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Clinical Science
Screening for Cushing’s Syndrome in Obese Patients
Ozay Tiryakioglu, Serdal Ugurlu, Serap Yalin, Sibel Yirmibescik, Erkan Caglar, Demet Ozgil Yetkin, Pinar Kadioglu
Corresponding author
kadioglup@yahoo.com

Tel: 90 216 4623114
Division of Endocrinology and Metabolism, Department of Internal Medicine, Cerrahpasa Medical Faculty - 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">Obesity is the most common metabolic problem in industrialized countries&#46; In the USA&#44; 32&#37; of adults are classified as overweight&#44; and 22&#46;5&#37; of these individuals are obese&#46;<a class="elsevierStyleCrossRef" href="#bib1">1</a> Both overweight and obese subjects are at an increased risk for cardiovascular diseases&#44;<a class="elsevierStyleCrossRef" href="#bib2">2</a> some types of cancer&#44;<a class="elsevierStyleCrossRef" href="#bib3">3</a> diabetes<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#44; and even premature death&#46;<a class="elsevierStyleCrossRef" href="#bib5">5</a> Obesity is often accompanied by other chronic disorders including hypertension&#44; osteoarthritis&#44; bile stones&#44; and dyslipidemia&#46;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib12">12</a> In addition to these physical disorders&#44; obesity is commonly associated with psychological and psycho-social problems&#46;<a class="elsevierStyleCrossRef" href="#bib10">10</a></p><p id="para20" class="elsevierStylePara elsevierViewall">Obesity can coexist with diverse physical disorders&#44; and physicians should first focus on the differential diagnosis of possible underlying disorders before initiating any management procedure&#46; Obesity is a prominent feature of endocrine diseases including hypothyroidism&#44; insulin-excess syndromes&#44; polycystic ovary syndrome &#40;PCOS&#41;&#44; hypogonadism&#44; hypothalamic disease&#47;injury&#44; growth hormone deficiency&#44; leptin deficiency or leptin receptor defects&#44; pseudohypoparathyroidism&#44; and Cushing&#8217;s syndrome &#40;CS&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib11">11&#44;12</a></p><p id="para30" class="elsevierStylePara elsevierViewall">Diagnosis of CS is primarily based on the signs and symptoms of the disorder&#46; Nevertheless&#44; a significant number of CS patients present only with simple obesity<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib14">14</a> or with type 2 diabetes mellitus and poor glycemic control&#46;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib17">17</a> Metabolic syndrome may also indicate the presence of CS&#46; Patients without specific clinical features of CS have been referred to as sub-clinical Cushing&#8217;s syndrome &#40;SCS&#41;<a class="elsevierStyleCrossRef" href="#bib15">15</a> patients&#44; and the diagnosis of SCS affords a considerable challenge to the physician&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">We accordingly set out to determine the frequency of CS in patients presenting with simple obesity in the absence of other specific signs or symptoms indicative of CS&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">PATIENTS AND METHODS</span><p id="para50" class="elsevierStylePara elsevierViewall">This study included 150 consecutive simple obese patients &#40;129 female&#44; 21 male&#44; mean age&#58; 44&#46;41 &#177; 13&#46;34 yr&#44; body mass index &#40;BMI&#41; &#62; 25 kg&#47;m<span class="elsevierStyleSup">2</span>&#41; who were followed and treated at the Endocrinology Metabolism outpatient clinic at Cerrahpasa Medical Faculty between June 2003 and June 2004&#46; Written informed consent was obtained from all patients before commencement of the study&#46; Review of patient medical history was used to exclude subjects in which the dexamethasone suppression test could be biased either by medication &#40;including exogenous glucocorticoid intake&#41; or by other factors known to influence the test &#40;including drug use&#44; alcoholism&#44; obvious depression&#44; or pregnancy&#41;&#46; None of the patients had nephropathy &#40;creatinine clearance &#60;30 ml&#47;min&#41;&#44; acute illness&#44; or sleep disorders&#46;</p><p id="para60" class="elsevierStylePara elsevierViewall">All patients in our study had simple obesity&#59; none of them had diabetes mellitus&#46; Since the patients had simple obesity&#44; careful examinations did not reveal hirsutism&#44; buffalo hump&#44; easy bruising&#44; or any other manifestations suggestive of CS suggestive manifestations&#46;</p><p id="para70" class="elsevierStylePara elsevierViewall">Clinical characteristics recorded included BMI and anthropometric measurements&#46; Morning blood samples following fasting &#40;12 h&#41; were drawn from an antecubital vein for determination of the concentrations of adrenocorticorticotropic hormone &#40;ACTH&#41; &#40;N&#58; 0&#8211;46 pg&#47;ml&#41;&#44; cortisol &#40;N&#58; 5&#8211;28 &#956;g&#47;dL&#41;&#44; glucose&#44; insulin &#40;N&#58; 0&#8211;20 &#956;IU&#47;L&#41;&#44; serum lipids &#40;total cholesterol&#44; LDL&#44; HDL&#44; VLDL-cholesterol&#44; and triglyceride&#41;&#44; free thyroxin &#40;fT4&#41; &#40;N&#58; 0&#46;93&#8211;1&#46;77 ng&#47;dL&#41;&#44; and thyrotropin &#40;TSH&#41; &#40;N&#58; 0&#46;15&#8211;3&#46;7 IU&#47;ml&#41;&#46; Urine &#40;24 h&#41; was collected from each subject in order to perform urinary free cortisol &#40;UFC&#41; measurements&#46; Patients whose 24-h UFC excretion exceeded 100&#956;g&#47;dL were defined as abnormal&#46; All patients subsequently underwent a 1-mg overnight dexamethasone suppression test &#40;DMS&#41;&#46; Suppression of serum cortisol to &#60;1&#46;8 &#956;g&#47;dL after dexamethasone administration was the cut-off point for normal suppression without consideration of 24-h UFC&#46; Measurement of serum ACTH levels and an 8-mg DMS were performed as second-step investigations in all patients who failed to achieve serum cortisol suppression &#60;1&#46;8 &#956;g&#47;dL after administration of 1 mg DMS&#46; Complementary imaging studies&#44; magnetic resonance imaging &#40;MRI&#41; of the sella&#44; cavernous sinus sampling&#44; and abdominal computed tomography &#40;CT&#41; were performed when the results of the second-step evaluations were consistent with ACTH-dependent or ACT-independent CS&#46;</p><p id="para80" class="elsevierStylePara elsevierViewall">Insulin&#44; cortisol&#44; fT4&#44; TSH&#44; and ACTH were assessed by radioimmunoassay &#40;RIA&#41; using a Packard Riastar gamma counter &#40;Perkin-Elmer&#44; Waltham&#44; MA&#44; USA&#41; and commercial assay kits&#46; Other biochemical laboratory tests were measured with an Olympus AU 600 autoanalyser &#40;Olympus&#44; Tokyo&#44; Japan&#41;&#46; Insulin resistance was assessed using the homeostasis model assessment ratio &#40;HOMA-R&#41; formula &#40;18&#41;&#46;</p><p id="para90" class="elsevierStylePara elsevierViewall">Calculations were done with SPSS software &#40;version 10&#59; SPSS Inc&#44; Chicago&#44; IL&#44; USA&#41;&#44; and differences in the values of the variables between the groups were evaluated by the Mann-Whitney U test&#46; The degree of the correlation between parameters was evaluated by regression analysis&#46; A value of p&#60;0&#46;05 was considered to be statistically significant&#46;</p></span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">RESULTS</span><p id="para100" class="elsevierStylePara elsevierViewall">We analyzed a series of patients presenting with simple obesity for the presence of sub-clinical CS&#46; The clinical characteristics and laboratory findings for these patients are summarized in <a class="elsevierStyleCrossRefs" href="#t1-cln_65p9">Tables 1 and 2</a>&#46;</p><elsevierMultimedia ident="t2-cln_65p9"></elsevierMultimedia><elsevierMultimedia ident="t1-cln_65p9"></elsevierMultimedia><p id="para110" class="elsevierStylePara elsevierViewall">In 37 patients &#40;24&#37;&#41;&#44; 24-h UFC excretion exceeded the cut-off point &#40;median&#44; 30&#59; interquartile range &#40;IQR&#41;&#44; 16&#8211;103 &#956;g&#47;24 h&#41;&#46; Fourteen patients had unsuppressed cortisol levels as indicated by the 1-mg dexamethasone suppression test&#46; Complementary imaging studies were performed on these 14 CS patients&#44; which revealed pituitary microadenoma in 9 patients&#44; adrenal adenoma in 3 patients&#44; and adrenal carcinoma in 1 patient&#46; Histological diagnosis was obtained in 13 patients&#59; one patient declined to undergo surgical intervention for definitive diagnosis &#40;<a class="elsevierStyleCrossRef" href="#t3-cln_65p9">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="t3-cln_65p9"></elsevierMultimedia><p id="para120" class="elsevierStylePara elsevierViewall">We compared the group of 14 obese patients with CS to the remaining group of 136 patients with simple obesity&#46; There was no significant difference in levels of ACTH &#40;p&#61;0&#46;43&#41; or basal cortisol &#40;p&#61;0&#46;88&#41; between the CS group and the group of simple obese patients without CS&#46; However&#44; 24-h UFC excretion &#40;<a class="elsevierStyleCrossRef" href="#f1-cln_65p9">Figure 1</a>&#41; and morning cortisol levels following administration of 1 mg DMS &#40;<a class="elsevierStyleCrossRef" href="#f2-cln_65p9">Figure 2</a>&#41; were significantly more elevated in obese patients with CS than in simple obese patients without CS&#46;</p><elsevierMultimedia ident="f1-cln_65p9"></elsevierMultimedia><elsevierMultimedia ident="f2-cln_65p9"></elsevierMultimedia><p id="para130" class="elsevierStylePara elsevierViewall">There were no significant differences between the groups in mean values for serum lipids&#44; glucose&#44; BMI&#44; systolic blood pressure&#44; or waist-to-hip ratio&#46; Diastolic pressure was higher in patients with CS &#40;p&#61;0&#46;02&#41;&#46; Although higher HOMA-R values were recorded in patients with CS &#40;median&#44; 4&#46;66 