Pulmonary stretch receptor activity during partial liquid ventilation in cats with healthy lungs

Aim: To study whether pulmonary stretch receptor (PSR) activity in mechanically ventilated young cats with healthy lungs during partial liquid ventilation (PLV) is different from that during gas ventilation (GV). Methods: In 10 young cats (4.4 +/- 0.4 months, 2.3 +/- 0.3 kg; mean B SD), PSR instantaneous impulse frequency (PSR f(imp)) was recorded from single fibres in the vagal nerve during GV and PLV with perfluorocarbon (30 ml/kg) at increasing positive inspiratory pressures (PIP; 1.2, 1.8, 2.2 and 2.7 kPa), and at a positive end-expiratory pressure of 0.5 kPa. Results: All PSRs studied during GV maintained their phasic character with increased impulse frequency during inspiration during PLV. Peak PSR fimp was lower at PIP 1.2 kPa (p < 0.05) and at PIP 2.7 kPa (p = 0.10) during PLV than during GV, giving a lower number of PSR impulses at these two settings during PLV (p < 0.05). Conclusion: The phasic character of PSR activity is similar during GV and PLV. PSR activity is not higher during PLV than during GV in cats with healthy lungs, indicating no extensive stretching of the lung during PLV. Copyright (C) 2004 S. Karger AG, Basel

Effects of closed-loop automatic control of the inspiratory fraction of oxygen (FiO(2)-C) on outcome of extremely preterm infants - study protocol of a randomized controlled parallel group multicenter trial for safety and efficacy

Background: Most extremely low gestational age neonates (ELGANS, postmenstrual age at birth (PMA) < 28 completed weeks) require supplemental oxygen and experience frequent intermittent hypoxemic and hyperoxemic episodes. Hypoxemic episodes and exposure to inadequately high concentrations of oxygen are associated with an increased risk of retinopathy of prematurity (ROP), chronic lung disease of prematurity (BPD), necrotizing enterocolitis (NEC), neurodevelopmental impairment (NDI), and death beyond 36 weeks PMA. Closed-loop automated control of the inspiratory fraction of oxygen (FiO2-C) reduces time outside the hemoglobin oxygen saturation (SpO2) target range, number and duration of hypo- and hyperoxemic episodes and caregivers’ workload. Effects on clinically important outcomes in ELGANs such as ROP, BPD, NEC, NDI and mortality have not yet been studied. Methods: An outcome-assessor-blinded, randomized controlled, parallel-group trial was designed and powered to study the effect of FiO2-C (in addition to routine manual control (RMC) of FiO2), compared to RMC only, on death and severe complications related to hypoxemia and/or hyperoxemia. 2340 ELGANS with a GA of 23 + 0/7 to 27 + 6/ 7 weeks will be recruited in approximately 75 European tertiary care neonatal centers. Study participants are randomly assigned to RMC (control-group) or FiO2-C in addition to RMC (intervention-group). Central randomization is stratified for center, gender and PMA at birth (< 26 weeks and ≥ 26 weeks). FiO2-C is provided by commercially available and CE-marked ventilators with an FiO2-C algorithm intended for use in newborn infants. The primary outcome variable (composite of death, severe ROP, BPD or NEC) is assessed at 36 weeks PMA (or, in case of ROP, until complete vascularization of the retina, respectively). The co-primary outcome variable (composite outcome of death, language/cognitive delay, motor impairment, severe visual impairment or hearing impairment) is assessed at 24 months corrected age. Discussion: Short-term studies on FiO2-C showed improved time ELGANs spent within their assigned SpO2 target range, but effects of FiO2-C on clinical outcomes are yet unknown and will be addressed in the FiO2-C trial. This will ensure an appropriate assessment of safety and efficacy before FiO2-C may be implemented as standard therap

