Analysis of the harmonic content of the tidal flow waveforms in infants.

The aim of this study was to examine whether the spectral characteristics of tidal flow waveform reflect the interaction between the control of breathing and lung mechanics in 10 healthy infants (H), 10 infants with a history of wheezing disorders (W), and 10 infants with chronic lung disease (CLD). From the flow waveform, we calculated a shape index, the harmonic distortion (k(d)), which quantifies the extent to which a periodic signal deviates from a sine wave. The k(d) of the entire tidal flow waveform did not significantly discriminate between diagnostic groups. However, k(d) was sensitive to maturation: it increased from 0.26 at 1 mo to 0.37 at 6 mo of age (P < 0.002). Furthermore, the frequency (f) spectra of the flow (V) amplitudes between 0.13 and 10 Hz followed a power law: V(f) approximately f(-s), where s (slope) is the exponent in the power law. The exponent of the healthy infants s(H) was 4.24 [95% confidence interval (CI) = 0.2] at 1 mo, 4.39 (CI = 0.16) at 6 mo, and 4.35 (CI = 0.19) at 12 mo and not significantly changing with age. The mean value of s(W) was marginally lower (4.09 +/- 0.28; P < 0.05) than that of s(H). The mean s(CLD) was significantly lower (3.04 +/- 0.31; P < 0.001). Lower values of s and higher values of k(d) indicate an increased complexity of the feedback mechanisms determining tidal flow waveform and may be associated with disease.     

Low-frequency respiratory mechanical impedance in the rat

A modified forced oscillatory technique was used to determine the respiratory mechanical impedances in anesthetized, paralyzed rats between 0.25 and 10 Hz. From the total respiratory (Zrs) and pulmonary impedance (ZL), measured with pseudorandom oscillations applied at the airway opening before and after thoracotomy, respectively, the chest wall impedance (ZW) was calculated as ZW = Zrs - ZL. The pulmonary (RL) and chest wall resistances were both markedly frequency dependent: between 0.25 and 2 Hz they contributed equally to the total resistance falling from 81.4 +/- 18.3 (SD) at 0.25 Hz to 27.1 +/- 1.7 kPa.l-1 X s at 2 Hz. The pulmonary compliance (CL) decreased mildly, from 2.78 +/- 0.44 at 0.25 Hz to 2.36 +/- 0.39 ml/kPa at 2 Hz, and then increased at higher frequencies, whereas the chest wall compliance declined monotonously from 4.19 +/- 0.88 at 0.25 Hz to 1.93 +/- 0.14 ml/kPa at 10 Hz. Although the frequency dependence of ZW can be interpreted on the basis of parallel inhomogeneities alone, the sharp fall in RL together with the relatively constant CL suggests that at low frequencies significant losses are imposed by the non-Newtonian resistive properties of the lung tissue.     

Respiratory impedance to ambient pressure changes at low frequencies

Respiratory impedance may be studied by measuring airway flow (Vaw) when pressure is varied at the mouth (input impedance) or around the chest (transfer impedance). A third possibility, which had not been investigated so far, is to apply pressure variations simultaneously at the two places, that is to vary ambient pressure (Pam). This provides respiratory impedance to ambient pressure changes (Zapc = Vaw/Pam). In that situation airway impedance (Zaw) and tissue impedance (Zt) are mechanically in parallel, and both are in series with alveolar gas impedance (Zg): Zapc = Zaw + Zg + Zaw.Zg/Zt. We assessed the frequency dependence of Zapc from 0.05 to 2 Hz in nine normal subjects submitted to sinusoidal Pam changes of 2-4 kPa peak to peak. The real part of Zapc (Rapc) was of 6.2 kPa.1(-1).s at 0.05 Hz and decreased to 1.9 kPa.1(-1).s at 2 Hz. Similarly the effective compliance (Capc), computed from the imaginary part of Zapc, decreased from 0.045 1.kPa-1 at 0.05 Hz to 0.027 1.kPa-1 at 2 Hz. Breathing against an added resistance of 0.46 kPa.1(-1).s exaggerated the negative frequency dependence of both Rapc and Capc. When values of airway resistance and inertance derived from transfer impedance data were introduced, Zapc was used to compute effective tissue resistance (Rt) and compliance (Ct). Rt was found to decrease from 0.32 to 0.15 kPa.1(-1).s and Ct from 1.11 to 0.64 1.kPa-1 between 0.25 and 2 Hz. Ct was slightly lower with the added resistance. These results are in good agreement with the data obtained by other approaches.     

