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AIMS/HYPOTHESIS: The ATP-sensitive potassium (KATP) channel couples beta cell electrical activity to glucose-stimulated insulin secretion. Loss-of-function mutations in either the pore-forming (inwardly rectifying potassium channel 6.2 [Kir6.2], encoded by KCNJ11) or regulatory (sulfonylurea receptor 1, encoded by ABCC8) subunits result in congenital hyperinsulinism, whereas gain-of-function mutations cause neonatal diabetes. Here, we report a novel loss-of-function mutation (Ser118Leu) in the pore helix of Kir6.2 paradoxically associated with sulfonylurea-sensitive diabetes that presents in early adult life. METHODS: A 31-year-old woman was diagnosed with mild hyperglycaemia during an employee screen. After three pregnancies, during which she was diagnosed with gestational diabetes, the patient continued to show elevated blood glucose and was treated with glibenclamide (known as glyburide in the USA and Canada) and metformin. Genetic testing identified a heterozygous mutation (S118L) in the KCNJ11 gene. Neither parent was known to have diabetes. We investigated the functional properties and membrane trafficking of mutant and wild-type KATP channels in Xenopus oocytes and in HEK-293T cells, using patch-clamp, two-electrode voltage-clamp and surface expression assays. RESULTS: Functional analysis showed no changes in the ATP sensitivity or metabolic regulation of the mutant channel. However, the Kir6.2-S118L mutation impaired surface expression of the KATP channel by 40%, categorising this as a loss-of-function mutation. CONCLUSIONS/INTERPRETATION: Our data support the increasing evidence that individuals with mild loss-of-function KATP channel mutations may develop insulin deficiency in early adulthood and even frank diabetes in middle age. In this case, the patient may have had hyperinsulinism that escaped detection in early life. Our results support the importance of functional analysis of KATP channel mutations in cases of atypical diabetes.
Cerebrospinal fluid biomarker profiling of diverse pathophysiological domains in Alzheimer's disease
INTRODUCTION: While Alzheimer's disease (AD) is defined by amyloid-β plaques and tau tangles in the brain, it is evident that many other pathophysiological processes such as inflammation, neurovascular dysfunction, oxidative stress, and metabolic derangements also contribute to the disease process and that varying contributions of these pathways may reflect the heterogeneity of AD. Here, we used a previously validated panel of cerebrospinal fluid (CSF) biomarkers to explore the degree to which different pathophysiological domains are dysregulated in AD and how they relate to each other. METHODS: Twenty-five CSF biomarkers were analyzed in individuals with a clinical diagnosis of AD verified by positive CSF AD biomarkers (AD, n = 54) and cognitively unimpaired controls negative for CSF AD biomarkers (CU-N, n = 26) using commercial single- and multi-plex immunoassays. RESULTS: We noted that while AD was associated with increased levels of only three biomarkers (MMP-10, FABP3, and 8OHdG) on a group level, half of all AD participants had increased levels of biomarkers belonging to at least two pathophysiological domains reflecting the diversity in AD. LASSO modeling showed that a panel of FABP3, 24OHC, MMP-10, MMP-2, and 8OHdG constituted the most relevant and minimally correlated set of variables differentiating AD from CU-N. Interestingly, factor analysis showed that two markers of metabolism and oxidative stress (24OHC and 8OHdG) contributed independent information separate from MMP-10 and FABP3 suggestive of two independent pathophysiological pathways in AD, one reflecting neurodegeneration and vascular pathology, and the other associated with metabolism and oxidative stress. DISCUSSION: Better understanding of the heterogeneity among individuals with AD and the different contributions of pathophysiological processes besides amyloid-β and tau will be crucial for optimizing personalized treatment strategies. Highlights: A panel of 25 highly validated biomarker assays were measured in CSF. MMP10, FABP3, and 8OHdG were increased in AD in univariate analysis. Many individuals with AD had increased levels of more than one biomarker. Markers of metabolism and oxidative stress contributed to an AD multianalyte profile. Assessing multiple biomarker domains is important to understand disease heterogeneity.
The British government has instituted a wide range of educational reforms to tackle ethnic inequality. This article argues that over the past half century most of these have been driven by immediate political considerations and have failed to incorporate a broader, historical perspective. This has invariably led to short-term, and short cut, solutions to long-term, deeply entrenched problems that, in reality, transcend the world of education. The article evaluates all the major reform programs, ranging from assimilationism to multicultural education to anti-racist education. It concludes with discussion of the merits/demerits of faith schools and the use of school reorganization as a means of tackling ethnic segregation. © 2010 Elsevier Ltd. All rights reserved.
There is a wide swathe, and indeed long history, of UK literature featuring attempts to theorise differentials in housing position and shifting spatial settlement patterns in relation to ethnicity and 'race' (and also, more recently, faith group). Most of the earlier accounts were based on simplified versions of the structure-agency dualism or one or other variant of rational choice theory. Responding to criticisms that these relied too heavily on overly static notions of 'choice' and 'constraint', a few then turned to a form of theorisation that deployed a modified version of Giddens' structuration theory. This paper seeks to take the debate further by developing a model that retains much of the essence of structuration yet embodies a more dynamic and theoretically nuanced interpretation of both structure and agency. Structure, normally seen predominantly as a form of social regulation, will be seen as multi-layered and multi-dimensional and also, importantly, as subject to often unpredictable exogenous factors. The concept of social agency will also be subjected to a radical re-conceptualisation that reflects, amongst other things, recent shifts in social capital theory interpreted in the light of rapid demographic change (influenced by geo-political factors), ongoing social inequality, racism, and heightened inter- and intra-communal tensions in some areas. © 2009 Taylor & Francis.
