Acampomelic Form of Campomelic Dysplasia with SOX9 Missense Mutation.

Campomelic dysplasia is a skeletal dysplasia characterized by flat face, Pierre Robin sequence, shortening and bowing of long bones and club feet. The authors describe a case of "acampomelic" campomelic dysplasia that differs from classical campomelic dysplasia by the absence of bone bowing. This condition is among the most common skeletal dysplasias but is often misdiagnosed in the absence of overt campomelia.

Adenosine A1 receptor activation is arrhythmogenic in the developing heart through NADPH oxidase/ERK- and PLC/PKC-dependent mechanisms.

Whether adenosine, a crucial regulator of the developing cardiovascular system, can provoke arrhythmias in the embryonic/fetal heart remains controversial. Here, we aimed to establish a mechanistic basis of how an adenosinergic stimulation alters function of the developing heart. Spontaneously beating hearts or dissected atria and ventricle obtained from 4-day-old chick embryos were exposed to adenosine or specific agonists of the receptors A(1)AR (CCPA), A(2A)AR (CGS-21680) and A(3)AR (IB-MECA). Expression of the receptors was determined by quantitative PCR. The functional consequences of blockade of NADPH oxidase, extracellular signal-regulated kinase (ERK), phospholipase C (PLC), protein kinase C (PKC) and L-type calcium channel (LCC) in combination with adenosine or CCPA, were investigated in vitro by electrocardiography. Furthermore, the time-course of ERK phosphorylation was determined by western blotting. Expression of A(1)AR, A(2A)AR and A(2B)AR was higher in atria than in ventricle while A(3)AR was equally expressed. Adenosine (100μM) triggered transient atrial ectopy and second degree atrio-ventricular blocks (AVB) whereas CCPA induced mainly Mobitz type I AVB. Atrial rhythm and atrio-ventricular propagation fully recovered after 60min. These arrhythmias were prevented by the specific A(1)AR antagonist DPCPX. Adenosine and CCPA transiently increased ERK phosphorylation and induced arrhythmias in isolated atria but not in ventricle. By contrast, A(2A)AR and A(3)AR agonists had no effect. Interestingly, the proarrhythmic effect of A(1)AR stimulation was markedly reduced by inhibition of NADPH oxidase, ERK, PLC, PKC or LCC. Moreover, NADPH oxidase inhibition or antioxidant MPG prevented both A(1)AR-mediated arrhythmias and ERK phosphorylation. These results suggest that pacemaking and conduction disturbances are induced via A(1)AR through concomitant stimulation of NADPH oxidase and PLC, followed by downstream activation of ERK and PKC with LCC as possible target.

Gaia photometry for white dwarfs

Context. White dwarfs can be used to study the structure and evolution of the Galaxy by analysing their luminosity function and initial mass function. Among them, the very cool white dwarfs provide the information for the early ages of each population. Because white dwarfs are intrinsically faint only the nearby (~ 20 pc) sample is reasonably complete. The Gaia space mission will drastically increase the sample of known white dwarfs through its 5-6 years survey of the whole sky up to magnitude V = 20-25. Aims. We provide a characterisation of Gaia photometry for white dwarfs to better prepare for the analysis of the scientific output of the mission. Transformations between some of the most common photometric systems and Gaia passbands are derived. We also give estimates of the number of white dwarfs of the different galactic populations that will be observed. Methods. Using synthetic spectral energy distributions and the most recent Gaia transmission curves, we computed colours of three different types of white dwarfs (pure hydrogen, pure helium, and mixed composition with H/He = 0.1). With these colours we derived transformations to other common photometric systems (Johnson-Cousins, Sloan Digital Sky Survey, and 2MASS). We also present numbers of white dwarfs predicted to be observed by Gaia. Results. We provide relationships and colourcolour diagrams among different photometric systems to allow the prediction and/or study of the Gaia white dwarf colours. We also include estimates of the number of sources expected in every galactic population and with a maximum parallax error. Gaia will increase the sample of known white dwarfs tenfold to about 200 000. Gaia will be able to observe thousands of very cool white dwarfs for the first time, which will greatly improve our understanding of these stars and early phases of star formation in our Galaxy.

