The transcription factor PAX6 is involved in the development of the eye and pancreatic islets, besides being associated with sleep-wake cycles. Here, we investigated a point mutation in the RED ...subdomain of PAX6, previously described in a human patient, to present a comprehensive study of a homozygous Pax6 mutation in the context of adult mammalian metabolism and circadian rhythm. Pax6
mice lack appropriate retinal structures for light perception and do not display normal daily rhythmic changes in energy metabolism. Despite β cell dysfunction and decreased insulin secretion, mutant mice have normal glucose tolerance. This is associated with reduced hepatic glucose production possibly due to altered circadian variation in expression of clock and metabolic genes, thereby evading hyperglycemia. Hence, our findings show that while the RED subdomain is important for β cell functional maturity, the Leca2 mutation impacts peripheral metabolism via loss of circadian rhythm, thus revealing pleiotropic effects of PAX6.
The Notch signaling pathway is an evolutionary conserved signal transduction pathway involved in embryonic patterning and regulation of cell fates during development and self-renewal. Recent studies ...have demonstrated that this pathway is integral to a complex system of interactions, involving as well other signal transduction pathways, and implicated in distinct human diseases. Delta-like 1 (Dll1) is one of the known ligands of the Notch receptors. The role of the Notch ligands is less well understood. Loss-of-function of Dll1 leads to embryonic lethality, but reduction of Delta-like 1 protein levels has not been studied in adult stage.
Here we present the haploinsufficient phenotype of Dll1 and a missense mutant Dll1 allele (Dll1(C413Y)). Haploinsufficiency leads to a complex phenotype with several biological processes altered. These alterations reveal the importance of Dll1 mainly in metabolism, energy balance and in immunology. The animals are smaller, lighter, with altered fat to lean ratio and have increased blood pressure and a slight bradycardia. The animals have reduced cholesterol and triglyceride levels in blood. At the immunological level a subtle phenotype is observed due to the effect and fine-tuning of the signaling network at the different levels of differentiation, proliferation and function of lymphocytes. Moreover, the importance of the proteolytic regulation of the Notch signaling network emphasized.
In conclusion, slight alterations in one player of Notch signaling alter the entire organism, emphasizing the fine-tuning character of this pathway in a high number of processes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To describe the resolution of regional atelectasis and the development of regional lung overdistension during a lung-recruitment protocol in children with acute lung injury.
Prospective ...interventional trial.
Pediatric intensive care unit.
Ten children with early (<72 hrs) acute lung injury.
Sustained inflation maneuver (positive airway pressure of 40 cm H2O for 40 secs), followed by a stepwise recruitment maneuver (escalating plateau pressures by 5 cm H2O every 15 mins) until physiologic lung recruitment, defined by PaO2 + PaCO2 ≥400 mm Hg, was achieved. Regional lung volumes and mechanics were measured using electrical impedance tomography.
Patients that responded to the stepwise lung-recruitment maneuver had atelectasis in 54% of the dependent lung regions, while nonresponders had atelectasis in 10% of the dependent lung regions (p = .032). In the pressure step preceding physiologic lung recruitment, a significant reversal of atelectasis occurred in 17% of the dependent lung regions (p = .016). Stepwise recruitment overdistended 8% of the dependent lung regions in responders, but 58% of the same regions in nonresponders (p < .001). Lung compliance in dependent lung regions increased in responders, while compliance in nonresponders did not improve. In contrast to the stepwise recruitment maneuver, the sustained inflation did not produce significant changes in atelectasis or oxygenation: atelectasis was only reversed in 12% of the lung (p = .122), and there was only a modest improvement in oxygenation (27 ± 14 mm Hg, p = .088).
Reversal of atelectasis in the most dependent lung region preceded improvements in gas exchange during a stepwise lung-recruitment strategy. Lung recruitment of dependent lung areas was accompanied by considerable overdistension of nondependent lung regions. Larger amounts of atelectasis in dependent lung areas were associated with a positive response to a stepwise lung-recruitment maneuver.
