1,012 results match your criteria Alpha1-Antitrypsin Deficiency


Geographic distribution of COPD prevalence in the World displayed by Geographic Information System maps.

Eur Respir J 2019 Apr 18. Epub 2019 Apr 18.

Marc Miravitlles, Pneumology Department, Hospital Universitari Vall d'Hebron/Vall d'Hebron Research Institute (VHIR), CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.00610-2019DOI Listing

Diagnosis and management of α-antitrypsin deficiency in Europe: an expert survey.

ERJ Open Res 2019 Feb 11;5(1). Epub 2019 Mar 11.

Dept of Respiratory Medicine, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland.

Despite recent improvements, α-antitrypsin deficiency (AATD) remains a rarely diagnosed and treated condition. To assess the variability of AATD diagnosis/treatment in Europe, and to evaluate clinicians' views on methods to optimise management, specialist AATD clinicians were invited to complete a web-based survey. Surveys were completed by 15 physicians from 14 centres in 13 European countries. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1183/23120541.00171-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409083PMC
February 2019
2 Reads

Reactive centre loop dynamics and serpin specificity.

Sci Rep 2019 Mar 7;9(1):3870. Epub 2019 Mar 7.

Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Victoria, 3800, Australia.

Serine proteinase inhibitors (serpins), typically fold to a metastable native state and undergo a major conformational change in order to inhibit target proteases. However, conformational lability of the native serpin fold renders them susceptible to misfolding and aggregation, and underlies misfolding diseases such as α-antitrypsin deficiency. Serpin specificity towards its protease target is dictated by its flexible and solvent exposed reactive centre loop (RCL), which forms the initial interaction with the target protease during inhibition. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-40432-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405850PMC
March 2019
2 Reads

Blood monocyte profiles in COPD patients with PiMM and PiZZ α1-antitrypsin.

Respir Med 2019 Mar 6;148:60-62. Epub 2019 Feb 6.

Department of Respiratory Medicine, Hannover Medical School, Biomedical Research in End-stage and Obstructive Lung Disease Hannover (BREATH), Member of German Centre for Lung Research (DZL), Hannover, Germany. Electronic address:

Human blood monocytes are divided into populations based on the differential expression of CD14 and CD16 receptors: CD14  CD16(classical), CD14  CD16  (intermediate), and CD14CD16 (non-classical). Given their functional differences and their role in pathogenesis of chronic obstructive pulmonary disease (COPD), monocyte profiling is of clinical interest. Here we investigated blood monocyte subsets in clinically stable COPD patients with alpha1-antitrypsin (AAT) deficiency (PiZZ, n = 7) and with normal AAT variant (PiMM, n = 7). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rmed.2019.02.001DOI Listing
March 2019
1 Read

The withdrawal of replacement therapy and outcomes in Alpha1-antitrypsin deficiency lung transplant recipients.

Eur Respir J 2019 Feb 28. Epub 2019 Feb 28.

National Heart and Lung Transplant centre, Mater Misericordiae University Hospital, Dublin, Ireland.

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.00055-2019DOI Listing
February 2019
1 Read

Emphysema: looking beyond alpha-1 antitrypsin deficiency.

Expert Rev Respir Med 2019 Apr 22;13(4):381-397. Epub 2019 Feb 22.

b Department of Respiratory Medicine , Maastricht University Medical Center , Maastricht , The Netherlands.

Introduction: Distinct pathologies can cause chronic obstructive pulmonary disease (COPD). Emphysema is a COPD-phenotype characterized by destruction of lung parenchyma. Alpha-1 antitrypsin deficiency (AATD) is a genetic cause of emphysema, whereas smoking is the most important risk factor of non-AATD emphysema. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1080/17476348.2019.1580575DOI Listing
April 2019
12 Reads

Precise RNA editing by recruiting endogenous ADARs with antisense oligonucleotides.

Nat Biotechnol 2019 02 28;37(2):133-138. Epub 2019 Jan 28.

Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.

Site-directed RNA editing might provide a safer or more effective alternative to genome editing in certain clinical scenarios. Until now, RNA editing has relied on overexpression of exogenous RNA editing enzymes or of endogenous human ADAR (adenosine deaminase acting on RNA) enzymes. Here we describe the engineering of chemically optimized antisense oligonucleotides that recruit endogenous human ADARs to edit endogenous transcripts in a simple and programmable way, an approach we call RESTORE (recruiting endogenous ADAR to specific transcripts for oligonucleotide-mediated RNA editing). Read More

View Article

Download full-text PDF

Source
http://www.nature.com/articles/s41587-019-0013-6
Publisher Site
http://dx.doi.org/10.1038/s41587-019-0013-6DOI Listing
February 2019
6 Reads

An analog of glibenclamide selectively enhances autophagic degradation of misfolded α1-antitrypsin Z.

