The Endothelial Glycocalyx: Physiology and Pathology in Neonates, Infants and Children

The endothelial glycocalyx (EG) as part of the endothelial surface layer (ESL) is an important regulator of vascular function and homeostasis, including permeability, vascular tone, leukocyte recruitment and coagulation. Located at the interface between the endothelium and the blood stream, this highly fragile structure is prone to many disruptive factors such as inflammation and oxidative stress. Shedding of the EG has been described in various acute and chronic diseases characterized by endothelial dysfunction and angiopathy, such as sepsis, trauma, diabetes and cardiovascular disease. Circulating EG components including syndecan-1, hyaluronan and heparan sulfate are being evaluated in animal and clinical studies as diagnostic and prognostic markers in several pathologies, and advances in microscopic techniques have enabled in vivo assessment of the EG. While research regarding the EG in adult physiology and pathology has greatly advanced throughout the last decades, our knowledge of the development of the glycocalyx and its involvement in pathological conditions in the pediatric population is limited. Current evidence suggests that the EG is present early during fetal development and plays a critical role in vessel formation and maturation. Like in adults, EG shedding has been demonstrated in acute inflammatory conditions in infants and children and chronic diseases with childhood-onset. However, the underlying mechanisms and their contribution to disease manifestation and progression still need to be established. In the future, the glycocalyx might serve as a marker to identify pediatric patients at risk for vascular sequelae and as a potential target for early interventions

Enabling Large-Scale Testing of IaaS Cloud Platforms on the Grid'5000 Testbed

International audienceAlmost ten years after its premises, the Grid'5000 platform has become one of the most complete testbeds for designing or evaluating large-scale distributed systems. Initially dedicated to the study of High Performance Computing, the infrastructure has evolved to address wider concerns related to Desktop Computing, the Internet of Services and more recently the Cloud Computing paradigm. In this paper, we present the latest mechanisms we designed to enable the automated deployment of the major open-source IaaS cloudkits (i.e., Nimbus, OpenNebula, CloudStack, and OpenStack) on Grid'5000. Providing automatic, isolated and reproducible deployments of cloud environments lets end-users study and compare each solution or simply leverage one of them to perform higher-level cloud experiments (such as investigating Map/Reduce frameworks or applications)

Noninvasive Ventilation in Preterm Infants: Factors Influencing Weaning Decisions and the Role of the Silverman-Andersen Score

The factors influencing weaning of preterm infants from noninvasive ventilation (NIV) are poorly defined and the weaning decisions are often driven by subjective judgement rather than objective measures. To standardize quantification of respiratory effort, the Silverman-Andersen Score (SAS) was included in our nursing routine. We investigated the factors that steer the weaning process and whether the inclusion of the SAS would lead to more stringent weaning. Following SAS implementation, we prospectively evaluated 33 neonates born <= 32 + 0 weeks gestational age. Age-, weight- and sex-matched infants born before routine SAS evaluation served as historic control. In 173 of 575 patient days, NIV was not weaned despite little respiratory distress (SAS <= 2), mainly due to bradycardias (60% of days without weaning), occurring alone (40%) or in combination with other factors such as apnea/desaturations. In addition, soft factors that are harder to grasp impact on weaning decisions, whereas the SAS overall played a minor role. Consequently, ventilation times did not differ between the groups. In conclusion, NIV weaning is influenced by various factors that override the absence of respiratory distress limiting the predictive value of the SAS. An awareness of the factors that influence weaning decisions is important as prolonged use of NIV has been associated with adverse outcome. Guidelines are necessary to standardize NIV weaning practice

Effects of Prematurity on the Cutaneous Microcirculatory Network in the First Weeks of Life

Background: Preterm infants are at increased risk for hypertension in adolescence. Microcirculatory dysfunction has been identified as an underlying cause for cardiovascular disease. Our goal was to document the development of the cutaneous microcirculation in preterm infants during the first weeks of life and to compare it to the situation in term infants at birth.Methods: In 20 preterm infants, microcirculatory parameters were obtained prospectively by Sidestream Dark Field (SDF) Imaging at the upper inner arm once a week until discharge or 37 weeks of gestational age. A single microcirculatory measurement was obtained in 30 term infants during the first 3 days of life. Videos were blinded and analyzed with the AVA software.Results: Microcirculatory parameters in preterm infants differ significantly from term infants with a lower vessel surface (VS), a lower percentage of large and medium but higher percentage of small vessels, a higher Functional Vessel Density (FVD), and a higher Microcirculatory Flow Index (MFI). In multivariable linear regression models we could demonstrate a statistically significant association between the dependent microcirculatory variables (VS, diameter distribution, MFI) and gestational age as independent predictor variable while adjusting for postnatal days of life. Looking at the longitudinal follow-up data of preterm infants by means of a multivariable mixed-effects linear regression model adjusting for clinical variables, there is a significant decrease in FVD with increasing postnatal age, however no other significant changes in microcirculatory parameters over time. Accordingly, comparing the microcirculatory parameters of near term former preterm infants with term born neonates, we could still find significant differences with a higher FVD, lower VS and differences in vessel diameters in the former premature group.Conclusion: Infants born prematurely exhibit distinct microcirculatory alterations compared to term neonates with gestational age at birth being associated with microvascular parameters. Interestingly, this premature vascular phenotype persists even close to corrected term age. In view of the known increased cardiovascular risk of former preterm infants, our observations might have important clinical impact. The factors governing the development of the microvascular network in preterm infants and the contribution of microcirculatory changes observed here to vascular pathology in later life need to be further investigated

