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Clinical Science
Determination of Serum Adenosine Deaminase and Xanthine Oxidase Levels in Patients with Crimean–Congo Hemorrhagic Fever
V. Kenan CelikI,
Corresponding author
vkcelik@cumhuriyet.edu.tr

Tel: 90 346 2581492
, Ismail SariI, Aynur EnginII, Gürsel YildizIII, Hüseyin AydinI, Sevtap BakirI
I Department of Biochemistry, Cumhuriyet University, School of Medicine - Sivas, Turkey
II Department of Infectious Diseases and Clinical Microbiology, Cumhuriyet University, School of Medicine - Sivas, Turkey
III Department of Nephrology, Cumhuriyet University, School of Medicine - Sivas, Turkey
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Crimean&#8211;Congo hemorrhagic fever &#40;CCHF&#41; is an acute viral disease with a high mortality &#40;3&#8211;30&#37;&#41; rate&#46;<a class="elsevierStyleCrossRefs" href="#bib1">1&#44;2</a> It is caused by the CCHF virus &#40;CCHFV&#41;&#46; The virus belongs to the genus <span class="elsevierStyleItalic">Nairovirus</span> in the Bunyaviridae family&#46; CCHF was first described in the 1940s&#44; when more than 200 human cases occurred in the Crimean peninsula of the former Soviet Union&#44; and it is now described in about 30 countries in Africa&#44; Asia&#44; Europe and the Middle East&#46;<a class="elsevierStyleCrossRef" href="#bib3">3</a></p><p id="para20" class="elsevierStylePara elsevierViewall">CCHF&#44; seen in approximately 30 countries worldwide&#44; is a tick-borne disease with increasing importance and prevalence worldwide&#46;<a class="elsevierStyleCrossRefs" href="#bib4">4&#8211;11</a> Humans are infected through tick bites &#40;especially <span class="elsevierStyleItalic">Hyalomma</span> species&#41;&#44; by crushing infected ticks&#44; or by contact with blood or tissue from acute-phase CCHF patients or viremic livestock&#46; Most human cases occur in workers in the livestock and agriculture industries&#44; slaughterhouses&#44; and veterinary practices&#46;<a class="elsevierStyleCrossRef" href="#bib12">12</a> Most patients &#40;90&#37;&#41; with CCHF in Turkey have been farmers who were infected during outbreaks&#46;<a class="elsevierStyleCrossRefs" href="#bib2">2&#44;4&#44;5</a></p><p id="para30" class="elsevierStylePara elsevierViewall">There is a history of tick bite in approximately half &#40;50&#8211;60&#37;&#41; of CCHF patients&#46;<a class="elsevierStyleCrossRefs" href="#bib2">2&#44;4&#44;5</a> The incidence of the disease is 20&#37; among those who are infected&#46;<a class="elsevierStyleCrossRef" href="#bib13">13</a> The course of CCHF infection has four distinct periods&#58; incubation&#44; prehemorrhagic&#44; hemorrhagic&#44; and convalescence&#46;<a class="elsevierStyleCrossRef" href="#bib3">3</a> The incubation period for CCHF ranges from 2 to 12 days after the tick bite&#46; This period ranges from 3 to 10 days in nosocomial cases&#46;<a class="elsevierStyleCrossRefs" href="#bib14">14&#44;15</a> The prehemorrhagic period ranges from 1 to 7 days&#46; The typical clinical symptoms during this period are sudden onset of fever &#40;39&#8211;41&#176;C&#41;&#44; severe headache&#44; myalgia&#44; and dizziness&#46;<a class="elsevierStyleCrossRefs" href="#bib2">2&#8211;5&#44;15&#44;16</a> Additional symptoms include diarrhea&#44; nausea and vomiting&#46;<a class="elsevierStyleCrossRefs" href="#bib1">1&#44;15&#44;16</a> Cutaneous flushing or rash occur on the face&#44; neck and chest during this period&#46; Bradycardia and fever-pulse discordance are also observed&#46;<a class="elsevierStyleCrossRef" href="#bib17">17</a> The hemorrhagic period develops rapidly and usually begins between the fifth and seventh days of disease&#46;<a class="elsevierStyleCrossRef" href="#bib1">1</a> Patients may show signs of progressive hemorrhagic diathesis&#44; such as petechiae&#44; mucous membranes hemorrhage&#44; conjunctival hemorrhage&#44; nosebleed&#44; hemoptysis&#44; hematuria&#44; hematemesis&#44; and melena&#46;<a class="elsevierStyleCrossRefs" href="#bib1">1&#44;17&#44;18</a> Hepatomegaly and splenomegaly have been reported to occur in one-third of patients&#46;<a class="elsevierStyleCrossRef" href="#bib3">3</a> The convalescence period begins in survivors approximately 10&#8211;20 days after the onset of illness&#46; Patients usually require hospitalization for about 9&#8211;10 days&#46;<a class="elsevierStyleCrossRefs" href="#bib1">1&#44;16</a> During the convalescence period&#44; tachycardia&#44; temporary complete hair loss&#44; polyneuritis&#44; difficulty