PLoS One 2019 23;14(1):e0209748. Epub 2019 Jan 23.

Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.

The classical form of α1-antitrypsin deficiency (ATD) is characterized by intracellular accumulation of the misfolded variant α1-antitrypsin Z (ATZ) and severe liver disease in some of the affected individuals. In this study, we investigated the possibility of discovering novel therapeutic agents that would reduce ATZ accumulation by interrogating a C. elegans model of ATD with high-content genome-wide RNAi screening and computational systems pharmacology strategies. Read More

View Article

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209748PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343872PMC
January 2019
8 Reads
3.234 Impact Factor

Making gene editing a therapeutic reality.

F1000Res 2018 21;7. Epub 2018 Dec 21.

Bioengineering, UC Berkeley, Berkeley, CA, 94720, USA.

This review discusses current bottlenecks in making CRISPR-Cas9-mediated genome editing a therapeutic reality and it outlines recent strategies that aim to overcome these hurdles as well as the scope of current clinical trials that pioneer the medical translation of CRISPR-Cas9. Additionally, this review outlines the specifics of disease-modifying gene editing in recessive versus dominant genetic diseases with the focus on genetic myopathies that are exemplified by Duchenne muscular dystrophy and myotonic dystrophies. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.12688/f1000research.16106.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305220PMC
March 2019
2 Reads

Liver disease related to alpha1-antitrypsin deficiency in French children: The DEFI-ALPHA cohort.

Liver Int 2018 Dec 27. Epub 2018 Dec 27.

Hépatologie, Gastroentérologie et Nutrition pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Lyon, France.

Background & Aims: To identify prognostic factors for liver disease in children with alpha-1 antitrypsin deficiency, irrespective of phenotype, using the DEFI-ALPHA cohort.

Methods: Retrospective, then prospective from 2010, multicentre study including children known to have alpha-1 antitrypsin blood concentration below 0.8 g/L, born in France since 1989. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1111/liv.14035DOI Listing
December 2018
2 Reads

Challenges in interpreting trends in testing for α-antitrypsin deficiency in COPD patients from UK primary care.

Authors:
Joan B Soriano

Eur Respir J 2018 Dec 20;52(6). Epub 2018 Dec 20.

Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.02064-2018DOI Listing
December 2018
1 Read

Challenges in interpreting trends in testing for α-antitrypsin deficiency in COPD patients from UK primary care.

Authors:
Daniel R Morales

Eur Respir J 2018 Dec 20;52(6). Epub 2018 Dec 20.

Division of Population Health and Genomics, University of Dundee, Dundee, UK

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.01986-2018DOI Listing
December 2018
1 Read

Conditions and Factors Associated With Spontaneous Coronary Artery Dissection (from a National Population-Based Cohort Study).

Am J Cardiol 2019 Jan 30;123(2):249-253. Epub 2018 Oct 30.

Brigham and Women's Hospital Heart & Vascular Center, Harvard Medical School, Boston, Massachusetts. Electronic address:

The pathophysiology of spontaneous coronary artery dissection (SCAD) is heterogeneous, associated with systemic arteriopathies and inflammatory diseases, and often compounded by environmental precipitants, genetics, or stressors. However, the frequency of these associated conditions with SCAD on a population level remains unknown. Therefore, the objective of this analysis was to evaluate heterogeneous phenotypes of SCAD in the United States using data from the Nationwide Inpatient Sample collected from January 1, 2004, to September 31, 2015. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjcard.2018.10.012DOI Listing
January 2019
16 Reads
3.280 Impact Factor

Alpha1-Antitrypsin Deficiency: Transition of Care for the Child With AAT Deficiency into Adulthood.

Curr Pediatr Rev 2019 ;15(1):53-61

Division of Pediatric Gastroenterology, Hepatology and Nutrition MUSC Children's Hospital, South Carolina, SC, United States.

