Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies.

Inherited peripheral neuropathies are a genetically heterogeneous group of disorders characterized by distal muscle weakness and sensory loss. Mutations in genes encoding aminoacyl-tRNA synthetases have been implicated in peripheral neuropathies, suggesting that these tRNA charging enzymes are uniquely important for the peripheral nerve. Recently, a mutation in histidyl-tRNA synthetase (HARS) was identified in a single patient with a late-onset, sensory-predominant peripheral neuropathy; however, the genetic evidence was lacking, making the significance of the finding unclear. Here, we present clinical, genetic, and functional data that implicate HARS mutations in inherited peripheral neuropathies. The associated phenotypic spectrum is broad and encompasses axonal and demyelinating motor and sensory neuropathies, including four young patients presenting with pure motor axonal neuropathy. Genome-wide linkage studies in combination with whole-exome and conventional sequencing revealed four distinct and previously unreported heterozygous HARS mutations segregating with autosomal dominant peripheral neuropathy in four unrelated families (p.Thr132Ile, p.Pro134His, p.Asp175Glu and p.Asp364Tyr). All mutations cause a loss of function in yeast complementation assays, and p.Asp364Tyr is dominantly neurotoxic in a Caenorhabditis elegans model. This study demonstrates the role of HARS mutations in peripheral neuropathy and expands the genetic and clinical spectrum of aminoacyl-tRNA synthetase-related human disease.

Systems Medicine and Integrated Care to Combat Chronic Noncommunicable Diseases.

We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.

Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects.

BACKGROUND: After no research in humans for >40 years, there is renewed interest in using lysergic acid diethylamide (LSD) in clinical psychiatric research and practice. There are no modern studies on the subjective and autonomic effects of LSD, and its endocrine effects are unknown. In animals, LSD disrupts prepulse inhibition (PPI) of the acoustic startle response, and patients with schizophrenia exhibit similar impairments in PPI. However, no data are available on the effects of LSD on PPI in humans. METHODS: In a double-blind, randomized, placebo-controlled, crossover study, LSD (200 μg) and placebo were administered to 16 healthy subjects (8 women, 8 men). Outcome measures included psychometric scales; investigator ratings; PPI of the acoustic startle response; and autonomic, endocrine, and adverse effects. RESULTS: Administration of LSD to healthy subjects produced pronounced alterations in waking consciousness that lasted 12 hours. The predominant effects induced by LSD included visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization phenomena. Subjective well-being, happiness, closeness to others, openness, and trust were increased by LSD. Compared with placebo, LSD decreased PPI. LSD significantly increased blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine. Adverse effects produced by LSD completely subsided within 72 hours. No severe acute adverse effects were observed. CONCLUSIONS: In addition to marked hallucinogenic effects, LSD exerts methylenedioxymethamphetamine-like empathogenic mood effects that may be useful in psychotherapy. LSD altered sensorimotor gating in a human model of psychosis, supporting the use of LSD in translational psychiatric research. In a controlled clinical setting, LSD can be used safely, but it produces significant sympathomimetic stimulation.

Incidence and consequence of major bleeding in primary percutaneous intervention for ST-elevation myocardial infarction in the era of radial access: an analysis of the international randomized Acute myocardial infarction Treated with primary angioplasty and intravenous enoxaparin Or unfractionated heparin to Lower ischemic and bleeding events at short- and Long-term follow-up trial.

AIMS: The aims of the study are to compare the outcome with and without major bleeding and to identify the independent correlates of major bleeding complications and mortality in patients described in the ATOLL study. METHODS: The ATOLL study included 910 patients randomly assigned to either 0.5 mg/kg intravenous enoxaparin or unfractionated heparin before primary percutaneous coronary intervention. Incidence of major bleeding and ischemic end points was assessed at 1 month, and mortality, at 1 and 6 months. Patients with and without major bleeding complication were compared. A multivariate model of bleeding complications at 1 month and mortality at 6 months was realized. Intention-to-treat and per-protocol analyses were performed. RESULTS: The most frequent bleeding site appears to be the gastrointestinal tract. Age >75 years, cardiac arrest, and the use of insulin or >1 heparin emerged as independent correlates of major bleeding at 1 month. Patients presenting with major bleeding had significantly higher rates of adverse ischemic complications. Mortality at 6 months was higher in bleeders. Major bleeding was found to be one of the independent correlates of 6-month mortality. The addition or mixing of several anticoagulant drugs was an independent factor of major bleeding despite the predominant use of radial access. CONCLUSIONS: This study shows that major bleeding is independently associated with poor outcome, increasing ischemic events, and mortality in primary percutaneous coronary intervention performed mostly with radial access.

