Delirium and cognitive decline: more than a coincidence.

PURPOSE OF REVIEW: To review the recent findings on the relationships between delirium and cognitive decline in the elderly. RECENT FINDINGS: Current advances in the field include substantial new evidence that delirium increases the risk of dementia in patients without previous cognitive impairment and accelerates cognitive decline in patients with Alzheimer's disease. Findings on cognitive trajectories and domains affected contribute to better understanding of the clinical nature of cognitive impairment after delirium. Volume loss and disruption of white matter integrity may represent early MRI markers for long-term cognitive impairment. Neurodegenerative and low-level chronic inflammatory processes predispose to exaggerated response to incident stimuli that may precipitate both acute brain dysfunction and persisting cerebral damage. SUMMARY: Still little is known about the relationship between delirium and cognitive trajectories in the elderly, and the underlying pathophysiological mechanisms. The association of neurodegenerative and inflammatory processes appears to play an important role in the pathogenesis and the clinical course of cognitive impairment after delirium. The hypothetical role of several other factors remains to be clarified. Further clinical studies are needed to evaluate whether prevention and treatment approaches that proved to be useful to reduce delirium incidence and severity may also improve long-term outcomes, and prevent cognitive decline.

Combining RT-PCR-seq and RNA-seq to catalog all genic elements encoded in the human genome.

Within the ENCODE Consortium, GENCODE aimed to accurately annotate all protein-coding genes, pseudogenes, and noncoding transcribed loci in the human genome through manual curation and computational methods. Annotated transcript structures were assessed, and less well-supported loci were systematically, experimentally validated. Predicted exon-exon junctions were evaluated by RT-PCR amplification followed by highly multiplexed sequencing readout, a method we called RT-PCR-seq. Seventy-nine percent of all assessed junctions are confirmed by this evaluation procedure, demonstrating the high quality of the GENCODE gene set. RT-PCR-seq was also efficient to screen gene models predicted using the Human Body Map (HBM) RNA-seq data. We validated 73% of these predictions, thus confirming 1168 novel genes, mostly noncoding, which will further complement the GENCODE annotation. Our novel experimental validation pipeline is extremely sensitive, far more than unbiased transcriptome profiling through RNA sequencing, which is becoming the norm. For example, exon-exon junctions unique to GENCODE annotated transcripts are five times more likely to be corroborated with our targeted approach than with extensive large human transcriptome profiling. Data sets such as the HBM and ENCODE RNA-seq data fail sampling of low-expressed transcripts. Our RT-PCR-seq targeted approach also has the advantage of identifying novel exons of known genes, as we discovered unannotated exons in ~11% of assessed introns. We thus estimate that at least 18% of known loci have yet-unannotated exons. Our work demonstrates that the cataloging of all of the genic elements encoded in the human genome will necessitate a coordinated effort between unbiased and targeted approaches, like RNA-seq and RT-PCR-seq.

Stage-specific integration of maternal and embryonic peroxisome proliferator-activated receptor delta signaling is critical to pregnancy success.

Successful pregnancy depends on well coordinated developmental events involving both maternal and embryonic components. Although a host of signaling pathways participate in implantation, decidualization, and placentation, whether there is a common molecular link that coordinates these processes remains unknown. By exploiting genetic, molecular, pharmacological, and physiological approaches, we show here that the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR) delta plays a central role at various stages of pregnancy, whereas maternal PPARdelta is critical to implantation and decidualization, and embryonic PPARdelta is vital for placentation. Using trophoblast stem cells, we further elucidate that a reciprocal relationship between PPARdelta-AKT and leukemia inhibitory factor-STAT3 signaling pathways serves as a cell lineage sensor to direct trophoblast cell fates during placentation. This novel finding of stage-specific integration of maternal and embryonic PPARdelta signaling provides evidence that PPARdelta is a molecular link that coordinates implantation, decidualization, and placentation crucial to pregnancy success. This study is clinically relevant because deferral of on time implantation leads to spontaneous pregnancy loss, and defective trophoblast invasion is one cause of preeclampsia in humans.

