Role of UDP-Glucuronosyltransferase Isoforms in 13-cis Retinoic Acid Metabolism in Humans

ABSTRACT: 13-cis Retinoic acid (13cisRA, isotretinoin) is an important drug in both dermatology, and the treatment of high-risk neuroblastoma. 13cisRA is known to undergo cytochrome P450-mediated oxidation, mainly by CYP2C8, but phase II metabolic pathways have not been characterized. In the present study, the glucuronidation activities of human liver (HLM) and intestinal microsomes (HIM), as well as a panel of human UDP-glucuronosyltransferases (UGTs) toward both 13cisRA and the 4-oxo metabolite, 4-oxo 13cisRA, were compared using high-performance liquid chromatography. Both HLM and, to a greater extent, HIM catalyzed the glucuronidation of 13cisRA and 4-oxo 13cisRA. Based on the structures of 13cisRA and 4-oxo 13cisRA, the glucuronides formed are conjugated at the terminal carboxylic acid. Further analysis revealed that UGT1A1, UGT1A3, UGT1A7, UGT1A8, and UGT1A9 were the major isoforms responsible for the glucuronidation of both substrates. For 13cisRA, a pronounced substrate inhibition was observed with individual UGTs and with HIM. UGT1A3 exhibited the highest rate of activity toward both substrates, and a high rate of activity toward 13cisRA glucuronidation was also observed with UGT1A7. However, for both substrates, K m values were above concentrations reported in clinical studies. Therefore, UGT1A9 is likely to be the most important enzyme in the glucuronidation of both substrates as this enzyme had the lowest K m and is expressed in both the intestine and at high levels in the liver

‘Re-reading Raphael Samuel: Politics, Personality and Performance’

For British historian Raphael Samuel, history and politics were inextricable. Best known as the founder of the history workshop movement, the controversial historian took his stance on the democratisation of history-making, becoming an outspoken advocate for public history. Despite making a significant contribution to contemporary historiography, he remains a neglected, even disparaged, figure. This paper contends that the most significant aspect of Samuel’s historical work was not one or other theory of history or argument about the past but his entire way of being an historian. Samuel embodied as much as expressed his ideas, consciously using his personality as a powerful political tool. It is further argued that conventional approaches to intellectual history, focusing on textual outputs, do not fully recognise the significance of performative modes of thinking. Theoretical approaches to performance as identity offer important insight here but can be too schematic in their view of applied and enacted thought. A biographical approach, by contrast, provides the intimate perspective necessary to fully appreciate the fluidity and complexity of such a personality. The paper first situates Samuel in the context of his earlier life, focusing on how and why he created such a public persona and how he adapted it in response to changing circumstances. It then considers the implications and effectiveness of this persona by assessing how it was perceived and narrated by others, acknowledging, in the process, why different groups engaged with and interpreted it differently

Fenofibrate in the management of AbdoMinal aortic anEurysm (FAME): Study protocol for a randomised controlled trial

Background: Abdominal aortic aneurysm (AAA) is a slowly progressive destructive process of the main abdominal artery. Experimental studies indicate that fibrates exert beneficial effects on AAAs by mechanisms involving both serum lipid modification and favourable changes to the AAA wall. Methods/design: Fenofibrate in the management of AbdoMinal aortic anEurysm (FAME) is a multicentre, randomised, double-blind, placebo-controlled clinical trial to assess the effect of orally administered therapy with fenofibrate on key pathological markers of AAA in patients undergoing open AAA repair. A total of 42 participants scheduled for an elective open AAA repair will be randomly assigned to either 145 mg of fenofibrate per day or identical placebo for a minimum period of 2 weeks prior to surgery. Primary outcome measures will be macrophage number and osteopontin (OPN) concentration within the AAA wall as well as serum concentrations of OPN. Secondary outcome measures will include levels of matrix metalloproteinases and proinflammatory cytokines within the AAA wall, periaortic fat and intramural thrombus and circulating concentrations of AAA biomarkers. Discussion: At present, there is no recognised medical therapy to limit AAA progression. The FAME trial aims to assess the ability of fenofibrate to alter tissue markers of AAA pathology. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12612001226897. Registered on 20 November 2012. © 2017 The Author(s)

Efficacy of brief behavioral counselling by allied health professionals to promote physical activity in people with peripheral arterial disease (BIPP): study protocol for a multi-center randomized controlled trial

