6 research outputs found
The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface
No full textThis is a pre-copy-editing, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review. The definitive publisher-authenticated version Human Molecular Genetics 2006 15(23):3436-3445. is available online at: http://hmg.oxfordjournals.org/cgi/content/full/15/23/3436Autosomal dominant lateral temporal epilepsy (ADTLE) is a partial epilepsy caused by mutations in LGI1, a multidomain protein of unknown function. To begin to understand the biological function of LGI1, we have determined its pattern of glycosylation, subcellular expression and capacity for secretion. LGI1 is expressed as two different isoforms in the brain, and we show that the long isoform is a secreted protein, whereas the short isoform is retained in an intracellular pool. ADLTE-related mutants of the long form are defective for secretion and are retained in the endoplasmic reticulum and Golgi complex. Finally, we show that normal secreted LGI1 specifically binds to the cell surface of differentiated PC12 cells. We propose that LGI1 is a secreted factor important for neuronal development and that ADTLE is a disease that results from the loss of regulation in the protein available either extracellular or intracellularly.This work was supported by grants from the Ministerio de Educación y Ciencia (SAF2002-00060 and SAF2005-00136) to J.P.T. and from the Canadian Institute of Heath Research (PPP147918) to P.A.B. S.S.P. is funded by a fellowship of the Generalitat Valenciana (CTBPRB/2002/35), J.M.M.R. is funded by an FPU and a Bancaixa fellowship. Support from the Ministerio de Educación y Ciencia (BES-2003-0243, to A.A.I.) and from the Ministerio de Sanidad y Consumo (BF03/00182, to V.H.P.) is also acknowledged. K.F. is funded by a Canadian NSERC award.Peer reviewe
OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes
No full textThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License.-- et al.Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an autosomal-dominant trait (DOA). We here report on eight patients from six independent families showing that mutations in the OPA1 gene can also be responsible for a syndromic form of DOA associated with sensorineural deafness, ataxia, axonal sensory-motor polyneuropathy, chronic progressive external ophthalmoplegia and mitochondrial myopathy with cytochrome c oxidase negative and Ragged Red Fibres. Most remarkably, we demonstrate that these patients all harboured multiple deletions of mitochondrial DNA (mtDNA) in their skeletal muscle, thus revealing an unrecognized role of the OPA1 protein in mtDNA stability. The five OPA1 mutations associated with these DOA 'plus' phenotypes were all mis-sense point mutations affecting highly conserved amino acid positions and the nuclear genes previously known to induce mtDNA multiple deletions such as POLG1, PEO1 (Twinkle) and SLC25A4 (ANT1) were ruled out. Our results show that certain OPA1 mutations exert a dominant negative effect responsible for multi-systemic disease, closely related to classical mitochondrial cytopathies, by a mechanism involving mtDNA instability. © 2007 The Author(s).This study has been supported by Telethon-Italy (grant#GGP06233 to V.C.), fondazione Gino Galletti (grant to V.C.), and progetto di ricerca sanitaria finalizzata (grant to V.C. and M.R.). P.A.B., P.R., D.B., A.B. and G.L. were supported by INSERM, the University Hospital of Angers (PHRC 04-12), the University of Angers and Montpellier I and II, France and by grants from Retina France and ‘Ouvrir les yeux’ patients Association. Further financial support comes from the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI060205 to B.B. and PI060547 to M.A.M.) and Ministerio de Educación y Ciencia, Spain (BFU2004-04591 to R.G.). Funding to pay the Open Access publication charges for this article was provided by the RFO University of Bologna 2006 grant.Peer Reviewe
The genetic and epigenetic landscapes of the epithelium in asthma
No full text© 2016 The Author(s). Asthma is a global health problem with increasing prevalence. The airway epithelium is the initial barrier against inhaled noxious agents or aeroallergens. In asthma, the airway epithelium suffers from structural and functional abnormalities and as such, is more susceptible to normally innocuous environmental stimuli. The epithelial structural and functional impairments are now recognised as a significant contributing factor to asthma pathogenesis. Both genetic and environmental risk factors play important roles in the development of asthma with an increasing number of genes associated with asthma susceptibility being expressed in airway epithelium. Epigenetic factors that regulate airway epithelial structure and function are also an attractive area for assessment of susceptibility to asthma. In this review we provide a comprehensive discussion on genetic factors; from using linkage designs and candidate gene association studies to genome-wide association studies and whole genome sequencing, and epigenetic factors; DNA methylation, histone modifications, and non-coding RNAs (especially microRNAs), in airway epithelial cells that are functionally associated with asthma pathogenesis. Our aims were to introduce potential predictors or therapeutic targets for asthma in airway epithelium. Overall, we found very small overlap in asthma susceptibility genes identified with different technologies. Some potential biomarkers are IRAKM, PCDH1, ORMDL3/GSDMB, IL-33, CDHR3 and CST1 in airway epithelial cells. Recent studies on epigenetic regulatory factors have further provided novel insights to the field, particularly their effect on regulation of some of the asthma susceptibility genes (e.g. methylation of ADAM33). Among the epigenetic regulatory mechanisms, microRNA networks have been shown to regulate a major portion of post-transcriptional gene regulation. Particularly, miR-19a may have some therapeutic potential