Dissection of hormone-responsive plasma membrane to nucleus signaling of Bravis Radix : its role in vascular differentiation and root meristem growth

AbstractPlants continuously grow during their complete life span and understanding the mechanisms that qualitatively regulate their traits remains a challenging topic in biology. The hormone auxin has been identified as a crucial molecule for shaping plant growth, as it has a role in most developmental processes. In the root, the directional, so-called polar transport of auxin generates a peak of concentration that specifies and maintains the stem cell niche and a subsequent gradient of decreasing concentration that also regulates cell proliferation and differentiation. For these reasons, auxin is considered the main morphogen of the root, as it is fundamental for its organization and maintenance. Recently, in Arabidopsis thaliana, a natural variation screen allowed the discovery of BREVIS RADIX (BRX) gene as a limiting factor for auxin responsive gene expression and thus for root growth.In this study, we discovered that BRX is a direct target of auxin that positively feeds back on auxin signaling, as a transcriptional co-regulator, through interaction with the Auxin Response Factor (ARF) MONOPTEROS (MP), modulating the auxin gene response magnitude during the transition between division and differentiation in the root meristem. Moreover, we provide evidence that BRX is activated at the plasma membrane level as an associated protein before moving into the nucleus to modulate cellular growth.To investigate the discrepancy between the auxin concentration and the expression pattern of its downstream targets, we combined experimental and computational approaches. Expression profiles deviating from the auxin gradient could only be modeled after intersection of auxin activity with the observed differential endocytosis pattern and with positive auto- regulatory feedback through plasma- membrane-to-nucleus transfer of BRX. Because BRX is required for expression of certain auxin response factor targets, our data suggest a cell-type-specific endocytosis-dependent input into transcriptional auxin perception. This input sustains expression of a subset of auxin-responsive genes across the root meristem's division and transition zones and is essential for meristem growth. Thus, the endocytosis pattern provides specific positional information to modulate auxin response. RésuméLes plantes croissent continuellement tout au long de leur cycle de vie. Comprendre et expliquer les mécanismes impliqués dans ce phénomène reste à l'heure actuelle, un défi. L'hormone auxine a été identifiée comme une molécule essentielle à la régulation de la croissance des plantes, car impliquée dans la plupart des processus développementaux. Dans la racine, le transport polaire de l'auxine, par la génération d'un pic de concentration, spécifie et maintient la niche de cellules souches, et par la génération d'un gradient de concentration, contrôle la prolifération et la différentiation cellulaire. Puisque l'auxine est essentielle pour l'organisation et la maintenance du système racinaire, il est considéré comme son principal morphogène. Récemment, dans la plante modèle, Arabidopsis thalinana, un criblage des variations génétique a permis d'identifier le gène Brevis radix (BRX) comme facteur limitant l'expression des gènes de réponse à l'auxine et par là même, la croissance de la racine.Dans ce travail, nous avons découvert que BRX est une cible direct de l'auxine qui rétroactive positivement le signalement de l'hormone, agissant ainsi comme un régulateur transcriptionnel à travers l'interaction avec la protéine Monopteros (MP) de la famille des facteurs de réponse à l'auxine (Auxin Responsive Factor, ARF), et modulant ainsi la magnitude de la réponse des gènes reliés à l'auxine durant la division et la différentiation cellulaire dans le méristème de la racine. De plus, nous fournissons des preuves que BRX est activées au niveau de la membrane plasmique, tel une protéine associée se déplaçant à l'intérieur du noyau et modulant la croissance cellulaire.Pour mener à bien l'investigation des divergences entre la concentration de l'auxine et les schémas d'expression de ses propres gènes cibles, nous avons combiné les approches expérimentales et computationnelles. Les profiles d'expressions déviant du gradient d'auxine pourraient seulement être modéliser après intersection de l'activité de l'auxine avec les schémas différentiels d'endocytose observés et les boucles de rétroaction positives et autorégulatrices par le transfert de BRX de la membrane plasmique au noyau. Puisque BRX est requis pour l'expression de certains gènes cibles des facteurs de réponse à l'auxine, nos données suggèrent une contribution dépendante d'une endocytose spécifique au type de cellule dans la perception transcriptionnelle à l'auxine Cette contribution soutient l'expression d'un sous-set de gène de réponse à l'auxine dans la division du méristème racinaire et la zone de transition, et par conséquent, est essentielle pour la croissance méristematique. Ainsi, le schéma d'endocytose fournit des informations positionnelles spécifiques à la modulation de la réponse à l'auxine.

