Efficacy and Mechanism Evaluation Programme, funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.
Introduction Automatic titration modes of non-invasive ventilation, including average volume assured pressure support (AVAPS), are hybrid technologies that target a set volume by automated adjustment of pressure support (PS). These automated modes could offer potential advantages over fixed level PS, in particular, in patients who are super obese. Methods Consecutive patients with obesity hypoventilation syndrome were enrolled in a two-centre prospective single-blind randomised controlled trial of AVAPS versus fixed-level PS using a strict protocolised setup. Measurements The primary outcome was change in daytime arterial PCO 2 (PaCO 2 ) at 3 months. Body composition, physical activity (7-day actigraphy) and health-related quality of life (severe respiratory insufficiency questionnaire, SRI) were secondary outcome measures. Results 50 patients (body mass index 5067 kg/m 2 ; 55611 years; 53% men) were enrolled with a mean PaCO 2 of 6.960.8 kPa and SRI of 53617. 46 patients (23 AVAPS and 23 PS) completed the trial. At 3 months, improvements in PaCO 2 were observed in both groups (AVAPS Δ0.6 kPa, 95% CI 0.2 to 1.1, p<0.01 vs PS Δ0.6 kPa, 95% CI 0.1 to 1.1, p¼0.02) but no betweengroup difference (ΔÀ0.1 kPa, 95% CI À0.7 to 0.6, p¼0.87). SRI also improved in both groups (AVAPS Δ11, 95% CI 6 to 17, p<0.001 vs PS Δ7, 95% CI 1 to 12, p¼0.02; between groups Δ5, 95% CI À3 to 12, p¼0
Retinoic acid (RA) is the biologically active metabolite of vitamin A. It is a low molecular weight, lipophilic molecule that acts on the nucleus to induce gene transcription. In amphibians and mammals, it induces the regeneration of several tissues and organs and these examples are reviewed here. RA induces the "super-regeneration" of organs that can already regenerate such as the urodele amphibian limb by respecifying positional information in the limb. In organs that cannot normally regenerate such as the adult mammalian lung, RA induces the complete regeneration of alveoli that have been destroyed by various noxious treatments. In the mammalian central nervous system (CNS), which is another tissue that cannot regenerate, RA does not induce neurite outgrowth as it does in the embryonic CNS, because one of the retinoic acid receptors, RAR2, is not up-regulated. When RAR2 is transfected into the adult spinal cord in vitro, then neurite outgrowth is stimulated. In all these cases, RA is required for the development of the organ, in the first place suggesting that the same gene pathways are likely to be used for both development and regeneration. This suggestion, therefore, might serve as a strategy for identifying potential tissue or organ targets that have the capacity to be stimulated to regenerate. Developmental Dynamics 226:237-244, 2003.
Recent data suggest that exogenous retinoic acid (RA), the biologically active derivative of vitamin A, can induce alveolar regeneration in a rat model of experimental emphysema. Here, we describe a mouse model of disrupted alveolar development using dexamethasone administered postnatally. We show that the effects of dexamethasone are concentration dependent, dose dependent, long lasting and result in a severe loss of alveolar surface area. When RA is administered to these animals as adults, lung architecture and the surface area per unit of body weight are completely restored to normal. This remarkable effect may be because RA is required during normal alveolar development and administering RA re-awakens gene cascades used during development. We provide evidence that RA is required during alveologenesis in the mouse by showing that the levels of the retinoid binding proteins, the RA receptors and two RA synthesizing enzymes peak postnatally. Furthermore, an inhibitor of RA synthesis, disulphiram, disrupts alveologenesis. We also show that RA is required throughout life for the maintenance of lung alveoli because when rats are deprived of dietary retinol they lose alveoli and show the features of emphysema. Alveolar regeneration with RA may therefore be an important novel therapeutic approach to the treatment of respiratory diseases characterized by a reduced gas-exchanging surface area such as bronchopulmonary dysplasia and emphysema for which there are currently no treatments.
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