Importance: Alpha1-antitrypsin (AAT) deficiency is a common, but an underdiagnosed genetic condition, affecting 1 in 1500 individuals. It can present insidiously with liver disease in children. Although clinical practice guidelines exist for the management of AAT deficiency, especially with regards to pulmonary involvement, there are no published recommendations that specifically relate to the management of the liver disease and monitoring for lung disease associated with this condition, particularly in children. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1573396314666181113094517DOI Listing
January 2019
31 Reads

Safety and pharmacokinetics of Alpha-1 MP (Prolastin-C) in Japanese patients with alpha-antitrypsin (AAT) deficiency.

Respir Investig 2019 Jan 8;57(1):89-96. Epub 2018 Nov 8.

Grifols Japan KK, Osaka, Japan.

Background: Alpha-Proteinase Inhibitor, Modified Process (Alpha-1 MP) is used for augmentation therapy in alpha1-antitrypsin deficiency (AATD), an extremely rare disease in Japan. Weekly doses of 60 mg/kg Alpha-1 MP have been shown to be safe and well tolerated in non-Japanese subjects, but the safety and pharmacokinetics (PK) have not been evaluated in Japanese subjects. The objectives of this study were to evaluate the safety and PK of 60 mg/kg Alpha-1 MP administered by weekly IV infusions over 8 weeks in Japanese subjects with AATD. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.resinv.2018.09.006DOI Listing
January 2019
4 Reads

Alpha 1 antitrypsin distribution in an allergic asthmatic population sensitized to house dust mites.

Clin Transl Allergy 2018 2;8:44. Epub 2018 Nov 2.

5Allergy Unit, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain.

Background And Objective: Severe alpha1 antitrypsin deficiency has been clearly associated with pulmonary emphysema, but its relationship with bronchial asthma remains controversial. Some deficient alpha 1 antitrypsin (AAT) genotypes seem to be associated with asthma development. The objective of this study was to analyze the distribution of AAT genotypes in asthmatic patients allergic to house dust mites (HDM), and to asses a possible association between these genotypes and severe asthma. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13601-018-0231-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214172PMC
November 2018
2 Reads

Geographical Distribution of COPD Prevalence in the Americas.

COPD 2018 Jun-Aug;15(4):317-325. Epub 2018 Oct 30.

f Pneumology Department , Hospital Universitari Vall d'Hebron , Barcelona , Spain.

Surveys estimating chronic obstructive pulmonary disease (COPD) prevalence are unevenly distributed in the Americas, which make it difficult to estimate accurately its geographical distribution. The geographic information system inverse distance weighted (IDW) interpolation technique has proved to be an effective tool in spatial distribution estimation of epidemiological variables, even when real data are few or widely spread. We aimed to represent cartographically the COPD prevalence in the Americas by means of a blue to red scale representation of the prevalence data, where different values are represented as different colours, and a population density filtered IDW interpolation mapping, where areas with a population density <0. Read More

View Article

Download full-text PDF

Source
https://www.tandfonline.com/doi/full/10.1080/15412555.2018.1
Publisher Site
http://dx.doi.org/10.1080/15412555.2018.1481936DOI Listing
October 2018
20 Reads

Author Correction: α1-Antitrypsin deficiency.

Nat Rev Dis Primers 2018 Oct 29;4(1):40. Epub 2018 Oct 29.

Department of Medicine, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.

In Figure 6 of this article (PDF and HTML) the arrows labelled 'Depolymerization' and 'Polymerization' should be labelled 'Polymerization' and 'Depolymerization', respectively. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41572-018-0043-2DOI Listing
October 2018
1 Read

Oxidation-resistant and thermostable forms of alpha-1 antitrypsin from inclusion bodies.

FEBS Open Bio 2018 Oct 17;8(10):1711-1721. Epub 2018 Sep 17.

Key Laboratory for Microorganisms and Biotransformation College of Life Science South-Central University for Nationalities Wuhan China.

Native α1-antitrypsin (AAT) is a 52-kDa glycoprotein that acts as an antiprotease and is the physiological inhibitor of neutrophil serine proteases. The main function of AAT is to protect the lung from proteolytic damage induced by inflammation. AAT deficiency (AATD) is a codominant autosomal disorder caused by pathogenic mutations in SERPINA1 gene, leading to reduced levels of serum AAT. Read More

View Article

Download full-text PDF

Source
http://doi.wiley.com/10.1002/2211-5463.12515
Publisher Site
http://dx.doi.org/10.1002/2211-5463.12515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168689PMC
October 2018
14 Reads

Expression, Purification, and Characterization of Recombinant Human α-Antitrypsin Produced Using Silkworm-Baculovirus Expression System.

