Patients who develop oedema on initiating thiazolidinedione therapy have an improved glycaemic response: a MASTERMIND study

Special Issue: Abstracts of the Diabetes UK Professional Conference 2015, ExCeL London, 11–13 March 2015This is the author accepted manuscript. The final version is available from WileyBackground/aim: Oedema is a common and serious side effect ofthiazolidinedione therapy. A stratified medicine approach wouldaim to give thiazolidinediones to patients likely to have a goodglycaemic response but not to develop oedema. We investigatedwhether oedema was associated with glycaemic response tothiazolidinedione therapy.Methods: We studied 10,486 patients initiating a thiazolidinedionefrom Clinical Practice Research Datalink (CPRD), and identifiedmedical records of oedema in the subsequent 12 months. Responsewas defined as change in HbA1c at 12 months and was adjusted forbaseline HbA1c, baseline body mass index, gender and adherence(medication possession ratio). In secondary analyses we restrictedoedema classification to patients with concomitant weight gain. As acomparison the same analysis was performed in 13,089 patientsinitiating a sulfonylurea.Results: The 3% of patients with recorded oedema onthiazolidinediones had a mean (confidence interval) 3 (1.7–4.3)mmol/mol greater fall in HbA1c (p 3kg (p 8kg (p 3kg (p=0.19).Conclusion: Patients with Type 2 diabetes who develop oedemaon initiating thiazolidinediones have an improved glycaemicresponse, and more severe oedema is associated with greaterHbA1c reduction. This supports glycaemic lowering andfluid retention being mediated by a common pathway ofthiazolidinedione drug action

The Real Combination Problem : Panpsychism, Micro-Subjects, and Emergence

Panpsychism harbors an unresolved tension, the seriousness of which has yet to be fully appreciated. I capture this tension as a dilemma, and offer panpsychists advice on how to resolve it. The dilemma, briefly, is as follows. Panpsychists are committed to the perspicuous explanation of macro-mentality in terms of micro-mentality. But panpsychists take the micro-material realm to feature not just mental properties, but also micro-subjects to whom these properties belong. Yet it is impossible to explain the constitution of a macro-subject (like one of us) in terms of the assembly of micro-subjects, for, I show, subjects cannot combine. Therefore the panpsychist explanatory project is derailed by the insistence that the world’s ultimate material constituents (ultimates) are subjects of experience. The panpsychist faces a choice of abandoning her explanatory project, or recanting the claim that the ultimates are subjects. This is the dilemma. I argue that the latter option is to be preferred. This needn’t constitute a wholesale abandonment of panpsychism, however, since panpsychists can maintain that the ultimates possess phenomenal qualities, despite not being subjects of those qualities. This proposal requires us to make sense of phenomenal qualities existing independently of experiencing subjects, a challenge I tackle in the penultimate section. The position eventually reached is a form of neutral monism, so another way to express the overall argument is to say that, keeping true to their philosophical motivations, panpsychists should really be neutral monists.Peer reviewedFinal Accepted Versio

Effective Lagrangian approach to vector mesons, their structure and decays∗)^{*)}

An improved update of the structure and decays of $\rho^0$, $\omega$ and $\phi$ mesons based on a chiral SU(3) Lagrangian, including anomaly terms is presented. We demonstrate that a consistent and quantitatively successful description of both pion and kaon electromagnetic form factors can be achieved. We also discuss the $e^+e^- \to \pi^+ \pi^0 \pi^-$ cross section, the Dalitz decay $\omega \to \pi^0 \mu^+ \mu^-$ and aspects of $\rho^0 \omega$ and $\omega \phi$ mixing. Relations to previous versions of the Vector Meson Dominance model will be examined.Comment: 35 pages, TeX, 14 ps figures, submitted to Z.Phys.

The systematic guideline review: method, rationale, and test on chronic heart failure

