Publications by authors named "Paul Potter"

89 Publications

Modification of an aggressive model of Alport Syndrome reveals early differences in disease pathogenesis due to genetic background.

Sci Rep 2019 12 31;9(1):20398. Epub 2019 Dec 31.

Renal and Vascular Inflammation Section, Department of Medicine, Imperial College, London, W12 0N, UK.

The link between mutations in collagen genes and the development of Alport Syndrome has been clearly established and a number of animal models, including knock-out mouse lines, have been developed that mirror disease observed in patients. However, it is clear from both patients and animal models that the progression of disease can vary greatly and can be modified genetically. We have identified a point mutation in Col4a4 in mice where disease is modified by strain background, providing further evidence of the genetic modification of disease symptoms. Our results indicate that C57BL/6J is a protective background and postpones end stage renal failure from 7 weeks, as seen on a C3H background, to several months. We have identified early differences in disease progression, including expression of podocyte-specific genes and podocyte morphology. In C57BL/6J mice podocyte effacement is delayed, prolonging normal renal function. The slower disease progression has allowed us to begin dissecting the pathogenesis of murine Alport Syndrome in detail. We find that there is evidence of differential gene expression during disease on the two genetic backgrounds, and that disease diverges by 4 weeks of age. We also show that an inflammatory response with increasing MCP-1 and KIM-1 levels precedes loss of renal function.
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http://dx.doi.org/10.1038/s41598-019-56837-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938516PMC
December 2019

Fresh frozen plasma for on-demand hereditary angioedema treatment in South Africa and Iran.

World Allergy Organ J 2019 Sep 12;12(9):100049. Epub 2019 Oct 12.

Allergy and Clinical Immunology, Department of Medicine, University of Cape Town, South Africa & Allergy and Immunology Unit, University of Cape Town Lung Institute, Cape Town, South Africa.

Background: International guideline-recommended on-demand treatments for hereditary angioedema (HAE) include: C1-esterase inhibitor (plasma-derived or recombinant), or bradykinin-receptor antagonists. In most low- and middle-income countries (LMIC) these products are not registered or are unaffordable. Solvent-detergent, fresh or freeze-dried plasma therapy is thus the only available on-demand treatment in these settings; but published data on efficacy and safety are limited. This study evaluated the efficacy and safety of on-demand plasma treatment of acute HAE in two LMICs.

Methods: A retrospective folder or patient registry review of acute swelling episodes necessitating emergency room attendance amongst known HAE patients was conducted at treatment centers in South Africa and Iran. Data collected included the site of angioedema, timing and amount of fresh frozen plasma (FFP) administered, time-to-resolution, hospital length of stay and adverse events.

Results: There were 176 acute swelling episodes amongst 43 HAE patients; 98 were treated with FFP. The face, upper airway, and abdomen were involved in 15.3% (15/98), 53.1% (52/98) and 29.6% (29/98) of episodes treated with FFP respectively. Median (interquartile range ([IQR]) of FFP administered was 400 (280-560) mLs. In all episodes except two, FFP led to resolution, with median (IQR) hours to resolution 4 (2-12). Five transfusion reactions occurred, with one case of anaphylaxis and no deaths; giving an adverse reaction rate of 5%. Differences between South Africa and Iran included: (1) proportion of HAE type II(2) median (IQR) hours to FFP administration and hospitalization, (3) number of intubations after FFP infusion. Healthcare cost for FFP treatment was USD369- 791 in South Africa and USD275-550 in Iran, largely influenced by hospital length of stay.

Conclusions: Plasma (fresh-frozen) remains the only available effective on-demand treatment for acute HAE in many countries. FFP is effective and safe, but time-to-resolution is slower and adverse events are more frequent than published data on targeted therapies. Overall healthcare cost of FFP approaches that of targeted therapies - now available through global access programs - when hospitalization is prolonged.
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http://dx.doi.org/10.1016/j.waojou.2019.100049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796769PMC
September 2019

Quantifying Microsatellite Mutation Rates from Intestinal Stem Cell Dynamics in Msh2-Deficient Murine Epithelium.

Genetics 2019 07 24;212(3):655-665. Epub 2019 May 24.

Li Ka Shing Centre, Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE, United Kingdom

Microsatellite sequences have an enhanced susceptibility to mutation, and can act as sentinels indicating elevated mutation rates and increased risk of cancer. The probability of mutant fixation within the intestinal epithelium is dictated by a combination of stem cell dynamics and mutation rate. Here, we exploit this relationship to infer microsatellite mutation rates. First a sensitive, multiplexed, and quantitative method for detecting somatic changes in microsatellite length was developed that allowed the parallel detection of mutant [CA] sequences from hundreds of low-input tissue samples at up to 14 loci. The method was applied to colonic crypts in , and enabled detection of mutant subclones down to 20% of the cellularity of the crypt (∼50 of 250 cells). By quantifying age-related increases in clone frequencies for multiple loci, microsatellite mutation rates in wild-type and Msh2-deficient epithelium were established. An average 388-fold increase in mutation per mitosis rate was observed in Msh2-deficient epithelium (2.4 × 10) compared to wild-type epithelium (6.2 × 10).
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http://dx.doi.org/10.1534/genetics.119.302268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614890PMC
July 2019

ARIA pharmacy 2018 "Allergic rhinitis care pathways for community pharmacy": AIRWAYS ICPs initiative (European Innovation Partnership on Active and Healthy Ageing, DG CONNECT and DG Santé) POLLAR (Impact of Air POLLution on Asthma and Rhinitis) GARD Demonstration project.