Ancient dispersal of the human fungal pathogen Cryptococcus gattii from the Amazon rainforest

Over the past two decades, several fungal outbreaks have occurred, including the high-profile 'Vancouver Island' and 'Pacific Northwest' outbreaks, caused by Cryptococcus gattii, which has affected hundreds of otherwise healthy humans and animals. Over the same time period, C. gattii was the cause of several additional case clusters at localities outside of the tropical and subtropical climate zones where the species normally occurs. In every case, the causative agent belongs to a previously rare genotype of C. gattii called AFLP6/VGII, but the origin of the outbreak clades remains enigmatic. Here we used phylogenetic and recombination analyses, based on AFLP and multiple MLST datasets, and coalescence gene genealogy to demonstrate that these outbreaks have arisen from a highly-recombining C. gattii population in the native rainforest of Northern Brazil. Thus the modern virulent C. gattii AFLP6/VGII outbreak lineages derived from mating events in South America and then dispersed to temperate regions where they cause serious infections in humans and animals.

The Besançon Galaxy Model renewed. I. Constraints on the Galactic thin disc evolution from Tycho data

Context. The understanding of Galaxy evolution can be facilitated by the use of population synthesis models, which allow to test hypotheses on the star formation history, star evolution, as well as chemical and dynamical evolution of the Galaxy. Aims. The new version of the Besanc¸on Galaxy Model (hereafter BGM) aims to provide a more flexible and powerful tool to investigate the Initial Mass Function (IMF) and Star Formation Rate (SFR) of the Galactic disc. Methods. We present a new strategy for the generation of thin disc stars which assumes the IMF, SFR and evolutionary tracks as free parameters. We have updated most of the ingredients for the star count production and, for the first time, binary stars are generated in a consistent way. We keep in this new scheme the local dynamical self-consistency as in Bienayme et al (1987). We then compare simulations from the new model with Tycho-2 data and the local luminosity function, as a first test to verify and constrain the new ingredients. The effects of changing thirteen different ingredients of the model are systematically studied. Results. For the first time, a full sky comparison is performed between BGM and data. This strategy allows to constrain the IMF slope at high masses which is found to be close to 3.0, excluding a shallower slope such as Salpeter"s one. The SFR is found decreasing whatever IMF is assumed. The model is compatible with a local dark matter density of 0.011 M pc−3 implying that there is no compelling evidence for significant amount of dark matter in the disc. While the model is fitted to Tycho2 data, a magnitude limited sample with V<11, we check that it is still consistent with fainter stars. Conclusions. The new model constitutes a new basis for further comparisons with large scale surveys and is being prepared to become a powerful tool for the analysis of the Gaia mission data.

Sensitivity analysis, dominant factors, and robustness of the ECETOC TRA v3, Stoffenmanager 4.5, and ART 1.5 occupational exposure models

Occupational exposure modeling is widely used in the context of the E.U. regulation on the registration, evaluation, authorization, and restriction of chemicals (REACH). First tier tools, such as European Centre for Ecotoxicology and TOxicology of Chemicals (ECETOC) targeted risk assessment (TRA) or Stoffenmanager, are used to screen a wide range of substances. Those of concern are investigated further using second tier tools, e.g., Advanced REACH Tool (ART). Local sensitivity analysis (SA) methods are used here to determine dominant factors for three models commonly used within the REACH framework: ECETOC TRA v3, Stoffenmanager 4.5, and ART 1.5. Based on the results of the SA, the robustness of the models is assessed. For ECETOC, the process category (PROC) is the most important factor. A failure to identify the correct PROC has severe consequences for the exposure estimate. Stoffenmanager is the most balanced model and decision making uncertainties in one modifying factor are less severe in Stoffenmanager. ART requires a careful evaluation of the decisions in the source compartment since it constitutes ∼75% of the total exposure range, which corresponds to an exposure estimate of 20-22 orders of magnitude. Our results indicate that there is a trade off between accuracy and precision of the models. Previous studies suggested that ART may lead to more accurate results in well-documented exposure situations. However, the choice of the adequate model should ultimately be determined by the quality of the available exposure data: if the practitioner is uncertain concerning two or more decisions in the entry parameters, Stoffenmanager may be more robust than ART.

