Alpha-1 antitrypsin deficiency caused by a novel mutation (p.Leu263Pro): Pi*ZQ0gaia – Q0gaia allele
Read
9356
Timeswas read the article
2525
Total PDF
6831
Total HTML
Share statistics
array:20 [ "pii" => "X0873215915459735" "issn" => "08732159" "doi" => "10.1016/j.rppnen.2015.07.002" "estado" => "S300" "fechaPublicacion" => "2015-11-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Rev Port Pneumol. 2015;21:341-3" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 3928 "formatos" => array:3 [ "EPUB" => 232 "HTML" => 2744 "PDF" => 952 ] ] "itemSiguiente" => array:16 [ "pii" => "X0873215915459743" "issn" => "08732159" "doi" => "10.1016/j.rppnen.2015.07.005" "estado" => "S300" "fechaPublicacion" => "2015-11-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Rev Port Pneumol. 2015;21:344-5" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 3628 "formatos" => array:3 [ "EPUB" => 234 "HTML" => 2526 "PDF" => 868 ] ] "en" => array:8 [ "idiomaDefecto" => true "titulo" => "Positional sleep apnea: An issue of therapeutic adherence" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "344" "paginaFinal" => "345" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "P. Matos, F. Fradinho, A. Catarino, P. Lopes, M.J. Matos" "autores" => array:5 [ 0 => array:2 [ "Iniciales" => "P." "apellidos" => "Matos" ] 1 => array:2 [ "Iniciales" => "F." "apellidos" => "Fradinho" ] 2 => array:2 [ "Iniciales" => "A." "apellidos" => "Catarino" ] 3 => array:2 [ "Iniciales" => "P." "apellidos" => "Lopes" ] 4 => array:2 [ "Iniciales" => "M.J." "apellidos" => "Matos" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0873215915459743?idApp=UINPBA00004E" "url" => "/08732159/0000002100000006/v0_201604141141/X0873215915459743/v0_201604141141/en/main.assets" ] "itemAnterior" => array:16 [ "pii" => "X0873215915459727" "issn" => "08732159" "doi" => "10.1016/j.rppnen.2015.03.005" "estado" => "S300" "fechaPublicacion" => "2015-11-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Rev Port Pneumol. 2015;21:334-40" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 8500 "formatos" => array:3 [ "EPUB" => 266 "HTML" => 7038 "PDF" => 1196 ] ] "en" => array:11 [ "idiomaDefecto" => true "titulo" => "Multidisciplinary rehabilitation in ventilator-dependent patients: Call for action in specialized inpatient facilities" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "334" "paginaFinal" => "340" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "320v21n06-90445972fig1.jpg" "Alto" => 1735 "Ancho" => 975 "Tamanyo" => 906284 ] ] "descripcion" => array:1 [ "en" => "A ventilator-dependent tracheostomized patient walking with assistance from the staff." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. Winck, R. Camacho, N. Ambrosino" "autores" => array:3 [ 0 => array:2 [ "Iniciales" => "J." "apellidos" => "Winck" ] 1 => array:2 [ "Iniciales" => "R." "apellidos" => "Camacho" ] 2 => array:2 [ "Iniciales" => "N." "apellidos" => "Ambrosino" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0873215915459727?idApp=UINPBA00004E" "url" => "/08732159/0000002100000006/v0_201604141141/X0873215915459727/v0_201604141141/en/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "titulo" => "Alpha-1 antitrypsin deficiency caused by a novel mutation (p.Leu263Pro): Pi*ZQ0gaia – Q0gaia allele" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "341" "paginaFinal" => "343" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "M.J. Oliveira, S. Seixas, I. Ladeira, R. Monteiro, T. Shiang, M. Guimarães, R. Lima" "autores" => array:7 [ 0 => array:4 [ "Iniciales" => "M.J." "apellidos" => "Oliveira" "email" => array:1 [ 0 => "maria.joaooliveira@chvng.min-saude.pt" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor1" ] ] ] 1 => array:3 [ "Iniciales" => "S." "apellidos" => "Seixas" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] ] ] 2 => array:3 [ "Iniciales" => "I." "apellidos" => "Ladeira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 3 => array:3 [ "Iniciales" => "R." "apellidos" => "Monteiro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 4 => array:3 [ "Iniciales" => "T." "apellidos" => "Shiang" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 5 => array:3 [ "Iniciales" => "M." "apellidos" => "Guimarães" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 6 => array:3 [ "Iniciales" => "R." "apellidos" => "Lima" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Pulmonology, Centro Hospitalar de Vila Nova de Gaia/Espinho, Portugal" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Investigação e Inovação em Saúde (I3S), University of Porto, Portugal" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, Portugal" "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "<span class="elsevierStyleSup">*</span>" "correspondencia" => "Corresponding author. maria.joaooliveira@chvng.min-saude.pt" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "320v21n06-90445973fig1.jpg" "Alto" => 1068 "Ancho" => 1555 "Tamanyo" => 162808 ] ] "descripcion" => array:1 [ "en" => "Characterization of Q0Gaia allele. (A) Protein gel electrophoresis. Index case ZQ0 displays only a band corresponding to PI*Z allele. (B) Electropherogram of the index case. The arrow shows the region of the T to C mutation in codon 263." ] ] ] "textoCompleto" => "<a name="sec0005" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Introduction</span><p class="elsevierStylePara">Human alpha-1 antitrypsin (AAT), also called proteinase inhibitor (PI), belongs to the serine protease inhibitors superfamily (SERPIN) and is a mature glycoprotein; it is composed of a single chain of 394 amino acids, and three side chains of carbohydrates, weighting approximately 52 kDa. AAT is also the major SERPIN in the serum and a water soluble molecule with a half-life of 4–5 days, encoded by <span class="elsevierStyleItalic">SERPINA1</span> gene located on chromosome 14.<a href="#bib14" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> More than 80% of AAT is synthesized and secreted by hepatocytes, with humans producing about 34 mg/kg/day, which results in serum concentrations of 1–2 g/L. Approximately, 80% diffuses from serum into interstitial tissues and 0.5–10% reaches other biological fluids like alveolar fluid, saliva, tears, milk, semen, bile and urine.<a href="#bib15" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">, </span><a href="#bib16" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">, </span><a href="#bib17" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleItalic">SERPINA1</span> has numerous gene variants among common and rare alleles, and normal, deficiency and null variants, which determine protein serum levels in an autosomal codominant mode. Severe AAT deficiency (AATD) is probably one of the most common hereditary conditions, estimated to affect between 70,000 and 100,000 individuals in Europe and defined by serum AAT levels below 35% of the expected value (50 mg/dL and 11 mmol/L or 80 mg/dL, as measured by nephelometry and radial immunodiffusion, respectively).<a href="#bib18" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">5</span></a> DAAT is generally associated with PI*ZZ genotype and less often with combinations of PI*Z, PI*S, and other rarer deficiency or null (Q0) alleles.<a href="#bib16" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">, </span><a href="#bib17" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">, </span><a href="#bib19" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">6</span></a> Severe AATD predisposes patients to various diseases, including pulmonary emphysema, liver disease, systemic vasculitis and panniculitis. In Portugal the incidence of chronic obstructive pulmonary disease (COPD) is 14.2% in patients over 40 years old,<a href="#bib20" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">7</span></a> and even though the prevalence of AATD in COPD patients is not well established, it is estimated to be about 1–3%.<a href="#bib16" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a> Pulmonary emphysema associated with AATD is characterized by early onset (between 35 and 45 years), which is usually accelerated by patient smoking history.