Quantification of dose nonuniformities by voxel-based dosimetry in patients receiving 90Y-ibritumomab-tiuxetan.

OBJECTIVE: To assess the impact of nonuniform dose distribution within lesions and tumor-involved organs of patients receiving Zevalin, and to discuss possible implications of equivalent uniform biological effective doses (EU-BED) on treatment efficacy and toxicity. MATLAB? -based software for voxel-based dosimetry was adopted for this purpose. METHODS: Eleven lesions from seven patients with either indolent or aggressive non-Hodgkin lymphoma were analyzed, along with four organs with disease. Absorbed doses were estimated by a direct integration of single-voxel kinetic data from serial tomographic images. After proper corrections, differential BED distributions and surviving cell fractions were estimated, allowing for the calculation of EU-BED. To quantify dose uniformity in each target area, a heterogeneity index was defined. RESULTS: Average doses were below those prescribed by conventional radiotherapy to eradicate lymphoma lesions. Dose heterogeneity and effect on tumor control varied among lesions, with no apparent relation to tumor mass. Although radiation doses to involved organs were safe, unexpected liver toxicity occurred in one patient who presented with a pattern of diffuse infiltration. CONCLUSION: Voxel-based dosimetry and radiobiologic modeling can be successfully applied to lesions and tumor-involved organs, representing a methodological advance over estimation of mean absorbed doses. However, effects on tumor control and organ toxicity still cannot be easily predicted.

The impact of vascular burden on late-life depression.

Small vessel pathology and microvascular lesions are no longer considered as minor players in the fields of cognitive impairment and mood regulation. Although frequently found in cognitively intact elders, both neuroimaging and neuropathological data revealed the negative impact on cognitive performances of their presence within neocortical association areas, thalamus and basal ganglia. Unlike cognition, the relationship between these lesions and mood dysregulation is still a matter of intense debate. Early studies focusing on the role of macroinfarct location in the occurrence of post-stroke depression (PSD) led to conflicting data. Later on, the concept of vascular depression proposed a deleterious effect of subcortical lacunes and deep white matter demyelination on mood regulation in elders who experienced the first depressive episode. More recently, the chronic accumulation of lacunes in thalamus, basal ganglia and deep white matter has been considered as a strong correlate of PSD. We provide here a critical overview of neuroimaging and neuropathological sets of evidence regarding the affective repercussions of vascular burden in the aging brain and discuss their conceptual and methodological limitations. Based on these observations, we propose that the accumulation of small vascular and microvascular lesions constitutes a common neuropathological platform for both cognitive decline and depressive episodes in old age.

Activity of ancestral restriction factors against ancient retroviruses

Analysis of TRIM5α and APOBEC3G genes suggests that these two restriction factors underwent strong positive selection throughout primate evolution. This pressure was possibly imposed by ancient exogenous retroviruses, of which endogenous retroviruses are remnants. Our study aims to assess in vitro the activity of these factors against ancient retroviruses by reconstructing their ancestral gag sequences, as well as the ancestral TRIM5α and APOBEC3G for primates. Based on evolutionary genomics approach, we reconstructed ancestors of the two largest families of human endogenous retroviruses (HERV), namely HERV-K and HERV-H, as well as primate ancestral TRIM5α and APOBEC3G variants. The oldest TRIM5α sequence was the catarhinne TRIM5α, common ancestor of Old World monkeys and hominoids, dated from 25 million years ago (mya). From the oldest, to the youngest, ancestral TRIM5α variants showed less restriction of HIV-1 in vitro [1]. Likewise three ancestral APOBEC3Gs sequences common to hominoids (18 mya), Old World monkeys, and catarhinnes (25 mya) were reconstructed. All ancestral APOBEC3G variants inhibited efficiently HIV-1Δvif in vitro, compared to modern APOBEC3Gs. The ability of Vif proteins (HIV-1, HIV-2, SIVmac and SIVagm) to counteract their activity tallied with the residue 128 on ancestral APOBEC3Gs. Moreover we are attempting to reconstruct older ancestral sequences of both restriction factors by using prosimian orthologue sequences. An infectious onemillion- years-old HERV-KCON previously reconstituted was shown to be resistant to modern TRIM5α and APOBEC3G [2]. Our ancestral TRIM5α and APOBEC3G variants were inactive against HERV-KCON. Besides we reconstructed chimeric HERV-K bearing ancestral capsids (up to 7 mya) that resulted in infectious viruses resistant to modern and ancestral TRIM5α. Likewise HERV-K viruses bearing ancestral nucleocapsids will be tested for ancestral and modern APOBEC3G restriction. In silico reconstruction and structural modeling of ancestral HERV-H capsids resulted in structures homologous to that of the gammaretrovirus MLV. Thus we are attempting to construct chimeric MLV virus bearing HERV-H ancestral capsids. These chimeric ancestral HERVs will be tested for infectivity and restriction by ancestral TRIM5α. Similarly chimeric MLV viruses bearing ancestral HERV-H nucleocapsids will be reconstructed and tested for APOBEC3G restriction.

