Aseptic meningoencephalitis mimicking transient ischaemic attacks.

PURPOSE: To highlight meningoencephalitis as a transient ischaemic attack (TIA) mimic and suggest clinical clues for differential diagnosis. METHODS: This was an observational study of consecutively admitted patients over a 9.75-year period presenting as TIAs at a stroke unit. RESULTS: A total of 790 patients with TIAs and seven with TIA-like symptoms but a final diagnosis of viral meningoencephalitis were recognised. The most frequent presentations of meningoencephalitis patients were acute sensory hemisyndrome (6) and cognitive deficits (5). Signs of meningeal irritation were minor or absent on presentation. Predominantly lymphocytic pleocytosis, hyperproteinorachia and a normal cerebrospinal fluid (CSF)/serum glucose index (in 5 out of 6 documented patients) were present. Meningeal thickening on a brain magnetic resonance imaging (MRI) scan was the only abnormal imaging finding. Six patients received initial vascular treatment; one thrombolysed. Finally, six patients were treated with antivirals and/or antibiotics. Although neither bacterial nor viral agents were identified on extensive testing, viral meningoencephalitis was the best explanation for all clinical and laboratory findings. CONCLUSIONS: Aseptic meningoencephalitis should be part of the differential diagnosis in patients presenting as TIA. The threshold for a lumbar puncture in such patients should be set individually and take into account the presence of mild meningeal symptoms, age and other risk factors for vascular disease, the results of brain imaging and the basic diagnostic work-up for a stroke source.

Social personality trait and fitness.

Several recent studies have explored various aspects of animal personality and their ecological consequences. However, the processes responsible for the maintenance of personality variability within a population are still largely unknown. We have recently demonstrated that social personality traits exist in the common lizard (Lacerta vivipara) and that the variation in sociability provides an explanation for variable dispersal responses within a given species. However, we need to know the fitness consequences of variation in sociability across environmental contexts in order to better understand the maintenance of such variation. In order to achieve this, we investigated the relationship between sociability and survival, body growth and fecundity, in one-year-old individuals in semi-natural populations with varying density. 'Asocial' and 'social' lizards displayed different fitness outcomes in populations of different densities. Asocial lizards survived better in low-density populations, while social females reproduced better. Spatiotemporal variation in environmental conditions might thus be the process underlying the maintenance of these personality traits within a population. Finally, we also discuss the position of sociability in a more general individual behavioural pattern including boldness, exploration and aggressiveness.

Immune system's role in viral encephalitis.

Viral infections can be a major thread for the central nervous system (CNS), therefore, the immune system must be able to mount a highly proportionate immune response, not too weak, which would allow the virus to proliferate, but not too strong either, to avoid collateral damages. Here, we aim at reviewing the immunological mechanisms involved in the host defense in viral CNS infections. First, we review the specificities of the innate as well as the adaptive immune responses in the CNS, using several examples of various viral encephalitis. Then, we focus on three different modes of interactions between viruses and immune responses, namely human Herpes virus-1 encephalitis with the defect in innate immune response which favors this disease; JC virus-caused progressive multifocal leukoencephalopathy and the crucial role of adaptive immune response in this example; and finally, HIV infection with the accompanying low grade chronic inflammation in the CNS in some patients, which may be an explanation for the presence of cognitive disorders, even in some well-treated HIV-infected patients. We also emphasize that, although the immune response is generally associated with viral replication control and limited cellular death, an exaggerated inflammatory reaction can lead to tissue damage and can be detrimental for the host, a feature of the immune reconstitution inflammatory syndrome (IRIS). We will briefly address the indication of steroids in this situation.

H-2D ligand expression by Ly49A+ natural killer (NK) cells precludes ligand uptake from environmental cells: implications for NK cell function.

