Effect of Exposure to Atmospheric Ultrafine Particles on Production of Free Fatty Acids and Lipid Metabolites in the Mouse Small Intestine

Background: Exposure to ambient ultrafine particulate matter (UFP) is a well-recognized risk factor for cardiovascular and respiratory diseases. However, little is known about the effects of air pollution on gastrointestinal disorders.Objective: We sought to assess whether exposure to ambient UFP (diameter < 180 nm) increased free fatty acids and lipid metabolites in the mouse small intestine.Methods: Ldlr-null mice were exposed to filtered air (FA) or UFP collected at an urban Los Angeles, California, site that was heavily affected by vehicular emissions; the exposure was carried out for 10 weeks in the presence or absence of D-4F, an apolipoprotein A-I mimetic peptide with antioxidant and anti-inflammation properties on a high-fat or normal chow diet.Results: Compared with FA, exposure to UFP significantly increased intestinal hydroxyeicosatetraenoic acids (HETEs), including 15-HETE, 12-HETE, 5-HETE, as well as hydroxyoctadecadienoic acids (HODEs), including 13-HODE and 9-HODE. Arachidonic acid (AA) and prostaglandin D₂ (PGD₂) as well as some of the lysophosphatidic acids (LPA) in the small intestine were also increased in response to UFP exposure. Administration of D-4F significantly reduced UFP-mediated increase in HETEs, HODEs, AA, PGD₂, and LPA. Although exposure to UFP further led to shortened villus length accompanied by prominent macrophage and neutrophil infiltration into the intestinal villi, administration of D-4F mitigated macrophage infiltration.Conclusions: Exposure to UFP promotes lipid metabolism, villus shortening, and inflammatory responses in mouse small intestine, whereas administration of D-4F attenuated these effects. Our findings provide a basis to further assess the mechanisms underlying UFP-mediated lipid metabolism in the digestive system with clinical relevance to gut homeostasis and diseases.Citation: Li R, Navab K, Hough G, Daher N, Zhang M, Mittelstein D, Lee K, Pakbin P, Saffari A, Bhetraratana M, Sulaiman D, Beebe T, Wu L, Jen N, Wine E, Tseng CH, Araujo JA, Fogelman A, Sioutas C, Navab M, Hsiai TK. 2015. Effect of exposure to atmospheric ultrafine particles on production of free fatty acids and lipid metabolites in the mouse small intestine. Environ Health Perspect 123:34–41; http://dx.doi.org/10.1289/ehp.1307036     

Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone

Cellular subpopulations in the bone marrow play distinct and unexplored functions in skeletal homeostasis. This study delineated a unique role of osteal macrophages in bone and parathyroid hormone (PTH)-dependent bone anabolism using murine models of targeted myeloid-lineage cell ablation. Depletion of c-fms⁺ myeloid lineage cells [via administration of AP20187 in the macrophage Fas-induced apoptosis (MAFIA) mouse model] reduced cortical and trabecular bone mass and attenuated PTH-induced trabecular bone anabolism, supporting the positive function of macrophages in bone homeostasis. Interestingly, using a clodronate liposome model with targeted depletion of mature phagocytic macrophages an opposite effect was found with increased trabecular bone mass and increased PTH-induced anabolism. Apoptotic cells were more numerous in MAFIA versus clodronate-treated mice and flow cytometric analyses of myeloid lineage cells in the bone marrow showed that MAFIA mice had reduced CD68⁺ cells, whereas clodronate liposome-treated mice had increased CD68⁺ and CD163⁺ cells. Clodronate liposomes increased efferocytosis (clearance of apoptotic cells) and gene expression associated with alternatively activated M2 macrophages as well as expression of genes associated with bone formation including Wnt3a, Wnt10b, and Tgfb1. Taken together, depletion of early lineage macrophages resulted in osteopenia with blunted effects of PTH anabolic actions, whereas depletion of differentiated macrophages promoted apoptotic cell clearance and transformed the bone marrow to an osteogenic environment with enhanced PTH anabolism. These data highlight a unique function for osteal macrophages in skeletal homeostasis.The skeleton provides not only physical support but also housing for numerous subtypes of hematopoietic and immune cells. Several lines of evidence suggest that these skeletal and hematopoietic systems in the bone microenvironment are not only structurally adjacent, but also functionally interactive (1–4). Maintenance of the hematopoietic stem cell niche and B-lymphocyte differentiation has been attributed to osteoblasts (1, 2, 5). T lymphocytes support anabolic actions of parathyroid hormone (PTH) in bone via production of osteoblast stimulating Wnt-10b (6).Daily intermittent parathyroid hormone (PTH 1–34) administration has prominent anabolic actions in bone and is currently the only approved anabolic agent in the United States for the treatment of osteoporosis. PTH also supports the hematopoietic system by stimulating osteoblastic production of several cytokines, including IL-6 (7, 8), CXCL12 (9), MCP-1 (also known as CCL2) (10, 11), and the soluble IL-6 receptor (sIL6R) (4). PTH improved the success rate of hematopoietic stem cell (HSC) engraftment in hematopoietic malignancies and autoimmune diseases via supporting HSC repopulation of the marrow (12–14). The dependence of hematopoietic lineage cells for PTH anabolic actions is unknown.Macrophages are mononuclear cells of the myeloid lineage derived from HSCs. Different types of tissue-resident macrophages include Kupffer cells in the liver, Langerhans cells in the lung, and microglia in the brain. In bone, resorbing osteoclasts have been considered the tissue-resident macrophages. However, recent data showed that distinct from osteoclasts bone contains other resident macrophages, especially in the endosteal and periosteal areas (15). These “osteal” macrophages support osteoblast differentiation and mineralization in vitro (15) and play a role in intramembranous bone healing at fracture sites (16). Furthermore, osteal macrophages contribute to the maintenance of the endosteal HSC niches, and loss of osteal macrophages results in the egress of HSCs to the bloodstream (17). Collectively, osteal macrophages play novel roles in both skeletal and hematopoietic systems, yet knowledge of their functional capacities is limited. PTH anabolic actions have been linked to cells of the myeloid lineage via osteoblast derived sIL6R and Stat3 phosphorylation of CD11b⁺ cells (4). The purpose of this study was to investigate the role of osteal macrophages in bone remodeling and anabolic actions of PTH in bone.     