Detecting, quantifying and adjusting for publication bias in meta-analyses: protocol of a systematic review on methods.

BACKGROUND: Health professionals and policymakers aspire to make healthcare decisions based on the entire relevant research evidence. This, however, can rarely be achieved because a considerable amount of research findings are not published, especially in case of 'negative' results - a phenomenon widely recognized as publication bias. Different methods of detecting, quantifying and adjusting for publication bias in meta-analyses have been described in the literature, such as graphical approaches and formal statistical tests to detect publication bias, and statistical approaches to modify effect sizes to adjust a pooled estimate when the presence of publication bias is suspected. An up-to-date systematic review of the existing methods is lacking. METHODS/DESIGN: The objectives of this systematic review are as follows:âeuro¢ To systematically review methodological articles which focus on non-publication of studies and to describe methods of detecting and/or quantifying and/or adjusting for publication bias in meta-analyses.âeuro¢ To appraise strengths and weaknesses of methods, the resources they require, and the conditions under which the method could be used, based on findings of included studies.We will systematically search Web of Science, Medline, and the Cochrane Library for methodological articles that describe at least one method of detecting and/or quantifying and/or adjusting for publication bias in meta-analyses. A dedicated data extraction form is developed and pilot-tested. Working in teams of two, we will independently extract relevant information from each eligible article. As this will be a qualitative systematic review, data reporting will involve a descriptive summary. DISCUSSION: Results are expected to be publicly available in mid 2013. This systematic review together with the results of other systematic reviews of the OPEN project (To Overcome Failure to Publish Negative Findings) will serve as a basis for the development of future policies and guidelines regarding the assessment and handling of publication bias in meta-analyses.

Computational analysis of the genetic and environmental contributions to disease-related human phenotypes: From predicting adverse lipid response of HIV patients receiving antiretroviral therapy to genome-wide association studies of cardiovascular and lipid related disorders