in breathing&#44; xerostomia&#44; poor vision&#44; loss of hearing&#44; and loss of memory have been reported&#46;<a class="elsevierStyleCrossRef" href="#bib3">3</a> Death usually occurs after 6&#8211;14 days of the disease&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">It has been reported that mononuclear phagocytes&#44; hepatocytes&#44; and endothelial cells are major targets of CCHF virus infection&#46;<a class="elsevierStyleCrossRef" href="#bib19">19</a> Despite increasing knowledge about hemorrhagic fever viruses&#44; little is known about the pathogenesis of CCHF&#46;<a class="elsevierStyleCrossRef" href="#bib29">29</a></p><p id="para50" class="elsevierStylePara elsevierViewall">Adenosine deaminase &#40;ADA&#59; EC 3&#46;5&#46;4&#46;4&#41; is an enzyme that transforms&#44; respectively&#44; adenosine and deoxyadenosine to inosine and deoxyinosine&#44; a stage of purine metabolism&#46; In the ensuing reaction hypoxanthine is formed&#46; The oxidation of hypoxanthine to xanthine and the oxidation of xanthine to uric acid are catalyzed by xanthine oxidase &#40;XO&#59; EC 1&#46;1&#46;3&#46;22&#41;&#46; ADA has two principal isoenzymes&#44; ADA-1 and ADA-2&#46; The low-molecular-weight ADA-1 is found in many tissues but predominantly in lymphocytes&#46; The high-molecular-weight ADA-2 is predominantly found in monocytes and macrophages&#46;<a class="elsevierStyleCrossRefs" href="#bib21">21&#44;22</a> ADA-1 and ADA-2 play an important role in the function of immune cells&#46; Increased serum&#47;plasma ADA activity&#44; comprising both ADA-1 and ADA-2 activity&#44; has been used as a biochemical marker for infectious diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib22">22&#8211;24</a> Increased serum ADA has been reported in infectious diseases such as viral and bacterial pneumonia&#44; HIV infection&#44; extra-pulmonary and pulmonary tuberculosis&#44; visceral leishmaniasis&#44; and mononucleosis&#46;<a class="elsevierStyleCrossRefs" href="#bib21">21&#44;22&#44;25</a></p><p id="para60" class="elsevierStylePara elsevierViewall">Xanthine oxidase is another intracellular enzyme that plays a role in nucleotide metabolism&#46; It is involved in the catabolism of hypoxanthine and xanthine&#44; which are formed during adenosine catabolism&#46; The reactive oxygen species formed as a result of this reaction induce tissue damage in some viral diseases such as influenza&#46;<a class="elsevierStyleCrossRef" href="#bib26">26</a></p><p id="para70" class="elsevierStylePara elsevierViewall">The aim of the present study was to investigate the serum levels of ADA-2 &#40;the main source of ADA activity in the serum&#44; which plays crucial roles in immune function&#41; and xanthine oxidase &#40;which increases tissue damage via the formation of free oxygen radicals&#41; in CCHF patients and to compare the results with those obtained for healthy controls&#46; We also determined whether the activities of these two intracellular enzymes were related to the severity of disease&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">MATERIALS AND METHODS</span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Study population</span><p id="para80" class="elsevierStylePara elsevierViewall">This prospective study was conducted between April 1 and July 31&#44; 2008 in Cumhuriyet University Hospital in Sivas&#44; a city located in central Anatolia&#46; The study protocol was approved by the Human Ethics Committee of the Cumhuriyet University Faculty of Medicine&#46; Informed consent was obtained from each patient&#46;</p><p id="para90" class="elsevierStylePara elsevierViewall">Thirty consecutive hospitalized patients&#44; diagnosed with CCHF by laboratory tests&#44; and 35 healthy volunteer adults&#44; as controls who had no infections or immune system diseases such as rheumatoid arthritis&#44; psoriasis and sarcoidosis&#44; were included in this study&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">Blood collection</span><p id="para100" class="elsevierStylePara elsevierViewall">Venous blood samples were collected in tubes after an 8-h fast and immediately stored at 4&#176; C&#46; Next&#44; the serum was separated from the cells and fibrines by centrifugation at 1610xg for 10 min and stored in several aliquots at &#8722;80&#176; C until assayed&#46; A second blood sample from each patient was obtained and sent to the Virology Laboratory of Refik Saydam Hygiene Central Institute&#44; Ankara&#44; Turkey&#44; for serologic and virologic