Analysis of behavior of the respiratory system in ARDS patients : effects of flow, volume, and time

The effects of inspiratory flow (V) and inflation volume (delta V) on the mechanical properties of the respiratory system in eight ARDS patients were investigated using the technique of rapid airway occlusion during constant-flow inflation. We measured interrupter resistance (Rint,rs), which in humans represents airway resistance, the additional resistance (delta Rrs) due to viscoelastic pressure dissipations and time constant inequalities, and static (Est,rs) and dynamic (Edyn,rs) elastance. The results were compared with a previous study on 16 normal anesthetized paralyzed humans (D'Angelo et al. J. Appl. Physiol. 67: 2556-2564, 1989). We observed that 1) resistance and elastance were higher in ARDS patients; 2) with increasing V, Rint,rs and Est,rs did not change, delta Rrs decreased progressively, and Edyn,rs increased progressively; 3) with increasing delta V, Rint,rs decreased slightly, delta Rrs increased progressively, and Est,rs and Edyn,rs showed an initial decrease followed by a secondary increase noted only in the ARDS patients. The above findings could be explained in terms of a model incorporating a standard resistance in parallel with a standard elastance and a series spring-and-dashpot body that represents the stress adaptation units within the tissues of the respiratory system

Inhibition of Upf2-dependent nonsense-mediated decay leads to behavioral and neurophysiological abnormalities by activating the immune response

In humans, disruption of nonsense-mediated decay (NMD) has been associated with neurodevelopmental disorders (NDDs) such as autism spectrum disorder and intellectual disability. However, the mechanism by which deficient NMD leads to neurodevelopmental dysfunction remains unknown, preventing development of targeted therapies. Here we identified novel protein-coding UPF2 (UP-Frameshift 2) variants in humans with NDD, including speech and language deficits. In parallel, we found that mice lacking Upf2 in the forebrain (Upf2 fb-KO mice) show impaired NMD, memory deficits, abnormal long-term potentiation (LTP), and social and communication deficits. Surprisingly, Upf2 fb-KO mice exhibit elevated expression of immune genes and brain inflammation. More importantly, treatment with two FDA-approved anti-inflammatory drugs reduced brain inflammation, restored LTP and long-term memory, and reversed social and communication deficits. Collectively, our findings indicate that impaired UPF2-dependent NMD leads to neurodevelopmental dysfunction and suggest that anti-inflammatory agents may prove effective for treatment of disorders with impaired NMD.Jennifer L. Johnson, Loredana Stoica, Yuwei Liu, Ping Jun Zhu, Abhisek Bhattacharya, Shelly A. Buffington, Redwan Huq, N. Tony Eissa, Ola Larsson, Bo T. Porse, Deepti Domingo, Urwah Nawaz, Renee Carroll, Lachlan Jolly, Tom S. Scerri, Hyung-Goo Kim, Amanda Brignell, Matthew J. Coleman, Ruth Braden, Usha Kini, Victoria Jackson, Anne Baxter, Melanie Bahlo, Ingrid E. Scheffer, David J. Amor, Michael S. Hildebrand, Penelope E. Bonnen, Christine Beeton, Jozef Gecz, Angela T. Morgan, and Mauro Costa-Mattiol