Feasibility of direct mapping of cerebral fluorodeoxy-D-glucose metabolism in situ at subcellular resolution using soft X-ray fluorescence.

Glucose metabolism is difficult to image with cellular resolution in mammalian brain tissue, particularly with (18) fluorodeoxy-D-glucose (FDG) positron emission tomography (PET). To this end, we explored the potential of synchrotron-based low-energy X-ray fluorescence (LEXRF) to image the stable isotope of fluorine (F) in phosphorylated FDG (DG-6P) at 1 μm(2) spatial resolution in 3-μm-thick brain slices. The excitation-dependent fluorescence F signal at 676 eV varied linearly with FDG concentration between 0.5 and 10 mM, whereas the endogenous background F signal was undetectable in brain. To validate LEXRF mapping of fluorine, FDG was administered in vitro and in vivo, and the fluorine LEXRF signal from intracellular trapped FDG-6P over selected brain areas rich in radial glia was spectrally quantitated at 1 μm(2) resolution. The subsequent generation of spatial LEXRF maps of F reproduced the expected localization and gradients of glucose metabolism in retinal Müller glia. In addition, FDG uptake was localized to periventricular hypothalamic tanycytes, whose morphological features were imaged simultaneously by X-ray absorption. We conclude that the high specificity of photon emission from F and its spatial mapping at ≤1 μm resolution demonstrates the ability to identify glucose uptake at subcellular resolution and holds remarkable potential for imaging glucose metabolism in biological tissue. © 2012 Wiley Periodicals, Inc.

Cost Analysis of Long-Term Treatment of Patients with Symptomatic Gastroesophageal Reflux Disease (GERD) with Esomeprazole On-Demand Treatment or Esomeprazole Continuous Treatment: An Open, Randomized, Multicenter Study in Switzerland.

Objectives: To assess the difference in direct medical costs between on-demand (OD) treatment with esomeprazole (E) 20 mg and continuous (C) treatment with E 20 mg q.d. from a clinical practice view in patients with gastroesophageal reflux disease (GERD) symptoms. Methods: This open, randomized study (ONE: on-demand Nexium evaluation) compared two long-term management options with E 20 mg in endoscopically uninvestigated patients seeking primary care for GERD symptoms who demonstrated complete relief of symptoms after an initial treatment of 4 weeks with E 40 mg. Data on consumed quantities of all cost items were collected in the study, while data on prices during the time of study were collected separately. The analysis was done from a societal perspective. Results: Forty-nine percent (484 of 991) of patients randomized to the OD regimen and 46% (420 of 913) of the patients in the C group had at least one contact with the investigator that would have occurred nonprotocol-driven. The difference of the adjusted mean direct medical costs between the treatment groups was CHF 88.72 (95% confidence interval: CHF 41.34-153.95) in favor of the OD treatment strategy (Wilcoxon rank-sum test: P < 0.0001). Adjusted direct nonmedical costs and productivity loss were similar in both groups. Conclusions: The adjusted direct medical costs of a 6-month OD treatment with esomeprazole 20 mg in uninvestigated patients with symptoms of GERD were significantly lower compared with a continuous treatment with E 20 mg once a day. The OD therapy represents a cost-saving alternative to the continuous treatment strategy with E.

Glucocorticoids exert direct toxicity on microvasculature: analysis of cell death mechanisms.

Glucocorticoids (GCs) are routinely administered systemically or injected into the eye when treating numerous ocular diseases; however, their toxicity on the retinal microvasculature has not been previously investigated. In this article, the effects of hydrocortisone (Hydro), dexamethasone, dexamethasone-phosphate and triamcinolone acetonide (TA) were evaluated in vitro on human skin microcirculation cells and, bovine endothelial retinal cells, ex-vivo, on flat mounted rat retinas. The degree of GCs induced endothelial cell death varied according to the endothelial cell type and GCs chemical properties. GCs toxicity was higher in skin microvascular endothelial cells and for hydrophobic GC formulations. The mechanism of cell death differed between GCs, Hydro and TA activated the leukocyte elastase inhibitor/L-DNase II pathways but did not activate caspases. The mechanisms of cell death observed in cell cultures were similar to those observed in rat retinal explants. Taken together these results indicate that particular attention should be paid to the potential vascular side effects when administrating GCs clinically and in particular when developing sustained-release intraocular devices.