analyses to confirm the diagnosis of CCHF&#46; The definitive diagnosis of CCHF infection was based on typical clinical and epidemiological findings and the detection of CCHF virus-specific IgM by enzyme-linked immunosorbent assay &#40;ELISA&#41; or of genomic segments of the CCHF virus by reverse-transcription polymerase chain reaction &#40;RT-PCR&#41;&#46; All CCHF patients were classified into two groups in terms of disease severity &#40;severe&#44; non-severe&#41;&#44; according to the predictive factors for fatal outcome criteria reported by Swanepoel and co-workers&#46;<a class="elsevierStyleCrossRef" href="#bib15">15</a></p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Chemicals</span><p id="para110" class="elsevierStylePara elsevierViewall">Adenosine and hypoxanthine were supplied by Sigma-Aldrich &#40;Steinheim&#44; Germany&#41;&#46; All other chemicals used were obtained from Merck Darmstadt &#40;Germany&#41; and were of analytical grade&#46;</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">Measurement of enzyme activities</span><p id="para120" class="elsevierStylePara elsevierViewall">ADA activity was estimated by the sensitive colorimetric method described by Giusti&#44; and XO activity was determined by the method of Worthington&#46;<a class="elsevierStyleCrossRefs" href="#bib27">27&#44;28</a> The assay results are expressed as specific activity &#40;units per milligram of protein&#41;&#46;</p></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">Statistical analysis</span><p id="para130" class="elsevierStylePara elsevierViewall">Parametric data are expressed as the mean &#177; standard deviation and categorical data as percentages&#46; The Statistical Package for the Social Sciences &#40;SPSS&#41; version 14 for Windows &#40;SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41; was used for the statistical analysis&#46; Parametric data were evaluated by the independent sample t-test and categorical data by the chi-squared test&#46; A p value &#8804;0&#46;05 was considered as significant&#46;</p></span></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">RESULTS</span><p id="para140" class="elsevierStylePara elsevierViewall">Thirty patients with CCHF and 35 control subjects were recruited for the study&#46; Of the CCHF patients&#44; 14 &#40;47&#37;&#41; were male and 16 &#40;53&#37;&#41; female&#44; and the mean age was 42&#46;6&#177;21 years&#46; In the control group&#44; twenty &#40;57&#37;&#41; individuals were male and 15 &#40;43&#37;&#41; were female&#44; with a mean age of 42&#46;9&#177;19&#46;1 years&#46; There were no significant differences in the age or sex ratio between patients with CCHF and controls &#40;p&#62;0&#46;05&#41;&#46;</p><p id="para150" class="elsevierStylePara elsevierViewall">All of the CCHF patients presented positive IgM and&#47;or RT-PCR results for CCHF virus in the blood samples&#46; Five &#40;17&#37;&#41; of 30 patients had CCHFV-specific IgM antibodies&#44; 6&#47;30 &#40;20&#37;&#41; had a positive RT-PCR test for CCHFV&#44; and 19&#47;30 &#40;63&#37;&#41; were positive in both tests during the acute and&#47;or convalescent phase of the disease&#46; According to the severity score&#44; 11 &#40;37&#37;&#41; CCHF patients were classified as &#8220;severe&#8221;&#44; whereas the remaining 19 &#40;63&#37;&#41; patients were classified as &#8220;non-severe&#8221;&#46; Only one patient with CCHF died during the hospitalization period&#46; <a class="elsevierStyleCrossRef" href="#t1-cln_65p697">Table 1</a> shows the demographic&#44; clinical and laboratory data for the patients and controls&#46;</p><elsevierMultimedia ident="t1-cln_65p697"></elsevierMultimedia><p id="para160" class="elsevierStylePara elsevierViewall">Serum ADA and XO levels in patients with CCHF were significantly higher than were those determined for the control group &#40;p&#60;0&#46;05&#41;&#44; as shown in <a class="elsevierStyleCrossRef" href="#t2-cln_65p697">Table 2</a>&#46; We found no significant difference in the serum ADA or XO level between severe and non-severe patients&#46; Furthermore&#44; no relationship was detected between XO and ALT levels in patients with CCHF &#40;p&#62;0&#46;05&#41;&#46;</p><elsevierMultimedia ident="t2-cln_65p697"></elsevierMultimedia></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">DISCUSSION</span><p id="para170" class="elsevierStylePara elsevierViewall">Patients infected with CCHFV were first reported in Turkey in 2002&#46;<a class="elsevierStyleCrossRef" href="#bib4">4</a> Since 