Hepatitis C virus nonstructural protein 4B: a journey into unexplored territory.

Hepatitis C virus (HCV) is a positive-strand RNA virus that replicates its genome in a membrane-associated replication complex. Nonstructural protein 4B (NS4B) induces the specific membrane alteration, designated as membranous web (MW), that harbours this complex. HCV NS4B is an integral membrane protein predicted to comprise four transmembrane segments in its central part. The N-terminal part comprises two amphipathic alpha-helices of which the second has the potential to traverse the membrane bilayer, likely upon oligomerisation. The C-terminal part comprises a predicted highly conserved alpha-helix, a membrane-associated amphipathic alpha-helix and two reported palmitoylation sites. NS4B interacts with other viral nonstructural proteins and has been reported to bind viral RNA. In addition, it was found to harbour an NTPase activity. Finally, NS4B has recently been found to have a role in viral assembly. Much work needs to be done with respect to further dissecting these multiple functions as well as providing a refined membrane topology and complete structure of NS4B. Progress in this direction should yield important insights into the functional architecture of the HCV replication complex and may reveal new opportunities for antiviral intervention against a leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide.

MR-based follow-up of the superior cerebellar artery after radiosurgery for trigeminal neuralgia.

Purpose: To study with a non invasive method any potential radiological change on the superior cerebellar artery (SCA) in patients treated radiosurgically for classic trigeminal neuralgia (CTN).Materials and methods: A retrospective measure of maximal dose received by SCA was performed analyzing the treatment planning in 55 consecutive patients treated by Gamma Knife radiosurgery for an CTN, then, a prospective study was designed using high resolution MR, with T2 SPIR, T1 without and with gadolinium enhancement, Proton density, 3D TONE and MIP reconstructions. Inclusion criteria were: patients followed at our institution, follow-up of one year or more, dose received by the SCA of 15 Gy or more and voluntary patient participation in the study. Patients with repeated Gamma Knife radiosurgery for failure or recurrence were excluded. The end points were: SCA occlusion, stenosis or infarction in the territory supplied by SCA.Results: Sixteen patients were studied, with a mean follow-up of 25.2 months (12-42 months). The mean maximal dose received by the SCA was 57.5 Gy. (15-87 Gy). Among these 16 patients studied, neither obstruction of the SCA nor infarction was demonstrated. In one patient a suspicion of asymptomatic SCA stenosis was visualized distant to the irradiation field.Conclusions: SCA can receive a high dose of irradiation during radiosurgical treatment for CTN. This study does not confirm any vascular damage to the SCA after radiosurgery for CTN. (C) 2011 Elsevier B.V. All rights reserved.

Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy.

PURPOSE: Studies of diffuse large B-cell lymphoma (DLBCL) are typically evaluated by using a time-to-event approach with relapse, re-treatment, and death commonly used as the events. We evaluated the timing and type of events in newly diagnosed DLBCL and compared patient outcome with reference population data. PATIENTS AND METHODS: Patients with newly diagnosed DLBCL treated with immunochemotherapy were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER) and the North Central Cancer Treatment Group NCCTG-N0489 clinical trial from 2002 to 2009. Patient outcomes were evaluated at diagnosis and in the subsets of patients achieving event-free status at 12 months (EFS12) and 24 months (EFS24) from diagnosis. Overall survival was compared with age- and sex-matched population data. Results were replicated in an external validation cohort from the Groupe d'Etude des Lymphomes de l'Adulte (GELA) Lymphome Non Hodgkinien 2003 (LNH2003) program and a registry based in Lyon, France. RESULTS: In all, 767 patients with newly diagnosed DLBCL who had a median age of 63 years were enrolled onto the MER and NCCTG studies. At a median follow-up of 60 months (range, 8 to 116 months), 299 patients had an event and 210 patients had died. Patients achieving EFS24 had an overall survival equivalent to that of the age- and sex-matched general population (standardized mortality ratio [SMR], 1.18; P = .25). This result was confirmed in 820 patients from the GELA study and registry in Lyon (SMR, 1.09; P = .71). Simulation studies showed that EFS24 has comparable power to continuous EFS when evaluating clinical trials in DLBCL. CONCLUSION: Patients with DLBCL who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. EFS24 will be useful in patient counseling and should be considered as an end point for future studies of newly diagnosed DLBCL.