Mol Biotechnol 2018 Dec;60(12):924-934

Laboratory of Insect Genome Science, Kyushu University Graduate School of Bioresource and Bioenvironmental Science, Hakozaki 6-10-1, Higashi-ku, Fukuoka, 812-8581, Japan.

Human α-antitrypsin (AAT) is the most abundant serine proteinase inhibitor (serpin) in the human plasma. Commercially available AAT for the medications of deficiency of α-antitrypsin is mainly purified from human plasma. There is a high demand for a stable and low-cost supply of recombinant AAT (rAAT). Read More

View Article

Download full-text PDF

Source
http://link.springer.com/10.1007/s12033-018-0127-y
Publisher Site
http://dx.doi.org/10.1007/s12033-018-0127-yDOI Listing
December 2018
7 Reads

Lung volume reduction surgery beyond the NETT selection criteria.

J Thorac Dis 2018 Aug;10(Suppl 23):S2748-S2753

Department of Thoracic Surgery, University Hospital Zurich, Switzerland.

Lung volume reduction surgery (LVRS) for symptomatic patients with advanced emphysema was proven to be successful in a large randomized multi-center trial (NETT) and in several smaller randomized single center trials. This evidence primarily concerns patients with heterogeneous, upper-lobe predominant emphysema and low exercise tolerance within certain selection criteria regarding lung function values. As the most important effect of LVRS is generated by reducing the hyperinflation, even patients with homogeneous emphysema morphology profit from the procedure. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.21037/jtd.2018.08.93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129809PMC
August 2018
3 Reads

Update on α-antitrypsin deficiency.

Breathe (Sheff) 2018 Jun;14(2):e17-e24

Center for Diagnosis of Inherited Alpha1-antitrypsin Deficiency, Dept of Internal Medicine and Therapeutics, Pneumology Unit, Fondazione IRCCS Policlinico San Matteo, Università di Pavia, Pavia, Italy.

α-Antitrypsin deficiency (AATD) is an inherited metabolic disorder in which mutations in the coding sequence of the gene prevent secretion of α-antitrypsin (α-AT) and cause predisposition to pulmonary and liver diseases. The heterogeneity of clinical manifestations in AATD is related to the complexity of biological function of α-AT. The role of smoking is crucial in the natural history of lung damage progression in severe AATD individuals, even if it also partly explains the heterogeneity in lung disease. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1183/20734735.015018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095240PMC
June 2018
7 Reads

Liver disease in adults with α1-antitrypsin deficiency.

United European Gastroenterol J 2018 Jun 28;6(5):710-718. Epub 2018 Feb 28.

Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Background: The natural history of adult liver disease due to α1-antitrypsin deficiency (A1AD) remains poorly understood.

Objective: We investigated whether heterozygosity for the Z-allele predisposes for the development of clinically significant portal hypertension (CSPH). Moreover, we aimed to non-invasively assess the prevalence of liver fibrosis and hepatic steatosis in adults with A1AD treated by pulmonologists. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1177/2050640618764057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068794PMC
June 2018
11 Reads

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

Gut 2018 Aug 1. Epub 2018 Aug 1.

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Objective: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.

Design: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2018-316228DOI Listing
August 2018
16 Reads

NorUDCA promotes degradation of α1-antitrypsin mutant Z protein by inducing autophagy through AMPK/ULK1 pathway.

PLoS One 2018 1;13(8):e0200897. Epub 2018 Aug 1.

Pediatrics and Biochemistry, Saint Louis University, and Cardinal Glennon Children's Medical Center, St. Louis, Missouri, United States of America.

Alpha-1 Antitrypsin (α1AT) Deficiency is a genetic disease in which accumulation of α1AT mutant Z (α1ATZ) protein in the ER of hepatocytes causes chronic liver injury, liver fibrosis, and hepatocellular carcinoma. No effective medical therapy is currently available for the disease. We previously found that norUDCA improves the α1AT deficiency associated liver disease by promoting autophagic degradation of α1ATZ protein in liver in a mouse model of the disease. Read More

View Article

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200897PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070232PMC
January 2019
4 Reads

Advances in managing COPD related to α -antitrypsin deficiency: An under-recognized genetic disorder.

Allergy 2018 Nov 26;73(11):2110-2121. Epub 2018 Jul 26.

Department of Medicine, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania.

