Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.

BACKGROUND: Assisted reproductive technology (ART) involves the manipulation of early embryos at a time when they may be particularly vulnerable to external disturbances. Environmental influences during the embryonic and fetal development influence the individual's susceptibility to cardiovascular disease, raising concerns about the potential consequences of ART on the long-term health of the offspring. METHODS AND RESULTS: We assessed systemic (flow-mediated dilation of the brachial artery, pulse-wave velocity, and carotid intima-media thickness) and pulmonary (pulmonary artery pressure at high altitude by Doppler echocardiography) vascular function in 65 healthy children born after ART and 57 control children. Flow-mediated dilation of the brachial artery was 25% smaller in ART than in control children (6.7±1.6% versus 8.6±1.7%; P<0.0001), whereas endothelium-independent vasodilation was similar in the 2 groups. Carotid-femoral pulse-wave velocity was significantly (P<0.001) faster and carotid intima-media thickness was significantly (P<0.0001) greater in children conceived by ART than in control children. The systolic pulmonary artery pressure at high altitude (3450 m) was 30% higher (P<0.001) in ART than in control children. Vascular function was normal in children conceived naturally during hormonal stimulation of ovulation and in siblings of ART children who were conceived naturally. CONCLUSIONS: Healthy children conceived by ART display generalized vascular dysfunction. This problem does not appear to be related to parental factors but to the ART procedure itself. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT00837642.

Coagulation factor Xa activates thrombin in ischemic neural tissue.

Thrombin is involved in mediating neuronal death in cerebral ischemia. We investigated its so far unknown mode of activation in ischemic neural tissue. We used an in vitro approach to distinguish the role of circulating coagulation factors from endogenous cerebral mechanisms. We modeled ischemic stroke by subjecting rat organotypic hippocampal slice cultures to 30-min oxygen (5%) and glucose (1 mmol/L) deprivation (OGD). Perinuclear activated factor X (FXa) immunoreactivity was observed in CA1 neurons after OGD. Selective FXa inhibition by fondaparinux during and after OGD significantly reduced neuronal death in the CA1 after 48 h. Thrombin enzyme activity was increased in the medium 24 h after OGD and this increase was prevented by fondaparinux suggesting that FXa catalyzes the conversion of prothrombin to thrombin in neural tissue after ischemia in vitro. Treatment with SCH79797, a selective antagonist of the thrombin receptor protease-activated receptor-1 (PAR-1), significantly decreased neuronal cell death indicating that thrombin signals ischemic damage via PAR-1. The c-Jun N-terminal kinase (JNK) pathway plays an important role in excitotoxicity and cerebral ischemia and we observed activation of the JNK substrate, c-Jun in our model. Both the FXa inhibitor, fondaparinux and the PAR-1 antagonist SCH79797, decreased the level of phospho-c-Jun Ser73. These results indicate that FXa activates thrombin in cerebral ischemia, which leads via PAR-1 to the activation of the JNK pathway resulting in neuronal death.

Neural regulation of pancreatic islet cell mass and function.

Intracellular glucose signalling pathways control the secretion of glucagon and insulin by pancreatic islet α- and β-cells, respectively. However, glucose also indirectly controls the secretion of these hormones through regulation of the autonomic nervous system that richly innervates this endocrine organ. Both parasympathetic and sympathetic nervous systems also impact endocrine pancreas postnatal development and plasticity in adult animals. Defects in these autonomic regulations impair β-cell mass expansion during the weaning period and β-cell mass adaptation in adult life. Both branches of the autonomic nervous system also regulate glucagon secretion. In type 2 diabetes, impaired glucose-dependent autonomic activity causes the loss of cephalic and first phases of insulin secretion, and impaired suppression of glucagon secretion in the postabsorptive phase; in diabetic patients treated with insulin, it causes a progressive failure of hypoglycaemia to trigger the secretion of glucagon and other counterregulatory hormones. Therefore, identification of the glucose-sensing cells that control the autonomic innervation of the endocrine pancreatic and insulin and glucagon secretion is an important goal of research. This is required for a better understanding of the physiological control of glucose homeostasis and its deregulation in diabetes. This review will discuss recent advances in this field of investigation.

Wild-type ALK and activating ALK-R1275Q and ALK-F1174L mutations upregulate Myc and initiate tumor formation in murine neural crest progenitor cells.

The anaplastic lymphoma kinase (ALK) gene is overexpressed, mutated or amplified in most neuroblastoma (NB), a pediatric neural crest-derived embryonal tumor. The two most frequent mutations, ALK-F1174L and ALK-R1275Q, contribute to NB tumorigenesis in mouse models, and cooperate with MYCN in the oncogenic process. However, the precise role of activating ALK mutations or ALK-wt overexpression in NB tumor initiation needs further clarification. Human ALK-wt, ALK-F1174L, or ALK-R1275Q were stably expressed in murine neural crest progenitor cells (NCPC), MONC-1 or JoMa1, immortalized with v-Myc or Tamoxifen-inducible Myc-ERT, respectively. While orthotopic implantations of MONC- 1 parental cells in nude mice generated various tumor types, such as NB, osteo/ chondrosarcoma, and undifferentiated tumors, due to v-Myc oncogenic activity, MONC-1-ALK-F1174L cells only produced undifferentiated tumors. Furthermore, our data represent the first demonstration of ALK-wt transforming capacity, as ALK-wt expression in JoMa1 cells, likewise ALK-F1174L, or ALK-R1275Q, in absence of exogenous Myc-ERT activity, was sufficient to induce the formation of aggressive and undifferentiated neural crest cell-derived tumors, but not to drive NB development. Interestingly, JoMa1-ALK tumors and their derived cell lines upregulated Myc endogenous expression, resulting from ALK activation, and both ALK and Myc activities were necessary to confer tumorigenic properties on tumor-derived JoMa1 cells in vitro.