Enjeux éthiques des nouvelles technologies de la reproduction : une conception de la justice à l'interface de l'éthique du "care" et de l'approche des "capabilités"

L'émergence des nouvelles technologies de la reproduction (NTR) est allée de pair avec un certain nombre de discours. Un discours promettant d'une part une extension de la palette de choix reproductifs des individus, une extension de leur liberté et de leur autonomie reproductives, dont la forme la plus extrême peut se traduire par la formule : un enfant quand je veux et comme je veux. D'autre part, un discours annonçant une série de « catastrophes » à venir, telles que l'effondrement de l'institution de la famille et la modification de l'espèce humaine. En d'autres termes, une tension entre promesses et catastrophes qui place les sociétés contemporaines face à de nombreux défis sociaux, politiques et éthiques, notamment quant à la question de la régulation de la PMA (procréation médicalement assistée) : qui peut y avoir accès ? Quelles techniques doit-on autoriser ? Ou au contraire limiter ? Tant de questions auxquelles aucune réponse simple et évidente n'existe. La diversité des réponses législatives quant à ces questions illustre cette complexité. L'éthique peut, ici, jouer un rôle fondamental. Sans toutefois prétendre donner des réponses toutes faites et facilement applicables, elle offre un espace de réflexion, le privilège de prendre une certaine distance face à des enjeux contemporains. C'est dans cette perspective que nous avons ancré ce travail de recherche en questionnant les enjeux éthiques de la PMA à partir d'une perspective de justice. Toutefois, au sein des études en bioéthique, majoritairement issues de la tradition libérale, la tension énoncée précédemment mène la bioéthique à justifier un certain nombre d'inégalités plutôt que de veiller à les dépasser. Ainsi, une évaluation de la pratique de la PMA à partir d'une perspective de la justice, exige, au préalable, une réévaluation du concept même de justice. Ce faisant, par une articulation entre l'éthique du care de Joan Tronto et l'approche des capabilités de Martha Nussbaum qui placent la vulnérabilité au coeur de la personne, nous avons proposé une conception de la justice fondée sur une anthropologie de la vulnérabilité. Cette conception nous permet d'identifier, dans le cadre de la pratique de la PMA en Suisse et en partant de la loi sur la procréation assistée (LPMA), les constructions normatives qui mènent à la non-reconnaissance et, ce faisant, à la mise à l'écart, de certaines formes de vulnérabilité : une vulnérabilité générique et une vulnérabilité socio-économique. Traitant la question de la vulnérabilité générique principalement, nos analyses ont une incidence sur les conceptions de la famille, du bien de l'enfant, de la femme et de la nature, telles qu'elles sont actuellement véhiculées par une conception naturalisée de la PMA. Répondre aux vulnérabilités identifiées, en veillant à leur donner une place, signifie alors déplacer ces conceptions naturalisées, afin que les vulnérabilités soient intégrées aux pratiques sociales et que les exigences de justice soient ainsi remplies. - The emergence of assisted reproductive technologies (ART) came along with several discourses. On the one hand a discourse promising an extension of the individuals' reproductive choices, their procreative liberty and autonomy. On the other hand a discourse announced a series of disasters to come such as the collapse of the family institution and the modification of human kind. In other words, a growing tension appears between promises and disasters and contemporary societies are facing inevitable social, political and ethical challenges, in particular with regard to the issue of ART regulation: who has access? What procedures should be authorized? Which ones should be limited? These complex questions have no simple or obvious answers. The variety of legislative responses to these questions highlights complexity. Ethics can play a fundamental role, and without claiming to give simple answers, also offer a space for reflection as well as the privilege to distance itself with regard to contemporary issues. It is in this perspective that this study questions the ethical considerations of ART in a perspective of justice. However, in previous studies in bioethics mainly following a liberal tradition, previously mentioned tension has lead bioethics to justify some inequalities instead of trying to overcome them. As a consequence, evaluating practices of ART from a perspective of justice requires to first reevaluate the concept of justice itself. In doing so we offer a conception of justice founded on the anthropology of vulnerability. This conception draws on an articulation of the ethic of care of Joan Tronto and the capability approach of Martha Nussbaum, which places vulnerability at the center of the person. This conception allows us to identify, within the framework of ARTS in Switzerland and starting with the laws of medically assisted procreation (LPMA), some normative constructions. These constructions lead to the non-recognition and the disregard of some forms of vulnerability: a generic vulnerability as well as socio-economic counterpart. Focusing mainly on the issue of generic vulnerability, our analysis has implications for the conceptions of family, the best interests of the child, woman, and nature in the way they are defined in a naturalized conception of ART. Responding to such failures by taking into account these vulnerabilities thus means to move these conceptions in order for vulnerabilities to be integrated in social practices and requirements for justice to be fulfilled.

