metricas
covid
Buscar en
Annals of Hepatology
Toda la web
Inicio Annals of Hepatology Relationship of Severity of Hepatitis A with Polymorphisms in Hepatitis A Virus ...
Journal Information

Statistics

Follow this link to access the full text of the article

Relationship of Severity of Hepatitis A with Polymorphisms in Hepatitis A Virus Cellular Receptor 1 (HAVCR1) Gene
Mercilena Benjamin*, Shikha Agnihotry**, Anshu Srivastava***, Rishi Bolia***, SK Yachha***, Rakesh Aggarwal
,**,
Corresponding author
aggarwal.ra@gmail.com

Correspondence and reprint request:
* Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, UP, India
** Biomedical Informatics Centre, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, UP, India
*** Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, UP, India
Read
2041
Times
was read the article
456
Total PDF
1585
Total HTML
Share statistics
 array:24 [
  "pii" => "S1665268119304788"
  "issn" => "16652681"
  "doi" => "10.5604/01.3001.0012.0917"
  "estado" => "S300"
  "fechaPublicacion" => "2018-07-01"
  "aid" => "70299"
  "copyright" => "Fundación Clínica Médica Sur, A.C."
  "copyrightAnyo" => "2018"
  "documento" => "article"
  "crossmark" => 0
  "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
  "subdocumento" => "fla"
  "cita" => "Ann Hepatol. 2018;17:561-8"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:2 [
    "total" => 130
    "formatos" => array:3 [
      "EPUB" => 12
      "HTML" => 80
      "PDF" => 38
    ]
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S166526811930479X"
    "issn" => "16652681"
    "doi" => "10.5604/01.3001.0012.0918"
    "estado" => "S300"
    "fechaPublicacion" => "2018-07-01"
    "aid" => "70300"
    "copyright" => "Fundación Clínica Médica Sur, A.C."
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
    "subdocumento" => "fla"
    "cita" => "Ann Hepatol. 2018;17:569-76"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 113
      "formatos" => array:3 [
        "EPUB" => 13
        "HTML" => 55
        "PDF" => 45
      ]
    ]
    "en" => array:11 [
      "idiomaDefecto" => true
      "titulo" => "Extracellular Matrix Proteins Substantiate IL-28B T allele Effect on Histological Outcome of Chronic Hepatitis C"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "569"
          "paginaFinal" => "576"
        ]
      ]
      "contieneResumen" => array:1 [
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "f0010"
          "etiqueta" => "Figure 2"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr2.jpeg"
              "Alto" => 1227
              "Ancho" => 1058
              "Tamanyo" => 151226
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Extracellular matrix proteins in patients with different IL-28B</span> rs12979860 <span class="elsevierStyleItalic">genotypes&#46; ECjM circulating levels in patients serum <span class="elsevierStyleBold">&#40;A&#41;</span> hyaluronic acid &#40;ng&#47;mL&#41;&#44; <span class="elsevierStyleBold">&#40;B&#41;</span> laminin &#40;ng&#47;mL&#41;&#44; <span class="elsevierStyleBold">&#40;C&#41;</span> collagen type IV and &#40;D&#41; N-terminal pro-peptide of collagen type III &#40;PIIINP&#41; &#40;ng&#47;mL&#41; were increased with an increasing number of T aleles&#46; <span class="elsevierStyleBold">&#40;E&#41;</span> Data represent fold increase of FibroScan and extracellular matrix proteins relative to IL-28B</span> rs12979860 <span class="elsevierStyleItalic">SNP in patients with liver diseases&#46;</span></p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Abdelfattah M&#46; Attallah, Dalia Omrang, Mohamed M&#46; Omran, Mohamed A&#46; Abdelrazek, Rania Zayed, Riham El Essawey, Sameh Saif, Azza Farid, Mohamed Hassany, Ayman Yosry, Ashraf Omar"
          "autores" => array:11 [
            0 => array:2 [
              "nombre" => "Abdelfattah M&#46;"
              "apellidos" => "Attallah"
            ]
            1 => array:2 [
              "nombre" => "Dalia"
              "apellidos" => "Omrang"
            ]
            2 => array:2 [
              "nombre" => "Mohamed M&#46;"
              "apellidos" => "Omran"
            ]
            3 => array:2 [
              "nombre" => "Mohamed A&#46;"
              "apellidos" => "Abdelrazek"
            ]
            4 => array:2 [
              "nombre" => "Rania"
              "apellidos" => "Zayed"
            ]
            5 => array:2 [
              "nombre" => "Riham El"
              "apellidos" => "Essawey"
            ]
            6 => array:2 [
              "nombre" => "Sameh"
              "apellidos" => "Saif"
            ]
            7 => array:2 [
              "nombre" => "Azza"
              "apellidos" => "Farid"
            ]
            8 => array:2 [
              "nombre" => "Mohamed"
              "apellidos" => "Hassany"
            ]
            9 => array:2 [
              "nombre" => "Ayman"
              "apellidos" => "Yosry"
            ]
            10 => array:2 [
              "nombre" => "Ashraf"
              "apellidos" => "Omar"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S166526811930479X?idApp=UINPBA00004N"
    "url" => "/16652681/0000001700000004/v1_201906150923/S166526811930479X/v1_201906150923/en/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S1665268119304776"
    "issn" => "16652681"
    "doi" => "10.5604/01.3001.0012.0916"
    "estado" => "S300"
    "fechaPublicacion" => "2018-07-01"
    "aid" => "70298"
    "copyright" => "Fundaci&#243;n Cl&#237;nica M&#233;dica Sur&#44; A&#46;C&#46;"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
    "subdocumento" => "rev"
    "cita" => "Ann Hepatol. 2018;17:547-60"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 732
      "formatos" => array:3 [
        "EPUB" => 11
        "HTML" => 539
        "PDF" => 182
      ]
    ]
    "en" => array:11 [
      "idiomaDefecto" => true
      "titulo" => "New Insights About Albumin and Liver Disease"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "547"
          "paginaFinal" => "560"
        ]
      ]
      "contieneResumen" => array:1 [
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "f0005"
          "etiqueta" => "Figure 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr1.jpeg"
              "Alto" => 414
              "Ancho" => 509
              "Tamanyo" => 63466
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Albumin structure&#46; Albumin has a single polypeptide sequence formed by 585 amino acids&#46; At position 34&#44; the cysteine residue is free and available for reaction with other molecules&#46; The protein has a heart-like shape&#44; possessing three homologous domains I-III&#44; each domain is divided into A and B subdomains&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Joana R&#46; Carvalho, Mariana Verdelho Machado"
          "autores" => array:2 [
            0 => array:2 [
              "nombre" => "Joana R&#46;"
              "apellidos" => "Carvalho"
            ]
            1 => array:2 [
              "nombre" => "Mariana Verdelho"
              "apellidos" => "Machado"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119304776?idApp=UINPBA00004N"
    "url" => "/16652681/0000001700000004/v1_201906150923/S1665268119304776/v1_201906150923/en/main.assets"
  ]
  "en" => array:17 [
    "idiomaDefecto" => true
    "titulo" => "Relationship of Severity of Hepatitis A with Polymorphisms in Hepatitis A Virus Cellular Receptor 1 <span class="elsevierStyleItalic">&#40;HAVCR1&#41;</span> Gene"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "561"
        "paginaFinal" => "568"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Mercilena Benjamin, Shikha Agnihotry, Anshu Srivastava, Rishi Bolia, SK Yachha, Rakesh Aggarwal"
        "autores" => array:6 [
          0 => array:3 [
            "nombre" => "Mercilena"
            "apellidos" => "Benjamin"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "aff0005"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "Shikha"
            "apellidos" => "Agnihotry"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;&#42;</span>"
                "identificador" => "aff0010"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "Anshu"
            "apellidos" => "Srivastava"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;&#42;&#42;</span>"
                "identificador" => "aff0015"
              ]
            ]
          ]
          3 => array:3 [
            "nombre" => "Rishi"
            "apellidos" => "Bolia"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;&#42;&#42;</span>"
                "identificador" => "aff0015"
              ]
            ]
          ]
          4 => array:3 [
            "nombre" => "SK"
            "apellidos" => "Yachha"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;&#42;&#42;</span>"
                "identificador" => "aff0015"
              ]
            ]
          ]
          5 => array:4 [
            "nombre" => "Rakesh"
            "apellidos" => "Aggarwal"
            "email" => array:1 [
              0 => "aggarwal.ra@gmail.com"
            ]
            "referencia" => array:3 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;&#42;</span>"
                "identificador" => "aff0010"
              ]
              2 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:3 [
          0 => array:3 [
            "entidad" => "Department of Gastroenterology&#44; Sanjay Gandhi Postgraduate Institute of Medical Sciences&#44; Lucknow&#44; UP&#44; India"
            "etiqueta" => "&#42;"
            "identificador" => "aff0005"
          ]
          1 => array:3 [
            "entidad" => "Biomedical Informatics Centre&#44; Sanjay Gandhi Postgraduate Institute of Medical Sciences&#44; Lucknow&#44; UP&#44; India"
            "etiqueta" => "&#42;&#42;"
            "identificador" => "aff0010"
          ]
          2 => array:3 [
            "entidad" => "Department of Pediatric Gastroenterology&#44; Sanjay Gandhi Postgraduate Institute of Medical Sciences&#44; Lucknow&#44; UP&#44; India"
            "etiqueta" => "&#42;&#42;&#42;"
            "identificador" => "aff0015"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#42;"