mg&#47;dL &#215; mU&#47;ml&#59; IQR&#44; 1&#46;38&#8211;9&#46;08&#41; compared to simple obese patients &#40;median&#44; 4&#46;02 mg&#47;dL &#215; mU&#47;ml&#59; IQR&#44; 1&#46;91&#8211;6&#46;59&#41;&#44; the difference between the two groups narrowly failed to achieve statistical significance &#40;p&#61;0&#46;06&#41;&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">DISCUSSION</span><p id="para140" class="elsevierStylePara elsevierViewall">Here&#44; we report on 150 obese patients screened for CS&#46; A diagnosis of CS was established in 14 patients &#40;9&#46;33&#37;&#41;&#46; This finding confirms the need to evaluate patients with simple obesity for CS despite the absence of other signs or symptoms of the disorder&#46;</p><p id="para150" class="elsevierStylePara elsevierViewall">This conclusion is supported by several previous studies&#46; Obesity is a frequent clinical sign of CS&#44; and adipose tissues in CS patients typically have a central distribution&#46; Obese patients with CS may live without any evident metabolic disorder associated with CS&#46; However&#44; CS screening in simple obesity is usually not performed unless the patient has other clinical features of CS&#44; such as poorly controlled hypertension&#44; diabetes&#44; osteoporosis with rapid progression&#44; or hypokalemia that is unresponsive to the therapy&#46; Delayed identification of SCS in obese patients results in the progression of CS&#44; with the risk of irreversible complications&#46; We therefore initiated a screening program for CS in our simple obese outpatients&#46; The use of sensitive assays resulted in a significant improvement in the identification of CS&#46; We documented 14 cases of CS in a sample of 150 simple obese patients&#46; The high proportion of patients with Cushing&#8217;s syndrome that we identified despite the rareness of CS could be because we screened for CS in an obese population&#46; These findings argue that every patient with simple obesity should be investigated for CS&#46;</p><p id="para160" class="elsevierStylePara elsevierViewall">Some patients with type 2 diabetes and poor glycemic control may also have subclinical CS &#40;SCS&#41;&#44; and these patients should be screened for CS&#46; Recent studies have provided a rationale for the systemic screening of CS in patients with type 2 diabetes&#46;<a class="elsevierStyleCrossRefs" href="#bib16">16&#44;17</a> Hypercortisolism can result in insulin resistance&#59; glucose intolerance &#40;or type 2 diabetes&#41; secondary to insulin resistance occurs in approximately 75&#37; of patients with CS&#46; In this subgroup&#44; 50&#37; of the subjects had overt type 2 diabetes &#40;20&#8211;25&#37; of all CS patients&#41;&#46; It has been well documented since the 1960s that patients with CS typically suffer from hyperinsulinemia&#44; insulin resistance&#44; and type 2 diabetes&#46;<a class="elsevierStyleCrossRefs" href="#bib19">19&#44;20</a></p><p id="para170" class="elsevierStylePara elsevierViewall">Catargi et al&#46; screened 200 overweight inpatients with type 2 diabetes and poor glycemic control &#40;HbA1c &#62;8&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib15">15</a> None displayed the specific clinical features of CS in addition to their poorly-controlled type 2 diabetes&#46; A total of 52 &#40;26&#37;&#41; patients had impaired 1-mg DMS &#40;failure to suppress cortisol &#60;2&#46;1 &#956;g&#47;dL&#41;&#46; Of these&#44; 17 &#40;8&#46;5&#37;&#41; displayed at least one additional biological abnormality of the hypothalamic-pituitary-adrenal axis&#46; Imaging studies showed abnormalities in 11 of these 17 patients &#40;5&#46;5&#37; of the whole series&#41;&#46; Definitive occult CS was identified in 4 patients &#40;2&#37;&#41;&#44; with 3 &#40;1&#46;5&#37;&#41; having Cushing&#8217;s disease and 1 &#40;0&#46;5&#37;&#41; with surgically proven adrenal adenoma&#46; However&#44; definitive diagnosis of CS in the remaining seven patients &#40;3&#46;5&#37;&#41; required further investigation&#46; A unilateral adrenal tumor of 10&#8211;29 mm was subsequently revealed by abdominal CT and iodocholesterol scintigraphy&#46; These seven patients&#44; therefore&#44; had probable adrenal-dependent CS but did not undergo surgery&#46; Six months after treatment for CS&#44; a mean 5&#46;5&#37; reduction in body weight and a mean 2&#46;5&#37; reduction in HbA1c were reported in four patients&#46; Oral antidiabetic medications were resumed in one patient&#44; and the daily insulin dose was dramatically reduced in another&#46; This study highlights the need to perform prospective CS screening on overweight&#44; poorly controlled type 2 diabetic patients&#46; <a class="elsevierStyleCrossRef" href="#bib15">15</a></p><p id="para180" class="elsevierStylePara elsevierViewall">Assessment of 24-h UFC is a convenient screening test for CS in outpatient clinics&#46; The false-negative rate for UFC is extremely low&#44; though false-positive rates tend