Hollywood Films in the Non-Western World: What Are the Criteria Followed by the Chinese Government When Choosing Hollywood Film Imports?

This dissertation argues that the Government of the People’s Republic of China, when it made the decision to import a quota of Hollywood films in 1994 to revive the failing domestic film industry, had different possible criteria in mind. This project has studied four of them: first, importing films that gave a negative image of the United States; second, importing films that featured Chinese talent or themes; third, importing films that were box office hits in the United States; and fourth, importing films with a strong technological innovation ingredient. In order to find out the most important criteria for the Chinese Government, this dissertation offers a dataset that analyzes a population of 262 Hollywood films released in the PRC between 1994 and 2010. For each unit, a method has been developed to compile data that will determine whether the film reflects any of the four criteria, and findings in the form of yearly percentages have been drawn. Results show that, out of the four studied criteria, the two predominant reasons for China to import films were technological innovation and box office hits. This tells us that, at this point, the Chinese Government shows more interest in obtaining big revenues and learning from technically innovative American films than in delivering underlying political messages. This dissertation contributes to the existing literature by analyzing the content of all the films imported by China between 1994 and 2010, while integrating in the analysis variables based on the existing knowledge.

Le rôle des associations de patients face au don d'organes en Suisse romande [Organ donation and the role of patients' associations in Western Switzerland].

In the context of lay mobilization in health-related areas, this article addresses the role and activities of patients' associations in connection with organ donation, on the basis of interviews carried out with thirty members of transplant patients' associations in the French-speaking part of Switzerland. First, we describe the three main categories of activities conducted by these associations. While self-help and public awareness activities are predominant, policy-oriented actions are marginal. Then, we examine the factors likely to explain why these associations have a limited capacity to be active, especially in the public sphere. Such a lack of social visibility is all the more important in the current political context, characterized by the implementation of a national action plan designed to improve organ donation.

Microglial cells in astroglial cultures: a cautionary note

Primary rodent astroglial-enriched cultures are the most popular model to study astroglial biology in vitro. From the original methods described in the 1970's a great number of minor modifications have been incorporated into these protocols by different laboratories. These protocols result in cultures in which the astrocyte is the predominant cell type, but astrocytes are never 100% of cells in these preparations. The aim of this review is to bring attention to the presence of microglia in astroglial cultures because, in my opinion, the proportion of and the role that microglial cells play in astroglial cultures are often underestimated. The main problem with ignoring microglia in these cultures is that relatively minor amounts of microglia can be responsible for effects observed on cultures in which the astrocyte is the most abundant cell type. If the relative contributions of astrocytes and microglia are not properly assessed an observed effect can be erroneously attributed to the astrocytes. In order to illustrate this point the case of NO production in activated astroglial-enriched cultures is examined. Lipopolysaccharide (LPS) induces nitric oxide (NO) production in astroglial-enriched cultures and this effect is very often attributed to astrocytes. However, a careful review of the published data suggests that LPS-induced NO production in rodent astroglial-enriched cultures is likely to be mainly microglial in origin. This review considers cell culture protocol factors that can affect the proportion of microglial cells in astroglial cultures, strategies to minimize the proportion of microglia in these cultures, and specific markers that allow the determination of such microglial proportions.

Permissivity of insect cells to Waddlia chondrophila, Estrella lausannensis and Parachlamydia acanthamoebae.

Recent large scale studies questioning the presence of intracellular bacteria of the Chlamydiales order in ticks and fleas revealed that arthropods, similarly to mammals, reptiles, birds or fishes, can be colonized by Chlamydia-related bacteria with a predominant representation of the Rhabdochlamydiaceae and Parachlamydiaceae families. We thus investigated the permissivity of two insect cell lines towards Waddlia chondrophila, Estrella lausannensis and Parachlamydia acanthamoebae, three bacteria representative of three distinct families within the Chlamydiales order, all documented in ticks and/or in other arthropods. We demonstrated that W. chondrophila and E. lausannensis are able to very efficiently multiply in these insect cell lines. E. lausannensis however induced a rapid cytopathic effect, which somehow restricted its replication. P. acanthamoebae was not able to grow in these cell lines even if inclusions containing a few replicating bacteria could occasionally be observed.

