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antitrypsin deficiency

T Dau, E V Edeleva, S A I Seidel, R A Stockley, D Braun, D E Jenne
High abundance proteins like protease inhibitors of plasma display a multitude of interactions in natural environments. Quantitative analysis of such interactions in vivo is essential to study diseases, but have not been forthcoming, as most methods cannot be directly applied in a complex biological environment. Here, we report a quantitative microscale thermophoresis assay capable of deciphering functional deviations from in vitro inhibition data by combining concentration and affinity measurements. We obtained stable measurement signals for the substrate-like interaction of the disease relevant inhibitor α-1-antitrypsin (AAT) Z-variant with catalytically inactive elastase...
October 14, 2016: Scientific Reports
Nupur Aggarwal, Beatriz Martinez Delgado, Sandeep Salipalli, Nerea Matamala, Jessica Rademacher, Nicolaus Schwerk, Tobias Welte, Sabina Janciauskiene, Felix C Ringshausen
Recurrent infections of the upper airways in early life may be a warning sign of inherited α1-antitrypsin deficiency
April 2016: ERJ Open Research
Kumar Kanishka, Anand Yogeshman, Jha Kumar Rajendra, Kachhap Sushil
No abstract text is available yet for this article.
January 2016: Journal of the Association of Physicians of India
Nikolas Bernhard, Robert Bals, Sebastian Fähndrich
Alpha-1-antitrypsin deficiency is a genetic risk factor for the development of chronic obstructive airway disease (COPD) and liver cirrhosis. The disease is widely underdiagnosed. The hallmarks of therapy are smoking cessation, prevention from environmental dust exposure and augmentation therapy. Findings from the recently published prospective, placebo-controlled and randomized RAPID trial proved effectiveness of AAT augmentation therapy for slowing progression of emphysema, measured by CT lung density. CT lung density may be more sensitive than forced exspiratory volume in one second (FEV1) or monoxid diffusion capacity (DLCO)...
September 2016: Deutsche Medizinische Wochenschrift
Marcin Surmiak, Marek Sanak
BACKGROUND: One of characteristic findings in granulomatosis with polyangiitis (GPA) is the presence of proteinase-3 (anti-PR3) specific antibodies. These antibodies can cause neutrophil activation, degranulation and generation of reactive oxygen species (ROS). Each of these inflammatory events can be suppressed by circulating alpha-1 antitrypsin (A1AT). A1AT is an acute phase protein increasing during inflammation, however, it may circulate as an inactive polymeric protein. AIM OF THE STUDY: The aim was to analyze how different types of A1AT can affect anti-PR3 mediated neutrophil activation...
August 5, 2016: Pharmacological Reports: PR
Inga Jarosch, Sebastian Gehlert, Daniel Jacko, Rembert Andreas Koczulla, Marion Wencker, Tobias Welte, Wilhelm Bloch, Sabina Janciauskiene, Klaus Kenn
BACKGROUND: Pulmonary rehabilitation (PR) improves oxidative capacity of peripheral muscles in patients with chronic obstructive pulmonary disease (COPD). The exercise-induced oxidative skeletal muscle adaptation in COPD patients with inherited alpha-1 antitrypsin deficiency (A1ATD) has not been studied. OBJECTIVES: To compare PR effects on skeletal muscle adaptation in COPD patients with and without A1ATD. METHODS: Nine COPD patients with A1ATD (genotype PiZZ, 6 receiving A1AT augmentation therapy), and 10 'usual' COPD patients (genotype PiMM) performed an incremental cycling test and underwent musculus vastus lateralis biopsies before and after a 3-week PR program including exercise training...
September 30, 2016: Respiration; International Review of Thoracic Diseases
Adel Boueiz, Sharon M Lutz, Michael H Cho, Craig P Hersh, Russell P Bowler, George R Washko, Eitan Halper-Stromberg, Per Bakke, Amund Gulsvik, Nan M Laird, Terri H Beaty, Harvey O Coxson, James D Crapo, Edwin K Silverman, Peter J Castaldi, Dawn L DeMeo
RATIONALE: Emphysema has considerable variability in the severity and distribution of parenchymal destruction throughout the lungs. Upper lobe predominant emphysema has emerged as an important predictor of response to lung volume reduction surgery. Yet, aside from alpha-1 antitrypsin deficiency, the genetic determinants of emphysema distribution remain largely unknown. OBJECTIVES: To identify the genetic influences of emphysema distribution in non-alpha-1 antitrypsin deficient smokers...