            "correspondencia" => "Correspondence and reprint request&#58;"
          ]
        ]
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:7 [
        "identificador" => "f0015"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 637
            "Ancho" => 1057
            "Tamanyo" => 134643
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Electropherograms showing the results of sequencing for the region of interest &#40;the region of 157insMTTTVP&#41; in exon 4 of the</span> HAVCR1 <span class="elsevierStyleItalic">gene in persons who were homozygous for the three haplotypes &#40;Panel A&#58; homozygous for reference sequence &#91;haplotype C&#93;&#59; Panel B&#58; homozygous for a 15-nucleotide &#40;nt&#41; deletion &#91;haplotype A&#93;&#59; Panel C&#58; homozygous for a 3-nt insertion &#91;haplotype B&#93;&#41;&#46; Panel D shows the electropherogram for a subject who was heterozygous for haplotypes A and B&#59; the panel below this electropherogram shows the sequences for the two haplotypes and the expected merged sequence &#40;the ambiguous codes are represented as per the notation laid down by the International Union of Pure and Applied Chemistry&#41;&#46;</span></p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0015">Introduction</span><p id="p0005" class="elsevierStylePara elsevierViewall">Hepatitis A virus &#40;HAV&#41; is a hepatotropic virus with 27-nm sized virions that contain a 7&#46;5-Kb long&#44; single-stranded RNA genome of positive polarity&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It is excreted in the feces of infected persons and is transmitted by the enteric route&#46; The infection is distributed worldwide&#44; though the risk of transmission varies widely across countries&#44; depending on socioeconomic status&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The severity of clinical disease following HAV infection depends heavily on the age at infection&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Thus&#44; infection during early childhood is most often asymptomatic&#46; By contrast&#44; infection in older children or adults more often leads to icteric illness&#44; and to fulminant liver failure and death&#46; Infection provides life-long immunity against reinfection&#46;</p><p id="p0010" class="elsevierStylePara elsevierViewall">The association of risk of HAV infection with hygiene and sanitation&#44; the dependence of disease severity on age at infection&#44; and the induction of lifelong immunity following HAV infection&#44; result in varying epidemiologic patterns of this disease in different geographical areas&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Thus&#44; in low-income countries&#44; HAV infection is highly endemic with a high transmission rate&#44; leading to nearly universal exposure during early childhood and a high seropositivity rate by adolescence&#44; albeit with little disease&#46; By contrast&#44; in high-income countries with low endemicity&#44; HAV transmission is infrequent&#44; leading to low rates of seroprevalence as well as disease&#46; A third pattern&#44; with intermediate endemicity&#44; is seen in developing countries that are transitioning to better hygiene&#59; falling transmission in these areas has led to an increase in average age at exposure to HAV&#44; with a paradoxical increase in disease rates and mortality&#46;</p><p id="p0015" class="elsevierStylePara elsevierViewall">Hepatitis A virus cellular receptor 1 &#40;HAVCR1&#41;&#44; a protein expressed on human hepatocyte membrane&#44; has been identified as the cellular receptor for HAV&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> This protein&#44; also known as T-cell immunoglobulin and mucin domain 1 &#40;TIM-1&#41; or kidney injury molecule 1 &#40;KIM-1&#41; protein&#44; has additional physiological roles&#44; including in the induction of cellular immunity&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">The gene for HAVCR1 is located on chromosome <span class="elsevierStyleItalic">5q33&#46;3</span>&#44; and shows marked genetic polymorphism&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Being the receptor for HAV&#44; variations in it have been proposed to affect an individual&#8217;s susceptibility to HAV infection&#46; Recently&#44; in Argentina&#44; a 6-amino acid insertion at residue 157 of the HAVCR1 protein &#40;termed 157insMTTTVP&#41; was shown to be associated with an increased risk of severe hepatitis A&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> This association is believed to be mediated by a more efficient binding of HAV by the longer HAVCR1 variant on hepatocytes&#44; and by a higher cytotoxicity against HAV-infected cells of natural killer T cells that carry this variant HAVCR1 protein&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="p0025" class="elsevierStylePara elsevierViewall">However&#44; in the Argentine study&#44; the statistical measure of association between severe hepatitis A disease and presence of HAVCR1 157insMTTTVP polymorphism was marginal&#46; Thus&#44; there is a need for further studies on this relationship&#44; particularly from other geographical regions with different epidemiologic patterns of this disease&#46; We&#44; therefore&#44; undertook such a study in India&#44; where HAV infection is highly endemic&#46;</p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0020">Material and Methods</span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Subjects</span><p id="p0030" class="elsevierStylePara elsevierViewall">Between May 2013 and July 2015&#44; we enrolled children with acute viral hepatitis A &#40;AVH-A&#41; attending the outpatient or inpatient services of the Department of Pediatric Gastroenterology at our institution&#46; The diagnosis of AVH-A was based on suggestive clinical picture&#44; elevated serum transaminase levels &#40;&#62; 3-fold the upper limit normal&#41; and positive IgM anti-HAV &#91;Mini Vidas&#59; bioM&#233;rieux&#44; Marcy l&#8217;Etoile&#44; France&#93;&#41;&#46; Persons with clinical or laboratory findings suggesting another concomitant disease or chronic liver disease were excluded&#46;</p><p id="p0035" class="elsevierStylePara elsevierViewall">Patients were examined for the presence of hepatic encephalopathy &#40;HE&#41;&#46; HE&#44; if present&#44; was graded using the standard criteria in children aged &#62; 3 years&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> For younger children&#44; a set of modified criteria&#44; which have been recommended for this age group&#44; were used&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> In addition&#44; prothrombin time-international normalized ratio &#40;PT-INR&#41; was measured after parenteral administration of one dose of vitamin K&#46; Children with AVH-A who fulfilled the criteria laid down by the Pediatric Acute Liver Failure Study Group&#44;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> i&#46;e&#46; if HE was present and PT-INR was &#62; 1&#46;5&#44; or if the PT-INR was &#62; 2&#46;0 even in the absence of HE&#44; were classified as having acute liver failure &#40;ALF-A&#41;&#59; the remaining children were considered to have uncomplicated AVH-A&#46;</p><p id="p0040" class="elsevierStylePara elsevierViewall">In addition&#44; left-over blood specimens from a group of healthy adult blood donors were used as controls&#46;</p></span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030"><span class="elsevierStyleItalic">HAVCR-1</span> genotyping</span><p id="p0045" class="elsevierStylePara elsevierViewall">Genomic DNA was extracted from whole blood collected in EDTA using the phenol-chloroform method&#44; and its purity and concentration were determined using Nanodrop spectrophotometer 1000 &#40;Thermo Fisher Scientific&#44; Waltham&#44; MA&#44; USA&#41;&#46; A 441-basepair region of <span class="elsevierStyleItalic">HAVCR-1</span> gene was amplified using specific primers &#40;forward&#58; 5&#8217;-TCT GTC ATT GGT GTG CTA GGG-3&#8217; and reverse&#58; 5&#8217;-TGG TCC GCA GCT CCT CAT TA-3&#8217;&#59; <a class="elsevierStyleCrossRef" href="#f0005">Figure <span class="elsevierStyleSup">1</span></a>&#41;&#46; Each PCR reaction &#40;20 <span class="elsevierStyleItalic">&#181;</span>L&#41; contained 40 ng of DNA template&#44; 1X Invitrogen buffer&#44; 1&#46;5 mM MgCl<span class="elsevierStyleInf">2</span>&#44; 0&#46;2 <span class="elsevierStyleItalic">&#181;</span>M dNTPs&#44; 5 pmol of each primer and 2 units of TaqDNA polymerase &#40;Invitrogen&#44; Waltham&#44; MA&#44; USA&#41;&#46; Cycling conditions were&#58; denaturation at 94 &#176;C for 5 min&#44; 36 cycles&#44; each consisting of denaturation at 94 &#176;C for 30 sec&#44; annealing at 63 &#176;C for 30 sec and extension at 72 &#176;C for 90 sec&#44; and a final extension at 72 &#176;C for 7 min&#46; The amplicons were purified using PureLink PCR purification kit &#40;Invitrogen&#44; Thermo Fisher&#41;&#44; and sequenced in both directions using the Big Dye Terminator v3&#46;1 &#40;Life Technologies&#44; Thermo Fisher&#41; chemistry and an ABI 3130 genetic analyzer&#46;</p><elsevierMultimedia ident="f0005"></elsevierMultimedia></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Data analysis</span><p id="p0050" class="elsevierStylePara elsevierViewall">The sequencing electropherograms were analyzed using FinchTV &#40;<a href="http://www.uptodate.com">http&#58;&#47;&#47;www&#46;geospiza&#46;com&#47;Products&#47;finchtv</a>&#46; shtml&#41;&#46; The sequences were further analyzed by aligning these to the reference genomic sequence of HAVCR1 gene &#40;NG&#95;017001&#46;1&#59; NCBI nucleotide database&#41;&#44; using BioEdit software version 7 &#40;<a href="http://www.uptodate.com">www&#46;mbio&#46;ncsu&#46;edu&#47;bioedit&#47;bioedit</a>&#46; html&#41;&#44; to identify nucleotide substitutions and insertion&#47; deletions &#40;indels&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> In particular&#44; two previously-reported&#44; overlapping indels in exon 4 of the HAVCR1 gene &#40;<a class="elsevierStyleCrossRef" href="#f0005">Figure <span class="elsevierStyleSup">1</span></a>&#41;&#44; namely p&#46;Met158&#95;Pro162del &#40;rs141023871&#41; and p&#46;Thr160&#95;Val161insThr &#40;rs139041445&#41;&#44; were mapped for each subject&#46; The sequences were also analyzed for the presence of another 3-nucleotide indel &#40;p&#46;Thr200del&#59; rs45439103&#41;&#46; Frequencies of various alleles among controls were tested for Hardy-Weinberg equilibrium&#46; The allele and genotype frequencies were compared between groups using the &#967;<span class="elsevierStyleSup">2</span> test&#46;</p><p id="p0055" class="elsevierStylePara elsevierViewall">The study was approved by our institution&#8217;s Ethics Committee&#46; Informed consent was obtained from each study subject or from one of the parents&#46;</p></span></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Results</span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Study subjects</span><p id="p0060" class="elsevierStylePara elsevierViewall">A total of 75 children with AVH-A were enrolled&#44; of whom 46 had uncomplicated AVH-A and 29 had ALF-A&#46; Specimens from 73 blood donors were studied as controls&#46; Clinical and laboratory details of the study patients are shown in <a class="elsevierStyleCrossRef" href="#t0005">table <span class="elsevierStyleSup">1</span></a>&#46;</p><elsevierMultimedia ident="t0005"></elsevierMultimedia></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050"><span class="elsevierStyleItalic">HAVCR1</span> genotyping results&#58; rs141023871 and rs139041445 polymorphisms</span><p id="p0065" class="elsevierStylePara elsevierViewall">For the region of interest with two overlapping indels&#44; three haplotypes were observed &#40;<a class="elsevierStyleCrossRef" href="#f0010">Figures <span class="elsevierStyleSup">2</span></a> and <a class="elsevierStyleCrossRef" href="#f0015"><span class="elsevierStyleSup">3</span></a>&#41;&#46; These three haplotypes&#44; in the decreasing order of their frequencies&#44; were&#58;<ul class="elsevierStyleList" id="l0005"><li class="elsevierStyleListItem" id="u0005"><span class="elsevierStyleLabel">&#8226;</span><p id="p0070" class="elsevierStylePara elsevierViewall">rs141023871&#95;del and rs139041445&#95;del &#40;the shortest variant&#41;&#46;</p></li><li class="elsevierStyleListItem" id="u0010"><span class="elsevierStyleLabel">&#8226;</span><p id="p0075" class="elsevierStylePara elsevierViewall">rs141023871&#95;ins and rs139041445&#95;ins &#40;the longest variant&#41;&#44; with a 18 nucleotide insertion &#40;corresponding to a 6-amino acid insertion - 157insMTTTVP&#41;&#46;</p></li><li class="elsevierStyleListItem" id="u0015"><span class="elsevierStyleLabel">&#8226;</span><p id="p0080" class="elsevierStylePara elsevierViewall">rs141023871&#95;ins and rs139041445&#95;del &#40;corresponding to NCBI reference sequence&#44; NG&#95;017001&#46;1&#41;&#44; with a 15-nucleotide insertion &#40;5 amino acid &#8211; 157insMT-TVP&#41; as compared to the shortest variant&#46;</p></li></ul></p><elsevierMultimedia ident="f0010"></elsevierMultimedia><elsevierMultimedia ident="f0015"></elsevierMultimedia><p id="p0085" class="elsevierStylePara elsevierViewall">These haplotypes are referred to subsequently as haplotypes A&#44; B and C&#44; respectively&#46;</p><p id="p0090" class="elsevierStylePara elsevierViewall">The allele frequencies of the three haplotypes in patients with symptomatic AVH-A were similar to those in the control subjects &#40;<a class="elsevierStyleCrossRef" href="#t0010">Table <span class="elsevierStyleSup">2</span></a>&#41;&#46; In particular&#44; the allele frequencies of allele B&#44; the allele of interest&#44; were similar in patients and controls &#40;29&#47;150 &#91;19&#37;&#93; <span class="elsevierStyleItalic">vs&#46;</span> 43&#47;146 &#91;29&#37;&#93;&#41;&#46; Also&#44; the combined frequencies of genotypes with 157insMTT-TVP on either one or both alleles &#40;BB&#44; AB or BC genotype&#41; were similar in patients and controls &#40;29&#47;75 &#91;39&#37;&#93; <span class="elsevierStyleItalic">vs&#46;</span> 39&#47;73 &#91;53&#37;&#93;&#41;&#46;</p><elsevierMultimedia ident="t0010"></elsevierMultimedia><p id="p0095" class="elsevierStylePara elsevierViewall">Furthermore&#44; the patients with ALF-A and those with uncomplicated AVH-A had similar allele frequencies of allele B &#40;12&#47;58 &#91;21&#37;&#93; <span class="elsevierStyleItalic">vs&#46;</span> 17&#47;92 &#91;18&#37;&#93;&#59; p &#61; ns&#41; and composite frequencies of genotypes that contain allele B &#40;12&#47;29 &#91;41&#37;&#93; <span class="elsevierStyleItalic">vs&#46;</span> 17&#47;46 &#91;37&#37;&#93;&#59; p &#61; ns&#41;&#46;</p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">rs45439103 polymorphism</span><p id="p0100" class="elsevierStylePara elsevierViewall">This 3-nucletide deletion polymorphism was strongly associated with the rs139041445 polymorphism&#44; i&#46;e&#46; it was observed only in persons with the 157insMTTTVP insertion allele &#40;allele B&#41; at the latter locus&#46; The allelic frequency of this deletion was similar in patients with hepatitis A &#40;19&#47;150 &#91;13&#37;&#93;&#41; and the control subjects &#40;32&#47;146 &#91;22&#37;&#93;&#59; p &#61; ns&#41;&#46;</p></span></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">Discussion</span><p id="p0105" class="elsevierStylePara elsevierViewall">In this study&#44; we assessed the distribution of different haplotypes of a part of exon 4 of the <span class="elsevierStyleItalic">HAVCR1</span> gene&#44; which included two overlapping indel polymorphisms&#44; among patients with AVH-A as compared to healthy controls in the Indian population&#44; as also between patients with AVH-A of different severities&#46; It revealed that allele and genotype frequencies of the haplotype with a 6-amino acid MTTTVP insertion&#44; previously implicated in the causation of severe hepatitis A&#44; was comparable among patients with AVH-A and healthy controls&#44; as well as among patients with severe and mild forms of AVH-A&#46;</p><p id="p0110" class="elsevierStylePara elsevierViewall">The HAVCR1 protein belongs to the T-cell immunoglobulin mucin &#40;TIM&#41; protein family&#44; which contains several type I cell-surface transmembrane glycoproteins&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> It contains an immunoglobulin-like domain&#44; a heavily-glycosylated mucin domain&#44; a single transmembrane domain and a short C-terminal cytoplasmic tail&#46; It is initially expressed by all CD4&#43; T cells&#59; however&#44; during differentiation&#44; its expression on TH1 and TH<span class="elsevierStyleInf">17</span> cells declines whereas that on TH<span class="elsevierStyleInf">2</span> cells remains high&#46;</p><p id="p0115" class="elsevierStylePara elsevierViewall">HAVCR1 is expressed on hepatocyte membrane and serves as the cellular receptor for HAV&#46;<a class="elsevierStyleCrossRefs" href="#bib0060">12</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In particular&#44; its mucin-like domain plays a role in the uncoating and internalization of the virus&#46; It also appears to serve as the cellular receptor for Ebolavirus&#44; flaviviruses&#44; alphaviruses and arenaviruses&#46;<a class="elsevierStyleCrossRefs" href="#bib0075">15</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="p0120" class="elsevierStylePara elsevierViewall">The HAVCR1 protein&#44; in particular exon 4&#44; is highly polymorphic&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The 157insMTTTVP polymorphism&#44; located in this exon&#44;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> is located in the extracellular mucin-like region of the protein&#44; which is important for uncoating of HAV before its entry into the cell&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> An insertion at this site may be expected to affect the binding and internalization of HAV into the hepatocytes&#44; and hence influence the clinical outcome of HAV infection&#46;</p><p id="p0125" class="elsevierStylePara elsevierViewall">The association of 157insMTTTVP polymorphism with human disease was first studied in atopic conditions in which <span class="elsevierStyleItalic">HAVCR1</span> gene was suspected to play a role&#46; This was done using a cross-sectional study&#44; in which 375 individuals were evaluated for history of atopy&#44; serologic evidence of HAV infection and the presence of this insertion&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> In this study&#44; HAV seropositivity was found to protect against atopy in individuals with the 157insMTTTVP variant&#44; but not in those without this insertion&#46; This suggested the existence of an interaction between HAV infection and <span class="elsevierStyleItalic">HAVCR1</span> genotype that contributed to the occurrence of atopic diseases&#44; and provided a possible basis for the hygiene hypothesis&#46; This interaction was explained through a hypothesis that immune cells with the longer variant of HAVCR1 protein bind HAV better&#59; thus&#44; HAV infection in persons with this variant could alter the Th1&#47;Th2 balance and thus protect against atopy&#46; However&#44; subsequent studies on this issue have shown conflicting results&#44; with an association being observed in some population groups<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> but not in some others&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Interestingly&#44; the relationship between the insertion and atopy has varied even within studies done in the Chinese population&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> In addition&#44; several studies have also looked at the association of this polymorphism with autoimmune disorders with conflicting results&#46; Thus&#44; while two single-nucleotide polymorphisms in this gene were associated with susceptibility to rheumatoid arthritis in one study&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> no association of polymorphisms in this gene was found with systemic lupus erythematosus in another study&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> In Thailand&#44; persons with HAVCR1 exon 4 haplotypes with lower expression levels of TIM1 were found to have a delayed