Calculation of magnetic anisotropy energy in SmCo5

SmCo5 is an important hard magnetic material, due to its large magnetic anisotropy energy (MAE). We have studied the magnetic properties of SmCo5 using density functional theory (DFT) calculations where the Sm f-bands, which are difficult to include in DFT calculations, have been treated within the LDA+U formalism. The large MAE comes mostly from the Sm f-shell anisotropy, stemming from an interplay between the crystal field and the spin-orbit coupling. We found that both are of similar strengths, unlike some other Sm compounds, leading to a partial quenching of the orbital moment (f-states cannot be described as either pure lattice harmonics or pure complex harmonics), an optimal situation for enhanced MAE. A smaller portion of the MAE can be associated with the Co-d band anisotropy, related to the peak in the density of states at the Fermi energy. Our result for the MAE of SmCo5, 21.6 meV/f.u., agrees reasonably with the experimental value of 13-16 meV/f.u., and the calculated magnetic moment (including the orbital component) of 9.4 mu_B agrees with the experimental value of 8.9 mu_B.Comment: Submitted to Phys. Rev.

Sustained inflation versus intermittent positive pressure ventilation for preterm infants at birth: respiratory function and vital sign measurements

Objective To characterize respiratory function monitor (RFM) measurements of sustained inflations and intermittent positive pressure ventilation (IPPV) delivered non invasively to infants in the Sustained Aeration of Infant Lungs (SAIL) trial and to compare vital sign measurements between treatment arms.Study design We analyzed RFM data from SAIL participants at 5 trial sites. We assessed tidal volumes, rates of airway obstruction, and mask leak among infants allocated to sustained inflations and IPPV, and we compared pulse rate and oxygen saturation measurements between treatment groups.Results Among 70 SAIL participants (36 sustained inflations, 34 IPPV) with RFM measurements, 40 (57%) were spontaneously breathing prior to the randomized intervention. The median expiratory tidal volume of sustained inflations administered was 5.3 mUkg (IQR 1.1-9.2). Significant mask leak occurred in 15% and airway obstruction occurred during 17% of sustained inflations. Among 34 control infants, the median expiratory tidal volume of IPPV inflations was 4.3 mUkg (IQR 1.3-6.6). Mask leak was present in 3%, and airway obstruction was present in 17% of IPPV inflations. There were no significant differences in pulse rate or oxygen saturation measurements between groups at any point during resuscitation.Conclusion Expiratory tidal volumes of sustained inflations and IPPV inflations administered in the SAIL trial were highly variable in both treatment arms. Vital sign values were similar between groups throughout resuscitation. Sustained inflation as operationalized in the SAIL trial was not superior to IPPV to promote lung aeration after birth in this study subgroup.Developmen

Experimental Study of the Shortest Reset Word of Random Automata

In this paper we describe an approach to finding the shortest reset word of a finite synchronizing automaton by using a SAT solver. We use this approach to perform an experimental study of the length of the shortest reset word of a finite synchronizing automaton. The largest automata we considered had 100 states. The results of the experiments allow us to formulate a hypothesis that the length of the shortest reset word of a random finite automaton with $n$ states and 2 input letters with high probability is sublinear with respect to $n$ and can be estimated as $1.95 n^{0.55}.

Direct Observation of Dimerization between Different CREB1 Isoforms in a Living Cell

Cyclic AMP-responsive element binding protein 1 (CREB1) plays multiple functions as a transcription factor in gene regulation. CREB1 proteins are also known to be expressed in several spliced isoforms that act as transcriptional activators or repressors. The activator isoforms, possessing the functional domains for kinase induction and for interaction with other transcriptional regulators, act as transcriptional activators. On the other hand, some isoforms, lacking those functional domains, are reported to be repressors that make heterodimers with activator isoforms. The complex and ingenious function for CREB1 arises in part from the variation in their spliced isoforms, which allows them to interact with each other. To date, however, the dimerization between the activator and repressor isoforms has not yet been proved directly in living cells. In this study, we applied fluorescence cross-correlation spectroscopy (FCCS) to demonstrate direct observation of dimerization between CREB1 activator and repressor. The FCCS is a well established spectroscopic method to determine the interaction between the different fluorescent molecules in the aqueous condition. Using differently labeled CREB1 isoforms, we successfully observed the interaction of CREB1 activator and repressor via dimerization in the nuclei of cultured cells. As a result, we confirmed the formation of heterodimer between CREB1 activator and repressor isoforms in living cells