September 26, 2016: American Journal of Respiratory and Critical Care Medicine
Benjamin T Porebski, Shani Keleher, Jeffrey J Hollins, Adrian A Nickson, Emilia M Marijanovic, Natalie A Borg, Mauricio G S Costa, Mary A Pearce, Weiwen Dai, Liguang Zhu, James A Irving, David E Hoke, Itamar Kass, James C Whisstock, Stephen P Bottomley, Geoffrey I Webb, Sheena McGowan, Ashley M Buckle
The rugged folding landscapes of functional proteins puts them at risk of misfolding and aggregation. Serine protease inhibitors, or serpins, are paradigms for this delicate balance between function and misfolding. Serpins exist in a metastable state that undergoes a major conformational change in order to inhibit proteases. However, conformational labiality of the native serpin fold renders them susceptible to misfolding, which underlies misfolding diseases such as α1-antitrypsin deficiency. To investigate how serpins balance function and folding, we used consensus design to create conserpin, a synthetic serpin that folds reversibly, is functional, thermostable, and polymerization resistant...
September 26, 2016: Scientific Reports
Cristina Airoldi, Carlotta Ciaramelli, Marco Fumagalli, Rita Bussei, Valeria Mazzoni, Simona Viglio, Paolo Iadarola, Jan Stolk
The metabolomic analysis of exhaled breath condensate (EBC) may provide insights on both the pathology of pulmonary disorders and the response to therapy. This pilot study describes the ability of nuclear magnetic resonance (NMR)-based metabolomics to discriminate α1-antitrypsin deficient (AATD)-patients, who were diagnosed with moderate to severe emphysema, from healthy individuals. Comparative analysis of samples from these two homogeneous cohorts of individuals resulted in the generation of NMR profiles that were different from both a qualitative and a quantitative point-of-view...
October 5, 2016: Journal of Proteome Research
Peter C Gøtzsche, Helle Krogh Johansen
BACKGROUND: Alpha-1 antitrypsin deficiency is an inherited disorder that can cause chronic obstructive pulmonary disease (COPD). People who smoke are more seriously affected and have a greater risk of dying from the disease. Therefore, the primary treatment is to help people give up smoking. There are now also preparations available that contain alpha-1 antitrypsin, but it is uncertain what their clinical effect is. OBJECTIVES: To review the benefits and harms of augmentation therapy with intravenous alpha-1 antitrypsin in patients with alpha-1 antitrypsin deficiency and lung disease...
September 20, 2016: Cochrane Database of Systematic Reviews
Napat Angkathunyakul, Francesca Rosini, Nigel Heaton, Pierre Foskett, Alberto Quaglia
AIMS: Both homo- and heterozygous AAT deficiency patients are risk of hepatocellular carcinoma (HCC) but also of cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma. We report a series of bile duct adenoma (BDA) and intrahepatic cholangiocarcinoma (ICC), in AAT deficiency adult patients, observed in our institution over a five year period. Our observational study includes a detailed investigation of their immunohistochemical profile and BRAF V600E mutation status. METHODS AND RESULTS: Eleven biliary lesions from 5 AAT deficiency patients (6 BDAs from 3 cirrhotic patients with concurrent other liver diseases, 3 BDAs and 2 ICCs from 2 non-cirrhotic patients) were identified between 2010 and 2015 during routine histology...
September 14, 2016: Histopathology
Veeravich Jaruvongvanich, Ittikorn Spanuchart, T Scott Gallacher
We present a unique vascular complication of α-1 antitrypsin deficiency (AATD) in a patient with an acute onset of epigastric pain and hemodynamic instability. Abdominal computed tomography angiography detected hemoperitoneum and hematoma within the gastrohepatic ligament with active extravasation. Abdominal angiography revealed left gastric aneurysms. An association between AATD and vascular aneurysms has been suggested to be secondary to unopposed proteolytic activity against arterial structural proteins...
July 2016: ACG Case Reports Journal
Naoya Tanabe, Dragoş M Vasilescu, John E McDonough, Daisuke Kinose, Masaru Suzuki, Joel D Cooper, Peter D Paré, James C Hogg
RATIONALE: Very little is known about airways that are too small to be visible on thoracic MDCT but larger than the terminal bronchioles. OBJECTIVE: To examine the structure of preterminal bronchioles located one generation proximal to terminal bronchioles in centrilobular and panlobular emphysema. METHODS: Preterminal bronchioles were identified by backtracking from the terminal bronchioles and their centerlines were established along the entire length of their lumens...
