Non-invasive cardiac output monitoring (NICOM) in adult congenital heart disease patients with Fontan palliation

Rationale Fontan palliation for single ventricle malformations is an increasingly common reason for heart failure in the adult population. Cardiac output (CO) measurement in Fontan physiology is achieved by invasive cardiac catheterization (RHC). Noninvasive CO monitors using thoracic bioreactance (NICOM) have been validated in non-congenital patients but have not been studied in adult Fontan patients. Objective To compare RHC obtained values of CO using the Fick equation with those measured simultaneously by NICOM in a cohort of adults with Fontan palliation. Methods and results In nineteen patients undergoing routine outpatient RHC, we compared CO values as determined by Fick with those generated by the Starling SV NICOM device. Bland-Altman plots and intraclass correlation coefficients (ICCs) revealed internal consistency within NICOM measurements, however the agreement between RHC and NICOM for CO was poor (ICCs ​∼ ​0.40). We performed sub-analyses using two-sample T-tests and ICCs to determine if clinical cyanosis, acute desaturation, or Fontan pressure affected the difference observed between RHC and NICOM. Neither chronic hypoxia, acute desaturation, nor Fontan pressure measures were found to be associated with the observed difference between the RHC and NICOM measured CO. Discussion and conclusion Our study did not find a correlation between RHC and NICOM derived measures of CO in a cohort of Fontan patients, even in sub-analyses of confounders of Fontan physiology. We observed internal consistency within the device, which may open a role for monitoring of trends rather than absolute values in Fontan patients. Our study was limited due to small sample size

Modeling clonal hematopoiesis in umbilical cord blood cells by CRISPR/Cas9

To investigate clonal hematopoiesis associated gene mutations in vitro and to unravel the direct impact on the human stem and progenitor cell (HSPC) compartment, we targeted healthy, young hematopoietic progenitor cells, derived from umbilical cord blood samples, with CRISPR/Cas9 technology. Site-specific mutations were introduced in defined regions of DNMT3A, TET2, and ASXL1 in CD34(+) progenitor cells that were subsequently analyzed in short-term as well as long-term in vitro culture assays to assess self-renewal and differentiation capacities. Colony-forming unit (CFU) assays revealed enhanced self-renewal of TET2 mutated (TET2(mut)) cells, whereas ASXL1(mut) as well as DNMT3A(mut) cells did not reveal significant changes in short-term culture. Strikingly, enhanced colony formation could be detected in long-term culture experiments in all mutants, indicating increased self-renewal capacities. While we could also demonstrate preferential clonal expansion of distinct cell clones for all mutants, the clonal composition after long-term culture revealed a mutation-specific impact on HSPCs. Thus, by using primary umbilical cord blood cells, we were able to investigate epigenetic driver mutations without confounding factors like age or a complex mutational landscape, and our findings provide evidence for a direct impact of clonal hematopoiesis-associated mutations on self-renewal and clonal composition of human stem and progenitor cells

McClear: a new model estimating downwelling solar radiation at ground level in clear-sky conditions

International audienceA new fast clear-sky model called McClear was developed to estimate the downwelling shortwave direct and global irradiances received at ground level under clear skies. It is a fully physical model replacing empirical relations or simpler models used before. It exploits the recent results on aerosol properties, and total column content in water vapour and ozone produced by the MACC project (Monitoring Atmosphere Composition and Climate). It accurately reproduces the irradiance computed by the libRadtran reference radiative transfer model with a computational speed approximately 105 times greater by adopting the abaci, or look-up table, approach combined with interpolation functions. It is therefore suited for geostationary satellite retrievals or numerical weather prediction schemes with many pixels or grid points, respectively. McClear irradiances were compared to 1 min measurements made in clear-sky conditions at several stations within the Baseline Surface Radiation Network in various climates. The bias for global irradiance comprises between −6 and 25Wm−2. The RMSE ranges from 20Wm−2 (3% of the mean observed irradiance) to 36Wm−2 (5 %) and the correlation coefficient ranges between 0.95 and 0.99. The bias for the direct irradiance comprises between −48 and +33Wm−2. The root mean square error (RMSE) ranges from 33Wm−2 (5 %) to 64Wm−2 (10 %). The correlation coefficient ranges between 0.84 and 0.98. This work demonstrates the quality of the McClear model combined with MACC products, and indirectly the quality of the aerosol properties modelled by the MACC reanalysis

Birth mode is associated with development of atopic dermatitis in infancy and early childhood

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Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD

Transient Administration of Dopaminergic Precursor Causes Inheritable Overfeeding Behavior in Young Drosophila melanogaster Adults

