Obesity-induced changes in lipid mediators persist after weight loss.

BackgroundObesity induces significant changes in lipid mediators, however, the extent to which these changes persist after weight loss has not been investigated.Subjects/methodsWe fed C57BL6 mice a high-fat diet to generate obesity and then switched the diet to a lower-fat diet to induce weight loss. We performed a comprehensive metabolic profiling of lipid mediators including oxylipins, endocannabinoids, sphingosines and ceramides in key metabolic tissues (including adipose, liver, muscle and hypothalamus) and plasma.ResultsWe found that changes induced by obesity were largely reversible in most metabolic tissues but the adipose tissue retained a persistent obese metabolic signature. Prostaglandin signaling was perturbed in the obese state and lasting increases in PGD2, and downstream metabolites 15-deoxy PGJ2 and delta-12-PGJ2 were observed after weight loss. Furthermore expression of the enzyme responsible for PGD2 synthesis (hematopoietic prostaglandin D synthase, HPGDS) was increased in obese adipose tissues and remained high after weight loss. We found that inhibition of HPGDS over the course of 5 days resulted in decreased food intake in mice. Increased HPGDS expression was also observed in human adipose tissues obtained from obese compared with lean individuals. We then measured circulating levels of PGD2 in obese patients before and after weight loss and found that while elevated relative to lean subjects, levels of this metabolite did not decrease after significant weight loss.ConclusionsThese results suggest that lasting changes in lipid mediators induced by obesity, still present after weight loss, may play a role in the biological drive to regain weight

Outlier Edge Detection Using Random Graph Generation Models and Applications

Outliers are samples that are generated by different mechanisms from other normal data samples. Graphs, in particular social network graphs, may contain nodes and edges that are made by scammers, malicious programs or mistakenly by normal users. Detecting outlier nodes and edges is important for data mining and graph analytics. However, previous research in the field has merely focused on detecting outlier nodes. In this article, we study the properties of edges and propose outlier edge detection algorithms using two random graph generation models. We found that the edge-ego-network, which can be defined as the induced graph that contains two end nodes of an edge, their neighboring nodes and the edges that link these nodes, contains critical information to detect outlier edges. We evaluated the proposed algorithms by injecting outlier edges into some real-world graph data. Experiment results show that the proposed algorithms can effectively detect outlier edges. In particular, the algorithm based on the Preferential Attachment Random Graph Generation model consistently gives good performance regardless of the test graph data. Further more, the proposed algorithms are not limited in the area of outlier edge detection. We demonstrate three different applications that benefit from the proposed algorithms: 1) a preprocessing tool that improves the performance of graph clustering algorithms; 2) an outlier node detection algorithm; and 3) a novel noisy data clustering algorithm. These applications show the great potential of the proposed outlier edge detection techniques.Comment: 14 pages, 5 figures, journal pape

A phase 1 trial dose-escalation study of tipifarnib on a week-on, week-off schedule in relapsed, refractory or high-risk myeloid leukemia.

Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo anti-leukemia activity. We report the results of a phase 1 dose-escalation study of tipifarnib, an oral FT inhibitor, in patients with relapsed, refractory or newly diagnosed (if over age 70) acute myelogenous leukemia (AML), on a week-on, week-off schedule. Forty-four patients were enrolled, two patients were newly diagnosed, and the rest were relapsed or refractory to previous treatment, with a median age of 61 (range 33-79). The maximum tolerated dose was determined to be 1200 mg given orally twice daily (b.i.d.) on this schedule. Cycle 1 dose-limiting toxicities were hepatic and renal. There were three complete remissions seen, two at the 1200 mg b.i.d. dose and one at the 1000 mg b.i.d. dose, with minor responses seen at the 1400 mg b.i.d. dose level. Pharmacokinetic studies performed at doses of 1400 mg b.i.d. showed linear behavior with minimal accumulation between days 1-5. Tipifarnib administered on a week-on, week-off schedule shows activity at higher doses, and represents an option for future clinical trials in AML

Healthcare choice: Discourses, perceptions, experiences and practices

Policy discourse shaped by neoliberal ideology, with its emphasis on marketisation and competition, has highlighted the importance of choice in the context of healthcare and health systems globally. Yet, evidence about how so-called consumers perceive and experience healthcare choice is in short supply and limited to specific healthcare systems, primarily in the Global North. This special issue aims to explore how choice is perceived and utilised in the context of different systems of healthcare throughout the world, where choice, at least in policy and organisational terms, has been embedded for some time. The articles are divided into those emphasising: embodiment and the meaning of choice; social processes associated with choice; the uncertainties, risks and trust involved in making choices; and issues of access and inequality associated with enacting choice. These sociological studies reveal complexities not always captured in policy discourse and suggest that the commodification of healthcare is particularly problematic