</p><a name="sec0010" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Case report</span><p class="elsevierStylePara">We present a case of a 41 year old man, former smoker (18 PPY), who was referred to our pulmonology outpatient clinic in 2009, due to COPD. He had dyspnea (mMRC 2) and was treated with tiotropium bromide, formoterol, budesonide and aminophylline. The initial physical examination showed a lung auscultation with decrease breath sounds and no other significant changes. Additional exams revealed an already compromised respiratory function with very severe obstruction (FEV<span class="elsevierStyleInf">1</span>/FVC 41%, FEV<span class="elsevierStyleInf">1</span> 31% (1130 ml) and FVC 70%); arterial blood gas with hypoxemia (PaO2 65 mmHg) and normocapnia (35 mmHg). Furthermore, the study of alveolar capillary diffusion of carbon monoxide (DLCO) was moderately reduced (45%); chest computed tomography (CT) confirmed severe symptoms of diffuse emphysema; and AAT serum concentration was 22.2 mg/dl. Later, the evaluation of patient genotype showed incongruent results between protein electrophoresis (immunoelectrophoresis, pH 4.46 and 4.96) and protein chain reaction (PCR) multiplex screening of PI*Z and PI*S mutation,<a href="#bib21" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">, </span><a href="#bib22" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">9</span></a> a Z phenotype versus MZ genotype. This was explained by a novel mutation c.860T>C/p.(Leu263Pro) in exon III of <span class="elsevierStyleItalic">SERPINA1</span> (genomic reference NM_000295.4; for consistency with SERPINA1 literature the amino acid was numbered according to mature protein, 24 residues less UniProtKB: P01009), predicted by different bioinformatic tools to have damaging effects in protein structure and to be a likely disease causing mutation (scores: Polyphen-2 = 1.0, SIFT = 0, PROVEAN = −5.365 and Mutation Taster = 0.99)<a href="#bib23" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">, </span><a href="#bib24" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">, </span><a href="#bib25" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">12</span></a> and identified only after <span class="elsevierStyleItalic">SERPINA1</span> sequencing.<a href="#bib21" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">8</span></a> The p.Leu263Pro mutation is located in a highly conserved residue among SERPINA1 orthologs (placental mammals) and in the vicinity of p.Glu264Val (c.863A>T) variant, underlying the common deficiency S allele. Likewise, the substitution of p.Leu263Pro is likely to cause a distortion of the α-helix G and affect SERPINA1 gate structural domain. Regarding these findings, the absence of a corresponding band in protein gel electrophoresis and the patient birth place, this allele was named Q0gaia (<a href="#f0005" class="elsevierStyleCrossRefs">Figure 1</a>). Upon the diagnosis of pulmonary disease by AATD (COPD with severe airway obstruction), in a multidisciplinary meeting the patient was proposed for AAT replacement therapy. Despite the understanding of his clinical situation and the benefit he would have gained with the treatment, the patient delayed starting, due to the lack of availability for regular hospital visits. Over the past five years, the patient remained in follow-up and is currently proposed for AAT replacement therapy (60 mg/kg/week). Family screening was carried out, which identified the ZQ0 genotype in the patient's sister (a former smoker, who has FEV<span class="elsevierStyleInf">1</span> of 82%, mild reduced DLCO and no emphysema on CT chest scan).</p><a name="f0005" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"><img src="320v21n06-90445973fig1.jpg" alt="Characterization of Q0Gaia allele. (A) Protein gel electrophoresis. Index case ZQ0 displays only a band corresponding to PI*Z allele. (B) Electropherogram of the index case. The arrow shows the region of the T to C mutation in codon 263."></img></p><p class="elsevierStylePara">Figure 1. Characterization of Q0Gaia allele. (A) Protein gel electrophoresis. Index case ZQ0 displays only a band corresponding to PI*Z allele. (B) Electropherogram of the index case. The arrow shows the region of the T to C mutation in codon 263.