September 9, 2016: American Journal of Respiratory and Critical Care Medicine
Cecília Bittencourt Severo, Letícia Beatriz Matter, Flávio de Mattos Oliveira, Agueda Palmira Castagna Vargas, Sadi Marcelo Schio, José de Jesus Peixoto Camargo, Bruno Hochhegger, Luiz Carlos Severo
We report herein a case of thoracic infection due to Nocardia nova following lung re-transplantation performed for emphysema related to alpha-1-antitrypsin deficiency. The infection extended from the lung into the pleural space, thoracic wall, and mediastinum, presenting as pericarditis and empyema necessitatis. Nocardia nova was identified by 16S ribosomal deoxyribonucleic acid (rDNA) sequencing and phylogenetic analysis. According to a literature search of PubMed, LILACS and MEDLINE databases, we describe herein the first case of empyema necessitatis caused by N...
July 2016: Revista da Sociedade Brasileira de Medicina Tropical
Mark S Forshag
Registrational trials in rare and orphan diseases present complexities related to the identification of subjects, recruitment, logistical hurdles incumbent with far-flung study sites, and end points that are often less well defined than are those used in more common illnesses. Alpha-1 antitrypsin deficiency is an orphan disease of genetic origin that carries the additional challenges of variable penetration and slow disease progression. Registrational trials of augmentation therapy using plasma-derived alpha-1 antitrypsin carry all of the above-noted burdens, as well as competition from commercially available augmentation therapy in many countries...
August 2016: Annals of the American Thoracic Society
Robert A Sandhaus
Alpha-1 antitrypsin deficiency (AATD) is a condition caused by the inheritance of two mutated SERPINA1 gene alleles. Individuals with AATD are at increased risk of injury to the liver and lungs. The pulmonary manifestations include precocious onset of pulmonary emphysema and bronchiectasis. For nearly three decades, treatment has been available to individuals with emphysema caused by AATD, but this therapy-augmentation of plasma and tissue alpha-1 antitrypsin levels by intravenous administration of human plasma-derived protein-was approved by regulatory authorities based on its biochemical efficacy...
August 2016: Annals of the American Thoracic Society
Maria J Chiuchiolo, Ronald G Crystal
Alpha-1 antitrypsin (AAT) deficiency, characterized by low plasma levels of the serine protease inhibitor AAT, is associated with emphysema secondary to insufficient protection of the lung from neutrophil proteases. Although AAT augmentation therapy with purified AAT protein is efficacious, it requires weekly to monthly intravenous infusion of AAT purified from pooled human plasma, has the risk of viral contamination and allergic reactions, and is costly. As an alternative, gene therapy offers the advantage of single administration, eliminating the burden of protein infusion, and reduced risks and costs...
August 2016: Annals of the American Thoracic Society
Matthias Griese, Gerhard Scheuch
Treatment with exogenous alpha-1 antitrypsin (AAT), a potent serine protease inhibitor, was developed originally for chronic obstructive pulmonary disease associated with AAT deficiency; however, other lung conditions involving neutrophilic inflammation and proteolytic tissue injury related to neutrophil elastase and other serine proteases may also be considered for AAT therapy. These conditions include bronchiectasis caused by primary ciliary dyskinesia, cystic fibrosis, and other diseases associated with an increased free elastase activity in the airways...
August 2016: Annals of the American Thoracic Society
Gerard M Turino, Shuren Ma, Jerome O Cantor, Yong Y Lin
Biomarkers of pathogenesis in chronic obstructive pulmonary disease (COPD) can significantly accelerate drug development. In COPD related to alpha-1 antitrypsin deficiency, the role of neutrophil elastase and its inhibition by alpha-1 antitrypsin protein focused interest on elastin degradation and the development of pulmonary emphysema. Amino acids desmosine and isodesmosine are unique cross-links in mature elastin fibers and can serve as biomarkers of elastin degradation when measured in body fluids. This review gives a perspective on what has been learned by the earliest measurements of desmosine and isodesmosine followed by later studies using methods of increased sensitivity and specificity and the meaning for developing new therapies...
August 2016: Annals of the American Thoracic Society
Robert A Stockley
Alpha-1 antitrypsin deficiency (AATD) is a recognized genetic cause of rapidly progressive loss of lung function conventionally assessed by the decline in FEV1. However, there is less information concerning other physiological measures and the impact on quality of life. Data derived predominantly from the UK national registry show that AATD presents with various physiological phenotypes with differing clinical impact and progression. In general, the decline in quality of life is surprisingly slow despite rapid loss of lung function, which may reflect the benefits of centralized services for patients with AATD...
August 2016: Annals of the American Thoracic Society
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