Background: Evidence-based guidelines have the potential to improve healthcare. However, their de-novo-development requires substantial resources-especially for complex conditions, and adaptation may be biased by contextually influenced recommendations in source guidelines. In this paper we describe a new approach to guideline development-the systematic guideline review method (SGR), and its application in the development of an evidence-based guideline for family physicians on chronic heart failure (CHF). Methods: A systematic search for guidelines was carried out. Evidence-based guidelines on CHF management in adults in ambulatory care published in English or German between the years 2000 and 2004 were included. Guidelines on acute or right heart failure were excluded. Eligibility was assessed by two reviewers, methodological quality of selected guidelines was appraised using the AGREE instrument, and a framework of relevant clinical questions for diagnostics and treatment was derived. Data were extracted into evidence tables, systematically compared by means of a consistency analysis and synthesized in a preliminary draft. Most relevant primary sources were re-assessed to verify the cited evidence. Evidence and recommendations were summarized in a draft guideline. Results: Of 16 included guidelines five were of good quality. A total of 35 recommendations were systematically compared: 25/35 were consistent, 9/35 inconsistent, and 1/35 un-rateable (derived from a single guideline). Of the 25 consistencies, 14 were based on consensus, seven on evidence and four differed in grading. Major inconsistencies were found in 3/9 of the inconsistent recommendations. We re-evaluated the evidence for 17 recommendations (evidence-based, differing evidence levels and minor inconsistencies) - the majority was congruent. Incongruity was found where the stated evidence could not be verified in the cited primary sources, or where the evaluation in the source guidelines focused on treatment benefits and underestimated the risks. The draft guideline was completed in 8.5 man-months. The main limitation to this study was the lack of a second reviewer. Conclusion: The systematic guideline review including framework development, consistency analysis and validation is an effective, valid, and resource saving-approach to the development of evidence-based guidelines

Two distinct sequences of blue straggler stars in the globular cluster M30

Stars in globular clusters are generally believed to have all formed at the same time, early in the Galaxy's history. 'Blue stragglers' are stars massive enough that they should have evolved into white dwarfs long ago. Two possible mechanisms have been proposed for their formation: mass transfer between binary companions and stellar mergers resulting from direct collisions between two stars. Recently, the binary explanation was claimed to be dominant. Here we report that there are two distinct parallel sequences of blue stragglers in M30. This globular cluster is thought to have undergone 'core collapse', during which both the collision rate and the mass transfer activity in binary systems would have been enhanced. We suggest that the two observed sequences arise from the cluster core collapse, with the bluer population arising from direct stellar collisions and the redder one arising from the evolution of close binaries that are probably still experiencing an active phase of mass transfer.Comment: Published on the 24th December 2009 issue of Natur

Circulating microRNAs Reveal Time Course of Organ Injury in a Porcine Model of Acetaminophen-Induced Acute Liver Failure

Acute liver failure is a rare but catastrophic condition which can progress rapidly to multi-organ failure. Studies investigating the onset of individual organ injury such as the liver, kidneys and brain during the evolution of acute liver failure, are lacking. MicroRNAs are short, non-coding strands of RNA that are released into the circulation following tissue injury. In this study, we have characterised the release of both global microRNA and specific microRNA species into the plasma using a porcine model of acetaminophen-induced acute liver failure. Pigs were induced to acute liver failure with oral acetaminophen over 19h±2h and death occurred 13h±3h thereafter. Global microRNA concentrations increased 4h prior to acute liver failure in plasma (P<0.0001) but not in isolated exosomes, and were associated with increasing plasma levels of the damage-associated molecular pattern molecule, genomic DNA (P<0.0001). MiR122 increased around the time of onset of acute liver failure (P<0.0001) and was associated with increasing international normalised ratio (P<0.0001). MiR192 increased 8h after acute liver failure (P<0.0001) and was associated with increasing creatinine (P<0.0001). The increase in miR124-1 occurred concurrent with the pre-terminal increase in intracranial pressure (P<0.0001) and was associated with decreasing cerebral perfusion pressure (P<0.002)

The impact of preoperative anxiety and education level on long-term mortality after cardiac surgery

<p>Abstract</p> <p>Background</p> <p>Psychosocial factors have shown independent predictive value in the development of cardiovascular diseases. Although there is strong evidence to support the role of psychosocial factors in cardiovascular mortality, there is a scarcity of knowledge about how these factors are related. Therefore, we investigated the relationship between depression, anxiety, education, social isolation and mortality 7.5 years after cardiac surgery.</p> <p>Methods</p> <p>After informed consent, 180 patients undergoing cardiac surgery between July 2000 and May 2001 were prospectively enrolled and followed for ten years. During the follow-up period, the patients were contacted annually by mail. Anxiety (Spielberger State-Trait Anxiety Inventory, STAI-S/STAI-T), depression (Beck Depression Inventory, BDI) and the number and reason for rehospitalizations were assessed each year. Those patients who did not respond were contacted by telephone, and national registries were searched for deaths.</p> <p>Results</p> <p>During a median follow-up of 7.6 years (25^th to 75^th percentile, 7.4 to 8.1 years), the mortality rate was 23.6% (95% confidence interval [CI] 17.3-29.9; 42 deaths). In a Cox regression model, the risk factors associated with an increased risk of mortality were a higher EUROSCORE (points; Adjusted Hazard Ratio (AHR):1.30, 95%CI:1.07-1.58)), a higher preoperative STAI-T score (points; AHR:1.06, 95%CI 1.02-1.09), lower education level (school years; AHR:0.86, 95%CI:0.74-0.98), and the occurrence of major adverse cardiac and cerebral events during follow up (AHR:7.24, 95%CI:2.65-19.7). In the postdischarge model, the same risk factors remained.</p> <p>Conclusions</p> <p>Our results suggest that the assessment of psychosocial factors, particularly anxiety and education may help identify patients at an increased risk for long-term mortality after cardiac surgery.</p

