Evaluation of a service intervention to improve awareness and uptake of bowel cancer screening in ethnically-diverse areas

The Policy Research Unit in Cancer Awareness, Screening and Early Diagnosis receives funding for a research programme from the UK Department of Health Policy Research Programme (grant no. 106/0001). It is a collaboration between researchers from seven institutions (the Queen Mary University of London, the UCL, the King’s College London, the London School of Hygiene and Tropical Medicine, the Hull York Medical School, the Durham University and the Peninsula Medical School)

The HLA class II allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. Methods/Principal Findings: HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DLCO) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). Conclusions/Significance: DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease

The role of gonadotrophin-releasing hormone antagonists in the treatment of patients with advanced hormone-dependent prostate cancer in the UK.

PURPOSE: Comparing gonadotrophin-releasing hormone (GnRH) antagonists and agonists as androgen deprivation therapy for advanced prostate cancer (PC). METHODS: This article stems from a round-table meeting in December 2014 to compare the properties of GnRH agonists and antagonists in the published literature in order to identify the patient groups most likely to benefit from GnRH antagonist therapy. A broad PubMed and congress abstract search was carried out in preparation for the meeting to ensure that the latest data and opinion were available for the discussions. RESULTS: In randomised, controlled trials, GnRH antagonist therapy provides more rapid suppression of luteinising hormone, follicle-stimulating hormone and testosterone than GnRH agonist treatment. Compared with the GnRH agonist, there is evidence of improved disease control by a GnRH antagonist, with longer interval to prostate-specific antigen progression and greater reduction of serum alkaline phosphatase. In a post hoc analysis of six randomised trials, the risk of cardiac events within 1 year of initiating therapy was significantly lower among men receiving GnRH antagonist than agonist. Pre-clinical laboratory data suggest a number of mechanisms whereby GnRH antagonist therapy may benefit men with pre-existing cardiovascular disease (CVD), the most plausible hypothesis being that, unlike GnRH agonists, GnRH antagonists do not activate T lymphocytes, which act to increase atherosclerotic plaque rupture. CONCLUSION: When making treatment decisions, clinicians should consider comorbidities, particularly CVD, in addition to effects on PC. GnRH antagonists may be appropriate in patients with significant CV risk, existing osteopenia, lower urinary tract symptoms and significant metastatic disease

Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility.

Heterogeneity of embryological origins is a hallmark of vascular smooth muscle cells (SMCs) and may influence the development of vascular disease. Differentiation of human pluripotent stem cells (hPSCs) into developmental origin-specific SMC subtypes remains elusive. Here we describe a chemically defined protocol in which hPSCs were initially induced to form neuroectoderm, lateral plate mesoderm or paraxial mesoderm. These intermediate populations were further differentiated toward SMCs (>80% MYH11(+) and ACTA2(+)), which displayed contractile ability in response to vasoconstrictors and invested perivascular regions in vivo. Derived SMC subtypes recapitulated the unique proliferative and secretory responses to cytokines previously documented in studies using aortic SMCs of distinct origins. Notably, this system predicted increased extracellular matrix degradation by SMCs derived from lateral plate mesoderm, which was confirmed using rat aortic SMCs from corresponding origins. This differentiation approach will have broad applications in modeling origin-dependent disease susceptibility and in developing bioengineered vascular grafts for regenerative medicine

Shake a tail feather: the evolution of the theropod tail into a stiff aerodynamic surface

Theropod dinosaurs show striking morphological and functional tail variation; e.g., a long, robust, basal theropod tail used for counterbalance, or a short, modern avian tail used as an aerodynamic surface. We used a quantitative morphological and functional analysis to reconstruct intervertebral joint stiffness in the tail along the theropod lineage to extant birds. This provides new details of the tail's morphological transformation, and for the first time quantitatively evaluates its biomechanical consequences. We observe that both dorsoventral and lateral joint stiffness decreased along the non-avian theropod lineage (between nodes Theropoda and Paraves). Our results show how the tail structure of non-avian theropods was mechanically appropriate for holding itself up against gravity and maintaining passive balance. However, as dorsoventral and lateral joint stiffness decreased, the tail may have become more effective for dynamically maintaining balance. This supports our hypothesis of a reduction of dorsoventral and lateral joint stiffness in shorter tails. Along the avian theropod lineage (Avialae to crown group birds), dorsoventral and lateral joint stiffness increased overall, which appears to contradict our null expectation. We infer that this departure in joint stiffness is specific to the tail's aerodynamic role and the functional constraints imposed by it. Increased dorsoventral and lateral joint stiffness may have facilitated a gradually improved capacity to lift, depress, and swing the tail. The associated morphological changes should have resulted in a tail capable of producing larger muscular forces to utilise larger lift forces in flight. Improved joint mobility in neornithine birds potentially permitted an increase in the range of lift force vector orientations, which might have improved flight proficiency and manoeuvrability. The tail morphology of modern birds with tail fanning capabilities originated in early ornithuromorph birds. Hence, these capabilities should have been present in the early Cretaceous, with incipient tail-fanning capacity in the earliest pygostylian birds