Instruments measuring spirituality in clinical research: a systematic review.

INTRODUCTION: Numerous instruments have been developed to assess spirituality and measure its association with health outcomes. This study's aims were to identify instruments used in clinical research that measure spirituality; to propose a classification of these instruments; and to identify those instruments that could provide information on the need for spiritual intervention. METHODS: A systematic literature search in MEDLINE, CINHAL, PsycINFO, ATLA, and EMBASE databases, using the terms "spirituality" and "adult$," and limited to journal articles was performed to identify clinical studies that used a spiritual assessment instrument. For each instrument identified, measured constructs, intended goals, and data on psychometric properties were retrieved. A conceptual and a functional classification of instruments were developed. RESULTS: Thirty-five instruments were retrieved and classified into measures of general spirituality (N = 22), spiritual well-being (N = 5), spiritual coping (N = 4), and spiritual needs (N = 4) according to the conceptual classification. Instruments most frequently used in clinical research were the FACIT-Sp and the Spiritual Well-Being Scale. Data on psychometric properties were mostly limited to content validity and inter-item reliability. According to the functional classification, 16 instruments were identified that included at least one item measuring a current spiritual state, but only three of those appeared suitable to address the need for spiritual intervention. CONCLUSIONS: Instruments identified in this systematic review assess multiple dimensions of spirituality, and the proposed classifications should help clinical researchers interested in investigating the complex relationship between spirituality and health. Findings underscore the scarcity of instruments specifically designed to measure a patient's current spiritual state. Moreover, the relatively limited data available on psychometric properties of these instruments highlight the need for additional research to determine whether they are suitable in identifying the need for spiritual interventions.

Preclinical evaluation of implantable cardioverter-defibrillator developed for magnetic resonance imaging use.

BACKGROUND: Many patients with an implantable cardioverter-defibrillator (ICD) have indications for magnetic resonance imaging (MRI). However, MRI is generally contraindicated in ICD patients because of potential risks from hazardous interactions between the MRI and ICD system. OBJECTIVE: The purpose of this study was to use preclinical computer modeling, animal studies, and bench and scanner testing to demonstrate the safety of an ICD system developed for 1.5-T whole-body MRI. METHODS: MRI hazards were assessed and mitigated using multiple approaches: design decisions to increase safety and reliability, modeling and simulation to quantify clinical MRI exposure levels, animal studies to quantify the physiologic effects of MRI exposure, and bench testing to evaluate safety margin. RESULTS: Modeling estimated the incidence of a chronic change in pacing capture threshold >0.5V and 1.0V to be less than 1 in 160,000 and less than 1 in 1,000,000 cases, respectively. Modeling also estimated the incidence of unintended cardiac stimulation to occur in less than 1 in 1,000,000 cases. Animal studies demonstrated no delay in ventricular fibrillation detection and no reduction in ventricular fibrillation amplitude at clinical MRI exposure levels, even with multiple exposures. Bench and scanner testing demonstrated performance and safety against all other MRI-induced hazards. CONCLUSION: A preclinical strategy that includes comprehensive computer modeling, animal studies, and bench and scanner testing predicts that an ICD system developed for the magnetic resonance environment is safe and poses very low risks when exposed to 1.5-T normal operating mode whole-body MRI.

