99 research outputs found
Signaling Cascade Involved in Rapid Stimulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Dexamethasone
Impairment of mucociliary clearance with reduced airway fluid secretion leads to
chronically inflamed airways. Cystic fibrosis transmembrane conductance regulator (CFTR) is
crucially involved in airway fluid secretion and dexamethasone (dexa) has previously been shown to
elevate CFTR activity in airway epithelial cells. However, the pathway by which dexa increases CFTR
activity is largely unknown. We aimed to determine whether the increase of CFTR activity by dexa
is achieved by non-genomic signaling and hypothesized that the phosphoinositide 3-kinase (PI3K)
pathway is involved in CFTR stimulation. Primary rat airway epithelial cells and human bronchial
submucosal gland-derived Calu-3 cells were analyzed in Ussing chambers and kinase activation was
determined byWestern blots. Results demonstrated a critical involvement of PI3K and protein kinase
B (AKT) signaling in the dexa-induced increase of CFTR activity, while serum and glucocorticoid
dependent kinase 1 (SGK1) activity was not essential. We further demonstrated a reduced neural
precursor cell expressed, developmentally downregulated 4-like (NEDD4L) ubiquitin E3 ligase
activity induced by dexa, possibly responsible for the elevated CFTR activity. Finally, increases of
CFTR activity by dexa were demonstrated within 30 min accompanied by rapid activation of AKT.
In conclusion, dexa induces a rapid stimulation of CFTR activity which depends on PI3K/AKT
signaling in airway epithelial cells. Glucocorticoids might thus represent, in addition to their
immunomodulatory actions, a therapeutic strategy to rapidly increase airway fluid secretion
Glucocorticoids Equally Stimulate Epithelial Na+ Transport in Male and Female Fetal Alveolar Cells
Preterm infants frequently suffer from respiratory distress syndrome (RDS), possibly due
to lower expression of epithelial Na+ channels (ENaC). RDS incidence is sex-specific, affecting males
almost twice as often. Despite the use of antenatal glucocorticoids (GCs), the sex difference persists.
It is still controversial whether both sexes benefit equally from GCs. We previously showed that
Na+ transport is higher in female compared with male fetal distal lung epithelial (FDLE) cells.
Since GCs increase Na+ transport, we hypothesized that their stimulating effect might be sex-specific.
We analyzed FDLE cells with Ussing chambers and RT-qPCR in the presence or absence of fetal serum.
In serum-free medium, GCs increased the ENaC activity and mRNA expression, independent of sex.
In contrast, GCs did not increase the Na+ transport in serum-supplemented media and abolished the
otherwise observed sex difference. Inhibition of the GC receptor in the presence of serum did not
equalize Na+ transport between male and female cells. The GC-induced surfactant protein mRNA
expression was concentration and sex-specific. In conclusion, female and male FDLE cells exhibit no
sex difference in response to GCs with regard to Na+ transport, and GR activity does not contribute
to the higher Na+ transport in females
Development and Functional Characterization of Fetal Lung Organoids
Preterminfants frequently suffer frompulmonary complications due to a physiological and
structural lung immaturity resulting in significant morbidity and mortality. Novel in vitro and
in vivo models are required to study the underlying mechanisms of late lung maturation
and to facilitate the development of new therapeutic strategies. Organoids recapitulate
essential aspects of structural organization and possibly organ function, and can be
used to model developmental and disease processes. We aimed at generating fetal
lung organoids (LOs) and to functionally characterize this in vitro model in comparison
to primary lung epithelial cells and lung explants ex vivo. LOs were generated with
alveolar and endothelial cells from fetal rat lung tissue, using a Matrigel-gradient and
air-liquid-interface culture conditions. Immunocytochemical analysis showed that the LOs
consisted of polarized epithelial cell adhesion molecule (EpCAM)-positive cells with the
apical membrane compartment facing the organoid lumen. Expression of the alveolar
type 2 cell marker, RT2-70, and the Club cell marker, CC-10, were observed. Na+
transporter and surfactant protein mRNA expression were detected in the LOs. First
time patch clamp analyses demonstrated the presence of several ion channels with
specific electrophysiological properties, comparable to vital lung slices. Furthermore, the
responsiveness of LOs to glucocorticoids was demonstrated. Finally, maturation of LOs
induced by mesenchymal stem cells confirmed the convenience of the model to test and
establish novel therapeutic strategies. The results showed that fetal LOs replicate key
biological lung functions essential for lung maturation and therefore constitute a suitable
in vitro model system to study lung development and related diseases