2002&#44; CCHF outbreaks have been reported in rural areas of Turkey every year&#44; especially in the spring and summer&#46; To date&#44; nearly 1800 confirmed CCHF cases have been reported in Turkey&#46;<a class="elsevierStyleCrossRef" href="#bib29">29</a> Although the reported mortality rate for CCHF is 3&#8211;30&#37;&#44;<a class="elsevierStyleCrossRefs" href="#bib1">1&#44;2</a> the fatality rate in Turkey is 5&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib29">29</a> Midilli et al&#46; reported that all strains clustered within the same group with the Europe&#47;Turkey isolates&#44; despite their origins in eight different geographic areas of Turkey&#46;<a class="elsevierStyleCrossRef" href="#bib30">30</a> It is not clear why those similar virus strains cause an asymptomatic clinical course in some patients but have a fatal outcome in others&#46;</p><p id="para180" class="elsevierStylePara elsevierViewall">ADA deficiency is the major metabolic cause of severe combined immunodeficiency disease&#46;<a class="elsevierStyleCrossRefs" href="#bib31">31&#44;32</a> ADA is important for the development of the immune system in humans&#46; It seems to be associated with the differentiation of epithelial cells and monocytes and with neurotransmission&#46;<a class="elsevierStyleCrossRef" href="#bib33">33</a> Monocyte&#47;macrophage activation by intracellular infection and inflammatory diseases leads to the release of ADA and elevated levels in the serum&#46;<a class="elsevierStyleCrossRef" href="#bib34">34</a> Monocyte involvement in CCHF has been well described&#46;<a class="elsevierStyleCrossRef" href="#bib19">19</a> However&#44; no studies have reported the ADA&#47;XO levels in patients with CCHF&#46;</p><p id="para190" class="elsevierStylePara elsevierViewall">Increased serum ADA has been reported in infectious diseases such as viral and bacterial pneumonia&#44; HIV infection&#44; extra-pulmonary and pulmonary tuberculosis&#44; visceral leishmaniasis&#44; and mononucleosis&#46;<a class="elsevierStyleCrossRefs" href="#bib21">21&#44;22&#44;25</a></p><p id="para200" class="elsevierStylePara elsevierViewall">XO is another intracellular enzyme that plays a role in nucleotide metabolism&#46; Vorbach and co-workers<a class="elsevierStyleCrossRef" href="#bib35">35</a> suggest that xanthine oxidoreductase &#40;XOR&#41; is central to the development and function of innate immunity&#46; In purine catabolism&#44; XOR catalyzes the oxidative hydroxylation of hypoxanthine to xanthine and subsequently of xanthine to uric acid&#46; In this reaction&#44; reactive oxygen species &#40;ROS&#41; such as superoxide anions &#40;O<span class="elsevierStyleSup">2&#8211;</span>&#41;&#44; hydroxyl radicals &#40;OH<span class="elsevierStyleSup">&#8722;</span>&#41; and hydrogen peroxide &#40;H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span>&#41; are produced&#46; ROS may contribute to tissue damage in some viral infections such as influenza&#46;<a class="elsevierStyleCrossRef" href="#bib9">9</a> XOR exists in two forms&#58; xanthine dehydrogenase &#40;XD&#59; EC 1&#46;1&#46;1&#46;204&#41; and xanthine oxidase &#40;XO&#59; EC 1&#46;1&#46;3&#46;22&#41;&#46; In the normal physiological state&#44; the XO activity in many tissues is very low&#44; but it has been shown to increase dramatically following viral infection&#46;<a class="elsevierStyleCrossRef" href="#bib26">26</a></p><p id="para210" class="elsevierStylePara elsevierViewall">There have been numerous recent studies on CCHF&#46; These studies have focused on clinical and laboratory features or genetic characteristics&#46;<a class="elsevierStyleCrossRefs" href="#bib30">30&#44;36&#8211;38</a> However&#44; there are no reports concerning serum ADA and XO levels in CCHF patients&#46;</p><p id="para220" class="elsevierStylePara elsevierViewall">In the present study&#44; we investigated serum ADA and serum XO activity in CCHF patients and controls&#46; Serum ADA and XO levels in patients with CCHF were significantly higher than were those determined for the control group &#40;p&#60;0&#46;05&#41;&#44; whereas no significant association was observed between the serum ADA or XO level and the severity of disease in CCHF patients &#40;p&#62;0&#46;05&#41;&#46;</p><p id="para230" class="elsevierStylePara elsevierViewall">An increased serum level of ADA has been reported in infectious diseases such as HIV infection&#44; tuberculosis&#44; and visceral leishmaniasis&#46;<a class="elsevierStyleCrossRefs" href="#bib22">22&#44;25&#44;39</a> However&#44; the