The benefit of treating acute lung injury with recruitment manoeuvres is controversial. An impediment to settling this debate is the difficulty in visualizing how distinct lung regions respond to the ...manoeuvre. Here, regional lung mechanics were studied by electrical impedance tomography (EIT) during a stepwise recruitment manoeuvre in a porcine model with acute lung injury. The following interaction between dependent and non-dependent regions consistently occurred: atelectasis in the most dependent region was reversed only after the non-dependent region became overdistended. EIT estimates of overdistension and atelectasis were validated by histological examination of lung tissue, confirming that the dependent region was primarily atelectatic and the non-dependent region was primarily overdistended. The pulmonary pressure-volume equation, originally designed for modelling measurements at the airway opening, was adapted for EIT-based regional estimates of overdistension and atelectasis. The adaptation accurately modelled the regional EIT data from dependent and non-dependent regions (R2 > 0.93, P < 0.0001) and predicted their interaction during recruitment. In conclusion, EIT imaging of regional lung mechanics reveals that overdistension in the non-dependent region precedes atelectasis reversal in the dependent region during a stepwise recruitment manoeuvre.
The Notch signaling pathway is an evolutionarily conserved transduction pathway involved in embryonic patterning and regulation of cell fates during development. Recent studies have demonstrated that ...this pathway is integral to a complex system of interactions, which are also involved in distinct human diseases. Delta1 is one of the known ligands of the Notch receptors. Mice homozygous for a loss-of-function allele of the Delta1 gene Dll1(lacZ/lacZ) die during embryonic development. Here, we present the results of two phenotype-driven modifier screens. Heterozygous Dll1(lacZ) knockout animals were crossed with ENU-mutagenized mice and screened for dysmorphological, clinical chemical, and immunological variants that are dependent on the Delta1 loss-of-function allele. First, we show that mutagenized heterozygous Dll1(lacZ) offspring have reduced body weight and altered specific clinical chemical parameters, including changes in metabolites and electrolytes relevant for kidney function. In our mutagenesis screen we have successfully generated 35 new mutant lines. Of major interest are 7 mutant lines that exhibit a Dll1(lacZ/+)-dependent phenotype. These mutant mouse lines provide excellent in vivo tools for studying the role of Notch signaling in kidney and liver function, cholesterol and iron metabolism, cell-fate decisions, and during maturation of T cells in the immune system.
Global pressure-volume (PV) curves are an adjunct measure to describe lung characteristics in patients with acute respiratory distress syndrome (ARDS). There is convincing evidence that high peak ...inspiratory pressures (PIP) cause barotrauma, while optimized positive end-expiratory pressure (PEEP) helps avoid mechanical injury to the lungs by preventing repeated alveolar opening and closing. The optimal values of PIP and PEEP are deduced from the shape of the PV curve by the identification of so-called lower and upper inflection points. However, it has been demonstrated using electrical impedance tomography (EIT) that the inflection points vary across the lung. This study employs a simple curve-fitting technique to automatically define inflection points on both pressure-volume (PV) and pressure-impedance (PI) curves to asses the differences between global PV and regional PI estimates in animals before and after induced lung injury. The results demonstrate a clear increase in lower inflection point (LIP) along the gravitational axis both before and after lung injury. Moreover, it is clear from comparison of the local EIT-derived LIPs with those derived from global PV curves that a ventilation strategy based on the PV curve alone may leave dependent areas of the lung collapsed. EIT-based PI curve analysis may help choosing an optimal ventilation strategy.
There is emerging evidence that the ventilation strategy used in acute lung injury (ALI) makes a significant difference in outcome and that an inappropriate ventilation strategy may produce ...ventilator-associated lung injury. Most harmful during mechanical ventilation are lung overdistension and lung collapse or atelectasis. Electrical impedance tomography (EIT) as a non-invasive imaging technology may be helpful to identify lung areas at risk. Currently, no automated method is routinely available to identify lung areas that are overdistended, collapsed or ventilated appropriately. We propose a fuzzy logic-based algorithm to analyse EIT images obtained during stepwise changes of mean airway pressures during mechanical ventilation. The algorithm is tested on data from two published studies of stepwise inflation-deflation manoeuvres in an animal model of ALI using conventional and high-frequency oscillatory ventilation. The timing of lung opening and collapsing on segmented images obtained using the algorithm during an inflation-deflation manoeuvre is in agreement with well-known effects of surfactant administration and changes in shunt fraction. While the performance of the algorithm has not been verified against a gold standard, we feel that it presents an important first step in tackling this challenging and important problem.
To investigate regional lung volume changes occurring during an inflation-deflation maneuver using high-frequency oscillatory ventilation.
Prospective animal trial.
Animal research laboratory.
Six ...Yorkshire swine.
Electrical impedance tomography was used to quantify regional ventilation during high-frequency oscillatory ventilation. The electrical impedance tomography-derived center of ventilation was used to describe the distribution of regional ventilation, whereas spectral analysis was used to describe regional ventilation-induced impedance changes. Lung injury was induced using surfactant lavage. Animals were transitioned to high-frequency oscillatory ventilation and a slow inflation-deflation maneuver was performed by changing mean airway pressure by 5 cm H2O every 15 mins to a maximum mean airway pressure of 40 cm H2O.