</p><a name="sec0015" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Discussion</span><p class="elsevierStylePara">In this case report, COPD should probably be attributed to AATD owing to a reduced protection of the lung tissue against the neutrophil elastase, which leads to a progressive destruction of the parenchyma, and emphysema. Specifically, the increased risk of serious illness was caused by two alleles, both associated to severe AATD: PI*Z, a dysfunctional allele characterized by low secretion of AAT and an extremely rare variant Q0gaia (p.Leu263Pro) associated with very low or missing serum concentrations of AAT. Indeed, several examples from the literature show that Leu-Pro and Pro-Leu substitutions are linked to serious distortions in SERPIN structure. This is the case of SERPINA1 alleles Mprocida (p.Leu41Pro) and Mheerlen (p.Pro369Leu), which cause the distortions in A α-helix and in 1C-4B β-sheet strands, respectively, and are linked to dramatic reductions in serum levels (less than 95%), due to intracellular protein degradation.<a href="#bib26" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">13</span></a> Here, the biochemical properties of the leucine and proline residues may correlate to mutation pathogenesis, while leucine is a hydrophobic residue displaying a preference for α-helices, the proline is a small amino acid with unique properties, able to introduce kinks in protein structure. In addition, the severe lung disease was presented in a young patient with a former history of smoking. This case report aims to demonstrate not only a novel null allele underlying AATD and its associated disease risk, but also the challenge that AAT replacement therapy may represent to the life of a patient, who takes the decision not to be treated.</p><a name="sec0020" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Ethical disclosures</span><a name="sec0025" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Protection of human and animal subjects</span><p class="elsevierStylePara">The authors declare that no experiments were performed on humans or animals for this study.</p><a name="sec0030" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Confidentiality of data</span><p class="elsevierStylePara">The authors declare that they have followed the protocols of their work center on the publication of patient data.</p><a name="sec0035" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Right to privacy and informed consent</span><p class="elsevierStylePara">The authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.</p><a name="sec0040" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p class="elsevierStylePara">The authors have no conflicts of interest to declare.</p><p class="elsevierStylePara">Received 18 May 2015 <br></br>Accepted 8 July 2015 </p><p class="elsevierStylePara">Corresponding author. maria.joaooliveira@chvng.min-saude.pt</p>" "pdfFichero" => "320v21n06a90445973pdf001.pdf" "tienePdf" => true "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec640968" "palabras" => array:3 [ 0 => "Alpha-1 antitrypsin deficiency" 1 => "Null allele" 2 => "COPD" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:1 [ "resumen" => "<span class="elsevierStyleSectionTitle"> Abstract</span><br/><p class="elsevierStylePara"> Severe alpha-1 antitrypsin deficiency (AATD) is generally associated with PI*ZZ genotype and less often with combinations of PI*Z, PI*S, and other rarer deficiency or null (Q0) alleles. Severe AATD predisposes patients to various diseases, including pulmonary emphysema. Presented here is a case report of a young man with COPD and AATD. The investigation of the AATD showed a novel mutation p.Leu263Pro (c.860T>C), which was named Q0gaia (Pi*ZQ0gaia). Q0gaia is associated with very low or no detectable serum concentrations of AAT.</p>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "320v21n06-90445973fig1.jpg" "Alto" => 1068 "Ancho" => 1555 "Tamanyo" => 162808 ] ] "descripcion" => array:1 [ "en" => "Characterization of Q0Gaia allele. (A) Protein gel electrophoresis. Index case ZQ0 displays only a band corresponding to PI*Z allele. (B) Electropherogram of the index case. The arrow shows the region of the T to C mutation in codon 263." ] ] 1 => array:6 [ "identificador" => "fig2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "descripcion" => array:1 [ "en" => "Characterization of Q0Gaia allele. (A) Protein gel electrophoresis. Index case ZQ0 displays only a band corresponding to PI*Z allele. (B) Electropherogram of the index case. The arrow shows the region of the T to C mutation in codon 263." ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:13 [ 0 => array:3 [ "identificador" => "bib14" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Alpha-1 antitrypsin deficiency. The experience of Pulido Valente Hospital with augmentation therapy. Rev Port Pneumol. 