fifteenth centuries.

This thesis examines three main aspects of the merchant class of York, Beverley, and Hull: their economic activities, political dominance and social and religious concerns. It argues that in each town, merchants played a significant role, and as their commercial fortunes were affected by endogenous factors, so was their position within each town. Chapter 1 gives a brief historical outline of each town's development, up to and including the period under study. Chapter 2 offers an overview of the fluctuating patterns of international trade, and of the changing fortunes of each town's investment in overseas trade. Within that context, chapter 4 focuses on individual merchant's business 'biographies', using them as a basis for a general discussion of the range and quality of the involvement of each town's merchant class in overseas trade. The second part of the chapter explores the evidence of capital accumulation by individuals, assessing the role of real estate, cash and credit in their enterprises. This analysis reveals the wide range in levels of commercial success to be found within the merchant class. Chapter 5 looks at the degree to which merchants dominated the government of each town, highlighting the notable differences between them. It concludes that the merchant oligarchs of each were tenacious in defending their position, until their commercial failure inexorably lead to their political demise. Chapter 6 offers insights into the ways in which merchants underpinned their commercial and political association through social networks. Inter-marriage, the poor survival rate of male heirs, household structure and family provision, all reflect a high degree of interdependence. The second section of the chapter concentrates on merchant benevolence and piety, concluding that their priorities were similar to those of other townsfolk and their religious beliefs as conservative

A new media landscape? The BBFC, extreme cinema as cult, and technological change

Disreputable films involving explicit representations of sex and violence have long attracted the attention of the censors and cult film audiences alike. In late 2012, the British Board of Film Classification (BBFC) announced it was tightening its regulation of representations of sadistic and sexual violence, simultaneously enhancing the subcultural capital and potential cult status of the films in question (Thornton, Club Cultures: Music, Media and Subcultural Capital, Cambridge: Polity Press, 1995, 11). The subsequent publication of the BBFC's revised guidelines in January 2014 confirmed its increasingly censorial stance (British Board of Film Classification, The Guidelines, London: BBFC, 2014a). The Board's rationale for implementing these changes was that a succession of technological developments had created ‘a new media and entertainment landscape’ requiring stricter regulation (British Board of Film Classification, BBFC Guidelines 2014: Research Report, London: BBFC, 2014b, 15). This paper traces a series of changes in film regulation during the post-Ferman era, focusing in particular on the pedagogical turn taken by the BBFC under the directorship of David Cooke (2004–14). Drawing on a range of reports and documents, I argue that by discursively framing these policy adjustments in the context of the so-called ‘sexualisation of culture’ debate, the BBFC have obscured a more fundamental shift in their purpose and remit during the Cooke era

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.status: publishe