Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we will assume that you are happy to receive all cookies and you will not see this message again. Click 'Find out more' for information on how to change your cookie settings.
  • Implementation of a modified version of NICE CG95 on chest pain of recent onset: Experience in a DGH

    15 October 2018

    National Institute for Health and Care Excellence (NICE) clinical guideline 95 (CG95) was introduced to rapidaccess chest pain clinics (RACPC) to aid investigation of possible stable angina based on pretest probability of coronary artery disease (CAD). Following a six-month audit of its implementation we introduced a modified version: patients with low/ moderate risk of CAD were referred for computed tomography coronary angiography (CTCA), while those at high/ very high risk were referred for invasive angiography. Patient records of 546 patients referred to our RACPC over a six-month period were retrospectively analysed. Pretest probability of CAD, referral for initial investigation, and outcomes at a minimum follow-up time of six months were documented. Incidence of CAD correlated well with pretest probability. Moderaterisk patients had a low incidence of CAD and revascularisation. High/ very high-risk patients had a high incidence of revascularisation, and this was predominantly for prognostically significant disease. In conclusion, low rates of CAD in lowand moderate-risk groups justifies the use of CTCA as a first-line investigation in these patients. Routine investigation of very high-risk patients allows a high proportion to undergo revascularisation for prognostically significant disease. Strict adherence to NICE CG95 could lead to these patients being missed.

  • Cited1 deficiency suppresses intestinal tumorigenesis.

    7 November 2018

    Conditional deletion of Apc in the murine intestine alters crypt-villus architecture and function. This process is accompanied by multiple changes in gene expression, including upregulation of Cited1, whose role in colorectal carcinogenesis is unknown. Here we explore the relevance of Cited1 to intestinal tumorigenesis. We crossed Cited1 null mice with Apc(Min/+) and AhCre(+)Apc(fl/fl) mice and determined the impact of Cited1 deficiency on tumour growth/initiation including tumour multiplicity, cell proliferation, apoptosis and the transcriptome. We show that Cited1 is up-regulated in both human and murine tumours, and that constitutive deficiency of Cited1 increases survival in Apc(Min/+) mice from 230.5 to 515 days. However, paradoxically, Cited1 deficiency accentuated nearly all aspects of the immediate phenotype 4 days after conditional deletion of Apc, including an increase in cell death and enhanced perturbation of differentiation, including of the stem cell compartment. Transcriptome analysis revealed multiple pathway changes, including p53, PI3K and Wnt. The activation of Wnt through Cited1 deficiency correlated with increased transcription of β-catenin and increased levels of dephosphorylated β-catenin. Hence, immediately following deletion of Apc, Cited1 normally restrains the Wnt pathway at the level of β-catenin. Thus deficiency of Cited1 leads to hyper-activation of Wnt signaling and an exaggerated Wnt phenotype including elevated cell death. Cited1 deficiency decreases intestinal tumourigenesis in Apc(Min/+) mice and impacts upon a number of oncogenic signaling pathways, including Wnt. This restraint imposed by Cited1 is consistent with a requirement for Cited1 to constrain Wnt activity to a level commensurate with optimal adenoma formation and maintenance, and provides one mechanism for tumour repression in the absence of Cited1.

  • Gonadal defects in Cited2-mutant mice indicate a role for SF1 in both testis and ovary differentiation.

    7 November 2018

    Sex determination is regulated by a molecular antagonism between testis- and ovary-determining pathways in the supporting cell lineage of the gonadal primordia. Genes important for maintaining this lineage play critical roles in early gonadal development, but their influence on testis and ovary differentiation is unclear due to the severity of loss-of-function phenotypes. The transcription factor SF1 (Nr5a1/Ad4BP) is one such factor, required for establishing the supporting cell lineage, and for propagating the male pathway. In the gonad, Sf1 expression is enhanced by the transcriptional co-factor Cited2. We have used the reduced levels of Sf1 expression in Cited2(-/-) mice as a hypomorphic model to gain insight into the sex-specific roles of SF1 function in gonadal development. In XY mutant mice, we found that testis development was delayed in Cited2(-/-) gonads, and that testis structure was permanently disrupted. In XX Cited2(-/-) gonads, ectopic cell migration was observed which correlated with a transient upregulation of Fgf9, and a delay in Wnt4 then Foxl2 expression. These data suggest a novel role for SF1 in promoting ovarian development in addition to its roles in testis differentiation.

  • de Wet Group

    16 December 2013

    Role of ABC transporters in gut endocrine K-and L-cells

  • Bajo Lorenzana Group

    26 May 2015

    Hearing Loss and Tinnitus

  • Kohl Group

    10 July 2016

    Information encoding in the brain

  • Booth Group

    14 March 2014

    Optical engineering and microscopy for neuroscience and biomedical imaging

  • Ashcroft Group

    10 July 2016

    ATP-sensitive potassium (K-ATP) channels, insulin secretion and diabetes

  • Wade-Martins Group

    10 July 2016

    Understanding molecular mechanisms of age-related neurodegenerative diseases to generate novel molecular therapies

  • Walker Group

    16 September 2013

    We investigate how the activity of neurons in the brain give rise to our perception of sound.

  • Webber Group

    10 July 2016

    Computational Disease Genomics and Networks

  • Wilkins Group

    10 July 2016

    Membrane transport in cartilage and cancer cells

  • Wilson Group

    10 July 2016

    Cell Biology of Exosome Signalling, Secretion and Growth in Normal and Cancer Cells at Super-Resolution