Genetic variants influence the risk to develop certain diseases or give rise to differences in drug response. Recent progresses in cost-effective, high-throughput genome-wide techniques, such as microarrays measuring Single Nucleotide Polymorphisms (SNPs), have facilitated genotyping of large clinical and population cohorts. Combining the massive genotypic data with measurements of phenotypic traits allows for the determination of genetic differences that explain, at least in part, the phenotypic variations within a population. So far, models combining the most significant variants can only explain a small fraction of the variance, indicating the limitations of current models. In particular, researchers have only begun to address the possibility of interactions between genotypes and the environment. Elucidating the contributions of such interactions is a difficult task because of the large number of genetic as well as possible environmental factors.In this thesis, I worked on several projects within this context. My first and main project was the identification of possible SNP-environment interactions, where the phenotypes were serum lipid levels of patients from the Swiss HIV Cohort Study (SHCS) treated with antiretroviral therapy. Here the genotypes consisted of a limited set of SNPs in candidate genes relevant for lipid transport and metabolism. The environmental variables were the specific combinations of drugs given to each patient over the treatment period. My work explored bioinformatic and statistical approaches to relate patients' lipid responses to these SNPs, drugs and, importantly, their interactions. The goal of this project was to improve our understanding and to explore the possibility of predicting dyslipidemia, a well-known adverse drug reaction of antiretroviral therapy. Specifically, I quantified how much of the variance in lipid profiles could be explained by the host genetic variants, the administered drugs and SNP-drug interactions and assessed the predictive power of these features on lipid responses. Using cross-validation stratified by patients, we could not validate our hypothesis that models that select a subset of SNP-drug interactions in a principled way have better predictive power than the control models using "random" subsets. Nevertheless, all models tested containing SNP and/or drug terms, exhibited significant predictive power (as compared to a random predictor) and explained a sizable proportion of variance, in the patient stratified cross-validation context. Importantly, the model containing stepwise selected SNP terms showed higher capacity to predict triglyceride levels than a model containing randomly selected SNPs. Dyslipidemia is a complex trait for which many factors remain to be discovered, thus missing from the data, and possibly explaining the limitations of our analysis. In particular, the interactions of drugs with SNPs selected from the set of candidate genes likely have small effect sizes which we were unable to detect in a sample of the present size (<800 patients).In the second part of my thesis, I performed genome-wide association studies within the Cohorte Lausannoise (CoLaus). I have been involved in several international projects to identify SNPs that are associated with various traits, such as serum calcium, body mass index, two-hour glucose levels, as well as metabolic syndrome and its components. These phenotypes are all related to major human health issues, such as cardiovascular disease. I applied statistical methods to detect new variants associated with these phenotypes, contributing to the identification of new genetic loci that may lead to new insights into the genetic basis of these traits. This kind of research will lead to a better understanding of the mechanisms underlying these pathologies, a better evaluation of disease risk, the identification of new therapeutic leads and may ultimately lead to the realization of "personalized" medicine.

Combined transcriptomic and proteomic studies reveal non-canonical signaling functions in the jasmonate pathway

Abstract Lipid derived signals mediate many stress and defense responses in multicellular eukaryotes. Among these are the jasmonates, potently active signaling compounds in plants. Jasmonic acid (JA) and 12-oxo-phytodienoic acid (OPDA) are the two best known members of the large jasmonate family. This thesis further investigates their roles as signals using genomic and proteomic approaches. The study is based on a simple genetic model involving two key genes. The first is ALLENE OXIDE SYNTHASE (AOS), encoding the most important enzyme in generating jasmonates. The second is CORONATINE INSENSITIVE 1 (COI1), a gene involved in all currently documented canonical signaling responses. We asked the simple question: do null mutations in AOS and COI1 have analogous effects on the transcriptome ? We found that they do not. If most COI1-dependent genes were also AOS-dependent, the expression of a zinc-finger protein was AOS-dependent but was unaffected by the coi1-1 mutation. We thus supposed that a jasmonate member, most probably OPDA, can alter gene expression partially independently of COI1. Conversely, the expression of at least three genes, one of these is a protein kinase, was shown to be COI1-dependent but did not require a functional AOS protein. We conclude that a non-jasmonate signal might alter gene expression through COIL Proteomic comparison of coi1-1 and aos plants confirmed these observations and highlighted probable protein degradation processes controlled by jasmonates and COI1 in the wounded leaf. This thesis revealed new functions for COI1 and for AOS-generated oxylipins in the jasmonate signaling pathway. Résumé Les signaux dérivés d'acides gras sont des médiateurs de réponses aux stress et de la défense des eucaryotes multicellulaires. Parmi eux, les jasmonates sont de puissants composés de sig¬nalisation chez les plantes. L'acide jasmonique (JA) et l'acide 12-oxo-phytodienoïc (OPDA) sont les deux membres les mieux caractérisés de la grande famille des jasmonates. Cette thèse étudie plus profondément leurs rôles de signalisation en utilisant des approches génomique et protéomique. Cette étude est basée sur un modèle génétique simple n'impliquant que deux gènes. Le premier est PALLENE OXYDE SYNTHASE (AOS) qui encode l'enzyme la plus importante pour la fabrication des jasmonates. Le deuxième est CORONATINE INSENSITIVE 1 (COI1) qui est impliqué dans la totalité des réponses aux jasmonates connues à ce jour. Nous avons posé la question suivante : est-ce que les mutations nulles dans les gènes AOS et COI1 ont des effets analogues sur le transcriptome ? Nous avons trouvé que ce n'était pas le cas. Si la majorité des gènes dépendants de COI1 sont également dépendants d'AOS, l'expression d'un gène codant pour une protéine formée de doigts de zinc n'est pas affectée par la mutation de COI1 tout en étant dépendante d'AOS. Nous avons donc supposé qu'un membre de la famille des jasmonates, probablement OPDA, pouvait modifier l'expression de certains gènes indépendamment de COI1. Inversement, nous avons montré que, tout en étant dépendante de COI1, l'expression d'au moins trois gènes, dont un codant pour une protéine kinase, n'était pas affectée par l'absence d'une protéine AOS fonctionnelle. Nous en avons conclu qu'un signal autre qu'un jasmonate devait modifier l'expression de certains gènes à travers COI1. La comparaison par protéomique de plantes aos et coi1-1 a confirmé ces observations et a mis en évidence un probable processus de dégradation de protéines contrôlé par les jasmonates et COU_ Cette thèse a mis en avant de nouvelles fonctions pour COI1 et pour des oxylipines générées par AOS dans le cadre de la signalisation par les jasmonates.