Ligninolytic activity of Phanerochaete chrysosporium: Physiology of suppression by NH 4 + and l-glutamate

Previous research showed that addition of nutrient nitrogen to ligninolytic (stationary, nitrogen-starved) cultures of the wood-decomposing basidiomycete Phanerochaete chrysosporium causes a suppression of lignin degradation. The present study examined early effects on nitrogen metabolism that followed addition of NH ₄ ⁺ and l-glutamate at concentrations that yield similar patterns of suppression. Both nitrogenous compounds were rapidly assimilated (>80% in 6 h). Both caused an initial 80% or greater increase in the intracellular glutamate pool and had similar effects in increasing the specific activities of NADP- and NAD-glutamate dehydrogenases and glutamine synthetase. Differences between the effects of added NH ₄ ⁺ and glutamate showed that suppression was not correlated with intracellular pools of arginine or glutamine, nor was the maintenance of an elevated glutamate pool required to maintain the suppressed state. While a portion of the initial glutamate suppression could be attributed to an effect on central carbon metabolism through glutamate catabolism by NAD-glutamate dehydrogenase, the long term suppression by glutamate and the suppression by NH ₄ ⁺ were more specific. Suppression by NH ₄ ⁺ or glutamate in the presence or absence of protein synthesis (cycloheximide) followed essentially identical kinetics during 12 h. These results indicate that nitrogen additions cause a biochemical repression of enzymes associated with lignin degradation. Results are consistent with the hypothesis that nitrogen metabolism via glutamate plays a role in initiation of repression.Non-Standard Abbreviations DMS 2,2-dimethylsuccinate - TCA trichloroacetic acid     

Low-frequency pulmonary impedance in rabbits and its response to inhaled methacholine.

We assessed pulmonary mechanics in six open-chest rabbits (3 young and 3 adult) by the forced oscillation technique between 0.16 and 10.64 Hz. Under control conditions, pulmonary resistance (RL) decreased markedly between 0.16 and 4 Hz, after which it became reasonably constant. Measurements of alveolar pressure from two alveolar capsules in each rabbit showed that the large decrease of RL with increasing frequency below 4 Hz was due to lung tissue rheology and that tissue resistance was close to zero above 4 Hz. Estimates of resistance and elastance, also obtained by fitting tidal ventilation data at 1 Hz to the equation of the linear single-compartment model, gave values for RL motion that were slightly higher than those obtained by forced oscillations at the same frequency, presumably because of the flow dependence of airways resistance. After treatment with increasing doses of aerosolized methacholine, RL and pulmonary elastance between 0.16 and 1.34 Hz progressively increased, as did the point at which the pulmonary reactance crossed zero (the resonant frequency). The alveolar pressure measurements showed the lung to become increasingly inhomogeneously ventilated in all six animals, whereas in the three younger rabbits lobar atelectasis developed at high methacholine concentrations and the alveolar capsules ceased to communicate with the central airways. We conclude that the low-frequency pulmonary impedance of rabbits exhibits the same qualitative features observed in other species and that it is a sensitive indicator of the changes in pulmonary mechanics occurring during bronchoconstriction.     

Neonatal incubator or artificial womb? Distinguishing ectogestation and ectogenesis using the metaphysics of pregnancy

A 2017 Nature report was widely touted as hailing the arrival of the artificial womb. But the scientists involved claim their technology is merely an improvement in neonatal care. This raises an under-considered question: what differentiates neonatal incubation from artificial womb technology? Considering the nature of gestation—or metaphysics of pregnancy—(a) identifies more profound differences between fetuses and neonates/babies than their location (in or outside the maternal body) alone: fetuses and neonates have different physiological and physical characteristics; (b) characterizes birth as a physiological, mereological and topological transformation as well as a (morally relevant) change of location; and (c) delivers a clear distinction between neonatal incubation and ectogestation: the former supports neonatal physiology; the latter preserves fetal physiology. This allows a detailed conceptual classification of ectogenetive and ectogestative technologies according to which the 2017 system is not just improved neonatal incubation, but genuine ectogestation. But it is not an artificial womb, which is a term that is better put to rest. The analysis reveals that any ethical discussion involving ectogestation must always involve considerations of possible risks to the mother as well as her autonomy and rights. It also adds a third and potentially important dimension to debates in reproductive ethics: the physiological transition from fetus/gestateling to baby/neonate.     

Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases

A range of 3,6-di(hetero)arylimidazo[1,2-a]pyrazine ATP-competitive inhibitors of CHK1 were developed by scaffold hopping from a weakly active screening hit. Efficient synthetic routes for parallel synthesis were developed to prepare analogues with improved potency and ligand efficiency against CHK1. Kinase profiling showed that the imidazo[1,2-a]pyrazines could inhibit other kinases, including CHK2 and ABL, with equivalent or better potency depending on the pendant substitution. These 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines appear to represent a general kinase inhibitor scaffold.