Numerical Relativity in D dimensional space-times: Collisions of unequal mass black holes
We present unequal mass head-on collisions of black holes in D = 5 dimensional space-times. We have simulated BH systems with mass ratios q = 1,1/2,1/3,1/4. We extract the total energy radiated throughout the collision and compute the linear momentum flux and the recoil velocity of the final black hole. The numerical results show very good agreement with point particle calculations when extrapolated to this limit
Numerical Relativity in D dimensional space-times: Collisions of unequal mass black holes
We present unequal mass head-on collisions of black holes in D = 5 dimensional space-times. We have simulated BH systems with mass ratios q = 1,1/2,1/3,1/4. We extract the total energy radiated throughout the collision and compute the linear momentum flux and the recoil velocity of the final black hole. The numerical results show very good agreement with point particle calculations when extrapolated to this limit
Numerical Relativity in D dimensional space-times: Collisions of unequal mass black holes
We present unequal mass head-on collisions of black holes in D = 5 dimensional space-times. We have simulated BH systems with mass ratios q = 1,1/2,1/3,1/4. We extract the total energy radiated throughout the collision and compute the linear momentum flux and the recoil velocity of the final black hole. The numerical results show very good agreement with point particle calculations when extrapolated to this limit
A descriptive analysis of human milk dispensed by the Leipzig Donor Human Milk Bank for neonates between 2012 and 2019
BackgroundHuman milk banking has become an important aspect of Nutritional medicine. It is not just about the provision of mother’s own milk (MOM) or donor human milk (DHM) in the hospital, but also a strategy to encourage breastfeeding in the clinical setting and beyond.ObjectiveTo describe the feeding patterns of hospitalised infants including human milk dispensed by the Leipzig Donor Human Milk Bank (LMB).DesignA descriptive analysis of daily data on milk feeds dispensed by LMB for hospitalised infants distinguishing between MOM or DHM, either fresh or frozen, and raw/pasteurised milk from 2012–2019.ResultsWe included 2,562 infants with median hospitalisation of 23 days, for whom human milk was dispensed on median 76% of those days and other nutrition on the remaining days. Raw MOM and raw DHM comprised 52% and 8% of the dispensed milk, respectively. Dispensing exclusive DHM instead of MOM for at least one full day was required for 55% of the infants, mostly at the beginning but also later during hospitalisation. Exclusive raw DHM was dispensed on at least 1 day for 37% of the infants, in different birthweight strata <1,000 g: 10%, 1,000-1500 g: 11%, 1,500-2500 g: 13% and > 2,500 g: 3%. At discharge, MOM was dispensed for more than 60% of the infants.ConclusionDuring an infant’s hospital stay, LMB dispenses various human milk feeds with interspersed DHM resulting in complex intra-individual and time-variant feeding patterns. LMB dispenses raw MOM and especially raw DHM with the intention to retain the properties of human milk unlike a diet containing pasteurised DHM and/or formula. Although raw DHM comprises a small percentage of all dispensed milk, raw DHM is dispensed for a substantial portion of infants. Our results document that dispensing raw DHM, is possible in routine settings
Nabelvenenkatheter- und periphere zentrale katheterassoziierte Komplikationen bei Frühgeborenen mit einem Geburtsgewicht < 1250 g : Ergebnisse einer Umfrage in Österreich und Deutschland
Background and objective
Umbilical venous catheters (UVC) and peripherally inserted central catheters (PICC) are commonly used in preterm infants but have been associated with a number of serious complications. We performed a survey in Austria and Germany to assess the use of UVCs and PICCs in preterm infants with a birth weight < 1250 g and associated rates of catheter-related adverse events.
Methods
Electronic survey of participating centers of the NeoVitaA trial. Main outcome parameter was the reported rates of UVC- and PICC-associated complications (infection, thrombosis, emboli, organ injury, arrhythmia, dislocation, miscellaneous).
Results
In total, 20 neonatal intensive care units (NICU) providing maximal intensive care in Austria and Germany (level I) were contacted, with a senior neonatologist response rate of 12/20 (60%). The reported rates for UVC with a dwell time of 1–10 days were bacterial infection: 4.2 ± 3.4% (range 0–10%); thrombosis: 7.3 ± 7.1% (0–20%); emboli: 0.9 ± 2.0% (0–5%); organ injury: 1.1 ± 1.9% (0–5%); cardiac arrhythmia: 2.2 ± 2.5% (0–5%); and dislocation: 5.4 ± 8.7% (0–30%); and for PICCs with a dwell time of 1–14 days bacterial infection: 15.0 ± 3.4% (range 2.5–30%); thrombosis; 4.3 ± 3.5% (0–10%); emboli: 0.8 ± 1.6% (0–5%); organ injury: 1.5 ± 2.3% (0–5%); cardiac arrhythmia: 1.5 ± 2.3% (0–5%), and dislocation: 8.5 ± 4.6% (0–30%).