α -Antitrypsin deficiency (AATD) predisposes individuals to chronic obstructive pulmonary disease (COPD) and liver disease. Despite being commonly described as rare, AATD is under-recognized, with less than 10% of cases identified. The following is a comprehensive review of AATD, primarily for physicians who treat COPD or asthma, covering the genetics, epidemiology, clinical presentation, screening and diagnosis, and treatments of AATD. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.13558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282978PMC
November 2018
10 Reads

Alpha1 antitrypsin deficiency due to an homozygous PI* Null Q0Cairo mutation: Early onset of pulmonary manifestations and variability of clinical expression.

Respir Med Case Rep 2018 10;24:58-62. Epub 2018 Apr 10.

CHU Lille, Service de Biochimie et Biologie Moléculaire Hormonologie, Métabolisme-Nutrition, Oncologie, F-59000 Lille, France.

Alpha-1 antitrypsin deficiency is an autosomal, codominant disorder caused by mutations of the gene. This genetic disorder is mainly associated with development of pulmonary emphysema and/or chronic liver disease and cirrhosis. Here we report a very rare alpha-1 antitrypsin Null Q0cairo homozygous mutation characterized by a complete absence of alpha-1 antitrypsin in the plasma, in a non-consanguineous Moroccan family. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rmcr.2018.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010612PMC
April 2018
6 Reads

Testing for alpha-1 antitrypsin in COPD in outpatient respiratory clinics in Spain: A multilevel, cross-sectional analysis of the EPOCONSUL study.

PLoS One 2018 28;13(6):e0198777. Epub 2018 Jun 28.

Pulmonary Department, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, España.

Background: Alpha-1 antitrypsin deficiency (AATD) is the most common hereditary disorder in adults, but is under-recognized. In Spain, the number of patients diagnosed with AATD is much lower than expected according to epidemiologic studies. The objectives of this study were to assess the frequency and determinants of testing serum α1-antitrypsin (AAT) levels in COPD patients, and to describe factors associated with testing. Read More

View Article

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198777PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023216PMC
December 2018
25 Reads

Hermansky-Pudlak syndrome with a novel genetic variant in and subsequent accelerated pulmonary fibrosis: significance for phenocopy diseases.

Thorax 2018 11 25;73(11):1085-1088. Epub 2018 Jun 25.

Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.

The Hermansky-Pudlak syndrome (HPS) is a collection of autosomal-recessive disorders characterised by tyrosinase-positive oculocutaneous albinism (OCA), bleeding diatheses and, in selected individuals, early-onset accelerated pulmonary fibrosis, neutropaenia and granulomatous colitis. We describe a young man who presented following a self-directed literature review prompted by severe bleeding complications following minor surgical and dental procedures in the context of OCA. HPS was clinically suspected, with subsequent genetic testing confirming biallelic mutations in the gene. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1136/thoraxjnl-2018-211920DOI Listing
November 2018
21 Reads

Similarities in the Computed Tomography Appearance in α1-Antitrypsin Deficiency and Smoking-Related Chronic Obstructive Pulmonary Disease in a Smoking Collective.

Respiration 2018 25;96(3):231-239. Epub 2018 Jun 25.

Department of Diagnostic and Interventional Radiology, University Hospital of Heidelberg, Heidelberg, Germany.

Background: Emphysematous destruction of lung parenchyma visible in computed tomography (CT) can be attributed to chronic obstructive pulmonary disease (COPD) or to α1-antitrypsin deficiency (AATD).

Objectives: We evaluated if visual semiquantitative phenotyping of CT data helps identifying individuals with AATD in a group of smokers with severe emphysema and airflow limitation.

Method: n = 14 patients with AATD and n = 15 with COPD and a minimum of 10 pack years underwent CT, clinical assessment, and full-body plethysmography. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1159/000489177DOI Listing
June 2018
8 Reads

Diagnosis of alpha1-antitrypsin deficiency not just in severe COPD.

Pulmonology 2018 Nov - Dec;24(6):351-353. Epub 2018 Jun 18.

Pneumology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Electronic address:

Alpha1-antitrypsin deficiency (AATD) is a well known genetic risk factor for pulmonary disease and is the most frequent hereditary disease diagnosed in adults. Despite being one of the most common hereditary diseases, AATD remains under-diagnosed because of its variable clinical presentation and the poor knowledge of this disease by physicians. With the aim of identifying clinical differences that could influence early diagnosis, we compared two groups of six AATD Pi*ZZ patients with different lung function severity and clinical expression at diagnosis. Read More

View Article

Download full-text PDF

Source
https://linkinghub.elsevier.com/retrieve/pii/S25310437183008
Publisher Site
http://dx.doi.org/10.1016/j.pulmoe.2018.05.005DOI Listing
June 2018
3 Reads

Innate Immune System Status of Sulphur Mustard-Poisoned Iranian Veterans Three Decades after Exposure.

