Asymmetric Dimethylarginine in Chronic Obstructive Pulmonary Disease (ADMA in COPD)

l-Arginine metabolism including the nitric oxide (NO) synthase and arginase pathways is important in the maintenance of airways function. We have previously reported that accumulation of asymmetric dimethylarginine (ADMA) in airways, resulting in changes in l-arginine metabolism, contributes to airways obstruction in asthma and cystic fibrosis. Herein, we assessed l-arginine metabolism in airways of patients with chronic obstructive pulmonary disease (COPD). Lung function testing, measurement of fractional exhaled NO (FeNO) and sputum NO metabolites, as well as quantification of l-arginine metabolites (l-arginine, l-ornithine, l-citrulline, ADMA and symmetric dimethylarginine) using liquid chromatography-mass spectrometry (LC-MS) were performed. Concentrations of l-ornithine, the product of arginase activity, correlated directly with l-arginine and ADMA sputum concentrations. FeNO correlated directly with pre- and post-bronchodilator forced expiratory volume in one second (FEV₁). Sputum arginase activity correlated inversely with total NO metabolite (NO_x) and nitrite concentrations in sputum, and with pre- and post-bronchodilator FEV₁. These findings suggest that ADMA in COPD airways results in a functionally relevant shift of l-arginine breakdown by the NO synthases towards the arginase pathway, which contributes to airway obstruction in these patients.     

Evaluation of particle dispersal from mining and milling operations using lead isotopic fingerprinting techniques, Rio Pilcomayo Basin, Bolivia

Mining and milling of ores from the Cerro Rico de Potosí precious metal-polymetallic tin deposits of Bolivia have led to severe contamination of water and sediments of the Rio Pilcomayo drainage system. Lead (Pb) isotopic data were used in this study to first document downstream dispersal patterns of Pb contaminated sediment within the channel of the Rio Pilcomayo, and then to determine the relative contribution of Pb from Cerro Rico within alluvial terrace soils that are used for agriculture. The concentration and isotopic composition of Pb within channel bed sediments differed significantly between 2000, 2002, and 2004. These differences presumably reflect changes in the type of ore mined and milled at Cerro Rico, and alterations in dispersal and grain-size dilution mechanisms associated with interannual variations in rainfall and runoff. Within agricultural terrace soils, both Pb concentrations and the percentage of Pb from Cerro Rico: (1) semi-systematically decrease downstream, (2) were found to decrease with terrace height above the channel, and (3) reflect the use of contaminated irrigation water. In upstream reaches (within 30 km of the mills), Pb from mining represents the most significant Pb source, accounting for more than 80% of Pb in the examined agricultural fields. At Sotomayor, located approximately 170 km from the mills, the relative contribution of Pb from Cerro Rico is highly variable between fields, but can be significant, ranging from approximately 15% to 35%. The analysis demonstrates that Pb isotopic ratios can be used to effectively trace contaminated particles through river systems and into adjacent alluvial soils, even where multiple Pb sources exist and Pb concentrations are similar to background values.     

Keratin Profiling by Single-Cell RNA-Sequencing Identifies Human Prostate Stem Cell Lineage Hierarchy and Cancer Stem-Like Cells

Single prostate stem cells can generate stem and progenitor cells to form prostaspheres in 3D culture. Using a prostasphere-based label retention assay, we recently identified keratin 13 (KRT13)-enriched prostate stem cells at single-cell resolution, distinguishing them from daughter progenitors. Herein, we characterized the epithelial cell lineage hierarchy in prostaspheres using single-cell RNA-seq analysis. Keratin profiling revealed three clusters of label-retaining prostate stem cells; cluster I represents quiescent stem cells (PSCA, CD36, SPINK1, and KRT13/23/80/78/4 enriched), while clusters II and III represent active stem and bipotent progenitor cells (KRT16/17/6 enriched). Gene set enrichment analysis revealed enrichment of stem and cancer-related pathways in cluster I. In non-label-retaining daughter progenitor cells, three clusters were identified; cluster IV represents basal progenitors (KRT5/14/6/16 enriched), while clusters V and VI represent early and late-stage luminal progenitors, respectively (KRT8/18/10 enriched). Furthermore, MetaCore analysis showed enrichment of the “cytoskeleton remodeling–keratin filaments” pathway in cancer stem-like cells from human prostate cancer specimens. Along with common keratins (KRT13/23/80/78/4) in normal stem cells, unique keratins (KRT10/19/6C/16) were enriched in cancer stem-like cells. Clarification of these keratin profiles in human prostate stem cell lineage hierarchy and cancer stem-like cells can facilitate the identification and therapeutic targeting of prostate cancer stem-like cells.     

Caregiver models of self and others, coping, and depression: Predictors of depression in children with chronic pain.

In a sample of 59 chronically ill pediatric patients and their maternal caregivers, both child-reported pain and caregiver-reported depression predicted child-reported depression. Results further suggested that the association between pain and depression in children is ameliorated by caregiver coping strategies and that how caregivers cope is a function of their attachment-related representations of the self and others. Caregivers with a negative model of the self were more depressed, and those with a negative model of others were more prone to use avoidant coping strategies, and, in turn, to be more depressed. However, the extent to which caregivers with negative models of self used more avoidant and less approach coping appeared to depend on whether they perceived that others were likely to respond to their needs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)