Background: Physical activity is recommended for people with peripheral arterial disease (PAD), and can improve walking capacity and quality of life; and reduce pain, requirement for surgery and cardiovascular events. This trial will assess the efficacy of a brief behavioral counselling intervention delivered by allied health professionals to improve physical activity in people with PAD. Methods: This is a multi-center randomised controlled trial in four cities across Australia. Participants (N = 200) will be recruited from specialist vascular clinics, general practitioners and research databases and randomised to either the control or intervention group. Both groups will receive usual medical care, a written PAD management information sheet including advice to walk, and four individualised contacts from a protocol-trained allied health professional over 3 months (weeks 1, 2, 6, 12). The control group will receive four 15-min telephone calls with general discussion about PAD symptoms and health and wellbeing. The intervention group will receive behavioral counselling via two 1-h face-to-face sessions and two 15-min telephone calls. The counselling is based on the 5A framework and will promote interval walking for 3 × 40 min/week. Assessments will be conducted at baseline, and 4, 12 and 24 months by staff blinded to participant allocation.Objectively assessed outcomes include physical activity (primary), sedentary behavior, lower limb body function, walking capacity, cardiorespiratory fitness, event-based claudication index, vascular interventions, clinical events, cardiovascular function, circulating markers, and anthropometric measures. Self-reported outcomes include physical activity and sedentary behavior, walking ability, pain severity, and health-related quality of life. Data will be analysed using an intention-to-treat approach. An economic evaluation will assess whether embedding the intervention into routine care would likely be value for money. A cost-effectiveness analysis will estimate change in cost per change in activity indicators due to the intervention, and a cost-utility analysis will assess change in cost per quality-adjusted life year. A full uncertainty analysis will be undertaken, including a value of information analysis, to evaluate the economic case for further research. Discussion: This trial will evaluate the efficacy and cost-effectiveness of a brief behavioral counselling intervention for a common cardiovascular disease with significant burden. Trial registration: ACTRN 12614000592640 Australian New Zealand Clinical Trials Registry. Registration Date 4 June 2014

Extensive recombination events and horizontal gene transfer shaped the Legionella pneumophila genomes

<p>Abstract</p> <p>Background</p> <p><it>Legionella pneumophila </it>is an intracellular pathogen of environmental protozoa. When humans inhale contaminated aerosols this bacterium may cause a severe pneumonia called Legionnaires' disease. Despite the abundance of dozens of <it>Legionella </it>species in aquatic reservoirs, the vast majority of human disease is caused by a single serogroup (Sg) of a single species, namely <it>L. pneumophila </it>Sg1. To get further insights into genome dynamics and evolution of Sg1 strains, we sequenced strains Lorraine and HL 0604 1035 (Sg1) and compared them to the available sequences of Sg1 strains Paris, Lens, Corby and Philadelphia, resulting in a comprehensive multigenome analysis.</p> <p>Results</p> <p>We show that <it>L. pneumophila </it>Sg1 has a highly conserved and syntenic core genome that comprises the many eukaryotic like proteins and a conserved repertoire of over 200 Dot/Icm type IV secreted substrates. However, recombination events and horizontal gene transfer are frequent. In particular the analyses of the distribution of nucleotide polymorphisms suggests that large chromosomal fragments of over 200 kbs are exchanged between <it>L. pneumophila </it>strains and contribute to the genome dynamics in the natural population. The many secretion systems present might be implicated in exchange of these fragments by conjugal transfer. Plasmids also play a role in genome diversification and are exchanged among strains and circulate between different <it>Legionella </it>species.</p> <p>Conclusion</p> <p>Horizontal gene transfer among bacteria and from eukaryotes to <it>L. pneumophila </it>as well as recombination between strains allows different clones to evolve into predominant disease clones and others to replace them subsequently within relatively short periods of time.</p

Setting the Stage: Performing Politics in Theatres of Memory

The British historian Raphael Samuel is best known as a founding figure in the first British New Left and the driving force behind the history workshop movement which set out to democratise history-making in post Britain. Whilst the workshop has attracted attention for its radical pedagogical practice, Samuel’s distinctive approach to the writing of history has been less acknowledged. This paper contends that Theatres of Memory (1994), Samuel’s only sole-authored book published in his lifetime, both articulates and performs its author’s activist, participatory politics. If the workshop was intended to turn the formality of the historical conference or seminar on its head, Theatres applied the same subversive spirit to that icon of professional scholarship: the monograph. Written in the wake of and in response to the post-war fragmentation of the political left, Samuel sought a means of escaping the ideological and epistemological impasse that had arisen between factions. Rather than taking a stance on ‘people’s history’, Theatres recognised, and advocated for, history making as a common social activity. By making participation its core principle, it reconstituted socialism as an ethics of practice, an adjective rather than a noun, that could accommodate many variations. Drawing on a dramaturgical analysis to illuminate its dynamics of action, this article examines how the book enacted this participatory politics through a range of compositional techniques aimed at stimulating active readership. In doing so, it demonstrated, rather than described, a blueprint for the historian’s role in an expanding, pluralist, historical culture

