Dendritic cell-specific antigen delivery by coronavirus vaccine vectors induces long-lasting protective antiviral and antitumor immunity.

Efficient vaccination against infectious agents and tumors depends on specific antigen targeting to dendritic cells (DCs). We report here that biosafe coronavirus-based vaccine vectors facilitate delivery of multiple antigens and immunostimulatory cytokines to professional antigen-presenting cells in vitro and in vivo. Vaccine vectors based on heavily attenuated murine coronavirus genomes were generated to express epitopes from the lymphocytic choriomeningitis virus glycoprotein, or human Melan-A, in combination with the immunostimulatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). These vectors selectively targeted DCs in vitro and in vivo resulting in vector-mediated antigen expression and efficient maturation of DCs. Single application of only low vector doses elicited strong and long-lasting cytotoxic T-cell responses, providing protective antiviral and antitumor immunity. Furthermore, human DCs transduced with Melan-A-recombinant human coronavirus 229E efficiently activated tumor-specific CD8(+) T cells. Taken together, this novel vaccine platform is well suited to deliver antigens and immunostimulatory cytokines to DCs and to initiate and maintain protective immunity.

Unraveling the complex metabolic nature of astrocytes.

Since the initial description of astrocytes by neuroanatomists of the nineteenth century, a critical metabolic role for these cells has been suggested in the central nervous system. Nonetheless, it took several technological and conceptual advances over many years before we could start to understand how they fulfill such a role. One of the important and early recognized metabolic function of astrocytes concerns the reuptake and recycling of the neurotransmitter glutamate. But the description of this initial property will be followed by several others including an implication in the supply of energetic substrates to neurons. Indeed, despite the fact that like most eukaryotic non-proliferative cells, astrocytes rely on oxidative metabolism for energy production, they exhibit a prominent aerobic glycolysis capacity. Moreover, this unusual metabolic feature was found to be modulated by glutamatergic activity constituting the initial step of the neurometabolic coupling mechanism. Several approaches, including biochemical measurements in cultured cells, genetic screening, dynamic cell imaging, nuclear magnetic resonance spectroscopy and mathematical modeling, have provided further insights into the intrinsic characteristics giving rise to these key features of astrocytes. This review will provide an account of the different results obtained over several decades that contributed to unravel the complex metabolic nature of astrocytes that make this cell type unique.

IL-6 activated integrated BATF/IRF4 functions in lymphocytes are T-bet-independent and reversed by subcutaneous immunotherapy.

IL-6 plays a central role in supporting pathological TH2 and TH17 cell development and inhibiting the protective T regulatory cells in allergic asthma. TH17 cells have been demonstrated to regulate allergic asthma in general and T-bet-deficiency-induced asthma in particular. Here we found an inverse correlation between T-bet and Il-6 mRNA expression in asthmatic children. Moreover, experimental subcutaneous immunotherapy (SIT) in T-bet((-/-)) mice inhibited IL-6, IL-21R and lung TH17 cells in a setting of asthma. Finally, local delivery of an anti-IL-6R antibody in T-bet((-/-)) mice resulted in the resolution of this allergic trait. Noteworthy, BATF, crucial for the immunoglobulin-class-switch and TH2,TH17 development, was found down-regulated in the lungs of T-bet((-/-)) mice after SIT and after treatment with anti-IL-6R antibody, indicating a critical role of IL-6 in controlling BATF/IRF4 integrated functions in TH2, TH17 cells and B cells also in a T-bet independent fashion in allergic asthma.

Creatine, central nervous system and creatine deficiency syndromes

It was long thought that most of brain creatine was of peripheral origin. However, recentworks have demonstrated that creatine crosses blood-brain barrier only with poor efficiency, and thatCNS must ensure parts of its creatine needs by its own creatine synthesis pathway, thank to the brainexpression of AGAT and GAMT (creatine synthesis) and SLC6A8 (creatine transporter). This newunderstanding of creatine metabolism and transport in CNS allows a better comprehension of creatinedeficiency syndromes, which are due to deficiencies in AGAT, GAMT and SLC6A8 and mainly affectthe brain of patients who show severe neurodevelopmental delay and present neurological symptomsin early infancy.