A Confluence of Risks: Control and Compliance in the World of Unstructured Data, Big Data and the Cloud

The emergence of powerful new technologies, the existence of large quantities of data, and increasing demands for the extraction of added value from these technologies and data have created a number of significant challenges for those charged with both corporate and information technology management. The possibilities are great, the expectations high, and the risks significant. Organisations seeking to employ cloud technologies and exploit the value of the data to which they have access, be this in the form of "Big Data" available from different external sources or data held within the organisation, in structured or unstructured formats, need to understand the risks involved in such activities. Data owners have responsibilities towards the subjects of the data and must also, frequently, demonstrate that they are in compliance with current standards, laws and regulations. This thesis sets out to explore the nature of the technologies that organisations might utilise, identify the most pertinent constraints and risks, and propose a framework for the management of data from discovery to external hosting that will allow the most significant risks to be managed through the definition, implementation, and performance of appropriate internal control activities.

De la conception à la pratique Reconfiguration d'un dispositif de formation des enseignants aux technologies de l'information et de la communication.

Constatant que la formation des enseignants aux technologies de l'information et de la communication (TIC) pose des problèmes spécifiques, cet article a pour but d'engager une réflexion sur ce thème. Nos réflexions s'appuient sur une expérience de formation réalisée dans 23 écoles professionnelles suisses engagées dans un programme national de soutien à l'utilisation pédagogique des TIC. L'article décrit la manière dont le dispositif de formation prévu a été mis en pratique, les difficultés auxquelles il a donné lieu et les réponses que les acteurs ont élaborées pour faire face à ces difficultés. Nous montrons qu'une analyse du déroulement effectif d'un dispositif de formation et des transformations qu'il subit constitue un élément essentiel pour orienter les futures actions de formation et penser la place des apprenants dans un dispositif de formation.

Prevalence of Neural Tube Defects (NTD) in Younger Mothers in Europe 2000-2008: Analysis of the EUROCAT Database - Report to Bayer Schiering Pharma

M.C. Addor is included in the Eurocat Working Group

Two high throughput technologies to detect segmental aneuploidies identify new Williams-Beuren syndrome patients with atypical deletions.

OBJECTIVE: To develop and compare two new technologies for diagnosing a contiguous gene syndrome, the Williams-Beuren syndrome (WBS). METHODS: The first proposed method, named paralogous sequence quantification (PSQ), is based on the use of paralogous sequences located on different chromosomes and quantification of specific mismatches present at these loci using pyrosequencing technology. The second exploits quantitative real time polymerase chain reaction (QPCR) to assess the relative quantity of an analysed locus. RESULTS: A correct and unambiguous diagnosis was obtained for 100% of the analysed samples with either technique (n = 165 and n = 155, respectively). These methods allowed the identification of two patients with atypical deletions in a cohort of 182 WBS patients. Both patients presented with mild facial anomalies, mild mental retardation with impaired visuospatial cognition, supravalvar aortic stenosis, and normal growth indices. These observations are consistent with the involvement of GTF2IRD1 or GTF2I in some of the WBS facial features. CONCLUSIONS: Both PSQ and QPCR are robust, easy to interpret, and simple to set up. They represent a competitive alternative for the diagnosis of segmental aneuploidies in clinical laboratories. They have advantages over fluorescence in situ hybridisation or microsatellites/SNP genotyping for detecting short segmental aneuploidies as the former is costly and labour intensive while the latter depends on the informativeness of the polymorphisms.

Neural networks as mechanisms to regulate division of labor.

Abstract In social insects, workers perform a multitude of tasks, such as foraging, nest construction, and brood rearing, without central control of how work is allocated among individuals. It has been suggested that workers choose a task by responding to stimuli gathered from the environment. Response-threshold models assume that individuals in a colony vary in the stimulus intensity (response threshold) at which they begin to perform the corresponding task. Here we highlight the limitations of these models with respect to colony performance in task allocation. First, we show with analysis and quantitative simulations that the deterministic response-threshold model constrains the workers' behavioral flexibility under some stimulus conditions. Next, we show that the probabilistic response-threshold model fails to explain precise colony responses to varying stimuli. Both of these limitations would be detrimental to colony performance when dynamic and precise task allocation is needed. To address these problems, we propose extensions of the response-threshold model by adding variables that weigh stimuli. We test the extended response-threshold model in a foraging scenario and show in simulations that it results in an efficient task allocation. Finally, we show that response-threshold models can be formulated as artificial neural networks, which consequently provide a comprehensive framework for modeling task allocation in social insects.

Neural differentiation and therapeutic potential of adipose tissue derived stem cells.

Neural tissue has historically been regarded as having poor regenerative capacity but recent advances in the growing fields of tissue engineering and regenerative medicine have opened new hopes for the treatment of nerve injuries and neurodegenerative disorders. Adipose tissue has been shown to contain a large quantity of adult stem cells (ASC). These cells can be easily harvested with low associated morbidity and because of their potential to differentiate into multiple cell types, their use has been suggested for a wide variety of therapeutic applications. In this review we examine the evidence indicating that ASC can stimulate nerve regeneration by both undergoing neural differentiation and through the release of a range of growth factors. We also discuss some of the issues that need to be addressed before ASC can be developed as an effective cellular therapy for the treatment of neural tissue disorders.