to be high&#46; CS can&#44; therefore&#44; be excluded if 24-h UFC is normal&#46; In patients with elevated 24-h UFC levels&#44; a diagnosis of CS should be confirmed by a 1-mg overnight dexamethasone suppression test&#46; In our study group&#44; only 14 of 30 patients having elevated UFC were confirmed as having CS by the 1-mg DMS test&#46; The remaining 16 obese patients were considered to be false-positives&#46; Wood et al&#46; established that suppression of plasma cortisol to less than 1&#46;8 &#956;g&#47;dL excluded CS without an increase in the false-positive rate&#46; <a class="elsevierStyleCrossRef" href="#bib21">21</a> A study by Baid SK et al&#46; demonstrated that the results of screening tests specific to CS may be falsely abnormal in overweight and obese populations&#46;<a class="elsevierStyleCrossRef" href="#bib22">22</a></p><p id="para190" class="elsevierStylePara elsevierViewall">In our study&#44; definitive CS was identified in 13 of 14 patients with unsuppressed serum cortisol after the results of the 1-mg DMS test were considered&#46; One patient declined further investigation&#46; The remaining 13 patients underwent further biochemical and imaging studies&#46; Definitive diagnoses of CS were proven by histological analysis of surgically-removed material&#46; Among 30 patients with elevated 24-h UFC&#44; levels were significantly more elevated in the group of patients with unsuppressed cortisol after administration of 1 mg DMS &#40;p&#61;0&#46;002&#41; than in simple obese patients with suppressed cortisol levels&#46;</p><p id="para200" class="elsevierStylePara elsevierViewall">Distinguishing simple obese patients from CS presents a challenge for the physician&#46; Future studies on larger patient populations will be required to address the true prevalence of CS&#46; Appropriate study groups will include patients with relevant clinical features&#44; including simple obesity&#44; poorly controlled diabetes&#44; osteoporosis&#44; and PCOS&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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        0 => array:2 [
          "identificador" => "xpalclavsec1582921"
          "titulo" => "KEYWORDS&#58;"
        ]
        1 => array:2 [
          "identificador" => "cesec10"
          "titulo" => "INTRODUCTION"
        ]
        2 => array:2 [
          "identificador" => "cesec20"
          "titulo" => "PATIENTS AND METHODS"
        ]
        3 => array:2 [
          "identificador" => "cesec30"
          "titulo" => "RESULTS"
        ]
        4 => array:2 [
          "identificador" => "cesec40"
          "titulo" => "DISCUSSION"
        ]
        5 => array:1 [
          "titulo" => "REFERENCES"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2009-09-11"
    "fechaAceptado" => "2009-10-08"
    "PalabrasClave" => array:1 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "KEYWORDS&#58;"
          "identificador" => "xpalclavsec1582921"
          "palabras" => array:5 [
            0 => "Cushing&#8217;s syndrome"
            1 => "Obesity"
            2 => "Screening"
            3 => "Cortisol"
            4 => "Adrenocorticorticotropic hormone"
          ]
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    "resumen" => array:1 [
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVES&#58;</span><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">The aim of this study was to examine the frequency of Cushing&#8217;s syndrome &#40;CS&#41; in obese patients devoid of specific clinical symptoms of Cushing&#8217;s syndrome&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS&#58;</span><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">A total of 150 obese patients &#40;129 female&#44; 21 male&#59; mean age 44&#46;41 &#177; 13&#46;34 yr&#59; mean BMI 35&#46;76 &#177; 7&#46;13&#41; were included in the study&#46; As a first screening step&#44; we measured 24-h urinary free cortisol &#40;UFC&#41;&#46; An overnight 1-mg dexamethasone suppression test was also performed on all patients&#46; Urinary free cortisol levels above 100 &#956;g&#47;24 h were considered to be abnormal&#46; Suppression of serum cortisol &#60;1&#46;8 &#956;g&#47;dL after administration of 1 mg dexamethasone was the cut-off point for normal suppression&#46; The suppression of the serum cortisol levels failed in all of the patients&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS&#58;</span><p id="spara100" class="elsevierStyleSimplePara elsevierViewall">Measured laboratory values were as follows&#58; ACTH&#44; median level 28 pg&#47;ml&#44; interquartile range &#40;IQR&#41; 14&#8211;59 pg&#47;ml&#59; fasting glucose&#44; 100 &#40;91&#8211;113&#41; mg&#47;dL&#59; insulin&#44; 15&#46;7 &#40;7&#46;57&#8211;24&#46;45&#41; mU&#47;ml&#59; fT<span class="elsevierStyleInf">4</span>&#44; 1&#46;17 &#40;1&#46;05&#8211;1&#46;4&#41; ng&#47;dL&#59; TSH&#44; 1&#46;70 &#40;0&#46;91&#8211;2&#46;90&#41; mIU&#47;L&#59; total cholesterol&#44; 209 &#40;170&#46;5&#8211;250&#41; mg&#47;dL&#59; LDL-c&#44; 136 &#40;97&#46;7&#8211;163&#41; mg&#47;dL&#59; HDL-c&#44; 44 &#40;37&#46;25&#8211;50&#46;75&#41; mg&#47;dL&#59; VLDL-c&#44; 24 &#40;17&#8211;36&#41; mg&#47;dL&#59; triglycerides&#44; 120&#46;5 &#40;86&#8211;165&#41; mg&#47;dL&#46; The median UFC level of the patients was 30 &#956;g&#47;24 h &#40;IQR 16&#8211;103&#41;&#46; High levels of UFC &#40;&#62;100 &#956;g&#47;24 h&#41; were recorded in 37 patients &#40;24&#37;&#41;&#46; Cushing&#8217;s syndrome was diagnosed in 14 of the 150 patients &#40;9&#46;33&#37;&#41;&#46; Etiologic reasons for Cushing&#8217;s syndrome were pituitary microadenoma &#40;9 patients&#41;&#44; adrenocortical adenoma &#40;3 patients&#41;&#44; and adrenocortical carcinoma &#40;1 patient&#41;&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSION&#58;</span><p id="spara110" class="elsevierStyleSimplePara elsevierViewall">A significant proportion &#40;9&#46;33&#37;&#41; of patients with simple obesity were found to have Cushing&#8217;s syndrome&#46; These findings argue that obese patients should be routinely screened for Cushing&#8217;s syndrome&#46;</p></span>"
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            "titulo" => "METHODS&#58;"
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            "titulo" => "RESULTS&#58;"
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Twenty-four-hour free cortisol levels in patients with Cushing&#8217;s syndrome and simple obesity</p>"
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">The comparison of the 1-mg dexamethasone suppression test results for both groups</p>"
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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
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                  \t\t\t\t  " align="center" valign="top" 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="center" valign="top" scope="col">&#40;Mean &#177; SD&#41; &#40;n&#61;150&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">BMI &#40;kg&#47;m<span class="elsevierStyleSup">2</span>&#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">35&#46;76 &#177; 7&#46;13&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">Waist &#40;cm&#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">104&#46;07 &#177; 15&#46;77&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">Waist-to-hip ratio&nbsp;\t\t\t\t\t\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">0&#46;98 &#177; 0&#46;92&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">Systolic blood pressure &#40;mm&#47;Hg&#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">135&#46;13 &#177; 20&#46;49&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">Diastolic blood pressure &#40;mm&#47;Hg&#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">87&#46;23 &#177; 13&#46;03&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spara50" class="elsevierStyleSimplePara elsevierViewall">Values are medians and interquartile ranges&#46;</p><p id="spara60" class="elsevierStyleSimplePara elsevierViewall">DMST&#58; 1-mg dexamethasone suppression test</p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t  " align="center" valign="top" scope="col">Simple obesity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top" scope="col">Cushing&#8217;s syndrome&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">p</span></span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">35 <span class="elsevierStyleItalic">&#91;13&#46;5</span>&#8211;<span class="elsevierStyleItalic">94&#46;5&#93;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">10&#46;2 <span class="elsevierStyleItalic">&#91;7&#46;8</span>&#8211;<span class="elsevierStyleItalic">14&#46;8&#93;</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="center" valign="top">9&#46;4 <span class="elsevierStyleItalic">&#91;8&#46;1</span>&#8211;<span class="elsevierStyleItalic">13&#46;5&#93;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">99 <span class="elsevierStyleItalic">&#91;91</span>&#8211;<span class="elsevierStyleItalic">113&#93;</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="center" valign="top">100 <span class="elsevierStyleItalic">&#91;93&#46;5</span>&#8211;<span class="elsevierStyleItalic">114&#93;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">0&#46;91&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">14&#46;7 <span class="elsevierStyleItalic">&#91;7&#46;4</span>&#8211;<span class="elsevierStyleItalic">24&#46;2&#93;</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="center" valign="top">18&#46;9 <span class="elsevierStyleItalic">&#91;14&#46;9</span>&#8211;<span class="elsevierStyleItalic">28&#46;5&#93;</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="center" valign="top">0&#46;07&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">f T4 &#40;ng&#47;dL&#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">1&#46;2 <span class="elsevierStyleItalic">&#91;1&#46;07</span>&#8211;<span