Postoperative management of adult central neurosurgical patients: systemic and neuro-monitoring.

Postoperative neurosurgical patients are at risk of developing complications. Systemic and neuro-monitoring are used to identify patients who deteriorate in order to treat the underlying cause and minimize the impact on outcome. Hypotension and hypoxia are likely to be the most frequent insults and can be detected easily with blood pressure monitoring and pulse oximetry. Repeated clinical examination, however, is probably the most important monitor in the postoperative setting. Clinical scores such as the Glasgow Coma Score and the more recently introduced FOUR Score are important tools to standardize the clinical assessment. Intracranial pressure monitoring, cerebral blood flow monitoring, electroencephalography, and brain imaging are often used postoperatively. Despite the numerous publications on this topic only few studies address the impact of postoperative monitoring on outcome. Accordingly, in most patients the decision on which monitors are to be used must be based on the patient's presentation and clinical judgment.

Intracisternal delivery of NFκB-inducible scAAV2/9 reveals locoregional neuroinflammation induced by systemic kainic acid treatment.

We have previously demonstrated disease-dependent gene delivery in the brain using an AAV vector responding to NFκB activation as a probe for inflammatory responses. This vector, injected focally in the parenchyma prior to a systemic kainic acid (KA) injection mediated inducible transgene expression in the hippocampus but not in the cerebellum, regions, respectively, known to be affected or not by the pathology. However, such a focal approach relies on previous knowledge of the model parameters and does not allow to predict the whole brain response to the disease. Global brain gene delivery would allow to predict the regional distribution of the pathology as well as to deliver therapeutic factors in all affected brain regions. We show that self-complementary AAV2/9 (scAAV2/9) delivery in the adult rat cisterna magna allows a widespread but not homogenous transduction of the brain. Indeed, superficial regions, i.e., cortex, hippocampus, and cerebellum were more efficiently transduced than deeper regions, such as striatum, and substantia nigra. These data suggest that viral particles penetration from the cerebrospinal fluid (CSF) into the brain is a limiting factor. Interestingly, AAV2/9-2YF a rationally designed capsid mutant (affecting surface tyrosines) increased gene transfer efficiency approximately fivefold. Neurons, astrocytes, and oligodendrocytes, but not microglia, were transduced in varying proportions depending on the brain region and the type of capsid. Finally, after a single intracisternal injection of scAAV2/9-2YF using the NFκB-inducible promoter, KA treatment induced transgene expression in the hippocampus and cortex but not in the cerebellum, corresponding to the expression of the CD11b marker of microglial activation. These data support the use of disease-inducible vectors administered in the cisterna magna as a tool to characterize the brain pathology in systemic drug-induced or transgenic disease models. However, further improvements are required to enhance viral particles penetration into the brain.

Influence of a lifestyle intervention in preschool children on physiological and psychological parameters (Ballabeina): study design of a cluster randomized controlled trial.

Childhood obesity and physical inactivity are increasing dramatically worldwide. Children of low socioeconomic status and/or children of migrant background are especially at risk. In general, the overall effectiveness of school-based programs on health-related outcomes has been disappointing. A special gap exists for younger children and in high risk groups. This paper describes the rationale, design, curriculum, and evaluation of a multicenter preschool randomized intervention study conducted in areas with a high migrant population in two out of 26 Swiss cantons. Twenty preschool classes in the German (canton St. Gallen) and another 20 in the French (canton Vaud) part of Switzerland were separately selected and randomized to an intervention and a control arm by the use of opaque envelopes. The multidisciplinary lifestyle intervention aimed to increase physical activity and sleep duration, to reinforce healthy nutrition and eating behaviour, and to reduce media use. According to the ecological model, it included children, their parents and the teachers. The regular teachers performed the majority of the intervention and were supported by a local health promoter. The intervention included physical activity lessons, adaptation of the built infrastructure; promotion of regional extracurricular physical activity; playful lessons about nutrition, media use and sleep, funny homework cards and information materials for teachers and parents. It lasted one school year. Baseline and post-intervention evaluations were performed in both arms. Primary outcome measures included BMI and aerobic fitness (20 m shuttle run test). Secondary outcomes included total (skinfolds, bioelectrical impedance) and central (waist circumference) body fat, motor abilities (obstacle course, static and dynamic balance), physical activity and sleep duration (accelerometry and questionnaires), nutritional behaviour and food intake, media use, quality of life and signs of hyperactivity (questionnaires), attention and spatial working memory ability (two validated tests). Researchers were blinded to group allocation. The purpose of this paper is to outline the design of a school-based multicenter cluster randomized, controlled trial aiming to reduce body mass index and to increase aerobic fitness in preschool children in culturally different parts of Switzerland with a high migrant population. Trial Registration: (clinicaltrials.gov) NCT00674544.