Pharmacogentic factors influencing the metabolism of 13-cis retinoic acid

5203 L $$aThe administration of 13-cis retinoic acid (13cisRA) improves 3-year event free survival rates in children with high-risk neuroblastoma. However, more than half of patients suffer relapse within 3 years. A high degree of variability in UcisRA pharmacokinetics has been reported, suggesting that individualisation of dosing may further improve therapy. Several cytochrome P450 (CYP) and UDPglucuronosyltransferase (UGT) enzymes play a role in the metabolism of retinoic icid. Thus, genetic variation in CYP and UGT activity could underlie the individual differences in 13c/5RA metabolism and bioavailability.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Fenofibrate and telmisartan in the management of abdominal aortic aneurysm

Objective This mini-review provides the rationale and updated progress for ongoing randomized controlled trials assessing fenofibrate and telmisartan efficacy to limit abdominal aortic aneurysm (AAA) growth. Methods / Results Data from preclinical and human studies investigating the efficacy of fenofibrate and telmisartan to limit AAA growth is presented and provides the rationale for three current randomized controlled trials assessing these medications as potential interventions to limit aneurysm growth in AAA patients. Conclusions Fenofibrate and telmisartan have potential as repurposed medications to limit AAA growth and randomized trials for further assessment in AAA patients are ongoing

Relationship between requirement to stop during a six-minute walk test and health-related quality of life, physical activity and physical performance amongst people with intermittent claudication

Aim: A simple objective test is required to identify people with impaired physical aspects of health-related quality of life (QOL) due to intermittent claudication. This study assessed the relationship of QOL, function and physical activity to the need to stop during a six-minute walking test (6MWT) amongst people with intermittent claudication. Method: This was a prospective case-control study conducted at two centers in Australia. 173 participants with a history of intermittent claudication and peripheral artery disease diagnosed by ankle brachial pressure index <0.9, completed two 6MWTs one week apart. QOL was assessed with the short form (SF)-36. Physical activity was assessed by an accelerometer to record step count, stepping time and energy expenditure over 7 days. Physical performance was assessed by the Short Physical Performance Battery (SPPB) test. The associations of the need to stop at least once during the 6MWT with QOL, function and activity were assessed using Mann Whitney U test and analysis of covariates. Results: Participants that had to stop at least once during the two 6MWTs (46; 26.6%) had significantly lower scores for three of the domains (physical functioning, role-physical and bodily pain) and the physical component summary (PCS) measure of the SF-36 compared to those who did not need to stop (n = 127; 73.4%). After adjusting for the risk factor co-variates (diabetes, hypertension and ankle brachial pressure index) which were significantly unequally distributed, needing to stop during the 6MWTs was significantly associated with a lower PCS score (adjusted mean 36.5, standard error 0.8 vs. 30.5, standard error 1.3; F = 14.0; P < 0.001; partial eta squared 0.077). Participants that had to stop at least once during the two 6MWTs had significantly lower 7-day step count, time stepping and energy expenditure, but not total SPPB score, compared to those who did not need to stop. Conclusions: Needing to stop during a 6MWT identified participants with intermittent claudication with poorer QOL and less physical activity compared to those that do not need to stop

The predictive accuracy of the american college of surgeons national surgical quality improvement program surgical risk calculator in patients undergoing major vascular surgery

Aim: The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) Surgical Risk Calculator (SRC) was developed to estimate the rates of complications for patients undergoing a variety of surgical procedures, based on the patient's preoperative demographics and medical conditions. Its predictive ability has been evaluated in a number of studies for a variety of surgical fields. There has so far been no assessment of the SRC in patients undergoing vascular surgery. This study assesses whether the ACS NSQIP SRC can accurately predict risk of complications in patients undergoing major vascular surgery at a tertiary hospital. Methods: A retrospective review of prospectively collected data was performed on all patients who underwent an open abdominal aortic aneurysm (AAA) repair, an endovascular aneurysm repair (EVAR), or a femoral-popliteal bypass graft (FPBG) from July 2016 to April 2017. A total of 95 patients had their demographics entered into the ACS NSQIP SRC, and the predicted rates of complications were compared to the observed rates of complications. Results: Statistical analysis was performed with Brier scores and C-statistics. This analysis found the ACS NSQIP SRC accurately estimated the risk of complications with a Brier score of 0.044 for EVAR, 0.068 for open AAA repair, and 0.0752 for FPBG. The C-statistics for serious complications, any complications, and discharge to a nursing home or rehabilitation indicated the model was good at accurately predicting the risk of these outcomes. Conclusion: The ACS NSQIP SRC accurately predicts the rates of complications in patients undergoing vascular surgery