The induction of lung injury was associated with a significant shift of the center of ventilation toward nondependent areas and an increase in shunt fraction (p < .001). During the following inflation-deflation maneuver using high-frequency oscillatory ventilation, inflation was associated with a shift of the center of ventilation from nondependent to dependent areas. Center of ventilation was significantly correlated with the shunt fraction (p < .001). Analyzing different lung layers along the gravitational axis separately, nondependent lung areas showed significantly decreased regional ventilation-induced impedance changes at higher pressures, suggesting overdistension, whereas dependent lung areas showed increased impedance changes, suggesting recruitment. The reverse was observed during deflation (all p < .05).
The center of ventilation during high-frequency oscillatory ventilation correlated with oxygenating efficiency as measured by the shunt fraction. Lung recruitment during high-frequency oscillatory ventilation produced a significant shift of regional ventilation toward dependent areas of the lung and led to overdistension of nondependent areas.
Children's and adolescents' lives drastically changed during COVID lockdowns worldwide. To compare accident- and injury-related admissions to pediatric intensive care units (PICU) during the first ...German COVID lockdown with previous years, we conducted a retrospective multicenter study among 37 PICUs (21.5% of German PICU capacities). A total of 1444 admissions after accidents or injuries during the first lockdown period and matched periods of 2017-2019 were reported and standardized morbidity ratios (SMR) were calculated. Total PICU admissions due to accidents/injuries declined from an average of 366 to 346 (SMR 0.95 (CI 0.85-1.05)). Admissions with trauma increased from 196 to 212 (1.07 (0.93-1.23). Traffic accidents and school/kindergarten accidents decreased (0.77 (0.57-1.02 and 0.26 (0.05-0.75)), whereas household and leisure accidents increased (1.33 (1.06-1.66) and 1.34 (1.06-1.67)). Less neurosurgeries and more visceral surgeries were performed (0.69 (0.38-1.16) and 2.09 (1.19-3.39)). Non-accidental non-suicidal injuries declined (0.73 (0.42-1.17)). Suicide attempts increased in adolescent boys (1.38 (0.51-3.02)), but decreased in adolescent girls (0.56 (0.32-0.79)). In summary, changed trauma mechanisms entailed different surgeries compared to previous years. We found no evidence for an increase in child abuse cases requiring intensive care. The increase in suicide attempts among boys demands investigation.
OBJECTIVE:Regional differences in lung volume have been described in adults with acute respiratory distress syndrome, but it remains unclear to what extent they occur in children. To quantify ...regional alveolar collapse that occurred during mechanical ventilation during a standardized suctioning maneuver, we evaluated regional and global relative impedance changes (relative ΔZ) in children with acute respiratory distress syndrome using electrical impedance tomography.
DESIGN:Prospective observational trial.
SETTING:A 30-bed pediatric intensive care unit.
PATIENTS:Six children with acute respiratory distress syndrome.
INTERVENTIONS:Standardized suctioning maneuver.
MEASUREMENTS AND MAIN RESULTS:By comparing layers from nondependent (layers 1 and 2) to dependent lung areas (layers 3 and 4), it was demonstrated that the middle layers (2 and 3) had the greatest ventilation-induced change in relative ΔZ; layer 4 showed the least ventilation-induced change in relative ΔZ. During suctioning, layers 1, 2, and 3 showed a negative change in relative ΔZ, whereas layer 4 showed no significant change in relative ΔZ. The derecruitment-induced change in relative ΔZ representing the lung-volume loss was −9.8 (−3.0 mL/kg) during the first suctioning maneuver, −16.1 (−5.4 mL/kg) during the second, and −21.7 (−7.4 mL/kg) during the third. The ventilation-induced change in relative ΔZ during mechanical ventilation remained unchanged after suctioning (mean change in relative ΔZ before vs. after suctioning, 40.1 ± 9.1 vs. 41.4 ± 10.8; p = .30). Dynamic compliance was 11.8 ± 6.1 mL·cm H2O before and 11.8 ± 6.9 mL·cm H2O after the suctioning sequence (p = .90).
CONCLUSIONS:Considerable regional heterogeneity was present during ventilation and a derecruitment maneuver. Significantly lower change in relative ΔZ in the most dependent lung regions suggests alveolar collapse during ventilation before suctioning.
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