Conclusion
The catheter-related complication rates reported in this survey differed between UVCs and PICCs and were higher than those reported in the literature. To generate more reliable data on this clinically important issue, we plan to perform a large prospective multicenter randomized controlled trial investigating the non-inferiority of a prolonged UVC dwell time (up to 10 days) against the early change (up to 5 days) to a PICC.Hintergrund und Ziel
Nabelvenenkatheter („umbilical venous catheters“ [UVC]) und periphere zentrale Venenkatheter (PICC) werden häufig bei Frühgeborenen eingesetzt, sind jedoch mit einer Reihe von schwerwiegenden Komplikationen verbunden. In Österreich und Deutschland wurde eine Umfrage durchgeführt, um die Verwendung von UVC und PICC bei Frühgeborenen mit einem Geburtsgewicht < 1250 g und die damit verbundenen Raten von katheterbedingten unerwünschten Ereignissen zu bewerten.
Methoden
Elektronische Befragung der teilnehmenden Zentren der NeoVitaA-Studie. Hauptergebnisparameter waren die gemeldeten Raten von UVC- und PICC-assoziierten Komplikationen (Infektion, Thrombose, Embolie, Organverletzung, Arrhythmie, Dislokation, Sonstiges).
Ergebnisse
Insgesamt wurden 20 neonatale Intensivstationen (NICU) mit maximaler Intensivpflege in Österreich und Deutschland (Level I) kontaktiert, wobei 12/20 (60 %) von leitenden Neonatologen beantwortet wurden. Die gemeldeten Raten für UVC mit einer Verweildauer von 1 bis 10 Tagen waren bakterielle Infektionen: 4,2 ± 3,4 % (Bereich: 0–10 %); Thrombose: 7,3 ± 7,1 % (0–20 %); Embolie: 0,9 ± 2,0 % (0–5 %); Organverletzung: 1,1 ± 1,9 % (0–5 %); Herzrhythmusstörungen: 2,2 ± 2,5 % (0–5 %); und Dislokation: 5,4 ± 8,7% (0–30 %); und bei PICC mit einer Verweildauer von 1 bis 14 Tagen bakterielle Infektionen: 15,0 ± 3,4 % (Bereich: 2,5–30 %); Thrombose: 4,3 ± 3,5 % (0–10 %); Embolie: 0,8 ± 1,6 % (0–5 %); Organverletzung: 1,5 ± 2,3 % (0–5 %); Herzrhythmusstörungen: 1,5 ± 2,3 % (0–5 %) und Verrenkungen: 8,5 ± 4,6 % (0–30 %).
Schlussfolgerung
Die in dieser Umfrage berichteten katheterbedingten Komplikationsraten unterschieden sich zwischen UVC und PICC und waren höher als die in der Literatur berichteten. Um zuverlässigere Daten zu diesem klinisch wichtigen Thema zu erhalten, ist eine große prospektive, multizentrische, randomisierte, kontrollierte Studie geplant, in der die Nichtunterlegenheit einer verlängerten UVC-Verweildauer (bis zu 10 Tage) gegenüber dem frühen Wechsel (bis zu 5 Tage) zu einem PICC untersucht werden soll
Measurements of branching fraction ratios and CP-asymmetries in suppressed B^- -> D(-> K^+ pi^-)K^- and B^- -> D(-> K^+ pi^-)pi^- decays
We report the first reconstruction in hadron collisions of the suppressed
decays B^- -> D(-> K^+ pi^-)K^- and B^- -> D(-> K^+ pi^-)pi^-, sensitive to the
CKM phase gamma, using data from 7 fb^-1 of integrated luminosity collected by
the CDF II detector at the Tevatron collider. We reconstruct a signal for the
B^- -> D(-> K^+ pi^-)K^- suppressed mode with a significance of 3.2 standard
deviations, and measure the ratios of the suppressed to favored branching
fractions R(K) = [22.0 \pm 8.6(stat)\pm 2.6(syst)]\times 10^-3, R^+(K) =
[42.6\pm 13.7(stat)\pm 2.8(syst)]\times 10^-3, R^-(K)= [3.8\pm 10.3(stat)\pm
2.7(syst]\times 10^-3, as well as the direct CP-violating asymmetry A(K) =
-0.82\pm 0.44(stat)\pm 0.09(syst) of this mode. Corresponding quantities for
B^- -> D(-> K^+ pi^-)pi^- decay are also reported.Comment: 8 pages, 1 figure, accepted by Phys.Rev.D Rapid Communications for
Publicatio
Towards the clinical implementation of pharmacogenetics in bipolar disorder.
BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD
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