The Early Toarcian anoxia, a synchronous event in the Western Tethys? An approach by quantitative biochronology (Unitary Associations), applied on calcareous nannofossils

During the Early Toarcian, major paleoenvironnemental and paleoceanographical changes occurred, leading to an oceanic anoxic event (OAE) and to a perturbation of the carbon isotope cycle. Although the standard biochronology of the Lower Jurassic is essentially based upon ammonites, in recent years biostratigraphy based on calcareous nannofossils and dinoflagellate cysts is increasingly used to date Jurassic rocks. However, the precise dating and correlation of the Early Toarcian OAE, and of the associated delta C-13 anomaly in different settings of the western Tethys, are still partly problematic, and it is still unclear whether these events are synchronous or not. In order to allow more accurate correlations of the organic rich levels recorded in the Lower Toarcian OAE, this account proposes a new biozonation based on a quantitative biochronology approach, the Unitary Associations (UA), applied to calcareous nannofossils. This study represents the first attempt to apply the UA method to Jurassic nannofossils. The study incorporates eighteen sections distributed across western Tethys and ranging from the Pliensbachian to Aalenian, comprising 1220 samples and 72 calcareous nannofossil taxa. The BioGraph [Savary, J., Guex, J., 1999. Discrete biochronological scales and unitary associations: description of the Biograph Computer program. Memoires de Geologie de Lausanne 34, 282 pp] and UA-Graph (Copyright Hammer O., Guex and Savary, 2002) softwares provide a discrete biochronological framework based upon multi-taxa concurrent range zones in the different sections. The optimized dataset generates nine UAs using the co-occurrences of 56 taxa. These UAs are grouped into six Unitary Association Zones (UA-Z), which constitute a robust biostratigraphic synthesis of all the observed or deduced biostratigraphic relationships between the analysed taxa. The UA zonation proposed here is compared to ``classic'' calcareous nannofossil biozonations, which are commonly used for the southern and the northern sides of Tethys. The biostratigraphic resolution of the UA-Zones varies from one nannofossil subzone or part of it to several subzones, and can be related to the pattern of calcareous nannoplankton originations and extinctions during the studied time interval. The Late Pliensbachian - Early Toarcian interval (corresponding to the UA-Z II) represents a major step in the Jurassic nannoplankton radiation. The recognized UA-Zones are also compared to the carbon isotopic negative excursion and TOC maximum in five sections of central Italy, Germany and England, with the aim of providing a more reliable correlation tool for the Early Toarcian OAE, and of the associated isotopic anomaly, between the southern and northern part of western Tethys. The results of this work show that the TOC maximum and delta C-13 negative excursion correspond to the upper part of the UA-Z II (i.e., UA 3) in the sections analysed. This suggests that the Early Toarcian OAE was a synchronous event within the western Tethys. (c) 2006 Elsevier B.V. All rights reserved.

Real-life versus package insert: a post-marketing study on adverse-event rates of the virosomal hepatitis A vaccine Epaxal® in healthy travellers.