To study the adaptation of natural killer (NK) cells to their major histocompatibility complex (MHC) class I environment we have established a novel mouse model with mosaic expression of H-2D(d) using a Cre/loxP system. In these mice, we noticed that NK cells expressing the inhibitory receptor for D(d), Ly49A, were specifically underrepresented among cells with low D(d) levels. That was due to the acquisition of D(d) molecules by the Ly49A+ NK cells that have lost their D(d) transgene. The uptake of H-2D molecules via the Ly49A receptor was restricted to strong ligands of Ly49A. Surprisingly, when Ly49A+ NK cells were D(d+), uptake of the alternative ligand D(k) was not detectable. Similarly, one anti-Ly49A mAb (A1) bound inefficiently when Ly49A was expressed on D(d+) NK cells. Concomitantly, functional assays demonstrated a reduced capacity of Ly49A to inhibit H-2(b)D(d) as compared with H-2(b) NK cells, rendering Ly49A+ NK cells in D(d+) mice particularly reactive. Minor reductions of D(d) levels and/or increases of activating ligands on environmental cells may thus suffice to abrogate Ly49A-mediated NK cell inhibition. The mechanistic explanation for all these phenomena is likely the partial masking of Ly49A by D(d) on the same cell via a lateral binding site in the H-2D(d) molecule.

Questioning the utility of RNA-DNA chimera in gene repair.

In principle, we should be glad that Eric Kmiec and his colleagues published in Science's STKE (1) a detailed experimental protocol of their gene repair method (2, 3). However, a careful reading of their contribution raises more doubts about the method. The research published in Science five years ago by Kmiec and his colleagues was said to demonstrate that chimeric RNA-DNA oligonucleotides could correct the mutation responsible for sickle cell anemia with 50% efficiency (4). Such a remarkable result prompted many laboratories to attempt to replicate the research or utilize the method on their own systems. However, if the method worked at all, which it rarely did, the achieved efficiency was usually lower by several orders of magnitude. Now, in the Science's STKE protocol, we are given crucial information about the method and why it is so important to utilize these expensive chimeric RNA-DNA constructs. In the introduction we are told that the RNA-DNA duplex is more stable than a DNA-DNA duplex and so extends the half-life of the complexes formed between the targeted DNA and the chimeric RNA-DNA oligonucleotides. This logical explanation, however, conflicts with the statement in the section entitled "Transfection with Oligonucleotides and Plasmid DNA" that Kmiec and colleagues have recently demonstrated that classical single-stranded DNA oligonucleotides with a few protective phosphothioate linkages have a "gene repair conversion frequency rivaling that of the RNA/DNA chimera". Indeed, the research cited for that result actually states that single-stranded DNA oligonucleotides are in fact several-fold more efficient (3.7-fold) than the RNA-DNA chimeric constructs (5). If that is the case, it raises the question of why Kmiec and colleagues emphasize the importance of the RNA in their original chimeric constructs. Their own new results show that modified single-stranded DNA oligonucleotides are more effective than the expensive RNA-DNA hybrids. Moreover, the current efficiency of the gene repair by RNA-DNA hybrids, according to Kmiec and colleagues in their recent paper is only 4×10-4 even after several hours of pre-selection permitting multiplification of bacterial cells with the corrected plasmid (5). This efficiency is much lower than the 50% value reported five years ago, but is assuredly much closer to the reality.

Preferential binding of the methyl-CpG binding domain protein 2 at methylated transcriptional start site regions.

Methyl-CpG Binding Domain (MBD) proteins are thought to be key molecules in the interpretation of DNA methylation signals leading to gene silencing through recruitment of chromatin remodeling complexes. In cancer, the MBD-family member, MBD2, may be primarily involved in the repression of genes exhibiting methylated CpG at their 5' end. Here we ask whether MBD2 randomly associates methylated sequences, producing chance effects on transcription, or exhibits a more specific recognition of some methylated regions. Using chromatin and DNA immunoprecipitation, we analyzed MBD2 and RNA polymerase II deposition and DNA methylation in HeLa cells on arrays representing 25,500 promoter regions. This first whole-genome mapping revealed the preferential localization of MBD2 near transcription start sites (TSSs), within the region analyzed, 7.5 kb upstream through 2.45 kb downstream of 5' transcription start sites. Probe by probe analysis correlated MBD2 deposition and DNA methylation. Motif analysis did not reveal specific sequence motifs; however, CCG and CGC sequences seem to be overrepresented. Nonrandom association (multiple correspondence analysis, p < 0.0001) between silent genes, DNA methylation and MBD2 binding was observed. The association between MBD2 binding and transcriptional repression weakened as the distance between binding site and TSS increased, suggesting that MBD2 represses transcriptional initiation. This hypothesis may represent a functional explanation for the preferential binding of MBD2 at methyl-CpG in TSS regions.

