Braskrhodes6542

BACKGROUND The role of bronchoalveolar lavage fluid (BAL) lymphocyte% to diagnose chronic hypersensitivity pneumonitis (CHP) is unclear. We conducted a systematic review and meta-analysis of BAL lymphocyte% in the diagnosis of CHP. METHODS We searched Medline, Embase and Cochrane library from inception to August 2019. Individual patient data were obtained to test performance characteristics of BAL lymphocyte% at different thresholds. Random-effects models were used for pooled estimates, with comparisons made between CHP and non-CHP interstitial lung diseases (ILD). RESULTS Fifty-three studies were included in the systematic review and 42 in the meta-analysis. The pooled estimate for BAL lymphocyte% was 42.8% (95%CI 37.7-47.8, I2=95.3%) in CHP, 10.0% (95%CI 6.9-13.1, I2=91.2%) in idiopathic pulmonary fibrosis (IPF), 23.1% (95% CI 3.0-43.2, I2=85.2%) in non-IPF idiopathic interstitial pneumonia (IIP), 23.4% (95%CI 11.0-35.9, I2=45.7%) in connective-tissue disease ILD (CTD-ILD), and 31.2% (95% CI 17.6-44.8, I2=95.2%) in sarcoidosis. Results differed between CHP and IPF (p20% provided sensitivity of 68.1% and specificity of 64.8% for CHP. Higher thresholds provided lower sensitivity with higher specificity. Older age and ever having smoked were associated with lower lymphocyte% in CHP. CONCLUSIONS BAL lymphocyte% is higher in CHP compared to IPF and other IIP, with higher thresholds providing improved specificity at the cost of sensitivity. However, parent studies are at risk of incorporation bias, and prospective studies should evaluate the additive discriminate value of BAL lymphocyte% to accurately diagnose CHP. Copyright ©ERS 2020.In January 2019, a European Respiratory Society (ERS) Research Seminar entitled "Targeting the detrimental effects of sleep disturbances and disorders" was held in Dublin, Ireland. GSK-3 activity It provided the opportunity to critically review the current evidence of pathophysiological responses of sleep disturbances, such as sleep deprivation, sleep fragmentation or circadian misalignment and of abnormalities in physiological gases such as oxygen and carbon dioxide which are frequently occurring in respiratory conditions during sleep. A specific emphasis of the seminar was placed on the evaluation of the current state of knowledge of the pathophysiology of cardiovascular and metabolic diseases in obstructive sleep apnoea (OSA). Identification of the detailed mechanisms of these processes is of major importance to the field and this seminar offered an ideal platform to exchange knowledge, to discuss pitfalls of current models and the design of future collaborative studies. We also debated the limitations of current treatment strategies for cardiometabolic complications in OSA and discussed potentially valuable alternative approaches. Copyright ©ERS 2020.Disrupted clearance of all-trans retinal (atRAL), a component of the visual (retinoid) cycle in the retina, may cause photoreceptor atrophy in autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (AMD). However, the mechanisms underlying atRAL-induced photoreceptor loss remain elusive. Here, we report that atRAL activates c-Jun N-terminal kinase (JNK) signaling at least partially through reactive oxygen species (ROS) production, which promoted mitochondria-mediated caspase- and DNA damage-dependent apoptosis in photoreceptor cells. Damage to mitochondria in atRAL-exposed photoreceptor cells resulted from JNK activation, leading to decreased expression of Bcl2 apoptosis regulator (Bcl2), increased Bcl2 antagonist/killer (Bak) levels, and cytochrome c (Cyt c) release into the cytosol. Cytosolic Cyt c specifically provoked caspase-9 and caspase-3 activation and thereby initiated apoptosis. Phosphorylation of JNK in atRAL-loaded photoreceptor cells induced the appearance of γH2A.X variant histone (γH2AX), a sensitive marker for DNA damage, and was also associated with apoptosis onset. Suppression of JNK signaling protected photoreceptor cells against atRAL-induced apoptosis. Moreover, photoreceptor cells lacking Jnk1 and Jnk2 genes were more resistant to atRAL-associated cytotoxicity. The Abca4-/-Rdh8-/- mouse model displays defects in atRAL clearance that are characteristic of STGD1 and dry AMD. We found that JNK signaling was activated in the neural retina of light-exposed Abca4-/-Rdh8-/- mice. Of note, intraperitoneal administration of JNK-IN-8, which inhibits JNK phosphorylation, effectively ameliorated photoreceptor degeneration and apoptosis in light-exposed Abca4-/-Rdh8-/- mice. We propose that pharmacological inhibition of JNK signaling may represent a therapeutic strategy for preventing photoreceptor loss in retinopathies arising from atRAL overload. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.The incidence of pancreatic cancer increases with age, suggesting that chronological aging is a significant risk factor for this disease. Fibroblasts are the major non-malignant cell type in the stroma of human pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated whether the chronological aging of normal human fibroblasts (NHFs), a previously underappreciated area in pancreatic cancer research, influences the progression and therapeutic outcomes of PDAC. Results from experiments with murine xenografts and 2D and 3D co-cultures of NHFs and PDAC cells revealed that older NHFs stimulate proliferation of and confer resistance to radiation therapy of PDAC. MS-based metabolite analysis indicated that older NHFs have significantly increased arachidonic acid 12-lipoxygenase (ALOX12) expression and elevated levels of its mitogenic metabolite, 12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-(S)-HETE) compared with their younger counterparts. In co-cultures with older rather than with younger NHFs, PDAC cells exhibited increases in mitogen-activated protein kinase (MAPK) signaling and cellular metabolism, as well as a lower oxidation-state that correlated with their enhanced proliferation and resistance to radiation therapy. Expression of ALOX12 was found to be significantly lower in PDAC cell lines and tumor biopsies, suggesting that PDAC cells rely on a stromal supply of mitogens for their proliferative needs. Pharmacological (hydroxytyrosol) and molecular (siRNA) interventions of ALOX12 in older NHFs suppressed their ability to stimulate proliferation of PDAC cells. We conclude that chronological aging of NHFs contributes to PDAC progression and that ALOX12 and 12-(S)-HETE may be potential stromal-targets for interventions that seek to halt progression and improve therapy outcomes. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.