Basic Clin Pharmacol Toxicol 2018 Nov 8;123(5):635-639. Epub 2018 Aug 8.

Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Sulphur mustard (SM) is an incapacitating chemical warfare agent which causes acute and chronic toxicities in different body organs of affected individuals. The aim of this study was to investigate the innate immune status of the Iranian veterans who were exposed to SM around 30 years earlier and had more than 25% disabilities. In this regard, most functional and non-functional parameters of innate immunity were evaluated in 35 veterans. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcpt.13053DOI Listing
November 2018
33 Reads

hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α-antitrypsin deficiency.

J Hepatol 2018 Oct 5;69(4):851-860. Epub 2018 Jun 5.

Wellcome Trust and MRC Cambridge Stem Cell Institute, Department of Surgery, University of Cambridge, UK; Wellcome Trust Sanger Institute, Genome Campus Hinxton, UK. Electronic address:

Background & Aims: α-Antitrypsin deficiency (A1ATD) is an autosomal recessive disorder caused by mutations in the SERPINA1 gene. Individuals with the Z variant (Gly342Lys) retain polymerised protein in the endoplasmic reticulum (ER) of their hepatocytes, predisposing them to liver disease. The concomitant lack of circulating A1AT also causes lung emphysema. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2018.05.028DOI Listing
October 2018
50 Reads

Trends of testing for and diagnosis of α-antitrypsin deficiency in the UK: more testing is needed.

Eur Respir J 2018 07 4;52(1). Epub 2018 Jul 4.

Dept of Respiratory Medicine, Cambridge NIHR BRC, Addenbrookes Hospital, Cambridge, UK.

α-antitrypsin deficiency (AATD) significantly increases the risk of developing chronic obstructive pulmonary disease (COPD), and testing of all COPD patients for AATD is recommended by the World Health Organization, European Respiratory Society and Global Initiative for Chronic Obstructive Lung Disease (GOLD). We aimed to determine trends for testing and diagnosing AATD from 1990 to 2014.This study analysed all patients diagnosed with COPD from about 550 UK Optimum Patient Care Research Database general practices, including a subgroup of those diagnosed before the age of 60 years. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.00360-2018DOI Listing
July 2018
15 Reads

Serum α1-Antitrypsin Concentration in the Diagnosis of α1-Antitrypsin Deficiency.

JAMA 2018 May;319(19):2034-2035

The Pulmonary Center, Boston University School of Medicine, Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Boston Medical Center, Boston, Massachusetts.

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2018.3888DOI Listing
May 2018
5 Reads

NFκB mitigates the pathological effects of misfolded α1-antitrypsin by activating autophagy and an integrated program of proteostasis mechanisms.

Cell Death Differ 2019 Mar 23;26(3):455-469. Epub 2018 May 23.

Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.

Intrahepatocytic accumulation of misfolded α1-antitrypsin Z variant (ATZ) is responsible for liver disease in some individuals with α1-antitrypsin deficiency (ATD), characterized by fibrosis/cirrhosis and predisposition to carcinogenesis. Previous results showing that accumulation of ATZ in model systems activates the NFκB signaling pathway have led us to hypothesize that downstream targets of NFκB are elements of a proteostasis response network for this type of proteinopathy. Here we show that only a subset of downstream targets within the NFκB transcriptomic repertoire are activated in model systems of this proteinopathy. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41418-018-0130-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370812PMC
March 2019
10 Reads

Vascular inflammation and aortic stiffness: potential mechanisms of increased vascular risk in chronic obstructive pulmonary disease.

Respir Res 2018 05 24;19(1):100. Epub 2018 May 24.

Division of Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, UK.

Background: Chronic obstructive pulmonary disease (COPD) is a complex inflammatory condition in which an important extra-pulmonary manifestation is cardiovascular disease. We hypothesized that COPD patients would have increased aortic inflammation and stiffness, as candidate mechanisms mediating increased cardiovascular risk, compared to two negative control groups: healthy never-smokers and smokers without COPD. We also studied patients with COPD due to alpha antitrypsin deficiency (αATD) as a comparator lung disease group. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12931-018-0792-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968523PMC
May 2018
21 Reads

α-Antitrypsin Polymerizes in Alveolar Macrophages of Smokers With and Without α-Antitrypsin Deficiency.

Chest 2018 Sep 12;154(3):607-616. Epub 2018 May 12.

