Functional effects of polymorphisms on glucocorticoid receptor modulation of human anxiogenic substance-P gene promoter activity in primary amygdala neurones

This work was funded by The BBSRC (BB/D004659/1) the Wellcome Trust (080980/Z/06/Z) and the Medical Research Council (G0701003). Colin Hay was funded by the Chief Scientist Office, Scotland. Scott Davidson was funded by a BBSRC strategic studentship (BBS/S/2005/12001). Philip Cowie was funded by the Scottish Universities Life Sciences Alliance (SULCA).Peer reviewedPublisher PD

Geographic Market Definition in an International Context

Market definition is generally regarded as a key step in antitrust analysis. Market definition has two components. Product market definition seeks to include all products that are meaningful substitutes. Geographic market definition seeks to incorporate all relevant sources of the product in question. This paper is concerned with geographic market definition and, in particular, how geographic markets are defined in situations where competition may, at least to some extent, transcend national boundaries. The subject of the paper may be of some current interest for two reasons. First, the perception is widespread that, over the past twenty or so years, competition in many products and services has become increasingly international in scope and that this trend will continue. Second, the way in which foreign competition is taken into account in performing the antitrust analysis can have a dramatic impact on the legal or policy conclusions that are reached in a particular instance. The legality of a proposed merger, for example, may turn entirely on how competition from foreign sellers is treated. For antitrust purposes, when we say that competition has become more international in scope, we mean primarily that the range of possible suppliers for many goods and services to U.S. consumers increasingly includes sellers who do not produce or are not primarily headquartered in the United States or that an increasing portion of sales by American-based firms are to customers abroad. Many aspects of antitrust are potentially affected by these changes. Some of the more complex issues involve jurisdictional considerations and these will not be discussed here. As we will see, however, the subject of market definition exposes almost all of the substantive (as opposed to jurisdictional) considerations that come into play when we take account of the international aspect of certain markets. The paper has three main parts. The first focuses on the role market definition plays in antitrust analysis and, in particular, the link between market definition and market power. The second explores the particular issues that are raised with respect to market definition when there is an international aspect to competition. The final section addresses some of the empirical questions raised by the largely theoretical analysis of the first two parts of the paper

Geographic Market Definition in an International Context

Market definition is generally regarded as a key step in antitrust analysis. Market definition has two components. Product market definition seeks to include all products that are meaningful substitutes. Geographic market definition seeks to incorporate all relevant sources of the product in question. This paper is concerned with geographic market definition and, in particular, how geographic markets are defined in situations where competition may, at least to some extent, transcend national boundaries. The subject of the paper may be of some current interest for two reasons. First, the perception is widespread that, over the past twenty or so years, competition in many products and services has become increasingly international in scope and that this trend will continue. Second, the way in which foreign competition is taken into account in performing the antitrust analysis can have a dramatic impact on the legal or policy conclusions that are reached in a particular instance. The legality of a proposed merger, for example, may turn entirely on how competition from foreign sellers is treated. For antitrust purposes, when we say that competition has become more international in scope, we mean primarily that the range of possible suppliers for many goods and services to U.S. consumers increasingly includes sellers who do not produce or are not primarily headquartered in the United States or that an increasing portion of sales by American-based firms are to customers abroad. Many aspects of antitrust are potentially affected by these changes. Some of the more complex issues involve jurisdictional considerations and these will not be discussed here. As we will see, however, the subject of market definition exposes almost all of the substantive (as opposed to jurisdictional) considerations that come into play when we take account of the international aspect of certain markets. The paper has three main parts. The first focuses on the role market definition plays in antitrust analysis and, in particular, the link between market definition and market power. The second explores the particular issues that are raised with respect to market definition when there is an international aspect to competition. The final section addresses some of the empirical questions raised by the largely theoretical analysis of the first two parts of the paper

Exercise therapy after corticosteroid injection for moderate to severe shoulder pain: large pragmatic randomised trial

Objective To compare the effectiveness of subacromial corticosteroid injection combined with timely exercise and manual therapy (injection plus exercise) or exercise and manual therapy alone (exercise only) in patients with subacromial impingement syndrome

Defining childhood severe falciparum malaria for intervention studies.

