Long-term treatment with insulin induces apoptosis in brown adipocytes: role of oxidative stress

Trying to define the precise role played by insulin regulating the survival of brown adipocytes, we have used rat fetal brown adipocytes maintained in primary culture. The effect of insulin on apoptosis and the mechanisms involved were assessed. Different from the known effects of insulin as a survival factor, we have found that long-term treatment (72 h) with insulin induces apoptosis in rat fetal brown adipocytes. This process is dependent on the phosphatidylinositol 3-kinase/mammalian target of rapamycin/p70 S6 kinase pathway. Short-term treatment with the conditioned medium from brown adipocytes treated with insulin for 72 h mimicked the apoptotic effect of insulin. During the process, caspase 8 activation, Bid cleavage, cytochrome c release, and activation of caspases 9 and 3 are sequentially produced. Treatment with the caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (Z-VAD), prevents activation of this apoptotic cascade. The antioxidants, ascorbic acid and superoxide dismutase, also impair this process of apoptosis. Moreover, generation of reactive oxygen species (ROS), probably through reduced nicotinamide adenine dinucleotide phosphate oxidases, and a late decrease in reduced glutathione content are produced. According to this, antioxidants prevent caspase 8 activation and Bid cleavage, suggesting that ROS production is an important event mediating this process of apoptosis. However, the participation of uncoupling protein-1, -2, and -3 regulating ROS is unclear because their levels remain unchanged upon insulin treatment for 72 h. Our data suggest that the prolonged hyperinsulinemia might cause insulin resistance through the loss of brown adipose tissue.

Long term trends in prevalence of neural tube defects in Europe: population based study.

STUDY QUESTION: What are the long term trends in the total (live births, fetal deaths, and terminations of pregnancy for fetal anomaly) and live birth prevalence of neural tube defects (NTD) in Europe, where many countries have issued recommendations for folic acid supplementation but a policy for mandatory folic acid fortification of food does not exist? METHODS: This was a population based, observational study using data on 11 353 cases of NTD not associated with chromosomal anomalies, including 4162 cases of anencephaly and 5776 cases of spina bifida from 28 EUROCAT (European Surveillance of Congenital Anomalies) registries covering approximately 12.5 million births in 19 countries between 1991 and 2011. The main outcome measures were total and live birth prevalence of NTD, as well as anencephaly and spina bifida, with time trends analysed using random effects Poisson regression models to account for heterogeneities across registries and splines to model non-linear time trends. SUMMARY ANSWER AND LIMITATIONS: Overall, the pooled total prevalence of NTD during the study period was 9.1 per 10 000 births. Prevalence of NTD fluctuated slightly but without an obvious downward trend, with the final estimate of the pooled total prevalence of NTD in 2011 similar to that in 1991. Estimates from Poisson models that took registry heterogeneities into account showed an annual increase of 4% (prevalence ratio 1.04, 95% confidence interval 1.01 to 1.07) in 1995-99 and a decrease of 3% per year in 1999-2003 (0.97, 0.95 to 0.99), with stable rates thereafter. The trend patterns for anencephaly and spina bifida were similar, but neither anomaly decreased substantially over time. The live birth prevalence of NTD generally decreased, especially for anencephaly. Registration problems or other data artefacts cannot be excluded as a partial explanation of the observed trends (or lack thereof) in the prevalence of NTD. WHAT THIS STUDY ADDS: In the absence of mandatory fortification, the prevalence of NTD has not decreased in Europe despite longstanding recommendations aimed at promoting peri-conceptional folic acid supplementation and existence of voluntary folic acid fortification. FUNDING, COMPETING INTERESTS, DATA SHARING: The study was funded by the European Public Health Commission, EUROCAT Joint Action 2011-2013. HD and ML received support from the European Commission DG Sanco during the conduct of this study. No additional data available.

Long-term persistence of immunity induced by OVA-coupled gas-filled microbubble vaccination partially protects mice against infection by OVA-expressing Listeria.