progression of human immunodeficiency virus infection to acquired immunodeficiency syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><p id="p0130" class="elsevierStylePara elsevierViewall">If a genetic variation in the HAVCR1 protein affects its binding to HAV&#44; one may expect it to affect the risk and outcome of HAV infection&#46; This was examined by Kim&#44; <span class="elsevierStyleItalic">et al&#46;</span>&#44; who looked for the presence of 157insMTTTVP allele in 30 Argentine patients with ALF-A and 102 controls who had HAV antibodies but no history of liver disease<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and found the insertion allele to be significantly associated &#40;22&#47;60 &#91;37&#37;&#93; <span class="elsevierStyleItalic">vs&#46;</span> 57&#47;204 &#91;28&#37;&#93;&#59; p &#61; 0&#46;037&#41; with HAV-induced liver disease&#46; They further showed that the variant HAVCR1 protein with this 6-amino acid insertion had more efficient <span class="elsevierStyleItalic">in vitro</span> binding to HAV than the protein without this insertion&#46; Furthermore&#44; human natural killer T cells that expressed the longer HAVCR1 protein showed greater cytotoxic activity against HAV-infected liver cells than those expressing its shorter form&#46; These findings appeared to provide a pathogenetic explanation for the greater disease severity among persons with the MTTTVP insertion haplotype&#46; However&#44; though the frequency of the insertion allele in that study was significantly higher in persons with disease than in controls&#44; the absolute difference &#40;37&#37; <span class="elsevierStyleItalic">vs&#46;</span> 28&#37;&#41; was small&#46; We may add here that our study had a much larger number of cases with AVH-A &#40;n &#61; 75&#41; than this the previous study &#40;n &#61; 30&#41;&#46; No other study has yet assessed the relationship of the 157insMTTTVP insertion with the severity of hepatitis A&#46;</p><p id="p0135" class="elsevierStylePara elsevierViewall">By contrast&#44; in our study&#44; frequency of the 157insMTT-TVP insertion in patients with AVH-A was similar to that in healthy controls&#46; If anything&#44; the frequency of this insertion was somewhat lower in our patient group than in the control group&#44; as opposed to the higher frequency in patients in the previous study&#46; This suggests that this polymorphism did not have a role in determining the severity of liver injury in our population&#46; Further&#44; we also compared the frequency of this allele in patients with ALF-A and those with uncomplicated AVH-A&#44; and found these to be similar&#59; the previous study did not do such a comparison&#46; Thus&#44; our findings indicate that this polymorphism may not have a role in determining the severity of HAV disease in at least some settings&#46; This is somewhat similar to the association between this insertion and the occurrence of atopy&#44; which has also been found in some populations but not in the others&#46;</p><p id="p0140" class="elsevierStylePara elsevierViewall">What could be the possible reasons for the differences between the results obtained in our and the Argentine studies&#63; First&#44; the two populations have different ethnic origins&#46; Despite the similar frequencies of the <span class="elsevierStyleItalic">HAVCR1</span> 157insMTTTVP haplotype in the two populations&#44; being 28&#37; in the Argentine study and 30&#37; in our population&#44; the two populations would be expected to have several other genetic differences&#44; which could have influenced the relationship between the presence of the 157insMTTTVP insertion and disease severity&#46;</p><p id="p0145" class="elsevierStylePara elsevierViewall">Second&#44; the HAV strains prevalent in India and Argentina could be different&#46; Thus&#44; differences in amino acid sequences&#44; and structures of proteins in viral strains prevalent in the two regions could influence the association of severity of HAV disease with <span class="elsevierStyleItalic">HAVCR1</span> alleles in these sites&#46; We are unable to comment on this since we did not assess the viral characteristics&#46; However&#44; all HAV genotypes are known to share one highly conserved antigenic neutralization site and have a single serotype with cross-protection across genotypes&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> making this explanation less likely&#46;</p><p id="p0150" class="elsevierStylePara elsevierViewall">It may be pertinent to point out a limitation of our study&#46; Subjects enrolled as controls were not tested for IgG anti-HAV&#44; a marker of prior HAV infection&#46; However&#44; previously published data<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> and our unpublished experience show that &#62; 95&#37; of adult blood donors in this area are positive for this antibody&#46;</p><p id="p0155" class="elsevierStylePara elsevierViewall">Overall&#44; our study indicates that there may be an association between genomic variations in the <span class="elsevierStyleItalic">HAVCR1</span> gene and severity of disease associated with HAV infection in some settings but not in others&#46; This suggests that further studies in various populations are needed to confirm or refute this association&#44; and to determine the factors that influence the presence or absence of a relationship&#46; These studies should also help us better understand the factors which influence the severity of hepatitis A disease&#44; and possibly methods to prevent and treat such severe disease&#46;</p></span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">Abbreviations</span><p id="p0160" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="u0020"><span class="elsevierStyleLabel">&#8226;</span><p id="p0165" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">ALF-A&#58;</span> acute liver failure due to hepatitis A&#46;</p></li><li class="elsevierStyleListItem" id="u0025"><span class="elsevierStyleLabel">&#8226;</span><p id="p0170" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">AVH-A&#58;</span> acute viral hepatitis A&#46;</p></li><li class="elsevierStyleListItem" id="u0030"><span class="elsevierStyleLabel">&#8226;</span><p id="p0175" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HAV&#58;</span> hepatitis A virus&#46;</p></li><li class="elsevierStyleListItem" id="u0035"><span class="elsevierStyleLabel">&#8226;</span><p id="p0180" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HAVCR1&#58;</span> Hepatitis A virus cellular receptor 1&#46;</p></li><li class="elsevierStyleListItem" id="u0040"><span class="elsevierStyleLabel">&#8226;</span><p id="p0185" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HE&#58;</span> hepatic encephalopathy&#46;</p></li><li class="elsevierStyleListItem" id="u0045"><span class="elsevierStyleLabel">&#8226;</span><p id="p0190" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">INR&#58;</span> international normalized ratio&#46;</p></li><li class="elsevierStyleListItem" id="u0050"><span class="elsevierStyleLabel">&#8226;</span><p id="p0195" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">KIM-1&#58;</span> kidney injury molecule 1&#46;</p></li><li class="elsevierStyleListItem" id="u0055"><span class="elsevierStyleLabel">&#8226;</span><p id="p0200" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">PT-INR&#58;</span> prothrombin time-international normalized ratio&#46;</p></li><li class="elsevierStyleListItem" id="u0060"><span class="elsevierStyleLabel">&#8226;</span><p id="p0205" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">TIM&#58;</span> T-cell immunoglobulin mucin&#46;</p></li><li class="elsevierStyleListItem" id="u0065"><span class="elsevierStyleLabel">&#8226;</span><p id="p0210" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">TIM-1&#58;</span> T-cell immunoglobulin and mucin domain 1&#46;</p></li></ul></p></span><span id="s0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">Compliance with Ethical Standards</span><span id="s0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0075">Disclosure of Potential Conflicts of Interest</span><p id="p0215" class="elsevierStylePara elsevierViewall">None of the authors has any conflict of interest&#46;</p></span><span id="s0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0080">Research Involving Human Participants and&#47;or Animals</span><p id="p0220" class="elsevierStylePara elsevierViewall">The study was approved by the Ethics Committee of Sanjay Gandhi Postgraduate Institute of Medical Sciences&#44; Lucknow&#44; India&#46; Funding information is not applicable&#46;</p></span><span id="s0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0085">Informed Consent</span><p id="p0225" class="elsevierStylePara elsevierViewall">Informed consent was obtained from each study subject or from one of the parents&#46;</p></span></span><span id="s0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0090">Author Contributions</span><p id="p0230" class="elsevierStylePara elsevierViewall">Mercilena Benjamin&#58; Study design and laboratory work&#46; Shikha Agnihotry&#58; Analysis of sequencing data&#46; Anshu Srivastava&#58; Finalization of study design&#44; and clinical work-up of subjects&#46; Rishi Bolia&#58; Enrolment and clinical work-up of subjects&#58; SK Yachha&#58; Clinical work-up of subjects&#46; Rakesh Aggarwal&#58; Conception and design of the study&#44; conduct&#44; and supervision of laboratory work&#44; analysis of data including those related to sequence data&#44; writing the manuscript&#46;</p><p id="p0235" class="elsevierStylePara elsevierViewall">In addition&#44; all the authors participated in critical revision of the manuscript drafts and approved the final version of the manuscript&#46; RA takes overall responsibility for the work&#46;</p></span><span id="s0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0095">Acknowledgments</span><p id="p0240" class="elsevierStylePara elsevierViewall">The Bioinformatics Center at Sanjay Gandhi Postgraduate Institute of Medical Sciences&#44; Lucknow is funded by Indian Council of Medical Research &#40;ICMR&#41;&#44; New Delhi&#46; Mercilena Benjamin and Shikha Agnihotry were funded by ICMR during this work&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:11 [