Department of Cardiac, Thoracic, and Vascular Sciences, University of Padua, Padua, Italy; Respiratory Division, Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada.

Background: The deficiency of α-antitrypsin (AAT) is secondary to misfolding and polymerization of the abnormal Z-AAT in liver cells and is associated with lung emphysema. Alveolar macrophages (AMs) produce AAT; however, it is not known whether Z-AAT can polymerize in AMs, further decreasing lung AAT and promoting lung inflammation. Our intention was to investigate whether AAT polymerizes in human AMs and to study the possible relation between polymerization and degree of lung inflammation. Read More

View Article

Download full-text PDF

Source
https://linkinghub.elsevier.com/retrieve/pii/S00123692183072
Publisher Site
http://dx.doi.org/10.1016/j.chest.2018.04.039DOI Listing
September 2018
17 Reads

Analysis of MCFD2- and LMAN1-deficient mice demonstrates distinct functions in vivo.

Blood Adv 2018 05;2(9):1014-1021

Genomic Medicine Institute, Lerner Research Institute of Cleveland Clinic, Cleveland, OH.

The LMAN1-MCFD2 complex serves as a cargo receptor for efficient transport of factor V (FV) and FVIII from the endoplasmic reticulum (ER) to the Golgi. Genetic deficiency of or in humans results in the moderate bleeding disorder combined FV and FVIII deficiency, with a similar phenotype previously observed in LMAN1-deficient mice. We now report that MCFD2-deficient mice generated by gene targeting also demonstrate reduced plasma FV and FVIII, with levels lower than those in LMAN1-deficient mice, similar to previous observations in LMAN1- and MCDF2-deficient humans. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2018018317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942004PMC
May 2018
3 Reads

Liver - master and servant of serum proteome.

J Hepatol 2018 Aug 28;69(2):512-524. Epub 2018 Apr 28.

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; The Interdisciplinary Center for Clinical Research (IZKF), University Hospital Aachen, Aachen, Germany. Electronic address:

Hepatocytes synthesise the majority of serum proteins. This production occurs in the endoplasmic reticulum (ER) and is adjusted by complex local and systemic regulatory mechanisms. Accordingly, serum levels of hepatocyte-made proteins constitute important biomarkers that reflect both systemic processes and the status of the liver. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2018.04.018DOI Listing
August 2018
9 Reads

Comparison of non-invasive assessment of liver fibrosis in patients with alpha1-antitrypsin deficiency using magnetic resonance elastography (MRE), acoustic radiation force impulse (ARFI) Quantification, and 2D-shear wave elastography (2D-SWE).

PLoS One 2018 26;13(4):e0196486. Epub 2018 Apr 26.

Department of Radiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Purpose: Although it has been known for decades that patients with alpha1-antitrypsin deficiency (AATD) have an increased risk of cirrhosis and hepatocellular carcinoma, limited data exist on non-invasive imaging-based methods for assessing liver fibrosis such as magnetic resonance elastography (MRE) and acoustic radiation force impulse (ARFI) quantification, and no data exist on 2D-shear wave elastography (2D-SWE). Therefore, the purpose of this study is to evaluate and compare the applicability of different elastography methods for the assessment of AATD-related liver fibrosis.

Methods: Fifteen clinically asymptomatic AATD patients (11 homozygous PiZZ, 4 heterozygous PiMZ) and 16 matched healthy volunteers were examined using MRE and ARFI quantification. Read More

View Article

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196486PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919507PMC
August 2018
6 Reads

Alpha1-antitrypsin deficiency: what's new after European Respiratory Society Statement.

Panminerva Med 2018 Sep 24;60(3):101-108. Epub 2018 Apr 24.

Division of Pulmonology, Cardiothoracic and Vascular Department, AOU Città della Salute e della Scienza, Turin, Italy.

Alpha-1 antitrypsin deficiency (AATD) is a clinically under-recognized inherited disorder affecting the lungs and the liver. The most common manifestations are pulmonary emphysema, bronchiectasis and liver disease. The recent publication of the European Respiratory Society statement on diagnosis and treatment of pulmonary diseases has replaced the 2003 American Thoracic Society and European Respiratory Society one. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.23736/S0031-0808.18.03450-XDOI Listing
September 2018
12 Reads

In Vivo Genome Editing Partially Restores Alpha1-Antitrypsin in a Murine Model of AAT Deficiency.

Hum Gene Ther 2018 08 14;29(8):853-860. Epub 2018 May 14.

