Recreational physical inactivity and mortality in women with invasive epithelial ovarian cancer: evidence from the Ovarian Cancer Association Consortium

Background: Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association Consortium to investigate the association between pre-diagnostic physical inactivity and mortality. Methods: Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years. Results: In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18–1.52) and without (HR=1.22, 95% CI: 1.12–1.33) further adjustment for residual disease, respectively. Conclusion: In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

The passage of azidodeoxythymidine into and within the central nervous system: does it follow the parent compound, thymidine? J Pharmacol Exp Ther 1997; 281

ABSTRACT The transport of azidodeoxythymidine (AZT) into and within the central nervous system (CNS) has special clinical significance due to the ability of AZT to alleviate certain neurological symptoms associated with the acquired immunodeficiency syndrome (AIDS). AZT was thought to be similar to its parent compound, thymidine, in that it entered the CNS via the choroid plexuses (blood-CSF barrier) and could not cross the bloodbrain barrier (BBB). However, a saturable transport system for thymidine at the BBB has recently been identified. The aim of this study was to test the hypothesis that AZT follows its physiological counterpart in its mode of entry into and movement within the CNS. Initial experiments using the in situ brain perfusion technique indicated that the blood-to-CNS transfer constants for [ 3 H]AZT (blood-to-cerebrum; 0.95 Ϯ 0.12 l/ min/g) were significantly lower than those determined fo

Uneven distribution of nucleoside transporters and intracellular enzymatic degradation prevent transport of intact [¹⁴C] adenosine across the sheep choroid plexus epithelium as a monolayer in primary culture

Abstract Background Efflux transport of adenosine across the choroid plexus (CP) epithelium might contribute to the homeostasis of this neuromodulator in the extracellular fluids of the brain. The aim of this study was to explore adenosine transport across sheep CP epithelial cell monolayers in primary culture. Methods To explore transport of adenosine across the CP epithelium, we have developed a method for primary culture of the sheep choroid plexus epithelial cells (CPEC) on plastic permeable supports and analysed [14C] adenosine transport across this cellular layer, [14C] adenosine metabolism inside the cells, and cellular uptake of [14C] adenosine from either of the chambers. The primary cell culture consisted of an enriched epithelial cell fraction from the sheep fourth ventricle CP and was grown on laminin-precoated filter inserts. Results and conclusion CPEC grew as monolayers forming typical polygonal islands, reaching optical confluence on the third day after the seeding. Transepithelial electrical resistance increased over the time after seeding up to 85 ± 9 Ω cm2 at day 8, while permeability towards [14C] sucrose, a marker of paracellular diffusion, simultaneously decreased. These cells expressed some features typical of the CPEC in situ, including three nucleoside transporters at the transcript level that normally mediate adenosine transport across cellular membranes. The estimated permeability of these monolayers towards [14C] adenosine was low and the same order of magnitude as for the markers of paracellular diffusion. However, inhibition of the intracellular enzymes, adenosine kinase and adenosine deaminase, led to a significant increase in transcellular permeability, indicating that intracellular phosphorylation into nucleotides might be a reason for the low transcellular permeability. HPLC analysis with simultaneous detection of radioactivity revealed that [14C] radioactivity which appeared in the acceptor chamber after the incubation of CPEC monolayers with [14C] adenosine in the donor chamber was mostly present as [14C] hypoxanthine, a product of adenosine metabolic degradation. Therefore, it appears that CPEC in primary cultures act as an enzymatic barrier towards adenosine. Cellular uptake studies revealed that concentrative uptake of [14C] adenosine was confined only to the side of these cells facing the upper or apical chamber, indicating uneven distribution of nucleoside transporters.</p

The characteristics of nucleobase transport and metabolism by the perfused sheep choroid plexus

Abstract The uptake of nucleobases was investigated across the basolateral membrane of the sheep choroid plexus perfused in situ. The maximal uptake (U ) for hypoxanthine and adenine, was 35.5161.50% and 30.7160.49% and for guanine, thymine and uracil was max 12.0060.53%, 13.0760.48% and 12.3060.55%, respectively with a negligible backflux, except for that of thymine (35.1165.37% of the U ). HPLC analysis revealed that the purine nucleobase hypoxanthine and the pyrimidine nucleobase thymine can pass intact through max the choroid plexus and enter the cerebrospinal fluid CSF so the lack of backflux for hypoxanthine was not a result of metabolic trapping in the cell. Competition studies revealed that hypoxanthine, adenine and thymine shared the same transport system, while guanine and uracil were transported by a separate mechanism and that nucleosides can partially share the same transporter. HPLC analysis of sheep CSF collected in vivo revealed only two nucleobases were present adenine and hypoxanthine; with an R 0.1960.02 and 3.4360.20, CSF / Plasma respectively. Xanthine and urate, the final products of purine catabolism, could not be detected in the CSF even in trace amounts. These results suggest that the activity of xanthine oxidase in the brain of the sheep is very low so the metabolic degradation of purines is carried out only as far as hypoxanthine which then accumulates in the CSF. In conclusion, the presence of saturable transport systems for nucleobases at the basolateral membrane of the choroidal epithelium was demonstrated, which could be important for the distribution of the salvageable nucleobases, adenine and hypoxanthine in the central nervous system