Diagnostic approach to eosinophilic oesophagitis: Pearls and pitfalls.

Eosinophilic oesophagitis (EoE) has first been described a little over 20 years ago. EoE has been defined by a panel of international experts as a "chronic, immune/antigen-mediated, oesophageal disease, characterized clinically by symptoms related to oesophageal dysfunction and histologically by eosinophil-predominant inflammation". A value of ≥ 15 eosinophils has been defined as histologic diagnostic cutoff. Other conditions associated with oesophageal eosinophilia, such as gastro-oesophageal reflux disease (GERD), PPI-responsive oesophageal eosinophilia, or Crohn's disease should be excluded before EoE can be diagnosed. This review highlights the latest insights regarding the diagnosis and differential diagnosis of EoE.

Divergence with gene flow and fine-scale phylogeographical structure in the wedge-billed woodcreeper, Glyphorynchus spirurus, a Neotropical rainforest bird.

Determining the relative roles of vicariance and selection in restricting gene flow between populations is of central importance to the evolutionary process of population divergence and speciation. Here we use molecular and morphological data to contrast the effect of isolation (by mountains and geographical distance) with that of ecological factors (altitudinal gradients) in promoting differentiation in the wedge-billed woodcreeper, Glyphorynchus spirurus, a tropical forest bird, in Ecuador. Tarsus length and beak size increased relative to body size with altitude on both sides of the Andes, and were correlated with the amount of moss on tree trunks, suggesting the role of selection in driving adaptive divergence. In contrast, molecular data revealed a considerable degree of admixture along these altitudinal gradients, suggesting that adaptive divergence in morphological traits has occurred in the presence of gene flow. As suggested by mitochondrial DNA sequence data, the Andes act as a barrier to gene flow between ancient subspecific lineages. Genome-wide amplified fragment length polymorphism markers reflected more recent patterns of gene flow and revealed fine-scale patterns of population differentiation that were not detectable with mitochondrial DNA, including the differentiation of isolated coastal populations west of the Andes. Our results support the predominant role of geographical isolation in driving genetic differentiation in G. spirurus, yet suggest the role of selection in driving parallel morphological divergence along ecological gradients.

Differences between genders in coping: different strategies or different stressors?

These study analysed gender specificity in coping behaviours by taking into account the types of problem faced by Spanish adolescents attending school. It was focused on the ten problems most frequently reported by participants (828 adolescents, 355 boys, and 473 girls; Mage = 14.07, SD = 1.34), which were classified using a multi-axial classification system. Coping was examined as a two separate measures of approach and avoidance coping, and as a combined measure indicating the predominant use of coping, and total coping effort. A MANCOVA and subsequent univariate tests were conducted to analyse the specificity of coping according to problem and gender, controlled by age. The results showed that the percentage of types of problems reported by adolescents differed according to gender. The influence of gender on coping was scarcely relevant when the type of problem was controlled for. There were no gender differences when the predominant type of coping was considered, but when a total coping effort measure was analysed girls showed more coping efforts than boys to face interpersonal relationship problems and personal illness. Keywords: adolescence, coping, gender differences, stressors.

Can chest high-resolution computed tomography findings diagnose pulmonary alveolar microlithiasis?

AbstractObjective:The present study was aimed at retrospectively reviewing high-resolution computed tomography (HRCT) findings in patients with pulmonary alveolar microlithiasis in order to evaluate the frequency of tomographic findings and their distribution in the lung parenchyma.Materials and Methods:Thirteen patients (9 females and 4 males; age, 9 to 59 years; mean age, 34.5 years) were included in the present study. The HRCT images were independently evaluated by two observers whose decisions were made by consensus. The inclusion criterion was the presence of abnormalities typical of pulmonary alveolar microlithiasis at HRCT, which precludes lung biopsy. However, in 6 cases lung biopsy was performed.Results:Ground-glass opacities and small parenchymal nodules were the predominant tomographic findings, present in 100% of cases, followed by small subpleural nodules (92.3%), subpleural cysts (84.6%), subpleural linear calcifications (69.2%), crazy-paving pattern (69.2%), fissure nodularity (53.8%), calcification along interlobular septa (46.2%) and dense consolidation (46.2%).Conclusion:As regards distribution of the lesions, there was preferential involvement of the lower third of the lungs. No predominance of distribution in axial and anteroposterior directions was observed.