2009; 15(3):473-82." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Alpha-1 antitrypsin deficiency. The experience of Pulido Valente Hospital with augmentation therapy." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Costa CA" 1 => "Santos C." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Port Pneumol. " "fecha" => "2009" "volumen" => "15" "paginaInicial" => "473" "paginaFinal" => "482" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19401796" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib15" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Role of alpha-1 antitrypsin in human health and disease. J Intern Med. 2014; 276(4):311-35." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Role of alpha-1 antitrypsin in human health and disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "de Serres F" 1 => "Blanco I." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/joim.12239" "Revista" => array:6 [ "tituloSerie" => "J Intern Med. " "fecha" => "2014" "volumen" => "276" "paginaInicial" => "311" "paginaFinal" => "335" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24661570" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib16" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha1-antitrypsin deficiency. Am J Respir Crit Care Med. 2003; 168:818-900." "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha1-antitrypsin deficiency." "idioma" => "en" ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/rccm.168.7.818" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med. " "fecha" => "2003" "volumen" => "168" "paginaInicial" => "818" "paginaFinal" => "900" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14522813" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib17" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "A review of a1-antitrypsin deficiency. Am J Respir Crit Care Med. 2012; 185:246-59." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "A review of a1-antitrypsin deficiency." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Stoller JK" 1 => "Aboussouan LS." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/rccm.201108-1428CI" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med. " "fecha" => "2012" "volumen" => "185" "paginaInicial" => "246" "paginaFinal" => "259" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21960536" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib18" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Worldwide racial and ethnic distribution of alpha 1-antitrypsin deficiency. Chest. 2002; 122:1818-29." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Worldwide racial and ethnic distribution of alpha 1-antitrypsin deficiency." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "de Serres FJ." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Chest. " "fecha" => "2002" "volumen" => "122" "paginaInicial" => "1818" "paginaFinal" => "1829" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12426287" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib19" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Indications for active case searches and intravenous alpha-1 antitrypsin treatment for patients with alpha-1 antitrypsin deficiency chronic pulmonary obstructive disease: an update. Arch Bronconeumol. 2015; 51:185-92." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Indications for active case searches and intravenous alpha-1 antitrypsin treatment for patients with alpha-1 antitrypsin deficiency chronic pulmonary obstructive disease: an update." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Casas F" 1 => "Blanco I" 2 => "Martínez MT" 3 => "Bustamante A" 4 => "Miravitlles M" 5 => "Cadenas S" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.arbres.2014.05.008" "Revista" => array:6 [ "tituloSerie" => "Arch Bronconeumol. " "fecha" => "2015" "volumen" => "51" "paginaInicial" => "185" "paginaFinal" => "192" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25027067" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib20" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Prevalência da doença pulmonar obstrutiva crónica em Lisboa, Portugal: estudo Burden of Obstructive Lung Disease. Rev Port Pneumol. 