present study is the first to describe increased serum ADA and XO in CCHF patients&#46;</p><p id="para240" class="elsevierStylePara elsevierViewall">Chittiprol and co-workers found high levels of plasma ADA in HIV-infected patients compared with controls&#44; and this high level of ADA was associated with lymphocyte and monocyte infection by HIV&#46; A similar mechanism of infection may occur in CCHF patients because monocytes can be infected by CCHFV&#46;<a class="elsevierStyleCrossRef" href="#bib22">22</a></p><p id="para250" class="elsevierStylePara elsevierViewall">Whereas XO causes tissue damage by producing ROS&#44; it can also protect against some infections by causing the production of uric acid and superoxide radicals&#46;<a class="elsevierStyleCrossRefs" href="#bib33">33&#44;35</a> ROS generated by xanthine oxidase&#44; such as superoxide anion radicals &#40;O<span class="elsevierStyleSup">2&#8211;</span>&#41; and hydrogen peroxide &#40;H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span>&#41;&#44; may contribute to the tissue damage&#46; The overproduction of these highly reactive oxygen metabolites can initiate lethal radical chain reactions involving the oxidation and damage of structures that are crucial for cellular integrity and survival&#46;</p><p id="para260" class="elsevierStylePara elsevierViewall">XOR is highly expressed in the liver for purine catabolism&#46; Stirpe and co-workers reported that the level of total XOR was significantly higher in liver with virus-related cirrhosis but not in virus-negative cirrhosis&#44; as compared to the controls&#46;<a class="elsevierStyleCrossRefs" href="#bib35">35&#44;40&#44;41</a> The level of XOR was increased in cirrhotic liver&#44; in association with viral infection&#46; This increase correlated with ALT&#44; suggesting a relationship between XOR activity and the extent of liver injury caused by viral replication&#46; The extent of oxidase activity seems to be correlated with tissue damage and consequent liver impairment&#46; However&#44; in our study&#44; the XO level was highest in the patient group&#44; and no relationship was observed between XO and ALT levels&#46;</p><p id="para270" class="elsevierStylePara elsevierViewall">Tumor necrosis factor &#40;TNF&#41;-&#945; and IL-6 are increased in CCHF infection&#46;<a class="elsevierStyleCrossRefs" href="#bib42">42&#44;43</a> The inflammatory reaction results in the expression of various cytokines&#44; and XOR is stimulated by interferon &#40;IFN&#41;-&#947;&#44; IFN-&#945;&#44; TNF-&#945;&#44; interleukin &#40;IL&#41;-1 and IL-3&#59; some of these factors also initiate the conversion from the XD to the XO form&#46;<a class="elsevierStyleCrossRef" href="#bib35">35</a> Increased TNF-&#945; or liver cell damage in CCHF patients may contribute to the increased XO level&#46; However&#44; this study was not designed to investigate the cause of the elevated ADA and XO levels in CCHF patients&#46; Therefore&#44; larger-scale studies are needed to explain this phenomenon&#46;</p><p id="para280" class="elsevierStylePara elsevierViewall">We hypothesize that the elevated serum XO activity in patients with CCHF is related to the free radicals generated by the xanthine&#47;XO system&#46; In addition&#44; elevated lipid peroxidation may contribute to cell damage and hemorrhage&#46; Therefore&#44; serum ADA&#47;XO activity&#44; a relatively simple laboratory test parameter&#44; particularly in the absence or in the event of delays in molecular procedures such as PCR and CCHF IgM detection&#44; could supplement the laboratory approach for CCHF diagnosis and could be used to take preventive measures&#46;</p><p id="para290" class="elsevierStylePara elsevierViewall">In conclusion&#44; we showed that ADA and XO levels were increased in patients with CCHF&#46; However&#44; we found no significant association between the serum ADA or XO level and the severity of disease in CCHF patients&#46;</p></span></span>"
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          "identificador" => "cesec10"
          "titulo" => "INTRODUCTION"
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        2 => array:3 [
          "identificador" => "cesec20"
          "titulo" => "MATERIALS AND METHODS"
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              "identificador" => "cesec30"
              "titulo" => "Study population"
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              "titulo" => "Blood collection"
