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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Introdu&#231;&#227;o</span><p id="par0005" class="elsevierStylePara elsevierViewall">Os p&#234;nfigos s&#227;o doen&#231;as bolhosas autoimunes&#44; caracterizados pela produ&#231;&#227;o de autoanticorpos IgG contra as desmogle&#237;nas &#40;Dsg&#41; 1 e 3&#44; os quais rompem a ades&#227;o dos queratin&#243;citos causando acant&#243;lise&#46; No p&#234;nfigo foli&#225;ceo &#40;PF&#41;&#44; a produ&#231;&#227;o de anti&#8208;Dsg1 &#233; respons&#225;vel pelo acometimento exclusivo da pele&#59; no p&#234;nfigo vulgar &#40;PV&#41;&#44; a produ&#231;&#227;o de anti&#8208;Dsg3 afeta as mucosas&#44; e&#44; quando a pele est&#225; envolvida&#44; s&#227;o detectados anti&#8208;Dsg1 e anti&#8208;Dsg3&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">1&#44;2</span></a> Tanto o PF quanto o PV s&#227;o prevalentes no Sudeste do Brasil&#44; e a determina&#231;&#227;o do perfil HLA dos pacientes com PF e PV confirmou tratar&#8208;se de doen&#231;as bolhosas distintas&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">A participa&#231;&#227;o da Dsg2 &#233; pouco estudada na patog&#234;nese dos p&#234;nfigos&#46; Em contraste com as express&#245;es das Dsg1 e Dsg3&#44; que s&#227;o restritas a epit&#233;lios estratificados&#44; a Dsg2 &#233; amplamente expressa em todos os epit&#233;lios que cont&#234;m desmossomos&#44; incluindo tecidos pulmonar&#44; gastrintestinal&#44; renal e o mioc&#225;rdio&#44; e em tumores da pele&#44; ov&#225;rio&#44; pulm&#227;o e est&#244;mago&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">5&#8211;11</span></a> Na pele humana&#44; a Dsg2 &#233; pouco expressa&#44; restringindo&#8208;se &#224; camada basal da epiderme&#44; enquanto sua express&#227;o se assemelha &#224;s express&#245;es da Dsg1 e Dsg3 em linhagens de c&#233;lulas imortalizadas de carcinoma de c&#233;lulas escamosas&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">12</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Para contribuir com a participa&#231;&#227;o da Dsg2 na patog&#234;nese dos p&#234;nfigos&#44; comparou&#8208;se a produ&#231;&#227;o de autoanticorpos contra as Dsg 1&#44; 2 e 3 em ampla amostragem de pacientes com PF e PV&#44; seus familiares e controles saud&#225;veis&#44; residentes na regi&#227;o nordeste do estado de S&#227;o Paulo&#44; Brasil&#44; onde ambos PF e PV s&#227;o prevalentes&#46; Foram determinadas&#44; ainda&#44; as express&#245;es proteica e g&#234;nica das Dsg 1&#44; 2 e 3 em amostras de pele e mucosa&#44; obtidas de pacientes com PF e PV&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Materiais e m&#233;todos</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">&#201;tica</span><p id="par0020" class="elsevierStylePara elsevierViewall">O Comit&#234; de &#201;tica Humana &#40;CAAE&#58; 56944116&#46;1&#46;0000&#46;5440&#41; aprovou este estudo de acordo com os padr&#245;es &#233;ticos da Declara&#231;&#227;o de Helsinque da Associa&#231;&#227;o M&#233;dica Mundial&#46; Todos os participantes assinaram o termo de consentimento livre e esclarecido&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Popula&#231;&#227;o do estudo</span><p id="par0025" class="elsevierStylePara elsevierViewall">Amostras de soro de pacientes com PF e PV&#44; diagnosticados por exame cl&#237;nico&#44; histopatol&#243;gico&#44; e exames de imunofluoresc&#234;ncia direta e&#47;ou indireta&#59; de familiares de primeiro e segundo graus e de controles &#40;CTL&#41;&#44; que acompanharam os pacientes durante a consulta ambulatorial&#44; foram obtidas de 1997 a 2016&#46; Cinco grupos foram analisados&#58; 202 pacientes com PF e 131 com PV&#44; 50 familiares do PF &#40;FPF&#41; e 57 FPV&#44; e 114 CTL&#46; Os pacientes virgens de tratamento foram classificados de acordo com a forma cl&#237;nica &#8211; isto &#233;&#44; PF localizado ou generalizado e PV forma mucosa exclusiva ou mucocut&#226;nea&#46; Os pacientes com PF e PV foram divididos em cinco subgrupos&#44; de acordo com a atividade da doen&#231;a e vig&#234;ncia ou n&#227;o de tratamento no momento da coleta do soro&#58; virgens de tratamento&#59; com les&#245;es ativas e sem tratamento h&#225; mais de 60 dias&#59; em tratamento com les&#245;es ativas&#59; em tratamento sem les&#245;es ativas&#59; e em remiss&#227;o &#40;pacientes sem les&#245;es ativas e sem tratamento imunossupressor h&#225; pelo menos 60 dias&#41; &#8211; <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Detec&#231;&#227;o de autoanticorpos IgG contra Dsg1 e Dsg3 por ELISA</span><p id="par0030" class="elsevierStylePara elsevierViewall">As amostras foram testadas com ELISA comercial &#40;MBL&#44; Nagoya&#44; Jap&#227;o&#41;&#44; segundo as recomenda&#231;&#245;es do fabricante &#40;<span class="elsevierStyleItalic">cut&#8208;off</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20 U&#47;mL&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Detec&#231;&#227;o de autoanticorpos IgG contra Dsg2 por ELISA in house</span><p id="par0035" class="elsevierStylePara elsevierViewall">Resumidamente&#44; 5 ng&#47;&#956;L da Dsg2 &#40;Leinco&#44; Fenton&#44; EUA&#41; dilu&#237;dos em solu&#231;&#227;o de carbonato&#8208;bicarbonato &#40;pH 7&#44;4&#41; foram incubados &#40;50 &#956;L&#47;po&#231;o&#41; em microplaca de 96 po&#231;os &#40;Sigma&#8208;Aldrich&#44; St&#46; Louis&#44; EUA&#41; a 4<span class="elsevierStyleHsp" style=""></span>&#176;C durante a noite&#46; Ap&#243;s quatro lavagens com 0&#44;05&#37; de PBS&#47;Tween e incuba&#231;&#227;o com solu&#231;&#227;o de bloqueio &#40;PBS&#47;Tween 0&#44;05&#37;&#47;leite desnatado 5&#37;&#41; por uma hora&#44; 50 &#956;L de amostras de soro &#40;dilu&#237;das a 1&#58;100 em solu&#231;&#227;o de bloqueio&#41;&#44; em duplicata&#44; foram adicionadas e incubadas &#224; temperatura ambiente &#40;TA&#41; durante 2 horas&#46; Ap&#243;s quatro lavagens&#44; 50 &#956;L &#40;dilu&#237;do a 1&#58;5000 em solu&#231;&#227;o de bloqueio&#41; de anticorpo HRP conjugado com IgG anti&#8208;humano &#40;Abcam&#44; Cambridge&#44; EUA&#41; foram incubados em TA por 2 horas&#46; Ap&#243;s quatro novas lavagens&#44; 50 &#956;L de substrato de peroxidase ABTS &#40;&#225;cido 2&#44;2&#8217;&#8208;azino&#8208;bis &#91;3&#8208;etilbenzotiazolina&#8208;6&#8208;sulf&#244;nico&#93;&#41; foram adicionados e mantidos em TA por 15 minutos no escuro&#44; e a rea&#231;&#227;o foi finalmente interrompida com 50 &#956;L de H2SO4 1<span class="elsevierStyleHsp" style=""></span>M&#46; Os t&#237;tulos em densidade &#243;ptica &#40;DO&#41; foram determinados em leitor de placas ELISA &#40;Biochrom Asys Expert Plus Microplate Reader&#44; Cambourne&#44; UK&#41; a 405<span class="elsevierStyleHsp" style=""></span>nm&#46; Anticorpo comercial anti&#8208;Dsg2 &#40;Abcam&#44; Cambridge&#44; EUA&#41; foi empregado como controle positivo&#46; O valor do <span class="elsevierStyleItalic">cut&#8208;off</span> de 0&#44;1365 DO foi estabelecido por curva ROC &#40;<a class="elsevierStyleCrossRef" href="#sec0120">fig&#46; 1 suplementar</a>&#41;&#46; T&#237;tulos maiores que 0&#44;400 DO foram obtidos em quatro amostras do grupo CTL e foram exclu&#237;dos do c&#225;lculo porque excederam a curva de normalidade&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">ELISA de adsor&#231;&#227;o para especificidade de anti&#8208;Dsg2</span><p id="par0040" class="elsevierStylePara elsevierViewall">Para excluir rea&#231;&#227;o cruzada dos anticorpos anti&#8208;Dsg2 com as prote&#237;nas Dsg1 e Dsg3&#44; seis amostras de soro do PF e seis do PV com t&#237;tulos elevados de anti&#8208;Dsg 1&#44; 2 e 3 foram selecionadas&#46; Foram realziados ensaios ELISA para adsor&#231;&#227;o s&#233;rica em s&#233;rie com Dsg2 &#40;Leinco&#44; Fenton&#44; EUA&#41; at&#233; que o n&#237;vel de anti&#8208;Dsg2 ficasse abaixo do valor <span class="elsevierStyleItalic">cut&#8208;off</span>&#46; Posteriormente&#44; o soro remanescente foi colocado em placa de ELISA comercial anti&#8208;Dsg1 e anti&#8208;Dsg3 &#40;MBL&#44; Nagoya&#44; Jap&#227;o&#41; para comparar os t&#237;tulos pr&#233;&#8208; e p&#243;s&#8208;adsor&#231;&#227;o&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Amostras de bi&#243;psia</span><p id="par0045" class="elsevierStylePara elsevierViewall">As bi&#243;psias de pele e&#47;ou mucosa foram realizadas em tr&#234;s pacientes com PF e tr&#234;s com PV&#44; virgens de tratamento ou com les&#245;es ativas e sem tratamento por mais de 60 dias&#46; As bi&#243;psias foram feitas de pele &#237;ntegra &#40;PI&#41; perilesional e de les&#245;es bolhosas&#44; assim denominadas&#58; pele lesional &#40;PL&#41; ou mucosa lesional &#40;ML&#41;&#46; Como controle&#44; coletou&#8208;se biopsia de mucosa &#237;ntegra &#40;MI&#41; de um paciente com PF&#46; Uma amostra de pele de abdominoplastia e a amostra de MI do PF foram usadas como controles na IHQ&#44; e duas amostras de pele de cirurgia de <span class="elsevierStyleItalic">lifting</span> facial &#40;LF&#41; foram usadas como controles no ensaio de qPCR&#46; Biopsias com <span class="elsevierStyleItalic">punch</span> 4<span class="elsevierStyleHsp" style=""></span>mm foram seccionadas em dois fragmentos&#58; um deles foi armazenado em meio Tissue&#8208;Tek &#40;Sakura finetek&#44; Torrance&#44; EUA&#41; para colora&#231;&#227;o com hematoxilina &#38; eosina e imuno&#8208;histoqu&#237;mica &#40;IHQ&#41;&#44; e o outro foi armazenado em RNAlater&#174; &#40;Life Technologies&#44; Carlsbad&#44; EUA&#41; a &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C para extra&#231;&#227;o de RNA e subsequente ensaio de qPCR&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Imuno&#8208;histoqu&#237;mica &#40;IHQ&#41;</span><p id="par0050" class="elsevierStylePara elsevierViewall">O sistema de detec&#231;&#227;o HRP&#8208;Polymer MACH 1 &#40;Biocare Medical&#44; Concord&#44; EUA&#41; foi usado de acordo com as recomenda&#231;&#245;es do fabricante&#46; Os fragmentos congelados foram fixados em acetona &#40;Merck&#44; Darmstadt&#44; Germany&#41; a 4<span class="elsevierStyleHsp" style=""></span>&#176;C por 10 minutos e lavados em PBS Ph 7&#44;4&#59; a peroxidase end&#243;gena foi inibida pela incuba&#231;&#227;o com H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span> 0&#44;3&#37; &#40;Labsynth&#44; Diadema&#44; Brasil&#41; por 10 minutos&#46; Em seguida&#44; os fragmentos foram incubados com solu&#231;&#227;o de bloqueio Sniper em TA por 10 minutos&#44; seguido pela adi&#231;&#227;o de 5 &#956;g&#47;mL de anticorpo monoclonal anti&#8208;Dsg1&#44; anti&#8208;Dsg2 e anti&#8208;Dsg3 &#40;Abcam&#44; Cambridge&#44; Reino Unido&#41; por 2 horas&#46; Os cortes foram lavados com PBS por 3 minutos&#44; duas vezes&#46; Em seguida&#44; a sonda foi adicionada por 15 minutos&#46; Os cortes foram lavados em PBS novamente e incubados com o pol&#237;mero HRP por 30 minutos&#46; Ap&#243;s a lavagem&#44; a rea&#231;&#227;o foi completada com a adi&#231;&#227;o do substrato cromog&#234;nico diaminobenzidina por 2 minuots&#44; preparado de acordo com as instru&#231;&#245;es do fabricante &#40;Biocare Medical&#44; Concord&#44; EUA&#41;&#46; A seguir&#44; os cortes foram contrastados com hematoxilina de Harris &#40;Merck Millipore&#44; Burlington&#44; EUA&#41; por 40 segundos e lavados em &#225;gua corrente&#46; Para a montagem das l&#226;minas&#44; os cortes foram desidratados em banhos crescentes de etanol e diafanizados em banhos de xilol e&#44; a seguir&#44; montadas com Entellan &#40;Merck&#44; Darmstadt&#44; Alemanha&#41; e os cortes cobertos com lam&#237;nula para observa&#231;&#227;o em microsc&#243;pio &#243;ptico &#40;Imager&#8208;A1&#44; Zeiss&#44; Alemanha&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Extra&#231;&#227;o de RNA e s&#237;ntese de cDNA</span><p id="par0055" class="elsevierStylePara elsevierViewall">RNA total foi extra&#237;do de bi&#243;psias de pele ou mucosa usando o reagente Trizol&#44; de acordo com as instru&#231;&#245;es do fabricante &#40;Invitrogen&#44; Carlsbad&#44; EUA&#41;&#46; Ap&#243;s a extra&#231;&#227;o&#44; as amostras foram incubadas com DNAse &#40;Promega&#44; Madison&#44; EUA&#41; e quantificadas em espectrofot&#244;metro NanoVue&#174; Plus &#40;GE Healthcare Life Sciences&#44; Chicago&#44; EUA&#41;&#59; 40 ng de RNA foram transcritos reversamente com o kit de s&#237;ntese de cDNA &#40;Promega&#44; Madison&#44; EUA&#41;&#44; seguindo as instru&#231;&#245;es do fabricante&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Rea&#231;&#227;o em cadeia da polimerase quantitativa em tempo real &#40;qPCR&#41; e sequenciamento das Dsg1&#44; Dsg2 e Dsg3</span><p id="par0060" class="elsevierStylePara elsevierViewall">SYBR Green qPCR foi realizada em volume final de 22&#44;5 &#956;L&#44; com 12&#44;5 &#956;L de MIX SYBR Green PCR &#40;Promega&#44; Madison&#44; EUA&#41;&#44; 0&#44;5 &#956;L de cada primer &#40;10 &#956;M&#41;&#44; 6&#44;5 &#956;L de &#225;gua ultrapura e 2&#44;5 &#956;L de cDNA &#40;1&#58;4&#41;&#44; no termociclador Rotor Gene&#8208;Q&#174; &#40;Qiagen&#44; Hilden&#44; Alemanha&#41;&#46; Foram utilizadas as sequ&#234;ncias de primers que amplificam fragmentos dos genes Dsg1&#44; Dsg2 e Dsg3 e do gene ribossomal humano &#40;18S&#41; como gene end&#243;geno&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">13&#8211;15</span></a> As sequ&#234;ncias dos primers&#44; o produto amplificado resultante &#40;amplicon&#41; e os par&#226;metros dos ciclos de amplifica&#231;&#227;o s&#227;o detalhados na <a class="elsevierStyleCrossRef" href="#tbl0005">Tabela 1 suplementar</a>&#46; As express&#245;es g&#234;nicas relativas de Dsg1&#44; Dsg2 e Dsg3 foram calculadas usando a equa&#231;&#227;o 2 <span class="elsevierStyleSup">&#40;&#8722;&#916;cT&#41;</span>&#44; tendo o 18S rRNA como gene de refer&#234;ncia&#59; &#916;cT foi calculado subtraindo o valor do cicle Threshold &#40;cT&#41; do gene alvo &#40;Dsg1&#44; Dsg2 ou Dsg3&#41; do valor de cT do gene de refer&#234;ncia &#40;18S&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">16</span></a> Para verificar a especificidade de cada sequ&#234;ncia&#44; o amplicon obtido foi purificado &#40;ExoSAP&#8208;IT&#174;&#41;&#44; sequenciado &#40;3500 Genetic Analyzer&#44; Applied Biosystems&#44; EUA&#41; e analisado no NCBI BLAST&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">An&#225;lise estat&#237;stica</span><p id="par0065" class="elsevierStylePara elsevierViewall">As vari&#225;veis categ&#243;ricas foram analisadas por teste Qui&#8208;quadrado &#40;&#215;2&#41; ou teste exato de Fisher quando os dados eram escassos&#46; Kruskall&#8208;Wallis seguido pelo teste de