Morphostructural analysis of an alpine debris flows catchment: implication for debris supply

Rock slope instabilities are implicitly linked to the supply of sediment and debris recharging channels prone to debris flow. Hence, the incorporation of bedrock structure and terrain morphology can be relevant in the analysis of sediment budget and debris flow hazard assessment. Here, the mode of debris production of the Manival catchment (northern French Alps) is documented by the study of its morphostructural aspects extracted from high resolution DEM. Terrain implication in the process of debris supply is evaluated by: a) A systematic classification of the major morphological units based on the slope gradient that enables a spatial analysis of zones of debris production and deposition. b) A detailed structural analysis performed on DEM in order to identify potential unstable slopes. c) An analysis of the gullies orientation that informs in term of structural control of the sources zones. d) Localisation of high density joints sets that document about whether sources of continuous debris production are controlled by the structural setting of the catchment. These DEM-based indicators can be used as proxies for assessing the influences of the current topography and enable to quantify a degree of susceptibility to mass wasting and hillslope erosion activity. This present contribution suggests some directions for characterizing sediment flux dynamic in small alpine catchment.

Spirometry reference equations for central European populations from school age to old age.

BACKGROUND: Spirometry reference values are important for the interpretation of spirometry results. Reference values should be updated regularly, derived from a population as similar to the population for which they are to be used and span across all ages. Such spirometry reference equations are currently lacking for central European populations. OBJECTIVE: To develop spirometry reference equations for central European populations between 8 and 90 years of age. MATERIALS: We used data collected between January 1993 and December 2010 from a central European population. The data was modelled using "Generalized Additive Models for Location, Scale and Shape" (GAMLSS). RESULTS: The spirometry reference equations were derived from 118'891 individuals consisting of 60'624 (51%) females and 58'267 (49%) males. Altogether, there were 18'211 (15.3%) children under the age of 18 years. CONCLUSION: We developed spirometry reference equations for a central European population between 8 and 90 years of age that can be implemented in a wide range of clinical settings.

Relationship Between the Development of the Spinal Canal and the Etiopathogenesis of Lumbar Spinal Stenosis