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              "identificador" => "cesec50"
              "titulo" => "Chemicals"
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            3 => array:2 [
              "identificador" => "cesec60"
              "titulo" => "Measurement of enzyme activities"
            ]
            4 => array:2 [
              "identificador" => "cesec70"
              "titulo" => "Statistical analysis"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "cesec80"
          "titulo" => "RESULTS"
        ]
        4 => array:2 [
          "identificador" => "cesec90"
          "titulo" => "DISCUSSION"
        ]
        5 => array:1 [
          "titulo" => "REFERENCES"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2010-03-20"
    "fechaAceptado" => "2010-04-28"
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          "clase" => "keyword"
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          "identificador" => "xpalclavsec1581262"
          "palabras" => array:5 [
            0 => "Crimean&#8211;Congo hemorrhagic fever"
            1 => "Adenosine deaminase"
            2 => "Xanthine oxidase"
            3 => "intracellular enzyme"
            4 => "Nairovirus"
          ]
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      ]
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVE&#58;</span><p id="spara40" class="elsevierStyleSimplePara elsevierViewall">Crimean&#8211;Congo hemorrhagic fever is an acute viral hemorrhagic fever with a high mortality rate&#46; Despite increasing knowledge about hemorrhagic fever viruses&#44; little is known about the pathogenesis of Crimean&#8211;Congo hemorrhagic fever&#46; In this study&#44; we measured serum adenosine deaminase and xanthine oxidase levels in Crimean&#8211;Congo hemorrhagic fever patients&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS&#58;</span><p id="spara50" class="elsevierStyleSimplePara elsevierViewall">Serum adenosine deaminase levels were measured with a sensitive colorimetric method described by Giusti and xanthine oxidase levels by the method of Worthington in 30 consecutive hospitalized patients &#40;mean age 42&#46;6 &#177; 21&#46;0&#41;&#46; Laboratory tests confirmed their diagnoses of Crimean&#8211;Congo hemorrhagic fever&#46; Thirty-five subjects &#40;mean age 42&#46;9 &#177; 19&#46;1&#41; served as the control group&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS&#58;</span><p id="spara60" class="elsevierStyleSimplePara elsevierViewall">There was a significant difference in adenosine deaminase and xanthine oxidase levels between cases and controls &#40;p&#60;0&#46;05&#41;&#46; However&#44; neither adenosine deaminase nor xanthine oxidase levels varied with the severity of disease in the cases assessed &#40;p&#62;0&#46;05&#41;&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSION&#58;</span><p id="spara70" class="elsevierStyleSimplePara elsevierViewall">Adenosine deaminase and xanthine oxidase levels were increased in patients with Crimean&#8211;Congo hemorrhagic fever&#46; Elevated serum xanthine oxidase activity in patients with Crimean&#8211;Congo hemorrhagic fever may be associated with reactive oxygen species generated by the xanthine&#47;xanthine oxidase system during inflammatory responses&#46; In addition&#44; elevated lipid peroxidation may contribute to cell damage and hemorrhage&#46; The association of cell damage and hemorrhage with xanthine oxidase activity should be further investigated in large-scale studies&#46;</p></span>"
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          2 => array:2 [
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            "titulo" => "RESULTS&#58;"
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            "titulo" => "CONCLUSION&#58;"
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                  \t\t\t\t  " align="center" valign="top" scope="col">CCHF &#40;n&#61;30&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top" scope="col">Control Group &#40;n&#61;35&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top" scope="col">P value&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleBold">Mean age</span> &#40;year&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">42&#46;6 &#177; 21&#46;0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">42&#46;9 &#177; 19&#46;1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">16&#47;14&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">15&#47;20&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">26 &#40;86&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\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="center" valign="top">26 &#40;86&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;Conjunctival hyperemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">6 &#40;20&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&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="center" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;Maculopapular rash&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="center" valign="top">7 &#40;23&#41;&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="center" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;Petechia&#47;ecchymosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">6 &#40;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&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="center" valign="top">&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  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;Bleeding<a class="elsevierStyleCrossRef" href="#tfn4-cln_65p697">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">7 &#40;23&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleBold">Laboratory findings</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="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;Thrombocytopenia<a class="elsevierStyleCrossRef" href="#tfn2-cln_65p697"><span class="elsevierStyleBold">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">29 &#40;96&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;Leukopenia<a class="elsevierStyleCrossRef" href="#tfn3-cln_65p697"><span class="elsevierStyleBold">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">27 &#40;90&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;Elevated AST&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">21 &#40;70&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;Elevated ALT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">16 &#40;53&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleBold">Risk factors for CCHF</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="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;History of tick bite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">19 &#40;63&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8195;History of tick removal from animal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">5 &#40;17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top" style="border-bottom: 2px solid black"><span class="elsevierStyleHsp" style=""></span>&#8195;No tick exposure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top" style="border-bottom: 2px solid black">6 &#40;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "notaPie" => array:4 [
            0 => array:3 [
              "identificador" => "tfn1-cln_65p697"
              "etiqueta" => "<span class="elsevierStyleBold"><span class="elsevierStyleSup">a</span></span>"
              "nota" => "<p class="elsevierStyleNotepara" id="cenpara10">Armpit&#44; &#8805;38&#176;C&#59;</p>"
            ]
            1 => array:3 [
              "identificador" => "tfn2-cln_65p697"
              "etiqueta" => "<span class="elsevierStyleBold"><span class="elsevierStyleSup">b</span></span>"
              "nota" => "<p class="elsevierStyleNotepara" id="cenpara20">thrombocytopenia&#44; platelet count &#60;150x10<span class="elsevierStyleSup">9</span>&#59;</p>"
            ]
            2 => array:3 [
              "identificador" => "tfn3-cln_65p697"
              "etiqueta" => "<span class="elsevierStyleBold"><span class="elsevierStyleSup">c</span></span>"
              "nota" => "<p class="elsevierStyleNotepara" id="cenpara30">leukopenia&#44; leukocyte count &#60;4x10<span class="elsevierStyleSup">3</span>&#46; <span class="elsevierStyleBold">NS</span>&#44; non-significant&#59; <span class="elsevierStyleBold">AST</span>&#44; aspartate aminotransferase&#59; <span class="elsevierStyleBold">ALT</span>&#44; alanine aminotransferase&#59; <span class="elsevierStyleBold">CCHF</span>&#44; Crimean&#8211;Congo hemorrhagic fever&#46;</p>"
            ]
            3 => array:3 [
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Demographic&#44; clinical and laboratory data for patients with Crimean&#8211;Congo hemorrhagic fever and the control group&#46;</p>"