Mitotic figure counts are significantly overestimated in resection specimens of invasive breast carcinomas.

Several authors have demonstrated an increased number of mitotic figures in breast cancer resection specimen when compared with biopsy material. This has been ascribed to a sampling artifact where biopsies are (i) either too small to allow formal mitotic figure counting or (ii) not necessarily taken form the proliferating tumor periphery. Herein, we propose a different explanation for this phenomenon. Biopsy and resection material of 52 invasive ductal carcinomas was studied. We counted mitotic figures in 10 representative high power fields and quantified MIB-1 immunohistochemistry by visual estimation, counting and image analysis. We found that mitotic figures were elevated by more than three-fold on average in resection specimen over biopsy material from the same tumors (20±6 vs 6±2 mitoses per 10 high power fields, P=0.008), and that this resulted in a relative diminution of post-metaphase figures (anaphase/telophase), which made up 7% of all mitotic figures in biopsies but only 3% in resection specimen (P<0.005). At the same time, the percentages of MIB-1 immunostained tumor cells among total tumor cells were comparable in biopsy and resection material, irrespective of the mode of MIB-1 quantification. Finally, we found no association between the size of the biopsy material and the relative increase of mitotic figures in resection specimen. We propose that the increase in mitotic figures in resection specimen and the significant shift towards metaphase figures is not due to a sampling artifact, but reflects ongoing cell cycle activity in the resected tumor tissue due to fixation delay. The dwindling energy supply will eventually arrest tumor cells in metaphase, where they are readily identified by the diagnostic pathologist. Taken together, we suggest that the rapidly fixed biopsy material better represents true tumor biology and should be privileged as predictive marker of putative response to cytotoxic chemotherapy.

La gestion des services environnementaux: entre règles et régulation négociée. Six études de cas de services forestiers pour la production d'eau potable dans trois pays