Anti-impérialisme et nouvelle gauche radicale dans la Suisse des années 68

Cette thèse entend apporter un éclairage sur l'histoire politique et sociale de la Suisse des années 68, en étudiant l'articulation entre les mouvements anti-impérialistes et la nouvelle gauche radicale, alors foisonnante. Il s'agit d'analyser cette période de contestation au prisme de l'anti-impérialisme révolutionnaire, lequel, dans le contexte de l'opposition à la guerre du Vietnam, a fortement imprégné le mouvement protestataire, en assignant notamment au tiers-monde le rôle de sujet de l'émancipation mondiale. Combinant une triple approche - chronologique, thématique et biographique - ce travail est structuré en quatre parties. La première partie esquisse un panorama des mouvements anti-impérialistes des années 1960 et 1970 en Suisse, avec une focalisation sur les «années anti-imp», entre 1968 et 1975. La deuxième interroge le rapport entre anti¬impérialisme et nouvelle gauche radicale, en proposant une typologie des principaux courants. La troisième partie s'attache à examiner le système de représentations du monde et de la Suisse véhiculé par le discours de l'extrême gauche. Prenant pour objet le militantisme, la dernière partie esquisse un portrait de groupe de la « génération anti-imp », fondé sur une enquête prosopographique et sur un corpus d'entretiens réalisés avec des militants de l'époque. L'étude révèle que l'anti-impérialisme a fourni à la contestation soixante-huitarde un cadre conceptuel et analytique, un facteur de structuration, ainsi qu'un vecteur de mobilisation. Il a en particulier permis à la gauche radicale suisse d'inscrire sa lutte anticapitaliste locale dans un horizon global d'émancipation. L'analyse de l'anti-impérialisme révolutionnaire, qui a connu son apogée dans les années 68 avant de connaître un déclin rapide et presque total, invite à appréhender cette « décennie mouvementée » comme la fin d'un long cycle politique. -- This thesis aims to shed light on the social and political history of Switzerland in the 1960s and 1970s by studying the relationship between anti-imperialist movements and the emerging new radical left. It analyses this time of rebellion through the prism of revolutionary anti-imperialism. In the context of opposition to the Vietnam War, anti-imperialism strongly influenced protest movements, notably by assigning to the Third World the role of main actor in the fight for global emancipation. Combining a threefold approach - chronological, thematic and biographical - this work is structured in four parts. The first part provides a panorama of the anti-imperialist movements of the long 1960s in Switzerland with a focus on the « anti-imp years » between 1968 and 1975. The second part questions the relationship between anti-imperialism and the new radical left and proposes a typology of its main currents. The third part examines how the radical left's discourse represented the world, and Switzerland in particular. The last part addresses the question of activism and outlines a group portrait of the « anti-imp generation » based on a prosopographical study and on a body of interviews with former activists. This study reveals that anti-imperialism, besides serving as an agent of mobilization, provided a conceptual and ideological framework, as well as a structuring factor, to the protest movements. In particular, it enabled the Swiss radical left to fit its local anti-capitalist struggle into a global horizon of emancipation. This analysis of revolutionary anti- imperialism, which had its heyday in the 1960s and 1970s before experiencing a rapid and almost total decline, thus invites us to see this « turbulent decade » as the end of a long political cycle.

Topographic ERP analyses: a step-by-step tutorial review.

In this tutorial review, we detail both the rationale for as well as the implementation of a set of analyses of surface-recorded event-related potentials (ERPs) that uses the reference-free spatial (i.e. topographic) information available from high-density electrode montages to render statistical information concerning modulations in response strength, latency, and topography both between and within experimental conditions. In these and other ways these topographic analysis methods allow the experimenter to glean additional information and neurophysiologic interpretability beyond what is available from canonical waveform analyses. In this tutorial we present the example of somatosensory evoked potentials (SEPs) in response to stimulation of each hand to illustrate these points. For each step of these analyses, we provide the reader with both a conceptual and mathematical description of how the analysis is carried out, what it yields, and how to interpret its statistical outcome. We show that these topographic analysis methods are intuitive and easy-to-use approaches that can remove much of the guesswork often confronting ERP researchers and also assist in identifying the information contained within high-density ERP datasets.