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          "leyenda" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">Data are expressed as the mean &#177;standard deviation&#46; <span class="elsevierStyleBold">CCHF</span>&#44; Crimean&#8211;Congo hemorrhagic fever&#59; <span class="elsevierStyleBold">ADA</span>&#44; adenosine deaminase&#59; <span class="elsevierStyleBold">XO</span>&#44; xanthine oxidase&#46;</p>"
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                0 => """
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                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold">Control Group &#40;n&#61;35&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="top">1&#46;16 &#177; 0&#44;47&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">0&#46;27 &#177; 0&#44;06&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">0&#46;000&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="top" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">XO specific activity</span> &#40;U&#47;mg protein&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top" style="border-bottom: 2px solid black">2&#46;23 &#177; 1&#44;18&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="center" valign="top" style="border-bottom: 2px solid black">0&#46;23 &#177; 0&#44;19&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top" style="border-bottom: 2px solid black">0&#46;000&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Serum ADA and XO levels in CCHF patients and controls&#46;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "REFERENCES"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "cebibsec10"
          "bibliografiaReferencia" => array:43 [
            0 => array:3 [
              "identificador" => "bib1"
              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Crimean-Congo Hemorrhagic fever"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              DM Watts \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              TG Ksiasek \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              KJ Linthicum \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              H Hoogstraal \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:6 [
                        "editores" => "TPMonath"
                        "titulo" => "The arboviruses&#58; epidemiology and ecology"
                        "paginaInicial" => "177"
                        "paginaFinal" => "260"
                        "serieVolumen" => "2"
                        "serieFecha" => "1988"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib2"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The characteristics of Crimean-Congo Hemorrhagic Fever in a recent outbreak in Turkey and the impact of oral ribavirin therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => """
                              O Erg&#246;n&#252;l \n
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                              """
                            1 => """
                              A &#199;elikba&#351; \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              B Dokuzoguz \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              S Eren \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              N Baykam \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              H Esener \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1086/422000"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Infect Dis"
                        "fecha" => "2004"
                        "volumen" => "39"
                        "paginaInicial" => "284"
                        "paginaFinal" => "287"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15307042"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib3"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Crimean-Congo haemorrhagic fever"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              O Erg&#246;n&#252;l \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S1473-3099(06)70435-2"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Infect Dis"
                        "fecha" => "2006"
                        "volumen" => "6"
                        "paginaInicial" => "203"
                        "paginaFinal" => "214"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16554245"
                            "web" => "Medline"
                          ]
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es en pt

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

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

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