Cette thèse est construite en quatre parties : trois annexes qui présentent six études de cas (env. 800 pages), précédées par une analyse transversale, plus synthétique (env. 150 pages), dont traite ce résumé. Chaque annexe contient une synthèse détaillée des études de cas. Cette thèse aborde la « gestion des ressources naturelles » en affirmant d'emblée que l'appellation est inappropriée, car ce ne sont pas les ressources qui sont gérées, mais leurs usages. Il s'agit donc d'identifier et d'analyser ce qui influence les comportements humains en lien avec la ressource. Cette affirmation fonde la perspective des sciences sociales sur la gestion des ressources naturelles, dans laquelle s'inscrit cette thèse. L'approche néo-institutionnaliste considère que les usages sont influencés par des institutions, qui sont elles-mêmes influencées par les usagers. Ces institutions sont des constructions humaines qui composent le contexte institutionnel dans lequel les acteurs décident de leurs usages (abattre un arbre, prélever de l'eau, etc.). Les usages des ressources ne sont donc jamais libres et il s'agit de comprendre comment ces règles du jeu influencent les pratiques. Elles sont nombreuses, interdépendantes et forment la trame sur laquelle se décident les usages. Pour saisir cette complexité, l'auteur applique le cadre d'analyse des régimes institutionnels des ressources (RIR) qui se limite à l'analyse de deux types de droits d'usages : ceux issues des règles de la propriété (titres de propriété, servitudes, etc.) et ceux issus des politiques publiques (lois, ordonnances, etc.). Le RIR permet d'identifier un « régime institutionnel », spécifique à la ressource étudiée, dont les évolutions peuvent être comparées dans le temps ou entre plusieurs lieux. Dans cette recherche, ce cadre d'analyse a été appliqué au même objet - la gestion forestière dans les zones de captage d'eau souterraine destinée au réseau public - dans trois pays : en France, en Suisse et en Indonésie. Trois années de recherche de terrain ont permis à l'auteur de s'intéresser non seulement aux règles prédéterminées (la réglementation), mais aussi aux règles effectivement activées sur le terrain (la régulation) par les acteurs rencontrés. Les études de cas montrent que les règles prévues sont inégalement activées et que les acteurs privilégient parfois la négociation directe pour résoudre leurs rivalités d'usages, à la place d'invoquer leurs droits acquis. Ce constat conduit l'auteur à proposer un élargissement de la focale du RIR, qui constitue le coeur de sa thèse. On ne s'intéresse plus seulement à ce qui « est » régulé, mais aussi à ce qui ne l'« est pas » et qui échappe à l'application classique du RIR. Ce renversement de perspective est crucial pour comprendre les usages concrets des ressources dans les régimes peu intégrés, où les pratiques s'expliquent davantage par la marge de manoeuvre laissée aux acteurs que par les règles prédéterminées. Cette relecture, testée avec succès dans cette thèse, permet d'intégrer la marge de manoeuvre à l'analyse au moyen du RIR. Elle se concrétise par l'identification des lacunes et incohérences dans les régimes institutionnels étudiés. Le champ d'application du RIR s'en trouve élargi et sa vulgarisation pour des non-spécialistes est facilitée, notamment pour les environnementalistes. La complémentarité entre les approches s'en trouve renforcée. Les résultats montrent deux choses : premièrement les acteurs disposent toujours d'une marge de manoeuvre pour négocier des régulations ponctuelles, qui sont autant d'alternatives à l'application des règles prévues. Deuxièmement, la conclusion d'accords issus de la négociation bi-/multilatérale dépend directement de la marge de manoeuvre laissée par le contexte institutionnel. Ceci explique pourquoi la négociation entre les propriétaires forestiers et les exploitants de captages s'imposent en Indonésie, est envisageable en France, mais n'aboutit pas en Suisse. Les nombreuses tentatives infructueuses de mise en oeuvre de solutions négociées, notamment sous forme de paiements pour services environnementaux (PSE), trouvent ici une explication. - This thesis (written in French) is built in four parts: three annexes that present six case studies (approx. 800 pages), preceded by a transverse, more conceptual analysis (approx. 150 pages), which this summary is about. Each annexe contains a detailed summary of the case studies. 'Natural resource management' is an inappropriate designation because it is not the resources that are managed but the uses made of them, therefore this thesis addresses the identification and analysis of the influences on human behaviour in relation to the resource. This statement roots the social sciences perspective on the management of natural resources, in which this thesis fits. A neoinstitutionalist approach considers that the uses are influenced by institutions, which are themselves influenced by users. These institutions are human constructions that form the institutional context in which the actors decide on the use of resources (felling a tree, collecting water, etc.). Thus, the uses of resources are never independent from institutional influences and it becomes necessary to understand how these rules of the game affect practices. They are numerous, interrelated and form the basis for the uses of resources. To understand this complexity, the author applies the institutional regime resource framework (IRR) which limits the analysis to two types of use rights: those resulting from the property rights (deeds, easements, etc.) and those from public policies (laws, ordinances, etc.). The IRR identifies an 'institutional regime', specific to the resource, from which developments can be compared over time or between several places. In this research, this analytical framework has been applied to the same topic - forest management in the recharging areas of groundwater piped for public supply - in three countries: France, Switzerland and Indonesia. Three years of field research allow the author to look not only at predetermined rules (rules), but also at regulations that are actually activated on the ground (rules-in-use). The case studies show that the predetermined rules are unevenly applied and that sometimes actors favour direct negotiation to resolve their rivalry of uses, instead of invoking their vested rights. From this observation the author proposes an enlargement of the IRR's scope, forming the core of his thesis. The interest covers not only what 'is' regulated, but what 'is not' and so is beyond the classical application of the IRR. This shift in perspective is crucial to understand the concrete uses of resources in poorly integrated regimes, where practices are explained by the margin of manoeuvre left to the actors rather than predetermined rules. This reinterpretation, tested successfully in this research, allows the margin of manoeuvre to be integrated in the analysis using the IRR and is made concrete by the identification of gaps and inconsistencies in the investigated institutional context. The new interpretation of the IRR in this thesis complements and enhances its classical application. In particular, its use and understanding by non-specialists, especially environmentalists, is facilitated. The results show two things: first the actors always have leeway to negotiate ad hoc regulations, which are alternatives to the application of the predefined rules. Second, the conclusion of bi/multilateral negotiated agreements depends directly on the leeway left by the institutional context. This explains why the negotiation between forest owners and operators of water catchments is needed in Indonesia, is possible in France, but does not succeed in Switzerland. This offers an explanation for many unsuccessful attempts to implement negotiated solutions, notably payments for environmental services (PES).