Study of the impact of tissue density heterogeneities on 3-dimensional abdominal dosimetry: comparison between dose kernel convolution and direct monte carlo methods.

Dose kernel convolution (DK) methods have been proposed to speed up absorbed dose calculations in molecular radionuclide therapy. Our aim was to evaluate the impact of tissue density heterogeneities (TDH) on dosimetry when using a DK method and to propose a simple density-correction method. METHODS: This study has been conducted on 3 clinical cases: case 1, non-Hodgkin lymphoma treated with (131)I-tositumomab; case 2, a neuroendocrine tumor treatment simulated with (177)Lu-peptides; and case 3, hepatocellular carcinoma treated with (90)Y-microspheres. Absorbed dose calculations were performed using a direct Monte Carlo approach accounting for TDH (3D-RD), and a DK approach (VoxelDose, or VD). For each individual voxel, the VD absorbed dose, D(VD), calculated assuming uniform density, was corrected for density, giving D(VDd). The average 3D-RD absorbed dose values, D(3DRD), were compared with D(VD) and D(VDd), using the relative difference Δ(VD/3DRD). At the voxel level, density-binned Δ(VD/3DRD) and Δ(VDd/3DRD) were plotted against ρ and fitted with a linear regression. RESULTS: The D(VD) calculations showed a good agreement with D(3DRD). Δ(VD/3DRD) was less than 3.5%, except for the tumor of case 1 (5.9%) and the renal cortex of case 2 (5.6%). At the voxel level, the Δ(VD/3DRD) range was 0%-14% for cases 1 and 2, and -3% to 7% for case 3. All 3 cases showed a linear relationship between voxel bin-averaged Δ(VD/3DRD) and density, ρ: case 1 (Δ = -0.56ρ + 0.62, R(2) = 0.93), case 2 (Δ = -0.91ρ + 0.96, R(2) = 0.99), and case 3 (Δ = -0.69ρ + 0.72, R(2) = 0.91). The density correction improved the agreement of the DK method with the Monte Carlo approach (Δ(VDd/3DRD) < 1.1%), but with a lesser extent for the tumor of case 1 (3.1%). At the voxel level, the Δ(VDd/3DRD) range decreased for the 3 clinical cases (case 1, -1% to 4%; case 2, -0.5% to 1.5%, and -1.5% to 2%). No more linear regression existed for cases 2 and 3, contrary to case 1 (Δ = 0.41ρ - 0.38, R(2) = 0.88) although the slope in case 1 was less pronounced. CONCLUSION: This study shows a small influence of TDH in the abdominal region for 3 representative clinical cases. A simple density-correction method was proposed and improved the comparison in the absorbed dose calculations when using our voxel S value implementation.

Does a mandatory telemedicine call prior to visiting a physician reduce costs or simply attract good risks?

This paper aims to estimate empirically the efficiency of a Swiss telemedicine service introduced in 2003. We used claims' data gathered by a major Swiss health insurer, over a period of 6 years and involving 160 000 insured adults. In Switzerland, health insurance is mandatory, but everyone has the option of choosing between a managed care plan and a fee-for-service plan. This paper focuses on a conventional fee-for-service plan including a mandatory access to a telemedicine service; the insured are obliged to phone this medical call centre before visiting a physician. This type of plan generates much lower average health expenditures than a conventional insurance plan. Reasons for this may include selection, incentive effects or efficiency. In our sample, about 90% of the difference in health expenditure can be explained by selection and incentive effects. The remaining 10% of savings due to the efficiency of the telemedicine service amount to about SFr 150 per year per insured, of which approximately 60% is saved by the insurer and 40% by the insured. Although the efficiency effect is greater than the cost of the plan, the big winners are the insured who not only save monetary and non-monetary costs but also benefit from reduced premiums. Copyright © 2010 John Wiley & Sons, Ltd.