Inhibition of breathing after surfactant depletion is achieved at a higher arterial PCO(2 )during ventilation with liquid than with gas

BACKGROUND: Inhibition of phrenic nerve activity (PNA) can be achieved when alveolar ventilation is adequate and when stretching of lung tissue stimulates mechanoreceptors to inhibit inspiratory activity. During mechanical ventilation under different lung conditions, inhibition of PNA can provide a physiological setting at which ventilatory parameters can be compared and related to arterial blood gases and pH. OBJECTIVE: To study lung mechanics and gas exchange at inhibition of PNA during controlled gas ventilation (GV) and during partial liquid ventilation (PLV) before and after lung lavage. METHODS: Nine anaesthetised, mechanically ventilated young cats (age 3.8 ± 0.5 months, weight 2.3 ± 0.1 kg) (mean ± SD) were studied with stepwise increases in peak inspiratory pressure (PIP) until total inhibition of PNA was attained before lavage (with GV) and after lavage (GV and PLV). Tidal volume (V(t)), PIP, oesophageal pressure and arterial blood gases were measured at inhibition of PNA. One way repeated measures analysis of variance and Student Newman Keuls-tests were used for statistical analysis. RESULTS: During GV, inhibition of PNA occurred at lower PIP, transpulmonary pressure (Ptp) and Vt before than after lung lavage. After lavage, inhibition of inspiratory activity was achieved at the same PIP, Ptp and Vt during GV and PLV, but occurred at a higher PaCO(2 )during PLV. After lavage compliance at inhibition was almost the same during GV and PLV and resistance was lower during GV than during PLV. CONCLUSION: Inhibition of inspiratory activity occurs at a higher PaCO(2 )during PLV than during GV in cats with surfactant-depleted lungs. This could indicate that PLV induces better recruitment of mechanoreceptors than GV

Lymphatic function is required prenatally for lung inflation at birth

Mammals must inflate their lungs and breathe within minutes of birth to survive. A key regulator of neonatal lung inflation is pulmonary surfactant, a lipoprotein complex which increases lung compliance by reducing alveolar surface tension (Morgan, 1971). Whether other developmental processes also alter lung mechanics in preparation for birth is unknown. We identify prenatal lymphatic function as an unexpected requirement for neonatal lung inflation and respiration. Mice lacking lymphatic vessels, due either to loss of the lymphangiogenic factor CCBE1 or VEGFR3 function, appear cyanotic and die shortly after birth due to failure of lung inflation. Failure of lung inflation is not due to reduced surfactant levels or altered development of the lung but is associated with an elevated wet/dry ratio consistent with edema. Embryonic studies reveal active lymphatic function in the late gestation lung, and significantly reduced total lung compliance in late gestation embryos that lack lymphatics. These findings reveal that lymphatic vascular function plays a previously unrecognized mechanical role in the developing lung that prepares it for inflation at birth. They explain respiratory failure in infants with congenital pulmonary lymphangiectasia, and suggest that inadequate late gestation lymphatic function may also contribute to respiratory failure in premature infants

Modulation of epithelial sodium channel (ENaC) expression in mouse lung infected with Pseudomonas aeruginosa

BACKGROUND: The intratracheal instillation of Pseudomonas aeruginosa entrapped in agar beads in the mouse lung leads to chronic lung infection in susceptible mouse strains. As the infection generates a strong inflammatory response with some lung edema, we tested if it could modulate the expression of genes involved in lung liquid clearance, such as the α, β and γ subunits of the epithelial sodium channel (ENaC) and the catalytic subunit of Na(+)-K(+)-ATPase. METHODS: Pseudomonas aeruginosa entrapped in agar beads were instilled in the lung of resistant (BalB/c) and susceptible (DBA/2, C57BL/6 and A/J) mouse strains. The mRNA expression of ENaC and Na(+)-K(+)-ATPase subunits was tested in the lung by Northern blot following a 3 hours to 14 days infection. RESULTS: The infection of the different mouse strains evoked regulation of α and β ENaC mRNA. Following Pseudomonas instillation, the expression of αENaC mRNA decreased to a median of 43% on days 3 and 7 after infection and was still decreased to a median of 45% 14 days after infection (p < 0.05). The relative expression of βENaC mRNA was transiently increased to a median of 241%, 24 h post-infection before decreasing to a median of 43% and 54% of control on days 3 and 7 post-infection (p < 0.05). No significant modulation of γENaC mRNA was detected although the general pattern of expression of the subunit was similar to α and β subunits. No modulation of α(1)Na(+)-K(+)-ATPase mRNA, the catalytic subunit of the sodium pump, was recorded. The distinctive expression profiles of the three subunits were not different, between the susceptible and resistant mouse strains. CONCLUSIONS: These results show that Pseudomonas infection, by modulating ENaC subunit expression, could influence edema formation and clearance in infected lungs

AMP-activated protein kinase deficiency reduces ozone-induced lung injury and oxidative stress in mice

<p>Abstract</p> <p>Background</p> <p>Acute ozone exposure causes lung oxidative stress and inflammation leading to lung injury. At least one mechanism underlying the lung toxicity of ozone involves excessive production of reactive oxygen and nitrogen intermediates such as peroxynitrite. In addition and beyond its major prooxidant properties, peroxynitrite may nitrate tyrosine residues altering phosphorylation of many protein kinases involved in cell signalling. It was recently proposed that peroxynitrite activates 5'-AMP-activated kinase (AMPK), which regulates metabolic pathways and the response to cell stress. AMPK activation as a consequence of ozone exposure has not been previously evaluated. First, we tested whether acute ozone exposure in mice would impair alveolar fluid clearance, increase lung tissue peroxynitrite production and activate AMPK. Second, we tested whether loss of AMP-activated protein kinase alpha1 subunit in mouse would prevent enhanced oxidative stress and lung injury induced by ozone exposure.</p> <p>Methods</p> <p>Control and AMPKα1 deficient mice were exposed to ozone at a concentration of 2.0 ppm for 3 h in glass cages. Evaluation was performed 24 h after ozone exposure. Alveolar fluid clearance (AFC) was evaluated using fluorescein isothiocyanate tagged albumin. Differential cell counts, total protein levels, cytokine concentrations, myeloperoxidase activity and markers of oxidative stress, i.e. malondialdehyde and peroxynitrite, were determined in bronchoalveolar lavage (BAL) and lung homogenates (LH). Levels of AMPK-Thr¹⁷²phosphorylation and basolateral membrane Na(+)-K(+)-ATPase abundance were determined by Western blot.</p> <p>Results</p> <p>In control mice, ozone exposure induced lung inflammation as evidence by increased leukocyte count, protein concentration in BAL and myeloperoxidase activity, pro-inflammatory cytokine levels in LH. Increases in peroxynitrite levels (3 vs 4.4 nM, p = 0.02) and malondialdehyde concentrations (110 vs 230 μmole/g wet tissue) were detected in LH obtained from ozone-exposed control mice. Ozone exposure consistently increased phosphorylated AMPK-Thr¹⁷²to total AMPK ratio by 80% in control mice. Ozone exposure causes increases in AFC and basolateral membrane Na(+)-K(+)-ATPase abundance in control mice which did not occur in AMPKα1 deficient mice.</p> <p>Conclusions</p> <p>Our results collectively suggest that AMPK activation participates in ozone-induced increases in AFC, inflammation and oxidative stress. Further studies are needed to understand how the AMPK pathway may provide a novel approach for the prevention of ozone-induced lung injury.</p