        0 => array:3 [
          "identificador" => "xres1207239"
          "titulo" => "Abstract"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abs0010"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec1124285"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "s0005"
          "titulo" => "Introduction"
        ]
        3 => array:3 [
          "identificador" => "s0010"
          "titulo" => "Material and Methods"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "s0015"
              "titulo" => "Subjects"
            ]
            1 => array:2 [
              "identificador" => "s0020"
              "titulo" => "HAVCR-1 genotyping"
            ]
            2 => array:2 [
              "identificador" => "s0025"
              "titulo" => "Data analysis"
            ]
          ]
        ]
        4 => array:3 [
          "identificador" => "s0030"
          "titulo" => "Results"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "s0035"
              "titulo" => "Study subjects"
            ]
            1 => array:2 [
              "identificador" => "s0040"
              "titulo" => "HAVCR1 genotyping results&#58; rs141023871 and rs139041445 polymorphisms"
            ]
            2 => array:2 [
              "identificador" => "s0045"
              "titulo" => "rs45439103 polymorphism"
            ]
          ]
        ]
        5 => array:2 [
          "identificador" => "s0050"
          "titulo" => "Discussion"
        ]
        6 => array:2 [
          "identificador" => "s0055"
          "titulo" => "Abbreviations"
        ]
        7 => array:3 [
          "identificador" => "s0060"
          "titulo" => "Compliance with Ethical Standards"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "s0065"
              "titulo" => "Disclosure of Potential Conflicts of Interest"
            ]
            1 => array:2 [
              "identificador" => "s0070"
              "titulo" => "Research Involving Human Participants and&#47;or Animals"
            ]
            2 => array:2 [
              "identificador" => "s0075"
              "titulo" => "Informed Consent"
            ]
          ]
        ]
        8 => array:2 [
          "identificador" => "s0080"
          "titulo" => "Author Contributions"
        ]
        9 => array:2 [
          "identificador" => "s0085"
          "titulo" => "Acknowledgments"
        ]
        10 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2017-08-19"
    "fechaAceptado" => "2017-10-06"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1124285"
          "palabras" => array:3 [
            0 => "Disease pathogenesis"
            1 => "Disease severity"
            2 => "Liver failure"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><p id="sp0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Introduction and aim&#46;</span> HAVCR1 protein is the cellular receptor for hepatitis A virus &#40;HAV&#41;&#46; Genetic polymorphism in this gene may alter the outcome of HAV infection&#46; In a previous study&#44; a 6-amino acid insertion &#40;157insMTTTVP&#41; in HAVCR1 gene was associated with more severe disease&#46; We decided to investigate this association further&#46;</p><p id="sp1025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Material and methods&#46;</span> We sequenced exon 4 of the <span class="elsevierStyleItalic">HAVCR1</span> gene in patients with clinical hepatitis A attending our institution&#44; and a group of healthy controls in a disease-endemic setting in India&#46; Frequencies of different haplotypes of a genomic region with two overlapping insertion-deletion polymorphisms &#40;indels&#59; rs141023871 and rs139041445&#41; were compared between patients and controls&#44; as well as between patients with and without a severe form of disease &#40;liver failure&#41;&#46;</p><p id="sp1030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Results&#46;</span> The gene had three haplotypes in the region of interest - a short form&#44; an intermediate-form with a 5-amino acid 157insMTTVP insertion and a long-form with a 6-amino acid 157insMTTTVP insertion&#46; The allele frequency &#40;29&#47;150 &#91;19&#37;&#93; <span class="elsevierStyleItalic">vs&#46;</span> 43&#47;146 &#91;29&#37;&#93;&#59; p &#61; ns&#41; and haplotype frequency &#40;29&#47;75 &#91;39&#37;&#93; <span class="elsevierStyleItalic">vs&#46;</span> 39&#47;73 &#91;53&#37;&#93;&#59; p &#61; ns&#41; of the 157insMTTTVP variant were similar in hepatitis A patients and healthy controls &#40;30&#37;&#41;&#46; Further&#44; the allele frequency &#40;12&#47;58 &#91;21&#37;&#93; <span class="elsevierStyleItalic">vs&#46;</span> 17&#47;92 &#91;18&#37;&#93;&#59; p &#61; ns&#41; and haplotype frequency &#40;12&#47;29 &#91;41&#37;&#93; vs&#46;17&#47;46 &#91;37&#37;&#93;&#59; p &#61; ns&#41; of the longest variant were also similar in patients with severe and mild disease&#46;</p><p id="sp1035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Discussion&#46;</span> In the study population&#44; the 157insMTTTVP variant of <span class="elsevierStyleItalic">HAVCR1</span> gene was not associated with more severe outcome of HAV infection&#46; Further studies in other populations around the world are needed to assess the relation of this genetic variation with disease outcome&#46;</p></span>"
      ]
    ]
    "multimedia" => array:5 [
      0 => array:7 [
        "identificador" => "f0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 284
            "Ancho" => 1057
            "Tamanyo" => 107461
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">A part of the reference sequence &#40;NG&#95;017001&#46;1&#59; GenBank database&#41; of</span> HAVCR1 <span class="elsevierStyleItalic">gene showing exon 4 &#40;upper case letters&#41; with parts of surrounding introns &#40;lower case letters&#41;&#46; The locations of primers used for amplification of the exon 4 are shown using solid underlined arrows&#46; The large box in the sequence shows a 15-base &#40;TGA CGA CTG TTC CAA&#41; ins&#47;del polymorphism &#40;rs141023871&#41;&#46; Within this region is located a 3-base &#40;AAC&#41; ins&#47;del polymorphism &#40;rs139041445&#41; shown in the margin&#46; The smaller box in the main sequence shows a 3-base &#40;CAA&#41; ins&#47;del polymorphism &#40;rs45439103&#41;&#46;</span></p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "f0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 662
            "Ancho" => 1057
            "Tamanyo" => 255928
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Alignment of <span class="elsevierStyleBold">&#40;A&#41;</span> nucleotide sequences and <span class="elsevierStyleBold">&#40;B&#41;</span> translated amino acid sequences of three different haplotypes observed at a polymorphic site in exon 4 of</span> HAVCR1 <span class="elsevierStyleItalic">gene&#46; Allele C is the GenBank reference sequence &#40;GenBank ID&#58; NG&#95;017001&#46;1&#41;&#46;</span></p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "f0015"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 637
            "Ancho" => 1057
            "Tamanyo" => 134643
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Electropherograms showing the results of sequencing for the region of interest &#40;the region of 157insMTTTVP&#41; in exon 4 of the</span> HAVCR1 <span class="elsevierStyleItalic">gene in persons who were homozygous for the three haplotypes &#40;Panel A&#58; homozygous for reference sequence &#91;haplotype C&#93;&#59; Panel B&#58; homozygous for a 15-nucleotide &#40;nt&#41; deletion &#91;haplotype A&#93;&#59; Panel C&#58; homozygous for a 3-nt insertion &#91;haplotype B&#93;&#41;&#46; Panel D shows the electropherogram for a subject who was heterozygous for haplotypes A and B&#59; the panel below this electropherogram shows the sequences for the two haplotypes and the expected merged sequence &#40;the ambiguous codes are represented as per the notation laid down by the International Union of Pure and Applied Chemistry&#41;&#46;</span></p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "t0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="np0005" class="elsevierStyleSimplePara elsevierViewall">The data are shown as median &#40;range&#41; or number &#40;percent&#41;&#46; AVH-A&#58; acute viral hepatitis A &#40;uncomplicated&#41;&#46; ALF-A&#58; acute liver failure due to hepatitis A&#46; INR&#58; international normalized ratio&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Parameter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">All patients with AVH-A &#40;n &#61;75&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Uncomplicated AVH-A &#40;n &#61;46&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ALF-A &#40;n &#61; 29<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">P P value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;1-17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;1-17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;3-16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Male&#58; female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&#58;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&#58;15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&#58;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;00&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serum bilirubin &#40;mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;5 &#40;0&#46;8-52&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;25 &#40;0&#46;8-51&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#46;2 &#40;4&#46;5-52&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60; 0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serum protein &#40;g&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;8 &#40;3&#46;9-8&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;0 &#40;5&#46;7-8&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;1 &#40;3&#46;9-8&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60; 0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serum albumin &#40;g&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;5 &#40;1&#46;9-4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;9 &#40;2&#46;2-4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;2 &#40;1&#46;9-4&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60; 0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serum alanine aminotransferase &#40;IU&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">942 &#40;43-5&#44;000&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1080 &#40;43-5&#44;000&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">643 &#40;55-4&#44;762&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serum aspartate aminotransferase &#40;IU&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">750 &#40;68-7&#44;999&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">742 &#40;68-7&#44;999&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">758 &#40;148-5&#44;014&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;99&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prothrombin time &#40;INR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;2 &#40;0&#46;8-15&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;1 &#40;0&#46;8-1&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;8 &#40;1&#46;4-15&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60; 0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Outcome &#40;mortality&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 &#40;16&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 &#40;41&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60; 0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2060600.png"
              ]
            ]
          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "&#42;"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005"><span class="elsevierStyleItalic">Children with ALF-A included 21 with encephalopathy &#40;grade I&#58; 4&#44; II&#58; 4&#44; III&#58; 3&#44; IV&#58; 10&#41; and 8 with coagulopathy in the absence of encephalopathy&#46; All deaths occurred among those with encephalopathy&#46;</span></p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="sp1020" class="elsevierStyleSimplePara elsevierViewall">Clinical and laboratory characteristics of study subjects&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "t0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="np0010" class="elsevierStyleSimplePara elsevierViewall">The data are shown as number &#40;percent&#41;&#46; A&#44; B and C represent three alternative haplotypes as follows&#58; A&#58; rs141023871 Del&#47;rs139041445 Del &#40;15 bases shorter than the reference sequence&#44; NG&#95;017001&#46;1&#41; &#8211; corresponds to the absence of 157insMTTTVP&#46; B&#58; rs141023871Ins&#47;rs139041445Ins &#40;3 bases longer than the reference sequences&#41; - corresponds to a 6-amino acid 157insMTTTVP insertion&#46; C&#58; rs141023871Ins &#47; rs139041445 Del &#40;reference sequence&#41; &#8211; corresponds to a 5-amino acid 157insMTTVP insertion&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Healthy controls &#40;n &#61; 73&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="3" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patients with symptomatic acute hepatitis A</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Uncomplicated acute viral hepatitis A &#40;n &#61; 46&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Acute liver failure due to hepatitis A &#40;n &#61; 29&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">All patients with acute hepatitis A &#40;n &#61; 75&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="top">Haplotype</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">97 &#40;66&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">68 &#40;74&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44 &#40;76&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">112 &#40;75&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43 &#40;29&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;18&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 &#40;21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29 &#40;19&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9 &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="top">Genotype</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A&#47;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29 &#40;40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26 &#40;57&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15 &#40;52&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41 &#40;55&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&#47;B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">C&#47;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A&#47;B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;47&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 &#40;30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 &#40;41&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26 &#40;35&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A&#47;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&#47;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Any B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39 &#40;53&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#40;37&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 &#40;41&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29 &#40;39&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;BB&#44; AB or BC&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2060599.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">Genotype and haplotype frequencies in different subjects groups&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bs0010"
          "bibliografiaReferencia" => array:28 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis A virus&#58; host interactions&#44; molecular epidemiology and evolution"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Vaughan G&#46;"
                            1 => "Goncalves Rossi L&#46;M&#46;"
                            2 => "Forbi J&#46;C&#46;"
                            3 => "de Paula V&#46;S&#46;"
                            4 => "Purdy M&#46;A&#46;"
                            5 => "Xia G&#46;"
                            6 => "Khudyakov Y&#46;E&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.meegid.2013.10.023"
                      "Revista" => array:6 [
                        "tituloSerie" => "Infect Genet Evol"
                        "fecha" => "2014"
                        "volumen" => "21"
                        "paginaInicial" => "227"
                        "paginaFinal" => "243"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24200587"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis A&#58; epidemiology in resource-poor countries"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Aggarwal R&#46;"
                            1 => "Goel A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/QCO.0000000000000188"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Infect Dis"
                        "fecha" => "2015"
                        "volumen" => "28"
                        "paginaInicial" => "488"
                        "paginaFinal" => "496"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26203853"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis A virus infections in the United States&#58; model-based estimates and implications for childhood immunization"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Armstrong G&#46;L&#46;"
                            1 => "Bell B&#46;P&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1542/peds.109.5.839"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatrics"
                        "fecha" => "2002"
                        "volumen" => "109"
                        "paginaInicial" => "839"
                        "paginaFinal" => "845"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11986444"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The human homolog of HAVcr-1 codes for a hepatitis A virus cellular receptor"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Feigelstock D&#46;"
                            1 => "Thompson P&#46;"
                            2 => "Mattoo P&#46;"
                            3 => "Zhang Y&#46;"
                            4 => "Kaplan G&#46;G&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Virol"
                        "fecha" => "1998"
                        "volumen" => "72"
                        "paginaInicial" => "6621"
                        "paginaFinal" => "6628"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9658108"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "New roles for TIM family members in immune regulation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Kuchroo V&#46;K&#46;"
                            1 => "Dardalhon V&#46;"
                            2 => "Xiao S&#46;"
                            3 => "Anderson A&#46;C&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nri2366"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Immunol"
                        "fecha" => "2008"
                        "volumen" => "8"
                        "paginaInicial" => "577"
                        "paginaFinal" => "580"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18617884"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evidence for natural selection in the HAVCR1 gene&#58; high degree of amino-acid variability in the mucin domain of human HAVCR1 protein"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Nakajima T&#46;"
                            1 => "Wooding S&#46;"
                            2 => "Satta Y&#46;"
                            3 => "Jinnai N&#46;"
                            4 => "Goto S&#46;"
                            5 => "Hayasaka I&#46;"
                            6 => "Saitou N&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.gene.6364215"
                      "Revista" => array:6 [
                        "tituloSerie" => "Genes Immun"
                        "fecha" => "2005"
                        "volumen" => "6"