Authors:
Sinthia Bosnic-Anticevich Elisio Costa Enrica Menditto Olga Lourenço Ettore Novellino Slawomir Bialek Vitalis Briedis Roland Buonaiuto Henry Chrystyn Biljana Cvetkovski Stefania Di Capua Vicky Kritikos Alpana Mair Valentina Orlando Ema Paulino Johanna Salimäki Rojin Söderlund Rachel Tan Dennis M Williams Piotr Wroczynski Ioana Agache Ignacio J Ansotegui Josep M Anto Anna Bedbrook Claus Bachert Mike Bewick Carsten Bindslev-Jensen Jan L Brozek Giorgio Walter Canonica Victoria Cardona Warner Carr Thomas B Casale Niels H Chavannes Jaime Correia de Sousa Alvaro A Cruz Wienczyslawa Czarlewski Giuseppe De Carlo Pascal Demoly Philippe Devillier Mark S Dykewicz Mina Gaga Yehia El-Gamal João Fonseca Wytske J Fokkens Maria Antonieta Guzmán Tari Haahtela Peter W Hellings Maddalena Illario Juan Carlos Ivancevich Jocelyne Just Igor Kaidashev Musa Khaitov Nikolai Khaltaev Thomas Keil Ludger Klimek Marek L Kowalski Piotr Kuna Violeta Kvedariene Désirée E Larenas-Linnemann Daniel Laune Lan T T Le Karin C Lodrup Carlsen Bassam Mahboub Dieter Maier Joao Malva Patrick J Manning Mário Morais-Almeida Ralph Mösges Joaquim Mullol Lars Münter Ruth Murray Robert Naclerio Leyla Namazova-Baranova Kristof Nekam Tshipukane Dieudonné Nyembue Kimi Okubo Robyn E O'Hehir Ken Ohta Yoshitaka Okamoto Gabrielle L Onorato Susanna Palkonen Petr Panzner Nikolaos G Papadopoulos Hae-Sim Park Ruby Pawankar Oliver Pfaar Jim Phillips Davor Plavec Todor A Popov Paul C Potter Emmanuel P Prokopakis Regina E Roller-Wirnsberger Menachem Rottem Dermot Ryan Bolesław Samolinski Mario Sanchez-Borges Holger J Schunemann Aziz Sheikh Juan Carlos Sisul David Somekh Cristiana Stellato Teresa To Ana Maria Todo-Bom Peter Valentin Tomazic Sanna Toppila-Salmi Antonio Valero Arunas Valiulis Errka Valovirta Maria Teresa Ventura Martin Wagenmann Dana Wallace Susan Waserman Magnus Wickman Panayiotis K Yiallouros Arzu Yorgancioglu Osman M Yusuf Heather J Zar Mario E Zernotti Luo Zhang Mihaela Zidarn Torsten Zuberbier Jean Bousquet

Allergy 2019 07 30;74(7):1219-1236. Epub 2019 Apr 30.

MACVIA-France, Fondation Partenariale FMC VIA-LR, Montpellier, France.

Pharmacists are trusted health care professionals. Many patients use over-the-counter (OTC) medications and are seen by pharmacists who are the initial point of contact for allergic rhinitis management in most countries. The role of pharmacists in integrated care pathways (ICPs) for allergic diseases is important. This paper builds on existing studies and provides tools intended to help pharmacists provide optimal advice/interventions/strategies to patients with rhinitis. The Allergic Rhinitis and its Impact on Asthma (ARIA)-pharmacy ICP includes a diagnostic questionnaire specifically focusing attention on key symptoms and markers of the disease, a systematic Diagnosis Guide (including differential diagnoses), and a simple flowchart with proposed treatment for rhinitis and asthma multimorbidity. Key prompts for referral within the ICP are included. The use of technology is critical to enhance the management of allergic rhinitis. However, the ARIA-pharmacy ICP should be adapted to local healthcare environments/situations as regional (national) differences exist in pharmacy care.
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http://dx.doi.org/10.1111/all.13701DOI Listing
July 2019

Mouse mutations cause retinal degeneration and reduced mitochondrial function.

Dis Model Mech 2018 12 18;11(12). Epub 2018 Dec 18.

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK

Isocitrate dehydrogenase (IDH) is an enzyme required for the production of α-ketoglutarate from isocitrate. IDH3 generates the NADH used in the mitochondria for ATP production, and is a tetramer made up of two α, one β and one γ subunit. Loss-of-function and missense mutations in both and have previously been implicated in families exhibiting retinal degeneration. Using mouse models, we investigated the role of IDH3 in retinal disease and mitochondrial function. We identified mice with late-onset retinal degeneration in a screen of ageing mice carrying an ENU-induced mutation, E229K, in Mice homozygous for this mutation exhibit signs of retinal stress, indicated by GFAP staining, as early as 3 months, but no other tissues appear to be affected. We produced a knockout of and found that homozygous mice do not survive past early embryogenesis. compound heterozygous mutants exhibit a more severe retinal degeneration compared with homozygous mutants. Analysis of mitochondrial function in mutant cell lines highlighted a reduction in mitochondrial maximal respiration and reserve capacity levels in both and cells. Loss-of-function mutants do not exhibit the same retinal degeneration phenotype, with no signs of retinal stress or reduction in mitochondrial respiration. It has previously been reported that the retina operates with a limited mitochondrial reserve capacity and we suggest that this, in combination with the reduced reserve capacity in mutants, explains the degenerative phenotype observed in mutant mice.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/dmm.036426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307916PMC
December 2018

Modelling physical resilience in ageing mice.

Mech Ageing Dev 2019 01 2;177:91-102. Epub 2018 Oct 2.

MRC/Arthritis Research-UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Department of Oncology and Metabolism, The Medical School, Beech Hill Road, Sheffield, S10 2RX, United Kingdom. Electronic address:

Geroprotectors, a class of drugs targeting multiple deficits occurring with age, necessitate the development of new animal models to test their efficacy. The COST Action MouseAGE is a European network whose aim is to reach consensus on the translational path required for geroprotectors, interventions targeting the biology of ageing. In our previous work we identified frailty and loss of resilience as a potential target for geroprotectors. Frailty is the result of an accumulation of deficits, which occurs with age and reduces the ability to respond to adverse events (physical resilience). Modelling frailty and physical resilience in mice is challenging for many reasons. There is no consensus on the precise definition of frailty and resilience in patients or on how best to measure it. This makes it difficult to evaluate available mouse models. In addition, the characterization of those models is poor. Here we review potential models of physical resilience, focusing on those where there is some evidence that the administration of acute stressors requires integrative responses involving multiple tissues and where aged mice showed a delayed recovery or a worse outcome then young mice in response to the stressor. These models include sepsis, trauma, drug- and radiation exposure, kidney and brain ischemia, exposure to noise, heat and cold shock.
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http://dx.doi.org/10.1016/j.mad.2018.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445352PMC
January 2019

An -Ethyl--Nitrosourea (ENU) Mutagenized Mouse Model for Autosomal Dominant Nonsyndromic Kyphoscoliosis Due to Vertebral Fusion.