Vaccination aims at generating memory immune responses able to protect individuals against pathogenic challenges over long periods of time. Subunit vaccine formulations based on safe, but poorly immunogenic, antigenic entities must be combined with adjuvant molecules to make them efficient against infections. We have previously shown that gas-filled microbubbles (MB) are potent antigen-delivery systems. This study compares the ability of various ovalbumin-associated MB (OVA-MB) formulations to induce antigen-specific memory immune responses and evaluates long-term protection toward bacterial infections. When initially testing dendritic cells reactivity to MB constituents, palmitic acid exhibited the highest degree of activation. Subcutaneous immunization of naïve wild-type mice with the OVA-MB formulation comprising the highest palmitic acid content and devoid of PEG2000 was found to trigger the more pronounced Th1-type response, as reflected by robust IFN-γ and IL-2 production. Both T cell and antibody responses persisted for at least 6 months after immunization. At that time, systemic infection with OVA-expressing Listeria monocytgenes was performed. Partial protection of vaccinated mice was demonstrated by reduction of the bacterial load in both the spleen and liver. We conclude that antigen-bound MB exhibit promising properties as a vaccine candidate ensuring prolonged maintenance of protective immunity.

Accessing forgotten memory traces from long-term memory via visual movements

Because memory retrieval often requires overt responses, it is difficult to determine to what extend forgetting occurs as a problem in explicit accessing of long-term memory traces. In this study, we used eye-tracking measures in combination with a behavioural task that favoured high forgetting rates to investigate the existence of memory traces from long-term memory in spite of failure in accessing them consciously. In 2 experiments, participants were encouraged to encode a large set of sound-picture56 location associations. In a later test, sounds were presented and participants were instructed to visually scan, before a verbal memory report, for the correct location of the associated pictures in an empty screen. We found the reactivation of associated memories by sound cues at test biased oculomotor behaviour towards locations congruent with memory representations, even when participants failed to consciously provide a memory report of it. These findings reveal the emergence of a memory-guided behaviour that can be used to map internal representations of forgotten memories from long-term memory.

Evolution à long term du syndrom de Widal après chirurgie endoscopique endonasale

Ce travail de recherche a été effectué dans le cadre d'une formation post-graduée à l'Hôpital de La Chaux-de-Fonds, dans lequel le service ORL bénéficie d'un recrutement significatif pour les pathologies naso-sinusiennes, en particulier les polyposes. Ces pathologies sont grevées d'un handicap fonctionnel considérable, de par l'obstruction nasale, la limitation des efforts physiques et les troubles olfactifs comme principales répercussions. J'ai ainsi répertorié 303 interventions endonasales pour ablation de polypes et drainage des cavités sinusales. effectuées entre 1987 et 2006. L'étude s'est focalisée sur les 33 patients atteints d'une polypose nasale mais également d'un asthme et d'une intolérance à l'aspirine, réalisant la triade de Widal. La prévalence en Europe pour la polypose nasale est de 1 à 2 %, dont 10 à 20 % de syndromes de Widal. Cette entité est grevée d'une morbidité plus sévère en raison des mécanismes métaboliques induisant des récidives de polypes précoces, rendant la maladie plus difficile à contrôler. Ces patients ont été évalués d'une part subjectivement par une échelle visuelle analogique pour les symptômes rhinologiques et généraux, et d'autre part via une analyse objective du status endonasal de la polypose à la fin du suivi. Pour chaque patient, les troubles fonctionnels résiduels (obstruction nasale, rhinorrhée, troubles olfactifs, céphalées, éternuements, larmoiement) ainsi que le status endonasal à la fin du suivi ont été analysés pour détecter d'éventuelles associations significatives avec les caractéristiques pré-opératoires (âge, sexe, allergies, antécédants de chirurgie endonasale, données scanographiques, status endonasal). Deux groupes ont été identifiés selon la sévérité de l'atteinte fonctionnelle résiduelle. La valeur moyenne de la gêne à la fin du suivi pour l'ensemble du collectif est de 3.9/10 sur l'échelle visuelle analogique (0= absence de gêne, 10= gêne maximale). Les facteurs de mauvais pronostic qui ont été identifiés sont le sexe féminin et la présence de polyallergies, mais sans relation statistiquement significative. La seule différence statistiquement significative est le stade avancé de polypose nasale à la fin du suivi dans le groupe présentant l'atteinte fonctionnelle la plus importante (groupe 2). Malgré la combinaison des traitements chirurgicaux et médicamenteux par corticoïdes et anti-leucotriènes, la maladie de Widal est grevée d'une gêne fonctionnelle résiduelle non négligeable dans notre suivi moyen de 11,6 ans. Ceci relativise les résultats parfois trop optimistes des études avec un suivi plus court, sachant que les délais avant une deuxième intervention chirurgicale dans notre série ont été de 6,5 ans. L'évolution des traitements immuno-modulateurs topiques et systémiques combinés aux interventions chirurgicales ponctuelles renforce l'arsenal thérapeutique dans la prise en charge des patients atteints de la maladie de Widal. Cette étude pourra être élargie au collectif entier des ethmoïdectomies répertoriées (n=303) dans le service ORL et actualisées, afin de rechercher et mettre en évidence d'autres associations en comparant le groupe des polyposes simples au groupe des triades de Widal.