Predicted decrease in global climate suitability masks regional complexity of invasive fruit fly species response to climate change

Climate change affects the rate of insect invasions as well as the abundance, distribution and impacts of such invasions on a global scale. Among the principal analytical approaches to predicting and understanding future impacts of biological invasions are Species Distribution Models (SDMs), typically in the form of correlative Ecological Niche Models (ENMs). An underlying assumption of ENMs is that species-environment relationships remain preserved during extrapolations in space and time, although this is widely criticised. The semi-mechanistic modelling platform, CLIMEX, employs a top-down approach using species ecophysiological traits and is able to avoid some of the issues of extrapolation, making it highly applicable to investigating biological invasions in the context of climate change. The tephritid fruit flies (Diptera: Tephritidae) comprise some of the most successful invasive species and serious economic pests around the world. Here we project 12 tephritid species CLIMEX models into future climate scenarios to examine overall patterns of climate suitability and forecast potential distributional changes for this group. We further compare the aggregate response of the group against species-specific responses. We then consider additional drivers of biological invasions to examine how invasion potential is influenced by climate, fruit production and trade indices. Considering the group of tephritid species examined here, climate change is predicted to decrease global climate suitability and to shift the cumulative distribution poleward. However, when examining species-level patterns, the predominant directionality of range shifts for 11 of the 12 species is eastward. Most notably, management will need to consider regional changes in fruit fly species invasion potential where high fruit production, trade indices and predicted distributions of these flies overlap.

Fair value versus historic cost-valuation for biological assets: Implications for the quality of financial information

[spa] Este trabajo realiza un estudio empírico sobre los efectos, que se señalan en las discusiones teóricas, de la utilización del valor razonable (VR) frente al coste histórico (CH), utilizando dos muestras de explotaciones agrícolas, una de las cuales valora sus activos biológicos a CH y la otra a VR. No se encontraron diferencias significativas en los beneficios e ingresos entre ambas muestras, ni siquiera en sus volatilidades. Tampoco se encontraron diferencias significativas en rentabilidad, manipulación contable, ni en el poder de ambos criterios de valoración para predecir los flujos de tesorería. Por el contrario, la mayor parte de los tests realizados revelan un mayor poder de los beneficios calculados bajo el VR para la predicción de los beneficios futuros, respecto de cuando son calculados bajo el CH. El estudio proporciona también evidencia empírica de prácticas contables defectuosas de CH en el sector agrícola, concluyendo que el VR puede representar un criterio de valoración interesante para un sector, como el agrícola, caracterizado por el predominio de pequeñas explotaciones familiares.

Fair value versus historic cost-valuation for biological assets: Implications for the quality of financial information

[spa] Este trabajo realiza un estudio empírico sobre los efectos, que se señalan en las discusiones teóricas, de la utilización del valor razonable (VR) frente al coste histórico (CH), utilizando dos muestras de explotaciones agrícolas, una de las cuales valora sus activos biológicos a CH y la otra a VR. No se encontraron diferencias significativas en los beneficios e ingresos entre ambas muestras, ni siquiera en sus volatilidades. Tampoco se encontraron diferencias significativas en rentabilidad, manipulación contable, ni en el poder de ambos criterios de valoración para predecir los flujos de tesorería. Por el contrario, la mayor parte de los tests realizados revelan un mayor poder de los beneficios calculados bajo el VR para la predicción de los beneficios futuros, respecto de cuando son calculados bajo el CH. El estudio proporciona también evidencia empírica de prácticas contables defectuosas de CH en el sector agrícola, concluyendo que el VR puede representar un criterio de valoración interesante para un sector, como el agrícola, caracterizado por el predominio de pequeñas explotaciones familiares.