Genome-wide transcriptional responses to shade: Linking shade avoidance and auxin

Plants have the ability to use the composition of incident light as a cue to adapt development and growth to their environment. Arabidopsis thaliana as well as many crops are best adapted to sunny habitats. When subjected to shade, these plants exhibit a variety of physiological responses collectively called shade avoidance syndrome (SAS). It includes increased growth of hypocotyl and petioles, decreased growth rate of cotyledons and reduced branching and crop yield. These responses are mainly mediated by phytochrome photoreceptors, which exist either in an active, far-red light (FR) absorbing or an inactive, red light (R) absorbing isoform. In direct sunlight, the R to FR light (R/FR) ratio is high and converts the phytochromes into their physiologically active state. The phytochromes interact with downstream transcription factors such as PHYTOCHROME INTERACTING FACTOR (PIF), which are subsequently degraded. Light filtered through a canopy is strongly depleted in R, which result in a low R/FR ratio and renders the phytochromes inactive. Protein levels of downstream transcription factors are stabilized, which initiates the expression of shade-induced genes such as HFR1, PIL1 or ATHB-2. In my thesis, I investigated transcriptional responses mediated by the SAS in whole Arabidopsis seedlings. Using microarray and chromatin immunoprecipitation data, we identified genome-wide PIF4 and PIF5 dependent shade regulated gene as well as putative direct target genes of PIF5. This revealed evidence for a direct regulatory link between phytochrome signaling and the growth promoting phytohormone auxin (IAA) at the level of biosynthesis, transport and signaling. Subsequently, it was shown, that free-IAA levels are upregulated in response to shade. It is assumed that shade-induced auxin production takes predominantly place in cotyledons of seedlings. This implies, that IAA is subsequently transported basipetally to the hypocotyl and enhances elongation growth. The importance of auxin transport for growth responses has been established by chemical and genetic approaches. To gain a better understanding of spatio-temporal transcriptional regulation of shade-induce auxin, I generated in a second project, an organ specific high throughput data focusing on cotyledon and hypocotyl of young Arabidopsis seedlings. Interestingly, both organs show an opposite growth regulation by shade. I first investigated the spatio-transcriptional regulation of auxin re- sponsive gene, in order to determine how broad gene expression pattern can be explained by the hypothesized movement of auxin from cotyledons to hypocotyls in shade. The analysis suggests, that several genes are indeed regulated according to our prediction and others are regulated in a more complex manner. In addition, analysis of gene families of auxin biosynthetic and transport components, lead to the identification of essential family members for shade-induced growth re- sponses, which were subsequently experimentally confirmed. Finally, the analysis of expression pattern identified several candidate genes, which possibly explain aspects of the opposite growth response of the different organs.