2013; 19:96-105." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Prevalência da doença pulmonar obstrutiva crónica em Lisboa, Portugal: estudo Burden of Obstructive Lung Disease." "idioma" => "pt" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Bárbara C" 1 => "Rodrigues F" 2 => "Dias H" 3 => "Cardoso J" 4 => "Almeida J" 5 => "Matos MJ" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.rppneu.2012.11.004" "Revista" => array:6 [ "tituloSerie" => "Rev Port Pneumol. " "fecha" => "2013" "volumen" => "19" "paginaInicial" => "96" "paginaFinal" => "105" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23664024" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib21" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Severe α-1 antitrypsin deficiency caused by Q0(Ourém) allele: clinical features, haplotype characterization and history. Clin Genet. 2012; 81:462-9." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Severe α-1 antitrypsin deficiency caused by Q0(Ourém) allele: clinical features, haplotype characterization and history." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Rodrigues LV" 1 => "Costa F" 2 => "Marques P" 3 => "Mendonça C" 4 => "Rocha J" 5 => "Seixas S." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1399-0004.2011.01670.x" "Revista" => array:6 [ "tituloSerie" => "Clin Genet. " "fecha" => "2012" "volumen" => "81" "paginaInicial" => "462" "paginaFinal" => "469" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21457231" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib22" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Multiplex PCR assay for the detection of genetic variants of alpha1-antitrypsin. Clin Chem. 1999; 45:688-90." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Multiplex PCR assay for the detection of genetic variants of alpha1-antitrypsin." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Rieger S" 1 => "Riemer H" 2 => "Mannhalter C." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Chem. " "fecha" => "1999" "volumen" => "45" "paginaInicial" => "688" "paginaFinal" => "690" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10222359" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib23" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013. Chapter 7:Unit7.20" "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Predicting functional effect of human missense mutations using PolyPhen-2." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Adzhubei I" 1 => "Jordan DM" 2 => "Sunyaev SR." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:2 [ "tituloSerie" => "Curr Protoc Hum Genet. " "fecha" => "2013" ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib24" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Predicting the functional effect of amino acid substitutions and indels. PLoS ONE. 2012; 7(10):e46688." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Predicting the functional effect of amino acid substitutions and indels." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Choi Y" 1 => "Sims GE" 2 => "Murphy S" 3 => "Miller JR" 4 => "Chan AP." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pone.0046688" "Revista" => array:5 [ "tituloSerie" => "PLoS ONE. " "fecha" => "2012" "volumen" => "7" "paginaInicial" => "e46688" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23056405" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib25" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014; 11(4):361-2." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "MutationTaster2: mutation prediction for the deep-sequencing age." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Schwarz JM" 1 => "Cooper DN" 2 => "Schuelke M" 3 => "Seelow D." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nmeth.2890" "Revista" => array:6 [ "tituloSerie" => "Nat Methods. " "fecha" => "2014" "volumen" => "11" "paginaInicial" => "361" "paginaFinal" => "362" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24681721" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib26" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "What do dysfunctional serpins tell us about molecular mobility and disease?. Nat Struct Biol. 1995; 2:96-113." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "What do dysfunctional serpins tell us about molecular mobility and disease?." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Stein PE" 1 => "Carrell RW." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Nat Struct Biol. " "fecha" => "1995" "volumen" => "2" "paginaInicial" => "96" "paginaFinal" => "113" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7749926" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/08732159/0000002100000006/v0_201604141141/X0873215915459735/v0_201604141141/en/main.assets" "Apartado" => array:4 [ "identificador" => "50819" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Brief Communication" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/08732159/0000002100000006/v0_201604141141/X0873215915459735/v0_201604141141/en/320v21n06a90445973pdf001.pdf?idApp=UINPBA00004E&text.app=https://journalpulmonology.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0873215915459735?idApp=UINPBA00004E" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 9 | 7 | 16 |
| 2024 October | 71 | 24 | 95 |
| 2024 September | 99 | 20 | 119 |
| 2024 August | 134 | 33 | 167 |
| 2024 July | 105 | 34 | 139 |
| 2024 June | 72 | 23 | 95 |
| 2024 May | 86 | 33 | 119 |
| 2024 April | 125 | 41 | 166 |
| 2024 March | 124 | 29 | 153 |
| 2024 February | 80 | 19 | 99 |
| 2024 January | 59 | 26 | 85 |
| 2023 December | 95 | 28 | 123 |
| 2023 November | 63 | 37 | 100 |
| 2023 October | 60 | 38 | 98 |
| 2023 September | 42 | 32 | 74 |
| 2023 August | 72 | 19 | 91 |
| 2023 July | 56 | 28 | 84 |
| 2023 June | 49 | 16 | 65 |
| 2023 May | 54 | 27 | 81 |
| 2023 April | 61 | 20 | 81 |
| 2023 March | 89 | 21 | 110 |
| 2023 February | 62 | 26 | 88 |
| 2023 January | 56 | 19 | 75 |
| 2022 December | 70 | 17 | 87 |
| 2022 November | 123 | 31 | 154 |
| 2022 October | 70 | 34 | 104 |
| 2022 September | 63 | 30 | 93 |
| 2022 August | 77 | 35 | 112 |
| 2022 July | 55 | 45 | 100 |
| 2022 June | 49 | 24 | 73 |
| 2022 May | 61 | 43 | 104 |
| 2022 April | 69 | 42 | 111 |
| 2022 March | 74 | 55 | 129 |
| 2022 February | 83 | 36 | 119 |
| 2022 January | 72 | 25 | 97 |
| 2021 December | 33 | 40 | 73 |
| 2021 November | 48 | 37 | 85 |
| 2021 October | 52 | 51 | 103 |
| 2021 September | 30 | 26 | 56 |
| 2021 August | 31 | 15 | 46 |
| 2021 July | 51 | 29 | 80 |
| 2021 June | 47 | 18 | 65 |
| 2021 May | 56 | 25 | 81 |
| 2021 April | 104 | 60 | 164 |
| 2021 March | 108 | 20 | 128 |
| 2021 February | 99 | 17 | 116 |
| 2021 January | 61 | 21 | 82 |
| 2020 December | 56 | 13 | 69 |
| 2020 November | 51 | 15 | 66 |
| 2020 October | 52 | 18 | 70 |
| 2020 September | 63 | 28 | 91 |
| 2020 August | 85 | 27 | 112 |
| 2020 July | 89 | 20 | 109 |
| 2020 June | 96 | 25 | 121 |
| 2020 May | 78 | 22 | 100 |
| 2020 April | 78 | 8 | 86 |
| 2020 March | 86 | 17 | 103 |
| 2020 February | 81 | 24 | 105 |
| 2020 January | 87 | 14 | 101 |
| 2019 December | 74 | 17 | 91 |
| 2019 November | 74 | 21 | 95 |
| 2019 October | 96 | 20 | 116 |
| 2019 September | 89 | 24 | 113 |
| 2019 August | 127 | 20 | 147 |
| 2019 July | 126 | 13 | 139 |
| 2019 June | 113 | 22 | 135 |
| 2019 May | 144 | 21 | 165 |
| 2019 April | 115 | 39 | 154 |
| 2019 March | 155 | 16 | 171 |
| 2019 February | 124 | 13 | 137 |
| 2019 January | 128 | 26 | 154 |
| 2018 December | 51 | 4 | 55 |
| 2018 November | 27 | 1 | 28 |
| 2018 October | 28 | 9 | 37 |
| 2018 September | 35 | 5 | 40 |
| 2018 August | 35 | 23 | 58 |
| 2018 July | 45 | 17 | 62 |
| 2018 June | 42 | 16 | 58 |
| 2018 May | 47 | 16 | 63 |
| 2018 April | 66 | 17 | 83 |
| 2018 March | 49 | 18 | 67 |
| 2018 February | 24 | 12 | 36 |
| 2018 January | 31 | 8 | 39 |
| 2017 December | 35 | 28 | 63 |
| 2017 November | 32 | 14 | 46 |
| 2017 October | 14 | 16 | 30 |
| 2017 September | 32 | 17 | 49 |
| 2017 August | 52 | 14 | 66 |
| 2017 July | 29 | 20 | 49 |
| 2017 June | 24 | 11 | 35 |
| 2017 May | 46 | 15 | 61 |
| 2017 April | 24 | 3 | 27 |
| 2017 March | 26 | 6 | 32 |
| 2017 February | 18 | 9 | 27 |
| 2017 January | 25 | 10 | 35 |
| 2016 December | 28 | 16 | 44 |
| 2016 November | 31 | 15 | 46 |
| 2016 October | 37 | 21 | 58 |
| 2016 September | 30 | 13 | 43 |
| 2016 August | 22 | 22 | 44 |
| 2016 July | 19 | 51 | 70 |
| 2016 June | 0 | 54 | 54 |
| 2016 April | 30 | 14 | 44 |
| 2016 March | 27 | 13 | 40 |
| 2016 February | 40 | 38 | 78 |
| 2016 January | 70 | 48 | 118 |
| 2015 December | 84 | 52 | 136 |
Show all