Dunn foi empregado para comparar os t&#237;tulos de ELISA entre os grupos&#46; O teste de Spearman foi usado para correlacionar os t&#237;tulos de anticorpos contra as Dsgs&#44; bem como com a dura&#231;&#227;o da doen&#231;a e a idade dos pacientes&#46; O teste de Friedman foi usado para comparar os t&#237;tulos de anti&#8208;Dsg2 pr&#233;&#8208; e p&#243;s&#8208;adsor&#231;&#227;o s&#233;rica em s&#233;rie&#46; O teste de Wilcoxon foi aplicado para comparar os t&#237;tulos de anti&#8208;Dsg1 e anti&#8208;Dsg3 pr&#233;&#8208; e p&#243;s&#8208;adsor&#231;&#227;o com Dsg2&#46; A an&#225;lise de regress&#227;o log&#237;stica multivariada com o SPSS <span class="elsevierStyleItalic">Statistics</span> 17&#46;0 &#40;<span class="elsevierStyleItalic">software</span> IBM SPSS&#174;&#44; EUA&#41; foi utilizada para confirmar os resultados significativos obtidos na an&#225;lise univariada&#46; A signific&#226;ncia foi fixada em &#945;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#37;&#46; O <span class="elsevierStyleItalic">software</span> GraphPad Prism 8&#46;1 foi utilizado para as an&#225;lises estat&#237;sticas e para a constru&#231;&#227;o dos gr&#225;ficos &#40;GraphPad software Inc&#46;&#44; La Jolla&#44; EUA&#41;&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Resultados</span><p id="par0070" class="elsevierStylePara elsevierViewall">A <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a> resume os dados demogr&#225;ficos&#44; cl&#237;nicos e laboratoriais dos grupos estudados&#46; Os grupos PF e PV apresentaram t&#237;tulos &#40;DO&#41; semelhantes e maiores de anti&#8208;Dsg2 comparados ao grupo CTL &#40;0&#44;166&#59; 0&#44;180&#59; 0&#44;102&#44; respectivamente&#59; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41; &#8211; <a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a>A&#46; Ainda&#44; o grupo PF apresentou maiores t&#237;tulos de anti&#8208;Dsg2 comparado aos grupos FPF &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0046&#41; e FPV &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0004&#41;&#46; Esses resultados permaneceram estatisticamente significativos ap&#243;s an&#225;lise multivariada&#44; corrigida por idade&#44; sexo e t&#237;tulos de anticorpos contra Dsg1 e Dsg3&#46; Nos grupos de familiares e CTL&#44; observou&#8208;se produ&#231;&#227;o de autoanticorpos contra Dsg1 e&#47;ou Dsg3 &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>B e C&#41;&#46; T&#237;tulos de anti&#8208;Dsg2 foram mais elevados nos grupos PF e PV virgens de tratamento&#44; comparados ao grupo CTL &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#44; e no grupo PV sem tratamento comparado ao PV em tratamento &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0311&#59; <a class="elsevierStyleCrossRef" href="#sec0120">fig&#46; 2 suplementar</a>&#41;&#44; permanecendo significativo ap&#243;s an&#225;lise multivariada &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0500&#41;&#46; Os subgrupos PF n&#227;o diferiram quanto aos t&#237;tulos de anti&#8208;Dsg2 &#40;dados n&#227;o mostrados&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">A soropreval&#234;ncia de anti&#8208;Dsg2 nos grupos PF&#44; PV e FPV resultou semelhante &#40;63&#44;9&#37;&#59; 66&#44;4&#37;&#59; 73&#44;7&#37;&#44; respectivamente&#41;&#44; e maior que nos grupos FPF e CTL &#40;38&#37;&#59; 27&#44;2&#37;&#44; respectivamente &#8211; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41; &#8211; <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">N&#227;o houve correla&#231;&#227;o significativa dos t&#237;tulos de anti&#8208;Dsg2 com a dura&#231;&#227;o da doen&#231;a no PF &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;5365&#41; e no PV &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;1629&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0630&#41; &#8211; dados n&#227;o mostrados &#8211;&#44; assim como com a forma cl&#237;nica do PF &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;9636&#41; e do PV &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;3909&#41; &#8211; <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46; N&#227;o houve diferen&#231;a significativa dos t&#237;tulos de anti&#8208;Dsg2 nos subgrupos PF e PV com les&#245;es cut&#226;neas ativas e sem les&#245;es cut&#226;neas &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;3790 e p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;1312&#44; respectivamente&#41; &#8211; dados n&#227;o mostrados&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Houve correla&#231;&#227;o positiva dos t&#237;tulos de anti&#8208;Dsg2 com os t&#237;tulos de anti&#8208;Dsg1 no grupo PF &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;1628&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0206&#41;&#44; com tend&#234;ncia &#224; correla&#231;&#227;o positiva com os t&#237;tulos de anti&#8208;Dsg3 no PV &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;1675&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0568&#41; &#8211; <a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>D e E&#46; Considerando os subgrupos virgem de tratamento&#44; e sem tratamento h&#225; mais de 60 dias e com les&#245;es em atividade&#44; n&#227;o houve correla&#231;&#227;o dos t&#237;tulos de anti&#8208;Dsg2 com os de anti&#8208;Dsg1 no PF &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;2100&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0650&#41;&#44; assim como com os de anti&#8208;Dsg3 no PV &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;1481&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;4264&#41; &#8211; dados n&#227;o mostrados&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Ap&#243;s a adsor&#231;&#227;o dos soros de pacientes com PF e PV com o pept&#237;deo Dsg2&#44; os t&#237;tulos de anti&#8208;Dsg1 e de anti&#8208;Dsg3 permaneceram semelhantes &#224; pr&#233;&#8208;adsor&#231;&#227;o &#40;p &#62;<span class="elsevierStyleHsp" style=""></span>0&#44;9999 e p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;4063&#44; respectivamente&#41;&#44; confirmando a especificidade dos anticorpos anti&#8208;Dsg2 &#40;<a class="elsevierStyleCrossRef" href="#sec0120">tabelas 2 e 3 suplementares</a>&#41;&#46;</p><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Express&#227;o proteica das desmogle&#237;nas por IHQ</span><p id="par0095" class="elsevierStylePara elsevierViewall">A <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a> mostra os dados demogr&#225;ficos e sorol&#243;gicos dos pacientes com PF e PV submetidos &#224; bi&#243;psia de pele e&#47;ou mucosa para IHQ&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Na amostra de pele controle de abdominoplastia&#44; confirmou&#8208;se a distribui&#231;&#227;o epid&#233;rmica cl&#225;ssica das Dsgs&#58; a Dsg1 esteve expressa em toda a epiderme&#44; com predom&#237;nio nas camadas superiores&#44; enquanto as Dsg2 e Dsg3 predominaram nas camadas inferiores&#46; A express&#227;o da Dsg2 foi menos intensa do que a das Dsg1 e Dsg3 &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>A&#41;&#46; Diferentemente da amostra de pele controle&#44; a express&#227;o da Dsg2 foi mais intensa em todas as camadas da epiderme nas amostras de PI do PF e PV &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>B e C&#41;&#46; Na PL do PF&#44; houve express&#227;o intensa da Dsg2 no assoalho da bolha e&#44; no PV&#44; no teto e no assoalho da bolha&#44; incluindo sua express&#227;o nas c&#233;lulas acantol&#237;ticas &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>B e C&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">&#192; semelhan&#231;a da amostra de pele controle&#44; a express&#227;o da Dsg2 na MI do PF foi mais intensa nas camadas inferiores&#46; Ainda&#44; houve predom&#237;nio da express&#227;o da Dsg3 em todas as camadas da epiderme&#44; comparada &#224;s da Dsg1 e Dsg2 &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>A&#41;&#46; Na ML do PV&#44; houve predom&#237;nio da express&#227;o da Dsg3 no teto e no assoalho da bolha &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>B e C&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Na PL do PF&#44; gr&#226;nulos consp&#237;cuos intercelulares e intracitoplasm&#225;ticos&#44; correspondentes &#224; internaliza&#231;&#227;o da Dsg1&#44; foram observados em toda a extens&#227;o do assoalho da bolha&#44; da camada basal &#224; camada Malpighiana &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>A&#41;&#46; Gr&#226;nulos intracitoplasm&#225;ticos&#44; que poderiam representar a internaliza&#231;&#227;o da Dsg2&#44; n&#227;o foram observados nas amostras lesionais do PF e PV &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>B&#41;&#46; Na PL e na ML do PV&#44; gr&#226;nulos intercelulares finos e esparsos de Dsg3 foram demonstrados &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>C&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Express&#227;o g&#234;nica das desmogle&#237;nas por qPCR</span><p id="par0115" class="elsevierStylePara elsevierViewall">A <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a> detalha os dados demogr&#225;ficos e sorol&#243;gicos dos pacientes com PF e PV submetidos &#224; bi&#243;psia de pele e&#47;ou mucosa para os ensaios de qPCR&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">As curvas de amplifica&#231;&#227;o das amostras de cDNA s&#227;o mostradas na <a class="elsevierStyleCrossRef" href="#sec0120">figura 3 suplementar</a>&#46; Os resultados das express&#245;es g&#234;nicas relativas de Dsg 1&#44; 2 e 3 s&#227;o apresentados na <a class="elsevierStyleCrossRef" href="#fig0025">figura 5</a>&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">Considerando a amostra de pele controle de LF&#44; houve predom&#237;nio da express&#227;o g&#234;nica relativa da Dsg3&#44; seguida pelas express&#245;es das Dsg1 e Dsg2 &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>A e B&#41;&#46; As express&#245;es g&#234;nicas relativas das Dsg1 e Dsg3 foram menores no PV&#44; seguido pelo PF&#44; com distribui&#231;&#227;o semelhante das Dsgs &#224; amostra de LF &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>A eB&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">As express&#245;es das Dsg 1&#44; 2 e 3 apresentaram resultados distintos nas amostras de MI do PF e ML do PV&#44; com predom&#237;nio da express&#227;o da Dsg3 &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>C&#41;&#46; J&#225; a express&#227;o da Dsg2 mostrou&#8208;se maior na MI do PF e ML do PV&#44; comparada &#224;s das amostras de PI e de PL do PF e PV &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>D&#41;&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discuss&#227;o</span><p id="par0135" class="elsevierStylePara elsevierViewall">Neste estudo&#44; demonstramos a produ&#231;&#227;o de autoanticorpos IgG s&#233;ricos contra Dsg2 em grande amostragem de pacientes com PF e PV&#44; comparados aos grupos FPF&#44; FPV e CTL&#44; todos habitantes de regi&#227;o prevalente em PF e PV no Sudeste do Brasil&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">3</span></a> A soropreval&#234;ncia de anti&#8208;Dsg2 no grupo PF &#40;63&#37; de 202 PF&#41; foi maior quando comparada &#224; do estudo de Flores et al&#46; &#40;40&#37; de 106 PF&#41;&#44; o qual foi realizado em regi&#227;o end&#234;mica para PF no Brasil&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">17</span></a> J&#225; a soropreval&#234;ncia no grupo CTL foi semelhante em ambos &#40;20&#37; e 27&#37;&#44; respectivamente&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Em raz&#227;o da similaridade proteica das Dsg1&#44; Dsg2 e Dsg3&#44; aventou&#8208;se poss&#237;vel rea&#231;&#227;o cruzada dos anticorpos anti&#8208;Dsg2 com as prote&#237;nas Dsg1 e Dsg3&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">5</span></a> No entanto&#44; testes de adsor&#231;&#227;o n&#227;o mostraram diferen&#231;as nos t&#237;tulos de anti&#8208;Dsg1 e anti&#8208;Dsg3 quando comparados os resultados pr&#233;&#8208; e p&#243;s&#8208;adsor&#231;&#227;o com a Dsg2&#44; confirmando a produ&#231;&#227;o espec&#237;fica de anti&#8208;Dsg2&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Considerando a especificidade da produ&#231;&#227;o de autoanticorpos contra a Dsg2&#44; alguns questionamentos devem ser considerados&#58; &#40;a&#41; seriam patog&#234;nicos&#63;&#44; e &#40;b&#41; seriam produzidos pelo fen&#244;meno de <span class="elsevierStyleItalic">epitope&#8208;spreading</span>&#63;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">18</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Quanto &#224; primeira quest&#227;o&#44; a discuss&#227;o dos resultados aponta pela n&#227;o patogenicidade dos anticorpos anti&#8208;Dsg2 nos p&#234;nfigos&#46; T&#237;tulos maiores de anti&#8208;Dsg2 foram detectados nos grupos PF&#44; PV e FPV&#44; quando comparados aos grupos FPF e CTL&#46; A produ&#231;&#227;o de anti&#8208;Dsg1 e anti&#8208;Dsg3 por indiv&#237;duos saud&#225;veis &#233; conhecida&#59; portanto&#44; a presen&#231;a de anti&#8208;Dsg2 nos grupos FPF&#44; FPV e CTL n&#227;o excluiria sua participa&#231;&#227;o na patog&#234;nese do PF e PV&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">19&#8211;21</span></a> T&#237;tulos de anti&#8208;Dsg2 se correlacionaram com os de anti&#8208;Dsg1 no PF &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;1628&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0206&#41;&#44; tamb&#233;m relatado por Flores et al&#46;&#59;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">17</span></a> no entanto&#44; n&#227;o houve correla&#231;&#227;o de anti&#8208;Dsg2 com anti&#8208;Dsg3 no PV&#46; Ainda&#44; os t&#237;tulos de anti&#8208;Dsg2 n&#227;o se correlacionaram com a forma cl&#237;nica ou com a atividade da doen&#231;a nos grupos PF e PV&#44; em contraste com os t&#237;tulos s&#233;ricos de anti&#8208;Dsg1 e anti&#8208;Dsg3 que est&#227;o associados &#224; gravidade do PF e PV&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">22&#44;23</span></a> Al&#233;m disso&#44; t&#237;tulos mais elevados de anti&#8208;Dsg2 nos grupos PF e PV sem tratamento em compara&#231;&#227;o ao CTL&#44; e nos grupos PV n&#227;o tratado em compara&#231;&#227;o com PV em tratamento foram encontrados&#46; Assim&#44; a diminui&#231;&#227;o de anti&#8208;Dsg2 ap&#243;s o tratamento imunossupressor poderia favorecer a patogenicidade de anti&#8208;Dsg2 no PV&#59; por&#233;m&#44; esse resultado n&#227;o foi confirmado no grupo PF&#46; Finalizando essa discuss&#227;o&#44; &#233; conhecida a express&#227;o da Dsg2 em outros tecidos al&#233;m