class="elsevierStyleItalic">1&#46;4&#93;</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="center" valign="top">1&#46;1 <span class="elsevierStyleItalic">&#91;1&#46;04</span>&#8211;<span class="elsevierStyleItalic">1&#46;63&#93;</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">0&#46;56&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">TSH &#40;mIU&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">1&#46;64 <span class="elsevierStyleItalic">&#91;0&#46;9</span>&#8211;<span class="elsevierStyleItalic">2&#46;8&#93;</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="center" valign="top">1&#46;78 <span class="elsevierStyleItalic">&#91;1&#46;6</span>&#8211;<span class="elsevierStyleItalic">4&#46;2&#93;</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">0&#46;25&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">Cholesterol &#40;mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">203 <span class="elsevierStyleItalic">&#91;172</span>&#8211;<span class="elsevierStyleItalic">249&#93;</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">238&#46;5 <span class="elsevierStyleItalic">&#91;178</span>&#8211;<span class="elsevierStyleItalic">264&#93;</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">0&#46;24&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">LDL-c &#40;mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">129 <span class="elsevierStyleItalic">&#91;97</span>&#8211;<span class="elsevierStyleItalic">159&#93;</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">168 <span class="elsevierStyleItalic">&#91;122</span>&#8211;<span class="elsevierStyleItalic">168&#93;</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">0&#46;15&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">HDL-c &#40;mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">44 <span class="elsevierStyleItalic">&#91;37&#46;5</span>&#8211;<span class="elsevierStyleItalic">50&#46;5&#93;</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">46 <span class="elsevierStyleItalic">&#91;29</span>&#8211;<span class="elsevierStyleItalic">66&#93;</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">0&#46;72&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">VLDL-c &#40;mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">24 <span class="elsevierStyleItalic">&#91;17</span>&#8211;<span class="elsevierStyleItalic">33&#93;</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">38 <span class="elsevierStyleItalic">&#91;16&#46;2</span>&#8211;<span class="elsevierStyleItalic">50&#93;</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">0&#46;2&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">Triglyceride &#40;mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">120 <span class="elsevierStyleItalic">&#91;86</span>&#8211;<span class="elsevierStyleItalic">161&#93;</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">208 <span class="elsevierStyleItalic">&#91;89&#46;8</span>&#8211;<span class="elsevierStyleItalic">251&#93;</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">0&#46;15&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">Urine cortisol &#40;&#956;g&#47;24 h&#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">28 <span class="elsevierStyleItalic">&#91;15</span>&#8211;<span class="elsevierStyleItalic">92&#46;5&#93;</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">74 <span class="elsevierStyleItalic">&#91;27</span>&#8211;<span class="elsevierStyleItalic">133&#93;</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">0&#46;02&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">DMST cortisol &#40;&#956;g&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">0&#46;88 <span class="elsevierStyleItalic">&#91;0&#46;7</span>&#8211;<span class="elsevierStyleItalic">1&#46;15&#93;</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">3&#46;35 <span class="elsevierStyleItalic">&#91;2&#46;5</span>&#8211;<span class="elsevierStyleItalic">6&#46;5&#93;</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">&#60; 0&#46;0001&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">HOMA-R &#40;mg&#47;dl &#215; mU&#47;ml&#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">4&#46;02 <span class="elsevierStyleItalic">&#91;1&#46;91</span>&#8211;<span class="elsevierStyleItalic">6&#46;59&#93;</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" style="border-bottom: 2px solid black">4&#46;66 <span class="elsevierStyleItalic">&#91;4&#46;38</span>&#8211;<span class="elsevierStyleItalic">9&#46;08</span>&#93;&nbsp;\t\t\t\t\t\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">0&#46;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Increasing prevalance of overweight among US adults&#58; The National Health and Nutrition Examination Surveys&#44; 1960 to 1991"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              RJ Kuczmarski \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              KM Flegal \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              SM Campbell \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              CL Johnson \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