Predicting drug metabolism: experiment and/or computation?

Drug metabolism can produce metabolites with physicochemical and pharmacological properties that differ substantially from those of the parent drug, and consequently has important implications for both drug safety and efficacy. To reduce the risk of costly clinical-stage attrition due to the metabolic characteristics of drug candidates, there is a need for efficient and reliable ways to predict drug metabolism in vitro, in silico and in vivo. In this Perspective, we provide an overview of the state of the art of experimental and computational approaches for investigating drug metabolism. We highlight the scope and limitations of these methods, and indicate strategies to harvest the synergies that result from combining measurement and prediction of drug metabolism.

The contribution of individual and professional characteristics to general and work-related well-being

Cette thèse porte sur la contribution des caractéristiques individuelles et des situations professionnelles au bien-être. En combinant différentes perspectives théoriques, notamment la théorie de la construction de la carrière, la théorie de la justice organisationnelle, les modèles du bien-être au travail, et les conceptualisations de l'incivilité au travail, un certain nombre d'hypothèses sont proposées concernant le lien entre certaines caractéristiques individuelles et situationnelles et le bien-être général et professionnel. Les deux premières études se focalisent sur la validation d'une échelle d'adaptabilités de carrière et sur le rôle médiateur de cette adaptabilité dans la relation entre des dispositions et le bien-être. La troisième étude évolue l'hypothèse d'un possible effet de médiation de l'adaptabilité mais cette fois de la relation entre insécurité professionnelle et charge de travail d'une part et le bien-être d'autre part. La quatrième étude adopte une perspective longitudinale et analyse les associations entre les dimensions de la personnalité, l'adaptabilité de carrière et le bien-être dans quatre parcours professionnels différents. La cinquième étude porte sur une autre caractéristique individuelle, à savoir la croyance en un monde juste. Cette étude illustre comment la croyance en un monde juste influence les perceptions de justice organisationnelle une année après, qui ont une incidence importante sur le bien-être. Enfin, la dernière étude se concentre sur une population spécifique, les immigrants en Suisse, et souligne qu'être la cible d'incivilité sur le lieu de travail est généralement liée au pays d'origine. Globalement, cette thèse met en évidence que les caractéristiques individuelles ont des effets tant directs qu'indirects sur le bien-être et que ces mêmes caractéristiques explique en partie, les relations entre la situation professionnelle et le bien-être. Plus spécifiquement, des situations professionnelles peuvent influencer l'expression de certaines caractéristiques individuelles, soit en contribuant à leurs activations ou à leurs inhibitions. De plus, l'impact des caractéristiques individuelles sur le bien-être semble dépendre de la situation professionnelle. Il est donc important de considérer les influences simultanées et réciproques des caractéristiques individuelles et de la situation contextuelle et professionnelle pour rendre compte du bien-être général et professionnel. -- This thesis explores how individual characteristics and professional situations correspond to well-being. Drawing from various theoretical backgrounds, such as career construction theory, justice theory, models of job strain, and theories on subtle discrimination, a number of specific hypotheses are put forward pertaining to a selection of individual and professional aspects as well as general and work-related well-being. The six studies presented in this thesis focus on specific aspects and adopt different methodological and theoretical approaches. The first two studies concern the validation of the career adapt-abilities scale and test the potential of career adapt-abilities to mediate the relationship between dispositions and outcomes. The third study extends the hypothesis of career adapt-abilities as a mediator and finds that it mediates the effects of job insecurity and job strain on general and professional well-being. The fourth study adopts a longitudinal approach and tests the associations between personality traits and career adaptability and well-being in four different professional situations. Study five concerns another individual characteristic, belief in a just world, and illustrates how justice beliefs drive perceptions of organizational justice, which in turn impact, on well-being outcomes one year later. The final study focuses on the professional experiences of a specific population, immigrants in Switzerland, and confirms that being a target of incivilities is related to national origin. Globally, this thesis finds that individual characteristics have direct and indirect influences on well-being and that these characteristics may also mediate the associations between professional situations and outcomes. In particular, the professional situation may alter the display of individual characteristics, either by contributing to their activation or their depletion, and the ways in which individual factors influence well-being does seem to depend on the professional situation. It is thus necessary to adopt a "both...and" perspective when studying the impact of individual and professional characteristics as these factors mutually influence each other.

