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Manchester, United Kingdom

Petropoulos I.N.,Institute of Human Development
Investigative ophthalmology & visual science | Year: 2014

To assess the diagnostic validity of a fully automated image analysis algorithm of in vivo confocal microscopy images in quantifying corneal subbasal nerves to diagnose diabetic neuropathy. One hundred eighty-six patients with type 1 and type 2 diabetes mellitus (T1/T2DM) and 55 age-matched controls underwent assessment of neuropathy and bilateral in vivo corneal confocal microscopy (IVCCM). Corneal nerve fiber density (CNFD), branch density (CNBD), and length (CNFL) were quantified with expert, manual, and fully-automated analysis. The areas under the curve (AUC), odds ratios (OR), and optimal thresholds to rule out neuropathy were estimated for both analysis methods. Neuropathy was detected in 53% of patients with diabetes. A significant reduction in manual and automated CNBD (P < 0.001) and CNFD (P < 0.0001), and CNFL (P < 0.0001) occurred with increasing neuropathic severity. Manual and automated analysis methods were highly correlated for CNFD (r = 0.9, P < 0.0001), CNFL (r = 0.89, P < 0.0001), and CNBD (r = 0.75, P < 0.0001). Manual CNFD and automated CNFL were associated with the highest AUC, sensitivity/specificity and OR to rule out neuropathy. Diabetic peripheral neuropathy is associated with significant corneal nerve loss detected with IVCCM. Fully automated corneal nerve quantification provides an objective and reproducible means to detect human diabetic neuropathy.

Smith D.M.,University of Manchester | Taylor W.,Institute of Human Development | Lavender T.,University of Manchester
BJOG: An International Journal of Obstetrics and Gynaecology | Year: 2016

Objective To explore the experiences of postnatal women who are obese [body mass index (BMI) ≥ 30 kg/m2] in relation to making behaviour changes and use of behaviour change techniques (BCTs). Design Qualitative interview study. Setting Greater Manchester, UK. Population or Sample Women who were 1 year postnatal aged ≥18 years, who had an uncomplicated singleton pregnancy, and an antenatal booking BMI ≥ 30 kg/m2. Methods Eighteen semi-structured, audio-recorded interviews were conducted by a research midwife with women who volunteered to be interviewed 1 year after taking part in a pilot randomised controlled trial. The six stages of thematic analysis were followed to understand the qualitative data. The Behavior Change Technique Taxonomy (version 1) was used to label the behaviour change techniques (BCTs) reported by women. Main outcome measures Themes derived from 1-year postnatal interview transcripts. Results Two themes were evident: 1. A focused approach to postnatal weight management: women reported making specific changes to their eating and physical activity behaviours, and 2. Need for support: six BCTs were reported as helping women make changes to their eating and physical activity behaviours; three were reported more frequently than others: Self-monitoring of behaviour (2.3), Prompts/cues (7.1) and Social support (unspecified; 3.1). All of the BCTs required support from others for their delivery; food diaries were the most popular delivery method. Conclusion Behaviour change techniques are useful to postnatal women who are obese, and have the potential to improve their physical and mental wellbeing. Midwives and obstetricians should be aware of such techniques, to encourage positive changes. Tweetable abstract BCTs are useful to postnatal women who are obese, and have the potential to improve their wellbeing. © 2015 Royal College of Obstetricians and Gynaecologists.

King D.A.,Wellcome Trust Sanger Institute | Fitzgerald T.W.,Wellcome Trust Sanger Institute | Miller R.,Wellcome Trust Sanger Institute | Canham N.,North West Thames Regional Genetics Service | And 6 more authors.
Genome Research | Year: 2014