There are various methods to collect adverse events (AEs) in clinical trials. The methods how AEs are collected in vaccine trials is of special interest: solicited reporting can lead to over-reporting events that have little or no biological relationship to the vaccine. We assessed the rate of AEs listed in the package insert for the virosomal hepatitis A vaccine Epaxal(®), comparing data collected by solicited or unsolicited self-reporting. In an open, multi-centre post-marketing study, 2675 healthy travellers received single doses of vaccine administered intramuscularly. AEs were recorded based on solicited and unsolicited questioning during a four-day period after vaccination. A total of 2541 questionnaires could be evaluated (95.0% return rate). Solicited self-reporting resulted in significantly higher (p<0.0001) rates of subjects with AEs than unsolicited reporting, both at baseline (18.9% solicited versus 2.1% unsolicited systemic AEs) and following immunization (29.6% versus 19.3% local AEs; 33.8% versus 18.2% systemic AEs). This could indicate that actual reporting rates of AEs with Epaxal(®) may be substantially lower than described in the package insert. The distribution of AEs differed significantly between the applied methods of collecting AEs. The most common AEs listed in the package insert were reported almost exclusively with solicited questioning. The reporting of local AEs was more likely than that of systemic AEs to be influenced by subjects' sex, age and study centre. Women reported higher rates of AEs than men. The results highlight the need for detailing the methods how vaccine tolerability was reported and assessed.

Comparison of early cortical networks in efficient and inefficient visual search: an event-related potential study.

Functional magnetic resonance imaging studies have indicated that efficient feature search (FS) and inefficient conjunction search (CS) activate partially distinct frontoparietal cortical networks. However, it remains a matter of debate whether the differences in these networks reflect differences in the early processing during FS and CS. In addition, the relationship between the differences in the networks and spatial shifts of attention also remains unknown. We examined these issues by applying a spatio-temporal analysis method to high-resolution visual event-related potentials (ERPs) and investigated how spatio-temporal activation patterns differ for FS and CS tasks. Within the first 450 msec after stimulus onset, scalp potential distributions (ERP maps) revealed 7 different electric field configurations for each search task. Configuration changes occurred simultaneously in the two tasks, suggesting that contributing processes were not significantly delayed in one task compared to the other. Despite this high spatial and temporal correlation, two ERP maps (120-190 and 250-300 msec) differed between the FS and CS. Lateralized distributions were observed only in the ERP map at 250-300 msec for the FS. This distribution corresponds to that previously described as the N2pc component (a negativity in the time range of the N2 complex over posterior electrodes of the hemisphere contralateral to the target hemifield), which has been associated with the focusing of attention onto potential target items in the search display. Thus, our results indicate that the cortical networks involved in feature and conjunction searching partially differ as early as 120 msec after stimulus onset and that the differences between the networks employed during the early stages of FS and CS are not necessarily caused by spatial attention shifts.

Structural and metamorphic evolution of the northern Himachal Himalaya, NW India - (Spiti-eastern Lahul-Parvati valley traverse)

