Air Pollution and ST-Segment Depression in Elderly Subjects

Increased levels of daily ambient particle pollution have been associated with increased risk of cardiovascular morbidity. Black carbon (BC) is a measure of the traffic-related component of particles. We investigated associations between ambient pollution and ST-segment levels in a repeated-measures study including 269 observations on 24 active Boston residents 61–88 years of age, each observed up to 12 times from June through September 1999. The protocol involved continuous Holter electrocardiogram monitoring including 5 min of rest, 5 min of standing, 5 min of exercise outdoors, 5 min of recovery, and 20 cycles of paced breathing. Pollution-associated ST-depression was estimated for a 10th- to 90th-percentile change in BC. We calculated the average ST-segment level, referenced to the P-R isoelectric values, for each portion of the protocol. The mean BC level in the previous 12 hr, and the BC level 5 hr before testing, predicted ST-segment depression in most portions of the protocol, but the effect was strongest in the postexercise periods. During post-exercise rest, an elevated BC level was associated with −0.1 mm ST-segment depression (p = 0.02 for 12-hr mean BC; p = 0.001 for 5-hr BC) in continuous models. Elevated BC also predicted increased risk of ST-segment depression ≥0.5 mm among those with at least one episode of that level of ST-segment depression. Carbon monoxide was not a confounder of this association. ST-segment depression, possibly representing myocardial ischemia or inflammation, is associated with increased exposure to particles whose predominant source is traffic

Anatomically and functionally distinct lung mesenchymal populations marked by Lgr5 and Lgr6

The diversity of mesenchymal cell types in the lung that influence epithelial homeostasis and regeneration is poorly defined. We used genetic lineage tracing, single-cell RNA sequencing, and organoid culture approaches to show that Lgr5 and Lgr6, well-known markers of stem cells in epithelial tissues, are markers of mesenchymal cells in the adult lung. Lgr6+ cells comprise a subpopulation of smooth muscle cells surrounding airway epithelia and promote airway differentiation of epithelial progenitors via Wnt-Fgf10 cooperation. Genetic ablation of Lgr6+ cells impairs airway injury repair in vivo. Distinct Lgr5+ cells are located in alveolar compartments and are sufficient to promote alveolar differentiation of epithelial progenitors through Wnt activation. Modulating Wnt activity altered differentiation outcomes specified by mesenchymal cells. This identification of region- and lineage-specific crosstalk between epithelium and their neighboring mesenchymal partners provides new understanding of how different cell types are maintained in the adult lung.This work was supported by (J.-H.L. and J.C.) Wellcome Trust and the Royal Society (107633/Z/15/Z), European Research Council Starting Grant (679411), and the Cambridge Stem Cell Institute Core grant (07922/Z/11/Z) from Wellcome Trust and Medical Research Council; (J.-H.L.) the Hope Funds for Cancer Research; (M.P.) American Lung Association (400553); (A.R.) Howard Hughes Medical Institute, the Klarman Cell Observatory, and NCI grant 1U24CA180922; (A.R., T.T., and T.J.) the Koch Institute Core grant P30-CA14051 from the NCI; (T.T.) the National Cancer InstituteK99 CA187317, the Sigrid Juselius Foundation, the Hope Funds for Cancer Research; (T.J.) a Howard Hughes Medical Institute Investigator, a David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar; and (C.F.K.) R01 HL090136, R01 HL132266, R01 HL125821, U01 HL100402, Harvard Stem Cell Institute, Alfred and Gilda Slifka, Gail and Adam Slifka, and the CFMS Fund

Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation

Docosahexaenoic acid (DHA, 22:6) is an n-3 polyunsaturated fatty acid (n-3 PUFA) that influences immunological, metabolic, and neurological responses through complex mechanisms. One structural mechanism by which DHA exerts its biological effects is through its ability to modify the physical organization of plasma membrane signaling assemblies known as sphingomyelin/cholesterol (SM/chol)-enriched lipid rafts. Here we studied how DHA acyl chains esterified in the sn-2 position of phosphatidylcholine (PC) regulate the formation of raft and non-raft domains in mixtures with SM and chol on differing size scales. Coarse grained molecular dynamics simulations showed that 1-palmitoyl-2-docosahexaenoylphosphatylcholine (PDPC) enhances segregation into domains more than the monounsaturated control, 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC). Solid state 2H NMR and neutron scattering experiments provided direct experimental evidence that substituting PDPC for POPC increases the size of raft-like domains on the nanoscale. Confocal imaging of giant unilamellar vesicles with a non-raft fluorescent probe revealed that POPC had no influence on phase separation in the presence of SM/chol whereas PDPC drove strong domain segregation. Finally, monolayer compression studies suggest that PDPC increases lipid-lipid immiscibility in the presence of SM/chol compared to POPC. Collectively, the data across model systems provide compelling support for the emerging model that DHA acyl chains of PC lipids tune the size of lipid rafts, which has potential implications for signaling networks that rely on the compartmentalization of proteins within and outside of rafts

A randomized trial provided new evidence on the accuracy and efficiency of traditional vs. electronically annotated abstraction approaches in systematic reviews

Abstract Objectives Data Abstraction Assistant (DAA) is a software for linking items abstracted into a data collection form for a systematic review to their locations in a study report. We conducted a randomized cross-over trial that compared DAA-facilitated single-data abstraction plus verification ("DAA verification"), single data abstraction plus verification ("regular verification"), and independent dual data abstraction plus adjudication ("independent abstraction"). Study Design and Setting This study is an online randomized cross-over trial with 26 pairs of data abstractors. Each pair abstracted data from six articles, two per approach. Outcomes were the proportion of errors and time taken. Results Overall proportion of errors was 17% for DAA verification, 16% for regular verification, and 15% for independent abstraction. DAA verification was associated with higher odds of errors when compared with regular verification (adjusted odds ratio [OR] = 1.08; 95% confidence interval [CI]: 0.99–1.17) or independent abstraction (adjusted OR = 1.12; 95% CI: 1.03–1.22). For each article, DAA verification took 20 minutes (95% CI: 1–40) longer than regular verification, but 46 minutes (95% CI: 26 to 66) shorter than independent abstraction. Conclusion Independent abstraction may only be necessary for complex data items. DAA provides an audit trail that is crucial for reproducible research

Evaluation of Treatment-Related Mortality Among Paediatric Cancer Deaths: a population based analysis.

BACKGROUND: Objectives were to describe the proportion of deaths due to treatment-related mortality (TRM) and to identify risk factors and probable causes of TRM among paediatric cancer deaths in a population-based cohort. METHODS: We included children with cancer ⩽18 years diagnosed and treated in Ontario who died between January 2003 and December 2012. Deaths were identified using a provincial registry, the Pediatric Oncology Group of Ontario Networked Information System. Probable causes of TRM were described. RESULTS: Among the 964 deaths identified, 821 were included. The median age at diagnosis was 6.6 years (range 0-18.8) and 51.8% had at least one relapse. Of the deaths examined, TRM occurred in 217/821 (26.4%) while 604/821 (73.6%) were due to progressive cancer. Deaths from TRM did not change over time. Using multiple regression, younger age, leukaemia diagnosis and absence of relapse were independently positively associated with TRM. The most common probable causes of TRM were respiratory, infection and haemorrhage. CONCLUSIONS: TRM was responsible for 26.4% of deaths in paediatric cancer. Underlying diagnosis, younger age and absence of relapse were associated with TRM and causes of TRM differed by diagnosis group. Future work should evaluate TRM rate and risk factors among newly diagnosed cancer patients