JBMR Plus 2018 May 8;2(3):154-163. Epub 2018 Mar 8.

Academic Endocrine Unit Radcliffe Department of Medicine University of Oxford Oxford Centre for Diabetes, Endocrinology and Metabolism Churchill Hospital Headington UK.

Kyphosis and scoliosis are common spinal disorders that occur as part of complex syndromes or as nonsyndromic, idiopathic diseases. Familial and twin studies implicate genetic involvement, although the causative genes for idiopathic kyphoscoliosis remain to be identified. To facilitate these studies, we investigated progeny of mice treated with the chemical mutagen -ethyl--nitrosourea (ENU) and assessed them for morphological and radiographic abnormalities. This identified a mouse with kyphoscoliosis due to fused lumbar vertebrae, which was inherited as an autosomal dominant trait; the phenotype was designated as hereditary vertebral fusion (HVF) and the locus as . Micro-computed tomography (μCT) analysis confirmed the occurrence of nonsyndromic kyphoscoliosis due to fusion of lumbar vertebrae in HVF mice, consistent with a pattern of blocked vertebrae due to failure of segmentation. μCT scans also showed the lumbar vertebral column of HVF mice to have generalized disc narrowing, displacement with compression of the neural spine, and distorted transverse processes. Histology of lumbar vertebrae revealed HVF mice to have irregularly shaped vertebral bodies and displacement of intervertebral discs and ossification centers. Genetic mapping using a panel of single nucleotide polymorphic (SNP) loci arranged in chromosome sets and DNA samples from 23 HVF (eight males and 15 females) mice, localized to chromosome 4A3 and within a 5-megabase (Mb) region containing nine protein coding genes, two processed transcripts, three microRNAs, five small nuclear RNAs, three large intergenic noncoding RNAs, and 24 pseudogenes. However, genome sequence analysis in this interval did not identify any abnormalities in the coding exons, or exon-intron boundaries of any of these genes. Thus, our studies have established a mouse model for a monogenic form of nonsyndromic kyphoscoliosis due to fusion of lumbar vertebrae, and further identification of the underlying genetic defect will help elucidate the molecular mechanisms involved in kyphoscoliosis. © 2018 The Authors. is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124210PMC
May 2018

Allergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018): Change management in allergic rhinitis and asthma multimorbidity using mobile technology.

Authors:
Jean Bousquet Peter W Hellings Ioana Agache Flore Amat Isabella Annesi-Maesano Ignacio J Ansotegui Josep M Anto Claus Bachert Eric D Bateman Anna Bedbrook Kazi Bennoor Mickael Bewick Carsten Bindslev-Jensen Sinthia Bosnic-Anticevich Isabelle Bosse Jan Brozek Luisa Brussino Giorgio W Canonica Victoria Cardona Thomas Casale Alfonso M Cepeda Sarabia Niels H Chavannes Lorenzo Cecchi Jaime Correia de Sousa Elisio Costa Alvaro A Cruz Wienczyslawa Czarlewski Giuseppe De Carlo Giulia De Feo Pascal Demoly Philippe Devillier Mark S Dykewicz Yehia El-Gamal Esben E Eller Joao A Fonseca Jean-François Fontaine Wytske J Fokkens Maria-Antonieta Guzmán Tari Haahtela Maddalena Illario Juan-Carlos Ivancevich Jocelyne Just Igor Kaidashev Musa Khaitov Omer Kalayci Thomas Keil Ludger Klimek Marek L Kowalski Piotr Kuna Violeta Kvedariene Desiree Larenas-Linnemann Daniel Laune Lan T T Le Karin Lodrup Carlsen Olga Lourenço Bassam Mahboub Alpana Mair Enrica Menditto Branislava Milenkovic Mario Morais-Almeida Ralph Mösges Joaquim Mullol Ruth Murray Robert Naclerio Leyla Namazova-Baranova Ettore Novellino Robyn E O'Hehir Ken Ohta Yoshitaka Okamoto Kimi Okubo Gabrielle L Onorato Susanna Palkonen Petr Panzner Nikos G Papadopoulos Hae-Sim Park Ema Paulino Ruby Pawankar Oliver Pfaar Davor Plavec Ted A Popov Paul Potter Emmanuel P Prokopakis Menachem Rottem Dermot Ryan Johanna Salimäki Boleslaw Samolinski Mario Sanchez-Borges Holger J Schunemann Aziz Sheikh Juan-Carlos Sisul Rojin Rajabian-Söderlund Talant Sooronbaev Cristiana Stellato Teresa To Ana-Maria Todo-Bom Peter-Valentin Tomazic Sanna Toppila-Salmi Antonio Valero Arunas Valiulis Erkka Valovirta Maria-Teresa Ventura Martin Wagenmann De Yun Wang Dana Wallace Susan Waserman Magnus Wickman Arzu Yorgancioglu Luo Zhang Nanshan Zhong Mihaela Zidarn Torsten Zuberbier

J Allergy Clin Immunol 2019 03 29;143(3):864-879. Epub 2018 Sep 29.

Comprehensive Allergy Center Charité, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, and Global Allergy and Asthma European Network (GA2LEN), Berlin, Germany.

Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional.
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http://dx.doi.org/10.1016/j.jaci.2018.08.049DOI Listing
March 2019

Studying Osteoarthritis Pathogenesis in Mice.

Curr Protoc Mouse Biol 2018 Dec 21;8(4):e50. Epub 2018 Sep 21.

Disease Model Discovery, Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire, United Kingdom.

With the increasing availability and complexity of mouse models of disease, either spontaneous or induced, there is a concomitant increase in their use in the analysis of pathogenesis. Among such diseases is osteoarthritis, a debilitating disease with few treatment options. While advances in our understanding of the pathogenesis of osteoarthritis has advanced through clinical investigations and genome-wide association studies, there is still a large gap in our knowledge, hindering advances in therapy. Patient samples are available ex vivo, but these are generally in the very late stages of disease. However, with mice, we are able to induce disease at a defined time and track the progression in vivo and ex vivo, from inception to end stage, to delineate the processes involved in disease development. © 2018 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpmo.50DOI Listing
December 2018

Rupatadine oral solution for 2-5-year-old children with allergic rhinitis: a safety, open-label, prospective study.