Features and Effects of Information Technology-Based Interventions to Improve Self-Management in Chronic Kidney Disease Patients: a Systematic Review of the Literature

Slowing down the progression of chronic kidney disease (CKD) and its adverse health outcomes requires the patient’s self-management and attention to treatment recommendations. Information technology (IT)–based interventions are increasingly being used to support self-management in patients with chronic diseases such as CKD. We conducted a systematic review of randomized controlled trials (RCTs) to assess the features and effects of IT-based interventions on self-management outcomes of CKD patients. A comprehensive search was conducted in Medline, Scopus, and the Cochrane Library to identify relevant papers that were published until May 2016. RCT Studies that assessed at least one automated IT tool in patients with CKD stages 1 to 5, and reported at least one self-management outcome were included. Studies were appraised for quality using the Cochrane Risk of Bias assessment tool. Out of 12,215 papers retrieved, eight study met the inclusion criteria. Interventions were delivered via smartphones/personal digital assistants (PDAs) (three studies), wearable devices (three studies), computerized systems (one study), and multiple component (one study). The studies assessed 15 outcomes, including eight clinical outcomes and seven process of care outcomes. In 12 (80%) of the 15 outcomes, the studies had revealed the effects of the interventions as statistically significant positive. These positive effects were observed in 75% of the clinical outcomes and 86% of the process of care outcomes. The evidence indicates the potential of IT-based interventions (i.e. smartphones/PDAs, wearable devices, and computerized systems) in self-management outcomes (clinical and process of care outcomes) of CKD patients.     

An injectable depot system for sustained intraperitoneal chemotherapy of ovarian cancer results in favorable drug distribution at the whole body, peritoneal and intratumoral levels

The current study characterizes the impact of docetaxel (DTX) distribution on efficacy following sustained intraperitoneal (IP) chemotherapy in murine models of ovarian cancer. A polymer-lipid biodegradable depot (PoLigel) was used to deliver DTX in a sustained manner over 21-days following IP administration. Distribution and efficacy studies were carried out in SCID mice bearing SKOV3 IP solid tumors or C57BL/6 mice with ID8 IP ascites fluid. In addition, a subcutaneous (SC) SKOV3 model was used to determine whether systemic drug levels that result from IP administration of the PoLigel influence antitumor efficacy. Immunostained IP and SC SKOV3 tumor sections were used to study cell death, intratumoral drug distribution and tumor penetration. Sustained concentrations of DTX were observed in plasma, tissue, tumor and ascites over the entire study period. Drug accumulation was several fold greater in tumors and ascites when compared to plasma levels. Sustained chemotherapy resulted in significant reduction in tumor burden and ascites volume. IP tumors showed greater cell death compared to the SC tumors as seen by higher TUNEL and caspase-3 expression. At the intratumoral level, DTX distributed more towards the core of IP tumors compared to the SC tumors. Tumor penetration of drug from nearest blood vessel was 1.5 fold greater in the IP tumors than the SC tumors. Overall, favorable drug distribution at the whole-body, peritoneal and intratumoral levels in combination with local and systemic sustained drug exposure contribute to the high efficacy observed. These results encourage the clinical use of IP sustained chemotherapy for ovarian cancer.     

A neural cell adhesion molecule-derived peptide, FGL, attenuates glial cell activation in the aged hippocampus

Neuroglial activation is a typical hallmark of ageing within the hippocampus, and correlates with age-related cognitive deficits. We have used quantitative immunohistochemistry and morphometric analyses to investigate whether systemic treatment with the Neural Cell Adhesion Molecule (NCAM)-derived peptide FG Loop (FGL) specifically alters neuroglial activation and population densities within the aged rat hippocampus (22 months of age). A series of 50 μm paraformaldehyde/acrolein-fixed sections taken throughout the dorsal hippocampus (5 animals per group) were immunostained to detect astrocytes (GFAP and S100ß) and microglial cells (CD11b/OX42 and MHCII/OX6), and analysed using computerised image analysis and optical segmentation (Image-Pro Plus, Media Cybernetics). FGL treatment reduced the density of CD11b+ and MHCII+ microglia in aged animals, concomitant with a reduction in immunoreactivity for these phenotypic markers. FGL treatment also markedly reduced GFAP immunoreactivity within all hippocampal subfields in aged animals, without exerting an appreciable effect on the density of S100ß+ cells. These results demonstrate that FGL can indeed regulate neuroglial activation and reduce microglial cell density in the aged hippocampus, and support its potential use as a therapeutic agent in age-related brain disorders.     

Preoperative and intraoperative predictors of positive margins after breast-conserving surgery: a retrospective review

Background  

Breast-conserving therapy is an established treatment for early breast cancer. Current practice mandates reoperation for positive margins. Presently most patients are brought to the operating room with a diagnosis of breast cancer made on core biopsy. Preoperative and intraoperative predictors of margin status are needed.