Imbalances in dopaminergic signaling during development have been indicated as part of the underlying neurobiology of several psychiatric illnesses, including schizophrenia, major depression, bipolar disorder, and food addiction. Yet, how transient manipulation of dopaminergic signaling influences long-lasting behavioral consequences, or if these modifications can induce inheritable traits, it is still not understood. In this study, we used theDrosophila melanogastermodel to test if transient pharmacological activation of the dopaminergic system leads to modulations of feeding and locomotion in adult flies. We observed that transient administration of a dopaminergic precursor, levodopa, at 6 h, 3 days or 5 days post-eclosion, induced overfeeding behavior, while we did not find significant effects on locomotion. Moreover, this phenotype was inherited by the offspring of flies treated 6 h or 3 days post-eclosion, but not the offspring of those treated 5 days post-eclosion. These results indicate that transient alterations in dopaminergic signaling can produce behavioral alterations in adults, which can then be carried to descendants. These findings provide novel insights into the conditions in which environmental factors can produce transgenerational eating disorders

The Drosophila melanogaster Levodopa-Induced Depression Model Exhibits Negative Geotaxis Deficits and Differential Gene Expression in Males and Females

More than 320 million people live with depression in the world, a disorder that severely limits psychosocial functioning and diminishes quality of life. The prevalence of major depression is almost two times higher in women than in men. However, the molecular mechanisms of its sex-specific pathophysiology are still poorly understood. Drosophila melanogaster is an established model for neurobiological research of depression-like states, as well as for the study of molecular and genetic sex differences in the brain. Here, we investigated sex-specific effects on forced-climbing locomotion (negative geotaxis) and gene expression of a fly model of depression-like phenotypes induced by levodopa administration, which was previously shown to impair normal food intake, mating frequency, and serotonin concentration. We observed that both males and females show deficits in the forced-climbing paradigm; however, modulated by distinct gene expression patterns after levodopa administration. Our results suggest that Drosophila models can be a valuable tool for identifying the molecular mechanisms underlying the difference of depressive disorder prevalence between men and women

Placental glucocorticoid receptors are not affected by maternal depression or SSRI treatment.

Background: Prenatal depression is common, with an estimate that up to one in five pregnant women suffers from depressive symptoms. Maternal depression is associated with poor pregnancy outcomes such as preterm birth and low birth-weight. Such outcomes possibly affect offspring development. Previous studies suggest placental RNA levels of the glucocorticoid receptor are altered by maternal depression or anxiety; this stress may affect the placenta of male and female foetuses differently. However, it is unknown if the protein levels and activity of this receptor are additionally affected in women with depressive symptoms or being pharmacologically treated for depression.Methods: In this study, we investigated whether the glucocorticoid receptor (NR3C1) in the placenta is affected by maternal depression and/or selective serotonin reuptake inhibitor (SSRIs) treatment. Placentas from 45 women with singleton, term pregnancies were analysed by Western blot to determine glucocorticoid receptor levels, and by DNA-binding capacity to measure glucocorticoid receptor activation.Results: There were no differences in levels of the glucocorticoid receptor or activity between groups (control, depressive symptoms, and SSRI treatment; n = 45). Similarly, there was no difference in placental glucocorticoid receptor levels or activity dependent upon foetal sex.Conclusion: Maternal depression and SSRI treatment do not affect the glucocorticoid receptors in the placenta

Eukaryotic catecholamine hormones influence the chemotactic control of Vibrio campbellii by binding to the coupling protein CheW

In addition to their well-known role as stress-associated catecholamine hormones in animals and humans, epinephrine (EPI) and norepinephrine (NE) act as interkingdom signals between eukaryotic hosts and bacteria. However, the molecular basis of their effects on bacteria is not well understood. In initial phenotypic studies utilizing Vibrio campbellii as a model organism, we characterized the bipartite mode of action of catecholamines, which consists of promotion of growth under iron limitation, and enhanced colony expansion on soft agar. In order to identify the molecular targets of the hormones, we designed and synthesized tailored probes for chemical proteomic studies. As the catechol group in EPI and NE acts as iron chelator and is prone to form a reactive quinone moiety, we devised a photoprobe based on the adrenergic agonist phenylephrine (PE), which solely influenced colony expansion. Using this probe, we identified CheW, located at the core of the chemotaxis signaling network, as a major target. In vitro studies confirmed that EPI, NE, PE, as well as labetalol, a clinically applied antagonist, bind to purified CheW with affinity constants in the sub-micromolar range. In line with these findings, exposure of V. campbellii to these adrenergic agonists affects the chemotactic control of the bacterium. This study highlights a previously unknown effect of eukaryotic signaling molecules on bacterial motility