Long-term low-dose ketoconazole treatment in bilateral macronodular adrenal hyperplasia (BMAH)

Le traitement médicamenteux du syndrome de Cushing secondaire à une hyperplasie surrénalienne macro-nodulaire bilatérale (bilateral macronodular adrenal hyperplasia, (BMAH)) est généralement administré pour une période limitée avant de procéder à l'exérèse chirurgicale des surrénales. Les antagonistes des récepteurs surrênaïïens aberrants se sont révélés inefficaces à long terme pour empêcher la surrénalectomie. Nous reportons le cas d'une patiente avec BMAH traitée durant 10 ans par des petites doses de kétoconazole, afin de contrôler la sécrétion de Cortisol. A l'âge de 48 ans, elle a présenté des céphalées et une hypertension artérielle. Les investigations ont donné les résultats suivants: absence de signes cliniques de syndrome de Cushing ; hyperplasie nodulaire des surrénales ; valeurs normales de la creatinine, le potassium et l'aldostérone plasmatiques ; valeurs normales des métanéphrines et de l'aldostérone urinaires ; élévation du Cortisol libre et des métabolites stéroïdiens urinaires ; et suppression de l'ACTH et de l'activité de la rénine plasmatiques. Un protocole de dépistage des récepteurs surrénaliens aberrants n'a pas montré de dépendance hormonale illégitime. Le kétoconazole a permis une normalisation rapide du Cortisol et de l'ACTH avec un effet qui persiste après 10 ans de traitement, tandis que l'imagerie surrénalienne ne montre pas de changement de taille et d'aspect de celles-ci. La sécrétion stéroidienne chez les patients présentant une BMAH est moins importante que celle de surrénales normales ou de tumeurs secrétrices et peut être contrôlée avec de petites doses de kétoconazole. Ce traitement, bien toléré, constitue une alternative au traitement chirurgical.

The Stealthy Superbug: the Role of Asymptomatic Enteric Carriage in Maintaining a Long-Term Hospital Outbreak of ST228 Methicillin-Resistant Staphylococcus aureus.

UNLABELLED: Whole-genome sequencing (WGS) of 228 isolates was used to elucidate the origin and dynamics of a long-term outbreak of methicillin-resistant Staphylococcus aureus (MRSA) sequence type 228 (ST228) SCCmec I that involved 1,600 patients in a tertiary care hospital between 2008 and 2012. Combining of the sequence data with detailed metadata on patient admission and movement confirmed that the outbreak was due to the transmission of a single clonal variant of ST228, rather than repeated introductions of this clone into the hospital. We note that this clone is significantly more frequently recovered from groin and rectal swabs than other clones (P < 0.0001) and is also significantly more transmissible between roommates (P < 0.01). Unrecognized MRSA carriers, together with movements of patients within the hospital, also seem to have played a major role. These atypical colonization and transmission dynamics can help explain how the outbreak was maintained over the long term. This "stealthy" asymptomatic colonization of the gut, combined with heightened transmissibility (potentially reflecting a role for environmental reservoirs), means the dynamics of this outbreak share some properties with enteric pathogens such as vancomycin-resistant enterococci or Clostridium difficile. IMPORTANCE: Using whole-genome sequencing, we showed that a large and prolonged outbreak of methicillin-resistant Staphylococcus aureus was due to the clonal spread of a specific strain with genetic elements adapted to the hospital environment. Unrecognized MRSA carriers, the movement of patients within the hospital, and the low detection with clinical specimens were also factors that played a role in this occurrence. The atypical colonization of the gut means the dynamics of this outbreak may share some properties with enteric pathogens.

Emergence and development of a financial cluster: the evolution of Andorra’s banking deposits in the long-term, 1931-2007

This paper explores the origins of Andorra’s financial cluster. It shows that the free movement of currency, the protection of infant industry, and geographical concentration lie at the foundation of the cluster’s competitive advantage. Drawing on a new set of data, the paper also provides for the first time an estimate of the total deposits held by Andorra’s banks between 1931 and 2007. Based on this new information, the paper reaches the conclusion that the development of the cluster went through four distinct phases in which large companies, acting as leaders, played an important role in enhancing the cluster’s business capabilities.