Exome sequencing of parent-offspring trios is a popular strategy for identifying causative genetic variants in children with rare diseases. This method owes its strength to the leveraging of inheritance information, which facilitates de novo variant calling, inference of compound heterozygosity, and the identification of inheritance anomalies. Uniparental disomy describes the inheritance of a homologous chromosome pair from only one parent. This aberration is important to detect in genetic disease studies because it can result in imprinting disorders and recessive diseases. We have developed a software tool to detect uniparental disomy from child-mother-father genotype data that uses a binomial test to identify chromosomes with a significant burden of uniparentally inherited genotypes. This tool is the first to read VCF-formatted genotypes, to perform integrated copy number filtering, and to use a statistical test inherently robust for use in platforms of varying genotyping density and noise characteristics. Simulations demonstrated superior accuracy compared with previously developed approaches. We implemented the method on 1057 trios from the Deciphering Developmental Disorders project, a trio-based rare disease study, and detected six validated events, a significant enrichment compared with the population prevalence of UPD (1 in 3500), suggesting that most of these events are pathogenic. One of these events represents a known imprinting disorder, and exome analyses have identified rare homozygous candidate variants, mainly in the isodisomic regions of UPD chromosomes, which, among other variants, provide targets for further genetic and functional evaluation. © 2014 Moran et al.

Javed S.,University of Manchester | Petropoulos I.N.,Institute of Human Development | Alam U.,Foundation Medicine | Malik R.A.,Foundation Medicine | Malik R.A.,Cornell College
Therapeutic Advances in Chronic Disease | Year: 2015

Painful diabetic neuropathy (PDN) is a debilitating consequence of diabetes that may be present in as many as one in five patients with diabetes. The objective assessment of PDN is difficult, making it challenging to diagnose and assess in both clinical practice and clinical trials. No single treatment exists to prevent or reverse neuropathic changes or to provide total pain relief. Treatment of PDN is based on three major approaches: intensive glycaemic control and risk factor management, treatments based on pathogenetic mechanisms, and symptomatic pain management. Clinical guidelines recommend pain relief in PDN through the use of antidepressants such as amitriptyline and duloxetine, the γ-aminobutyric acid analogues gabapentin and pregabalin, opioids and topical agents such as capsaicin. Of these medications, duloxetine and pregabalin were approved by the US Food and Drug Administration (FDA) in 2004 and tapentadol extended release was approved in 2012 for the treatment of PDN. Proposed pathogenetic treatments include α-lipoic acid (stems reactive oxygen species formation), benfotiamine (prevents vascular damage in diabetes) and aldose-reductase inhibitors (reduces flux through the polyol pathway). There is a growing need for studies to evaluate the most potent drugs or combinations for the management of PDN to maximize pain relief and improve quality of life. A number of agents are potential candidates for future use in PDN therapy, including Nav 1.7 antagonists, N-type calcium channel blockers, NGF antibodies and angiotensin II type 2 receptor antagonists. © The Author(s), 2014.

Fresquet M.,University of Manchester | Jowitt T.A.,University of Manchester | Gummadova J.,University of Manchester | Collins R.,University of Manchester | And 5 more authors.
Journal of the American Society of Nephrology | Year: 2015

Phospholipase A2 receptor 1 (PLA2R) is a target autoantigen in 70% of patients with idiopathic membranous nephropathy. We describe the location of a major epitope in the N-terminal cysteine-rich ricin domain of PLA2R that is recognized by 90% of human anti-PLA2R autoantibodies. The epitope was sensitive to reduction and SDS denaturation in the isolated ricin domain and the larger fragment containing the ricin, fibronectin type II, first and second C-type lectin domains (CTLD). However, in nondenaturing conditions the epitope was protected against reduction in larger fragments, including the full-length extracellular region of PLA2R. To determine the composition of the epitope, we isolated immunoreactive tryptic fragments by Western blotting and analyzed them by mass spectrometry. The identified peptides were tested as inhibitors of autoantibody binding to PLA2R by surface plasmon resonance. Two peptides fromthe ricin domain showed strong inhibition, with a longer sequence covering both peptides (31-mer) producing 85% inhibition of autoantibody binding to PLA2R. Anti-PLA2R antibody directly bound this 31-mer peptide under nondenaturing conditions and binding was sensitive to reduction. Analysis of PLA2R and the PLA2R-anti-PLA2R complex using electron microscopy and homology-based representations allowed us to generate a structural model of thismajor epitope and its antibody binding site, which is independent of pH-induced conformational change in PLA2R. Identification of this major PLA2R epitope will enable further therapeutic advances for patients with idiopathic membranous nephropathy, including antibody inhibition therapy and immunoadsorption of circulating autoantibodies. Copyright © 2015 by the American Society of Nephrology.

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