Long-term follow-up of beryllium sensitized workers from a single employer

<p>Abstract</p> <p>Background</p> <p>Up to 12% of beryllium-exposed American workers would test positive on beryllium lymphocyte proliferation test (BeLPT) screening, but the implications of sensitization remain uncertain.</p> <p>Methods</p> <p>Seventy two current and former employees of a beryllium manufacturer, including 22 with pathologic changes of chronic beryllium disease (CBD), and 50 without, with a confirmed positive test were followed-up for 7.4 +/-3.1 years.</p> <p>Results</p> <p>Beyond predicted effects of aging, flow rates and lung volumes changed little from baseline, while D_LCO dropped 17.4% of predicted on average. Despite this group decline, only 8 subjects (11.1%) demonstrated physiologic or radiologic abnormalities typical of CBD. Other than baseline status, no clinical or laboratory feature distinguished those who clinically manifested CBD at follow-up from those who did not.</p> <p>Conclusions</p> <p>The clinical outlook remains favorable for beryllium-sensitized individuals over the first 5-12 years. However, declines in D_LCO may presage further and more serious clinical manifestations in the future. These conclusions are tempered by the possibility of selection bias and other study limitations.</p

The impact of contact tracing in clustered populations

The tracing of potentially infectious contacts has become an important part of the control strategy for many infectious diseases, from early cases of novel infections to endemic sexually transmitted infections. Here, we make use of mathematical models to consider the case of partner notification for sexually transmitted infection, however these models are sufficiently simple to allow more general conclusions to be drawn. We show that, when contact network structure is considered in addition to contact tracing, standard “mass action” models are generally inadequate. To consider the impact of mutual contacts (specifically clustering) we develop an improvement to existing pairwise network models, which we use to demonstrate that ceteris paribus, clustering improves the efficacy of contact tracing for a large region of parameter space. This result is sometimes reversed, however, for the case of highly effective contact tracing. We also develop stochastic simulations for comparison, using simple re-wiring methods that allow the generation of appropriate comparator networks. In this way we contribute to the general theory of network-based interventions against infectious disease

The DINGO dataset: a comprehensive set of data for the SAMPL challenge

Part of the latest SAMPL challenge was to predict how a small fragment library of 500 commercially available compounds would bind to a protein target. In order to assess the modellers’ work, a reasonably comprehensive set of data was collected using a number of techniques. These included surface plasmon resonance, isothermal titration calorimetry, protein crystallization and protein crystallography. Using these techniques we could determine the kinetics of fragment binding, the energy of binding, how this affects the ability of the target to crystallize, and when the fragment did bind, the pose or orientation of binding. Both the final data set and all of the raw images have been made available to the community for scrutiny and further work. This overview sets out to give the parameters of the experiments done and what might be done differently for future studies

Wave patterns in one-dimensional nonlinear degenerate diffusion equations

Several different types of wave patterns occur in physiology, chemistry and biology. In many cases such phenomena are modelled by reactive-diffusive parabolic systems (see, for example, Fisher 1937; Kolmogorov et al. 1937; Winfree 1988; Murray 1989; Swinney & Krinsky 1992). In many biological and physical situations, dispersal is modelled by a density-dependent diffusion coefficient, for example, the bacterium Rhizobium diffuses through the roots of some leguminosae plants according to a nonlinear diffusive law (Lara-Ochoa & Bustos 1990); nonlinear diffusion has been observed in the dispersion of some insects (Okubo 1980) and small rodents (Meyers & Krebs 1974)

Quality of Life Changes Following Peripheral Blood Stem Cell Transplantation and Participation in a Mixed-Type, Moderate-intensity, Exercise Program

Summary:The purpose of this investigation was to evaluate the impact of undertaking peripheral blood stem cell transplantation (PBST) on quality of life (QoL), and to determine the effect of participating in a mixed-type, moderate-intensity exercise program on QoL. It was also an objective to determine the relationship between peak aerobic capacity and QoL in PBST patients. QoL was assessed via the CARES questionnaire and peak aerobic capacity by a maximal graded treadmill test, pretransplant (PI), post transplant (PII) and following a 12-week intervention period (PIII). At PII, 12 patients were divided equally into a control or exercise intervention group. Undergoing a PBST was associated with a statistically but not clinically significant decline in QoL (P<0.05). Following the intervention, exercising patients demonstrated an improved QoL when compared with pretransplant ratings (P<0.01) and nonexercising transplant patients (P<0.05). Moreover, peak aerobic capacity and QoL were correlated (P<0.05). The findings demonstrated that exercise participation following oncology treatment is associated with a reduction in the number and severity of endorsed problems, which in turn leads to improvements in global, physical and psychosocial QoL. Furthermore, a relationship between fitness and QoL exists, with those experiencing higher levels of fitness also demonstrating higher QoL.Bone Marrow Transplantation (2004) 33, 553-558. doi:10.1038/sj.bmt.1704378 Published online 12 January 200

Transport phenomena in electrolyte solutions: Non-equilibrium thermodynamics and statistical mechanics

The theory of transport phenomena in multicomponent electrolyte solutions is presented here through the integration of continuum mechanics, electromagnetism, and non-equilibrium thermodynamics. The governing equations of irreversible thermodynamics, including balance laws, Maxwell's equations, internal entropy production, and linear laws relating the thermodynamic forces and fluxes, are derived. Green-Kubo relations for the transport coefficients connecting electrochemical potential gradients and diffusive fluxes are obtained in terms of the flux-flux time correlations. The relationship between the derived transport coefficients and those of the Stefan-Maxwell and infinitely dilute frameworks are presented, and the connection between the transport matrix and experimentally measurable quantities is described. To exemplify application of the derived Green-Kubo relations in molecular simulations, the matrix of transport coefficients for lithium and chloride ions in dimethyl sulfoxide is computed using classical molecular dynamics and compared with experimental measurements.Comment: fixed typos, added references, addressed comment