Gaining momentum: New options and opportunities for the treatment of advanced melanoma.

Before 2011, patients with advanced or metastatic melanoma had a particularly poor long-term prognosis. Since traditional treatments failed to confer a survival benefit, patients were preferentially entered into clinical trials of investigational agents. A greater understanding of the epidemiology and biology of disease has underpinned the development of newer therapies, including six agents that have been approved in the EU, US and/or Japan: a cytotoxic T-lymphocyte antigen-4 inhibitor (ipilimumab), two programmed cell death-1 receptor inhibitors (nivolumab and pembrolizumab), two BRAF inhibitors (vemurafenib and dabrafenib) and a MEK inhibitor (trametinib). The availability of these treatments has greatly improved the outlook for patients with advanced melanoma; however, a major consideration for physicians is now to determine how best to integrate these agents into clinical practice. Therapeutic decisions are complicated by the need to consider patient and disease characteristics, and individual treatment goals, alongside the different efficacy and safety profiles of agents with varying mechanisms of action. Long-term survival, an outcome largely out of reach with traditional systemic therapies, is now a realistic goal, creating the additional need to re-establish how clinical benefit is evaluated. In this review we summarise the current treatment landscape in advanced melanoma and discuss the promise of agents still in development. We also speculate on the future of melanoma treatment and discuss how combination and sequencing approaches may be used to optimise patient care in the future.

A definition and classification of status epilepticus - Report of the ILAE Task Force on Classification of Status Epilepticus.

The Commission on Classification and Terminology and the Commission on Epidemiology of the International League Against Epilepsy (ILAE) have charged a Task Force to revise concepts, definition, and classification of status epilepticus (SE). The proposed new definition of SE is as follows: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1 ). It is a condition, which can have long-term consequences (after time point t2 ), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. This definition is conceptual, with two operational dimensions: the first is the length of the seizure and the time point (t1 ) beyond which the seizure should be regarded as "continuous seizure activity." The second time point (t2 ) is the time of ongoing seizure activity after which there is a risk of long-term consequences. In the case of convulsive (tonic-clonic) SE, both time points (t1 at 5 min and t2 at 30 min) are based on animal experiments and clinical research. This evidence is incomplete, and there is furthermore considerable variation, so these time points should be considered as the best estimates currently available. Data are not yet available for other forms of SE, but as knowledge and understanding increase, time points can be defined for specific forms of SE based on scientific evidence and incorporated into the definition, without changing the underlying concepts. A new diagnostic classification system of SE is proposed, which will provide a framework for clinical diagnosis, investigation, and therapeutic approaches for each patient. There are four axes: (1) semiology; (2) etiology; (3) electroencephalography (EEG) correlates; and (4) age. Axis 1 (semiology) lists different forms of SE divided into those with prominent motor systems, those without prominent motor systems, and currently indeterminate conditions (such as acute confusional states with epileptiform EEG patterns). Axis 2 (etiology) is divided into subcategories of known and unknown causes. Axis 3 (EEG correlates) adopts the latest recommendations by consensus panels to use the following descriptors for the EEG: name of pattern, morphology, location, time-related features, modulation, and effect of intervention. Finally, axis 4 divides age groups into neonatal, infancy, childhood, adolescent and adulthood, and elderly.

Tropheryma whipplei bivalvular endocarditis and polyarthralgia: a case report.