da pele&#44; como tecidos pulmonar&#44; gastrintestinal&#44; renal e no mioc&#225;rdio&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">5&#44;8</span></a> Desse modo&#44; corroborando para que os anticorpos anti&#8208;Dsg2 n&#227;o sejam patog&#234;nicos&#44; excetuando&#8208;se o es&#244;fago no PV&#44; n&#227;o se evidencia comprometimento de &#243;rg&#227;os internos nos p&#234;nfigos&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">24</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Quanto &#224; segunda quest&#227;o&#44; seria mais plaus&#237;vel considerar que anticorpos anti&#8208;Dsg2 fossem produzidos por fen&#244;meno de <span class="elsevierStyleItalic">epitope&#8208;spreading</span> no PV&#44; visto que as Dsg2 e Dsg3 s&#227;o mais expressas nas camadas inferiores da epiderme&#46; Ainda&#44; pacientes com PV apresentaram t&#237;tulos de anti&#8208;Dsg2 mais elevados antecedendo o in&#237;cio do tratamento imunossupressor&#46; Assim&#44; poder&#237;amos supor que a Dsg2 &#233; exposta no in&#237;cio do processo acantol&#237;tico&#44; produzido por anti&#8208;Dsg3&#44; com consequente produ&#231;&#227;o de anti&#8208;Dsg2 por fen&#244;meno de <span class="elsevierStyleItalic">epitope&#8208;spreading</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">18</span></a> No entanto&#44; t&#237;tulos semelhantes de anti&#8208;Dsg2 foram observados no PF e PV&#46; Desse modo&#44; o fen&#244;meno de <span class="elsevierStyleItalic">epitope&#8208;spreading</span> estaria ocorrendo em ambos os processos patog&#234;nicos do PF e PV&#46; Retornaremos a essa discuss&#227;o ap&#243;s considerarmos os resultados de IHQ&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Uma vez que os pacientes com PF e PV produziram anti&#8208;Dsg2&#44; decidimos verificar as express&#245;es proteica e g&#234;nica da Dsg2 <span class="elsevierStyleItalic">in situ</span> por IHQ e qPCR&#44; respectivamente&#44; e comparar os resultados com as express&#245;es das Dsg1 e Dsg3&#46; Comparamos PI e PL do PF e PV com pele de abdominoplastia e LF &#224; IHQ e qPCR&#44; respectivamente&#46; A ML do PV foi comparada &#224; MI do PF&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Na amostra controle de abdominoplastia&#44; a express&#227;o proteica das Dsgs confirmou o padr&#227;o de distribui&#231;&#227;o cl&#225;ssico nas camadas da epiderme &#8211; a express&#227;o da Dsg2 foi restrita &#224;s camadas inferiores&#46; Al&#233;m disso&#44; as Dsg1 e Dsg3 foram predominantemente expressas nas membranas dos queratin&#243;citos&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">5&#44;12</span></a> Curiosamente&#44; as express&#245;es da Dsg2 e Dsg3 nas amostras de PI do PF e PV foram mais intensas do que na amostra de abdominoplastia&#44; e se estenderam a todas as camadas da epiderme&#46; Na PL do PF e PV&#44; a express&#227;o da Dsg2 foi intensa no teto e no assoalho das bolhas e nas c&#233;lulas acantol&#237;ticas&#46; Ainda&#44; nas amostras de PL do PF e PV&#44; observamos a presen&#231;a de gr&#226;nulos de Dsg1 e de Dsg3 intra e intercelulares nos queratin&#243;citos&#44; respectivamente&#46; Os gr&#226;nulos de Dsg1 estenderam&#8208;se por toda a camada Malpighiana no assoalho da bolha acantol&#237;tica do PF&#44; confirmando a internaliza&#231;&#227;o da Dsg1&#44; descrita h&#225; 30 anos&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">25&#8211;28</span></a> A internaliza&#231;&#227;o da Dsg3 na PL do PV foi menos evidente&#44; mas &#233; comumente descrita&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">29&#8211;32</span></a> Enquanto a Dsg2 esteve hiperexpressa na PI&#44; sua internaliza&#231;&#227;o esteve ausente na PL do PF e PV&#44; representando mais uma evid&#234;ncia de que anticorpos anti&#8208;Dsg2 n&#227;o t&#234;m papel patog&#234;nico no processo da acant&#243;lise do p&#234;nfigo&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Na amostra de LF&#44; a express&#227;o g&#234;nica relativa da Dsg2 foi menor do que a das Dsg1 e Dsg3&#44; condizente com a express&#227;o proteica avaliada por IHQ&#46; Com surpresa&#44; a express&#227;o g&#234;nica relativa da Dsg2 esteve aumentada na MI do PF e na ML do PV&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">O papel da hiperexpress&#227;o proteica e g&#234;nica da Dsg2 nas amostras de pele&#47;mucosa de pacientes com PF e PV merece aten&#231;&#227;o&#46; Iwatsuki et al&#46; mostraram que a internaliza&#231;&#227;o das Dsg1 e Dsg3 antecedia a acant&#243;lise em amostras de pele do PF e PV&#44; e esteve associada &#224; indu&#231;&#227;o da express&#227;o da Dsg2 para compensar a deple&#231;&#227;o das Dsg1 e Dsg3&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">13</span></a> Ainda&#44; Moll et al&#46; demonstraram forte express&#227;o da Dsg2 em modelo de cultura de pele criado para estudar a cicatriza&#231;&#227;o epitelial&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">33</span></a> Em camundongos transg&#234;nicos com superexpress&#227;o da Dsg2&#44; Brennan et al&#46; demonstraram hiperprolifera&#231;&#227;o de queratin&#243;citos epid&#233;rmicos e diminui&#231;&#227;o da apoptose&#44; e mostraram que a superexpress&#227;o da Dsg2 restringiu a forma&#231;&#227;o de bolhas epid&#233;rmicas por IgPF&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">34&#44;35</span></a> Depois&#44; Hartlieb et al&#46; demonstraram que&#44; embora a Dsg2 contribua menos do que a Dsg3 para a coes&#227;o dos queratin&#243;citos&#44; a Dsg2 compensou a perda de fun&#231;&#227;o da Dsg3&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">6&#44;36</span></a> Mais recentemente&#44; Sigmund et al&#46; demonstraram que a Dsg2 faz liga&#231;&#227;o heterof&#237;lica com a Dsg3 e pode minimizar a perda de ades&#227;o entre os queratin&#243;citos no processo da acant&#243;lise&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">37</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Somando os nossos resultados aos relatos da literatura&#44; a hiperexpress&#227;o da Dsg2 na pele e mucosa do PF e PV parece estar em conson&#226;ncia com os relatos mencionados&#58; a hiperexpress&#227;o da Dsg2&#44; para compensar a perda de fun&#231;&#227;o das Dsg1 e Dsg3&#44; poderia proteger o processo da acant&#243;lise e estar envolvida na repara&#231;&#227;o tecidual&#46; Al&#233;m disso&#44; a hiperexpress&#227;o da Dsg2 em todas as camadas da epiderme na PI e PL do PF e PV poderia justificar a produ&#231;&#227;o de autoanticorpos contra a Dsg2 pelo fen&#244;meno de <span class="elsevierStyleItalic">epitope&#8208;spreading</span>&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Por fim&#44; embora autoanticorpos anti&#8208;Dsg1 e anti&#8208;Dsg3 sejam relatados em popula&#231;&#245;es normais&#44; os resultados de t&#237;tulos aumentados de anti&#8208;Dsg2 no grupo FPV dever&#227;o ser mais bem avaliados&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">19&#8211;21</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Limita&#231;&#245;es do estudo</span><p id="par0190" class="elsevierStylePara elsevierViewall">Tamanho amostral pequeno para an&#225;lise estat&#237;stica das express&#245;es proteica e g&#234;nica da Dsg2 nos tecidos&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conclus&#227;o</span><p id="par0195" class="elsevierStylePara elsevierViewall">Nossos resultados permitem concluir que autoanticorpos contra Dsg2 n&#227;o s&#227;o patog&#234;nicos nos p&#234;nfigos&#44; e que a hiperexpress&#227;o proteica e g&#234;nica da Dsg2 em amostras de pele e mucosas de pacientes com PF e PV pode estar envolvida na prote&#231;&#227;o contra a acant&#243;lise</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Declara&#231;&#227;o de submiss&#227;o e verifica&#231;&#227;o</span><p id="par0200" class="elsevierStylePara elsevierViewall">Os resultados parciais do teste ELISA foram apresentados como p&#244;ster &#8220;Anticorpos contra desmogle&#237;na 2 est&#227;o presentes em amostras de pacientes com p&#234;nfigo foli&#225;ceo e p&#234;nfigo vulgar e em familiares e controles de regi&#227;o end&#234;mica&#8221; no XXXIV Encontro Anual de Dermatologistas da Am&#233;rica Latina&#44; 2016&#44; S&#227;o Paulo&#44; tendo sido contemplado em terceiro lugar&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Suporte financeiro</span><p id="par0205" class="elsevierStylePara elsevierViewall">Parcialmente financiado pela FAPESP &#40;Funda&#231;&#227;o de Amparo &#224; Pesquisa do Estado de S&#227;o Paulo&#41; &#40;&#35; 2010&#47;51729&#8208;2&#41; e FAEPA &#40;Funda&#231;&#227;o de Apoio ao Ensino&#44; Assist&#234;ncia e Pesquisa&#41;&#46; TJ recebeu bolsa de doutorado da FAPESP &#40;&#35;2016&#47;09011&#8208;3&#41; e SV recebeu bolsa de Doutorado da CAPES &#40;Coordena&#231;&#227;o de Aperfei&#231;oamento de Pessoal de N&#237;vel Superior&#41;&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Contribui&#231;&#227;o dos autores</span><p id="par0210" class="elsevierStylePara elsevierViewall">Marcela Calixto Brand&#227;o Miguel&#58; Contribuiu com obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; an&#225;lise estat&#237;stica&#59; revis&#227;o cr&#237;tica da literatura&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Tamiris Amanda Julio&#58; Contribuiu com obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; revis&#227;o cr&#237;tica do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Sebastian Vernal&#58; Contribuiu com a an&#225;lise dos dados&#59; revis&#227;o cr&#237;tica do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Nat&#225;lia Aparecida de Paula&#58; Contribuiu com obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; revis&#227;o cr&#237;tica do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Andre Lieber&#58; Contribuiu com o planejamento do estudo&#44; revis&#227;o cr&#237;tica do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Ana Maria Roselino&#58; Contribuiu com a concep&#231;&#227;o e planejamento do estudo&#59; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; revis&#227;o cr&#237;tica da literatura&#59; revis&#227;o cr&#237;tica do manuscrito e participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conflito de interesses</span><p id="par0240" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Fundamentos</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Autoanticorpos antidesmogle&#237;na 1 e 3 justificam a acant&#243;lise nos p&#234;nfigos&#59; por&#233;m&#44; a patog&#234;nese de antidesmogle&#237;na 2 &#233; hipot&#233;tica&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objetivo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Comparar a participa&#231;&#227;o das desmogle&#237;nas 1&#44; 2 e 3 pela produ&#231;&#227;o de autoanticorpos s&#233;ricos&#44; e express&#245;es proteica e g&#234;nica na pele&#47;mucosa de pacientes com p&#234;nfigo foli&#225;ceo e p&#234;nfigo vulgar&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">M&#233;todos</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Autoanticorpos foram titulados por ELISA em 202 amostras de p&#234;nfigo foli&#225;ceo&#44; 131 de p&#234;nfigo vulgar&#44; 50 e 57 familiares de p&#234;nfigo foli&#225;ceo e de p&#234;nfigo vulgar&#44; respectivamente&#44; e 114 controles&#46; Express&#245;es proteica e g&#234;nica foram determinadas por imuno&#8208;histoqu&#237;mica e qPCR na pele&#47;mucosa de tr&#234;s pacientes com p&#234;nfigo foli&#225;ceo e tr&#234;s com p&#234;nfigo vulgar&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">T&#237;tulos &#40;densidade &#243;ptica&#41; maiores de antidesmogle&#237;na 2 resultaram no p&#234;nfigo foli&#225;ceo e p&#234;nfigo vulgar&#44; comparados aos controles &#40;0&#44;166&#59; 0&#44;180&#59; 0&#44;102&#59; respectivamente&#59; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#46; Houve correla&#231;&#227;o entre t&#237;tulos de antidesmogle&#237;na 2 e antidesmogle&#237;na 1 no p&#234;nfigo foli&#225;ceo &#40;r<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;1680&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0206&#41;&#46; N&#227;o houve rea&#231;&#227;o cruzada de antidesmogle&#237;na 2 com desmogle&#237;nas 1 e 3&#46; Houve hiperexpress&#227;o proteica da desmogle&#237;na 2 na pele &#237;ntegra e lesional dos p&#234;nfigos&#44; comparada &#224; pele controle&#46; Foram observados gr&#226;nulos de internaliza&#231;&#227;o das desmogle&#237;nas 1 e 3&#44; mas n&#227;o da desmogle&#237;na 2&#44; na les&#227;o do p&#234;nfigo foli&#225;ceo e p&#234;nfigo vulgar&#44; respectivamente&#46; Houve hiperexpress&#227;o g&#234;nica da desmogle&#237;na 2 nas mucosas&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Limita&#231;&#245;es do estudo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Tamanho amostral pequeno para an&#225;lise estat&#237;stica das express&#245;es proteica e g&#234;nica&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclus&#227;o</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Autoanticorpos contra desmogle&#237;na 2 n&#227;o s&#227;o patog&#234;nicos nos p&#234;nfigos&#59; a hiperexpress&#227;o proteica e g&#234;nica da desmogle&#237;na 2 na pele e nas mucosas pode estar envolvida na repara&#231;&#227;o da acant&#243;lise&#46;</p></span>"
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          "pt" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Anticorpos IgG contra Dsg1&#44; Dsg2 e Dsg3 nos grupos estudados&#46; <span class="elsevierStyleBold">A&#44;</span> Anti&#8208;Dsg2 por ELISA in house&#46; PF&#44; PV e FPV apresentaram t&#237;tulos maiores comparados aos controles &#40;CTL&#41; &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#59; PF e FPV&#44; t&#237;tulos maiores do que FPF &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0046 e p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0004&#44; respectivamente&#41;&#46; <span class="elsevierStyleBold">B&#44;</span> Anti&#8208;Dsg1 por ELISA comercial&#46; PF apresentou t&#237;tulos maiores comparado a todos os grupos &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#59; PV&#44; t&#237;tulos maiores do que FPF&#44; FPV e CTL &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#46; <span class="elsevierStyleBold">C&#44;</span> Anti&#8208;Dsg3 por ELISA comercial&#46; PV apresentou t&#237;tulos maiores do que todos os grupos &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#46; A linha horizontal em cada coluna significa a mediana&#59; a linha pontilhada&#44; o valor de cut&#8208;off&#46; <span class="elsevierStyleItalic">PF</span>&#44; p&#234;nfigo foli&#225;ceo&#59; <span class="elsevierStyleItalic">PV</span>&#44; p&#234;nfigo vulgar&#59; <span class="elsevierStyleItalic">FPF</span>&#44; familiares do PF&#44; <span class="elsevierStyleItalic">FPV</span>&#44; familiares do PV&#46; An&#225;lise estat&#237;stica&#58; Kruskall&#8208;Wallis seguido pelo teste de Dunn&#46; <span class="elsevierStyleBold">D&#44;</span> Correla&#231;&#227;o de Spearman entre t&#237;tulos de anti&#8208;Dsg2 e anti&#8208;Dsg1 no PF&#46; <span class="elsevierStyleBold">E&#44;</span> Correla&#231;&#227;o de Spearman entre t&#237;tulos de anti&#8208;Dsg2 e anti&#8208;Dsg3 no PV&#46;</p>"
