PreImplantation Factor (PIF) promotes HLA-G, -E, -F, -C expression in JEG-3 choriocarcinoma cells and endogenous progesterone activity

BACKGROUND: Pregnancy success requires mandatory maternal tolerance of the semi/allogeneic embryo involving embryo-derived signals. Expression levels of PreImplantation Factor (PIF), a novel peptide secreted by viable embryos, correlate with embryo development, and its early detection in circulation correlates with a favourable pregnancy outcome. PIF enhances endometrial receptivity to promote embryo implantation. Via the p53 pathway, it increases trophoblast invasion, improving cell survival / immune privilege. PIF also reduces spontaneous and LPS-induced foetal death in immune naïve murine model. AIMS: To examine if PIF affects gene expression of human leukocyte antigen (HLA)-G, -E -F and -C in JEG-3 choriocarcinoma cells, and to examine the influence of PIF on local progesterone activity. Methods: PIF and progesterone (P4) effects on JEG-3 cells surface and intracellular HLA molecules was tested using monoclonal antibodies, flow cytometry, and Western blotting. PIF and IL17 effects on P4 and cytokines secretion was determined by ELISA. PIF and P4 effects on JEG-3 cells proteome was examined using 2D gel staining followed by spot analysis, mass spectrometry and bioinformatic analysis. RESULTS: In cytotrophoblastic JEG-3 cells PIF increased intracellular expression of HLA-G, HLA-F, HLA-E and HLA-C and surface expression of HLA-G, HLA-E and HLA-C in dose and time dependent manner. In case of HLA-E, F confirmed also by Western blotting. Proteome analysis confirmed an increase in HLA-G, pro-tolerance FOXP3+ regulatory T cells (Tregs), coagulation factors and complement regulator. In contrast, PIF reduced PRDX2 and HSP70s to negate oxidative stress and protein misfolding. PIF enhanced local progesterone activity, increasing steroid secretion and the receptor protein. It also promoted the secretion of the Th1/Th2 cytokines (IL-10, IL-1β, IL-8, GM-CSF and TGF-β1), resulting in improved maternal signalling. CONCLUSION: PIF can generate a pro-tolerance milieu by enhancing the expression of HLA molecules and by amplifying endogenous progesterone activity. A Fast-Track clinical trial for autoimmune disease has been satisfactorily completed. The acquired data warrants PIF use for the treatment of early pregnancy disorders

Randomised, double-blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial study

Objectives To determine the effect of long term inhaled corticosteroids on lung function, exacerbations, and health status in patients with moderate to severe chronic obstructive pulmonary disease. Design Double blind, placebo controlled study. Setting Eighteen UK hospitals. Participants 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second (FEV1) 50% of predicted normal. Interventions Inhaled fluticasone propionate 500 ìg twice daily from a metered dose inhaler or identical placebo. Main outcome measures Efficacy measures: rate of decline in FEV1 after the bronchodilator and in health status, frequency of exacerbations, respiratory withdrawals. Safety measures: morning serum cortisol concentration, incidence of adverse events. Results There was no significant difference in the annual rate of decline in FEV1 (P = 0.16). Mean FEV1 after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo (P < 0.001). Median exacerbation rate was reduced by 25% from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate (P = 0.026). Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate (P = 0.0043). Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group (25% v19%, P = 0.034). Conclusions Fluticasone propionate 500 ìg twice daily did not affect the rate of decline in FEV1 but did produce a small increase in FEV1. Patients on fluticasone propionate had fewer exacerbations and a slower decline in health status. These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease

HLA-DR genotyping and mitochondrial DNA analysis reveal the presence of family burials in a fourth century Romano-British Christian cemetery

In Colchester, Britain's oldest recorded town, during the Roman period there were areas which were clearly used solely as cemeteries. One o f the most significant is at Butt Road, which includes a late Roman probable Christian cemetery with an associated building, apparently a church, that overlies and developed from a pagan inhumation cemetery. DNA was extracted from the long bones (femurs) of 29 individuals, mostly from a large complex of burials centered on two timber vaults. These were thought to comprise a number of family groupings, deduced from osteological analysis, stratigraphical and other considerations. The use of a modified version of the silica-based purification method recovered nanogram quantities of DNA/gram of bone. Two-stage amplification, incorporating primer-extension preamplification-polymerase chain reaction, permitted simultaneous amplification of both mitochondrial and nuclear DNA. Sequence-specific oligonucleotide probes yielded human leukocyte antigen (HLA)-DR typing of seven samples, with four revealing the infrequent HLA-DR10 genotype. Examination of the control region of mitochondrial DNA (mtDNA) by direct sequencing revealed polymorphisms yet to be reported in the modern population. HLA-DRB typing and mtDNA analysis affirmatively supported kinship among some, if not all, individuals in the "vault complex" and demonstrate a continental European origin of the individuals investigated

Measurements of heterotypic associations between cluster of differentiation CD74 and CD44 in human breast cancer-derived cells