                        "paginaInicial" => "398"
                        "paginaFinal" => "406"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15889130"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Kim H&#46;Y&#46;"
                            1 => "Eyheramonho M&#46;B&#46;"
                            2 => "Pichavant M&#46;"
                            3 => "Gonzalez Cambaceres C&#46;"
                            4 => "Matangkasombut P&#46;"
                            5 => "Cervio G&#46;"
                            6 => "Kuperman S&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI44182"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "2011"
                        "volumen" => "121"
                        "paginaInicial" => "1111"
                        "paginaFinal" => "1118"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21339644"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Review of the final report of the 1998 Working Party on definition&#44; nomenclature and diagnosis of hepatic encephalopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Mullen K&#46;D&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1746-6342.2006.03216.x"
                      "Revista" => array:7 [
                        "tituloSerie" => "Aliment Pharmacol Ther"
                        "fecha" => "2007"
                        "volumen" => "25"
                        "numero" => "Suppl&#46; 1"
                        "paginaInicial" => "11"
                        "paginaFinal" => "16"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17295847"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute liver failure in children&#58; the first 348 patients in the pediatric acute liver failure study group"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Squires R&#46;H&#46; Jr"
                            1 => "Shneider B&#46;L&#46;"
                            2 => "Bucuvalas J&#46;"
                            3 => "Alonso E&#46;"
                            4 => "Sokol R&#46;J&#46;"
                            5 => "Narkewicz M&#46;R&#46;"
                            6 => "Dhawan A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jpeds.2005.12.051"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr"
                        "fecha" => "2006"
                        "volumen" => "148"
                        "paginaInicial" => "652"
                        "paginaFinal" => "658"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16737880"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "10&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "BioEdit&#58; A user-friendly biological sequence alignment program for Windows 95&#47;98&#47;NT"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Hall T&#46;A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Nucl Acids Symp Ser"
                        "fecha" => "1999"
                        "volumen" => "41"
                        "paginaInicial" => "95"
                        "paginaFinal" => "98"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Novel roles for TIM-1 in immunity and infection"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Rennert P&#46;D&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.imlet.2011.08.003"
                      "Revista" => array:6 [
                        "tituloSerie" => "Immunol Lett"
                        "fecha" => "2011"
                        "volumen" => "141"
                        "paginaInicial" => "28"
                        "paginaFinal" => "35"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21911007"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Identification of a surface glycoprotein on African green monkey kidney cells as a receptor for hepatitis A virus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Kaplan G&#46;"
                            1 => "Totsuka A&#46;"
                            2 => "Thompson P&#46;"
                            3 => "Akatsuka T&#46;"
                            4 => "Moritsugu Y&#46;"
                            5 => "Feinstone S&#46;M&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "EMBO J"
                        "fecha" => "1996"
                        "volumen" => "15"
                        "paginaInicial" => "4282"
                        "paginaFinal" => "4296"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8861957"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The Cys-rich region of hepatitis A virus cellular receptor 1 is required for binding of hepatitis A virus and protective monoclonal antibody 190&#47;4"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Thompson P&#46;"
                            1 => "Lu J&#46;"
                            2 => "Kaplan G&#46;G&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Virol"
                        "fecha" => "1998"
                        "volumen" => "72"
                        "paginaInicial" => "3751"
                        "paginaFinal" => "3761"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9557657"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neutralization of hepatitis A virus &#40;HAV&#41; by an immunoadhesin containing the cysteine-rich region of HAV cellular receptor-1"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Silberstein E&#46;"
                            1 => "Dveksler G&#46;"
                            2 => "Kaplan G&#46;G&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/JVI.75.2.717-725.2001"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Virol"
                        "fecha" => "2001"
                        "volumen" => "75"
                        "paginaInicial" => "717"
                        "paginaFinal" => "725"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11134285"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0075"
              "etiqueta" => "15&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Role of the phosphatidylserine receptor TIM-1 in enveloped-virus entry"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Moller-Tank S&#46;"
                            1 => "Kondratowicz A&#46;S&#46;"
                            2 => "Davey R&#46;A&#46;"
                            3 => "Rennert P&#46;D&#46;"
                            4 => "Maury W&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/JVI.01025-13"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Virol"
                        "fecha" => "2013"
                        "volumen" => "87"
                        "paginaInicial" => "8327"
                        "paginaFinal" => "8341"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23698310"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0080"
              "etiqueta" => "16&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "TIM-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Jemielity S&#46;"
                            1 => "Wang J&#46;J&#46;"
                            2 => "Chan Y&#46;K&#46;"
                            3 => "Ahmed A&#46;A&#46;"
                            4 => "Li W&#46;"
                            5 => "Monahan S&#46;"
                            6 => "Xia B&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1371/journal.ppat.1003232"
                      "Revista" => array:5 [
                        "tituloSerie" => "PLoS Pathog"
                        "fecha" => "2013"
                        "volumen" => "9"
                        "paginaInicial" => "e1003232"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23555248"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0085"
              "etiqueta" => "17&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Meertens L&#46;"
                            1 => "Carnec X&#46;"
                            2 => "Lecoin M&#46;P&#46;"
                            3 => "Ramdasi R&#46;"
                            4 => "Guivel-Benhassine F&#46;"
                            5 => "Lew E&#46;"
                            6 => "Greq L&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.chom.2012.08.009"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell Host Microbe"
                        "fecha" => "2012"
                        "volumen" => "12"
                        "paginaInicial" => "544"
                        "paginaFinal" => "557"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23084921"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0090"
              "etiqueta" => "18&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immunology&#58; hepatitis A virus link to atopic disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "McIntire J&#46;J&#46;"
                            1 => "Umetsu S&#46;E&#46;"
                            2 => "Macaubas C&#46;"
                            3 => "Hoyte E&#46;G&#46;"
                            4 => "Cinnioglu C&#46;"
                            5 => "Cavalli-Sforza L&#46;L&#46;"
                            6 => "Barsh G&#46;S&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Nature"
                        "fecha" => "2003"
                        "volumen" => "425"
                        "paginaInicial" => "576"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "19&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Alteration of hepatitis A virus &#40;HAV&#41; particles by a soluble form of HAV cellular receptor 1 containing the immunoglobin-and mucin-like regions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Silberstein E&#46;"
                            1 => "Xing L&#46;"
                            2 => "van de Beek W&#46;"
                            3 => "Lu J&#46;"
                            4 => "Cheng H&#46;"
                            5 => "Kaplan G&#46;G&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/jvi.77.16.8765-8774.2003"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Virol"
                        "fecha" => "2003"
                        "volumen" => "77"
                        "paginaInicial" => "8765"