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          "pt" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Painel de imuno&#8208;histoqu&#237;mica com express&#245;es de Dsg1&#44; Dsg2 e Dsg3 em amostras de pele e mucosa de pacientes com PF e PV&#46; <span class="elsevierStyleBold">A&#44;</span> Dsg1 em amostras de pele &#237;ntegra e lesional do paciente PF2 mostrando gr&#226;nulos consp&#237;cuos intercelulares e intracitoplasm&#225;ticos &#40;internaliza&#231;&#227;o da Dsg1&#41;&#44; amplamente distribu&#237;dos na pele lesional &#40;amplifica&#231;&#227;o original de 100&#215;&#41;&#46; <span class="elsevierStyleBold">B&#44;</span> Dsg2 comparando amostra de pele &#237;ntegra e lesional do paciente PF2&#44; confirmando a aus&#234;ncia de gr&#226;nulos &#40;amplifica&#231;&#227;o original de 100&#215;&#41;&#46; <span class="elsevierStyleBold">C&#44;</span> Dsg3 comparando amostra de mucosa &#237;ntegra do paciente PF2 e mucosa lesional do paciente PV3&#44; mostrando gr&#226;nulos finos intercelulares e intracitoplasm&#225;ticos &#40;internaliza&#231;&#227;o da Dsg3&#41; na mucosa lesional &#40;amplifica&#231;&#227;o original de 100&#215;&#41;&#46;</p>"
        ]
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      4 => array:7 [
        "identificador" => "fig0025"
        "etiqueta" => "Figura 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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          0 => array:4 [
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Express&#245;es g&#234;nicas relativas &#40;&#215;10&#8208;4&#41; de Dsg1&#44; Dsg2 e Dsg3 em amostras de pele e mucosas&#46; <span class="elsevierStyleBold">A&#44;</span> Pele &#237;ntegra &#40;PI&#41; e pele lesional &#40;PL&#41; do PF em compara&#231;&#227;o &#224; amostra controle de <span class="elsevierStyleItalic">lifting</span> &#40;LF&#41; mostrando predomin&#226;ncia da express&#227;o da Dsg3 em compara&#231;&#227;o &#224;s Dsg1 e Dsg2&#46; <span class="elsevierStyleBold">B&#44;</span> PI e PL do PV e LF&#46; As express&#245;es das Dsg1&#44; Dsg2 e Dsg3 foram menores do que na amostra de LF&#46; <span class="elsevierStyleBold">C&#44;</span> Mucosa lesional &#40;ML&#41; de PV em compara&#231;&#227;o com a mucosa &#237;ntegra &#40;MI&#41; de PF mostrando predomin&#226;ncia da express&#227;o de Dsg3 comparada &#224;s Dsg1 e Dsg2&#46; A express&#227;o da Dsg2 est&#225; aumentada em amostras da mucosa&#46; <span class="elsevierStyleBold">D&#44;</span> Compara&#231;&#227;o da express&#227;o da Dsg2 em todas as amostras PF e PV&#46; As express&#245;es g&#234;nicas relativas das Dsg1&#44; Dsg2&#44; Dsg3 foram calculadas usando 2<span class="elsevierStyleSup">&#40;&#8722;&#916;cT&#41;</span> e 18S rRNA como gene de refer&#234;ncia&#46;</p>"
        ]
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                  \t\t\t\t">Feminino</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">102 &#40;50&#44;2&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88 &#40;67&#44;7&#41;<span class="elsevierStyleSup">b</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36 &#40;72&#44;0&#41;<span class="elsevierStyleSup">c</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40 &#40;70&#44;2&#41;<span class="elsevierStyleSup">d</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">55 &#40;48&#44;2&#41;<span class="elsevierStyleSup">e</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;8150<span class="elsevierStyleSup">a&#44;e</span>&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="" 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><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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;0000<span class="elsevierStyleSup">c&#44;d</span>&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Masculino</td><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">101 &#40;49&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42 &#40;32&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 &#40;28&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;29&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59 &#40;51&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0022<span class="elsevierStyleSup">c&#44;e</span>&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="" 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><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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0088<span class="elsevierStyleSup">d&#44;e</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2878215.png"
              ]
            ]
            2 => 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">Dura&#231;&#227;o da doen&#231;a &#40;anos&#41;&#42;&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>199&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>130&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>1&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45 &#40;22&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31 &#40;23&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;8967&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 a &#8722;5&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">87 &#40;43&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">86 &#40;66&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0296&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 a &#8722;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32 &#40;16&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9 &#40;6&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0390&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 a 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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;5&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;2&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;2630&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62; 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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 &#40;12&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;0&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2878216.png"
              ]
            ]
            3 => 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">Forma cl&#237;nica &#40;pacientes virgens de tratamento&#41;&#42;&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>68&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>26&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mucosa exclusiva</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;30&#44;8&#41;<span class="elsevierStyleSup">b</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA</td><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"><span class="elsevierStyleSup">a</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;9636&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSup">b</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;3909&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mucocut&#226;nea&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18 &#40;69&#44;2&#41;<span class="elsevierStyleSup">b</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Localizada&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;50&#44;0&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Generalizada&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;50&#44;0&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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 => "xTab2878212.png"
              ]
            ]
            4 => 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">Tratamento na data da coleta de soro<a class="elsevierStyleCrossRef" href="#tblfn0015">&#42;</a>&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>186&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>127&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Virgens de tratamento&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43 &#40;23&#44;1&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20 &#40;15&#44;8&#41;<span class="elsevierStyleSup">b</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSup">a</span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sem tratamento com les&#245;es ativas&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;18&#44;3&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;8&#44;7&#41;<span class="elsevierStyleSup">b</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSup">b</span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Em tratamento sem les&#245;es ativas&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16 &#40;8&#44;6&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 &#40;18&#44;8&#41;<span class="elsevierStyleSup">b</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Em tratamento com les&#245;es ativas&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80 &#40;43&#44;0&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65 &#40;51&#44;2&#41;<span class="elsevierStyleSup">b</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&nbsp;\t\t\t\t\t\t\n
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                  \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">NA&nbsp;\t\t\t\t\t\t\n
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                  \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 => "xTab2878213.png"
              ]
            ]
            5 => array:2 [
              "tabla" => array:1 [
                0 => """
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0325<span class="elsevierStyleSup">c&#44;d</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Anti&#8208;Dsg3</span>&nbsp;\t\t\t\t\t\t\n
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                  \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
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                  \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
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                  \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><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001<span class="elsevierStyleSup">a&#44;b</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001<span class="elsevierStyleSup">b&#44;e</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abaixo do <span class="elsevierStyleItalic">cut&#8208;off</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t">193 &#40;95&#44;5&#41;</td><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t">46 &#40;92&#44;0&#41;</td><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t">57 &#40;100&#44;0&#41;</td><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">111 &#40;97&#44;4&#41;</td><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">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001<span class="elsevierStyleSup">b&#44;d</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0446<span class="elsevierStyleSup">c&#44;d</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  <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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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">Idade&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">G&#234;nero&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">Dura&#231;&#227;o da doen&#231;a &#40;meses&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Forma cl&#237;nica&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">Tratamento na data da bi&#243;psia&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">Anti&#8208;Dsg1 &#40;U&#47;mL&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&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">Anti&#8208;Dsg2 &#40;DO&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&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">Anti&#8208;Dsg3 &#40;U&#47;mL&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">PF1</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Masculino&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Generalizada&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Em tratamento h&#225; 30 dias&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">99&#44;80&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;088&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">PF2</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Masculino&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Generalizada&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Virgem de tratamento&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">193&#44;08&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;223&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#44;15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">PF3</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Masculino&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Localizada&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Virgem de tratamento&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">237&#44;90&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;894&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#44;70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">PV1</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Masculino&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mucocut&#226;nea&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sem tratamento h&#225; mais de 60 dias&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#44;87&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;211&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">172&#44;78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">PV2</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Masculino&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mucocut&#226;nea&nbsp;\t\t\t\t\t\t\n
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Artigo original
Autoanticorpos contra desmogleína 2 não são patogênicos nos pênfigos
Marcela Calixto Brandão Miguela, Tamiris Amanda Julioa, Sebastian Vernala, Natália Aparecida de Paulaa,b, Andre Lieberc, Ana Maria Roselinoa,b,
Corresponding author
amfrosel@fmrp.usp.br

Autor para correspondência.
a Divisão de Dermatologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
b Laboratório do Setor de Dermatologia, Divisão de Dermatologia, Departamento de Clínica Médica, Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
c Divisão de Genética Médica, Departamento de Patologia, University of Washington, Seattle, WA, Estados Unidos da América
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          "pt" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Painel de imuno&#8208;histoqu&#237;mica com express&#245;es de Dsg1&#44; Dsg2 e Dsg3 em amostras de pele e mucosa de pacientes com PF e PV&#46; <span class="elsevierStyleBold">A&#44;</span> Dsg1 em amostras de pele &#237;ntegra e lesional do paciente PF2 mostrando gr&#226;nulos consp&#237;cuos intercelulares e intracitoplasm&#225;ticos &#40;internaliza&#231;&#227;o da Dsg1&#41;&#44; amplamente distribu&#237;dos na pele lesional &#40;amplifica&#231;&#227;o original de 100&#215;&#41;&#46; <span class="elsevierStyleBold">B&#44;</span> Dsg2 comparando amostra de pele &#237;ntegra e lesional do paciente PF2&#44; confirmando a aus&#234;ncia de gr&#226;nulos &#40;amplifica&#231;&#227;o original de 100&#215;&#41;&#46; <span class="elsevierStyleBold">C&#44;</span> Dsg3 comparando amostra de mucosa &#237;ntegra do paciente PF2 e mucosa lesional do paciente PV3&#44; mostrando gr&#226;nulos finos intercelulares e intracitoplasm&#225;ticos &#40;internaliza&#231;&#227;o da Dsg3&#41; na mucosa lesional &#40;amplifica&#231;&#227;o original de 100&#215;&#41;&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Introdu&#231;&#227;o</span><p id="par0005" class="elsevierStylePara elsevierViewall">Os p&#234;nfigos s&#227;o doen&#231;as bolhosas autoimunes&#44; caracterizados pela produ&#231;&#227;o de autoanticorpos IgG contra as desmogle&#237;nas &#40;Dsg&#41; 1 e 3&#44; os quais rompem a ades&#227;o dos queratin&#243;citos causando acant&#243;lise&#46; No p&#234;nfigo foli&#225;ceo &#40;PF&#41;&#44; a produ&#231;&#227;o de anti&#8208;Dsg1 &#233; respons&#225;vel pelo acometimento exclusivo da pele&#59; no p&#234;nfigo vulgar &#40;PV&#41;&#44; a produ&#231;&#227;o de anti&#8208;Dsg3 afeta as mucosas&#44; e&#44; quando a pele est&#225; envolvida&#44; s&#227;o detectados anti&#8208;Dsg1 e anti&#8208;Dsg3&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">1&#44;2</span></a> Tanto o PF quanto o PV s&#227;o prevalentes no Sudeste do Brasil&#44; e a determina&#231;&#227;o do perfil HLA dos pacientes com PF e PV confirmou tratar&#8208;se de doen&#231;as bolhosas distintas&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">A participa&#231;&#227;o da Dsg2 &#233; pouco estudada na patog&#234;nese dos p&#234;nfigos&#46; Em contraste com as express&#245;es das Dsg1 e Dsg3&#44; que s&#227;o restritas a epit&#233;lios estratificados&#44; a Dsg2 &#233; amplamente expressa em todos os epit&#233;lios que cont&#234;m desmossomos&#44; incluindo tecidos pulmonar&#44; gastrintestinal&#44; renal e o mioc&#225;rdio&#44; e em tumores da pele&#44; ov&#225;rio&#44; pulm&#227;o e est&#244;mago&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">5&#8211;11</span></a> Na pele humana&#44; a Dsg2 &#233; pouco expressa&#44; restringindo&#8208;se &#224; camada basal da epiderme&#44; enquanto sua express&#227;o se assemelha &#224;s express&#245;es da Dsg1 e Dsg3 em linhagens de c&#233;lulas imortalizadas de carcinoma de c&#233;lulas escamosas&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">12</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Para contribuir com a participa&#231;&#227;o da Dsg2 na patog&#234;nese dos p&#234;nfigos&#44; comparou&#8208;se a produ&#231;&#227;o de autoanticorpos contra as Dsg 1&#44; 2 e 3 em ampla amostragem de pacientes com PF e PV&#44; seus familiares e controles saud&#225;veis&#44; residentes na regi&#227;o nordeste do estado de S&#227;o Paulo&#44; Brasil&#44; onde ambos PF e PV s&#227;o prevalentes&#46; Foram determinadas&#44; ainda&#44; as express&#245;es proteica e g&#234;nica das Dsg 1&#44; 2 e 3 em amostras de pele e mucosa&#44; obtidas de pacientes com PF e PV&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Materiais e m&#233;todos</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">&#201;tica</span><p id="par0020" class="elsevierStylePara elsevierViewall">O Comit&#234; de &#201;tica Humana &#40;CAAE&#58; 56944116&#46;1&#46;0000&#46;5440&#41; aprovou este estudo de acordo com os padr&#245;es &#233;ticos da Declara&#231;&#227;o de Helsinque da Associa&#231;&#227;o M&#233;dica Mundial&#46; Todos os participantes assinaram o termo de consentimento livre e esclarecido&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Popula&#231;&#227;o do estudo</span><p id="par0025" class="elsevierStylePara elsevierViewall">Amostras de soro de pacientes com PF e PV&#44; diagnosticados por exame cl&#237;nico&#44; histopatol&#243;gico&#44; e exames de imunofluoresc&#234;ncia direta e&#47;ou indireta&#59; de familiares de primeiro e segundo graus e de controles &#40;CTL&#41;&#44; que acompanharam os pacientes durante a consulta ambulatorial&#44; foram obtidas de 1997 a 2016&#46; Cinco grupos foram analisados&#58; 202 pacientes com PF e 131 com PV&#44; 50 familiares do PF &#40;FPF&#41; e 57 FPV&#44; e 114 CTL&#46; Os pacientes virgens de tratamento foram classificados de acordo com a forma cl&#237;nica &#8211; isto &#233;&#44; PF localizado ou generalizado e PV forma mucosa exclusiva ou mucocut&#226;nea&#46; Os pacientes com PF e PV foram divididos em cinco subgrupos&#44; de acordo com a atividade da doen&#231;a e vig&#234;ncia ou n&#227;o de tratamento no momento da coleta do soro&#58; virgens de tratamento&#59; com les&#245;es ativas e sem tratamento h&#225; mais de 60 dias&#59; em tratamento com les&#245;es ativas&#59; em tratamento sem les&#245;es ativas&#59; e em remiss&#227;o &#40;pacientes sem les&#245;es ativas e sem tratamento imunossupressor h&#225; pelo menos 60 dias&#41; &#8211; <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Detec&#231;&#227;o de autoanticorpos IgG contra Dsg1 e Dsg3 por ELISA</span><p id="par0030" class="elsevierStylePara elsevierViewall">As amostras foram testadas com ELISA comercial &#40;MBL&#44; Nagoya&#44; Jap&#227;o&#41;&#44; segundo as recomenda&#231;&#245;es do fabricante &#40;<span class="elsevierStyleItalic">cut&#8208;off</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20 U&#47;mL&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Detec&#231;&#227;o de autoanticorpos IgG contra Dsg2 por ELISA in house</span><p id="par0035" class="elsevierStylePara elsevierViewall">Resumidamente&#44; 5 ng&#47;&#956;L da Dsg2 &#40;Leinco&#44; Fenton&#44; EUA&#41; dilu&#237;dos em solu&#231;&#227;o de carbonato&#8208;bicarbonato &#40;pH 7&#44;4&#41; foram incubados &#40;50 &#956;L&#47;po&#231;o&#41; em microplaca de 96 po&#231;os &#40;Sigma&#8208;Aldrich&#44; St&#46; Louis&#44; EUA&#41; a 4<span class="elsevierStyleHsp" style=""></span>&#176;C durante a noite&#46; Ap&#243;s quatro lavagens com 0&#44;05&#37; de PBS&#47;Tween e incuba&#231;&#227;o com solu&#231;&#227;o de bloqueio &#40;PBS&#47;Tween 0&#44;05&#37;&#47;leite desnatado 5&#37;&#41; por uma hora&#44; 50 &#956;L de amostras de soro &#40;dilu&#237;das a 1&#58;100 em solu&#231;&#227;o de bloqueio&#41;&#44; em duplicata&#44; foram adicionadas e incubadas &#224; temperatura ambiente &#40;TA&#41; durante 2 horas&#46; Ap&#243;s quatro lavagens&#44; 50 &#956;L &#40;dilu&#237;do a 1&#58;5000 em solu&#231;&#227;o de bloqueio&#41; de anticorpo HRP conjugado com IgG anti&#8208;humano &#40;Abcam&#44; Cambridge&#44; EUA&#41; foram incubados em TA por 2 horas&#46; Ap&#243;s quatro novas lavagens&#44; 50 &#956;L de substrato de peroxidase ABTS &#40;&#225;cido 2&#44;2&#8217;&#8208;azino&#8208;bis &#91;3&#8208;etilbenzotiazolina&#8208;6&#8208;sulf&#244;nico&#93;&#41; foram adicionados e mantidos em TA por 15 minutos no escuro&#44; e a rea&#231;&#227;o foi finalmente interrompida com 50 &#956;L de H2SO4 1<span class="elsevierStyleHsp" style=""></span>M&#46; Os t&#237;tulos em densidade &#243;ptica &#40;DO&#41; foram determinados em leitor de placas ELISA &#40;Biochrom Asys Expert Plus Microplate Reader&#44; Cambourne&#44; UK&#41; a 405<span class="elsevierStyleHsp" style=""></span>nm&#46; Anticorpo comercial anti&#8208;Dsg2 &#40;Abcam&#44; Cambridge&#44; EUA&#41; foi empregado como controle positivo&#46; O valor do <span class="elsevierStyleItalic">cut&#8208;off</span> de 0&#44;1365 DO foi estabelecido por curva ROC &#40;<a class="elsevierStyleCrossRef" href="#sec0120">fig&#46; 1 suplementar</a>&#41;&#46; T&#237;tulos maiores que 0&#44;400 DO foram obtidos em quatro amostras do grupo CTL e foram exclu&#237;dos do c&#225;lculo porque excederam a curva de normalidade&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">ELISA de adsor&#231;&#227;o para especificidade de anti&#8208;Dsg2</span><p id="par0040" class="elsevierStylePara elsevierViewall">Para excluir rea&#231;&#227;o cruzada dos anticorpos anti&#8208;Dsg2 com as prote&#237;nas Dsg1 e Dsg3&#44; seis amostras de soro do PF e seis do PV com t&#237;tulos elevados de anti&#8208;Dsg 1&#44; 2 e 3 foram selecionadas&#46; Foram realziados ensaios ELISA para adsor&#231;&#227;o s&#233;rica em s&#233;rie com Dsg2 &#40;Leinco&#44; Fenton&#44; EUA&#41; at&#233; que o n&#237;vel de anti&#8208;Dsg2 ficasse abaixo do valor <span class="elsevierStyleItalic">cut&#8208;off</span>&#46; Posteriormente&#44; o soro remanescente foi colocado em placa de ELISA comercial anti&#8208;Dsg1 e anti&#8208;Dsg3 &#40;MBL&#44; Nagoya&#44; Jap&#227;o&#41; para comparar os t&#237;tulos pr&#233;&#8208; e p&#243;s&#8208;adsor&#231;&#227;o&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Amostras de bi&#243;psia</span><p id="par0045" class="elsevierStylePara elsevierViewall">As bi&#243;psias de pele e&#47;ou mucosa foram realizadas em tr&#234;s pacientes com PF e tr&#234;s com PV&#44; virgens de tratamento ou com les&#245;es ativas e sem tratamento por mais de 60 dias&#46; 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EUA&#41; a &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C para extra&#231;&#227;o de RNA e subsequente ensaio de qPCR&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Imuno&#8208;histoqu&#237;mica &#40;IHQ&#41;</span><p id="par0050" class="elsevierStylePara elsevierViewall">O sistema de detec&#231;&#227;o HRP&#8208;Polymer MACH 1 &#40;Biocare Medical&#44; Concord&#44; EUA&#41; foi usado de acordo com as recomenda&#231;&#245;es do fabricante&#46; Os fragmentos congelados foram fixados em acetona &#40;Merck&#44; Darmstadt&#44; Germany&#41; a 4<span class="elsevierStyleHsp" style=""></span>&#176;C por 10 minutos e lavados em PBS Ph 7&#44;4&#59; a peroxidase end&#243;gena foi inibida pela incuba&#231;&#227;o com H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span> 0&#44;3&#37; &#40;Labsynth&#44; Diadema&#44; Brasil&#41; por 10 minutos&#46; Em seguida&#44; os fragmentos foram incubados com solu&#231;&#227;o de bloqueio Sniper em TA por 10 minutos&#44; seguido pela adi&#231;&#227;o de 5 &#956;g&#47;mL de anticorpo monoclonal anti&#8208;Dsg1&#44; anti&#8208;Dsg2 e anti&#8208;Dsg3 &#40;Abcam&#44; Cambridge&#44; Reino Unido&#41; por 2 horas&#46; Os cortes foram lavados com PBS por 3 minutos&#44; duas vezes&#46; Em seguida&#44; a sonda foi adicionada por 15 minutos&#46; Os cortes foram lavados em PBS novamente e incubados com o pol&#237;mero HRP por 30 minutos&#46; Ap&#243;s a lavagem&#44; a rea&#231;&#227;o foi completada com a adi&#231;&#227;o do substrato cromog&#234;nico diaminobenzidina por 2 minuots&#44; preparado de acordo com as instru&#231;&#245;es do fabricante &#40;Biocare Medical&#44; Concord&#44; EUA&#41;&#46; A seguir&#44; os cortes foram contrastados com hematoxilina de Harris &#40;Merck Millipore&#44; Burlington&#44; EUA&#41; por 40 segundos e lavados em &#225;gua corrente&#46; Para a montagem das l&#226;minas&#44; os cortes foram desidratados em banhos crescentes de etanol e diafanizados em banhos de xilol e&#44; a seguir&#44; montadas com Entellan &#40;Merck&#44; Darmstadt&#44; Alemanha&#41; e os cortes cobertos com lam&#237;nula para observa&#231;&#227;o em microsc&#243;pio &#243;ptico &#40;Imager&#8208;A1&#44; Zeiss&#44; Alemanha&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Extra&#231;&#227;o de RNA e s&#237;ntese de cDNA</span><p id="par0055" class="elsevierStylePara elsevierViewall">RNA total foi extra&#237;do de bi&#243;psias de pele ou mucosa usando o reagente Trizol&#44; de acordo com as instru&#231;&#245;es do fabricante &#40;Invitrogen&#44; Carlsbad&#44; EUA&#41;&#46; Ap&#243;s a extra&#231;&#227;o&#44; as amostras foram incubadas com DNAse &#40;Promega&#44; Madison&#44; EUA&#41; e quantificadas em espectrofot&#244;metro NanoVue&#174; Plus &#40;GE Healthcare Life Sciences&#44; Chicago&#44; EUA&#41;&#59; 40 ng de RNA foram transcritos reversamente com o kit de s&#237;ntese de cDNA &#40;Promega&#44; Madison&#44; EUA&#41;&#44; seguindo as instru&#231;&#245;es do fabricante&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Rea&#231;&#227;o em cadeia da polimerase quantitativa em tempo real &#40;qPCR&#41; e sequenciamento das Dsg1&#44; Dsg2 e Dsg3</span><p id="par0060" class="elsevierStylePara elsevierViewall">SYBR Green qPCR foi realizada em volume final de 22&#44;5 &#956;L&#44; com 12&#44;5 &#956;L de MIX SYBR Green PCR &#40;Promega&#44; Madison&#44; EUA&#41;&#44; 0&#44;5 &#956;L de cada primer &#40;10 &#956;M&#41;&#44; 6&#44;5 &#956;L de &#225;gua ultrapura e 2&#44;5 &#956;L de cDNA &#40;1&#58;4&#41;&#44; no termociclador Rotor Gene&#8208;Q&#174; &#40;Qiagen&#44; Hilden&#44; Alemanha&#41;&#46; Foram utilizadas as sequ&#234;ncias de primers que amplificam fragmentos dos genes Dsg1&#44; Dsg2 e Dsg3 e do gene ribossomal humano &#40;18S&#41; como gene end&#243;geno&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">13&#8211;15</span></a> As sequ&#234;ncias dos primers&#44; o produto amplificado resultante &#40;amplicon&#41; e os par&#226;metros dos ciclos de amplifica&#231;&#227;o s&#227;o detalhados na <a class="elsevierStyleCrossRef" href="#tbl0005">Tabela 1 suplementar</a>&#46; As express&#245;es g&#234;nicas relativas de Dsg1&#44; Dsg2 e Dsg3 foram calculadas usando a equa&#231;&#227;o 2 <span class="elsevierStyleSup">&#40;&#8722;&#916;cT&#41;</span>&#44; tendo o 18S rRNA como gene de refer&#234;ncia&#59; &#916;cT foi calculado subtraindo o valor do cicle Threshold &#40;cT&#41; do gene alvo &#40;Dsg1&#44; Dsg2 ou Dsg3&#41; do valor de cT do gene de refer&#234;ncia &#40;18S&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">16</span></a> Para verificar a especificidade de cada sequ&#234;ncia&#44; o amplicon obtido foi purificado &#40;ExoSAP&#8208;IT&#174;&#41;&#44; sequenciado &#40;3500 Genetic Analyzer&#44; Applied Biosystems&#44; EUA&#41; e analisado no NCBI BLAST&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">An&#225;lise estat&#237;stica</span><p id="par0065" class="elsevierStylePara elsevierViewall">As vari&#225;veis categ&#243;ricas foram analisadas por teste Qui&#8208;quadrado &#40;&#215;2&#41; ou teste exato de Fisher quando os dados eram escassos&#46; Kruskall&#8208;Wallis seguido pelo teste de Dunn foi empregado para comparar os t&#237;tulos de ELISA entre os grupos&#46; O teste de Spearman foi usado para correlacionar os t&#237;tulos de anticorpos contra as Dsgs&#44; bem como com a dura&#231;&#227;o da doen&#231;a e a idade dos pacientes&#46; O teste de Friedman foi usado para comparar os t&#237;tulos de anti&#8208;Dsg2 pr&#233;&#8208; e p&#243;s&#8208;adsor&#231;&#227;o s&#233;rica em s&#233;rie&#46; O teste de Wilcoxon foi aplicado para comparar os t&#237;tulos de anti&#8208;Dsg1 e anti&#8208;Dsg3 pr&#233;&#8208; e p&#243;s&#8208;adsor&#231;&#227;o com Dsg2&#46; A an&#225;lise de regress&#227;o log&#237;stica multivariada com o SPSS <span class="elsevierStyleItalic">Statistics</span> 17&#46;0 &#40;<span class="elsevierStyleItalic">software</span> IBM SPSS&#174;&#44; EUA&#41; foi utilizada para confirmar os resultados significativos obtidos na an&#225;lise univariada&#46; A signific&#226;ncia foi fixada em &#945;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#37;&#46; O <span class="elsevierStyleItalic">software</span> GraphPad Prism 8&#46;1 foi utilizado para as an&#225;lises estat&#237;sticas e para a constru&#231;&#227;o dos gr&#225;ficos &#40;GraphPad software Inc&#46;&#44; La Jolla&#44; EUA&#41;&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Resultados</span><p id="par0070" class="elsevierStylePara elsevierViewall">A <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a> resume os dados demogr&#225;ficos&#44; cl&#237;nicos e laboratoriais dos grupos estudados&#46; Os