Interactions between pairs of membrane-bound receptors can enhance tumour development with implications for targeted therapies for cancer. Here we demonstrate clear heterotypic interaction between cluster of differentiation (CD) 74 and CD44, which might act in synergy and hence contribute to breast cancer progression. CD74, a type II transmembrane glycoprotein, is a chaperone for MHC class II biosynthesis and a receptor for the macrophage migration inhibitory factor (MIF). CD44 is the receptor for hyaluronic acid and is a type II transmembrane protein. Interactions between CD74, MIF and the intra-cytoplasmic domain of CD44 result in activation of ERK1/2, leading to increased cell proliferation and decreased apoptosis. The level of CD44 in the breast tumor cell lines CAMA-1, MDA-MB-231, MDA-MB-435 and the immortalized normal luminal cell line 226LDM was higher than that of CD74. It was also observed that CD74 and CD44 exhibit significant variation in expression levels across the cells. CD74 and CD44 were observed to accumulate in cytoplasmic compartments, suggesting they associate with each other to facilitate tumour growth and metastasis. Use of a novel and validated colocalisation and image processing approach, coupled with co-immunoprecipitation, confirmed that CD74 and CD44 physically interact, suggesting a possible role in breast tumour growth. This is the first time that CD74 and CD44 colocalization has been quantified in breast cancer cells using a non-invasive validated bioimaging procedure. Measuring the co-expression levels of CD74 and CD44 could potentially be used as a 'biomarker signature' to monitor different stages of breast cancer

Interpreting physical performance in professional soccer match-play: Should we be more pragmatic in our approach?

Academic and practitioner interest in the physical performance of male professional soccer players in the competition setting determined via time-motion analyses has grown substantially over the last four decades leading to a substantial body of published research and aiding development of a more systematic evidence-based framework for physical conditioning. Findings have forcibly shaped contemporary opinions in the sport with researchers and practitioners frequently emphasising the important role that physical performance plays in match outcomes. Time-motion analyses have also influenced practice as player conditioning programmes can be tailored according to the different physical demands identified across individual playing positions. Yet despite a more systematic approach to physical conditioning, data indicate that even at the very highest standards of competition, the contemporary player is still susceptible to transient and end-game fatigue. Over the course of this article, the author suggests that a more pragmatic approach to interpreting the current body of time-motion analysis data and its application in the practical setting is nevertheless required. Examples of this are addressed using findings in the literature to examine: a) the association between competitive physical performance and ‘success’ in professional soccer, b) current approaches to interpreting differences in time-motion analysis data across playing positions and, c) whether data can realistically be used to demonstrate the occurrence of fatigue in match-play. Gaps in the current literature and directions for future research are also identified

Neurotoxicity

Neurotoxicity refers to the direct or indirect effect of chemicals that disrupt the nervous system of humans or animals. Numerous chemicals can produce neurotoxic diseases in humans, and many more are used as experimental tools to probe molecular and cellular mechanisms of physiology and pathophysiology in the nervous system of animal tissues in vivo and in vitro, and in human neural progenitor cell lines. Some chemicals act directly on neural cells, others interfere with metabolic processes on which the nervous system is especially dependent. Emerging evidence suggests that toxic effects on physiological systems outside the brain, in particular the endocrine system, immune system and gut microbiome, may also adversely impact the nervous system. Some neurotoxic chemicals disrupt neural function, others alter normal developmental trajectories of the brain or cause damage to the adult nervous system. Perturbations may appear and disappear rapidly, evolve slowly over days or weeks and regress over months or years, or cause permanent deficits. Neurotoxicity is usually self-limiting after exposure ceases and rarely progressive in the absence of continued exposure, although there may be a significant delay between exposure and manifestation of neurotoxic effects

Bound states of spin-half particles in a static gravitational field close to the black hole field

We consider the bound-state energy levels of a spin-1/2 fermion in the gravitational field of a near-black hole object. In the limit that the metric of the body becomes singular, all binding energies tend to the rest-mass energy (i.e. total energy approaches zero). We present calculations of the ground state energy for three specific interior metrics (Florides, Soffel and Schwarzschild) for which the spectrum collapses and becomes quasi-continuous in the singular metric limit. The lack of zero or negative energy states prior to this limit being reached prevents particle pair production occurring. Therefore, in contrast to the Coulomb case, no pairs are produced in the non-singular static metric. For the Florides and Soffel metrics the singularity occurs in the black hole limit, while for the Schwarzschild interior metric it corresponds to infinite pressure at the centre. The behaviour of the energy level spectrum is discussed in the context of the semi-classical approximation and using general properties of the metric.Comment: 16 pages, 6 Figures. Submitted to General Relativity and Gravitatio