On the evolution of harming and recognition in finite panmictic and infinite structured populations.

Natural selection may favor two very different types of social behaviors that have costs in vital rates (fecundity and/or survival) to the actor: helping behaviors, which increase the vital rates of recipients, and harming behaviors, which reduce the vital rates of recipients. Although social evolutionary theory has mainly dealt with helping behaviors, competition for limited resources creates ecological conditions in which an actor may benefit from expressing behaviors that reduce the vital rates of neighbors. This may occur if the reduction in vital rates decreases the intensity of competition experienced by the actor or that experienced by its offspring. Here, we explore the joint evolution of neutral recognition markers and marker-based costly conditional harming whereby actors express harming, conditional on actor and recipient bearing different conspicuous markers. We do so for two complementary demographic scenarios: finite panmictic and infinite structured populations. We find that marker-based conditional harming can evolve under a large range of recombination rates and group sizes under both finite panmictic and infinite structured populations. A direct comparison with results for the evolution of marker-based conditional helping reveals that, if everything else is equal, marker-based conditional harming is often more likely to evolve than marker-based conditional helping.

Integrating life cycle costs and environmental impacts of composite rail car-bodies for a Korean train

Background, aim, and scope A coupled Life Cycle Costing and life cycle assessment has been performed for car-bodies of the Korean Tilting Train eXpress (TTX) project using European and Korean databases, with the objective of assessing environmental and cost performance to aid materials and process selection. More specifically, the potential of polymer composite car-body structures for the Korean Tilting Train eXpress (TTX) has been investigated. Materials and methods This assessment includes the cost of both carriage manufacturing and use phases, coupled with the life cycle environmental impacts of all stages from raw material production, through carriage manufacture and use, to end-of-life scenarios. Metallic carriages were compared with two composite options: hybrid steel-composite and full-composite carriages. The total planned production for this regional Korean train was 440 cars, with an annual production volume of 80 cars. Results and discussion The coupled analyses were used to generate plots of cost versus energy consumption and environmental impacts. The results show that the raw material and manufacturing phase costs are approximately half of the total life cycle costs, whilst their environmental impact is relatively insignificant (3-8%). The use phase of the car-body has the largest environmental impact for all scenarios, with near negligible contributions from the other phases. Since steel rail carriages weigh more (27-51%), the use phase cost is correspondingly higher, resulting in both the greatest environmental impact and the highest life cycle cost. Compared to the steel scenario, the hybrid composite variant has a lower life cycle cost (16%) and a lower environmental impact (26%). Though the full composite rail carriage may have the highest manufacturing cost, it results in the lowest total life cycle costs and lowest environmental impacts. Conclusions and recommendations This coupled cost and life cycle assessment showed that the full composite variant was the optimum solution. This case study showed that coupling of technical cost models with life cycle assessment offers an efficient route to accurately evaluate economic and environmental performance in a consistent way.

Arthro-IRM directe en traction axiale: technique et intérêt [Technique and value of direct MR arthrography applying articular distraction]

Direct MR arthrography has a better diagnostic accuracy than MR imaging alone. However, contrast material is not always homogeneously distributed in the articular space. Lesions of cartilage surfaces or intra-articular soft tissues can thus be misdiagnosed. Concomitant application of axial traction during MR arthrography leads to articular distraction. This enables better distribution of contrast material in the joint and better delineation of intra-articular structures. Therefore, this technique improves detection of cartilage lesions. Moreover, the axial stress applied on articular structures may reveal lesions invisible on MR images without traction. Based on our clinical experience, we believe that this relatively unknown technique is promising and should be further developed.