grupos PF e PV apresentaram t&#237;tulos &#40;DO&#41; semelhantes e maiores de anti&#8208;Dsg2 comparados ao grupo CTL &#40;0&#44;166&#59; 0&#44;180&#59; 0&#44;102&#44; respectivamente&#59; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41; &#8211; <a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a>A&#46; Ainda&#44; o grupo PF apresentou maiores t&#237;tulos de anti&#8208;Dsg2 comparado aos grupos FPF &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0046&#41; e FPV &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0004&#41;&#46; Esses resultados permaneceram estatisticamente significativos ap&#243;s an&#225;lise multivariada&#44; corrigida por idade&#44; sexo e t&#237;tulos de anticorpos contra Dsg1 e Dsg3&#46; Nos grupos de familiares e CTL&#44; observou&#8208;se produ&#231;&#227;o de autoanticorpos contra Dsg1 e&#47;ou Dsg3 &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>B e C&#41;&#46; T&#237;tulos de anti&#8208;Dsg2 foram mais elevados nos grupos PF e PV virgens de tratamento&#44; comparados ao grupo CTL &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#44; e no grupo PV sem tratamento comparado ao PV em tratamento &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0311&#59; <a class="elsevierStyleCrossRef" href="#sec0120">fig&#46; 2 suplementar</a>&#41;&#44; permanecendo significativo ap&#243;s an&#225;lise multivariada &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0500&#41;&#46; Os subgrupos PF n&#227;o diferiram quanto aos t&#237;tulos de anti&#8208;Dsg2 &#40;dados n&#227;o mostrados&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">A soropreval&#234;ncia de anti&#8208;Dsg2 nos grupos PF&#44; PV e FPV resultou semelhante &#40;63&#44;9&#37;&#59; 66&#44;4&#37;&#59; 73&#44;7&#37;&#44; respectivamente&#41;&#44; e maior que nos grupos FPF e CTL &#40;38&#37;&#59; 27&#44;2&#37;&#44; respectivamente &#8211; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41; &#8211; <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">N&#227;o houve correla&#231;&#227;o significativa dos t&#237;tulos de anti&#8208;Dsg2 com a dura&#231;&#227;o da doen&#231;a no PF &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;5365&#41; e no PV &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;1629&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0630&#41; &#8211; dados n&#227;o mostrados &#8211;&#44; assim como com a forma cl&#237;nica do PF &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;9636&#41; e do PV &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;3909&#41; &#8211; <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46; N&#227;o houve diferen&#231;a significativa dos t&#237;tulos de anti&#8208;Dsg2 nos subgrupos PF e PV com les&#245;es cut&#226;neas ativas e sem les&#245;es cut&#226;neas &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;3790 e p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;1312&#44; respectivamente&#41; &#8211; dados n&#227;o mostrados&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Houve correla&#231;&#227;o positiva dos t&#237;tulos de anti&#8208;Dsg2 com os t&#237;tulos de anti&#8208;Dsg1 no grupo PF &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;1628&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0206&#41;&#44; com tend&#234;ncia &#224; correla&#231;&#227;o positiva com os t&#237;tulos de anti&#8208;Dsg3 no PV &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;1675&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0568&#41; &#8211; <a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>D e E&#46; Considerando os subgrupos virgem de tratamento&#44; e sem tratamento h&#225; mais de 60 dias e com les&#245;es em atividade&#44; n&#227;o houve correla&#231;&#227;o dos t&#237;tulos de anti&#8208;Dsg2 com os de anti&#8208;Dsg1 no PF &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;2100&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0650&#41;&#44; assim como com os de anti&#8208;Dsg3 no PV &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;1481&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;4264&#41; &#8211; dados n&#227;o mostrados&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Ap&#243;s a adsor&#231;&#227;o dos soros de pacientes com PF e PV com o pept&#237;deo Dsg2&#44; os t&#237;tulos de anti&#8208;Dsg1 e de anti&#8208;Dsg3 permaneceram semelhantes &#224; pr&#233;&#8208;adsor&#231;&#227;o &#40;p &#62;<span class="elsevierStyleHsp" style=""></span>0&#44;9999 e p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;4063&#44; respectivamente&#41;&#44; confirmando a especificidade dos anticorpos anti&#8208;Dsg2 &#40;<a class="elsevierStyleCrossRef" href="#sec0120">tabelas 2 e 3 suplementares</a>&#41;&#46;</p><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Express&#227;o proteica das desmogle&#237;nas por IHQ</span><p id="par0095" class="elsevierStylePara elsevierViewall">A <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a> mostra os dados demogr&#225;ficos e sorol&#243;gicos dos pacientes com PF e PV submetidos &#224; bi&#243;psia de pele e&#47;ou mucosa para IHQ&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Na amostra de pele controle de abdominoplastia&#44; confirmou&#8208;se a distribui&#231;&#227;o epid&#233;rmica cl&#225;ssica das Dsgs&#58; a Dsg1 esteve expressa em toda a epiderme&#44; com predom&#237;nio nas camadas superiores&#44; enquanto as Dsg2 e Dsg3 predominaram nas camadas inferiores&#46; A express&#227;o da Dsg2 foi menos intensa do que a das Dsg1 e Dsg3 &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>A&#41;&#46; Diferentemente da amostra de pele controle&#44; a express&#227;o da Dsg2 foi mais intensa em todas as camadas da epiderme nas amostras de PI do PF e PV &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>B e C&#41;&#46; Na PL do PF&#44; houve express&#227;o intensa da Dsg2 no assoalho da bolha e&#44; no PV&#44; no teto e no assoalho da bolha&#44; incluindo sua express&#227;o nas c&#233;lulas acantol&#237;ticas &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>B e C&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">&#192; semelhan&#231;a da amostra de pele controle&#44; a express&#227;o da Dsg2 na MI do PF foi mais intensa nas camadas inferiores&#46; Ainda&#44; houve predom&#237;nio da express&#227;o da Dsg3 em todas as camadas da epiderme&#44; comparada &#224;s da Dsg1 e Dsg2 &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>A&#41;&#46; Na ML do PV&#44; houve predom&#237;nio da express&#227;o da Dsg3 no teto e no assoalho da bolha &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>B e C&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Na PL do PF&#44; gr&#226;nulos consp&#237;cuos intercelulares e intracitoplasm&#225;ticos&#44; correspondentes &#224; internaliza&#231;&#227;o da Dsg1&#44; foram observados em toda a extens&#227;o do assoalho da bolha&#44; da camada basal &#224; camada Malpighiana &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>A&#41;&#46; Gr&#226;nulos intracitoplasm&#225;ticos&#44; que poderiam representar a internaliza&#231;&#227;o da Dsg2&#44; n&#227;o foram observados nas amostras lesionais do PF e PV &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>B&#41;&#46; Na PL e na ML do PV&#44; gr&#226;nulos intercelulares finos e esparsos de Dsg3 foram demonstrados &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>C&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Express&#227;o g&#234;nica das desmogle&#237;nas por qPCR</span><p id="par0115" class="elsevierStylePara elsevierViewall">A <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a> detalha os dados demogr&#225;ficos e sorol&#243;gicos dos pacientes com PF e PV submetidos &#224; bi&#243;psia de pele e&#47;ou mucosa para os ensaios de qPCR&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">As curvas de amplifica&#231;&#227;o das amostras de cDNA s&#227;o mostradas na <a class="elsevierStyleCrossRef" href="#sec0120">figura 3 suplementar</a>&#46; Os resultados das express&#245;es g&#234;nicas relativas de Dsg 1&#44; 2 e 3 s&#227;o apresentados na <a class="elsevierStyleCrossRef" href="#fig0025">figura 5</a>&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">Considerando a amostra de pele controle de LF&#44; houve predom&#237;nio da express&#227;o g&#234;nica relativa da Dsg3&#44; seguida pelas express&#245;es das Dsg1 e Dsg2 &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>A e B&#41;&#46; As express&#245;es g&#234;nicas relativas das Dsg1 e Dsg3 foram menores no PV&#44; seguido pelo PF&#44; com distribui&#231;&#227;o semelhante das Dsgs &#224; amostra de LF &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>A eB&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">As express&#245;es das Dsg 1&#44; 2 e 3 apresentaram resultados distintos nas amostras de MI do PF e ML do PV&#44; com predom&#237;nio da express&#227;o da Dsg3 &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>C&#41;&#46; J&#225; a express&#227;o da Dsg2 mostrou&#8208;se maior na MI do PF e ML do PV&#44; comparada &#224;s das amostras de PI e de PL do PF e PV &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>D&#41;&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discuss&#227;o</span><p id="par0135" class="elsevierStylePara elsevierViewall">Neste estudo&#44; demonstramos a produ&#231;&#227;o de autoanticorpos IgG s&#233;ricos contra Dsg2 em grande amostragem de pacientes com PF e PV&#44; comparados aos grupos FPF&#44; FPV e CTL&#44; todos habitantes de regi&#227;o prevalente em PF e PV no Sudeste do Brasil&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">3</span></a> A soropreval&#234;ncia de anti&#8208;Dsg2 no grupo PF &#40;63&#37; de 202 PF&#41; foi maior quando comparada &#224; do estudo de Flores et al&#46; &#40;40&#37; de 106 PF&#41;&#44; o qual foi realizado em regi&#227;o end&#234;mica para PF no Brasil&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">17</span></a> J&#225; a soropreval&#234;ncia no grupo CTL foi semelhante em ambos &#40;20&#37; e 27&#37;&#44; respectivamente&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Em raz&#227;o da similaridade proteica das Dsg1&#44; Dsg2 e Dsg3&#44; aventou&#8208;se poss&#237;vel rea&#231;&#227;o cruzada dos anticorpos anti&#8208;Dsg2 com as prote&#237;nas Dsg1 e Dsg3&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">5</span></a> No entanto&#44; testes de adsor&#231;&#227;o n&#227;o mostraram diferen&#231;as nos t&#237;tulos de anti&#8208;Dsg1 e anti&#8208;Dsg3 quando comparados os resultados pr&#233;&#8208; e p&#243;s&#8208;adsor&#231;&#227;o com a Dsg2&#44; confirmando a produ&#231;&#227;o espec&#237;fica de anti&#8208;Dsg2&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Considerando a especificidade da produ&#231;&#227;o de autoanticorpos contra a Dsg2&#44; alguns questionamentos devem ser considerados&#58; &#40;a&#41; seriam patog&#234;nicos&#63;&#44; e &#40;b&#41; seriam produzidos pelo fen&#244;meno de <span class="elsevierStyleItalic">epitope&#8208;spreading</span>&#63;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">18</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Quanto &#224; primeira quest&#227;o&#44; a discuss&#227;o dos resultados aponta pela n&#227;o patogenicidade dos anticorpos anti&#8208;Dsg2 nos p&#234;nfigos&#46; T&#237;tulos maiores de anti&#8208;Dsg2 foram detectados nos grupos PF&#44; PV e FPV&#44; quando comparados aos grupos FPF e CTL&#46; A produ&#231;&#227;o de anti&#8208;Dsg1 e anti&#8208;Dsg3 por indiv&#237;duos saud&#225;veis &#233; conhecida&#59; portanto&#44; a presen&#231;a de anti&#8208;Dsg2 nos grupos FPF&#44; FPV e CTL n&#227;o excluiria sua participa&#231;&#227;o na patog&#234;nese do PF e PV&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">19&#8211;21</span></a> T&#237;tulos de anti&#8208;Dsg2 se correlacionaram com os de anti&#8208;Dsg1 no PF &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;1628&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0206&#41;&#44; tamb&#233;m relatado por Flores et al&#46;&#59;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">17</span></a> no entanto&#44; n&#227;o houve correla&#231;&#227;o de anti&#8208;Dsg2 com anti&#8208;Dsg3 no PV&#46; Ainda&#44; os t&#237;tulos de anti&#8208;Dsg2 n&#227;o se correlacionaram com a forma cl&#237;nica ou com a atividade da doen&#231;a nos grupos PF e PV&#44; em contraste com os t&#237;tulos s&#233;ricos de anti&#8208;Dsg1 e anti&#8208;Dsg3 que est&#227;o associados &#224; gravidade do PF e PV&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">22&#44;23</span></a> Al&#233;m disso&#44; t&#237;tulos mais elevados de anti&#8208;Dsg2 nos grupos PF e PV sem tratamento em compara&#231;&#227;o ao CTL&#44; e nos grupos PV n&#227;o tratado em compara&#231;&#227;o com PV em tratamento foram encontrados&#46; Assim&#44; a diminui&#231;&#227;o de anti&#8208;Dsg2 ap&#243;s o tratamento imunossupressor poderia favorecer a patogenicidade de anti&#8208;Dsg2 no PV&#59; por&#233;m&#44; esse resultado n&#227;o foi confirmado no grupo PF&#46; Finalizando essa discuss&#227;o&#44; &#233; conhecida a express&#227;o da Dsg2 em outros tecidos al&#233;m da pele&#44; como tecidos pulmonar&#44; gastrintestinal&#44; renal e no mioc&#225;rdio&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">5&#44;8</span></a> Desse modo&#44; corroborando para que os anticorpos anti&#8208;Dsg2 n&#227;o sejam patog&#234;nicos&#44; excetuando&#8208;se o es&#244;fago no PV&#44; n&#227;o se evidencia comprometimento de &#243;rg&#227;os internos nos p&#234;nfigos&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">24</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Quanto &#224; segunda quest&#227;o&#44; seria mais plaus&#237;vel considerar que anticorpos anti&#8208;Dsg2 fossem produzidos por fen&#244;meno de <span class="elsevierStyleItalic">epitope&#8208;spreading</span> no PV&#44; visto que as Dsg2 e Dsg3 s&#227;o mais expressas nas camadas inferiores da epiderme&#46; Ainda&#44; pacientes com PV apresentaram t&#237;tulos de anti&#8208;Dsg2 mais elevados antecedendo o in&#237;cio do tratamento imunossupressor&#46; Assim&#44; poder&#237;amos supor que a Dsg2 &#233; exposta no in&#237;cio do processo acantol&#237;tico&#44; produzido por anti&#8208;Dsg3&#44; com consequente produ&#231;&#227;o de anti&#8208;Dsg2 por fen&#244;meno de <span class="elsevierStyleItalic">epitope&#8208;spreading</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">18</span></a> No entanto&#44; t&#237;tulos semelhantes de anti&#8208;Dsg2 foram observados no PF e PV&#46; Desse modo&#44; o fen&#244;meno de <span class="elsevierStyleItalic">epitope&#8208;spreading</span> estaria ocorrendo em ambos os processos patog&#234;nicos do PF e PV&#46; Retornaremos a essa discuss&#227;o ap&#243;s considerarmos os resultados de IHQ&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Uma vez que os pacientes com PF e PV produziram anti&#8208;Dsg2&#44; decidimos verificar as express&#245;es proteica e g&#234;nica da Dsg2 <span class="elsevierStyleItalic">in situ</span> por IHQ e qPCR&#44; respectivamente&#44; e comparar os resultados com as express&#245;es das Dsg1 e Dsg3&#46; Comparamos PI e PL do PF e PV com pele de abdominoplastia e LF &#224; IHQ e qPCR&#44; respectivamente&#46; A ML do PV foi comparada &#224; MI do PF&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Na amostra controle de abdominoplastia&#44; a express&#227;o proteica das Dsgs confirmou o padr&#227;o de distribui&#231;&#227;o cl&#225;ssico nas camadas da epiderme &#8211; a express&#227;o da Dsg2 foi restrita &#224;s camadas inferiores&#46; Al&#233;m disso&#44; as Dsg1 e Dsg3 foram predominantemente expressas nas membranas dos queratin&#243;citos&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">5&#44;12</span></a> Curiosamente&#44; as express&#245;es da Dsg2 e Dsg3 nas amostras de PI do PF e PV foram mais intensas do que na amostra de abdominoplastia&#44; e se estenderam a todas as camadas da epiderme&#46; Na PL do PF e PV&#44; a express&#227;o da Dsg2 foi intensa no teto e no assoalho das bolhas e nas c&#233;lulas acantol&#237;ticas&#46; Ainda&#44; nas amostras de PL do PF e PV&#44; observamos a presen&#231;a de gr&#226;nulos de Dsg1 e de Dsg3 intra e intercelulares nos queratin&#243;citos&#44; respectivamente&#46; Os gr&#226;nulos de Dsg1 estenderam&#8208;se por toda a camada Malpighiana no assoalho da bolha acantol&#237;tica do PF&#44; confirmando a internaliza&#231;&#227;o da Dsg1&#44; descrita h&#225; 30 anos&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">25&#8211;28</span></a> A internaliza&#231;&#227;o da Dsg3 na PL do PV foi menos evidente&#44; mas &#233; comumente