This paper interrogates a concept at the core of a social policy agenda that has dominated thinking in the UK over the past decade. It argues that the notion of 'community cohesion' is based on a fundamentally flawed interpretation of the sources of tension and conflict in Britain's towns and cities. It overly ethnicizes societal divisions and essentializes ethnicity. Examining the development of government policy since 2001 the paper shows that the result has been a predominantly culturalist agenda that obscures key sources of division, most notably those related to social class and material inequality. It is argued that the hegemonic status of this policy stream has also undermined the equalities agenda. The paper concludes with a reflection on the implications of the emergence of a Conservative-led coalition government in May 2010. © The Author(s) 2012.
The concern of this article is with action at the local level to combat racial inequality in employment. It draws on the authors' evaluation of the 'West Midlands Common Standard', an innovative policy introduced by a consortium of West Midlands councils to ensure their contractors have, and implement, an equal opportunities in employment policy. The article assesses the impact of the initiative and its potential transferability. It is argued that the Common Standard provides a highly promising model for other local authorities to adopt.
Ethnic segregation is at the centre of debates about 'race' and 'difference', integration and citizenship in multicultural Britain. This paper critically examines discourses of segregation and challenges interpretations based on cultural 'otherness', normative assumptions about patterns of social and spatial integration and the 'whiteness' of the city. Drawing on research in Leeds and Bradford, the paper presents insights into how British Asians perceive, and make sense of, the spaces in which they are living and through which they are being enjoined to disperse. Their narratives of the city reveal multiple readings of ethnic segregation, the multi-ethnic inner city and the suburbs. © 2007 The Authors. Journal compilation © Royal Geographical Society (with The Institute of British Geographers) 2007.
New labour ambiguity, or neo-liberal consistency? The debate about racial inequality in employment and the use of contract compliance
In 2003 the UK government set an objective that in ten years' time Britain's minority ethnic groups should not face disproportionate barriers in the labour market. A key 'barrier' is discrimination by employers. This article examines one potential way forward: the use of contract compliance. First, the article presents findings from the authors' study of an innovative use of contract compliance by a group of local authorities in the West Midlands. If contract compliance can be made to work and New Labour is committed to addressing racial inequality in employment, this suggests that contract compliance is an approach that the government should be seeking to develop. The second part of the article therefore considers New Labour's stance on contract compliance, which can be seen to be highly ambiguous. It is argued that if contract compliance is located within the broader context of New Labour policy development, what is apparent is that the professed aspiration for social change is compromised by a dominant commitment to the maintenance of neo-liberal economic policies. The conclusion is that it is likely that only limited progress will be made in achieving racial equality in employment. © 2005 Cambridge University Press.
This article examines the impact of urban policy on Britain's inner city areas, and specifically on the various communities living within them. It is suggested that policies need to address the issue of ‘racial’ inequality directly, rather than relying on trickle-down effects from conventional economic regeneration models. Problems with current urban renewal service delivery policies are highlighted, and proposals are put forward for models of ‘good practice’. © 1992, Taylor & Francis Group, LLC. All rights reserved.
Colonial Immigrants in a British City (1979) analyses the relationship between West Indian and Asian immigrants and the class structure of a British city. Based on a four-year research project in the Handsworth area of Birmingham, the book is a study of race and community relations – political, social, economic and personal – in a major centre of immigrant settlement. It considers the relationship between housing class and class formations and consciousness in other sectors of allocation, such as employment and education. It includes a consideration of the changing political climate on race relations between 1950 and 1976.
Applications of rational choice theory in the sociological literature on ‘race’ and ethnicity are relatively scarce, and have tended to be implicit rather than explicit. They have been confined largely to the work of ethnographers and social anthropologists, and have been showcased in edited volumes such as Watson (1977) and Wallman (1979). In a more theoretical vein, there are the significant contributions of Banton (1983) and Hechter (1986). Over the past decade, the approach has to all intents and purposes disappeared, in terms of macro-sociological work at least, although vestiges of it remain in particular substantive areas, as we shall see. Even its strongest adherents, such as Hechter (1986: 265), have expressed some serious misgivings about its usefulness.
The British government has instituted a wide range of educational reforms to tackle ethnic inequality. This article argues that over the past half century most of these have been driven by immediate political considerations and have failed to incorporate a broader, historical perspective. This has invariably led to short-term, and short cut, solutions to long-term, deeply entrenched problems that, in reality, transcend the world of education. The article evaluates all the major reform programs, ranging from assimilationism to multicultural education to anti-racist education. It concludes with discussion of the merits/demerits of faith schools and the use of school reorganization as a means of tackling ethnic segregation.
The aim of this chapter is to examine multidimensional approaches to equality from a variety of perspectives: theoretical, policy, and practice. In particular, it examines the e?cacy of a certain mode of interventionism. First, however, we need to clarify what we mean by multidimensionality. Schiek rightly points out that the term is open to some confusion in that it may, for example, refer to di?erent conceptions of equality or to di?erent sets of grounds speci?ed in order 'to achieve equality for multi-faceted human beings in social reality'.1