Syncytiotrophoblast-derived extracellular vesicles carry apolipoprotein-E and affect lipid synthesis of liver cells in vitro.

In normal pregnancy, hepatic metabolism adaptation occurs with an increase in lipid biosynthesis. Placental shedding of syncytiotrophoblast-derived extracellular vesicles (STBEVs) into the maternal circulation constitutes a major signalling mechanism between foetus and mother. We investigated whether STBEVs from normal pregnant women might target liver cells in vitro and induce changes in lipid synthesis. This study was performed at the Nuffield Department of Women's & Reproductive Health, Oxford, UK. STBEVs were obtained by dual-lobe placental perfusion from 11 normal pregnancies at term. Medium/large and small STBEVs were collected by ultracentrifugation at 10,000g and 150,000g, respectively. STBEVs were analysed by Western blot analysis and flow cytometry for co-expression of apolipoprotein-E (apoE) and placental alkaline phosphatase (PLAP). The uptake of STBEVs by liver cells and the effect on lipid metabolism was evaluated using a hepatocarcinoma cell line (HepG2 cells). Data were analysed by one-way ANOVA and Student's t test. We demonstrated that: (a) STBEVs carry apoE; (b) HepG2 cells take up STBEVs through an apoE-LDL receptor interaction; (c) STBEV incorporation into HepG2 cells resulted in (i) increased cholesterol release (ELISA); (ii) increased expression of the genes SQLE and FDPS (microarray) involved in cholesterol biosynthesis; (iii) downregulation of the CLOCK gene (microarray and PCR), involved in the circadian negative control of lipid synthesis in liver cells. In conclusion, the placenta may orchestrate the metabolic adaptation of the maternal liver through release of apoE-positive STBEVs, by increasing lipid synthesis in a circadian-independent fashion, meeting the nutritional needs of the growing foetus.

Novel management of vaginal chronic graft-versus-host disease causing haematometra and haematocolpos.

Genital chronic graft-versus-host disease (GVHD) in women posthaematopoietic cell transplantation may cause vaginal mucosal sclerosis. Human papillomavirus (HPV) reactivation, also common post-transplantation, limits local immunosuppressive, but not oestrogen treatment. A 36-year-old nulliparous woman developed coincidental genital chronic GVHD and HPV 22 months after transplant for aplastic anaemia. Topical immunosuppression for GVHD led to an eruption of warts successfully treated with laser surgery and cone biopsy. She maintained normal ovarian function and used extended cycle combined hormonal contraception. A vaginal oestrogen ring used continuously limited most scarring for 8 years. Progressive apical vaginal scarring obstructed menstrual flow leading to haematocolpos and haematometra. Normal anatomy was restored with a cruciate incision in the cervicovaginal scar performed during menses. When HPV disease limits use of topical immunosuppression in women with vaginal GVHD, the local scar-reducing effect of a vaginal oestrogen ring is limited, and surgery may be needed and can be successful in treating haematocolpos.This study was registered in ClinicalTrials.gov with trial registration number of NCT00003838.

Primary Macrophage Chemotaxis Induced by Cannabinoid Receptor 2 Agonists Occurs Independently of the CB2 Receptor.

Activation of CB2 has been demonstrated to induce directed immune cell migration. However, the ability of CB2 to act as a chemoattractant receptor in macrophages remains largely unexplored. Using a real-time chemotaxis assay and a panel of chemically diverse and widely used CB2 agonists, we set out to examine whether CB2 modulates primary murine macrophage chemotaxis. We report that of 12 agonists tested, only JWH133, HU308, L-759,656 and L-759,633 acted as macrophage chemoattractants. Surprisingly, neither pharmacological inhibition nor genetic ablation of CB2 had any effect on CB2 agonist-induced macrophage chemotaxis. As chemotaxis was pertussis toxin sensitive in both WT and CB2(-/-) macrophages, we concluded that a non-CB1/CB2, Gi/o-coupled GPCR must be responsible for CB2 agonist-induced macrophage migration. The obvious candidate receptors GPR18 and GPR55 could not mediate JWH133 or HU308-induced cytoskeletal rearrangement or JWH133-induced ß-arrestin recruitment in cells transfected with either receptor, demonstrating that neither are the unidentified GPCR. Taken together our results conclusively demonstrate that CB2 is not a chemoattractant receptor for murine macrophages. Furthermore we show for the first time that JWH133, HU308, L-759,656 and L-759,633 have off-target effects of functional consequence in primary cells and we believe that our findings have wide ranging implications for the entire cannabinoid field.

The role of cardiac biomarkers for predicting left ventricular dysfunction and cardiovascular mortality in acute exacerbations of COPD.

The presence of cardiovascular comorbidities is frequently associated with poor outcomes in chronic obstructive pulmonary disease (COPD). No clear role has been defined for cardiac biomarkers in acute exacerbations of COPD (AECOPD). The aim of this systematic review was to examine the prognostic value of brain natriuretic peptide (BNP) and troponins in patients with AECOPD. Two independent authors searched the PubMed and Cochrane Library to collect clinical trials, observational studies and meta-analyses studying the prognostic value of cardiac biomarkers in AECOPD. The reference lists of all the included studies were also reviewed. A total of 14 studies were included in the review, of which 10 measured troponins, 7 measured BNP or NT-proBNP, and 3 measured both. Of the studies that used mortality in AECOPD as an end point, some but not all found that elevated BNP and/or troponins were associated with increased mortality. Of the studies that used left ventricular (LV) dysfunction in AECOPD as an end point, all found a significant association between elevated BNP and troponins in the diagnosis of LV dysfunction. In summary, it appears that there may be a link between an elevated level of BNP or NT-proBNP and increased cardiovascular mortality in AECOPD, although the data currently available are not conclusive. The inconsistencies in biomarkers measured, time points of measurements and the variability in outcome measured preclude more robust analysis.