descrita&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">29&#8211;32</span></a> Enquanto a Dsg2 esteve hiperexpressa na PI&#44; sua internaliza&#231;&#227;o esteve ausente na PL do PF e PV&#44; representando mais uma evid&#234;ncia de que anticorpos anti&#8208;Dsg2 n&#227;o t&#234;m papel patog&#234;nico no processo da acant&#243;lise do p&#234;nfigo&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Na amostra de LF&#44; a express&#227;o g&#234;nica relativa da Dsg2 foi menor do que a das Dsg1 e Dsg3&#44; condizente com a express&#227;o proteica avaliada por IHQ&#46; Com surpresa&#44; a express&#227;o g&#234;nica relativa da Dsg2 esteve aumentada na MI do PF e na ML do PV&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">O papel da hiperexpress&#227;o proteica e g&#234;nica da Dsg2 nas amostras de pele&#47;mucosa de pacientes com PF e PV merece aten&#231;&#227;o&#46; Iwatsuki et al&#46; mostraram que a internaliza&#231;&#227;o das Dsg1 e Dsg3 antecedia a acant&#243;lise em amostras de pele do PF e PV&#44; e esteve associada &#224; indu&#231;&#227;o da express&#227;o da Dsg2 para compensar a deple&#231;&#227;o das Dsg1 e Dsg3&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">13</span></a> Ainda&#44; Moll et al&#46; demonstraram forte express&#227;o da Dsg2 em modelo de cultura de pele criado para estudar a cicatriza&#231;&#227;o epitelial&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">33</span></a> Em camundongos transg&#234;nicos com superexpress&#227;o da Dsg2&#44; Brennan et al&#46; demonstraram hiperprolifera&#231;&#227;o de queratin&#243;citos epid&#233;rmicos e diminui&#231;&#227;o da apoptose&#44; e mostraram que a superexpress&#227;o da Dsg2 restringiu a forma&#231;&#227;o de bolhas epid&#233;rmicas por IgPF&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">34&#44;35</span></a> Depois&#44; Hartlieb et al&#46; demonstraram que&#44; embora a Dsg2 contribua menos do que a Dsg3 para a coes&#227;o dos queratin&#243;citos&#44; a Dsg2 compensou a perda de fun&#231;&#227;o da Dsg3&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">6&#44;36</span></a> Mais recentemente&#44; Sigmund et al&#46; demonstraram que a Dsg2 faz liga&#231;&#227;o heterof&#237;lica com a Dsg3 e pode minimizar a perda de ades&#227;o entre os queratin&#243;citos no processo da acant&#243;lise&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">37</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Somando os nossos resultados aos relatos da literatura&#44; a hiperexpress&#227;o da Dsg2 na pele e mucosa do PF e PV parece estar em conson&#226;ncia com os relatos mencionados&#58; a hiperexpress&#227;o da Dsg2&#44; para compensar a perda de fun&#231;&#227;o das Dsg1 e Dsg3&#44; poderia proteger o processo da acant&#243;lise e estar envolvida na repara&#231;&#227;o tecidual&#46; Al&#233;m disso&#44; a hiperexpress&#227;o da Dsg2 em todas as camadas da epiderme na PI e PL do PF e PV poderia justificar a produ&#231;&#227;o de autoanticorpos contra a Dsg2 pelo fen&#244;meno de <span class="elsevierStyleItalic">epitope&#8208;spreading</span>&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Por fim&#44; embora autoanticorpos anti&#8208;Dsg1 e anti&#8208;Dsg3 sejam relatados em popula&#231;&#245;es normais&#44; os resultados de t&#237;tulos aumentados de anti&#8208;Dsg2 no grupo FPV dever&#227;o ser mais bem avaliados&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">19&#8211;21</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Limita&#231;&#245;es do estudo</span><p id="par0190" class="elsevierStylePara elsevierViewall">Tamanho amostral pequeno para an&#225;lise estat&#237;stica das express&#245;es proteica e g&#234;nica da Dsg2 nos tecidos&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conclus&#227;o</span><p id="par0195" class="elsevierStylePara elsevierViewall">Nossos resultados permitem concluir que autoanticorpos contra Dsg2 n&#227;o s&#227;o patog&#234;nicos nos p&#234;nfigos&#44; e que a hiperexpress&#227;o proteica e g&#234;nica da Dsg2 em amostras de pele e mucosas de pacientes com PF e PV pode estar envolvida na prote&#231;&#227;o contra a acant&#243;lise</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Declara&#231;&#227;o de submiss&#227;o e verifica&#231;&#227;o</span><p id="par0200" class="elsevierStylePara elsevierViewall">Os resultados parciais do teste ELISA foram apresentados como p&#244;ster &#8220;Anticorpos contra desmogle&#237;na 2 est&#227;o presentes em amostras de pacientes com p&#234;nfigo foli&#225;ceo e p&#234;nfigo vulgar e em familiares e controles de regi&#227;o end&#234;mica&#8221; no XXXIV Encontro Anual de Dermatologistas da Am&#233;rica Latina&#44; 2016&#44; S&#227;o Paulo&#44; tendo sido contemplado em terceiro lugar&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Suporte financeiro</span><p id="par0205" class="elsevierStylePara elsevierViewall">Parcialmente financiado pela FAPESP &#40;Funda&#231;&#227;o de Amparo &#224; Pesquisa do Estado de S&#227;o Paulo&#41; &#40;&#35; 2010&#47;51729&#8208;2&#41; e FAEPA &#40;Funda&#231;&#227;o de Apoio ao Ensino&#44; Assist&#234;ncia e Pesquisa&#41;&#46; TJ recebeu bolsa de doutorado da FAPESP &#40;&#35;2016&#47;09011&#8208;3&#41; e SV recebeu bolsa de Doutorado da CAPES &#40;Coordena&#231;&#227;o de Aperfei&#231;oamento de Pessoal de N&#237;vel Superior&#41;&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Contribui&#231;&#227;o dos autores</span><p id="par0210" class="elsevierStylePara elsevierViewall">Marcela Calixto Brand&#227;o Miguel&#58; Contribuiu com obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; an&#225;lise estat&#237;stica&#59; revis&#227;o cr&#237;tica da literatura&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Tamiris Amanda Julio&#58; Contribuiu com obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; revis&#227;o cr&#237;tica do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Sebastian Vernal&#58; Contribuiu com a an&#225;lise dos dados&#59; revis&#227;o cr&#237;tica do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Nat&#225;lia Aparecida de Paula&#58; Contribuiu com obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; revis&#227;o cr&#237;tica do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Andre Lieber&#58; Contribuiu com o planejamento do estudo&#44; revis&#227;o cr&#237;tica do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Ana Maria Roselino&#58; Contribuiu com a concep&#231;&#227;o e planejamento do estudo&#59; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; revis&#227;o cr&#237;tica da literatura&#59; revis&#227;o cr&#237;tica do manuscrito e participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conflito de interesses</span><p id="par0240" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Fundamentos</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Autoanticorpos antidesmogle&#237;na 1 e 3 justificam a acant&#243;lise nos p&#234;nfigos&#59; por&#233;m&#44; a patog&#234;nese de antidesmogle&#237;na 2 &#233; hipot&#233;tica&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objetivo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Comparar a participa&#231;&#227;o das desmogle&#237;nas 1&#44; 2 e 3 pela produ&#231;&#227;o de autoanticorpos s&#233;ricos&#44; e express&#245;es proteica e g&#234;nica na pele&#47;mucosa de pacientes com p&#234;nfigo foli&#225;ceo e p&#234;nfigo vulgar&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">M&#233;todos</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Autoanticorpos foram titulados por ELISA em 202 amostras de p&#234;nfigo foli&#225;ceo&#44; 131 de p&#234;nfigo vulgar&#44; 50 e 57 familiares de p&#234;nfigo foli&#225;ceo e de p&#234;nfigo vulgar&#44; respectivamente&#44; e 114 controles&#46; Express&#245;es proteica e g&#234;nica foram determinadas por imuno&#8208;histoqu&#237;mica e qPCR na pele&#47;mucosa de tr&#234;s pacientes com p&#234;nfigo foli&#225;ceo e tr&#234;s com p&#234;nfigo vulgar&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">T&#237;tulos &#40;densidade &#243;ptica&#41; maiores de antidesmogle&#237;na 2 resultaram no p&#234;nfigo foli&#225;ceo e p&#234;nfigo vulgar&#44; comparados aos controles &#40;0&#44;166&#59; 0&#44;180&#59; 0&#44;102&#59; respectivamente&#59; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#46; Houve correla&#231;&#227;o entre t&#237;tulos de antidesmogle&#237;na 2 e antidesmogle&#237;na 1 no p&#234;nfigo foli&#225;ceo &#40;r<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;1680&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0206&#41;&#46; N&#227;o houve rea&#231;&#227;o cruzada de antidesmogle&#237;na 2 com desmogle&#237;nas 1 e 3&#46; Houve hiperexpress&#227;o proteica da desmogle&#237;na 2 na pele &#237;ntegra e lesional dos p&#234;nfigos&#44; comparada &#224; pele controle&#46; Foram observados gr&#226;nulos de internaliza&#231;&#227;o das desmogle&#237;nas 1 e 3&#44; mas n&#227;o da desmogle&#237;na 2&#44; na les&#227;o do p&#234;nfigo foli&#225;ceo e p&#234;nfigo vulgar&#44; respectivamente&#46; Houve hiperexpress&#227;o g&#234;nica da desmogle&#237;na 2 nas mucosas&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Limita&#231;&#245;es do estudo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Tamanho amostral pequeno para an&#225;lise estat&#237;stica das express&#245;es proteica e g&#234;nica&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclus&#227;o</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Autoanticorpos contra desmogle&#237;na 2 n&#227;o s&#227;o patog&#234;nicos nos p&#234;nfigos&#59; a hiperexpress&#227;o proteica e g&#234;nica da desmogle&#237;na 2 na pele e nas mucosas pode estar envolvida na repara&#231;&#227;o da acant&#243;lise&#46;</p></span>"
        "secciones" => array:6 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Fundamentos"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Objetivo"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "M&#233;todos"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Resultados"
          ]
          4 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Limita&#231;&#245;es do estudo"
          ]
          5 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Conclus&#227;o"
          ]
        ]
      ]
    ]
    "NotaPie" => array:2 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Como citar este artigo&#58; Miguel MC&#44; Julio TA&#44; Vernal S&#44; Paula NA&#44; Lieber A&#44; Roselino AM&#46; Autoantibodies against desmoglein 2 are not pathogenic in pemphigus&#46; An Bras Dermatol&#46; 2022&#59;97&#58;145&#8211;56&#46;</p>"
      ]
      1 => array:2 [
        "etiqueta" => "&#9734;&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Trabalho realizado no Hospital das Cl&#237;nicas&#44; Divis&#227;o de Dermatologia&#44; Faculdade de Medicina de Ribeir&#227;o Preto da Universidade de S&#227;o Paulo&#44; Ribeir&#227;o Preto&#44; SP&#44; Brasil&#46;</p>"
      ]
    ]
    "apendice" => array:1 [
      0 => array:1 [
        "seccion" => array:1 [
          0 => array:4 [
            "apendice" => "<p id="par0430" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Material suplementar"
            "identificador" => "sec0120"
          ]
        ]
      ]
    ]
    "multimedia" => array:8 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figura 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1476
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            "Tamanyo" => 189610
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        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Anticorpos IgG contra Dsg1&#44; Dsg2 e Dsg3 nos grupos estudados&#46; <span class="elsevierStyleBold">A&#44;</span> Anti&#8208;Dsg2 por ELISA in house&#46; PF&#44; PV e FPV apresentaram t&#237;tulos maiores comparados aos controles &#40;CTL&#41; &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#59; PF e FPV&#44; t&#237;tulos maiores do que FPF &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0046 e p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0004&#44; respectivamente&#41;&#46; <span class="elsevierStyleBold">B&#44;</span> Anti&#8208;Dsg1 por ELISA comercial&#46; PF apresentou t&#237;tulos maiores comparado a todos os grupos &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#59; PV&#44; t&#237;tulos maiores do que FPF&#44; FPV e CTL &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#46; <span class="elsevierStyleBold">C&#44;</span> Anti&#8208;Dsg3 por ELISA comercial&#46; PV apresentou t&#237;tulos maiores do que todos os grupos &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#46; A linha horizontal em cada coluna significa a mediana&#59; a linha pontilhada&#44; o valor de cut&#8208;off&#46; <span class="elsevierStyleItalic">PF</span>&#44; p&#234;nfigo foli&#225;ceo&#59; <span class="elsevierStyleItalic">PV</span>&#44; p&#234;nfigo vulgar&#59; <span class="elsevierStyleItalic">FPF</span>&#44; familiares do PF&#44; <span class="elsevierStyleItalic">FPV</span>&#44; familiares do PV&#46; An&#225;lise estat&#237;stica&#58; Kruskall&#8208;Wallis seguido pelo teste de Dunn&#46; <span class="elsevierStyleBold">D&#44;</span> Correla&#231;&#227;o de Spearman entre t&#237;tulos de anti&#8208;Dsg2 e anti&#8208;Dsg1 no PF&#46; <span class="elsevierStyleBold">E&#44;</span> Correla&#231;&#227;o de Spearman entre t&#237;tulos de anti&#8208;Dsg2 e anti&#8208;Dsg3 no PV&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figura 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 3037
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            "Tamanyo" => 625318
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        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Painel de imuno&#8208;histoqu&#237;mica com express&#245;es de Dsg1&#44; Dsg2 e Dsg3 em amostras de pele &#40;amplifica&#231;&#227;o original de 40&#215;&#41;&#46; <span class="elsevierStyleBold">A&#44;</span> Amostra de pele controle de abdominoplastia mostrando a distribui&#231;&#227;o t&#237;pica de Dsg1&#44; Dsg2 e Dsg3 na epiderme&#46; <span class="elsevierStyleBold">B&#44;</span> PF&#8208;pele &#237;ntegra mostrando express&#245;es aumentadas da Dsg2 e Dsg3 em toda a epiderme e PF&#8208;pele lesional mostrando express&#245;es aumentadas da Dsg2 e Dsg3 no teto e no assoalho da bolha acantol&#237;tica&#46; <span class="elsevierStyleBold">C&#44;</span> PV&#8208;pele &#237;ntegra mostrando express&#245;es aumentadas da Dsg2 e de Dsg3 em toda a epiderme e PV&#8208;pele lesional mostrando express&#245;es aumentadas da Dsg2 e Dsg3 no teto e no assoalho da bolha e nas c&#233;lulas acantol&#237;ticas&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Figura 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 3388
            "Ancho" => 2508
            "Tamanyo" => 1181251
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Painel de imuno&#8208;histoqu&#237;mica com express&#245;es de Dsg1&#44; Dsg2 e Dsg3 em amostras de mucosa&#46; <span class="elsevierStyleBold">A&#44;</span> PF&#8208;mucosa &#237;ntegra mostrando a distribui&#231;&#227;o t&#237;pica de Dsg1&#44; Dsg2 e Dsg3 na epiderme &#40;amplifica&#231;&#227;o original de 63&#215;&#41;&#46; <span class="elsevierStyleBold">B&#44;</span> PV&#8208;mucosa lesional mostrando express&#227;o da Dsg2 e Dsg3 circundando a bolha acantol&#237;tica &#40;amplifica&#231;&#227;o original de 100&#215; e 40&#215;&#41;&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig0020"
        "etiqueta" => "Figura 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 4175
            "Ancho" => 2341
            "Tamanyo" => 1335466
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Painel de imuno&#8208;histoqu&#237;mica com express&#245;es de Dsg1&#44; Dsg2 e Dsg3 em amostras de pele e mucosa de pacientes com PF e PV&#46; <span class="elsevierStyleBold">A&#44;</span> Dsg1 em amostras de pele &#237;ntegra e lesional do paciente PF2 mostrando gr&#226;nulos consp&#237;cuos intercelulares e intracitoplasm&#225;ticos &#40;internaliza&#231;&#227;o da Dsg1&#41;&#44; amplamente distribu&#237;dos na pele lesional &#40;amplifica&#231;&#227;o original de 100&#215;&#41;&#46; <span class="elsevierStyleBold">B&#44;</span> Dsg2 comparando amostra de pele &#237;ntegra e lesional do paciente PF2&#44; confirmando a aus&#234;ncia de gr&#226;nulos &#40;amplifica&#231;&#227;o original de 100&#215;&#41;&#46; <span class="elsevierStyleBold">C&#44;</span> Dsg3 comparando amostra de mucosa &#237;ntegra do paciente PF2 e mucosa lesional do paciente PV3&#44; mostrando gr&#226;nulos finos intercelulares e intracitoplasm&#225;ticos &#40;internaliza&#231;&#227;o da Dsg3&#41; na mucosa lesional &#40;amplifica&#231;&#227;o original de 100&#215;&#41;&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "fig0025"