Bilateral Assessment of Functional Tasks for Robot-assisted Therapy Applications

This article presents a novel evaluation system along with methods to evaluate bilateral coordination of arm function on activities of daily living tasks before and after robot-assisted therapy. An affordable bilateral assessment system (BiAS) consisting of two mini-passive measuring units modeled as three degree of freedom robots is described. The process for evaluating functional tasks using the BiAS is presented and we demonstrate its ability to measure wrist kinematic trajectories. Three metrics, phase difference, movement overlap, and task completion time, are used to evaluate the BiAS system on a bilateral symmetric (bi-drink) and a bilateral asymmetric (bi-pour) functional task. Wrist position and velocity trajectories are evaluated using these metrics to provide insight into temporal and spatial bilateral deficits after stroke. The BiAS system quantified movements of the wrists during functional tasks and detected differences in impaired and unimpaired arm movements. Case studies showed that stroke patients compared to healthy subjects move slower and are less likely to use their arm simultaneously even when the functional task requires simultaneous movement. After robot-assisted therapy, interlimb coordination spatial deficits moved toward normal coordination on functional tasks

Unintentional asphyxia, SIDS, and medically explained deaths:A descriptive study of outcomes of child death review (CDR) investigations following sudden unexpected death in infancy

Background: A comprehensive Child Death Review (CDR) program was introduced in England and Wales in 2008 but as yet data have only been analysed at a local level, limiting the learning from deaths. The aim of this study is to describe the profile of causes and risk factors for Sudden Unexpected Death in Infancy (SUDI) as determined by the new CDR program. Methods: This was a descriptive outcome study using data from Child Death Overview Panel (CDOP) Form C for SUDI cases dying during 2010-2 in the West Midlands region of England. The main outcome measures were: cause of death, risk factors and potential preventability of death, and determination of deaths probably due to unintentional asphyxia. Results: Data were obtained for 65/70 (93%) SUDI cases. 20/65 (31%) deaths were initially categorised as due to medical causes; 21/65 (32%) as SIDS, and 24/65 (37%) as undetermined. Reanalysis suggested that 2/21 SIDS and 7/24 undetermined deaths were probably due to unintentional asphyxia, with 6 of these involving co-sleeping and excessive parental alcohol consumption. Deaths classified as ‘undetermined’ had significantly higher total family and environmental risk factor scores (mean 2.6, 95% CI 2.0– 3.3) compared to those classified as SIDS (mean 1.6, 95% CI 1.2-1.9), or medical causes for death (mean 1.1, 95% CI 0.8-1.3). 9/20 (47%) of medical deaths, 19/21 (90%) SIDS and 23/24 (96%) undetermined deaths were considered to be potentially preventable. There were inadequacies in medical provision identified in 5/20 (25%) of medically explained deaths. Conclusions: The CDR program results in detailed information about risk factors for SUDI cases but failed to recognise deaths probably due to unintentional asphyxia. The misclassification of probable unintentional asphyxial deaths and SIDS as ‘undetermined deaths’ is likely to limit learning from these deaths and inhibit prevention strategies. Many SUDI occurred in families with mental illness, substance misuse and chaotic lifestyles and most in unsafe sleep-environments. This knowledge could be used to better target safe sleep advice for vulnerable families and prevent SUDI in the future

The reliability, validity and sensitivity of a novel soccer-specific reactive repeated-sprint test (RRST).

PURPOSE: The aim of this study was to determine the reliability, validity and sensitivity of a reactive repeated-sprint test (RRST). METHODS: Elite (n = 72) and sub-elite male (n = 87) and elite female soccer players (n = 12) completed the RRST at set times during a season. Total distance timed was 30 m and the RRST performance measure was the total time (s) across eight repetitions. Competitive match running performance was measured using GPS and high-intensity running quantified (≥ 19.8 km h(-1)). RESULTS: Test-retest coefficient of variation in elite U16 and sub-elite U19 players was 0.71 and 0.84 %, respectively. Elite U18 players' RRST performances were better (P < 0.01) than elite U16, sub-elite U16, U18, U19 and elite senior female players (58.25 ± 1.34 vs 59.97 ± 1.64, 61.42 ± 2.25, 61.66 ± 1.70, 61.02 ± 2.31 and 63.88 ± 1.46 s; ES 0.6-1.9). For elite U18 players, RRST performances for central defenders (59.84 ± 1.35 s) were lower (P < 0.05) than full backs (57.85 ± 0.77 s), but not attackers (58.17 ± 1.73 s) or central and wide midfielders (58.55 ± 1.08 and 58.58 ± 1.89 s; ES 0.7-1.4). Elite U16 players demonstrated lower (P < 0.01) RRST performances during the preparation period versus the start, middle and end of season periods (61.13 ± 1.53 vs 59.51 ± 1.39, 59.25 ± 1.42 and 59.20 ± 1.57 s; ES 1.0-1.1). Very large magnitude correlations (P < 0.01) were observed between RRST performance and high-intensity running in the most intense 5-min period of a match for both elite and sub-elite U18 players (r = -0.71 and -0.74), with the best time of the RRST also correlating with the arrowhead agility test for elite U16 and U18 players (r = 0.84 and 0.75). CONCLUSION: The data demonstrate that the RRST is a reliable and valid test that distinguishes between performance across standard, position and seasonal period