The Himalayan orogen is the result of the collision between the Indian and Asian continents that began 55-50 Ma ago, causing intracontinental thrusting and nappe formation. Detailed mapping as well as structural and microfabric analyses on a traverse from the Tethyan Himalaya southwestward through the High Himalayan Crystalline and the Main Central Thrust zone (MCT zone) to the Lesser Himalayan Sequence in the Spiti-eastern Lahul-Parvati valley area reveal eight main phases of deformation, a series of late stage phases and five stages of metamorphic crystallization. This sequence of events is integrated into a reconstruction of the tectonometamorphic evolution of the Himalayan orogen in northern Himachal Pradesh. The oldest phase D-1 is preserved as relies in the High Himalayan Crystalline. Its deformational conditions are poorly known, but the metamorphic evolution is well documented by a prograde metamorphism reaching peak conditions within the upper amphibolite facies. This indicates that D-1 was an important tectonometamorphic event including considerable crustal thickening. The structural, metamorphic and sedimentary record suggest that D-1 most probably represents an early stage of continental collision. The first event clearly attributed to the collision between India and Asia is documented by two converging nappe systems, the NE-verging Shikar Beh Nappe and the SW-verging north Himalayan nappes. The D-2 Shikar Beh Nappe is characterized by isoclinal folding and top-to-the NE shearing, representing the main deformation in the High Himalayan Crystalline. D-2 also caused the main metamorphism in the High Himalayan Crystalline that was of a Barrovian-type, reaching upper amphibolite facies peak conditions. The Shikar Beh Nappe is interpreted to have formed within the Indian crust SW of the subduction zone. Simultaneously with NE-directed nappe formation, incipient subduction of India below Asia caused stacking of the SW-verging north Himalayan Nappes, that were thrust from the northern edge of the subducted continent toward the front of the Shikar Beh Nappe. As a result, the SW-verging folds of the D-3 Main Fold Zone formed in the Tethyan Himalaya below the front of the north Himalayan nappes. D-3 represents the main deformation in the Tethyan Himalaya, associated with a greenschist facies metamorphism. Folding within the Main Fold Zone subsequently propagated toward SW into the High Himalayan Crystalline, where it overprinted the preexisting D-2 structures. After subduction at the base of the north Himalayan nappes, the subduction zone stepped to the base of the High Himalayan Crystalline, where D-3 folds were crosscut by SW-directed D-4 thrusting. During D-4, the Crystalline Nappe, comprising the Main Fold Zone and relies of the Shikar Beh Nappe was thrust toward SW over the Lesser Himalayan Sequence along the 4 to 5 kms thick Main Central Thrust zone. Thrusting was related to a retrograde greenschist facies overprint at the base of the Crystalline Nappe and to pro-grade greenschist facies conditions in the Lesser Himalayan Sequence. Simultaneously with thrusting at the base of the Crystalline Nappe, higher crustal levels were affected by NE-directed D-5 normal extensional shearing and by dextral strike-slip motion, indicating that the high-grade metamorphic Crystalline Nappe was extruded between the low-grade metamorphic Lesser Himalayan Sequence at the base and the north Himalayan nappes at the top. The upper boundary of the Crystalline Nappe is not clearly delimited and passes gradually into the low-grade rocks at the front of the north Himalayan nappes. Extrusion of the Crystalline Nappe was followed by the phase D-6, characterized by large-scale, upright to steeply inclined, NE-verging folds and by another series of normal and extensional structures D-7+D-8 that may be related to ongoing extrusion of the Crystalline Nappe. The late stage evolution is represented by the phases D-A and D-B that indicate shortening parallel to the axis of the mountain chain and by D-C that is interpreted to account for the formation of large-scale domes with NNW-SSE-trending axes, an example of which is exposed in the Larji-Kullu-Rampur tectonic window.

Detection of millimetric deformation using a terrestrial laser scanner: experiment and application to a rockfall event

Abstract. Terrestrial laser scanning (TLS) is one of the most promising surveying techniques for rockslope characteriza- tion and monitoring. Landslide and rockfall movements can be detected by means of comparison of sequential scans. One of the most pressing challenges of natural hazards is com- bined temporal and spatial prediction of rockfall. An outdoor experiment was performed to ascertain whether the TLS in- strumental error is small enough to enable detection of pre- cursory displacements of millimetric magnitude. This con- sists of a known displacement of three objects relative to a stable surface. Results show that millimetric changes cannot be detected by the analysis of the unprocessed datasets. Dis- placement measurement are improved considerably by ap- plying Nearest Neighbour (NN) averaging, which reduces the error (1σ ) up to a factor of 6. This technique was ap- plied to displacements prior to the April 2007 rockfall event at Castellfollit de la Roca, Spain. The maximum precursory displacement measured was 45 mm, approximately 2.5 times the standard deviation of the model comparison, hampering the distinction between actual displacement and instrumen- tal error using conventional methodologies. Encouragingly, the precursory displacement was clearly detected by apply- ing the NN averaging method. These results show that mil- limetric displacements prior to failure can be detected using TLS.

Global alcohol exposure estimates by country, territory and region for 2005--a contribution to the Comparative Risk Assessment for the 2010 Global Burden of Disease Study.