1 RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts.

CRISPR (clustered regularly interspaced short palindromic repeats) genome editing holds promise in the treatment of genetic diseases that currently lack effective long-term therapies. Patients with alpha-1 antitrypsin (AAT) deficiency develop progressive lung disease due to the loss of AAT's antiprotease function and liver disease due to a toxic gain of function of the common mutant allele. However, it remains unknown whether CRISPR-mediated AAT correction in the liver, where AAT is primarily expressed, can correct either or both defects. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1089/hum.2017.225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110121PMC
August 2018
13 Reads

Therapeutic Genome Editing With CRISPR/Cas9 in a Humanized Mouse Model Ameliorates α1-antitrypsin Deficiency Phenotype.

EBioMedicine 2018 Mar 19;29:104-111. Epub 2018 Feb 19.

Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

α1-antitrypsin (AAT) is a circulating serine protease inhibitor secreted from the liver and important in preventing proteolytic neutrophil elastase associated tissue damage, primarily in lungs. In humans, AAT is encoded by the SERPINA1 (hSERPINA1) gene in which a point mutation (commonly referred to as PiZ) causes aggregation of the miss-folded protein in hepatocytes resulting in subsequent liver damage. In an attempt to rescue the pathologic liver phenotype of a mouse model of human AAT deficiency (AATD), we used adenovirus to deliver Cas9 and a guide-RNA (gRNA) molecule targeting hSERPINA1. Read More

View Article

Download full-text PDF

Source
https://linkinghub.elsevier.com/retrieve/pii/S23523964183006
Publisher Site
http://dx.doi.org/10.1016/j.ebiom.2018.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925576PMC
March 2018
17 Reads

Functional characterization of the mouse Serpina1 paralog DOM-7.

Biol Chem 2018 05;399(6):577-582

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, D-30625 Hannover, Germany.

The generation of authentic mouse-models for human α1-antitrypsin (A1AT)-deficiency is difficult due to the high complexity of the mouse Serpina1 gene locus. Depending on the exact mouse strain, three to five paralogs are expressed, with different proteinase inhibitory properties. Nowadays with CRISPR-technology, genome editing of complex genomic loci is feasible and could be employed for the generation of A1AT-deficiency mouse models. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1515/hsz-2018-0154DOI Listing
May 2018
5 Reads

Imaging-Based Screen Identifies Laminin 411 as a Physiologically Relevant Niche Factor with Importance for i-Hep Applications.

Stem Cell Reports 2018 03 1;10(3):693-702. Epub 2018 Mar 1.

Centre for Stem Cells and Regenerative Medicine & Institute for Liver Studies, King's College London, London SE1 9RT, UK; The Gurdon Institute Imaging Facility, Cambridge University, Cambridge CB2 1QN, UK. Electronic address:

Use of hepatocytes derived from induced pluripotent stem cells (i-Heps) is limited by their functional differences in comparison with primary cells. Extracellular niche factors likely play a critical role in bridging this gap. Using image-based characterization (high content analysis; HCA) of freshly isolated hepatocytes from 17 human donors, we devised and validated an algorithm (Hepatocyte Likeness Index; HLI) for comparing the hepatic properties of cells against a physiological gold standard. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stemcr.2018.01.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919292PMC
March 2018
9 Reads

Lessons from the Past: Some Histories of Alpha-1 Antitrypsin Deficiency Before Its Discovery.

COPD 2018 02;15(1):1-3

g Microbiology and Infection Unit, Warwick Medical School , The University of Warwick , Warwick , United Kingdom.

A1AT deficiency- a genetically inherited autosomal codominant disease with more than 120 identified alleles- was first identified by Laurell and Eriksson in 1963. The most common hereditary disorder in adults, A1AT causes an increased risk of developing pulmonary emphysema and liver disease. In A1AT patients, lung disease generally presents at a younger age than "usual" chronic obstructive pulmonary disease (COPD) and it may be misdiagnosed as asthma. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1080/15412555.2017.1421151DOI Listing
February 2018
5 Reads

Mildly Elevated Liver Transaminase Levels: Causes and Evaluation.

Am Fam Physician 2017 Dec;96(11):709-715

Gastroenterology Consultants of Augusta, Augusta, GA, USA.

Mild, asymptomatic elevations (less than five times the upper limit of normal) of alanine transaminase and aspartate transaminase levels are common in primary care. It is estimated that approximately 10% of the U.S. Read More

View Article

Download full-text PDF

Source
December 2017
6 Reads