No abstract

We hypothesized that initiation of ventilation in preterm lambs with high volumes would cause lung injury and decrease the subsequent response to surfactant treatment. Preterm lambs were randomized to ventilation for 30 min after birth with 5 ml/kg (VT5), 10 ml/kg (VT10), or 20 ml/kg (VT20) tidal volumes and then ventilated with approximately 10 ml/kg tidal volumes to achieve arterial PCO2 values of approximately 50 Torr to 6 h of age. VT20 lambs had lower compliances, lower ventilatory efficiencies, higher recoveries of protein, and lower recoveries of surfactant in alveolar lavages and in surfactant that had decreased compliances when tested in preterm rabbits than VT5 or VT10 lambs. Other lambs randomized to treatment with surfactant at birth and ventilation with 6, 12, or 20 ml/kg tidal volumes for 30 min had no indicators of lung injury. An initial tidal volume of 20 ml/kg decreased the subsequent response to surfactant treatment, an effect that was prevented with surfactant treatment at birth.

Chromosomal aneuploidy and specific gene mutations are recognized early hallmarks of many oncogenic processes. However, the net effect of these abnormalities has generally not been explored. We focused on transient myeloproliferative disorder (TMD) in Down syndrome, which is characteristically associated with somatic mutations in GATA1. To better understand functional interplay between trisomy 21 and GATA1 mutations in hematopoiesis, we constructed cellular disease models using human induced pluripotent stem cells (iPSCs) and genome-editing technologies. Comparative analysis of these engineered iPSCs demonstrated that trisomy 21 perturbed hematopoietic development through the enhanced production of early hematopoietic progenitors and the upregulation of mutated GATA1, resulting in the accelerated production of aberrantly differentiated cells. These effects were mediated by dosage alterations of RUNX1, ETS2, and ERG, which are located in a critical 4-Mb region of chromosome 21. Our study provides insight into the genetic synergy that contributes to multi-step leukemogenesis.

Mice that are surfactant protein (SP) A deficient [SP-A(−/−)] have no apparent abnormalities in lung function. To understand the contributions of SP-A to surfactant, the biophysical properties and functional characteristics of surfactant from normal [SP-A(+/+)] and SP-A(−/−) mice were evaluated. SP-A-deficient surfactant had a lower buoyant density, a lower percentage of large-aggregate forms, an increased rate of conversion from large-aggregate to small-aggregate forms with surface area cycling, increased sensitivity to inhibition of minimum surface tension by plasma protein, and no tubular myelin by electron microscopy. Nevertheless, large-aggregate surfactants from SP-A(−/−) and SP-A(+/+) mice had similar adsorption rates and improved the lung volume of surfactant-deficient preterm rabbits similarly. Pulmonary edema and death caused by N-nitroso- N-methylurethane-induced lung injury were not different in SP-A(−/−) and SP-A(+/+) mice. The clearance of125I-labeled SP-A from lungs of SP-A(−/−) mice was slightly slower than from SP-A(+/+) mice. Although the absence of SP-A changed the structure and in vitro properties of surfactant, the in vivo function of surfactant in SP-A(−/−) mice was not changed under the conditions of these experiments.