Are isomeric alkenes used in species recognition among neo-tropical stingless bees (Melipona spp)

The majority of our understanding of the role of cuticular hydrocarbons (CHC) in recognition is based largely on temperate ant species and honey bees. The stingless bees remain relatively poorly studied, despite being the largest group of eusocial bees, comprising more than 400 species in some 60 genera. The Meliponini and Apini diverged between 80-130 Myr B.P. so the evolutionary trajectories that shaped the chemical communication systems in ants, honeybees and stingless bees may be very different. Therefore, the main aim of this study was to study if a unique species CHC signal existed in Neotropical stingless bees, as shown for many temperate species, and if so what compounds are involved. This was achieved by collecting CHC data from 24 colonies belonging to six species of Melipona from North-eastern Brazil and comparing this new data with all previously published CHC studies on Melipona. We found that each of the eleven Melipona species studied so far each produced a unique species CHC signal based around their alkene isomer production. A remarkable number of alkene isomers, up to 25 in M. asilvai, indicated the diversification of alkene positional isomers among the stingless bees. The only other group to have really diversified in alkene isomer production are the primitively eusocial Bumblebees (Bombus spp), which are the sister group of the stingless bees. Furthermore, among the eleven Neotropical Melipona species we could detect no effect of the environment on the proportion of alkane production as has been suggested for some other species

Challenging fear: Chemical alarm signals are not causing morphology changes in crucian carp (Carassius carassius)

Crucian carp develops a deep body in the presence of chemical cues from predators, which makes the fish less vulnerable to gape-limited predators. The active components originate in conspecifics eaten by predators, and are found in the filtrate of homogenised conspecific skin. Chemical alarm signals, causing fright reactions, have been the suspected inducers of such morphological changes. We improved the extraction procedure of alarm signals by collecting the supernatant after centrifugation of skin homogenates. This removes the minute particles that normally make a filtered sample get turbid. Supernatants were subsequently diluted and frozen into ice-cubes. Presence of alarm signals was confirmed by presenting thawed ice-cubes to crucian carp in behaviour tests at start of laboratory growth experiments. Frozen extracts were added further on three times a week. Altogether, we tested potential body-depth-promoting properties of alarm signals twice in the laboratory and once in the field. Each experiment lasted for a minimum of 50&nbsp;days. Despite growth of crucian carp in all experiments, no morphology changes were obtained. Accordingly, we conclude that the classical alarm signals that are releasing instant fright reactions are not inducing morphological changes in this species. The chemical signals inducing a body-depth increase are suspected to be present in the particles removed during centrifugation (i.e., in the precipitate). Tissue particles may be metabolized by bacteria in the intestine of predators, resulting in water-soluble cues. Such latent chemical signals have been found in other aquatic organisms, but hitherto not reported in fishe

Microsatellite discovery in an insular amphibian (Grandisonia alternans) with comments on cross-species utility and the accuracy of locus identification from unassembled Illumina data

The Seychelles archipelago is unique among isolated oceanic islands because it features an endemic radiation of caecilian amphibians (Gymnophiona). In order to develop population genetics resources for this system, we identified microsatellite loci using unassembled Illumina MiSeq data generated from a genomic library of Grandisonia alternans, a species that occurs on multiple islands in the archipelago. Applying a recently described method (PALFINDER) we identified 8001 microsatellite loci that were potentially informative for population genetics analyses. Of these markers, we screened 60 loci using five individuals, directly sequenced several amplicons to confirm their identity, and then used eight loci to score allele sizes in 64 G. alternans individuals originating from five islands. A number of these individuals were sampled using non-lethal methods, demonstrating the efficacy of non-destructive molecular sampling in amphibian research. Although two loci satisfied our criteria as diploid, neutrally evolving loci with the statistical power to detect population structure, our success in identifying reliable loci was very low. Additionally, we discovered some issues with primer redundancy and differences between Illumina and Sanger sequences that suggest some Illumina-inferred loci are invalid. We investigated cross-species utility for eight loci and found most could be successfully amplified, sequenced and aligned across other species and genera of caecilians from the Seychelles. Thus, our study in part supported the validity of using PALFINDER with unassembled reads for microsatellite discovery within and across species, but importantly identified major limitations to applying this approach to small datasets (ca. 1 million reads) and loci with small tandem repeat sizes