INTRODUCTION: The presence of a pre-existing narrow spinal canal may have an important place in the ethiopathogenesis of lumbar spinal stenosis. By consequence the study of the development of the spinal canal is crucial. The first goal of this work is to do a comprehensive literature search and to give an essential view on the development of spinal canal and its depending factors studied until now. The second goal is to give some considerations and hypothesize new leads for clinically useful researches. MATERIALS AND METHODS: A bibliographical research was executed using different search engines: PubMed, Google Schoolar ©, Ovid ® and Web Of Science ©. Free sources and avaible from the University of Lausanne (UNIL) and Centre Hospitalier Universitaire Vaudois (CHUV) were used. At the end of the bibliographic researches 114 references were found, 85 were free access and just 41 were cited in this work. Most of the found references are in English or in French. RESULTS AND DISCUSSION: The spinal canal is principally limited by the vertebrae which have a mesodermal origin. The nervous (ectodermal) tissue significantly influences the growth of the canal. The most important structure participating in the spinal canal growth is the neurocentral synchondrosis in almost the entire vertebral column. The fusion of the half posterior arches seems to have less importance for the canal size. The growth is not homogeneous but, depends on the vertebral level. Timing, rate and growth potentials differ by regions. Especially in the case of the lumbar segment, there is a craniocaudal tendency which entails a greater post-natal catch-up growth for distal vertebrae. Trefoil-shape of the L5 canal is the consequence of a sagittal growth deficiency. The spinal canal shares some developmental characteristics with different structures and systems, especially with the central nervous system. It may be the consequence of the embryological origin. It is supposed that not all the related structures would be affected by a growth impairment because of the different catch-up potentials. Studies found that narrower spinal canals might be related with cardiovascular and gastrointestinal symptoms, lower thymic function, bone mineral content, dental hypoplasia and Harris' lines. Anthropometric correlations found at birth disappear during the pediatric age. All factors which can affect bone and nervous growth might be relevant. Genetic predispositions are the only factors that can never be changed but the real impact is to ascertain. During the antenatal period, all the elements determining a good supply of blood and oxygen may influence the vertebral canal development, for example smoking during pregnancy. Diet is a crucial factor having an impact on both antenatal and postnatal growth. Proteins intake is the only proved dietetic relationship found in the bibliographic research of this work. The mechanical effects due to locomotion changes are unknown. Socioeconomic situation has an impact on several influencing factors and it is difficult to study it owing to numerous bias. CONCLUSIONS: A correct growth of spinal canal is evidently relevant to prevent not-degenerative stenotic conditions. But a "congenital" narrower canal may aggravate degenerative stenosis. This concerns specific groups of patient. If the size of the canal is highly involved in the pathogenesis of common back pains, a hypothetical measure to prevent developmental impairments could have a not- negligible impact on the society. It would be interesting to study more about dietetic necessities for a good spinal canal development. Understanding the relationship between nervous tissues and vertebra it might be useful in identifying what is needed for the ideal development. Genetic importance and the post-natal influences of upright standing on the canal growth remain unsolved questions. All these tracks may have a double purpose: knowing if it is possible to decrease the incidence of narrower spinal canal and consequently finding possible preventive measures. The development of vertebral canal is a complex subject which ranges over a wide variety of fields. The knowledge of this subject is an indispensable tool to understand and hypothesize the influencing factors that might lead to stenotic conditions. Unfortunately, a lack of information makes difficult to have a complete and satisfactory interdisciplinary vision.

Impact and cost of a 2-week community-based screening and awareness program for diabetes and cardiovascular risk factors in a Swiss canton.

BACKGROUND: Community-based diabetes screening programs can help sensitize the population and identify new cases. However, the impact of such programs is rarely assessed in high-income countries, where concurrent health information and screening opportunities are common place. INTERVENTION AND METHODS: A 2-week screening and awareness campaign was organized as part of a new diabetes program in the canton of Vaud (population of 697,000) in Switzerland. Screening was performed without appointment in 190 out of 244 pharmacies in the canton at the subsidized cost of 10 Swiss Francs per participant. Screening included questions on risk behaviors, measurement of body mass index, blood pressure, blood cholesterol, random blood glucose (RBG), and A1c if RBG was >/=7.0 mmol/L. A mass media campaign promoting physical activity and a healthy diet was channeled through several media, eg, 165 spots on radio, billboards in 250 public places, flyers in 360 public transport vehicles, and a dozen articles in several newspapers. A telephone survey in a representative sample of the population of the canton was performed after the campaign to evaluate the program. RESULTS: A total of 4222 participants (0.76% of all persons aged >/=18 years) underwent the screening program (median age: 53 years, 63% females). Among participants not treated for diabetes, 3.7% had RBG >/= 7.8 mmol/L and 1.8% had both RBG >/= 7.0 mmol/L and A1c >/= 6.5. Untreated blood pressure >/=140/90 mmHg and/or untreated cholesterol >/=5.2 mmol/L were found in 50.5% of participants. One or several treated or untreated modifiable risk factors were found in 78% of participants. The telephone survey showed that 53% of all adults in the canton were sensitized by the campaign. Excluding fees paid by the participants, the program incurred a cost of CHF 330,600. CONCLUSION: A community-based screening program had low efficiency for detecting new cases of diabetes, but it identified large numbers of persons with elevated other cardiovascular risk factors. Our findings suggest the convenience of A1c for mass screening of diabetes, the usefulness of extending diabetes screening to other cardiovascular risk factors, and the importance of a robust background communication campaign.