The likelihood approach to compare populations : a study on DNA evidence and pitfalls of intuitions

The paper follows on from earlier work [Taroni F and Aitken CGG. Probabilistic reasoning in the law, Part 1: assessment of probabilities and explanation of the value of DNA evidence. Science & Justice 1998; 38: 165-177]. Different explanations of the value of DNA evidence were presented to students from two schools of forensic science and to members of fifteen laboratories all around the world. The responses were divided into two groups; those which came from a school or laboratory identified as Bayesian and those which came from a school or laboratory identified as non-Bayesian. The paper analyses these responses using a likelihood approach. This approach is more consistent with a Bayesian analysis than one based on a frequentist approach, as was reported by Taroni F and Aitken CGG. [Probabilistic reasoning in the law, Part 1: assessment of probabilities and explanation of the value of DNA evidence] in Science & Justice 1998.

Policy Credibility and Delegation to Independent Regulatory Agencies: A Comparative Empirical Analysis

Independent regulatory agencies are one of the main institutional features of the 'rising regulatory state' in Western Europe. Governments are increasingly willing to abandon their regulatory competencies and to delegate them to specialized institutions that are at least partially beyond their control. This article examines the empirical consistency of one particular explanation of this phenomenon, namely the credibility hypothesis, claiming that governments delegate powers so as to enhance the credibility of their policies. Three observable implications are derived from the general hypothesis, linking credibility and delegation to veto players, complexity and interdependence. An independence index is developed to measure agency independence, which is then used in a multivariate analysis where the impact of credibility concerns on delegation is tested. The analysis relies on an original data set comprising independence scores for thirty-three regulators. Results show that the credibility hypothesis can explain a good deal of the variation in delegation. The economic nature of regulation is a strong determinant of agency independence, but is mediated by national institutions in the form of veto players.

Paper money and national distress: William Huskisson and the early theories of credit, speculation and crises

This paper examines the explanation of commercial crises offered by William Huskisson in 1810 in the wake of the debate on the Bullion Report. Huskisson argued that the suspension of convertibility made it possible to extend issues of paper currency beyond its proper limits. Such an expansion, being in the interest of all parties concerned, would actually take place and stimulate excessive speculations, which would eventually prove unsustainable and bring generalized ruin and distress. Although some elements of this explanations were not new (having been anticipated by writers sucha as James Currie in 1793, William Roscoe in 1793, William Anderson in 1797 and an anonymous in 1796), Huskisson's explanation is more systematic and better organized, and his emphasis on the endogenous character of the crisis and on the instability of the dynamics of trade and credit makes it an interesting foreshadower of the theories of crises that were advanced half a century later.

Änderung des Therapieziels am Lebensende: Effekte einer Klinik-Leitlinie [Changing the treatment goal at the end of life: effects of a guideline at a hospital].

BACKGROUND AND OBJECTIVE: Deciding about treatment goals at the end of life is a frequent and difficult challenge to medical staff. As more health care institutions issue ethico-legal guidelines to their staff the effects of such a guideline should be investigated in a pilot project.¦PARTICIPANTS AND METHODS: Prospective evaluation study using the pre-post method. Physicians and nurses working in ten intensive care units of a university medical center in Germany answered a specially designed questionnaire before and one year after issuance of the guideline.¦RESULTS: 197 analyzable answers were obtained from the first (pre-guideline) and 251 from the second (post-guideline) survey (54 % and 58 % response rate, respectively). Initially the clinicians expressed their need for guidelines, advice on ethical problems, and continuing education. One year after introduction of the guideline one third of the clinicians was familiar with the guideline's content and another third was aware of its existence. 90% of those who knew the document welcomed it. Explanation of the legal aspects was seen as its most useful element. The pre- and post-guideline comparison demonstrated that uncertainty in decision making and fear of legal consequences were reduced, while knowledge of legal aspects and the value given to advance directives increased. The residents had derived the greatest benefit.¦CONCLUSION: By promoting the knowledge of legal aspects and ethical considerations, guidelines given to medical staff can lead to more certainty when making in end of life decision.

Generation of polycyclic aromatic hydrocarbons (PAHs) during woodworking operations.