Risky single-occasion drinking: bingeing is not bingeing.

AIMS: To review the concept of binge drinking as a measure of risky single occasion drinking (RSOD), to illustrate its differential impact on selected health outcomes and to identify research gaps. METHODS: Narrative literature review with focus on conceptual and methodological differences, trajectories of RSOD and effects of RSOD on fetal outcomes, coronary heart disease (CHD) and injuries. RESULTS: Effects ascribed commonly to RSOD may often be the effects of an undifferentiated mixture of risky single occasions and regular heavy volume drinking, constituted by frequent, successive RSOD. This leads to the problem that additional risks due to RSOD are mis-specified and remain unidentified or underestimated in some cases, such as for injuries or CHD, but are probably overstated for some chronic consequences or for effects of maternal drinking on newborns. CONCLUSION: A stronger focus should be placed upon methods that can differentiate the effects of RSOD from those due to frequent occasions of heavy drinking that result in heavy volume drinking.

Risky single-occasion drinking: bingeing is not bingeing

Aims To review the concept of binge drinking as a measure of risky single occasion drinking (RSOD), to illustrate its differential impact on selected health outcomes and to identify research gaps.Methods Narrative literature review with focus on conceptual and methodological differences, trajectories of RSOD and effects of RSOD on fetal outcomes, coronary heart disease (CHD) and injuries.Results Effects ascribed commonly to RSOD may often be the effects of an undifferentiated mixture of risky single occasions and regular heavy volume drinking, constituted by frequent, successive RSOD. This leads to the problem that additional risks due to RSOD are mis-specified and remain unidentified or underestimated in some cases, such as for injuries or CHD, but are probably overstated for some chronic consequences or for effects of maternal drinking on newborns.Conclusion A stronger focus should be placed upon methods that can differentiate the effects of RSOD from those due to frequent occasions of heavy drinking that result in heavy volume drinking.

Plasticity of lifespan: a reaction norm perspective.

It is a well-appreciated fact that in many organisms the process of ageing reacts highly plastically, so that lifespan increases or decreases when the environment changes. The perhaps best-known example of such lifespan plasticity is dietary restriction (DR), a phenomenon whereby reduced food intake without malnutrition extends lifespan (typically at the expense of reduced fecundity) and which has been documented in numerous species, from invertebrates to mammals. For the evolutionary biologist, DR and other cases of lifespan plasticity are examples of a more general phenomenon called phenotypic plasticity, the ability of a single genotype to produce different phenotypes (e.g. lifespan) in response to changes in the environment (e.g. changes in diet). To analyse phenotypic plasticity, evolutionary biologists (and epidemiologists) often use a conceptual and statistical framework based on reaction norms (genotype-specific response curves) and genotype × environment interactions (G × E; differences in the plastic response among genotypes), concepts that biologists who are working on molecular aspects of ageing are usually not familiar with. Here I briefly discuss what has been learned about lifespan plasticity or, more generally, about plasticity of somatic maintenance and survival ability. In particular, I argue that adopting the conceptual framework of reaction norms and G × E interactions, as used by evolutionary biologists, is crucially important for our understanding of the mechanisms underlying DR and other forms of lifespan or survival plasticity.

The 2006 Eiger rockslide, European Alps

In July 2006, approximately 2 million m3 of massive limestone began to move on the east flank of the Eiger in central Switzerland. For more than two years after the initial failure, the rock mass moved at rates of up to 70 cm per day. A detailed analysis of the structures and velocities of the different moving blocks was conducted with the aid of terrestrial laser scanning. The moving rock mass included a rear block that subsided, pushing a frontal block forward. Movement directions were controlled by discontinuity sets that formed wedges bounded on one side by sub-vertical bedding planes. The instability was, until recently, buttressed by a glacier. Slope observations and results of continuum and discontinuum modeling indicate that the structure of the rock mass and topography were the main causes of the instability. Progressive weathering and mechanical fatigue of the rock mass appear to have led to the failure. A dynamic analytical model further indicates that the rockslide was primarily controlled by a reduction in the strength of discontinuities, the effects of ice deformation, and ? to a limited extent ? groundwater flow. This study shows that realistic and simple instability models can be constructed for rock-slope failures if high-resolution data are available.