                        "paginaFinal" => "8774"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12901378"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "20&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The association of the exon 4 variations of Tim-1 gene with allergic diseases in a Korean population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Chae S&#46;C&#46;"
                            1 => "Song J&#46;H&#46;"
                            2 => "Lee Y&#46;C&#46;"
                            3 => "Kim J&#46;W&#46;"
                            4 => "Chung H&#46;T&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bbrc.2003.10.125"
                      "Revista" => array:6 [
                        "tituloSerie" => "Biochem Biophys Res Commun"
                        "fecha" => "2003"
                        "volumen" => "312"
                        "paginaInicial" => "346"
                        "paginaFinal" => "350"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14637143"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "21&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association analysis of TIM-1-232G &#62; A and 5383&#95;5397 insertion&#47;deletion polymorphisms with childhood asthma and total serum immunoglobulin E levels in middle China"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Wu Q&#46;"
                            1 => "Hu L&#46;"
                            2 => "Cai P&#46;"
                            3 => "Li Y&#46;"
                            4 => "Chen F&#46;"
                            5 => "Kong L&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Investig Allergol Clin Immunol"
                        "fecha" => "2009"
                        "volumen" => "19"
                        "paginaInicial" => "146"
                        "paginaFinal" => "153"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19476019"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "22&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insertion&#47;deletion coding polymorphisms in hHAVcr-1 are not associated with atopic asthma in the Japanese population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Noguchi E&#46;"
                            1 => "Nakayama J&#46;"
                            2 => "Kamioka M&#46;"
                            3 => "Ichikawa K&#46;"
                            4 => "Shibasaki M&#46;"
                            5 => "Arinami T&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.gene.6363935"
                      "Revista" => array:6 [
                        "tituloSerie" => "Genes Immun"
                        "fecha" => "2003"
                        "volumen" => "4"
                        "paginaInicial" => "170"
                        "paginaFinal" => "173"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12618867"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "23&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Absence of association between two insertion&#47;deletion coding genetic polymorphisms of TIM-1 gene and asthma in Chinese Han population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Li J&#46;S&#46;"
                            1 => "Liu Q&#46;J&#46;"
                            2 => "Wang P&#46;"
                            3 => "Li H&#46;C&#46;"
                            4 => "Wei C&#46;H&#46;"
                            5 => "Guo C&#46;H&#46;"
                            6 => "Gong Y&#46;Q&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1744-313X.2006.00634.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Immunogenet"
                        "fecha" => "2006"
                        "volumen" => "33"
                        "paginaInicial" => "417"
                        "paginaFinal" => "422"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17117951"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "24&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphisms of the TIM-1 gene are associated with rheumatoid arthritis in the Chinese Hui minority ethnic population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Xu J&#46;R&#46;"
                            1 => "Yang Y&#46;"
                            2 => "Liu X&#46;M&#46;"
                            3 => "Sun J&#46;Y&#46;"
                            4 => "Wang Y&#46;J&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.4238/2012.January.9.7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Genet Mol Res"
                        "fecha" => "2012"
                        "volumen" => "11"
                        "paginaInicial" => "61"
                        "paginaFinal" => "69"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22290466"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "25&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphisms of the TIM-1 and TIM-3 genes are not associated with systemic lupus erythematosus in a Chinese population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Li W&#46;X&#46;"
                            1 => "Chen G&#46;M&#46;"
                            2 => "Yuan H&#46;"
                            3 => "Yao Y&#46;S&#46;"
                            4 => "Li R&#46;J&#46;"
                            5 => "Pan H&#46;F&#46;"
                            6 => "Li X&#46;P&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/mutage/ger009"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mutagenesis"
                        "fecha" => "2011"
                        "volumen" => "26"
                        "paginaInicial" => "507"
                        "paginaFinal" => "511"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21367814"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "26&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "TIM1 haplotype may control the disease progression to AIDS in a HIV-1-infected female cohort in Thailand"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Wichukchinda N&#46;"
                            1 => "Nakajima T&#46;"
                            2 => "Saipradit N&#46;"
                            3 => "Nakayama E&#46;E&#46;"
                            4 => "Ohtani H&#46;"
                            5 => "Rojanawiwat A&#46;"
                            6 => "Pathipvanich P&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/QAD.0b013e32833a8e6d"
                      "Revista" => array:6 [
                        "tituloSerie" => "AIDS"
                        "fecha" => "2010"
                        "volumen" => "24"
                        "paginaInicial" => "1625"
                        "paginaFinal" => "1631"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20479636"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "27&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neutralization escape mutants define a dominant immunogenic neutralization site on hepatitis A virus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Stapleton J&#46;T&#46;"
                            1 => "Lemon S&#46;M&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Virol"
                        "fecha" => "1987"
                        "volumen" => "61"
                        "paginaInicial" => "491"
                        "paginaFinal" => "498"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2433464"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "28&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Seroepidemiology of hepatitis A virus infection among school children in Delhi and north Indian patients with chronic liver disease&#58; implications for HAV vaccination"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Acharya S&#46;K&#46;"
                            1 => "Batra Y&#46;"
                            2 => "Bhatkal B&#46;"
                            3 => "Ojha B&#46;"
                            4 => "Kaur K&#46;"
                            5 => "Hazari S&#46;"
                            6 => "Saraya A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Gastroenterol Hepatol"
                        "fecha" => "2003"
                        "volumen" => "18"
                        "paginaInicial" => "822"
                        "paginaFinal" => "827"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12795755"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/16652681/0000001700000004/v1_201906150923/S1665268119304788/v1_201906150923/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "77721"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Original Article"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/16652681/0000001700000004/v1_201906150923/S1665268119304788/v1_201906150923/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119304788?idApp=UINPBA00004N"
]
Article information
ISSN: 16652681
Original language: English
The statistics are updated each day
Year/Month Html Pdf Total
2024 November 3 0 3
2024 October 20 2 22
2024 September 18 1 19
2024 August 22 4 26
2024 July 27 8 35
2024 June 46 9 55
2024 May 22 4 26
2024 April 22 7 29
2024 March 39 3 42
2024 February 30 7 37
2024 January 25 5 30
2023 December 29 2 31
2023 November 37 8 45
2023 October 32 8 40
2023 September 20 0 20
2023 August 19 5 24
2023 July 10 6 16
2023 June 21 9 30
2023 May 30 5 35
2023 April 48 6 54
2023 March 27 4 31
2023 February 12 7 19
2023 January 2 10 12
2022 December 21 5 26
2022 November 27 8 35
2022 October 11 5 16
2022 September 15 6 21
2022 August 28 7 35
2022 July 19 9 28
2022 June 20 6 26
2022 May 13 11 24
2022 April 22 9 31
2022 March 67 9 76
2022 February 49 4 53
2022 January 89 8 97
2021 December 35 10 45
2021 November 24 13 37
2021 October 59 11 70
2021 September 30 13 43
2021 August 36 5 41
2021 July 30 13 43
2021 June 8 9 17
2021 May 28 6 34
2021 April 36 9 45
2021 March 34 22 56
2021 February 26 7 33
2021 January 21 9 30
2020 December 22 11 33
2020 November 27 12 39
2020 October 30 12 42
2020 September 13 7 20
2020 August 24 10 34
2020 July 11 8 19
2020 June 21 4 25
2020 May 17 8 25
2020 April 15 4 19
2020 March 11 5 16
2020 February 19 6 25
2020 January 12 4 16
2019 December 14 3 17
2019 November 11 3 14
2019 October 7 4 11
2019 September 16 2 18
2019 August 3 1 4
2019 July 2 11 13
2019 June 1 7 8
Show all

Follow this link to access the full text of the article

es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos