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

Frequent oil baths and skin barrier during infancy in the PreventADALL study

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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

Genetic and epigenetic risk factors for asthma in infancy and childhood

Asthma is among the most common non-communicable diseases, with an increasing prevalence worldwide. The pathophysiology behind the disease is heterogeneous, including risk factors like genes, sex, allergies, virus infections, and wheezing episodes. In recent years, epigenetic changes have been found to be associated with the development of asthma, but there is a lack of knowledge about the exact mechanisms of how these genes and epigenetic alterations contribute to disease onset and progression. Furthermore, loss-of-function mutations in the skin barrier gene filaggrin (FLG) are associated with atopic dermatitis (AD) that most often precedes the development of childhood asthma. Airway obstruction is also related to asthma development; nevertheless, less is known about lower lung function and skin barrier impairment in early infancy. Therefore, the overall aim of the thesis was to examine genetic and epigenetic factors for asthma in infancy and childhood. Study I focused on the genetics of asthma by investigating CST1 and CCL26 to better understand their function in the development of asthma, as these genes were previously identified to have the highest expression in the nasal epithelium of dog dander-sensitized children. CST1 and CCL26 were overexpressed separately in the human alveolar basal epithelial cell line A549. RNA sequencing and protein analyses were performed to investigate the downstream effects. On the RNA level a significant downregulation of type I and III interferons and interferon-stimulated genes was observed in A549 cells overexpressing CST1 or CCL26 compared to the controls. No significant downregulation of the analyzed inflammation proteins was observed due to the overexpression of CST1, however, CXCL11, CCL20, CCL3 and CXCL10 were significantly downregulated due to the overexpression of CCL26. Overall, the overexpression of CCL26 caused a downregulation of interferon related genes and inflammatory proteins. Study II evaluated the epigenetics of asthma by analyzing 14 hypomethylated CpG sites previously identified in whole blood of asthmatic children. Seven genes that are inferred to be regulated by these CpG sites were selected for deeper analysis. The overall aim of the study was to better understand the downstream effects of the methylation differences on the gene expression and gene function and their contribution to asthma. The seven genes (SLC25A25, MED27, NTNG2, BBLN, PTGES2, NAIF1, LCN2) or their respective control vectors were separately overexpressed via transfection in the airway epithelial cell lines A549 and BEAS-2B. Transcriptomic and proteomic analyses were performed to identify the downstream effects. The overexpression of MED27, NTNG2 and BBLN separately caused mainly an upregulation of type I and III interferon genes as well as interferon-stimulated genes. Due to the location of one asthma associated CpG site within an intronic region of MED27, the overexpression of MED27 was also analyzed at different timepoints and demonstrated to affect the expression of type I and III interferons in a time-dependent manner. On the protein level, the overexpression of MED27 caused an upregulation of CCL3, TGF-alpha and CCL20, whereas CCL3 and CCL20 were downregulated due to the overexpression of NTNG2, BBLN, PTGES2, NAIF1 and LCN2. In general, MED27 might have an important role in the pathophysiology of asthma, due to the location of an asthma associated CpG site within the gene, its time-dependent effect on interferon genes and the increased protein expression which its overexpression causes. Study III placed the genetics in a clinical context and focused on AD, most often preceding asthma development. It is an epidemiological study of the Scandinavian mother-child cohort PreventADALL including 1836 infants with information on FLG genotyping. The objective was to investigate the role of the most common FLG loss-of-function mutations in the European population on skin barrier function, dry skin, eczema, and AD before one year of age. At 3 months, FLG mutations were associated with eczema and at 6 months, FLG mutation carriers had significantly higher transepidermal water loss (TEWL) than nonmutation carriers. Further, the risk for dry skin on the trunk and extensor limb surfaces was increased at 3 and 6 months for FLG mutation carriers. In conclusion, the study observed associations between FLG mutations and dry skin on the trunk and extensor limb surfaces, eczema, and AD before one year of age. Study IV was also an epidemiological study of the PreventADALL cohort and combined genetics, asthma, and asthma comorbidities. The study of 1337 children aimed to identify possible associations between early infant lung- and skin barrier function and asthma at age 3 years. Lower lung function and higher TEWL were associated with asthma at age 3 years, while eczema and FLG mutations were not. The strongest association was observed between lower lung function and asthma at age 3 years when the children had a diagnosis of either AD or allergic sensitization by 3 years. Taken together, lung- and skin barrier function at 3 months seemed to have already an effect on asthma at age 3 years. The four studies of the thesis contribute to the field of genetics and epigenetics in asthma with new findings. Potential functions were identified for genes previously identified in allergic children and for genes regulated by asthma associated CpG sites. The clinical studies of this doctoral thesis discovered that mutations in the skin barrier gene FLG influence the skin already before one year of age and assessed that skin barrier impairment as well as lower lung function in infancy were associated with asthma at age 3 years

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