296
1,551.25
5.24
1,016

Publication History View all

  • [Show abstract] [Hide abstract]
    ABSTRACT: Considerable evidence implies that an enteroviral infection may accelerate or precipitate type 1 diabetes (T1D) in some individuals. However, causality is not proven. We present and critically assess evidence suggesting that islet β cells can become infected with enterovirus, and argue that this may result in one of several consequences. Occasionally, a fully lytic infection may arise and this culminates in fulminant diabetes. Alternatively, an atypical persistent infection develops which can be either benign or promote islet autoimmunity. We propose a model in which the ‘strength’ of the β cell response to the establishment of a persistent enteroviral infection determines the final disease outcome.
    Trends in Endocrinology and Metabolism 12/2014; 25(12). DOI:10.1016/j.tem.2014.08.002
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human ageing is a complex and integrated gradual deterioration of cellular processes. There are nine major hallmarks of ageing, that include changes in DNA repair and DNA damage response, telomere shortening, changes in control over the expression and regulation of genes brought about by epigenetic and mRNA processing changes, loss of protein homeostasis, altered nutrient signaling, mitochondrial dysfunction, stem cell exhaustion, premature cellular senescence and altered intracellular communication. Like practically all other cellular processes, genes associated in features of ageing are regulated by miRNAs. In this review, I will outline each of the features of ageing, together with examples of specific miRNAs that have been demonstrated to be involved in each one. This will demonstrate the interconnected nature of the regulation of transcripts involved in human ageing, and the role of miRNAs in this process. Definition of the factors involved in degeneration of organismal, tissue and cellular homeostasis may provide biomarkers for healthy ageing and increase understanding of the processes that underpin the ageing process itself.
    09/2014; 5(3):656-670. DOI:10.3390/genes5030656
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this substudy of the effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes, we report the development of a novel nitrate depleted beetroot juice for use clinical trials and determine if dietary nitrate supplementation improved cognitive function in patients with type 2 diabetes mellitus.
    Nitric Oxide 05/2014; 40. DOI:10.1016/j.niox.2014.05.003
  • Source
    Diabetes care 12/2013; 36(12):e222. DOI:10.2337/dc13-0609
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Multisource feedback (MSF) ratings provided by patients and colleagues are often poorly correlated with doctors' self-assessments. Doctors' reactions to feedback depend on its agreement with their own perceptions, but factors influencing self-other agreement in doctors' MSF ratings have received little attention. We aimed to identify the characteristics of doctors and their rater groups that affect self-other agreement in MSF ratings. We invited 2454 doctors to obtain patient and colleague feedback using the UK General Medical Council's MSF questionnaires and to self-assess on core items from both patient (PQ) and colleague (CQ) questionnaires. Correlations and differences between doctor, patient and colleague mean feedback scores were examined. Regression analyses identified the characteristics of doctors and their rater groups that influenced self-other score agreement. 1065 (43%) doctors returned at least one questionnaire, of whom 773 (73%) provided self and patient PQ scores and 1026 (96%) provided self and colleague CQ scores. Most doctors rated themselves less favourably than they were rated by either their patients or their colleagues. This tendency to underrate performance in comparison to external feedback was influenced by the doctor's place of training, clinical specialty, ethnicity and the profile of his/her patient and colleague rater samples but, in contrast to studies undertaken in nonmedical settings, was unaffected by age or gender. Self-other agreement in MSF ratings is influenced by characteristics of both raters and ratees. Managers, appraisers, and others responsible for interpreting and reviewing feedback results with the doctor need to be aware of these influences.
    Journal of Continuing Education in the Health Professions 12/2013; 33(1):14-23. DOI:10.1002/chp.21162
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined. We report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known. The HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome in addition to the established beta cell phenotype.
    Journal of Medical Genetics 11/2013; 51(3). DOI:10.1136/jmedgenet-2013-102066
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Omission of relevant covariates can lead to bias when estimating treatment or exposure effects from survival data in both randomized controlled trials and observational studies. This paper presents a general approach to assessing bias when covariates are omitted from the Cox model. The proposed method is applicable to both randomized and non-randomized studies. We distinguish between the effects of three possible sources of bias: omission of a balanced covariate, data censoring and unmeasured confounding. Asymptotic formulae for determining the bias are derived from the large sample properties of the maximum likelihood estimator. A simulation study is used to demonstrate the validity of the bias formulae and to characterize the influence of the different sources of bias. It is shown that the bias converges to fixed limits as the effect of the omitted covariate increases, irrespective of the degree of confounding. The bias formulae are used as the basis for developing a new method of sensitivity analysis to assess the impact of omitted covariates on estimates of treatment or exposure effects. In simulation studies, the proposed method gave unbiased treatment estimates and confidence intervals with good coverage when the true sensitivity parameters were known. We describe application of the method to a randomized controlled trial and a non-randomized study.
    Biometrics 11/2013; 69(4). DOI:10.1111/biom.12096
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context:Increasing numbers of women are being treated with l-thyroxine in pregnancy for mild thyroid dysfunction because of its association with impaired neuropsychological development in their offspring and other adverse obstetric outcomes. However, there are limited data to indicate whether treatment should be continued outside of pregnancy.Objectives:We aimed to determine whether subclinical hypothyroidism and maternal hypothyroxinemia resolve postdelivery.Design, Setting, and Participants:A total of 523 pregnant healthy women with no known thyroid disorders were recruited during routine antenatal care and provided blood samples at 28 weeks of pregnancy and at a mean of 4.9 years postpregnancy.Main Outcome Measures:TSH, free T4, free T3, and thyroid peroxidase antibody levels were measured in serum taken in pregnancy and at follow-up.Results:Subclinical hypothyroidism in pregnancy (TSH >3 mIU/L) was present in 65 of 523 (12.4%) women. Of these, 49 (75.4%) women had normal thyroid function postpregnancy; 16 of 65 (24.6%) had persistent high TSH (TSH >4.5 mIU/L postpregnancy) with 3 women receiving l-thyroxine treatment. A total of 44 of 523 (8.4%) women had isolated maternal hypothyroxinemia in pregnancy (free T4 <10th centile and TSH ≤3 mIU/L). Only 2 of 44 (4.5%) had TSH >4.5 mIU/L outside pregnancy. Of the women with subclinical hypothyroidism in pregnancy with antibody measurements available, those with thyroid peroxidase antibodies in pregnancy were more likely to have persistently elevated TSH or be receiving l-thyroxine replacement after pregnancy (6 of 7 [86%] vs 10 of 57 [18%], P < .001).Conclusions:The majority of cases of subclinical hypothyroidism in pregnancy are transient, so treatment with l-thyroxine in these patients should be reviewed because it may not be warranted after pregnancy.
    The Journal of Clinical Endocrinology and Metabolism 11/2013; 98(12). DOI:10.1210/jc.2013-2768
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ∼400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease.
    Nature Genetics 11/2013; 46(1). DOI:10.1038/ng.2826
  • BMJ (online) 10/2013; 347:f6454. DOI:10.1136/bmj.f6454
Information provided on this web page is aggregated encyclopedic and bibliographical information relating to the named institution. Information provided is not approved by the institution itself. The institution’s logo (and/or other graphical identification, such as a coat of arms) is used only to identify the institution in a nominal way. Under certain jurisdictions it may be property of the institution.