Costs of female reproduction in a conifer tree: a whole-tree level assessment

1. Costs of reproduction lie at the core of basic ecological and evolutionary theories, and their existence is commonly invoked to explain adaptive processes. Despite their sheer importance, empirical evidence for the existence and quantification of costs of reproduction in tree species comes mostly from correlational studies, while more comprehensive approaches remain missing. Manipulative experiments are a preferred approach to study cost of reproduction, as they allow controlling for otherwise inherent confounding factors like size or genetic background. 2. Here, we conducted a manipulative experiment in a Pinus halepensis common garden, removing developing cones from a group of trees and comparing growth and reproduction after treatment with a control group. We also estimated phenotypic and genetic correlations between reproductive and vegetative traits. 3. Manipulated trees grew slightly more than control trees just after treatment, with just a transient, marginally non-significant difference. By contrast, larger differences were observed for the number of female cones initiated 1 year after treatment, with an increase of 70% more cones in the manipulated group. Phenotypic and genetic correlations showed that smaller trees invested a higher proportion of their resources in reproduction, compared with larger trees, which could be interpreted as an indirect evidence for costs of reproduction. 4. Synthesis. This research showed a high impact of current reproduction on reproductive potential, even when not significant on vegetative growth. This has strong implications for how we understand adaptive strategies in forest trees and should encourage further interest on their still poorly known reproductive life-history traits.

Anatomical exposure patterns of skin to sunlight: relative contributions of direct, diffuse and reflected ultraviolet radiation

Summary Background  The dose-response between ultraviolet (UV) exposure patterns and skin cancer occurrence is not fully understood. Sun-protection messages often focus on acute exposure, implicitly assuming that direct UV radiation is the key contributor to the overall UV exposure. However, little is known about the relative contribution of the direct, diffuse and reflected radiation components. Objective  To investigate solar UV exposure patterns at different body sites with respect to the relative contribution of the direct, diffuse and reflected radiation. Methods  A three-dimensional numerical model was used to assess exposure doses for various body parts and exposure scenarios of a standing individual (static and dynamic postures). The model was fed with erythemally weighted ground irradiance data for the year 2009 in Payerne, Switzerland. A year-round daily exposure (08:00-17:00 h) without protection was assumed. Results  For most anatomical sites, mean daily doses were high (typically 6·2-14·6 standard erythemal doses) and exceeded the recommended exposure values. Direct exposure was important during specific periods (e.g. midday during summer), but contributed moderately to the annual dose, ranging from 15% to 24% for vertical and horizontal body parts, respectively. Diffuse irradiation explained about 80% of the cumulative annual exposure dose. Acute diffuse exposures were also observed during cloudy summer days. Conclusions  The importance of diffuse UV radiation should not be underestimated when advocating preventive measures. Messages focused on avoiding acute direct exposures may be of limited efficiency to prevent skin cancers associated with chronic exposure.

Population genomics of eusocial insects: the costs of a vertebrate-like effective population size

The evolution of reproductive division of labour and social life in social insects has lead to the emergence of several life-history traits and adaptations typical of larger organisms: social insect colonies can reach masses of several kilograms, they start reproducing only when they are several years old, and can live for decades. These features and the monopolization of reproduction by only one or few individuals in a colony should affect molecular evolution by reducing the effective population size. We tested this prediction by analysing genome-wide patterns of coding sequence polymorphism and divergence in eusocial vs. noneusocial insects based on newly generated RNA-seq data. We report very low amounts of genetic polymorphism and an elevated ratio of nonsynonymous to synonymous changes - a marker of the effective population size - in four distinct species of eusocial insects, which were more similar to vertebrates than to solitary insects regarding molecular evolutionary processes. Moreover, the ratio of nonsynonymous to synonymous substitutions was positively correlated with the level of social complexity across ant species. These results are fully consistent with the hypothesis of a reduced effective population size and an increased genetic load in eusocial insects, indicating that the evolution of social life has important consequences at both the genomic and population levels.

Direct comparison of a radioiodinated intact chimeric anti-CEA MAb with its F(ab')2 fragment in nude mice bearing different human colon cancer xenografts.