On landslide risk, resilience and vulnerability of mountain communities in Central-Eastern Nepal

Executive SummaryIn Nepal, landslides are one of the major natural hazards after epidemics, killing over 100 persons per year. However, this figure is an underreported reflection of the actual impact that landslides have on livelihoods and food security in rural Nepal. With predictions of more intense rainfall patterns, landslide occurrence in the Himalayas is likely to increase and continue to be one of the major impediments to development. Due to the remoteness of many localities and lack of resources, responsibilities for disaster preparedness and response in mountain areas usually lie with the communities themselves. Everyday life is full of risk in mountains of Nepal. This is why mountain populations, as well as other populations living in harsh conditions have developed a number of coping strategies for dealing with adverse situations. Perhaps due to the dispersed and remote nature of landslides in Nepal, there have been few studies on vulnerability, coping- and mitigation strategies of landslide affected populations. There are also few recommendations available to guide authorities and populations how to reduce losses due to landslides in Nepal, and even less so, how to operationalize resilience and vulnerability.Many policy makers, international donors, NGOs and national authorities are currently asking what investments are needed to increase the so-called 'resilience' of mountain populations to deal with climate risks. However, mountain populations are already quite resilient to seasonal fluctuations, temperature variations, rainfall patterns and market prices. In spite of their resilience, they continue to live in places at risk due to high vulnerability caused by structural inequalities: access to land, resources, markets, education. This interdisciplinary thesis examines the concept of resilience by questioning its usefulness and validity as the current goal of international development and disaster risk reduction policies, its conceptual limitations and its possible scope of action. The goal of this study is two-fold: to better define and distinguish factors and relationships between resilience, vulnerability, capacities and risk; and to test and improve a participatory methodology for evaluating landslide risk that can serve as a guidance tool for improving community-based disaster risk reduction. The objective is to develop a simple methodology that can be used by NGOs, local authorities and communities to reduce losses from landslides.Through its six case studies in Central-Eastern Nepal, this study explores the relation between resilience, vulnerability and landslide risk based on interdisciplinary methods, including geological assessments of landslides, semi-structured interviews, focus groups and participatory risk mapping. For comparison, the study sites were chosen in Tehrathum, Sunsari and Dolakha Districts of Central/Eastern Nepal, to reflect a variety of landslide types, from chronic to acute, and a variety of communities, from very marginalized to very high status. The study uses the Sustainable Livelihoods Approach as its conceptual basis, which is based on the notion that access and rights to resources (natural, human/institutional, economic, environmental, physical) are the basis for coping with adversity, such as landslides. The study is also intended as a contribution to the growing literature and practices on Community Based Disaster Risk Reduction specifically adapted to landslide- prone areas.In addition to the six case studies, results include an indicator based methodology for assessing and measuring vulnerability and resilience, a composite risk assessment methodology, a typology of coping strategies and risk perceptions and a thorough analysis of the relation between risk, vulnerability and resilience. The methodology forassessing vulnerability, resilience and risk is relatively cost-effective and replicable in a low-data environment. Perhaps the major finding is that resilience is a process that defines a community's (or system's) capacity to rebound following adversity but it does not necessarily reduce vulnerability or risk, which requires addressing more structural issues related to poverty. Therefore, conclusions include a critical view of resilience as a main goal of international development and disaster risk reduction policies. It is a useful concept in the context of recovery after a disaster but it needs to be addressed in parallel with vulnerability and risk.This research was funded by an interdisciplinary grant (#26083591) from the Swiss National Science Foundation for the period 2009-2011 and a seed grant from the Faculty of Geosciences and Environment at the University of Lausanne in 2008.Résumé en françaisAu Népal, les glissements de terrain sont un des aléas les plus dévastateurs après les épidémies, causant 100 morts par an. Pourtant, ce