Occupational exposures to wood dust have been associated with an elevated risk of sinonasal cancer (SNC). Wood dust is recognized as a human carcinogen but the specific cancer causative agent remains unknown. One possible explanation is a co-exposure to; wood dust and polycyclic aromatic hydrocarbons (PAHs). PAHs could be generated during incomplete combustion of wood due to heat created by use of power tools. To determine if PAHs are generated from wood during common wood working operations, PAH concentrations in wood dust samples collected in an experimental chamber operated under controlled conditions were analyzed. In addition, personal air samples from workers exposed to wood dust (n = 30) were collected. Wood dust was generated using three different power tools: vibrating sander, belt sander, and saw; and six wood materials: fir, Medium Density Fiberboard (MDF), beech, mahogany, oak and wood melamine. Monitoring of wood workers was carried out by means of personal sampler device during wood working operations. We measured 21 PAH concentrations in wood dust samples by capillary gas chromatography-ion trap mass spectrometry (GC-MS). Total PAH concentrations in wood dust varied greatly (0.24-7.95 ppm) with the lowest being in MDF dust and the highest in wood melamine dust. Personal PAH exposures were between 37.5-119.8 ng m(-3) during wood working operations. Our results suggest that PAH exposures are present during woodworking operations and hence could play a role in the mechanism of cancer induction related to wood dust exposure.

Primary care at Swiss universities--current state and perspective.

BACKGROUND: There is increasing evidence that a strong primary care is a cornerstone of an efficient health care system. But Switzerland is facing a shortage of primary care physicians (PCPs). This pushed the Federal Council of Switzerland to introduce a multifaceted political programme to strengthen the position of primary care, including its academic role. The aim of this paper is to provide a comprehensive overview of the situation of academic primary care at the five Swiss universities by the end of year 2012. RESULTS: Although primary care teaching activities have a long tradition at the five Swiss universities with activities starting in the beginning of the 1980ies; the academic institutes of primary care were only established in recent years (2005 - 2009). Only one of them has an established chair. Human and financial resources vary substantially. At all universities a broad variety of courses and lectures are offered, including teaching in private primary care practices with 1331 PCPs involved. Regarding research, differences among the institutes are tremendous, mainly caused by entirely different human resources and skills. CONCLUSION: So far, the activities of the existing institutes at the Swiss Universities are mainly focused on teaching. However, for a complete academic institutionalization as well as an increased acceptance and attractiveness, more research activities are needed. In addition to an adequate basic funding of research positions, competitive research grants have to be created to establish a specialty-specific research culture.

Smad3 deficiency in mice protects against insulin resistance and obesity induced by a high-fat diet.

OBJECTIVE-Obesity and associated pathologies are major global health problems. Transforming growth factor-beta/Smad3 signaling has been implicated in various metabolic processes, including adipogenesis, insulin expression, and pancreatic beta-cell function. However, the systemic effects of Smad3 deficiency on adiposity and insulin resistance in vivo remain elusive. This study investigated the effects of Smad3 deficiency on whole-body glucose and lipid homeostasis and its contribution to the development of obesity and type 2 diabetes.RESEARCH DESIGN AND METHODS-We compared various metabolic profiles of Smad3-knockout and wild-type mice. We also determined the mechanism by which Smad3 deficiency affects the expression of genes involved in adipogenesis and metabolism. Mice were then challenged with a high-fat diet to study the impact of Smad3 deficiency on the development of obesity and insulin resistance.RESULTS-Smad3-knockout mice exhibited diminished adiposity with improved glucose tolerance and insulin sensitivity. Chromatin immunoprecipitation assay revealed that Smad3 deficiency increased CCAAT/enhancer-binding protein beta-C/EBP homologous protein 10 interaction and exerted a differential regulation on proliferator-activated receptor beta/delta and proliferator-activated receptor gamma expression in adipocytes. Focused gene expression profiling revealed an altered expression of genes involved in adipogenesis, lipid accumulation, and fatty acid beta-oxidation, indicative of altered adipose physiology. Despite reduced physical activity with no modification in food intake, these mutant mice were resistant to obesity and insulin resistance induced by a high-fat diet.CONCLUSIONS-Smad3 is a multifaceted regulator in adipose physiology and the pathogenesis of obesity and type 2 diabetes, suggesting that Smad3 may be a potential target for the treatment of obesity and its associated disorders.