Multiple AMPK activators inhibit L-Carnitine uptake in C2C12 skeletal muscle myotubes

Mutations in the gene that encodes the principal L-Carnitine transporter, OCTN2, can lead to a reduced intracellular L-Carnitine pool and the disease Primary Carnitine Deficiency. L-Carnitine supplementation is used therapeutically to increase intracellular L-Carnitine. As AMPK and insulin regulate fat metabolism and substrate uptake we hypothesised that AMPK activating compounds and insulin would increase L-Carnitine uptake in C2C12myotubes. The cells express all three OCTN transporters at the mRNA level and immunohistochemistry confirmed expression at the protein level. Contrary to our hypothesis, despite significant activation of PKB and 2DG uptake, insulin did not increase L-Carnitine uptake at 100nM. However, L-Carnitine uptake was modestly increased at a dose of 150nM insulin. A range of AMPK activators that increase intracellular calcium content [caffeine (10mM, 5mM, 1mM, 0.5mM), A23187 (10μM)], inhibit mitochondrial function [Sodium Azide (75μM), Rotenone (1μM), Berberine (100μM), DNP (500μM)] or directly activate AMPK [AICAR (250μM)] were assessed for their ability to regulate L-Carnitine uptake. All compounds tested significantly inhibited L-Carnitine uptake. Inhibition by caffeine was not dantrolene (10μM) sensitive. Saturation curve analysis suggested that caffeine did not competitively inhibit L-Carnitine transport. However, the AMPK inhibitor Compound C (10μM) partially rescued the effect of caffeine suggesting that AMPK may play a role in the inhibitory effects of caffeine. However, caffeine likely inhibits L-Carnitine uptake by alternative mechanisms independently of calcium release. PKA activation or direct interference with transporter function may play a role

Impact of Environmental Parameters on Marathon Running Performance

PURPOSE: The objectives of this study were to describe the distribution of all runners' performances in the largest marathons worldwide and to determine which environmental parameters have the maximal impact. METHODS: We analysed the results of six European (Paris, London, Berlin) and American (Boston, Chicago, New York) marathon races from 2001 to 2010 through 1,791,972 participants' performances (all finishers per year and race). Four environmental factors were gathered for each of the 60 races: temperature (°C), humidity (%), dew point (°C), and the atmospheric pressure at sea level (hPA); as well as the concentrations of four atmospheric pollutants: NO(2)-SO(2)-O(3) and PM(10) (μg x m(-3)). RESULTS: All performances per year and race are normally distributed with distribution parameters (mean and standard deviation) that differ according to environmental factors. Air temperature and performance are significantly correlated through a quadratic model. The optimal temperatures for maximal mean speed of all runners vary depending on the performance level. When temperature increases above these optima, running speed decreases and withdrawal rates increase. Ozone also impacts performance but its effect might be linked to temperature. The other environmental parameters do not have any significant impact. CONCLUSIONS: The large amount of data analyzed and the model developed in this study highlight the major influence of air temperature above all other climatic parameter on human running capacity and adaptation to race conditions

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Integrated Formal Methods with Richer Methodological Profiles for the Development of Multi-Perspective Systems

The thesis investigates some of the traditional problems with the established formal methods, such as requirements elicitation, the validation problem, divergence from current industrial practice, adverse effects on early problem solving and the incompleteness of perspective. Recent approaches to solving some of these problems are reviewed, including structured and formal methods integration, hybrid formal methods and multi-paradigmed approaches. The definition of a method first used by Kronlof is adopted and two reasons for integrating methods are hypothesised: ffl The integration of methods which result in a richer methodological profile, such as methods which address different stages of the life-cycle, and; ffl The integration of methods which result in a wider overall perspective, and are thus effective over a wider number of prospective problems, such as methods which consider different orthogonal aspects of requirements. Two pieces of work are then presented, one for each hypot..

Sedimentary records of coastal storm surges: Evidence of the 1953 North Sea event

The expression of storm events in the geological record is poorly understood; therefore, stratigraphic investigations of known events are needed. The 1953 North Sea storm surge was the largest natural disaster for countries bordering the southern North Sea during the twentieth century. We characterize the spatial distribution of a sand deposit from the 1953 storm surge in a salt marsh at Holkham, Norfolk (UK). Radionuclide measurements, core scanning X-ray fluorescence (Itrax), and particle size analyses, were used to date and characterise the deposit. The deposit occurs at the onset of detectable 137Cs - coeval with the first testing of nuclear weapons in the early 1950s. The sand layer is derived from material eroded from beach and dunes on the seaward side of the salt marsh. After the depositional event, accumulation of finer-grained silt and clay materials resumed. This work has important implications for understanding the responses of salt marshes to powerful storms and provides a near-modern analogue of storm surge events for calibration of extreme wave events in the geological record

Talking about History in Eleventh-Century England: the 'Encomium Emmae Reginae' and the court of Harthacnut

The Encomium Emmae Reginae was written in the early 1040s to support the interests of Queen Emma amidst the factionalism which marked the end of the period of Danish rule in England. This article argues that the Encomium was shaped by its production and reception in the distinctively multilingual environment of King Harthacnut's court. Attention to Emma's key role in negotiating the interaction of the English, Norse, French, Flemish and Latin literary and linguistic cultures which were present in the Anglo-Danish court reveals growing lay claims to Latin literary culture in eleventh-century England