Бронхиальная астма и COVID-19: обзор рекомендаций по ведению пациентов с бронхиальной астмой во время пандемии COVID-19
No full textThe emergence of a new disease COVID-19 (coronavirus disease 2019), caused by the coronavirus named SARS-CoV-2, has significantly changed the usual interaction pattern between a doctor and a patient. Previous large studies have identified risk factors for a severe course of COVID-19, including old age, hypertension, diabetes, cardiovascular diseases, and chronic obstructive pulmonary disease. However, asthma and respiratory allergy have not been identified as risk factors for the severe disease. These factors give clues to the pathogenesis of COVID-19, approaches to the controller medications, target therapy, allergen-specific immunotherapy (ASIT) in patients with various phenotypes and endotypes of asthma during the pandemic.The purpose of this review is to summarize the currently available knowledge about SARS-CoV-2, T2-endotype of asthma, eosinophilic inflammation. The article provides an overview of the data from studies of COVID-19 patients with asthma, the main recommendations of the Global Initiative for Asthma (2021) and the Ministry of Health of the Russian Federation. It shows that targeting the endotypes and phenotypes of asthma can influence the management of COVID-19 patients with asthma. The influence of the imbalance of the immune system, pro-inflammatory cytokines, and effector cells in patients with asthma on the development and progression of COVID-19 is considered. Recommendations are given for the controller medications, targeted therapy, allergen-specific immunotherapy during the pandemic.Conclusion. The current recommendations for asthma treatment, based on the latest research of COVID-19, deepen our understanding of the course of COVID-19 in patients with different phenotypes and endotypes of asthma, approaches to traditional methods of treating asthma according to clinical guidelines during the pandemic.При появлении нового заболевания COVID-19 (COronaVIrus Disease–2019), вызванного коронавирусом SARS-CoV-2, значительно изменилась привычная схема взаимодействия врача и пациента. По данным крупных исследований выявлен ряд факторов риска развития тяжелого течения заболевания COVID-19 – пожилой возраст, гипертония, сахарный диабет, сердечно-сосудистые заболевания, хроническая обструктивня болезнь легких. Однако бронхиальная астма (БА) и респираторная аллергия не идентифицированы как существенные факторы риска тяжелого течения заболевания, а выявление этих факторов дает важную информацию о патогенезе COVID-19, подходах к базисной, таргетной и аллерген-специфической терапии (АСИТ) в условиях пандемии при различных фенотипах и эндотипах БА.Целью обзора явилось обобщение имеющихся в настоящее время знаний о SARS‐CoV‐2, Т2-эндотипе БА, эозинофильном воспалении. Представлены данные исследований по изучению особенностей течения COVID-19 у пациентов с БА, основные рекомендации Глобальной инициативы по БА (Global Initiative for Asthma – GINA, 2021) и Министерства здравоохранения Российской Федерации. Показано, что ориентирование на эндотипы и фенотипы БА способствует выбору оптимальной тактики ведения пациентов с COVID-19 и БА. Рассмотрено влияние дисбаланса иммунной системы, провоспалительных цитокинов, эффекторных клеток у больных БА на развитие и прогрессирование COVID-19. Приведены рекомендации по ведению пациентов препаратами базисной, таргетной терапии, АСИТ в условиях пандемии.Заключение. Текущие рекомендации по лечению БА, основанные на результатах последних исследований, в контексте c COVID-19 углубляют понимание особенностей течения коорновирусной болезни у пациентов с различными фенотипами и эндотипами БА и подходов к традиционным методам ее лечения согласно клиническим рекомендациям в условиях пандемии
Global variation in anastomosis and end colostomy formation following left-sided colorectal resection
No full textBackground: End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods: This study comprised an analysis of GlobalSurg-1 and-2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle-and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results: In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 percent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low-compared with middle-and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion: Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone
Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study
No full textBackground: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. Methods: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. Results: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33–4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76–2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6% ) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42–0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14–0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11–0.44) and SSI (OR 0.21 95% CI 0.09–0.45). Conclusion: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. Trial registration: NCT02179112