Adding Virtualization Capabilities to Grid'5000

Ce rapport révisé a fait l'objet d'une publication, voir hal-00946971Almost ten years after its premises, the Grid'5000 testbed has become one of the most complete testbed for designing or evaluating large-scale distributed systems. Initially dedicated to the study of High Performance Computing, the infrastructure has evolved to address wider concerns related to Desktop Computing, the Internet of Services and more recently the Cloud Computing paradigm. This report present recent improvements of the Grid'5000 software and services stack to support large-scale experiments using virtualization technologies as building blocks. Such contributions include the deployment of customized software environments, the reservation of dedicated network domain and the possibility to isolate them from the others, and the automation of experiments with a REST API. We illustrate the interest of these contributions by describing three different use-cases of large-scale experiments on the Grid'5000 testbed. The first one leverages virtual machines to conduct larger experiments spread over 4000 peers. The second one describes the deployment of 10000 KVM instances over 4 Grid'5000 sites. Finally, the last use case introduces a one-click deployment tool to easily deploy major IaaS solutions. The conclusion highlights some important challenges of Grid'5000 related to the use of OpenFlow and to the management of applications dealing with tremendous amount of data.Dix ans environ après ses prémisses, la plate-forme Grid'5000 est devenue une des plates-formes les plus complètes utilisée pour la conception et l'évaluation de systèmes distribués à grande échelle. Dédiée initialement au calcul à haute performance, l'infrastructure a évolué pour supporter un ensemble de problèmes plus vaste liés au calcul de type Desktop, l'internet des objets et plus récemment l'informatique dans les nuages (aussi appelé Cloud Computing). Ce rapport présente les améliorations récentes apportées au logiciels et pile de services pour supporter les expérimentations à grande échelle utilisant les technologies de virtualisation comme blocs de base. Nos contributions incluent le déploiement d'environnements logiciels customisés, la réservation de domaines réseaux dédiés et la possibilité de les isoler entre eux, et l'automatisation des expérimentations grâce à une API REST. Nous illustrons l'intérêt de ces contributions en décrivant trois expériences à large échelle sur la plate-forme Grid'5000. La première expérience utilise des machines virtuelles pour conduire des expérimentations de grande taille sur 4000 pairs. La seconde expérience décrit le déploiement de 10000 instances KVM sur 4 sites Grid'5000. Enfin le dernier exemple présente un outil de déploiement simple pour déployer des solutions de Cloud de type IaaS. La conclusion discute de prochains défis importants de Grid'5000 liés à l'utilisation d'OpenFlow et à la gestion d'applications gérant des grandes masses de données

Adding Virtualization Capabilities to Grid'5000

Ce rapport révisé a fait l'objet d'une publication, voir hal-00946971Almost ten years after its premises, the Grid'5000 testbed has become one of the most complete testbed for designing or evaluating large-scale distributed systems. Initially dedicated to the study of High Performance Computing, the infrastructure has evolved to address wider concerns related to Desktop Computing, the Internet of Services and more recently the Cloud Computing paradigm. This report present recent improvements of the Grid'5000 software and services stack to support large-scale experiments using virtualization technologies as building blocks. Such contributions include the deployment of customized software environments, the reservation of dedicated network domain and the possibility to isolate them from the others, and the automation of experiments with a REST API. We illustrate the interest of these contributions by describing three different use-cases of large-scale experiments on the Grid'5000 testbed. The first one leverages virtual machines to conduct larger experiments spread over 4000 peers. The second one describes the deployment of 10000 KVM instances over 4 Grid'5000 sites. Finally, the last use case introduces a one-click deployment tool to easily deploy major IaaS solutions. The conclusion highlights some important challenges of Grid'5000 related to the use of OpenFlow and to the management of applications dealing with tremendous amount of data.Dix ans environ après ses prémisses, la plate-forme Grid'5000 est devenue une des plates-formes les plus complètes utilisée pour la conception et l'évaluation de systèmes distribués à grande échelle. Dédiée initialement au calcul à haute performance, l'infrastructure a évolué pour supporter un ensemble de problèmes plus vaste liés au calcul de type Desktop, l'internet des objets et plus récemment l'informatique dans les nuages (aussi appelé Cloud Computing). Ce rapport présente les améliorations récentes apportées au logiciels et pile de services pour supporter les expérimentations à grande échelle utilisant les technologies de virtualisation comme blocs de base. Nos contributions incluent le déploiement d'environnements logiciels customisés, la réservation de domaines réseaux dédiés et la possibilité de les isoler entre eux, et l'automatisation des expérimentations grâce à une API REST. Nous illustrons l'intérêt de ces contributions en décrivant trois expériences à large échelle sur la plate-forme Grid'5000. La première expérience utilise des machines virtuelles pour conduire des expérimentations de grande taille sur 4000 pairs. La seconde expérience décrit le déploiement de 10000 instances KVM sur 4 sites Grid'5000. Enfin le dernier exemple présente un outil de déploiement simple pour déployer des solutions de Cloud de type IaaS. La conclusion discute de prochains défis importants de Grid'5000 liés à l'utilisation d'OpenFlow et à la gestion d'applications gérant des grandes masses de données

Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood appr

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Effect of gestational age and postnatal age on the endothelial glycocalyx in neonates

Prematurity predisposes to cardiovascular disease; however the underlying mechanisms remain elusive. Disturbance of the endothelial glycocalyx (EG), an important regulator of vessel function, is thought to contribute to vascular pathology. Here, we studied the EG with respect to gestational and postnatal age in preterm and term neonates. The Perfused Boundary Region (PBR), an inverse measure of glycocalyx thickness, was measured postnatally in 85 term and 39 preterm neonates. Preterm neonates were further analyzed in two subgroups i.e., neonates born 30~weeks was significantly higher than in group B at birth, pointing towards an alteration of intrinsic maturational effects by extrinsic factors. These changes might contribute to the increased cardiovascular risk associated with extreme prematurity