chiffre est une sous-estimation de l'impact réel de l'effet des glissements sur les moyens de subsistance et la sécurité alimentaire au Népal. Avec des prévisions de pluies plus intenses, l'occurrence des glissements dans les Himalayas augmente et présente un obstacle au développement. Du fait de l'éloignement et du manque de ressources dans les montagnes au Népal, la responsabilité de la préparation et la réponse aux catastrophes se trouve chez les communautés elles-mêmes. Le risque fait partie de la vie quotidienne dans les montagnes du Népal. C'est pourquoi les populations montagnardes, comme d'autres populations vivant dans des milieux contraignants, ont développé des stratégies pour faire face aux situations défavorables. Peu d'études existent sur la vulnérabilité, ceci étant probablement dû à l'éloignement et pourtant, les stratégies d'adaptation et de mitigation des populations touchées par des glissements au Népal existent.Beaucoup de décideurs politiques, bailleurs de fonds, ONG et autorités nationales se demandent quels investissements sont nécessaires afin d'augmenter la 'resilience' des populations de montagne pour faire face aux changements climatiques. Pourtant, ces populations sont déjà résilientes aux fluctuations des saisons, des variations de température, des pluies et des prix des marchés. En dépit de leur résilience, ils continuent de vivre dans des endroits à fort risque à cause des vulnérabilités créées par les inégalités structurelles : l'accès à la terre, aux ressources, aux marchés et à l'éducation. Cette thèse interdisciplinaire examine le concept de la résilience en mettant en cause son utilité et sa validité en tant que but actuel des politiques internationales de développement et de réduction des risques, ainsi que ses limitations conceptuelles et ses possibles champs d'action. Le but de cette étude est double : mieux définir et distinguer les facteurs et relations entre la résilience, la vulnérabilité, les capacités et le risque ; Et tester et améliorer une méthode participative pour évaluer le risque des glissements qui peut servir en tant qu'outil indicatif pour améliorer la réduction des risques des communautés. Le but est de développer une méthodologie simple qui peut être utilisée par des ONG, autorités locales et communautés pour réduire les pertes dues aux glissements.A travers les études de cas au centre-est du Népal, cette étude explore le rapport entre la résilience, la vulnérabilité et les glissements basée sur des méthodes interdisciplinaires ; Y sont inclus des évaluations géologiques des glissements, des entretiens semi-dirigés, des discussions de groupes et des cartes de risques participatives. Pour la comparaison, les zones d'études ont été sélectionnées dans les districts de Tehrathum, Sunsari et Dolakha dans le centre-est du Népal, afin de refléter différents types de glissements, de chroniques à urgents, ainsi que différentes communautés, variant de très marginalisées à très haut statut. Pour son cadre conceptuel, cette étude s'appuie sur l'approche de moyens de subsistance durable, qui est basée sur les notions d'accès et de droit aux ressources (naturelles, humaines/institutionnelles, économiques, environnementales, physiques) et qui sont le minimum pour faire face à des situations difficiles, comme des glissements. Cette étude se veut aussi une contribution à la littérature et aux pratiques en croissantes sur la réduction des risques communautaires, spécifiquement adaptées aux zones affectées par des glissements.En plus des six études de cas, les résultats incluent une méthodologie basée sur des indicateurs pour évaluer et mesurer la vulnérabilité et la résilience, une méthodologie sur le risque composé, une typologie de stratégies d'adaptation et perceptions des risques ainsi qu'une analyse fondamentale de la relation entre risque, vulnérabilité et résilience. Les méthodologies pour l'évaluation de la vulnérabilité, de la résilience et du risque sont relativement peu coûteuses et reproductibles dans des endroits avec peu de données disponibles. Le résultat probablement le plus pertinent est que la résilience est un processus qui définit la capacité d'une communauté (ou d'un système) à rebondir suite à une situation défavorable, mais qui ne réduit pas forcement la vulnérabilité ou le risque, et qui requiert une approche plus fondamentale s'adressant aux questions de pauvreté. Les conclusions incluent une vue critique de la résilience comme but principal des politiques internationales de développement et de réduction des risques. C'est un concept utile dans le contexte de la récupération après une catastrophe mais il doit être pris en compte au même titre que la vulnérabilité et le risque.Cette recherche a été financée par un fonds interdisciplinaire (#26083591) du Fonds National Suisse pour la période 2009-2011 et un fonds de préparation de recherches par la Faculté des Géosciences et Environnement à l'Université de Lausanne en 2008.