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                    0 => array:2 [
                      "doi" => "10.1001/jama.272.3.205"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "1994"
                        "volumen" => "272"
                        "paginaInicial" => "205"
                        "paginaFinal" => "211"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8022039"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
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                      "titulo" => "A prospective study of obesity and risk of coronary heart disease in women"
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                            0 => """
                              JE Manson \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              GA Colditz \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              MJ Stampfer \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              WJ Willet \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              B Rosner \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              RR Manson \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM199003293221303"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "1990"
                        "volumen" => "322"
                        "paginaInicial" => "882"
                        "paginaFinal" => "889"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2314422"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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                      "titulo" => "Dual effects of weight and weight gain on breast cancer risk"
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                        0 => array:2 [
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                          "autores" => array:6 [
                            0 => """
                              Z Huang \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              SE Hankinson \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              GA Colditz \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              MJ Stampfer \n
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                              """
                            4 => """
                              DJ Hunter \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              JE Manson \n
                              \t\t\t\t\t\t\t\t
                              """
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                        "volumen" => "278"
                        "paginaInicial" => "1407"
                        "paginaFinal" => "1411"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9355998"
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                            0 => """
                              GA Colditz \n
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                            1 => """
                              WC Willet \n
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                            2 => """
                              MJ Stampfer \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              JE Manson \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              CE Hennekenz \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              RA Arky \n
                              \t\t\t\t\t\t\t\t
                              """
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                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Epidemiol"
                        "fecha" => "1990"
                        "volumen" => "132"
                        "paginaInicial" => "501"
                        "paginaFinal" => "513"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2389754"
                            "web" => "Medline"
                          ]
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                      "titulo" => "Body weight and mortality among women"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              JE Manson \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              WC Willet \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              MJ Stampfer \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              GA Golditz \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              DJ Hunter \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              SE Hankinson \n
                              \t\t\t\t\t\t\t\t
                              """
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                    0 => array:2 [
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es en pt

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