Long-term continuous-flow left ventricular assist devices (LVAD) as bridge to heart transplantation.

Heart transplantation (HTx) is the treatment of choice for end-stage heart failure but the limited availability of heart's donors still represents a major issue. So long-term mechanical circulatory support (MCS) has been proposed as an alternative treatment option to assist patients scheduled on HTx waiting list bridging them for a variable time period to cardiac transplantation-the so-called bridge-to-transplantation (BTT) strategy. Nowadays approximately 90% of patients being considered for MCS receive a left ventricular assist device (LVAD). In fact, LVAD experienced several improvements in the last decade and the predominance of continuous-flow over pulsatile-flow technology has been evident since 2008. The aim of the present report is to give an overview of continuous-flow LVAD utilization in the specific setting of the BTT strategy taking into consideration the most representative articles of the scientific literature and focusing the attention on the evolution, clinical outcomes, relevant implications on the HTx strategy and future perspectives of the continuous-flow LVAD technology.

A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance.

To what extent hypoxia alters the adenosine (ADO) system and impacts on cardiac function during embryogenesis is not known. Ectonucleoside triphosphate diphosphohydrolase (CD39), ecto-5'-nucleotidase (CD73), adenosine kinase (AdK), adenosine deaminase (ADA), equilibrative (ENT1,3,4), and concentrative (CNT3) transporters and ADO receptors A1, A2A, A2B, and A3 constitute the adenosinergic system. During the first 4 days of development chick embryos were exposed in ovo to normoxia followed or not followed by 6 h hypoxia. ADO and glycogen content and mRNA expression of the genes were determined in the atria, ventricle, and outflow tract of the normoxic (N) and hypoxic (H) hearts. Electrocardiogram and ventricular shortening of the N and H hearts were recorded ex vivo throughout anoxia/reoxygenation ± ADO. Under basal conditions, CD39, CD73, ADK, ADA, ENT1,3,4, CNT3, and ADO receptors were differentially expressed in the atria, ventricle, and outflow tract. In H hearts ADO level doubled, glycogen decreased, and mRNA expression of all the investigated genes was downregulated by hypoxia, except for A2A and A3 receptors. The most rapid and marked downregulation was found for ADA in atria. H hearts were arrhythmic and more vulnerable to anoxia-reoxygenation than N hearts. Despite downregulation of the genes, exposure of isolated hearts to ADO 1) preserved glycogen through activation of A1 receptor and Akt-GSK3β-GS pathway, 2) prolonged activity and improved conduction under anoxia, and 3) restored QT interval in H hearts. Thus hypoxia-induced downregulation of the adenosinergic system can be regarded as a coping response, limiting the detrimental accumulation of ADO without interfering with ADO signaling.

Gaia photometry for white dwarfs

Context. White dwarfs can be used to study the structure and evolution of the Galaxy by analysing their luminosity function and initial mass function. Among them, the very cool white dwarfs provide the information for the early ages of each population. Because white dwarfs are intrinsically faint only the nearby (~ 20 pc) sample is reasonably complete. The Gaia space mission will drastically increase the sample of known white dwarfs through its 5-6 years survey of the whole sky up to magnitude V = 20-25. Aims. We provide a characterisation of Gaia photometry for white dwarfs to better prepare for the analysis of the scientific output of the mission. Transformations between some of the most common photometric systems and Gaia passbands are derived. We also give estimates of the number of white dwarfs of the different galactic populations that will be observed. Methods. Using synthetic spectral energy distributions and the most recent Gaia transmission curves, we computed colours of three different types of white dwarfs (pure hydrogen, pure helium, and mixed composition with H/He = 0.1). With these colours we derived transformations to other common photometric systems (Johnson-Cousins, Sloan Digital Sky Survey, and 2MASS). We also present numbers of white dwarfs predicted to be observed by Gaia. Results. We provide relationships and colour-colour diagrams among different photometric systems to allow the prediction and/or study of the Gaia white dwarf colours. We also include estimates of the number of sources expected in every galactic population and with a maximum parallax error. Gaia will increase the sample of known white dwarfs tenfold to about 200 000. Gaia will be able to observe thousands of very cool white dwarfs for the first time, which will greatly improve our understanding of these stars and early phases of star formation in our Galaxy.