        "etiqueta" => "Figura 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 1667
            "Ancho" => 2286
            "Tamanyo" => 187212
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Express&#245;es g&#234;nicas relativas &#40;&#215;10&#8208;4&#41; de Dsg1&#44; Dsg2 e Dsg3 em amostras de pele e mucosas&#46; <span class="elsevierStyleBold">A&#44;</span> Pele &#237;ntegra &#40;PI&#41; e pele lesional &#40;PL&#41; do PF em compara&#231;&#227;o &#224; amostra controle de <span class="elsevierStyleItalic">lifting</span> &#40;LF&#41; mostrando predomin&#226;ncia da express&#227;o da Dsg3 em compara&#231;&#227;o &#224;s Dsg1 e Dsg2&#46; <span class="elsevierStyleBold">B&#44;</span> PI e PL do PV e LF&#46; As express&#245;es das Dsg1&#44; Dsg2 e Dsg3 foram menores do que na amostra de LF&#46; <span class="elsevierStyleBold">C&#44;</span> Mucosa lesional &#40;ML&#41; de PV em compara&#231;&#227;o com a mucosa &#237;ntegra &#40;MI&#41; de PF mostrando predomin&#226;ncia da express&#227;o de Dsg3 comparada &#224;s Dsg1 e Dsg2&#46; A express&#227;o da Dsg2 est&#225; aumentada em amostras da mucosa&#46; <span class="elsevierStyleBold">D&#44;</span> Compara&#231;&#227;o da express&#227;o da Dsg2 em todas as amostras PF e PV&#46; As express&#245;es g&#234;nicas relativas das Dsg1&#44; Dsg2&#44; Dsg3 foram calculadas usando 2<span class="elsevierStyleSup">&#40;&#8722;&#916;cT&#41;</span> e 18S rRNA como gene de refer&#234;ncia&#46;</p>"
        ]
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      5 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Tabela 1"
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        "detalles" => array:1 [
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            "identificador" => "at1"
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">NA</span>&#44; n&#227;o se aplica&#59; <span class="elsevierStyleItalic">Anti&#8208;Dsg1</span> e <span class="elsevierStyleItalic">anti&#8208;Dsg3</span>&#44; <span class="elsevierStyleItalic">cut&#8208;off</span> &#60;<span class="elsevierStyleHsp" style=""></span>20 U&#47;mL &#40;ELISA&#44; MBL&#44; Japan&#41;&#59; <span class="elsevierStyleItalic">Anti&#8208;Dsg2</span>&#44; <span class="elsevierStyleItalic">cut&#8208;off</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;1365 DO &#40;ELISA <span class="elsevierStyleItalic">in house</span>&#41;&#46;</p>"
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                  \t\t\t\t">30 &#40;19&#47;45&#41;<span class="elsevierStyleSup">d</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59 &#40;45&#47;71&#41;<span class="elsevierStyleSup">e</span></td><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">0&#44;0001<span class="elsevierStyleSup">a&#44;b</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62; 0&#44;9999<span class="elsevierStyleSup">a&#44;c</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001<span class="elsevierStyleSup">a&#44;e</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0001<span class="elsevierStyleSup">b&#44;d</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0068<span class="elsevierStyleSup">b&#44;e</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2878217.png"
              ]
            ]
            1 => 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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&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">n &#40;&#37;&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">n &#40;&#37;&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">n &#40;&#37;&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">n &#40;&#37;&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">n &#40;&#37;&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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">202&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">131&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">50&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">57&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">114&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">G&#234;nero</span></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><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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0033<span class="elsevierStyleSup">a&#44;b</span>&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="" 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><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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0027<span class="elsevierStyleSup">b&#44;e</span>&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Feminino</td><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">102 &#40;50&#44;2&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88 &#40;67&#44;7&#41;<span class="elsevierStyleSup">b</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36 &#40;72&#44;0&#41;<span class="elsevierStyleSup">c</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40 &#40;70&#44;2&#41;<span class="elsevierStyleSup">d</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">55 &#40;48&#44;2&#41;<span class="elsevierStyleSup">e</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;8150<span class="elsevierStyleSup">a&#44;e</span>&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="" 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><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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;0000<span class="elsevierStyleSup">c&#44;d</span>&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Masculino</td><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">101 &#40;49&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42 &#40;32&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 &#40;28&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;29&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59 &#40;51&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0022<span class="elsevierStyleSup">c&#44;e</span>&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="" 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><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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0088<span class="elsevierStyleSup">d&#44;e</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2878215.png"
              ]
            ]
            2 => 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">Dura&#231;&#227;o da doen&#231;a &#40;anos&#41;&#42;&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>199&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>130&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>1&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45 &#40;22&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31 &#40;23&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;8967&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 a &#8722;5&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">87 &#40;43&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">86 &#40;66&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0296&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 a &#8722;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32 &#40;16&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9 &#40;6&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0390&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 a 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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;5&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;2&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;2630&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62; 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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 &#40;12&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;0&#44;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2878216.png"
              ]
            ]
            3 => 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">Forma cl&#237;nica &#40;pacientes virgens de tratamento&#41;&#42;&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>68&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>26&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mucosa exclusiva</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;30&#44;8&#41;<span class="elsevierStyleSup">b</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA</td><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"><span class="elsevierStyleSup">a</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;9636&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSup">b</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;3909&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mucocut&#226;nea&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18 &#40;69&#44;2&#41;<span class="elsevierStyleSup">b</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Localizada&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;50&#44;0&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Generalizada&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;50&#44;0&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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 => "xTab2878212.png"
              ]
            ]
            4 => 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">Tratamento na data da coleta de soro<a class="elsevierStyleCrossRef" href="#tblfn0015">&#42;</a>&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>186&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>127&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Virgens de tratamento&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43 &#40;23&#44;1&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20 &#40;15&#44;8&#41;<span class="elsevierStyleSup">b</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSup">a</span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sem tratamento com les&#245;es ativas&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;18&#44;3&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;8&#44;7&#41;<span class="elsevierStyleSup">b</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSup">b</span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Em tratamento sem les&#245;es ativas&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16 &#40;8&#44;6&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 &#40;18&#44;8&#41;<span class="elsevierStyleSup">b</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Em tratamento com les&#245;es ativas&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80 &#40;43&#44;0&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65 &#40;51&#44;2&#41;<span class="elsevierStyleSup">b</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Em remiss&#227;o&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13 &#40;7&#44;0&#41;<span class="elsevierStyleSup">a</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;5&#44;5&#41;<span class="elsevierStyleSup">b</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&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 => "xTab2878213.png"
              ]
            ]
            5 => 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">Anti&#8208;Dsg2&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>202&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>131&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>57&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">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>114&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">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001<span class="elsevierStyleSup">a&#44;e</span>&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Acima do <span class="elsevierStyleItalic">cut&#8208;off</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">129 &#40;63&#44;9&#41;<span class="elsevierStyleSup">a</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">87 &#40;66&#44;4&#41;<span class="elsevierStyleSup">b</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19 &#40;38&#44;0&#41;<span class="elsevierStyleSup">c</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42 &#40;73&#44;7&#41;<span class="elsevierStyleSup">d</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31 &#40;27&#44;2&#41;<span class="elsevierStyleSup">e</span></td><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">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001<span class="elsevierStyleSup">b&#44;e</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;0012<span class="elsevierStyleSup">a&#44;c</span>&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abaixo do <span class="elsevierStyleItalic">cut&#8208;off</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">73 &#40;36&#44;1&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44 &#40;33&#44;6&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31 &#40;62&#44;0&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15 &#40;26&#44;3&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">83 &#40;72&#44;8&#41;</td><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">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001<span class="elsevierStyleSup">c&#44;d</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">Masculino&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Generalizada&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Em tratamento h&#225; 30 dias&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">99&#44;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;088&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">PF2</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Masculino&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Generalizada&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Virgem de tratamento&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="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#44;223&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="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">PF3</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">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="left" valign="\n
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                  \t\t\t\t">Masculino&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">36&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Localizada&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Virgem de tratamento&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">237&#44;90&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;894&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#44;70&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">PV1</span>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Masculino&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mucocut&#226;nea&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sem tratamento h&#225; mais de 60 dias&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="left" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#44;211&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">172&#44;78&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">PV2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">50&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Masculino&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="left" valign="\n
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                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Mucocut&#226;nea&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Virgem de tratamento&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="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#44;213&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">166&#44;91&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Masculino&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Virgem de tratamento&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#44;311&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="left" valign="\n
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                        "tituloSerie" => "Pemphigus&#46; Lancet"
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                      "titulo" => "class I and class II associations in pemphigus foliaceus and pemphigus vulgaris patients from a prevalent Southeastern Brazilian region"
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                            3 => "N&#46;H&#46;S&#46; Deghaide"
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ISSN: 26662752
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