J Asthma Allergy 2018 4;11:225-231. Epub 2018 Sep 4.

Allergy Diagnostic and Clinical Research Unit, Department of Medicine, University of Cape Town Lung Institute, Cape Town, South Africa.

Background: There are few clinical trials that assess the efficacy of antihistamines in very young children. Rupatadine is a second-generation antihistamine indicated for the treatment of allergic rhinitis (AR) and urticaria. In this study, AR symptoms were evaluated before and after daily 1 mg/mL rupatadine oral solution administration in 2-5-year-old children.

Methods: A multicenter open-label study was carried out in 2-5-year-old children with AR. Safety assessments were collected during the study including spontaneous adverse events, vital signs, and electrocardiogram (QTc interval). Additionally, evaluations of Total Five Symptoms Score (T5SS, including: nasal congestion; sneezing; rhinorrhoea; itchy nose, mouth, throat, and/or ears; and itchy, watery, and red eyes) were analyzed. Symptoms were evaluated by parents/legal guardian before and after 4 weeks of rupatadine administration, dosed according to body weight.

Results: A total of 44 children received the study treatment. Only 15 adverse events were reported. All of them were of mild intensity and considered not related to the study treatment. No patient exceeded the standard parameter of >450 ms in the last visit, for the QTc interval on their electrocardiograms. From a maximum score value of 15, T5SS values at Day 14 (6.35) and Day 28 (5.42) were both statistically significant different (<0.001) from the baseline T5SS value (mean 8.65), with a reduction of 26.6% and 37.4%, respectively. All individual symptoms, including nasal congestion, showed also a decrease from baseline at both 14 and 28 days.

Conclusion: Rupatadine 1 mg/mL oral solution was found to be safe in 2-5-year-old children, correlating with an improvement of AR symptoms, overall and each individually, after a daily dose administration. With this study, we enlarge the available information in this very young pediatric patients' group, in which there is a general lack of clinical evidence.
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http://dx.doi.org/10.2147/JAA.S164632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128281PMC
September 2018

A young testicular microenvironment protects Leydig cells against age-related dysfunction in a mouse model of premature aging.

FASEB J 2019 01 6;33(1):978-995. Epub 2018 Aug 6.

Medical Research Council (MRC) Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom.

Testicular Leydig cells (LCs) are the primary source of circulating androgen in men. As men age, circulating androgen levels decline. However, whether reduced LC steroidogenesis results from specific effects of aging within LCs or reflects degenerative alterations to the wider supporting microenvironment is unclear; inability to separate intrinsic LC aging from that of the testicular microenvironment in vivo has made this question difficult to address. To resolve this, we generated novel mouse models of premature aging, driven by CDGSH iron sulfur domain 2 ( Cisd2) deletion, to separate the effects of cell intrinsic aging from extrinsic effects of aging on LC function. At 6 mo of age, constitutive Cisd2-deficient mice display signs of premature aging, including testicular atrophy, reduced LC and Sertoli cell (SC) number, decreased circulating testosterone, increased luteinizing hormone/testosterone ratio, and decreased expression of steroidogenic mRNAs, appropriately modeling primary testicular dysfunction observed in aging men. However, mice with Cisd2 deletion (and thus premature aging) restricted to either LCs or SCs were protected against testicular degeneration, demonstrating that age-related LCs dysfunction cannot be explained by intrinsic aging within either the LC or SC lineages alone. We conclude that age-related LC dysfunction is largely driven by aging of the supporting testicular microenvironment.-Curley, M., Milne, L., Smith, S., Jørgensen, A., Frederiksen, H., Hadoke, P., Potter, P., Smith, L. B. A Young testicular microenvironment protects Leydig cells against age-related dysfunction in a mouse model of premature aging.
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http://dx.doi.org/10.1096/fj.201800612RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355079PMC
January 2019

Generation and Identification of Mutations Resulting in Chronic and Age-Related Phenotypes in Mice.

Curr Protoc Mouse Biol 2018 Jun 21;8(2):e42. Epub 2018 May 21.

Mammalian Genetics Unit, Medical Research Council, Harwell Science and Innovation Campus, Oxford, United Kingdom.

Aging is inevitable, and our society must deal with the consequences: namely, an increased incidence of disease and ill health. Many mouse models of disease are acute or early onset or are induced in young mice, despite the fact that aging is a significant risk factor for a range of significant diseases. To improve modeling of such diseases, we should incorporate aging into our models. Many systems are affected by aging, with a decline in mitochondrial function, an increase in senescence, a loss of resilience, telomere shortening, and a decline in immune function being key factors in the increased susceptibility to disease that is associated with aging. To develop novel models of age-related disease, we undertook a phenotype-driven screen of a pipeline of mutagenized mice. Here, we describe some of the underlying protocols and outline important aspects to consider when studying aged mice. © 2018 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpmo.42DOI Listing
June 2018

Mouse models of ageing and their relevance to disease.

Mech Ageing Dev 2016 12 4;160:41-53. Epub 2016 Oct 4.

Inflammation Research Center, VIB, Ghent, Belgium, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address:

Ageing is a process that gradually increases the organism's vulnerability to death. It affects different biological pathways, and the underlying cellular mechanisms are complex. In view of the growing disease burden of ageing populations, increasing efforts are being invested in understanding the pathways and mechanisms of ageing. We review some mouse models commonly used in studies on ageing, highlight the advantages and disadvantages of the different strategies, and discuss their relevance to disease susceptibility. In addition to addressing the genetics and phenotypic analysis of mice, we discuss examples of models of delayed or accelerated ageing and their modulation by caloric restriction.
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http://dx.doi.org/10.1016/j.mad.2016.10.001DOI Listing
December 2016

Novel gene function revealed by mouse mutagenesis screens for models of age-related disease.

Nat Commun 2016 08 18;7:12444. Epub 2016 Aug 18.

MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss.
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http://dx.doi.org/10.1038/ncomms12444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992138PMC
August 2016

With mouse age comes wisdom: A review and suggestions of relevant mouse models for age-related conditions.

Mech Ageing Dev 2016 12 21;160:54-68. Epub 2016 Jul 21.

Mammalian Genetics Unit, MRC Harwell, Oxfordshire, UK. Electronic address:

Ageing is a complex multifactorial process that results in many changes in physiological changes processes that ultimately increase susceptibility to a wide range of diseases. As such an ageing population is resulting in a pressing need for more and improved treatments across an assortment of diseases. Such treatments can come from a better understanding of the pathogenic pathways which, in turn, can be derived from models of disease. Therefore the more closely the model resembles the disease situation the more likely relevant the data will be that is generated from them. Here we review the state of knowledge of mouse models of a range of diseases and aspects of an ageing physiology that are all germane to ageing. We also give recommendations on the most common mouse models on their relevance to the clinical situations occurring in aged patients and look forward as to how research in ageing models can be carried out. As we continue to elucidate the pathophysiology of disease, often through mouse models, we also learn what is needed to refine these models. Such factors can include better models, reflecting the ageing patient population, or a better phenotypic understanding of existing models.
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http://dx.doi.org/10.1016/j.mad.2016.07.005DOI Listing
December 2016

Genome-wide association of multiple complex traits in outbred mice by ultra-low-coverage sequencing.

Nat Genet 2016 08 4;48(8):912-8. Epub 2016 Jul 4.

Wellcome Trust Centre for Human Genetics, Oxford, UK.

Two bottlenecks impeding the genetic analysis of complex traits in rodents are access to mapping populations able to deliver gene-level mapping resolution and the need for population-specific genotyping arrays and haplotype reference panels. Here we combine low-coverage (0.15×) sequencing with a new method to impute the ancestral haplotype space in 1,887 commercially available outbred mice. We mapped 156 unique quantitative trait loci for 92 phenotypes at a 5% false discovery rate. Gene-level mapping resolution was achieved at about one-fifth of the loci, implicating Unc13c and Pgc1a at loci for the quality of sleep, Adarb2 for home cage activity, Rtkn2 for intensity of reaction to startle, Bmp2 for wound healing, Il15 and Id2 for several T cell measures and Prkca for bone mineral content. These findings have implications for diverse areas of mammalian biology and demonstrate how genome-wide association studies can be extended via low-coverage sequencing to species with highly recombinant outbred populations.
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http://dx.doi.org/10.1038/ng.3595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966644PMC
August 2016

Does age matter? The impact of rodent age on study outcomes.

Lab Anim 2017 Apr 10;51(2):160-169. Epub 2016 Jul 10.

1 National Centre for the Replacement, Refinement and Reduction of Animals in Research, London, UK.

Rodent models produce data which underpin biomedical research and non-clinical drug trials, but translation from rodents into successful clinical outcomes is often lacking. There is a growing body of evidence showing that improving experimental design is key to improving the predictive nature of rodent studies and reducing the number of animals used in research. Age, one important factor in experimental design, is often poorly reported and can be overlooked. The authors conducted a survey to assess the age used for a range of models, and the reasoning for age choice. From 297 respondents providing 611 responses, researchers reported using rodents most often in the 6-20 week age range regardless of the biology being studied. The age referred to as 'adult' by respondents varied between six and 20 weeks. Practical reasons for the choice of rodent age were frequently given, with increased cost associated with using older animals and maintenance of historical data comparability being two important limiting factors. These results highlight that choice of age is inconsistent across the research community and often not based on the development or cellular ageing of the system being studied. This could potentially result in decreased scientific validity and increased experimental variability. In some cases the use of older animals may be beneficial. Increased scientific rigour in the choice of the age of rodent may increase the translation of rodent models to humans.
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http://dx.doi.org/10.1177/0023677216653984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367550PMC
April 2017

The Mammalian Genome special issue on ageing.

Authors:
Paul K Potter

Mamm Genome 2016 08;27(7-8):257-8

The MRC Harwell Institute, Harwell Science and Innovation Campus, Harwell, OX11 0RD, UK.

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http://dx.doi.org/10.1007/s00335-016-9652-9DOI Listing
August 2016

Investigating mechanisms underpinning the detrimental impact of a high-fat diet in the developing and adult hypermuscular myostatin null mouse.

Skelet Muscle 2015 7;5:38. Epub 2015 Dec 7.

School of Biological Sciences, University of Reading, Reading, RG6 6UB UK.

Background: Obese adults are prone to develop metabolic and cardiovascular diseases. Furthermore, over-weight expectant mothers give birth to large babies who also have increased likelihood of developing metabolic and cardiovascular diseases. Fundamental advancements to better understand the pathophysiology of obesity are critical in the development of anti-obesity therapies not only for this but also future generations. Skeletal muscle plays a major role in fat metabolism and much work has focused in promoting this activity in order to control the development of obesity. Research has evaluated myostatin inhibition as a strategy to prevent the development of obesity and concluded in some cases that it offers a protective mechanism against a high-fat diet.

Methods: Pregnant as well as virgin myostatin null mice and age matched wild type animals were raised on a high fat diet for up to 10 weeks. The effect of the diet was tested on skeletal muscle, liver and fat. Quantitate PCR, Western blotting, immunohistochemistry, in-vivo and ex-vivo muscle characterisation, metabonomic and lipidomic measurements were from the four major cohorts.

Results: We hypothesised that myostatin inhibition should protect not only the mother but also its developing foetus from the detrimental effects of a high-fat diet. Unexpectedly, we found muscle development was attenuated in the foetus of myostatin null mice raised on a high-fat diet. We therefore re-examined the effect of the high-fat diet on adults and found myostatin null mice were more susceptible to diet-induced obesity through a mechanism involving impairment of inter-organ fat utilization.

Conclusions: Loss of myostatin alters fatty acid uptake and oxidation in skeletal muscle and liver. We show that abnormally high metabolic activity of fat in myostatin null mice is decreased by a high-fat diet resulting in excessive adipose deposition and lipotoxicity. Collectively, our genetic loss-of-function studies offer an explanation of the lean phenotype displayed by a host of animals lacking myostatin signalling.
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http://dx.doi.org/10.1186/s13395-015-0063-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671215PMC
December 2015

Current strategies for mutation detection in phenotype-driven screens utilising next generation sequencing.

Mamm Genome 2015 Oct 8;26(9-10):486-500. Epub 2015 Oct 8.

Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell Campus, Oxfordshire, OX11 0RD, UK.

Mutagenesis-based screens in mice are a powerful discovery platform to identify novel genes or gene functions associated with disease phenotypes. An N-ethyl-N-nitrosourea (ENU) mutagenesis screen induces single nucleotide variants randomly in the mouse genome. Subsequent phenotyping of mutant and wildtype mice enables the identification of mutated pathways resulting in phenotypes associated with a particular ENU lesion. This unbiased approach to gene discovery conducts the phenotyping with no prior knowledge of the functional mutations. Before the advent of affordable next generation sequencing (NGS), ENU variant identification was a limiting step in gene characterization, akin to 'finding a needle in a haystack'. The emergence of a reliable reference genome alongside advances in NGS has propelled ENU mutation discovery from an arduous, time-consuming exercise to an effective and rapid form of mutation discovery. This has permitted large mouse facilities worldwide to use ENU for novel mutation discovery in a high-throughput manner, helping to accelerate basic science at the mechanistic level. Here, we describe three different strategies used to identify ENU variants from NGS data and some of the subsequent steps for mutation characterisation.
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http://dx.doi.org/10.1007/s00335-015-9603-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602060PMC
October 2015

Rupatadine is effective in the treatment of chronic spontaneous urticaria in children aged 2-11 years.

Pediatr Allergy Immunol 2016 Feb 12;27(1):55-61. Epub 2015 Nov 12.

Department of Dermatology and Allergy, Allergie-Centrum Charité/ECARF, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Background: Recommendations in current guidelines for the treatment of chronic spontaneous urticaria (CSU) in infants and children are mostly based on extrapolation of data obtained in adults. This study reports the efficacy and safety of rupatadine, a modern H1 and PAF antagonist recently authorized in Europe for children with allergic rhinitis and CSU.

Methods: A double-blind, randomized, parallel-group, multicentre, placebo-controlled compared study to desloratadine was carried out in children aged 2-11 years with CSU, with or without angio-oedema. Patients received either rupatadine (1 mg/ml), or desloratadine (0.5 mg/ml) or placebo once daily over 6 weeks. A modified 7-day cumulative Urticaria Activity Score (UAS7) was employed as the primary end-point.

Results: The absolute change of UAS7 at 42 days showed statistically significant differences between active treatments vs. placebo (-5.5 ± 7.5 placebo, -11.8 ± 8.7 rupatadine and -10.6 ± 9.6 desloratadine; p < 0.001) and without differences between antihistamines compounds. There was a 55.8% decrease for rupatadine followed by desloratadine (-48.4%) and placebo (-30.3%). Rupatadine but not desloratadine was statistically superior to placebo in reduction of pruritus (-57%). Active treatments also showed a statistically better improvement in children's quality of life compared to placebo. Adverse events were uncommon and non-serious in both active groups.

Conclusion: Rupatadine is effective and well tolerated in the relief of urticaria symptoms, improving quality of life over 6 weeks in children with CSU. This is the first study using a modified UAS to assess severity and efficacy outcome in CSU in children.
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http://dx.doi.org/10.1111/pai.12460DOI Listing
February 2016

Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics.

Authors:
Martin Hrabě de Angelis George Nicholson Mohammed Selloum Jacqui White Hugh Morgan Ramiro Ramirez-Solis Tania Sorg Sara Wells Helmut Fuchs Martin Fray David J Adams Niels C Adams Thure Adler Antonio Aguilar-Pimentel Dalila Ali-Hadji Gregory Amann Philippe André Sarah Atkins Aurelie Auburtin Abdel Ayadi Julien Becker Lore Becker Elodie Bedu Raffi Bekeredjian Marie-Christine Birling Andrew Blake Joanna Bottomley Mike Bowl Véronique Brault Dirk H Busch James N Bussell Julia Calzada-Wack Heather Cater Marie-France Champy Philippe Charles Claire Chevalier Francesco Chiani Gemma F Codner Roy Combe Roger Cox Emilie Dalloneau André Dierich Armida Di Fenza Brendan Doe Arnaud Duchon Oliver Eickelberg Chris T Esapa Lahcen El Fertak Tanja Feigel Irina Emelyanova Jeanne Estabel Jack Favor Ann Flenniken Alessia Gambadoro Lilian Garrett Hilary Gates Anna-Karin Gerdin George Gkoutos Simon Greenaway Lisa Glasl Patrice Goetz Isabelle Goncalves Da Cruz Alexander Götz Jochen Graw Alain Guimond Wolfgang Hans Geoff Hicks Sabine M Hölter Heinz Höfler John M Hancock Robert Hoehndorf Tertius Hough Richard Houghton Anja Hurt Boris Ivandic Hughes Jacobs Sylvie Jacquot Nora Jones Natasha A Karp Hugo A Katus Sharon Kitchen Tanja Klein-Rodewald Martin Klingenspor Thomas Klopstock Valerie Lalanne Sophie Leblanc Christoph Lengger Elise le Marchand Tonia Ludwig Aline Lux Colin McKerlie Holger Maier Jean-Louis Mandel Susan Marschall Manuel Mark David G Melvin Hamid Meziane Kateryna Micklich Christophe Mittelhauser Laurent Monassier David Moulaert Stéphanie Muller Beatrix Naton Frauke Neff Patrick M Nolan Lauryl Mj Nutter Markus Ollert Guillaume Pavlovic Natalia S Pellegata Emilie Peter Benoit Petit-Demoulière Amanda Pickard Christine Podrini Paul Potter Laurent Pouilly Oliver Puk David Richardson Stephane Rousseau Leticia Quintanilla-Fend Mohamed M Quwailid Ildiko Racz Birgit Rathkolb Fabrice Riet Janet Rossant Michel Roux Jan Rozman Ed Ryder Jennifer Salisbury Luis Santos Karl-Heinz Schäble Evelyn Schiller Anja Schrewe Holger Schulz Ralf Steinkamp Michelle Simon Michelle Stewart Claudia Stöger Tobias Stöger Minxuan Sun David Sunter Lydia Teboul Isabelle Tilly Glauco P Tocchini-Valentini Monica Tost Irina Treise Laurent Vasseur Emilie Velot Daniela Vogt-Weisenhorn Christelle Wagner Alison Walling Bruno Weber Olivia Wendling Henrik Westerberg Monja Willershäuser Eckhard Wolf Anne Wolter Joe Wood Wolfgang Wurst Ali Önder Yildirim Ramona Zeh Andreas Zimmer Annemarie Zimprich Chris Holmes Karen P Steel Yann Herault Valérie Gailus-Durner Ann-Marie Mallon Steve Dm Brown

Nat Genet 2015 Sep 27;47(9):969-978. Epub 2015 Jul 27.

MRC Harwell, Medical Research Council, Harwell, UK.

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.
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http://dx.doi.org/10.1038/ng.3360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564951PMC
September 2015

The interrelationship between disease and ageing and the implications for longevity.

Authors:
Paul K Potter

Curr Aging Sci 2015 ;8(1):89-94

Programme Leader Disease Models and Translation, MRC Harwell, Mammalian Genetics Unit, Oxfordshire OX11 ORD, UK.

Ageing is generally viewed as a detrimental phenotype; with age comes increasing susceptibility to disease and frailty. Recent data also suggests that disease can result in an increase in ageing phenotypes suggesting a positive feedback loop. It is clear that lifespan can be modified genetically and by interventions in certain organisms but the mechanisms by which this is achieved have not yet been fully elucidated, as indeed is the case for the ageing process itself. Because of the intimate relationship between disease, ageing and ultimately lifespan it is difficult to dissect the effects of individual changes. As we learn more about individual pathways and allelic variants influencing ageing and disease we can begin to unravel the influence of natural selection on these processes.
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July 2016

The Interrelationship between Disease and Ageing and the Implications for Longevity.

Authors:
Paul K Potter

Curr Aging Sci 2015 Apr 22. Epub 2015 Apr 22.

Programme Leader Disease Models and Translation MRC Harwell, Mammalian Genetics Unit, Oxfordshire OX11 ORD, UK.

Ageing is generally viewed as a detrimental phenotype; with age comes increasing susceptibility to disease and frailty. Recent data also suggests that disease can result in an increase in ageing phenotypes suggesting a positive feedback loop. It is clear that lifespan can be modified genetically and by interventions in certain organisms but the mechanisms by which this is achieved have not yet been fully elucidated, as indeed is the case for the ageing process itself. Because of the intimate relationship between disease, ageing and ultimately lifespan it is difficult to dissect the effects of individual changes. As we learn more about individual pathways and allelic variants influencing ageing and disease we can begin to unravel the influence of natural selection on these processes.
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April 2015

N-ethyl-N-Nitrosourea (ENU) induced mutations within the klotho gene lead to ectopic calcification and reduced lifespan in mouse models.

PLoS One 2015 10;10(4):e0122650. Epub 2015 Apr 10.

Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, United Kingdom.

Ectopic calcification (EC), which is the pathological deposition of calcium and phosphate in extra-skeletal tissues, may be associated with hypercalcaemic and hyperphosphataemic disorders, or it may occur in the absence of metabolic abnormalities. In addition, EC may be inherited as part of several monogenic disorders and studies of these have provided valuable insights into the metabolic pathways regulating mineral metabolism. For example, studies of tumoural calcinosis, a disorder characterised by hyperphosphataemia and progressive EC, have revealed mutations of fibroblast growth factor 23 (FGF23), polypeptide N-acetyl galactosaminyltransferase 3 (GALNT3) and klotho (KL), which are all part of a phosphate-regulating pathway. However, such studies in humans are limited by the lack of available large families with EC, and to facilitate such studies we assessed the progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for EC. This identified two mutants with autosomal recessive forms of EC, and reduced lifespan, designated Ecalc1 and Ecalc2. Genetic mapping localized the Ecalc1 and Ecalc2 loci to a 11.0 Mb region on chromosome 5 that contained the klotho gene (Kl), and DNA sequence analysis identified nonsense (Gln203Stop) and missense (Ile604Asn) Kl mutations in Ecalc1 and Ecalc2 mice, respectively. The Gln203Stop mutation, located in KL1 domain, was severely hypomorphic and led to a 17-fold reduction of renal Kl expression. The Ile604Asn mutation, located in KL2 domain, was predicted to impair klotho protein stability and in vitro expression studies in COS-7 cells revealed endoplasmic reticulum retention of the Ile604Asn mutant. Further phenotype studies undertaken in Ecalc1 (kl203X/203X) mice demonstrated elevations in plasma concentrations of phosphate, FGF23 and 1,25-dihydroxyvitamin D. Thus, two allelic variants of Kl that develop EC and represent mouse models for tumoural calcinosis have been established.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122650PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393098PMC
March 2016

Clinical and cytokine responses to house dust mite sublingual immunotherapy.

Ann Allergy Asthma Immunol 2015 Apr 3;114(4):327-34. Epub 2015 Feb 3.

Division of Immunology, National Health Laboratory Service and Department of Clinical Laboratory Sciences, University of Cape Town, Cape Town, South Africa.

Background: Cytokine responses accompanying sublingual immunotherapy (SLIT) responder phenotypes have not previously been reported.

Objective: To investigate clinical and cytokine responses of house dust mite (HDM) sensitive patients with allergic rhinitis receiving HDM SLIT or placebo for 2 years.

Methods: Sixty adults were randomized to receive SLIT or placebo. Clinical symptoms were measured using the Total 5 Symptom Score (TSS5) and Juniper Rhinitis Quality of Life Questionnaire. HDM specific IgE, IgG, skin prick tests, and HDM-stimulated release of interleukin (IL) 5 and interferon γ (IFN-γ) in peripheral blood mononuclear cells was studied at 0, 6, 12, and 24 months and IL-13, IL-4, and IL-10 at 0 and 24 months.

Results: A total of 32 of 39 SLIT and 16 of 21 placebo patients completed the study. There was significant clinical improvement in both the SLIT and placebo groups. Median T5SS decreased from 14.75 to 5.25 in the SLIT group (P < .001) and 12.7 to 6.0 in the placebo group (P = .003). The median quality-of-life score also decreased in the SLIT group (P < .001) and the placebo group (P < .001). A subgroup analysis of patients found a 60% or greater improvement (on the T5SS and the Juniper Rhinitis Quality of Life Questionnaire) in the good responders group and a 30% to 59% improvement or no improvement in the intermediate responders group. This subgroup analysis also found more good responders in the SLIT group (47%) compared with the placebo group (25%; P = .07). Significant decreases in the IL-5/IFN-γ (P < .001), IL-13/IFN-γ (P < .001), and IL-4/IFN-γ (P = .03) ratios were found in the combined good clinical improvement group at 24 months.

Conclusion: A good clinical response (≥60% improvement in both TSS5 and quality of life) is associated with significant decreases in IL-5, IL-13, and IL-4 relative to IFN-γ during 2 years of SLIT therapy for HDMs.
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http://dx.doi.org/10.1016/j.anai.2014.12.015DOI Listing
April 2015

Occupational sensitization to African penguin serum and mucus proteins.

Ann Allergy Asthma Immunol 2015 Apr 31;114(4):345-7. Epub 2015 Jan 31.

Allergy Diagnostic and Clinical Research Unit, University of Cape Town Lung Institute, Department of Medicine, Groote Schuur Hospital, Observatory, Cape Town, South Africa.

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http://dx.doi.org/10.1016/j.anai.2014.12.023DOI Listing
April 2015

A complement C5 gene mutation, c.754G>A:p.A252T, is common in the Western Cape, South Africa and found to be homozygous in seven percent of Black African meningococcal disease cases.

Mol Immunol 2015 Mar 19;64(1):170-6. Epub 2014 Dec 19.

Department of Clinical Sciences, University of Cape Town, South Africa; Institute of Infection and Immunity, Cardiff University, Cardiff, UK; Allergy Diagnostic and Clinical Research Unit, Department of Medicine, Lung Institute, University of Cape Town, South Africa. Electronic address:

Patients with genetically determined deficiency of complement component 5 are usually diagnosed because of recurrent invasive Neisseria meningitidis infections. Approximately 40 individual cases have been diagnosed worldwide. Nevertheless, reports of the responsible genetic defects have been sporadic, and we know of no previous reports of C5 deficiency being associated with a number of independent meningococcal disease cases in particular communities. Here we describe C5 deficiency in seven unrelated Western Cape, South African families. Three different C5 mutations c.55C>T:p.Q19X, c.754G>A:p.A252T and c.4426C>T:p.R1476X were diagnosed in index cases from two families who had both presented with recurrent meningococcal disease. p.Q19X and p.R1476X have already been described in North American Black families and more recently p.Q19X in a Saudi family. However, p.A252T was only reported in SNP databases and was not associated with disease until the present study was undertaken in the Western Cape, South Africa. We tested for p.A252T in 140 patients presenting with meningococcal disease in the Cape Town area, and found seven individuals in five families who were homozygous for the mutation p.A252T. Very low serum C5 protein levels (0.1-4%) and correspondingly low in vitro functional activity were found in all homozygous individuals. Allele frequencies of p.A252T in the Black African and Cape Coloured communities were 3% and 0.66% and estimated homozygosities are 1/1100 and 1/22,500 respectively. In 2012 we reported association between p.A252T and meningococcal disease. Molecular modelling of p.A252T has indicated an area of molecular stress in the C5 molecule which may provide a mechanism for the very low level in the circulation. This report includes seven affected families indicating that C5D is not rare in South Africa.
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http://dx.doi.org/10.1016/j.molimm.2014.11.010DOI Listing
March 2015

Food allergy in South African children with atopic dermatitis.

Pediatr Allergy Immunol 2014 Oct;25(6):572-9

Division of Allergology, Red Cross War Memorial Children's Hospital, Cape Town, South Africa.

Background: The prevalence of food allergy in South Africa is unknown, but previously thought to be rare in black South Africans. This study aimed to determine the prevalence of, and risk factors for, IgE-mediated food allergy in South African children with atopic dermatitis (AD).

Methodology: This was a prospective, observational study in a paediatric university hospital in Cape Town. Children with AD, aged 6 months to 10 yrs, were randomly recruited from the dermatology clinic. They were assessed for sensitization and allergy by questionnaire, skin prick tests, Immuno Solid Phase Allergen Chip (ISAC) test and incremental food challenges.

Results: 100 participants (59 black Africans and 41 of mixed race) were enrolled, median age 42 months. There were high overall rates of food sensitization (66%) and food allergy (40%). Egg (25%) and peanut (24%) were the most common allergies. Black participants had comparable sensitization (69% vs. 61%) but lower allergy rates (34% vs. 46%) than mixed race participants. This was especially evident for peanut allergy (15% Blacks vs. 37% mixed race allergic to peanut, p = 0.01). Early-onset AD (<6 months), severe eczema, and young age <2 yrs were significant risk factors for food allergy.

Conclusion: The prevalence of food allergy is unexpectedly high in South African children with AD, and comparable with food allergy rates in patients with AD in developed countries. There are ethnic differences, with significantly lower peanut allergy rates in Blacks compared to mixed race patients. These results are not generalizable to an unselected South African population, which requires further study.
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http://dx.doi.org/10.1111/pai.12270DOI Listing
October 2014

Genetic background influences age-related decline in visual and nonvisual retinal responses, circadian rhythms, and sleep.

Neurobiol Aging 2015 Jan 2;36(1):380-93. Epub 2014 Aug 2.

MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, UK. Electronic address:

The circadian system is entrained to the environmental light/dark cycle via retinal photoreceptors and regulates numerous aspects of physiology and behavior, including sleep. These processes are all key factors in healthy aging showing a gradual decline with age. Despite their importance, the exact mechanisms underlying this decline are yet to be fully understood. One of the most effective tools we have to understand the genetic factors underlying these processes are genetically inbred mouse strains. The most commonly used reference mouse strain is C57BL/6J, but recently, resources such as the International Knockout Mouse Consortium have started producing large numbers of mouse mutant lines on a pure genetic background, C57BL/6N. Considering the substantial genetic diversity between mouse strains we expect there to be phenotypic differences, including differential effects of aging, in these and other strains. Such differences need to be characterized not only to establish how different mouse strains may model the aging process but also to understand how genetic background might modify age-related phenotypes. To ascertain the effects of aging on sleep/wake behavior, circadian rhythms, and light input and whether these effects are mouse strain-dependent, we have screened C57BL/6J, C57BL/6N, C3H-HeH, and C3H-Pde6b+ mouse strains at 5 ages throughout their life span. Our data show that sleep, circadian, and light input parameters are all disrupted by the aging process. Moreover, we have cataloged a number of strain-specific aging effects, including the rate of cataract development, decline in the pupillary light response, and changes in sleep fragmentation and the proportion of time spent asleep.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.07.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270439PMC
January 2015