INTRODUCTION: Tropheryma whipplei infection should be considered in patients with suspected infective endocarditis with negative blood cultures. The case (i) shows how previous symptoms can contribute to the diagnosis of this illness, and (ii) elucidates current recommended diagnostic and therapeutic approaches to Whipple's disease. CASE PRESENTATION: A 71-year-old Swiss man with a past history of 2 years of diffuse arthralgia was admitted for a possible endocarditis with severe aortic and mitral regurgitation. Serial blood cultures were negative. Our patient underwent replacement of his aortic and mitral valve by biological prostheses. T. whipplei was documented by polymerase chain reactions on both removed valves and on stools, as well as by valve histology. A combination of hydroxychloroquine and doxycycline was initiated as lifetime treatment followed by the complete disappearance of his arthralgia. CONCLUSIONS: This case report underlines the importance of considering T. whipplei as a possible causal etiology of blood culture-negative endocarditis. Lifelong antibiotic treatment should be considered for this pathogen (i) due to the significant rate of relapses, and (ii) to the risk of reinfection with another strain since these patients likely have some genetic predisposition.

Local capitalism and neoliberalization in a Shenzhen former lineage-village

This article examines the process of neoliberalization in the Shenzhen special economic zone in Guangdong province, China. Building on the case study of a former peasant and almost single-lineage village that has become a part of Shenzhen city, I show how neoliberal principles aimed at advancing the transition to capitalism are combined with and countered by other ethical traditions. Owing to the long-standing conception of the lineage as an enterprise, the maintenance of the lineage structure in the transformation of the rural collectives has offered fertile ground for the emergence of a local capitalist coalition. Yet the current discourses on the necessity of obliterating the remains of the collective economy and introducing individual ownership run counter to the collectivist values of the lineage-village community and the embeddedness of its economy in kinship and territorial ties. I further illustrate this discordance by the way in which the villagers managed to save their founding ancestor's gravesite following government requests to clear the land by removing tombs. These policies form a complex blend of state interventions in the economy, neoliberal governance and Confucian principles.

Attenuated Levels of Hippocampal Connexin 43 and its Phosphorylation Correlate with Antidepressant- and Anxiolytic-Like Activities in Mice.

Clinical and preclinical studies have implicated glial anomalies in major depression. Conversely, evidence suggests that the activity of antidepressant drugs is based, at least in part, on their ability to stimulate density and/or activity of astrocytes, a major glial cell population. Despite this recent evidence, little is known about the mechanism(s) by which astrocytes regulate emotionality. Glial cells communicate with each other through gap junction channels (GJCs), while they can also directly interact with neurons by releasing gliotransmitters in the extracellular compartment via an hemichannels (HCs)-dependent process. Both GJCs and HCs are formed by two main protein subunits: connexins (Cx) 30 and 43 (Cx30 and Cx43). Here we investigate the role of hippocampal Cx43 in the regulation of depression-like symptoms using genetic and pharmacological approaches. The first aim of this study was to evaluate the impact of the constitutive knock-down of Cx43 on a set of behaviors known to be affected in depression. Conversely, the expression of Cx43 was assessed in the hippocampus of mice subjected to prolonged corticosterone (CORT) exposure, given either alone or in combination with an antidepressant drug, the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that the constitutive deficiency of Cx43 resulted in the expression of some characteristic hallmarks of antidepressant-/anxiolytic-like behavioral activities along with an improvement of cognitive performances. Moreover, in a new cohort of wild-type mice, we showed that CORT exposure elicited anxiety and depression-like abnormalities that were reversed by chronic administration of fluoxetine. Remarkably, CORT also increased hippocampal amounts of phosphorylated form of Cx43 whereas fluoxetine treatment normalized this parameter. From these results, we envision that antidepressant drugs may exert their therapeutic activity by decreasing the expression and/or activity of Cx43 resulting from a lower level of phosphorylation in the hippocampus.