Search for rare quark-annihilation decays, B --> Ds(*) Phi

We report on searches for B- --> Ds- Phi and B- --> Ds*- Phi. In the context of the Standard Model, these decays are expected to be highly suppressed since they proceed through annihilation of the b and u-bar quarks in the B- meson. Our results are based on 234 million Upsilon(4S) --> B Bbar decays collected with the BABAR detector at SLAC. We find no evidence for these decays, and we set Bayesian 90% confidence level upper limits on the branching fractions BF(B- --> Ds- Phi) Ds*- Phi)<1.2x10^(-5). These results are consistent with Standard Model expectations.Comment: 8 pages, 3 postscript figues, submitted to Phys. Rev. D (Rapid Communications

Effects of Shielding on Properties of Eddy Current Probes with Ferrite Cup Cores

In eddy current inspection the ability to detect small defects depends on the sensitivity of the system and on the relative sizes of the probe and the defect. To detect defects on the opposite surface the probe radius should be at least as great as the thickness of the material. This limits the sensitivity to small defects that can be achieved by decreasing the probe size. Assuming the instrumentation is a given, further sensitivity can be achieved by improving the sensitivity of the probe itself.</p

Pathogen Sensing Pathways in Human Embryonic Stem Cell Derived-Endothelial Cells: Role of NOD1 Receptors.

Human embryonic stem cell-derived endothelial cells (hESC-EC), as well as other stem cell derived endothelial cells, have a range of applications in cardiovascular research and disease treatment. Endothelial cells sense Gram-negative bacteria via the pattern recognition receptors (PRR) Toll-like receptor (TLR)-4 and nucleotide-binding oligomerisation domain-containing protein (NOD)-1. These pathways are important in terms of sensing infection, but TLR4 is also associated with vascular inflammation and atherosclerosis. Here, we have compared TLR4 and NOD1 responses in hESC-EC with those of endothelial cells derived from other stem cells and with human umbilical vein endothelial cells (HUVEC). HUVEC, endothelial cells derived from blood progenitors (blood outgrowth endothelial cells; BOEC), and from induced pluripotent stem cells all displayed both a TLR4 and NOD1 response. However, hESC-EC had no TLR4 function, but did have functional NOD1 receptors. In vivo conditioning in nude rats did not confer TLR4 expression in hESC-EC. Despite having no TLR4 function, hESC-EC sensed Gram-negative bacteria, a response that was found to be mediated by NOD1 and the associated RIP2 signalling pathways. Thus, hESC-EC are TLR4 deficient but respond to bacteria via NOD1. This data suggests that hESC-EC may be protected from unwanted TLR4-mediated vascular inflammation, thus offering a potential therapeutic advantage

Sit still and pay attention: Using the Wii Balance-Board to detect lapses in concentration in children during psychophysical testing.

During psychophysical testing, a loss of concentration can cause observers to answer incorrectly, even when the stimulus is clearly perceptible. Such lapses limit the accuracy and speed of many psychophysical measurements. This study evaluates an automated technique for detecting lapses based on body movement (postural instability). Thirty-five children (8-11 years of age) and 34 adults performed a typical psychophysical task (orientation discrimination) while seated on a Wii Fit Balance Board: a gaming device that measures center of pressure (CoP). Incorrect responses on suprathreshold catch trials provided the "reference standard" measure of when lapses in concentration occurred. Children exhibited significantly greater variability in CoP on lapse trials, indicating that postural instability provides a feasible, real-time index of concentration. Limitations and potential applications of this method are discussed