AIMS: This study aimed to estimate the prevalence of life-time abstainers, former drinkers and current drinkers, adult per-capita consumption of alcohol and pattern of drinking scores, by country and Global Burden of Disease region for 2005, and to forecast these indicators for 2010. DESIGN: Statistical modelling based on survey data and routine statistics. SETTING AND PARTICIPANTS: A total of 241 countries and territories. MEASUREMENTS: Per-capita consumption data were obtained with the help of the World Health Organization's Global Information System on Alcohol and Health. Drinking status data were obtained from Gender, Alcohol and Culture: An International Study, the STEPwise approach to Surveillance study, the World Health Survey/Multi-Country Study and other surveys. Consumption and drinking status data were triangulated to estimate alcohol consumption across multiple categories. FINDINGS: In 2005 adult per-capita annual consumption of alcohol was 6.1 litres, with 1.7 litres stemming from unrecorded consumption; 17.1 litres of alcohol were consumed per drinker, 45.8% of all adults were life-time abstainers, 13.6% were former drinkers and 40.6% were current drinkers. Life-time abstention was most prevalent in North Africa/Middle East and South Asia. Eastern Europe and Southern sub-Saharan Africa had the most detrimental pattern of drinking scores, while drinkers in Europe (Eastern and Central) and sub-Saharan Africa (Southern and West) consumed the most alcohol. CONCLUSIONS: Just over 40% of the world's adult population consumes alcohol and the average consumption per drinker is 17.1 litres per year. However, the prevalence of abstention, level of alcohol consumption and patterns of drinking vary widely across regions of the world.

Event-related potential analyses via single-subject topographic classification.

Introduction: Responses to external stimuli are typically investigated by averaging peri-stimulus electroencephalography (EEG) epochs in order to derive event-related potentials (ERPs) across the electrode montage, under the assumption that signals that are related to the external stimulus are fixed in time across trials. We demonstrate the applicability of a single-trial model based on patterns of scalp topographies (De Lucia et al, 2007) that can be used for ERP analysis at the single-subject level. The model is able to classify new trials (or groups of trials) with minimal a priori hypotheses, using information derived from a training dataset. The features used for the classification (the topography of responses and their latency) can be neurophysiologically interpreted, because a difference in scalp topography indicates a different configuration of brain generators. An above chance classification accuracy on test datasets implicitly demonstrates the suitability of this model for EEG data. Methods: The data analyzed in this study were acquired from two separate visual evoked potential (VEP) experiments. The first entailed passive presentation of checkerboard stimuli to each of the four visual quadrants (hereafter, "Checkerboard Experiment") (Plomp et al, submitted). The second entailed active discrimination of novel versus repeated line drawings of common objects (hereafter, "Priming Experiment") (Murray et al, 2004). Four subjects per experiment were analyzed, using approx. 200 trials per experimental condition. These trials were randomly separated in training (90%) and testing (10%) datasets in 10 independent shuffles. In order to perform the ERP analysis we estimated the statistical distribution of voltage topographies by a Mixture of Gaussians (MofGs), which reduces our original dataset to a small number of representative voltage topographies. We then evaluated statistically the degree of presence of these template maps across trials and whether and when this was different across experimental conditions. Based on these differences, single-trials or sets of a few single-trials were classified as belonging to one or the other experimental condition. Classification performance was assessed using the Receiver Operating Characteristic (ROC) curve. Results: For the Checkerboard Experiment contrasts entailed left vs. right visual field presentations for upper and lower quadrants, separately. The average posterior probabilities, indicating the presence of the computed template maps in time and across trials revealed significant differences starting at ~60-70 ms post-stimulus. The average ROC curve area across all four subjects was 0.80 and 0.85 for upper and lower quadrants, respectively and was in all cases significantly higher than chance (unpaired t-test, p<0.0001). In the Priming Experiment, we contrasted initial versus repeated presentations of visual object stimuli. Their posterior probabilities revealed significant differences, which started at 250ms post-stimulus onset. The classification accuracy rates with single-trial test data were at chance level. We therefore considered sub-averages based on five single trials. We found that for three out of four subjects' classification rates were significantly above chance level (unpaired t-test, p<0.0001). Conclusions: The main advantage of the present approach is that it is based on topographic features that are readily interpretable along neurophysiologic lines. As these maps were previously normalized by the overall strength of the field potential on the scalp, a change in their presence across trials and between conditions forcibly reflects a change in the underlying generator configurations. The temporal periods of statistical difference between conditions were estimated for each training dataset for ten shuffles of the data. Across the ten shuffles and in both experiments, we observed a high level of consistency in the temporal periods over which the two conditions differed. With this method we are able to analyze ERPs at the single-subject level providing a novel tool to compare normal electrophysiological responses versus single cases that cannot be considered part of any cohort of subjects. This aspect promises to have a strong impact on both basic and clinical research.