Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. Objectives: This study sought to test the association between the rs9349379 genotype and SCAD. Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD

Cultural Change: An Attempt to Teach Ethics to Police Leaders and Managers Within a Traditional Institution and Changing Social Milieu.

This inquiry describes an attempt to teach ethics to police leaders and managers within the unique institutional context of 'Bramshill' - the site of the Police Staff College within the National Police Training organisation. It shows how the subject 'ethics' was re-introduced to the curriculum of the middle-manager programmes of study and sets this re-introduction in the context of the wider strategic priorities and culture change aspirations of the police service in England, Wales and Northern Ireland. The study identifies a sequence of'action research' stages each reflecting a search to secure a positive evaluation for the emerging educational designs. This part of the account will illustrate how difficult it was to secure, consistently, a positive evaluation of and response to the learning designs from the client group. Finally, though, after a number of set-backs and disappointments it became possible to claim some degree of success for the educational project. The thesis presented here is a post-modern text in three senses; first, its construction is an example of a 'transitext' built up over time; second, it is postmodern in its content including materials from eclectic and diverse sources; third, it is 'local', contextually specific and highly personal. In this latter respect it recognises that a different author would create a different style of account and a different theoretical structure in the course of making sense of the inquiry and the facts of the inquiry. The first part of the thesis establishes the background to the project and foundations for the study. The second part charts the unfolding stages of the inquiry from the re-introduction of 'ethics' until its removal from the middle-management programme. The third part of the thesis develops a number of theoretical interpretations and concludes with the presentation of information concerning the 'moral world' of police leaders and managers. The concluding chapter re-affirms the significance of 'ethics' in police strategic discourse, summarises the main findings of the study and concludes optimistically by noting how 'ethics' has, at last, come to be positively valued by a consistent majority of the client group at the dawn of the new millennium

Cultural Change: An Attempt to Teach Ethics to Police Leaders and Managers Within a Traditional Institution and Changing Social Milieu.

This inquiry describes an attempt to teach ethics to police leaders and managers within the unique institutional context of 'Bramshill' - the site of the Police Staff College within the National Police Training organisation. It shows how the subject 'ethics' was re-introduced to the curriculum of the middle-manager programmes of study and sets this re-introduction in the context of the wider strategic priorities and culture change aspirations of the police service in England, Wales and Northern Ireland. The study identifies a sequence of'action research' stages each reflecting a search to secure a positive evaluation for the emerging educational designs. This part of the account will illustrate how difficult it was to secure, consistently, a positive evaluation of and response to the learning designs from the client group. Finally, though, after a number of set-backs and disappointments it became possible to claim some degree of success for the educational project. The thesis presented here is a post-modern text in three senses; first, its construction is an example of a 'transitext' built up over time; second, it is postmodern in its content including materials from eclectic and diverse sources; third, it is 'local', contextually specific and highly personal. In this latter respect it recognises that a different author would create a different style of account and a different theoretical structure in the course of making sense of the inquiry and the facts of the inquiry. The first part of the thesis establishes the background to the project and foundations for the study. The second part charts the unfolding stages of the inquiry from the re-introduction of 'ethics' until its removal from the middle-management programme. The third part of the thesis develops a number of theoretical interpretations and concludes with the presentation of information concerning the 'moral world' of police leaders and managers. The concluding chapter re-affirms the significance of 'ethics' in police strategic discourse, summarises the main findings of the study and concludes optimistically by noting how 'ethics' has, at last, come to be positively valued by a consistent majority of the client group at the dawn of the new millennium

Identifying culturally significant areas for marine spatial planning

Despite the growing recognition of their importance, immaterial cultural values associated with the sea still tend to be neglected in marine spatial planning (MSP). This socio-cultural evidence gap is due to inherent difficulties in defining and eliciting cultural values, but also to difficulties in linking cultural values to specific places, thus enabling an area-based approach to management. This paper addresses three aspects that are important for including marine cultural values in MSP: Defining cultural values, identifying places of cultural importance, and establishing the relative significance of places of cultural importance. We argue that common classification schemes such as cultural ecosystem services can be a helpful starting point for identifying cultural values, but only go so far in capturing communities' cultural connections with the sea. A method is proposed for structuring a community-based narrative on cultural values and “spatialising” them for MSP purposes, using five criteria that can lead to the definition of “culturally significant areas”. A baseline of culturally significant areas is suggested as an aid to planners to pinpoint places where cultural connections to the sea are particularly strong. Throughout, we emphasise the need for participative processes

Distinct and complementary roles for α and β isoenzymes of protein kinase C in mediating vasoconstrictor responses to acutely elevated glucose

Background and Purpose: We investigate the hypothesis that elevated glucose increases contractile responses in vascular smooth muscle, and that this enhanced constriction occurs due to the glucose-induced protein kinase C (PKC)-dependent inhibition of voltage-gated potassium channels. Experimental Approach: Patch-clamp electrophysiology in rat isolated mesenteric arterial myocytes was performed to investigate the glucose-induced inhibition of voltage-gated potassium (Kv) current. To determine the effects of glucose in whole vessel wire myography was performed in rat mesenteric, porcine coronary and human internal mammary arteries. Key Results: Glucose-induced inhibition of Kv was PKC-dependent and could be pharmacologically dissected using PKC isoenzyme-specific inhibitors to reveal a PKCβ-dependent component of Kv inhibition dominating between 0 and 10 mM glucose with an additional PKCα-dependent component becoming evident at concentrations greater than 10 mM. These findings were supported using wire myography in all artery types used, where contractile responses to vessel depolarization and vasoconstrictors were enhanced by increasing bathing glucose concentration, again with evidence for distinct and complementary PKCα/PKCβ-mediated components. Conclusions and Implications: Our study provides compelling evidence that glucose-induced PKCα/PKCβ-mediated inhibition of Kv current in vascular smooth muscle causes an enhanced constrictor response. Inhibition of Kv current causes a significant depolarization of vascular myocytes leading to marked vasoconstriction. The PKC-dependence of this enhanced constrictor response may present a potential therapeutic target for improving microvascular perfusion following percutaneous coronary intervention following myocardial infarction in hyperglycaemic patients