Background Clinical trials of interventions designed to prevent severe falciparum malaria in children require a clear endpoint. The internationally accepted definition of severe malaria is sensitive, and appropriate for clinical purposes. However, this definition includes individuals with severe nonmalarial disease and coincident parasitaemia, so may lack specificity in vaccine trials. Although there is no “gold standard” individual test for severe malaria, malaria-attributable fractions (MAFs) can be estimated among groups of children using a logistic model, which we use to test the suitability of various case definitions as trial endpoints. Methods and Findings A total of 4,583 blood samples were taken from well children in cross-sectional surveys and from 1,361 children admitted to a Kenyan District hospital with severe disease. Among children under 2 y old with severe disease and over 2,500 parasites per microliter of blood, the MAFs were above 85% in moderate- and low-transmission areas, but only 61% in a high-transmission area. HIV and malnutrition were not associated with reduced MAFs, but gastroenteritis with severe dehydration (defined by reduced skin turgor), lower respiratory tract infection (clinician's final diagnosis), meningitis (on cerebrospinal fluid [CSF] examination), and bacteraemia were associated with reduced MAFs. The overall MAF was 85% (95% confidence interval [CI] 83.8%–86.1%) without excluding these conditions, 89% (95% CI 88.4%–90.2%) after exclusions, and 95% (95% CI 94.0%–95.5%) when a threshold of 2,500 parasites/μl was also applied. Applying a threshold and exclusion criteria reduced sensitivity to 80% (95% CI 77%–83%). Conclusions The specificity of a case definition for severe malaria is improved by applying a parasite density threshold and by excluding children with meningitis, lower respiratory tract infection (clinician's diagnosis), bacteraemia, and gastroenteritis with severe dehydration, but not by excluding children with HIV or malnutrition

Disease associated polymorphisms within the conserved ECR1 enhancer differentially regulate the tissue specific activity of the cannabinoid‐1 receptor gene promoter; implications for cannabinoid pharmacogenetics

EH was funded by Medical Research Scotland (PhD-719-2013) and GW Pharmaceuticals. AMcE was funded by BBSRC project grant (BB/N017544/1). PB and DW are funded by the Scottish Government Rural and Environment Science and Analytical Services Division to the Rowett Institute. The authors declare no conflicts of interest.Peer reviewedPublisher PD

Alterations in hypothalamic gene expression following Roux-en-Y gastric bypass

Objective: The role of the central nervous system in mediating metabolic effects of Roux-en-Y gastric bypass (RYGB) surgery is poorly understood. Using a rat model of RYGB, we aimed to identify changes in gene expression of key hypothalamic neuropeptides known to be involved in the regulation of energy balance. Methods: Lean male Sprague-Dawley rats underwent either RYGB or sham surgery. Body weight and food intake were monitored bi-weekly for 60 days post-surgery. In situ hybridization mRNA analysis of hypothalamic AgRP, NPY, CART, POMC and MCH was applied to RYGB and sham animals and compared with ad libitum fed and food-restricted rats. Furthermore, in situ hybridization mRNA analysis of dopaminergic transmission markers (TH and DAT) was applied in the midbrain. Results: RYGB surgery significantly reduced body weight and intake of a highly palatable diet but increased chow consumption compared with sham operated controls. In the arcuate nucleus, RYGB surgery increased mRNA levels of orexigenic AgRP and NPY, whereas no change was observed in anorexigenic CART and POMC mRNA levels. A similar pattern was seen in food-restricted versus ad libitum fed rats. In contrast to a significant increase of orexigenic MCH mRNA levels in food-restricted animals, RYGB did not change MCH expression in the lateral hypothalamus. In the VTA, RYGB surgery induced a reduction in mRNA levels of TH and DAT, whereas no changes were observed in the substantia nigra relative to sham surgery. Conclusion: RYGB surgery increases the mRNA levels of hunger-associated signaling markers in the rat arcuate nucleus without concomitantly increasing downstream MCH expression in the lateral hypothalamus, suggesting that RYGB surgery puts a brake on orexigenic hypothalamic output signals. In addition, down-regulation of midbrain TH and DAT expression suggests that altered dopaminergic activity also contributes to the reduced intake of palatable food in RYGB rats. Keywords: Roux-en-Y gastric bypass, Energy homeostasis, Hypothalamus, Hedonic, Mesolimbic pathwa