Patterns of gravity induced aggregate migration during casting of fluid concretes

In this paper, aggregate migration patterns during fluid concrete castings are studied through experiments, dimensionless approach and numerical modeling. The experimental results obtained on two beams show that gravity induced migration is primarily affecting the coarsest aggregates resulting in a decrease of coarse aggregates volume fraction with the horizontal distance from the pouring point and in a puzzling vertical multi-layer structure. The origin of this multi layer structure is discussed and analyzed with the help of numerical simulations of free surface flow. Our results suggest that it finds its origin in the non Newtonian nature of fresh concrete and that increasing casting rate shall decrease the magnitude of gravity induced particle migration. (C) 2012 Elsevier Ltd. All rights reserved.

A study compared nine patient-specific indices for musculoskeletal disorders.

BACKGROUND AND OBJECTIVE: Patient-specific quality of life indices show great potential, but certain conceptual and methodological concerns have yet to be fully addressed. The present study reviewed nine patient-specific instruments used in musculoskeletal disorders: the Canadian Occupational Performance Measure (COPM), Juvenile Arthritis Quality of life Questionnaire (JAQQ), McMaster-Toronto Arthritis questionnaire (MACTAR), Measure Yourself Medical Outcome Profile (MYMOP), Patient-Specific Index (PASI) for total hip arthroplasty, Problem Elicitation Technique (PET), Patient Generated Index (PGI) of quality of life, Patient-Specific Functional Scale (PSFS), and Schedule for the Evaluation of Individual Quality of Life (SEIQoL). STUDY DESIGN AND SETTING: Each tool was evaluated for purpose, content validity, face validity, feasibility, psychometric properties, and responsiveness. RESULTS: This critical appraisal revealed important differences in terms of the concept underlying these indices, the domains covered, the item-generation techniques and the scoring (response scale, methods) in each scale. The nine indices would generate different responses and likely scores for the same patient, despite the fact that they all include patient-generated items. CONCLUSION: Although the value of these indices in treatment planning and monitoring at an individual level is strong, more studies are needed to improve our understanding of how to interpret the numeric scores of patient-specific indices at both an individual and a group level.

A new method to estimate the infilling of alluvial sediment of glacial valleys using a sloping local base level

A new method is used to estimate the volumes of sediments of glacial valleys. This method is based on the concept of sloping local base level and requires only a digital terrain model and the limits of the alluvial valleys as input data. The bedrock surface of the glacial valley is estimated by a progressive excavation of the digital elevation model (DEM) of the filled valley area. This is performed using an iterative routine that replaces the altitude of a point of the DEM by the mean value of its neighbors minus a fixed value. The result is a curved surface, quadratic in 2D. The bedrock surface of the Rhone Valley in Switzerland was estimated by this method using the free digital terrain model Shuttle Radar Topography Mission (SRTM) (~92 m resolution). The results obtained are in good agreement with the previous estimations based on seismic profiles and gravimetric modeling, with the exceptions of some particular locations. The results from the present method and those from the seismic interpretation are slightly different from the results of the gravimetric data. This discrepancy may result from the presence of large buried landslides in the bottom of the Rhone Valley.

The habenula encodes negative motivational value associated with primary punishment in humans.

Learning what to approach, and what to avoid, involves assigning value to environmental cues that predict positive and negative events. Studies in animals indicate that the lateral habenula encodes the previously learned negative motivational value of stimuli. However, involvement of the habenula in dynamic trial-by-trial aversive learning has not been assessed, and the functional role of this structure in humans remains poorly characterized, in part, due to its small size. Using high-resolution functional neuroimaging and computational modeling of reinforcement learning, we demonstrate positive habenula responses to the dynamically changing values of cues signaling painful electric shocks, which predict behavioral suppression of responses to those cues across individuals. By contrast, negative habenula responses to monetary reward cue values predict behavioral invigoration. Our findings show that the habenula plays a key role in an online aversive learning system and in generating associated motivated behavior in humans.