Tumour localisation and tumour to normal tissue ratios of a chimeric anti-carcinoembryonic antigen (CEA) monoclonal antibody (MAb), in intact form and as an F(ab')2 fragment labelled with 125I and 131I, were compared in groups of nude mice bearing four different colon cancer xenografts, T380, Co112 or LoVo, of human origin, or a rat colon cancer transfected with human CEA cDNA, called '3G7'. For each tumour, three to four mice per time point were analysed 6, 12, 24, 48 and 96 h after MAb injection. In the different tumours, maximal localisation of intact MAb was obtained at 24 to 48 h, and of F(ab')2 fragment 12 to 24 h after injection. Among the different tumours, localisation was highest with colon cancer T380, with 64% of the injected dose per gram (% ID/g) for the intact MAb and 57% for its F(ab')2 fragment, while in the three other tumours, maximal localisation ranged from 14 to 22% ID g-1 for the intact MAb and was about 11% for the F(ab')2. Tumour to normal tissue ratios of intact MAb increased rapidly until 24 h after injection and remained stable or showed only a minor increase thereafter. In contrast, for the F(ab')2 fragment, the tumour to normal tissue ratios increased steadily up to 4 days after injection reaching markedly higher values than those obtained with intact MAb. For the four different xenografts, tumour to blood ratios of F(ab')2 were about 2, 3 and 5 to 16 times higher than those of intact antibodies at 12, 24 and 96 h after injection, respectively.

Direct mapping of 19F in 19FDG-6P in brain tissue at subcellular resolution using soft X-ray fluorescence

Low energy x-ray fluorescence (LEXRF) detection was optimized for imaging cerebral glucose metabolism by mapping the fluorine LEXRF signal of 19 F in 19 FDG, trapped as intracellular 19 F-deoxyglucose-6-phosphate ( 19 FDG-6P) at 1μm spatial resolution from 3μm thick brain slices. 19 FDG metabolism was evaluated in brain structures closely resembling the general cerebral cytoarchitecture following formalin fixation of brain slices and their inclusion in an epon matrix. 2-dimensional distribution maps of 19 FDG-6P were placed in a cytoarchitectural and morphological context by simultaneous LEXRF mapping of N and O, and scanning transmission x-ray (STXM) imaging. A disproportionately high uptake and metabolism of glucose was found in neuropil relative to intracellular domains of the cell body of hypothalamic neurons, showing directly that neurons, like glial cells, also metabolize glucose. As 19 F-deoxyglucose-6P is structurally identical to 18 F-deoxyglucose-6P, LEXRF of subcellular 19 F provides a link to in vivo 18 FDG PET, forming a novel basis for understanding the physiological mechanisms underlying the 18 FDG PET image, and the contribution of neurons and glia to the PET signal.

Civil society organisations participating in ISO TC 228 and ISO TC 229: the INTERNORM project and its future

This paper presents the first results of the INTERNORM pilot project funded by the University of Lausanne (2010 - 2014) to support the involvement of civil society organisations (CSO) in two ISO technical committees (TC), the ISO TC 228 on "tourism and related services" and the ISO TC 229 on "nanotechnologies". It analyses how a distinct participatory mechanism can influence the institutional environment of technical diplomacy in which standards are shaped. The project is an attempt to respond to the democratic deficit attested in the field of international standardisation, formally open to civil society participation, but still largely dominated by expert knowledge and market players. Many international standards have direct implications on society as a whole, but CSOs (consumers and environmental associations, trade unions) are largely under-represented in negotiation arenas. The paper draws upon international relations literature on new institutional forms in global governance and studies of participation in science and technology to address three questions: to which extent do CSOs identify participation in standardisation as worth of their mobilisation? How is the pluralisation of knowledge and expertise supporting CSO position during the deliberation? To which extent can CSO access and influence standardisation beyond their consultative role? It argues that there are significant limitations to the rise of civil society participation in such global governance mechanisms. Despite high entry costs into technical diplomacy, participation is not so much a matter of upstream engagement, or of procedure and resources only, than of opportunistic CSOs mobilization, of distinct thematic incentives and concrete outcomes to be expected in standardisation arenas or in the broader use of international standards.